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Sample records for a-induced hepatic injury

  1. The Protective Effect of Resveratrol on Concanavalin-A-Induced Acute Hepatic Injury in Mice

    PubMed Central

    Zhou, Yingqun; Chen, Kan; He, Lei; Xia, Yujing; Dai, Weiqi; Wang, Fan; Li, Jingjing; Li, Sainan; Liu, Tong; Wang, Jianrong; Lu, Wenxia; Yin, Qin; Zhou, Yuqing; Lu, Jie; Teng, Hongfei; Guo, Chuanyong

    2015-01-01

    Pharmacologic Relevance. Resveratrol, an antioxidant derived from grapes, has been reported to modulate the inflammatory process. In this study, we investigated the effects of resveratrol and its mechanism of protection on concanavalin-A- (ConA-) induced liver injury in mice. Materials and Methods. Acute autoimmune hepatitis was induced by ConA (20 mg/kg) in Balb/C mice; mice were treated with resveratrol (10, 20, and 30 mg/kg) daily by oral gavage for fourteen days prior to a single intravenous injection of ConA. Eight hours after injection, histologic grading, proinflammatory cytokine levels, and hedgehog pathway activity were determined. Results. After ConA injection, the cytokines IL-2, IL-6, and TNF-α were increased, and Sonic hedgehog (Shh), Glioblastoma- (Gli-) 1, and Patched (Ptc) levels significantly increased. Pretreatment with resveratrol ameliorated the pathologic effects of ConA-induced autoimmune hepatitis and significantly inhibited IL-2, IL-6, TNF-α, Shh, Gli-1, and Ptc. The effects of resveratrol on the hedgehog pathway were studied by western blotting and immunohistochemistry. Resveratrol decreased Shh expression, possibly by inhibiting Shh expression in order to reduce Gli-1 and Ptc expression. Conclusion. Resveratrol protects against ConA-induced autoimmune hepatitis by decreasing cytokines expression in mice. The decreases seen in Gli-1 and Ptc may correlate with the amelioration of hedgehog pathway activity. PMID:26089871

  2. Epigallocatechin-3-gallate (EGCG) attenuates concanavalin A-induced hepatic injury in mice.

    PubMed

    Liu, Dongmei; Zhang, Xiaoli; Jiang, Li; Guo, Yun; Zheng, Changqing

    2014-05-01

    (-)-Epigallocatechin-3-gallate (EGCG) is the most abundant polyphenolic compound present in green tea and has been shown to possess anti-inflammatory and anti-oxidative properties. In this study, we investigated the protective effects of EGCG against concanavalin A (ConA)-induced liver injury and the underlying mechanisms. EGCG (5 mg/kg) was administered orally by gavage to mice twice daily for 10 days before an intravenous injection of ConA. We found that EGCG effectively rescued lethality, improved hepatic pathological damage, and decreased serum levels of alanine aminotransaminase (ALT) in ConA-challenged mice. Furthermore, EGCG also significantly prevented the release of tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-4, and IL-6 in serum, reduced malondialdehyde (MDA) levels, and restored glutathione (GSH) content and superoxide dismutase (SOD) activity in liver tissues from ConA-challenged mice. Finally, nuclear factor (NF)-κB activation and expression levels of Toll-like receptor (TLR) 2, TLR4 and TLR9 protein in liver tissues were significantly inhibited by EGCG pretreatment. Taken together, our data suggest that EGCG possesses hepatoprotective properties against ConA-induced liver injury through its anti-inflammatory and anti-oxidant actions. PMID:24373695

  3. 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

  4. Augmenter of liver regeneration (ALR) restrains concanavalin A-induced hepatitis in mice.

    PubMed

    Mu, Mao; Zhang, Zhenwei; Cheng, Yi; Liu, Guangze; Chen, Xiusheng; Wu, Xin; Zhuang, Caifang; Liu, Bingying; Kong, Xiangping; You, Song

    2016-06-01

    Augmenter of liver regeneration (ALR), produced and released by hepatocytes, has cytoprotective and immunoregulatory effects on liver injury, and has been used in many experimental applications. However, little attention has been paid to the effects of ALR on concanavalin A (Con A)-induced hepatitis. The purpose of this paper is to explore the protective effect of ALR on Con A-induced hepatitis and elucidate potential mechanisms. We found that the ALR pretreatment evidently reduced the amount of ALT and AST in serum. In addition, pro-inflammatory cytokines, chemokines and iNOS were suppressed. ALR pretreatment also decreased CD4(+), CD8(+) T cell infiltration in liver. Besides, we observed that ALR pretreatment was capable of suppressing the activation of several signaling pathways in Con A-induced hepatitis. These findings suggest that ALR can obviously weaken Con A-induced hepatitis and ALR has some certain immune regulation function. PMID:27085679

  5. Protective Effects of Dracocephalum heterophyllum in ConA-Induced Acute Hepatitis

    PubMed Central

    Wang, Qilan; Lu, Xiaohua; Shi, Qiangqiang; Zou, Junhui

    2016-01-01

    Dracocephalum heterophyllum (DH) is a Chinese herbal medicine used in treating hepatitis. However, the protective effects and pharmacological mechanisms of DH in hepatitis are unknown. In this study, we found that pretreatment with DH extract significantly ameliorated liver injury and suppressed the production of inflammatory cytokines, including tumor necrosis factor (TNF-α) and interferon-γ (IFN-γ) in Concanavalin A- (ConA-) induced hepatitis (CIH). DH recruited more CD11b+ Gr1+ myeloid-derived suppressor cells (MDSCs) to the liver and suppressed infiltration of macrophages (Kupffer cells) in the liver. The present work explores DH as an effective hepatoprotective medicine to inhibit inflammation and liver injury caused by hepatitis. PMID:27524863

  6. Ischaemic Markers in Acute Hepatic Injury

    PubMed Central

    Jena, Sushanta Kumar; Nanda, Rachita; Mangaraj, Manaswini; Nayak, Parsuram

    2016-01-01

    Introduction Hepatic injury of varied aetiology may progress to Acute Liver Failure (ALF). Compromised microcirculation is thought to be a deciding factor of hepatic hypoxia may be involved in disease progression that needs early detection. Ischaemia markers like serum Ischaemia- modified albumin (IMA), ALT-LDH ratio and ALT-LDH index have been suggested for its detection at early stage. Aim To find out the association of Ischaemia markers like serum IMA, ALT-LDH ratio and ALT-LDH index in acute hepatic injury cases. Materials and Methods Forty one diagnosed acute liver injury cases of varied aetiology admitted in Department of Medicine, and Gastroenterology of SCB Medical College, Cuttack were enrolled in the study along with 30 age and sex matched healthy controls. Blood collected at time of admission and at time of discharge (1st day and 7th day) were evaluated for FPG, RFT, LFT, Serum Albumin along with serum LDH, IMA, PT-INR and platelet count. Result Serum bilirubin, hepatic enzymes, IMA, PT-INR was more markedly raised in cases than controls on the 1st day of admission. ALT-LDH ratio and index were significantly low in complicated cases. However, on responding to treatment the ALT-LDH index on 7th day registered a rise in comparison to the 1st day, while serum IMA revealed an insignificant decline showing improvement in hepatic hypoxia. ALT-LDH ratio remains more or less same on response to treatment. Conclusion Serum IMA and ALT-LDH Index reveals association with disease process in Acute Hepatic Injury cases both clinically and biochemically and can be used as supportive parameters for the diagnosis of disease process. PMID:27190791

  7. Tonsil-derived mesenchymal stem cells alleviate concanavalin A-induced acute liver injury.

    PubMed

    Ryu, Kyung-Ha; Kim, So-Yeon; Kim, Ye-Ryung; Woo, So-Youn; Sung, Sun Hee; Kim, Han Su; Jung, Sung-Chul; Jo, Inho; Park, Joo-Won

    2014-08-01

    Acute liver failure, the fatal deterioration of liver function, is the most common indication for emergency liver transplantation, and drug-induced liver injury and viral hepatitis are frequent in young adults. Stem cell therapy has come into the limelight as a potential therapeutic approach for various diseases, including liver failure and cirrhosis. In this study, we investigated therapeutic effects of tonsil-derived mesenchymal stem cells (T-MSCs) in concanavalin A (ConA)- and acetaminophen-induced acute liver injury. ConA-induced hepatitis resembles viral and immune-mediated hepatic injury, and acetaminophen overdose is the most frequent cause of acute liver failure in the United States and Europe. Intravenous administration of T-MSCs significantly reduced ConA-induced hepatic toxicity, but not acetaminophen-induced liver injury, affirming the immunoregulatory capacity of T-MSCs. T-MSCs were successfully recruited to damaged liver and suppressed inflammatory cytokine secretion. T-MSCs expressed high levels of galectin-1 and -3, and galectin-1 knockdown which partially diminished interleukin-2 and tumor necrosis factor α secretion from cultured T-cells. Galectin-1 knockdown in T-MSCs also reversed the protective effect of T-MSCs on ConA-induced hepatitis. These results suggest that galectin-1 plays an important role in immunoregulation of T-MSCs, which contributes to their protective effect in immune-mediated hepatitis. Further, suppression of T-cell activation by frozen and thawed T-MSCs implies great potential of T-MSC banking for clinical utilization in immune-mediated disease. PMID:24954408

  8. Tenoxicam-associated hepatic injury: a case report and review.

    PubMed

    Katsinelos, P; Katsos, I; Patsiaoura, K; Xiarchos, P; Goulis, I; Eugenidis, N

    1997-04-01

    A 51-year-old woman developed jaundice while taking tenoxicam. A full evaluation, including ultrasound, computed tomography, endoscopic cholangiography and liver biopsy, confirmed the diagnosis of mixed hepatic injury. The patient's jaundice and all other liver function abnormalities normalized 1 month after she discontinued taking tenoxicam. This is the first case report of mixed hepatic injury, confirmed with biopsy, associated with tenoxicam. Tenoxicam should be considered as a potential cause of hepatic injury when other more common aetiologies have been excluded. PMID:9160206

  9. 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

  10. 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. PMID:26937641

  11. Hepatic Ischemia and Reperfusion Injury and Trauma: Current Concepts

    PubMed Central

    Papadopoulos, Dimitrios; Siempis, Thomas; Theodorakou, Eleni; Tsoulfas, Georgios

    2013-01-01

    Context Ischemia-reperfusion injury is a fascinating topic which has drawn a lot of interest in the last several years. Hepatic ischemia reperfusion injury may occur in a variety of clinical situations. These include transplantation, liver resection, trauma, and vascular surgery. Evidence Acquisition The purpose of this review was to outline the molecular mechanisms underlying hepatic I/R injury and present the latest approaches, both surgical and pharmacological, regarding the prevention of it. A comprehensive electronic literature search in MEDLINE/PubMed was performed to identify relative articles published within the last 2 years. Results The basic mechanism of hepatic ischemia – reperfusion injury is one of blood deprivation during ischemia, followed by the return of flow during reperfusion. It involves a complex series of events, such as mitochondrial deenergization, adenosine-5'-triphosphate depletion, alterations of electrolyte homeostasis, as well as Kupffer cell activation, oxidative stress changes and upregulation of proinflammatory cytokine signaling. The great number of variable pathways, with several mediators interacting with each other, leads to a high number of candidates for potential therapeutic intervention. As far as surgical approaches are concerned, the modification of existing clamping techniques and the ischemic preconditioning are the most promising techniques till recently. In the search for novel techniques of protecting against hepatic ischemia reperfusion injury, many different strategies have been used in experimental models. The biggest part of this research lies around antioxidant therapy, but other potential solutions have been explored as well. Conclusions The management of hepatic trauma, in spite of the fact that it has become increasingly nonoperative, there still remains the possibility of hepatic resection in the hepatic trauma setting, especially in severe injuries. Hence, clinicians should be familiar with the concept of

  12. 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

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

    PubMed

    Zhuang, Yan; Li, Yi; 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

  14. Calcium and ER stress mediate hepatic apoptosis after burn injury

    PubMed Central

    Gauglitz, Gerd G.; Song, Juquan; Kulp, Gabriela A.; Finnerty, Celeste C.; Cox, Robert A.; Barral, José M.; Herndon, David N.; Boehning, Darren

    2009-01-01

    Abstract A hallmark of the disease state following severe burn injury is decreased liver function, which results in gross metabolic derangements that compromise patient survival. The underlying mechanisms leading to hepatocyte dysfunction after burn are essentially unknown. The aim of the present study was to determine the underlying mechanisms leading to hepatocyte dysfunction and apoptosis after burn. Rats were randomized to either control (no burn) or burn (60% total body surface area burn) and sacrificed at various time‐points. Liver was either perfused to isolate primary rat hepatocytes, which were used for in vitro calcium imaging, or liver was harvested and processed for immunohistology, transmission electron microscopy, mitochondrial isolation, mass spectroscopy or Western blotting to determine the hepatic response to burn injury in vivo. We found that thermal injury leads to severely depleted endoplasmic reticulum (ER) calcium stores and consequent elevated cytosolic calcium concentrations in primary hepatocytes in vitro. Burn‐induced ER calcium depletion caused depressed hepatocyte responsiveness to signalling molecules that regulate hepatic homeostasis, such as vasopressin and the purinergic agonist ATP. In vivo, thermal injury resulted in activation of the ER stress response and major alterations in mitochondrial structure and function – effects which may be mediated by increased calcium release by inositol 1,4,5‐trisphosphate receptors. Our results reveal that thermal injury leads to dramatic hepatic disturbances in calcium homeostasis and resultant ER stress leading to mitochondrial abnormalities contributing to hepatic dysfunction and apoptosis after burn injury. PMID:20141609

  15. 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

  16. Mangafodipir Protects against Hepatic Ischemia-Reperfusion Injury in Mice

    PubMed Central

    Coriat, Romain; Leconte, Mahaut; Kavian, Niloufar; Bedda, Sassia; Nicco, Carole; Chereau, Christiane; Goulvestre, Claire; Weill, Bernard

    2011-01-01

    Introduction and Aim Mangafodipir is a contrast agent used in magnetic resonance imaging that concentrates in the liver and displays pleiotropic antioxidant properties. Since reactive oxygen species are involved in ischemia-reperfusion damages, we hypothesized that the use of mangafodipir could prevent liver lesions in a mouse model of hepatic ischemia reperfusion injury. Mangafodipir (MnDPDP) was compared to ischemic preconditioning and intermittent inflow occlusion for the prevention of hepatic ischemia-reperfusion injury in the mouse. Methods Mice were subjected to 70% hepatic ischemia (continuous ischemia) for 90 min. Thirty minutes before the ischemic period, either mangafodipir (10 mg/kg) or saline was injected intraperitoneally. Those experimental groups were compared with one group of mice preconditioned by 10 minutes' ischemia followed by 15 minutes' reperfusion, and one group with intermittent inflow occlusion. Hepatic ischemia-reperfusion injury was evaluated by measurement of serum levels of aspartate aminotransferase (ASAT) activity, histologic analysis of the livers, and determination of hepatocyte apoptosis (cytochrome c release, caspase 3 activity). The effect of mangafodipir on the survival rate of mice was studied in a model of total hepatic ischemia. Results Mangafodipir prevented experimental hepatic ischemia-reperfusion injuries in the mouse as indicated by a reduction in serum ASAT activity (P<0.01), in liver tissue damages, in markers of apoptosis (P<0.01), and by higher rates of survival in treated than in untreated animals (P<0.001). The level of protection by mangafodipir was similar to that observed following intermittent inflow occlusion and higher than after ischemic preconditioning. Conclusions Mangafodipir is a potential new preventive treatment for hepatic ischemia-reperfusion injury. PMID:22073237

  17. Hepatic miR-29ab1 expression modulates chronic hepatic injury

    PubMed Central

    Kogure, Takayuki; Costinean, Stefan; Yan, Irene; Braconi, Chiara; Croce, Carlo; Patel, Tushar

    2012-01-01

    MicroRNAs (miRNAs) are small, regulatory non-coding RNAs that have potent effects on gene expression. Several miRNA are deregulated in cellular processes involved in human liver diseases and regulation of cellular processes. Recent studies have identified the involvement of miR-29 in hepatic fibrosis and carcinogenesis. Although several targets of miR-29 have been identified, there is limited information regarding the cell-type specific roles of miR-29 in the liver, and we sought to evaluate the role of this miRNA in hepatic pathobiology. We report the generation of a tissue–specific knockout mouse to evaluate the role of miR-29 in hepatic fibrosis and carcinogenesis in response to injury. We hypothesized that miR-29 contributes to the hepatocyte driven response to chronic cellular injury that results in fibrosis. In support of this hypothesis, fibrosis and mortality were enhanced in miR29 knockout mice in response to carbon tetrachloride. Genome-wide gene expression analysis identified an over-representation of genes associated with fibrosis. The oncofetal RNA H19 was modulated in a miR-29 dependent manner following exposure to carbon tetrachloride in vivo. The impact of a hepatocyte specific miR-29 knockout on survival following chronic hepatic injury in vivo implicates this miRNA as a potential target for intervention. These results provide evidence of the involvement of miR-29 in chronic hepatic injury, and suggest a role for deregulated hepatocyte expression of miR-29 in the response to hepatic injury, fibrosis and carcinogenesis. PMID:22469499

  18. Hepatic miR-29ab1 expression modulates chronic hepatic injury.

    PubMed

    Kogure, Takayuki; Costinean, Stefan; Yan, Irene; Braconi, Chiara; Croce, Carlo; Patel, Tushar

    2012-11-01

    MicroRNAs (miRNAs) are small, regulatory non-coding RNAs that have potent effects on gene expression. Several miRNA are deregulated in cellular processes involved in human liver diseases and regulation of cellular processes. Recent studies have identified the involvement of miR-29 in hepatic fibrosis and carcinogenesis. Although several targets of miR-29 have been identified, there is limited information regarding the cell-type specific roles of miR-29 in the liver, and we sought to evaluate the role of this miRNA in hepatic pathobiology. We report the generation of a tissue-specific knockout mouse to evaluate the role of miR-29 in hepatic fibrosis and carcinogenesis in response to injury. We hypothesized that miR-29 contributes to the hepatocyte driven response to chronic cellular injury that results in fibrosis. In support of this hypothesis, fibrosis and mortality were enhanced in miR29 knockout mice in response to carbon tetrachloride. Genome-wide gene expression analysis identified an over-representation of genes associated with fibrosis. The oncofetal RNA H19 was modulated in a miR-29 dependent manner following exposure to carbon tetrachloride in vivo. The impact of a hepatocyte specific miR-29 knockout on survival following chronic hepatic injury in vivo implicates this miRNA as a potential target for intervention. These results provide evidence of the involvement of miR-29 in chronic hepatic injury, and suggest a role for deregulated hepatocyte expression of miR-29 in the response to hepatic injury, fibrosis and carcinogenesis. PMID:22469499

  19. Protective Effects of N-Acetylcysteine in Concanavalin A-Induced Hepatitis in Mice

    PubMed Central

    Wang, Chengfen; Xia, Yujing; Dai, Weiqi; Wang, Fan; Chen, Kan; Li, Jingjing; Li, Sainan; Zhu, Rong; Yang, Jing; Yin, Qin; Zhang, Huawei; Wang, Junshan; Lu, Jie; Zhou, Yingqun; Guo, Chuanyong

    2015-01-01

    This study was designed to study the protective effects and mechanisms of N-acetylcysteine (NAC) in concanavalin A-induced hepatitis in mice. In this study, pretreatment with NAC ameliorated the histopathological changes and suppressed inflammatory cytokines in ConA-induced hepatitis. The expression of IL-2, IL-6, TNF-α, and IFN-γ was significantly reduced in the NAC-treated groups. NAC activated PI3K/Akt pathway and inhibited the activation of NF-κB. Additionally, NAC reduced autophagosome formation, as assessed by detecting the expression of LC3 and Beclin 1. Our results demonstrate that NAC can alleviate ConA-induced hepatitis by regulating the PI3K/Akt pathway and reducing the late stages of autophagy. Our results described a new pharmaceutical to provide more effective therapies for immune hepatitis. PMID:25821351

  20. Antisense oligonucleotide for tissue factor inhibits hepatic ischemic reperfusion injury.

    PubMed

    Nakamura, Kenji; Kadotani, Yayoi; Ushigome, Hidetaka; Akioka, Kiyokazu; Okamoto, Masahiko; Ohmori, Yoshihiro; Yaoi, Takeshi; Fushiki, Shinji; Yoshimura, Rikio; Yoshimura, Norio

    2002-09-27

    Tissue factor (TF) is an initiation factor for blood coagulation and its expression is induced on endothelial cells during inflammatory or immune responses. We designed an antisense oligodeoxynucleotide (AS-1/TF) for rat TF and studied its effect on hepatic ischemic reperfusion injury. AS-1/TF was delivered intravenously to Lewis rats. After 10 h, hepatic artery and portal vein were partially clamped. Livers were reperfused after 180 min and harvested. TF expression was studied using immunohistochemical staining. One of 10 rats survived in a 5-day survival rate and TF was strongly stained on endothelial cells in non-treatment group. However, by treatment with AS-1/TF, six of seven survived and TF staining was significantly reduced. Furthermore, we observed that fluorescein-labeled AS-1/TF was absorbed into endothelial cells. These results suggest that AS-1/TF can strongly suppress the expression of TF and thereby inhibit ischemic reperfusion injury to the rat liver. PMID:12270110

  1. Potential mechanisms of hepatitis B virus induced liver injury.

    PubMed

    Suhail, Mohd; Abdel-Hafiz, Hany; Ali, Ashraf; Fatima, Kaneez; Damanhouri, Ghazi A; Azhar, Esam; Chaudhary, Adeel Ga; Qadri, Ishtiaq

    2014-09-21

    Chronic active hepatitis (CAH) is acknowledged as an imperative risk factor for the development of liver injury and hepatocellular carcinoma. The histological end points of CAH are chronic inflammation, fibrosis and cirrhosis which are coupled with increased DNA synthesis in cirrhotic vs healthy normal livers. The potential mechanism involved in CAH includes a combination of processes leading to liver cell necrosis, inflammation and cytokine production and liver scaring (fibrosis). The severity of liver damage is regulated by Hepatitis B virus genotypes and viral components. The viral and cellular factors that contribute to liver injury are discussed in this article. Liver injury caused by the viral infection affects many cellular processes such as cell signaling, apoptosis, transcription, DNA repair which in turn induce radical effects on cell survival, growth, transformation and maintenance. The consequence of such perturbations is resulted in the alteration of bile secretion, gluconeogenesis, glycolysis, detoxification and metabolism of carbohydrates, proteins, fat and balance of nutrients. The identification and elucidation of the molecular pathways perturbed by the viral proteins are important in order to design effective strategy to minimize and/or restore the hepatocytes injury. PMID:25253946

  2. Potential mechanisms of hepatitis B virus induced liver injury

    PubMed Central

    Suhail, Mohd; Abdel-Hafiz, Hany; Ali, Ashraf; Fatima, Kaneez; Damanhouri, Ghazi A; Azhar, Esam; Chaudhary, Adeel GA; Qadri, Ishtiaq

    2014-01-01

    Chronic active hepatitis (CAH) is acknowledged as an imperative risk factor for the development of liver injury and hepatocellular carcinoma. The histological end points of CAH are chronic inflammation, fibrosis and cirrhosis which are coupled with increased DNA synthesis in cirrhotic vs healthy normal livers. The potential mechanism involved in CAH includes a combination of processes leading to liver cell necrosis, inflammation and cytokine production and liver scaring (fibrosis). The severity of liver damage is regulated by Hepatitis B virus genotypes and viral components. The viral and cellular factors that contribute to liver injury are discussed in this article. Liver injury caused by the viral infection affects many cellular processes such as cell signaling, apoptosis, transcription, DNA repair which in turn induce radical effects on cell survival, growth, transformation and maintenance. The consequence of such perturbations is resulted in the alteration of bile secretion, gluconeogenesis, glycolysis, detoxification and metabolism of carbohydrates, proteins, fat and balance of nutrients. The identification and elucidation of the molecular pathways perturbed by the viral proteins are important in order to design effective strategy to minimize and/or restore the hepatocytes injury. PMID:25253946

  3. Hepatic Injury in Nonalcoholic Steatohepatitis Contributes to Altered Intestinal Permeability

    PubMed Central

    Luther, Jay; Garber, John J.; Khalili, Hamed; Dave, Maneesh; Bale, Shyam Sundhar; Jindal, Rohit; Motola, Daniel L.; Luther, Sanjana; Bohr, Stefan; Jeoung, Soung Won; Deshpande, Vikram; Singh, Gurminder; Turner, Jerrold R.; Yarmush, Martin L.; Chung, Raymond T.; Patel, Suraj J.

    2015-01-01

    BACKGROUND & AIMS Emerging data suggest that changes in intestinal permeability and increased gut microbial translocation contribute to the inflammatory pathway involved in nonalcoholic steatohepatitis (NASH) development. Numerous studies have investigated the association between increased intestinal permeability and NASH. Our meta-analysis of this association investigates the underlying mechanism. METHODS A meta-analysis was performed to compare the rates of increased intestinal permeability in patients with NASH and healthy controls. To further address the underlying mechanism of action, we studied changes in intestinal permeability in a diet-induced (methionine-and-choline-deficient; MCD) murine model of NASH. In vitro studies were also performed to investigate the effect of MCD culture medium at the cellular level on hepatocytes, Kupffer cells, and intestinal epithelial cells. RESULTS Nonalcoholic fatty liver disease (NAFLD) patients, and in particular those with NASH, are more likely to have increased intestinal permeability compared with healthy controls. We correlate this clinical observation with in vivo data showing mice fed an MCD diet develop intestinal permeability changes after an initial phase of liver injury and tumor necrosis factor-α (TNFα) induction. In vitro studies reveal that MCD medium induces hepatic injury and TNFα production yet has no direct effect on intestinal epithelial cells. Although these data suggest a role for hepatic TNFα in altering intestinal permeability, we found that mice genetically resistant to TNFα-myosin light chain kinase (MLCK)–induced intestinal permeability changes fed an MCD diet still develop increased permeability and liver injury. CONCLUSIONS Our clinical and experimental results strengthen the association between intestinal permeability increases and NASH and also suggest that an early phase of hepatic injury and inflammation contributes to altered intestinal permeability in a fashion independent of TNF

  4. Activated farnesoid X receptor attenuates apoptosis and liver injury in autoimmune hepatitis.

    PubMed

    Lian, Fan; Wang, Yu; Xiao, Youjun; Wu, Xiwen; Xu, Hanshi; Liang, Liuqin; Yang, Xiuyan

    2015-10-01

    Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease associated with interface hepatitis, the presence of autoantibodies, regulatory T‑cell dysfunction and raised plasma liver enzyme levels. The present study assessed the hepatoprotective and antiapoptotic role of farnesoid X receptor (FXR) in AIH. a mouse model of AIH was induced by treatment with concanavalin A (ConA). The FXR agonist, chenodeoxycholic acid (CDCA), was administered to mice exhibiting ConA‑induced liver injury and a normal control. Blood samples were obtained to detect the levels of aminotransferases and inflammatory cytokines. Liver specimens were collected, and hematoxylin‑eosin staining was used for histopathological examination and detection. Apoptosis was evaluated using the terminal deoxynucleotidyl-transferase‑mediated dUTP nick end labeling (TUNEL) method. The expression levels of apoptosis‑associated genes and proteins were determined by reverse transcription‑quantitative polymerase chain reaction and western blotting, respectively. The results demonstrated that FXR was downregulated at the mRNA and protein level in the liver specimens of mice induced with ConA‑induced hepatitis. Increased levels of aminotransferases and inflammatory cytokines, including interferon‑γ, tumor necrosis factor‑α, interleukin (IL)‑4 and IL‑2, were detected in ConA‑treated mice. The mice pretreated with the FXR agonist, CDCA, were more resistant to ConA hepatitis, as indicated by reduced levels of alanine transaminase/aspartate aminotransferase and aminotransferases. The activation of FXR ameliorated hepatocyte apoptosis, as demonstrated by TUNEL analysis and downregulation of the Fas/Fas ligand, tumor necrosis factor‑related apoptosis‑inducing ligand and caspase‑3. Taken together, FXR activation ameliorated liver injury and suppressed inflammatory cytokines in ConA‑induced hepatitis. FXR, therefore, exerts a protective role against ConA-induced apoptosis. PMID

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

    PubMed

    Guzman, Grace; Kallwitz, Eric R; Wojewoda, Christina; Chennuri, Rohini; Berkes, Jamie; Layden, Thomas J; Cotler, Scott J

    2009-01-01

    There are a growing number of cases detailing acute hepatic necrosis in patients taking black cohosh (Cimicifuga racemosa), an over-the-counter herbal supplement for management of menopausal symptoms. Our aim is to illustrate two cases of liver injury following the use of black cohosh characterized by histopathological features mimicking autoimmune hepatitis. Both patients reported black cohosh use for at least six months and had no evidence of another cause of liver disease. Their liver biopsies showed a component of centrilobular necrosis consistent with severe drug-induced liver injury. In addition, the biopsies showed characteristics of autoimmune-like liver injury with an interface hepatitis dominated by plasma cells. Although serum markers for autoimmune hepatitis were not particularly elevated, both patients responded to corticosteroids, supporting an immune-mediated component to the liver injury. Liver injury following the use of black cohosh should be included in the list of differential diagnoses for chronic hepatitis with features mimicking autoimmune hepatitis. PMID:20130783

  6. Integrative Metabolic Signatures for Hepatic Radiation Injury

    PubMed Central

    Su, Gang; Meng, Fan; Liu, Laibin; Mohney, Robert; Kulkarni, Shilpa; Guha, Chandan

    2015-01-01

    Background Radiation-induced liver disease (RILD) is a dose-limiting factor in curative radiation therapy (RT) for liver cancers, making early detection of radiation-associated liver injury absolutely essential for medical intervention. A metabolomic approach was used to determine metabolic signatures that could serve as biomarkers for early detection of RILD in mice. Methods Anesthetized C57BL/6 mice received 0, 10 or 50 Gy Whole Liver Irradiation (WLI) and were contrasted to mice, which received 10 Gy whole body irradiation (WBI). Liver and plasma samples were collected at 24 hours after irradiation. The samples were processed using Gas Chromatography/Mass Spectrometry and Liquid Chromatography/Mass Spectrometry. Results Twenty four hours after WLI, 407 metabolites were detected in liver samples while 347 metabolites were detected in plasma. Plasma metabolites associated with 50 Gy WLI included several amino acids, purine and pyrimidine metabolites, microbial metabolites, and most prominently bradykinin and 3-indoxyl-sulfate. Liver metabolites associated with 50 Gy WLI included pentose phosphate, purine, and pyrimidine metabolites in liver. Plasma biomarkers in common between WLI and WBI were enriched in microbial metabolites such as 3 indoxyl sulfate, indole-3-lactic acid, phenyllactic acid, pipecolic acid, hippuric acid, and markers of DNA damage such as 2-deoxyuridine. Metabolites associated with tryptophan and indoles may reflect radiation-induced gut microbiome effects. Predominant liver biomarkers in common between WBI and WLI were amino acids, sugars, TCA metabolites (fumarate), fatty acids (lineolate, n-hexadecanoic acid) and DNA damage markers (uridine). Conclusions We identified a set of metabolomic markers that may prove useful as plasma biomarkers of RILD and WBI. Pathway analysis also suggested that the unique metabolic changes observed after liver irradiation was an integrative response of the intestine, liver and kidney. PMID:26046990

  7. Hepatic artery injury during left hepatic trisectionectomy for colorectal liver metastasis treated by portal vein arterialization

    PubMed Central

    Hokuto, Daisuke; Nomi, Takeo; Yamato, Ichiro; Yasuda, Satoshi; Obara, Shinsaku; Yamada, Takatsugu; Kanehiro, Hiromichi; Nakajima, Yoshiyuki

    2015-01-01

    Portal vein arterialization (PVA) has been applied as a salvage procedure in hepatopancreatobiliary surgeries, including transplantation and liver resection, with revascularization for malignancies. Here we describe the use PVA as a salvage procedure following accidental injury of the hepatic artery to the remnant liver occurred during left hepatic trisectionectomy for colorectal liver metastases (CRLM). A 60-year-old man with cancer of the sigmoid colon and initially unresectable CRLM received 11 cycles of hepatic arterial infusion chemotherapy with 5-fluorouracil (1500 mg/week), after which CRLM was downstaged to resectable. One month after laparoscopic sigmoidectomy, a left trisectionectomy and wedge resection of segment 6 were performed. The posterior branch of the right hepatic artery, the only feeding artery to the remnant liver, was injured and totally dissected. Because microsurgical reconstruction of the artery was impossible, PVA was used; PVA is the sole known procedure available when hepatic artery reconstruction is impossible. The patient then suffered portal hypertension, and closure of arterio-portal anastomosis using an interventional technique with angiography was eventually performed on postoperative day 73. Therefore, it is considered that because PVA is associated with severe postoperative portal hypertension, closure of the arterio-portal shunt should be performed as soon as possible on diagnosing portal hypertension. PMID:26197094

  8. Hepatic artery injury during left hepatic trisectionectomy for colorectal liver metastasis treated by portal vein arterialization.

    PubMed

    Hokuto, Daisuke; Nomi, Takeo; Yamato, Ichiro; Yasuda, Satoshi; Obara, Shinsaku; Yamada, Takatsugu; Kanehiro, Hiromichi; Nakajima, Yoshiyuki

    2015-01-01

    Portal vein arterialization (PVA) has been applied as a salvage procedure in hepatopancreatobiliary surgeries, including transplantation and liver resection, with revascularization for malignancies. Here we describe the use PVA as a salvage procedure following accidental injury of the hepatic artery to the remnant liver occurred during left hepatic trisectionectomy for colorectal liver metastases (CRLM). A 60-year-old man with cancer of the sigmoid colon and initially unresectable CRLM received 11 cycles of hepatic arterial infusion chemotherapy with 5-fluorouracil (1500mg/week), after which CRLM was downstaged to resectable. One month after laparoscopic sigmoidectomy, a left trisectionectomy and wedge resection of segment 6 were performed. The posterior branch of the right hepatic artery, the only feeding artery to the remnant liver, was injured and totally dissected. Because microsurgical reconstruction of the artery was impossible, PVA was used; PVA is the sole known procedure available when hepatic artery reconstruction is impossible. The patient then suffered portal hypertension, and closure of arterio-portal anastomosis using an interventional technique with angiography was eventually performed on postoperative day 73. Therefore, it is considered that because PVA is associated with severe postoperative portal hypertension, closure of the arterio-portal shunt should be performed as soon as possible on diagnosing portal hypertension. PMID:26197094

  9. Isolated Right Segmental Hepatic Duct Injury Following Laparoscopic Cholecystectomy

    SciTech Connect

    Perini, Rafael F.; Uflacker, Renan Cunningham, John T.; Selby, J. Bayne; Adams, David

    2005-04-15

    Purpose. Laparoscopic cholecystectomy (LC) is the treatment of choice for gallstones. There is an increased incidence of bile duct injuries in LC compared with the open technique. Isolated right segmental hepatic duct injury (IRSHDI) represents a challenge not only for management but also for diagnosis. We present our experience in the management of IRSHDI, with long-term follow-up after treatment by a multidisciplinary approach. Methods. Twelve consecutive patients (9 women, mean age 48 years) were identified as having IRSHDI. Patients' demographics, clinical presentation, management and outcome were collected for analysis. The mean follow-up was 44 months (range 2-90 months). Results. Three patients had the LC immediately converted to open surgery without repair of the biliary injury before referral. Treatments before referral included endoscopic retrograde cholangiopancreatography (ERCP), percutaneous drainage and surgery, isolated or in combination. The median interval from LC to referral was 32 days. Eleven patients presented with biliary leak and biloma, one with obstruction of an isolated right hepatic segment. Post-referral management of the biliary lesion used a combination of ERCP stenting, percutaneous drainage and stent placement and surgery. In 6 of 12 patients ERCP was the first procedure, and in only one case was IRSHDI identified. In 6 patients, percutaneous transhepatic cholangiography (PTC) was performed first and an isolated right hepatic segment was demonstrated in all. The final treatment modality was endoscopic management and/or percutaneous drainage and stenting in 6 patients, and surgery in 6. The mean follow-up was 44 months. No mortality or significant morbidity was observed. Conclusion. Successful management of IRSHDI after LC requires adequate identification of the lesion, and multidisciplinary treatment is necessary. Half of the patients can be treated successfully by nonsurgical procedures.

  10. 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

  11. Inhibition of concanavalin A-induced mice hepatitis by coumarin derivatives.

    PubMed

    Okamoto, T; Yoshida, S; Kobayashi, T; Okabe, S

    2001-01-01

    The effects of coumarin derivatives, osthole, imperatorin, Pd-Ia, Pd-II and Pd-III, on mice concanavalin A (Con A) (0.2 mg/mouse, i.v.)-induced hepatitis were studied. At the dose of 200 mg/kg (i.p.), these coumarins inhibited more than 90% of the Con A-induced elevation of plasma alanine aminotransferase activity, but glycyrrhizin (200 mg/kg, i.p.) caused only 45% inhibition. At the dose of 100 mg/kg (i.p.), osthole produced the strongest inhibition among these coumarins. The inhibitory activity of osthole is lost when its 7-methoxy group is replaced by a 7-hydroxy group to form osthenol. The present results showed that coumarin derivatives inhibited Con A-induced hepatitis, with osthole being the most inhibitory. PMID:11243581

  12. Imaging findings and endovascular management of iatrogenic hepatic arterial injuries.

    PubMed

    Güneyli, Serkan; Gök, Mustafa; Çınar, Celal; Bozkaya, Halil; Korkmaz, Mehmet; Parıldar, Mustafa; Oran, İsmail

    2015-01-01

    Iatrogenic hepatic arterial injuries (IHAIs) include pseudoaneurysm, extravasation, arteriovenous fistula, arteriobiliary fistula, and dissection. IHAIs are usually demonstrated following percutaneous transhepatic biliary drainage, percutaneous liver biopsy, liver surgery, chemoembolization, radioembolization, and endoscopic retrograde cholangiopancreatography. The latency period between the intervention and diagnosis varies. The most common symptom is hemorrhage, and the most common lesion is pseudoaneurysm. Computed tomography angiography (CTA) is mostly performed prior to angiography, and IHAIs are demonstrated on CTA in most of the patients. Patients with IHAI are mostly treated by coils, but some patients may be treated by liquid embolic materials or stent-grafts. CTA can also be used in the follow-up period. Endovascular treatment is a safe and minimally invasive treatment option with high success rates. PMID:26359873

  13. Hepatic injury after whole-liver irradiation in the rat

    SciTech Connect

    Geraci, J.P.; Jackson, K.L.; Mariano, M.S.; Leitch, J.M.

    1985-03-01

    Radiation-induced hepatic injury in rats, which is characterized by marked ascites accompanied by liver necrosis, fibrosis, and vein lesions, is described in this study. These adverse sequelae are produced within 30 days after irradiation if there is surgical removal of two-thirds of the liver immediately after whole-liver irradiation. The LD/sub 50/30/ day and median survival time after liver irradiation and two-thirds partial hepatectomy is 24 Gy and 17 days, respectively. Death is preceded by reduction in liver function as measured by (/sup 131/I)-labeled rose bengal clearance. Prior to death, liver sepsis and endotoxemia were detected in most irradiated, partially hepatectomized animals. Pretreatment of the animals with endotoxin and/or antibiotic decontamination of the GI tract resulted in increased survival time, but no irradiated, partially hepatectomized animal survived beyond 63 days. This suggests that sepsis and endotoxemia resulting from the bacteria in the intestine are the immediate cause of death after 30-Gy liver irradiation and partial hepatectomy. It is concluded that the hepatectomized rat model is an economical and scientifically manageable experimental system to study a form of radiation hepatitis that occurs in compromised human livers.

  14. Protective effects of sevoflurane in hepatic ischemia-reperfusion injury.

    PubMed

    Li, Ji; Yuan, Tong; Zhao, Xin; Lv, Guo-Yue; Liu, Huan-Qiu

    2016-06-01

    The endothelial glycocalyx plays a critical role in the regulation of vascular structure and functions. Previous studies have demonstrated that sevoflurane, a volatile anesthetic, can preserve the endothelial glycocalyx in heart tissues against ischemia-reperfusion injury. However, little is known about the effects of sevoflurane pretreatment on the vascular structure and functions of liver tissues following ischemia-reperfusion injury. To this end, female Sprague-Dawley rats (n = 28) were anesthetized either with ketamine (80-120 mg/kg, i.p.) or with one minimum alveolar concentration (MAC) sevoflurane (2% v/v). Following in vivo hepatic ischemia procedure, the liver was isolated and reperfusion was produced. During the period of reperfusion, liver reperfusion samples were collected, and the concentrations of heparan sulfate and syndecan-1 (Syn-1), and the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) enzymes, were measured. The morphology of hepatocytes and endothelial glycocalyx were then assessed by using the light and electron microscopies, respectively. Ischemia-reperfusion increased the release of HS and Syn-1, and elevated the levels of ALT and AST in a time-dependent manner. However, sevoflurane pretreatment reduced the release of HS and Syn-1and attenuated the levels of ALT and AST, in a time-dependent manner, as compared with ketamine pretreatment. Furthermore, sevoflurane pretreatment decreased the shedding of endothelial glycocalyx and hepatocytes necrosis. Sevoflurane pretreatment preserved the endothelial glycocalyx in the liver tissue against ischemia-reperfusion injury. The effect appears to help protect hepatocytes against ischemia-reperfusion-induced necrosis. PMID:26966142

  15. Protective effects of L-carnosine on CCl4 -induced hepatic injury in rats.

    PubMed

    Alsheblak, Mehyar Mohammad; Elsherbiny, Nehal M; El-Karef, Amro; El-Shishtawy, Mamdouh M

    2016-03-01

    The present study was undertaken to investigate the possible protective effect of L-carnosine (CAR), an endogenous dipeptide of alanine and histidine, on carbon tetrachloride (CCl4)-induced hepatic injury. Liver injury was induced in male Sprague-Dawley rats by intraperitoneal (i.p.) injections of CCl4, twice weekly for six weeks. CAR was administered to rats daily, at dose of 250 mg/kg, i.p. At the end of six weeks, blood and liver tissue specimens were collected. Results show that CAR treatment attenuated the hepatic morphological changes, necroinflammation and fibrosis induced by CCl4, as indicated by hepatic histopathology scoring. In addition, CAR treatment significantly reduced the CCl4-induced elevation of liver-injury parameters in serum. CAR treatment also combatted oxidative stress; possibly by restoring hepatic nuclear factor erythroid 2-related factor 2 (Nrf-2) levels. Moreover, CAR treatment prevented the activation of hepatic stellate cells (HSCs), as indicated by reduced α-smooth muscle actin (α-SMA) expression in the liver, and decreased hepatic inflammation as demonstrated by a reduction in hepatic tumor necrosis factor-α (TNF-α) and restoration of interleukin-10 (IL-10) levels. In conclusion, CCl4-induced hepatic injury was alleviated by CAR treatment. The results suggest that these beneficial, protective effects are due, at least in part, to its anti-oxidant, anti-inflammatory and anti-fibrotic activities. PMID:27094155

  16. Amelioration of hepatic reperfusion injury by superoxide dismutase and catalase

    SciTech Connect

    Clemens, M.G.; Burke, F.; Chaudry, I.H.

    1986-03-05

    Oxygen-derived free radicals have been implicated in reperfusion injury in various tissues. The present study determined if enzymatic scavenging of free radicals could improve recovery of hepatic function following ischemia. Livers from fasted rats were perfused with Krebs-HCO/sub 3/ buffer with substrates for gluconeogenesis for 30 min (control) followed by 60 min warm ischemia and 90 min reperfusion. At the beginning and end of ischemia the liver was flushed with buffered Ringer's with superoxide dismutase + catalase (150,000 U/L each)(SOD) or without additions (Untreated). Bile flow and glucose release were monitored during control and reperfusion periods and tissue sampled at the end of the experiment to determine tissue water and electrolytes. Bile flow and gluconeogenesis were markedly depressed after ischemia in both groups. At the end of 90 min reperfusion bile flow in Untreated and SOD were 23 +/- 6 and 46 +/- 8 ..mu..l/15 min (20% and 41% of control respectively, p < .01). Gluconeogenesis recovered to 83 +/- 4% of control in Untreated vs 103 +/- 6% with SOD (p < .05). Tissue water and electrolytes were not different. These results suggest that generation of oxygen-derived free radicals contributes to functional deficits in the liver following ischemia and that these defects can be attenuated by enzymatic scavenging.

  17. 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. PMID:26721437

  18. Antioxidant Stress and Anti-Inflammation of PPARα on Warm Hepatic Ischemia-Reperfusion Injury

    PubMed Central

    Gao, Zhixin; Li, Yuan-Hai

    2012-01-01

    Hepatic ischemia-reperfusion (IR) injury is a serious clinical problem. Minimizing the adverse effect of ischemia-reperfusion injury after liver surgery or trauma is an urgent need. It has been proved that besides the effect of regulating the lipid and lipoprotein metabolism, PPARα also undertakes the task of organ protection. In this paper, related literature has been summarized and we come to the conclusion that administration of PPARα agonists can strengthen the antioxidant and anti-inflammation defense system by the upregulation of the expression of antioxidant enzymes and inhibition of NF-κB activity. This may provide a potential clinical treatment for hepatic ischemia-reperfusion injury. PMID:23213319

  19. Inhibiting monoacylglycerol acyltransferase 1 ameliorates hepatic metabolic abnormalities but not inflammation and injury in mice.

    PubMed

    Soufi, Nisreen; Hall, Angela M; Chen, Zhouji; Yoshino, Jun; Collier, Sara L; Mathews, James C; Brunt, Elizabeth M; Albert, Carolyn J; Graham, Mark J; Ford, David A; Finck, Brian N

    2014-10-24

    Abnormalities in hepatic lipid metabolism and insulin action are believed to play a critical role in the etiology of nonalcoholic steatohepatitis. Monoacylglycerol acyltransferase (MGAT) enzymes convert monoacylglycerol to diacylglycerol, which is the penultimate step in one pathway for triacylglycerol synthesis. Hepatic expression of Mogat1, which encodes an MGAT enzyme, is increased in the livers of mice with hepatic steatosis, and knocking down Mogat1 improves glucose metabolism and hepatic insulin signaling, but whether increased MGAT activity plays a role in the etiology of nonalcoholic steatohepatitis is unclear. To examine this issue, mice were placed on a diet containing high levels of trans fatty acids, fructose, and cholesterol (HTF-C diet) or a low fat control diet for 4 weeks. Mice were injected with antisense oligonucleotides (ASOs) to knockdown Mogat1 or a scrambled ASO control for 12 weeks while remaining on diet. The HTF-C diet caused glucose intolerance, hepatic steatosis, and induced hepatic gene expression markers of inflammation, macrophage infiltration, and stellate cell activation. Mogat1 ASO treatment, which suppressed Mogat1 expression in liver and adipose tissue, attenuated weight gain, improved glucose tolerance, improved hepatic insulin signaling, and decreased hepatic triacylglycerol content compared with control ASO-treated mice on HTF-C chow. However, Mogat1 ASO treatment did not reduce hepatic diacylglycerol, cholesterol, or free fatty acid content; improve histologic measures of liver injury; or reduce expression of markers of stellate cell activation, liver inflammation, and injury. In conclusion, inhibition of hepatic Mogat1 in HTF-C diet-fed mice improves hepatic metabolic abnormalities without attenuating liver inflammation and injury. PMID:25213859

  20. Inhibiting Monoacylglycerol Acyltransferase 1 Ameliorates Hepatic Metabolic Abnormalities but Not Inflammation and Injury in Mice*

    PubMed Central

    Soufi, Nisreen; Hall, Angela M.; Chen, Zhouji; Yoshino, Jun; Collier, Sara L.; Mathews, James C.; Brunt, Elizabeth M.; Albert, Carolyn J.; Graham, Mark J.; Ford, David A.; Finck, Brian N.

    2014-01-01

    Abnormalities in hepatic lipid metabolism and insulin action are believed to play a critical role in the etiology of nonalcoholic steatohepatitis. Monoacylglycerol acyltransferase (MGAT) enzymes convert monoacylglycerol to diacylglycerol, which is the penultimate step in one pathway for triacylglycerol synthesis. Hepatic expression of Mogat1, which encodes an MGAT enzyme, is increased in the livers of mice with hepatic steatosis, and knocking down Mogat1 improves glucose metabolism and hepatic insulin signaling, but whether increased MGAT activity plays a role in the etiology of nonalcoholic steatohepatitis is unclear. To examine this issue, mice were placed on a diet containing high levels of trans fatty acids, fructose, and cholesterol (HTF-C diet) or a low fat control diet for 4 weeks. Mice were injected with antisense oligonucleotides (ASOs) to knockdown Mogat1 or a scrambled ASO control for 12 weeks while remaining on diet. The HTF-C diet caused glucose intolerance, hepatic steatosis, and induced hepatic gene expression markers of inflammation, macrophage infiltration, and stellate cell activation. Mogat1 ASO treatment, which suppressed Mogat1 expression in liver and adipose tissue, attenuated weight gain, improved glucose tolerance, improved hepatic insulin signaling, and decreased hepatic triacylglycerol content compared with control ASO-treated mice on HTF-C chow. However, Mogat1 ASO treatment did not reduce hepatic diacylglycerol, cholesterol, or free fatty acid content; improve histologic measures of liver injury; or reduce expression of markers of stellate cell activation, liver inflammation, and injury. In conclusion, inhibition of hepatic Mogat1 in HTF-C diet-fed mice improves hepatic metabolic abnormalities without attenuating liver inflammation and injury. PMID:25213859

  1. Hepatoprotective effect of trans-Chalcone on experimentally induced hepatic injury in rats: inhibition of hepatic inflammation and fibrosis.

    PubMed

    Singh, Harsimran; Sidhu, Shabir; Chopra, Kanwaljit; Khan, M U

    2016-08-01

    The current study investigated the hepatoprotective effect of trans-Chalcone in carbon tetrachloride (CCl4) and paracetamol (PCM) induced liver damage in rats. Administration of CCl4 and PCM (1 mL/kg, i.p., 3 days, and 2 g/kg, p.o., single dose, respectively) produced hepatic injury. Ponderal changes (percent change in body mass and relative liver mass) and biochemical parameters (serum ALT, AST, ALP, bilirubin) were estimated. The markers of oxidative and nitrosative stress (TBARS, reduced GSH, nitrite and nitrate), hepatic fibrosis (TGF-β1, collagen content), hepatic inflammation (TNF-α), and histopathological study were evaluated. trans-Chalcone (5, 10, and 20 mg/kg, i.p.) was found to be beneficial as demonstrated by significant reversal of liver histology by perceptible reduction of inflammatory cell infiltration with regenerative changes in hepatocytes. Improvement in percent change in body mass and significant reduction in relative liver mass were observed. Marked reduction in serum levels of ALT, AST, ALP, and bilirubin were noted. Decreases in TBARS and nitrites and nitrates and increases in reduced GSH levels were noted. Hepatic fibrosis and inflammation were significantly decreased. The findings indicate a novel hepatoprotective role for trans-Chalcone by improving hepatic injury by possible actions such as anti-oxidant, anti-nitrosative, anti-fibrotic, and anti-inflammatory. Hence, it can be used as promising hepatoprotective agent. PMID:27191034

  2. The effects of tramadol on hepatic ischemia/reperfusion injury in rats

    PubMed Central

    Mahmoud, Mona F.; Gamal, Samar; Shaheen, Mohamed A.; El-Fayoumi, Hassan M.

    2016-01-01

    Objectives: Tramadol is a centrally acting synthetic analgesic. It has a cardioprotective effect against myocardial ischemia-reperfusion (I/R) injury in isolated rat heart. We hypothesized that tramadol may exert a similar protective effect on hepatic I/R injury. Hence, the current investigation was designed to study the possible protective effects of tramadol on experimentally-induced hepatic I/R injury in rats. Materials and Methods: Tramadol was administered 30 min before ischemia following which the rats were subjected to 45 min of ischemia followed by 1 h of reperfusion. Results: Tramadol attenuated hepatic injury induced by I/R as evidenced by the reduction of transaminases, structural changes, and apoptotic cell death. It decreased the level of inflammatory markers such as tumor necrosis factor-alpha (TNF-α), TNF-α/interleukin-10 (IL-10) ratio, and nuclear factor-κB gene expression. It also increased the anti-inflammatory cytokine, IL-10 levels in hepatic tissues. Furthermore, it reduced oxidative stress parameters except manganese superoxide dismutase activity. Conclusion: The results suggest that tramadol has hepatoprotective effects against hepatic I/R injury via anti-inflammatory, antiapoptotic, and antioxidant effects. PMID:27298497

  3. Protective effects of fish oil, allopurinol, and verapamil on hepatic ischemia-reperfusion injury in rats

    PubMed Central

    Messiha, Basim Anwar Shehata; Abo-Youssef, Amira M.

    2015-01-01

    Background: The major aim of this work was to study the protective effects of fish oil (FO), allopurinol, and verapamil on hepatic ischemia-reperfusion (IR)-induced injury in experimental rats. Materials and Methods: Sixty male Wistar albino rats were randomly assigned to six groups of 10 rats each. Group 1 served as a negative control. Group 2 served as hepatic IR control injury. Groups 3, 4, 5, and 6 received N-acetylcysteine (standard), FO, allopurinol, and verapamil, respectively, for 3 consecutive days prior to ischemia. All animals were fasted for 12 h, anesthetized and underwent midline laparotomy. The portal triads were clamped by mini-artery clamp for 30 min followed by reperfusion for 30 min. Blood samples were withdrawn for estimation of serum alanine transaminase (ALT) and aspartate transaminase (AST) activities as well as hepatic thiobarbituric acid reactive substances, reduced glutathione, myeloperoxidase, and total nitrate/nitrite levels, in addition to histopathological examination. Results: Fish oil, allopurinol, and verapamil reduced hepatic IR injury as evidenced by significant reduction in serum ALT and AST enzyme activities. FO and verapamil markedly reduced oxidative stress as compared to control IR injury. Levels of inflammatory biomarkers in liver were also reduced after treatment with FO, allopurinol, or verapamil. In accordance, a marked improvement of histopathological findings was observed with all of the three treatments. Conclusion: The findings of this study prove the benefits of FO, allopurinol, and verapamil on hepatic IR-induced liver injury and are promising for further clinical trials. PMID:26283828

  4. Correlating MDCT Liver Injury Grade and Clinical Outcome in Patients Without Significant Extra-hepatic Injury.

    PubMed

    Kumar, Ravi; Kumar, Atin; Baliyan, Vinit; Gamanagatti, Shivanand; Bhalla, Ashu Seith; Sharma, Raju; Gupta, Amit; Kumar, Subodh; Misra, M C

    2016-08-01

    The aim of the study was to correlate multi-detector computed tomography (MDCT) grading with clinical severity and outcome in liver trauma patients without significant extrahepatic injury. Over a period of 2 years (2011-2013), all patients showing evidence of liver injury on contrast-enhanced CT (CECT) abdomen and without significant extrahepatic trauma were prospectively included in the study. Correlation between the CT injury grade and outcome in terms of mortality, duration of ICU/hospital stay, fluid and blood requirements, need for intervention and complications were assessed. The significance of the difference in mortality, duration of ICU/hospital stay, fluid requirement and blood requirements among the patients with various injury grades was assessed by Kruskal-Wallis test. The significance of the difference in need for intervention and complications among the patients with various injury grades was assessed by Fisher's exact test. A total of 198 patients were found to have evidence of hepatic injury on CECT. Out of 198 patients, 117 had insignificant extrahepatic trauma. The overall mean age for these 117 patients was 25.74 ± 15.53 (age range 2-84 years). Death rates according to AAST grades were 0 % in grades II and III, 6.89 % in grade IV and 9.09 % in grade V (p = 0.053). The mean ICU and total hospital stay for grade II was 1.32 and 5.91 days, for grade III was 1.76 and 8.48, for grade IV was 2.86 and 10.31 days and for grade V was 6.54 and 12 days, respectively (p = 0.0001 for ICU, p = 0.0003 for total stay). Mean input and fluid deficit according to various grades were 8634/2607 ml for grade II, 9535/2555 ml for grade III, 15,549/6242 ml for grade IV and 19,958/8280 ml for grade V (p value input-0.0016, output-input (fluid deficit)-0.0001). Average unit of RBC and sum of the blood products transfused were 1.73 and 2.26 for grade II, 2.18 and 2.72 for grade III, 3.03 and 6.27 for grade IV, 6.85 and 38.12 for grade V

  5. Blunt Hepatic Injury: A Paradigm Shift From Operative to Nonoperative Management in the 1990s

    PubMed Central

    Malhotra, Ajai K.; Fabian, Timothy C.; Croce, Martin A.; Gavin, Timothy J.; Kudsk, Kenneth A.; Minard, Gayle; Pritchard, F. Elizabeth

    2000-01-01

    Objective To analyze the outcome of hemodynamically stable patients with blunt hepatic injury managed nonoperatively, and to examine the impact of this approach on the outcome of all patients with blunt hepatic injury. Summary Background Data Until recently, operative management has been the standard for liver injury. A prospective trial from the authors’ institution had shown that nonoperative management could safely be applied to hemodynamically stable patients with blunt hepatic injury. The present study reviewed the authors’ institutional experience with blunt hepatic trauma since that trial and compared the results with prior institutional experience. Methods Six hundred sixty-one patients with blunt hepatic trauma during the 5-year period ending December 1998 were reviewed (NONOP2). The outcomes were compared with two previous studies from this institution: operative 1985 to 1990 (OP) and nonoperative 1993 to 1994 (NONOP1). Results All 168 OP patients were managed operatively. Twenty-four (18%) of 136 NONOP1 patients and 101 (15%) of the 661 NONOP2 patients required immediate exploration for hemodynamic instability. Forty-two (7%) patients failed nonoperative management; 20 were liver-related. Liver-related failures of nonoperative management were associated with higher-grade injuries and with larger amounts of hemoperitoneum on computed tomography scanning. Twenty-four-hour transfusions, abdominal infections, and hospital length of stay were all significantly lower in the NONOP1 and NONOP2 groups versus the OP cohort. The liver-related death rate was constant at 4% in the three cohorts over the three time periods. Conclusions Although urgent surgery continues to be the standard for hemodynamically compromised patients with blunt hepatic trauma, there has been a paradigm shift in the management of hemodynamically stable patients. Approximately 85% of all patients with blunt hepatic trauma are stable. In this group, nonoperative management significantly

  6. Accordion phenomenon of the hepatic artery: mimicker of vasospasm or intimal injury

    PubMed Central

    Koyama, Yoshinori; Tsushima, Yoshito

    2016-01-01

    The accordion phenomenon occurs because of mechanical distortion of a straightened vessel during coronary and vascular interventions. To date, however, this phenomenon has not been reported in vessels of the upper abdomen. We therefore describe the accordion phenomenon of the hepatic artery during transarterial chemoembolization seen while treating a liver tumor. As the accordion phenomenon is now known to involve hepatic arteries, it should be differentiated from vascular complications such as vasospasm or intimal injury. PMID:27570635

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

    PubMed Central

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

    2016-01-01

    Purpose Acute hepatitis A (AHA) and acute hepatitis B (AHB) are caused by an acute infection of the hepatitis A virus and the hepatitis B virus, respectively. In both AHA and AHB, liver injury is known to be mediated by immune cells and cytokines. In this study, we measured serum levels of various cytokines and T-cell cytotoxic proteins in patients with AHA or AHB to identify liver injury-associated cytokines. Materials and Methods Forty-six patients with AHA, 16 patients with AHB, and 14 healthy adults were enrolled in the study. Serum levels of 17 cytokines and T-cell cytotoxic proteins were measured by enzyme-linked immunosorbent assays or cytometric bead arrays and analyzed for correlation with serum alanine aminotransferase (ALT) levels. Results Interleukin (IL)-18, IL-8, CXCL9, and CXCL10 were significantly elevated in both AHA and AHB. IL-6, IL-22, granzyme B, and soluble Fas ligand (sFasL) were elevated in AHA but not in AHB. In both AHA and AHB, the serum level of CXCL10 significantly correlated with the peak ALT level. Additionally, the serum level of granzyme B in AHA and the serum level of sFasL in AHB correlated with the peak ALT level. Conclusion We identified cytokines and T-cell cytotoxic proteins associated with liver injury in AHA and AHB. These findings deepen the existing understanding of immunological mechanisms responsible for liver injury in acute viral hepatitis. PMID:26996565

  8. Early activated hepatic stellate cell-derived molecules reverse acute hepatic injury

    PubMed Central

    Chang, Wen-Ju; Song, Lu-Jun; Yi, Tuo; Shen, Kun-Tang; Wang, Hong-Shan; Gao, Xiao-Dong; Li, Min; Xu, Jian-Min; Niu, Wei-Xin; Qin, Xin-Yu

    2015-01-01

    AIM: To test whether hepatic stellate cells (HSCs) at different activation stages play different roles in acetaminophen (APAP)-induced acute liver injury (ALI). METHODS: HSCs were isolated from mouse liver and cultured in vitro. Morphological changes of initiation HSCs [HSCs (5d)] and perpetuation HSCs [HSCs (p3)] were observed by immunofluorescence and transmission electron microscopy. The protective effects of HSC-derived molecules, cell lysates and HSC-conditioned medium (HSC-CM) were tested in vivo by survival and histopathological analyses. Liver injury was determined by measuring aminotransferase levels in the serum and by histologic examination of tissue sections under a light microscope. Additionally, to determine the molecular mediators of the observed protective effects of initiation HSCs, we examined HSC-CM using a high-density protein array. RESULTS: HSCs (5d) and HSCs (p3) had different morphological and phenotypic traits. HSCs (5d) presented a star-shaped appearance with expressing α-SMA at non-uniform levels between cells. However, HSCs (p3) evolved into myofibroblast-like cells without lipid droplets and expressed a uniform and higher level of α-SMA. HSC-CM (5d), but not HSC-CM (p3), provided a significant survival benefit and showed a dramatic reduction of hepatocellular necrosis and panlobular leukocyte infiltrates in mice exposed to APAP. However, this protective effect was abrogated at higher cell masses, indicating a therapeutic window of effectiveness. Furthermore, the protein array screen revealed that HSC-CM (5d) was composed of many chemokines and growth factors that correlated with inflammatory inhibition and therapeutic activity. When compared with HSC-CM (p3), higher levels of monocyte chemoattractant protein-1, macrophage inflammatory protein-1γ, hepatocyte growth factor, interleukin-10, and matrix metalloproteinase-2, but lower levels of stem cell factor and Fas-Ligand were observed in HSC-CM (5d). CONCLUSION: These data indicated

  9. MicroRNA-674-5p/5-LO axis involved in autoimmune reaction of Concanavalin A-induced acute mouse liver injury.

    PubMed

    Su, Kunkai; Wang, Qi; Qi, Luoyang; Hua, Dasong; Tao, Jingjing; Mangan, Connor J; Lou, Yijia; Li, Lanjuan

    2016-09-01

    Autoimmune hepatitis is characterized, in part, by the pathways involving cysteinyl-leukotriene metabolites of arachidonic acid, the dynamics of which remain unclear. Here, we explored post-transcriptional regulation in the 5-lipoxygenase (5-LO) pathway of arachidonic acid in a Concanavalin A (Con A) induced mouse model. We found that Con A administration lead to 5-LO overexpression and cysteinyl-leukotriene release in early hepatic injury, which was attenuated by cyclosporin A pretreatment. Subsequent microarray and qRT-PCR analysis further showed that microRNA-674-5p (miR-674-5p) displayed a significant decrease in expression in Con A-damaged liver. Noting that miR-674-5p harbors a potential binding region for 5-LO, we further transfected hepatic cell lines with overexpressing miR-674-5p mimic and discovered a negative regulating effect of miR-674-5p on 5-LO expression in the presence of IL-6 or TNF-α. These findings suggest that miR-674-5p might be a negative regulator in 5-LO mediated autoimmune liver injury, representing a compelling avenue towards future therapeutic interventions. PMID:27313091

  10. Hepatic sinusoids in liver injury, inflammation, and fibrosis: new pathophysiological insights.

    PubMed

    Greuter, Thomas; Shah, Vijay H

    2016-06-01

    Changes of hepatic sinusoids are crucial in the pathogenesis of liver cirrhosis and portal hypertension. Liver injury leads to distinct morphological abnormalities such as loss of sinusoidal fenestration, vasoconstriction, and angiogenesis as well as molecular changes. Communication between the two key cells in this hepatic microenvironment-hepatic stellate cells (HSC) and sinusoidal endothelial cells (SEC)-has been studied for many years and several canonical pathways have been elucidated, such as decreased eNOS activity or increased PDGF and TGF-β production leading to activation and migration of HSC. In recent studies, alternative pathways of intercellular communication in liver diseases have been described such as cell-derived extracellular vesicles called exosomes, which deliver cell compounds to their target cells. Moreover, such extracellular vesicles may link injury to inflammation in alcoholic hepatitis. While inflammation leading to liver fibrosis has been studied in detail, in some circumstances pathways other than the known canonical inflammatory pathways may contribute to hepatic fibrogenesis. For example, in congestive hepatopathy, sinusoidal dilatation and fibrosis have been shown to be mediated by non-inflammatory mechanisms and associated with sinusoidal thrombi. A recently developed murine model further enables experimental studies of this disease entity. Increasing knowledge about these alternative disease pathways in liver injury, inflammation, and fibrosis may reveal possible target molecules for future therapies. This article builds upon a seminar given at the recent 3rd JSGE International Topic Conference in Sendai, Japan, and reviews the areas outlined above. PMID:26939970

  11. Computed tomography arterial portography for assessment of portal vein injury after blunt hepatic trauma

    PubMed Central

    Fu, Chen-Ju; Wong, Yon-Cheong; Tsang, Yuk-Ming; Wang, Li-Jen; Chen, Huan-Wu; Ku, Yi-Kang; Wu, Cheng-Hsien; Chen, Huan-Wen; Kang, Shih-Ching

    2015-01-01

    PURPOSE Intrahepatic portal vein injuries secondary to blunt abdominal trauma are difficult to diagnose and can result in insidious bleeding. We aimed to compare computed tomography arterial portography (CTAP), reperfusion CTAP (rCTAP), and conventional computed tomography (CT) for diagnosing portal vein injuries after blunt hepatic trauma. METHODS Patients with blunt hepatic trauma, who were eligible for nonoperative management, underwent CTAP, rCTAP, and CT. The number and size of perfusion defects observed using the three methods were compared. RESULTS A total of 13 patients (seven males/six females) with a mean age of 34.5±14.1 years were included in the study. A total of 36 hepatic segments had perfusion defects on rCTAP and CT, while there were 47 hepatic segments with perfusion defects on CTAP. The size of perfusion defects on CT (239 cm3; interquartile range [IQR]: 129.5, 309.5) and rCTAP (238 cm3; IQR: 129.5, 310.5) were significantly smaller compared with CTAP (291 cm3; IQR: 136, 371) (both, P = 0.002). CONCLUSION Perfusion defects measured by CTAP were significantly greater than those determined by either rCTAP or CT in cases of blunt hepatic trauma. This finding suggests that CTAP is superior to rCTAP and CT in evaluating portal vein injuries after blunt liver trauma. PMID:26268303

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

    PubMed

    Liu, Bin; Qian, Jianmin; Wang, Qingbao; Wang, Fangrui; Ma, Zhenyu; Qiao, Yingli

    2014-01-01

    Hepatic ischemia/reperfusion (I/R) injury is an unavoidable consequence of major liver surgery, especially in liver transplantation with bowel congestion, during which endotoxemia is often evident. The inflammatory response aggravated by endotoxin after I/R contributes to liver dysfunction and failure. The purpose of the present study was to investigate the protective effect of butyrate, a naturally occurring four-carbon fatty acid in the body and a dietary component of foods such as cheese and butter, on hepatic injury complicated by enterogenous endotoxin, as well as to examine the underlying mechanisms involved. SD rats were subjected to a total hepatic ischemia for 30 min after pretreatment with either vehicle or butyrate, followed by 6 h and 24 h of reperfusion. Butyrate preconditioning markedly improved hepatic function and histology, as indicated by reduced transaminase levels and ameliorated tissue pathological changes. The inflammatory factors levels, macrophages activation, TLR4 expression, and neutrophil infiltration in live were attenuated by butyrate. Butyrate also maintained the intestinal barrier structures, reversed the aberrant expression of ZO-1, and decreased the endotoxin translocation. We conclude that butyrate inhibition of endotoxin translocation, macrophages activation, inflammatory factors production, and neutrophil infiltration is involved in the alleviation of total hepatic I/R liver injury in rats. This suggests that butyrate should potentially be utilized in liver transplantation. PMID:25171217

  13. Lithium Carbonate in the Treatment of Graves' Disease with ATD-Induced Hepatic Injury or Leukopenia

    PubMed Central

    Zheng, Rendong; Liu, Kemian; Chen, Kun; Cao, Wen; Cao, Lin; Zhang, Huifeng; Sun, Hongping; Liu, Chao

    2015-01-01

    Objective. GD with ATD-induced hepatic injury or leukopenia occurs frequently in clinical practice. The purpose of the present study was to observe the clinical effect of lithium carbonate on hyperthyroidism in patients with GD with hepatic injury or leukopenia. Methods. Fifty-one patients with GD with hepatic injury or leukopenia participated in the study. All patients were treated with lithium carbonate, in addition to hepatoprotective drugs or drugs that increase white blood cell count. Thyroid function, liver function, and white blood cells were measured. Clinical outcomes were observed after a 1-year follow-up. Results. After treatment for 36 weeks, symptoms of hyperthyroidism and the level of thyroid hormones were improved and liver function, and white blood cells returned to a normal level. Twelve patients (23.5%) obtained clinical remission, 6 patients (11.8%) relapsed after withdrawal, 25 patients (49.0%) received radioiodine therapy, and 8 patients (15.7%) underwent surgical procedures after lithium carbonate treatment. Conclusion. Lithium carbonate has effects on the treatment of mild-to-moderate hyperthyroidism caused by GD, and it is particularly suitable for patients with ATD-induced hepatic injury or leukopenia. PMID:26576153

  14. Spironolactone Effect in Hepatic Ischemia/Reperfusion Injury in Wistar Rats

    PubMed Central

    Jiménez Pérez, Julio César; Casillas Ramírez, Araní; Torres González, Liliana; Muñoz Espinosa, Linda Elsa; Perales Quintana, Marlene Marisol; Alarcón Galván, Gabriela; Zapata Chavira, Homero; Guzmán de la Garza, Francisco Javier; Cámara Lemarroy, Carlos Rodrigo; Fernández Garza, Nancy Esthela; Pérez Rodríguez, Edelmiro; Cordero Pérez, Paula

    2016-01-01

    Introduction. Ischemia/reperfusion (IR) injury, often associated with liver surgery, is an unresolved problem in the clinical practice. Spironolactone is an antagonist of aldosterone that has shown benefits over IR injury in several tissues, but its effects in hepatic IR are unknown. Objective. To evaluate the effect of spironolactone on IR-induced damage in liver. Materials and Methods. Total hepatic ischemia was induced in rats for 20 min followed by 60 min of reperfusion. Spironolactone was administered and hepatic injury, cytokine production, and oxidative stress were assessed. Results. After IR, increased transaminases levels and widespread acute inflammatory infiltrate, disorganization of hepatic hemorrhage trabeculae, and presence of apoptotic bodies were observed. Administration of SPI reduced biochemical and histological parameters of liver injury. SPI treatment increased IL-6 levels when compared with IR group but did not modify either IL-1β or TNF-α with respect to IR group. Regarding oxidative stress, increased levels of catalase activity were recorded in IR + SPI group in comparison with group without treatment, whereas MDA levels were similar in IR + SPI and IR groups. Conclusions. Spironolactone reduced the liver damage induced by IR, and this was associated with an increase in IL-6 production and catalase activity. PMID:26798418

  15. Acute hepatic injury with amphotericin B deoxycholate in an immunocompetent patient.

    PubMed

    Wagner, Jamie L; Bell, Allison M

    2016-01-01

    Amphotericin B deoxycholate (AmBd) is rarely used due to its adverse effect profile, which includes nephrotoxicity, infusion-related reactions, and hepatotoxicity. The incidence of hepatotoxicity related to AmBd is 18-23%, but the reports of this adverse effect are mainly in immunocompromised patients receiving chemotherapy. We report a case of AmBd-related acute hepatic injury in an immunocompetent male with multiple medical problems. The patient initially had acute hepatic injury likely caused by poor nutritional status and a diagnosis of failure to thrive, but was recovering. He was also diagnosed with bilateral renal fungal mycetomas and received systemic treatment initially with micafungin and then fluconazole after urine cultures returned with the growth of Candida glabrata. Therapy was expanded to systemic AmBd when the fungal balls persisted. The patient subsequently developed hepatic re-injury with 1 dose of AmBd, and the therapy was discontinued. Caution should be exerted when utilizing AmBd in treating patients with previous hepatic injury. PMID:27440960

  16. Acute hepatic injury with amphotericin B deoxycholate in an immunocompetent patient

    PubMed Central

    Wagner, Jamie L.; Bell, Allison M.

    2016-01-01

    Amphotericin B deoxycholate (AmBd) is rarely used due to its adverse effect profile, which includes nephrotoxicity, infusion-related reactions, and hepatotoxicity. The incidence of hepatotoxicity related to AmBd is 18–23%, but the reports of this adverse effect are mainly in immunocompromised patients receiving chemotherapy. We report a case of AmBd-related acute hepatic injury in an immunocompetent male with multiple medical problems. The patient initially had acute hepatic injury likely caused by poor nutritional status and a diagnosis of failure to thrive, but was recovering. He was also diagnosed with bilateral renal fungal mycetomas and received systemic treatment initially with micafungin and then fluconazole after urine cultures returned with the growth of Candida glabrata. Therapy was expanded to systemic AmBd when the fungal balls persisted. The patient subsequently developed hepatic re-injury with 1 dose of AmBd, and the therapy was discontinued. Caution should be exerted when utilizing AmBd in treating patients with previous hepatic injury.

  17. Study progress on mechanism of severe acute pancreatitis complicated with hepatic injury*

    PubMed Central

    Zhang, Xi-ping; Wang, Lei; Zhang, Jie

    2007-01-01

    Study on the action mechanism of inflammatory mediators generated by the severe acute pancreatitis (SAP) in multiple organ injury is a hotspot in the surgical field. In clinical practice, the main complicated organ dysfunctions are shock, respiratory failure, renal failure, encephalopathy, with the rate of hepatic diseases being closely next to them. The hepatic injury caused by SAP cannot only aggravate the state of pancreatitis, but also develop into hepatic failure and cause patient death. Its complicated pathogenic mechanism is an obstacle in clinical treatment. Among many pathogenic factors, the changes of vasoactive substances, participation of inflammatory mediators as well as OFR (oxygen free radical), endotoxin, etc. may play important roles in its progression. PMID:17444596

  18. Parthenolide ameliorates Concanavalin A-induced acute hepatitis in mice and modulates the macrophages to an anti-inflammatory state.

    PubMed

    Wang, Dan; Wang, Huafeng; Fu, Shuyu; Cheng, Xixi; Yang, Fengrui; Zhang, Qi; Li, Yan; Xue, Zhenyi; Zhang, Lijuan; Huang, Wenjing; Yang, Luhong; Na, Dongchen; Da, Yurong; Kong, Ying; Zhang, Rongxin

    2016-09-01

    Parthenolide, the principal sesquiterpene lactone present in medicinal plants such as feverfew, has anti-microbial, anti-inflammatory and anticancer activities. In the present study, we investigated the protective role of parthenolide against acute hepatitis in mice. Mice acute hepatitis were induced by Concanavalin A and treated by parthenolide in vivo. Results shown that parthenolide remarkably reduced the congestion and necroinflammation of the mice livers with Concanavalin A-induced acute hepatitis. Meanwhile, parthenolide treatment recover the liver function which indicated by decreased the serum alanine transaminase and alkaline phosphatase activities and promoted the expression of Ki67 in the livers of these mice. In addition, parthenolide administration suppressed the Concanavalin A-induced immune reaction, as indicated by the number of F4/80, CD49b and CD4 cells present in the liver. Furthermore, parthenolide also significantly reduced the expression of pro-inflammatory cytokines such as IFN-γ, TNF-α, IL-17A, IL-1β and IL-6 in lipopolysaccharide (LPS)-stimulated RAW264.7 cells in vitro. Moreover, parthenolide exposure decreased the phosphorylation of STAT3 and p38, and promoted the phosphorylation of p53 in RAW264.7 cells in vitro. In conclusion, parthenolide represents a drug candidate to protect the liver against Concanavalin A-induced acute hepatitis. The possible molecular mechanism involves the anti-inflammatory effects of parthenolide may by suppressing the STAT3/p38 signals and enhanced the p53 signals. PMID:27270078

  19. Cryptotanshinone Ameliorates Hepatic Normothermic Ischemia and Reperfusion Injury in Rats by Anti-mitochondrial Apoptosis.

    PubMed

    Sun, Ping-Ping; Yuan, Fang; Xu, Jing; Sai, Ke; Chen, Jie; Guan, Su

    2014-01-01

    Cryptotanshinone (CT), isolated from the dried roots of Salvia militorrhiza, has been reported to have protective effects on myocardial and cerebral ischemia/reperfusion (I/R) injury both in vitro and in vivo. However, its effects and underlying mechanism on hepatic I/R injury remain unclear. To investigate its effects on hepatic I/R injury, thirty male Sprague-Dawley rats were randomized into 3 groups: a sham group, a vehicle-treated hepatic I/R group and a CT-treated (50 mg/kg) group. The hepatic I/R and CT-treated groups were subjected to 60 min of normothermic ischemia of the left lateral lobe of the liver, followed by 4 h of reperfusion. The animals were then sacrificed to collect the serum and the left liver lobe for assay. Hepatic function was protected, as evidenced by significantly reduced alanine aminotransferase (ALT), aspartate aminotransferase (AST) and malondialdehyde (MDA) levels in the CT-treated group as compared with I/R group. The terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) demonstrated significantly decreased apoptosis in the CT-administration animals. Western blotting demonstrated upregulation of the proapoptotic protein Bcl-2, as well as decreased levels of the activated form of caspase-3 and the cleaved form of its substrate, poly(ADP-ribose) polymerase (PARP) in the CT-treated group compared with those of the I/R group. In addition, the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases (MAPKs) was inhibited by CT. Our data suggest that CT attenuates hepatic I/R injury by inhibiting the intrinsic pathway of apoptosis, mediated partly through the inhibition of JNK and p38 MAPK phosporylation. PMID:25366482

  20. Osthole attenuates hepatic injury in a rodent model of trauma-hemorrhage.

    PubMed

    Yu, Huang-Ping; Liu, Fu-Chao; Tsai, Yung-Fong; Hwang, Tsong-Long

    2013-01-01

    Recent evidences show that osthole possesses anti-inflammatory properties and protective effects following shock-like states, but the mechanism of these effects remains unknown. The p38 mitogen-activated protein kinase (p38 MAPK) pathway exerts anti-inflammatory effects in injury. The aim of this study was to investigate whether p38 MAPK plays any role in the osthole-mediated attenuation of hepatic injury after trauma-hemorrhage. Male Sprague-Dawley rats underwent trauma-hemorrhage (mean blood pressure maintained at approximately 35-40 mmHg for 90 minutes), followed by fluid resuscitation. During resuscitation, a single dose of osthole (3 mg/kg, intravenously) with and without a p38 MAPK inhibitor SB-203580 (2 mg/kg, intravenously), SB-203580 or vehicle was administered. Plasma alanine aminotransferase (ALT) with aspartate aminotransferase (AST) concentrations and various hepatic parameters were measured (n = 8 rats/group) at 24 hours after resuscitation. The results showed that trauma-hemorrhage increased hepatic myeloperoxidase activity, intercellular adhesion molecule-1 and interleukin-6 levels, and plasma ALT and AST concentrations. These parameters were significantly improved in the osthole-treated rats subjected to trauma-hemorrhage. Osthole treatment also increased hepatic phospho-p38 MAPK expression compared with vehicle-treated trauma-hemorrhaged rats. Co-administration of SB-203580 with osthole abolished the osthole-induced beneficial effects on the above parameters and hepatic injury. These results suggest that the protective effect of osthole administration on alleviation of hepatic injury after trauma-hemorrhage, which is, at least in part, through p38 MAPK-dependent pathway. PMID:23755293

  1. Caveolin-1 protects against hepatic ischemia/reperfusion injury through ameliorating peroxynitrite-mediated cell death.

    PubMed

    Gao, Lei; Chen, Xingmiao; Peng, Tao; Yang, Dan; Wang, Qi; Lv, Zhiping; Shen, Jiangang

    2016-06-01

    Nitrative stress is considered as an important pathological process of hepatic ischemia and reperfusion injury but its regulating mechanisms are largely unknown. In this study, we tested the hypothesis that caveolin-1 (Cav-1), a plasma membrane scaffolding protein, could be an important cellular signaling against hepatic I/R injury through inhibiting peroxynitrite (ONOO(-))-induced cellular damage. Male wild-type mice and Cav-1 knockout (Cav-1(-/-)) were subjected to 1h hepatic ischemia following 1, 6 and 12h of reperfusion by clipping and releasing portal vessels respectively. Immortalized human hepatocyte cell line (L02) was subjected to 1h hypoxia and 6h reoxygenation and treated with Cav-1 scaffolding domain peptide. The major discoveries included: (1) the expression of Cav-1 in serum and liver tissues of wild-type mice was time-dependently elevated during hepatic ischemia-reperfusion injury. (2) Cav-1 scaffolding domain peptide treatment inhibited cleaved caspase-3 expression in the hypoxia-reoxygenated L02 cells; (3) Cav-1 knockout (Cav-1(-/-)) mice had significantly higher levels of serum transaminases (ALT&AST) and TNF-α, and higher rates of apoptotic cell death in liver tissues than wild-type mice after subjected to 1h hepatic ischemia and 6hour reperfusion; (4) Cav-1(-/-) mice revealed higher expression levels of iNOS, ONOO(-) and 3-nitrotyrosine (3-NT) in the liver than wild-type mice, and Fe-TMPyP, a representative peroxynitrite decomposition catalyst (PDC), remarkably reduced level of ONOO(-) and 3-NT and ameliorated the serum ALT, AST and TNF-α levels in both wild-type and Cav-1(-/-) mice. Taken together, we conclude that Cav-1 could play a critical role in preventing nitrative stress-induced liver damage during hepatic ischemia-reperfusion injury. PMID:27021966

  2. Epidermal growth factor protects against carbon tetrachloride-induced hepatic injury.

    PubMed

    Berlanga, J; Caballero, M E; Ramirez, D; Torres, A; Valenzuela, C; Lodos, J; Playford, R J

    1998-03-01

    1. Epidermal growth factor (EGF) is known to protect the gastrointestinal tract against various noxious agents. Its potential value in preventing/ treating hepatic injury is, however, largely unexplored. We therefore examined whether EGF could influence CCl4-induced hepatic injury. 2. Female Sprague-Dawley rats (8 per group) received saline or recombinant EGF (500 or 750 micrograms/kg, intraperitoneal) 30 min before CCl4 (20% v/v, in olive oil, intraperitoneal). Eighteen hours later, animals were killed, serum was collected for assay of biochemical markers of hepatic injury and livers were removed for histological analyses. 3. Administration of CCl4 resulted in severe hepatic necrosis and caused a 10-fold rise in plasma alanine aminotransferase levels compared with levels seen in control animals (218 +/- 15 compared with 23 +/- 9 mumol/l in controls, mean +/- SEM, P < 0.01). Serum malondialdehyde levels, used as a marker of lipid peroxidation, showed a 2-fold rise in response to CCl4 treatment (median 4.0, quartile range 3.3-5.8 units/l compared with median 2.3, quartile range 2.1-2.5 units/l in controls, P < 0.05). Administration of EGF at 500 micrograms/kg, before the CCl4, did not protect against injury, as assessed by histology or rise in plasma alanine aminotransferase levels. In contrast, animals given EGF at 750 micrograms/kg, before the CCl4, had only minimal changes in histology, with only a minor rise in alanine aminotransferase levels (37 +/- 4 compared with 23 +/- 9 mumol/l in animals not given CCl4) and had no significant rise in malondialdehyde levels. 4. EGF protects against CCl4-induced hepatic injury and may provide a novel approach to the treatment of liver damage. PMID:9616254

  3. Role of hepatic resident and infiltrating macrophages in liver repair after acute injury.

    PubMed

    You, Qiang; Holt, Michael; Yin, Hao; Li, Guiying; Hu, Cheng-Jun; Ju, Cynthia

    2013-09-15

    Treatment of liver disease, caused by hepatotoxins, viral infections, alcohol ingestion, or autoimmune conditions, remains challenging and costly. The liver has a powerful capacity to repair and regenerate, thus a thorough understanding of this tightly orchestrated process will undoubtedly improve clinical means of restoring liver function after injury. Using a murine model of acute liver injury caused by overdose of acetaminophen (APAP), our studies demonstrated that the combined absence of liver resident macrophages (Kupffer cells, KCs), and infiltrating macrophages (IMs) resulted in a marked delay in liver repair, even though the initiation and extent of peak liver injury was not impacted. This delay was not due to impaired hepatocyte proliferation but rather prolonged vascular leakage, which is caused by APAP-induced liver sinusoidal endothelial cell (LSEC) injury. We also found that KCs and IMs express an array of angiogenic factors and induce LSEC proliferation and migration. Our mechanistic studies suggest that hypoxia-inducible factor (HIF) may be involved in regulating the angiogenic effect of hepatic macrophages (Macs), as we found that APAP challenge resulted in hypoxia and stabilization of HIF in the liver and hepatic Macs. Together, these data indicate an important role for hepatic Macs in liver blood vessel repair, thereby contributing to tissue recovery from acute injury. PMID:23876342

  4. [A case of hepatitis E differentially diagnosed from drug-induced liver injury].

    PubMed

    Ishiwata, Sho; Takagi, Hitoshi; Hoshino, Takashi; Naganuma, Atsushi; Sakamoto, Naomi; Koitabashi, Eri; Souma, Hiromitsu; Inui, Masayuki; Kudo, Tomohiro; Ogawa, Akira; Tahara, Hiroki; Kaneko, Mieko; Okamoto, Hiroaki

    2012-04-01

    A woman in her seventies was admitted because of general fatigue and liver dysfunction (ALT 2565 IU/l). She was diabetic and, 2 months ago, began eating kikuimo (Jerusalem artichoke) containing inulin, which is thought to decrease blood sugar level. Although tests showed no evidence of acute infection of HAV, HBV, HCV, EBV and CMV, a drug-induced lymphocyte stimulation test using kikuimo extract was positive. She was first diagnosed with drug-induced liver injury according to the Japanese diagnostic criteria for the disease. After a non-eventful recovery, her serum was found to be positive for hepatitis E-antibody and RNA (genotype 3), indicating recent, autochthonous infection of HEV. The patient might have been misdiagnosed with drug-induced liver injury unless the serum test for HEV had been performed. We believe that HEV screening is mandatory for accurate diagnosis of hepatitis E and drug-induced liver injury. PMID:22481264

  5. An epoxysuccinic acid derivative(loxistatin)-induced hepatic injury in rats and hamsters

    SciTech Connect

    Fukushima, K.; Arai, M.; Kohno, Y.; Suwa, T.; Satoh, T. )

    1990-08-01

    Loxistatin is a possible therapeutic agent of muscular dystrophy. A single oral administration of loxistatin to male rats caused focal necrosis of the liver with inflammatory cell infiltration. The severity of the lesions was dose-dependent up to 200 mg/kg and also manifest by an increase in serum alanine aminotransferase and aspartate aminotransferase activities. Hepatic glutathione (GSH) levels decreased with a maximum 20% depletion within 5 hr after the oral administration of loxistatin. Pretreatment with diethyl maleate did not potentiate the loxistatin-induced hepatic injury. On the other hand, the hepatoprotective effect of cysteamine was observed when cysteamine was administered 24 hr before loxistatin dosing, but the effect was not observed when the antidote was administered concomitantly with loxistatin. Pretreatment of rats with phenobarbital or trans-stilbene oxide provided partial protection against the hepatotoxic effect of loxistatin. Pretreatment with SKF-525A resulted in increased hepatic injury, while pretreatment with piperonyl butoxide, cimetidine, or 3-methylcholanthrene had no effect on hepatic damage by loxistatin. Five hours after (14C)loxistatin administration to rats, the covalent binding of the radioactivity to proteins was greatest in the liver, followed by the kidney, then muscle and blood to a lesser extent. (14C)Loxistatin acid, the pharmacologically active form of loxistatin, irreversibly bound to rat liver microsomal proteins; more binding occurred when the NADPH-generating system was omitted and when the microsomes were boiled first. GSH did not alter the extent of irreversible binding, whereas N-ethylmaleimide decreased the binding of (14C)loxistatin acid to rat liver microsomal proteins by 75%. Unlike the rat, administration of loxistatin to hamsters caused neither hepatic injury nor hepatic GSH depletion.

  6. Rodent models of hepatic ischemia-reperfusion injury: time and percentage-related pathophysiological mechanisms.

    PubMed

    Karatzas, Theodore; Neri, Anna-Aikaterini; Baibaki, Maria-Eleni; Dontas, Ismene A

    2014-10-01

    Ischemia and reperfusion (IR) injury remains one of the major problems in liver surgery and transplantation, which determines the viability of the hepatic tissue after resection and of the grafted organ. This review aims to elucidate the mechanisms involved in IR injury of the liver in rodent experimental studies and the preventative methods and pharmacologic agents that have been applied. Many time- and percentage-related liver IR injury rodent models have been used to examine the pathophysiological mechanisms and the parameters implicated with different morbidity, mortality, and pathology findings. The most preferred experimental rodent model of liver IR is the induction of 70% IR for 45 min, which is associated with almost 100% survival. In this model, plasma levels of several parameters such as alanine transaminase, aspartate aminotransferase, gamma-glutamyltransferase, endothelin-1, malonodialdehyde, tumor necrosis factor α, interleukin 1b, inducible nitric oxide synthase, and caspases are increased. The increase of caspases is associated with the initiation of hepatic cellular apoptosis. The main injuries observed 24 h after reperfusion are nuclear pyknosis, cytoplasmic hypereosinophilia, severe necrosis, and loss of intercellular borders. Both ischemic pre- and post-conditioning preventative methods and pharmacologic agents are successfully applied to alleviate the IR injuries. The selection of the time- and percentage-related liver IR injury rodent model and the potential preventative method should be related to the clinical question being answered. PMID:25033703

  7. Protein kinase C-β inhibitor treatment attenuates hepatic ischemia and reperfusion injury in diabetic rats

    PubMed Central

    MENG, GUANG-XING; YUAN, QIANG; WEI, LI-PING; MENG, HUA; WANG, YI-JUN

    2016-01-01

    Hepatic ischemia and reperfusion (I/R) injury plays an active role in hepatic resection and transplantation. While the effects of protein kinase C (PKC)-βII activation and the role of PKC-β inhibitors are well understood in myocardial I/R in diabetes, they remain unclear in liver I/R. The aim of this study was to explore the effect of PKC-β inhibition and the potential mechanism by which PKC-β inhibitor treatment protects against hepatic I/R injury in diabetic rats. Diabetic rats were established and randomized into two groups. These were an untreated group (n=10), which did not receive any treatment, and a treatment group (n=10), orally treated with ruboxistaurin at a dose of 5 mg/kg/day for 2 weeks. The rats from the two groups were subjected to hepatic I/R. Aspartate transaminase (AST) and lactate dehydrogenase (LDH) levels were measured by enzymatic methods at 1, 3 and 5 h after I/R. Tumor necrosis factor-α (TNF-α) and intercellular adhesion molecule 1 (ICAM-1) were examined by enzyme-linked immunosorbent assay at the same time-points. Nuclear factor-κB (NF-κB) p65 expression was analyzed by immunofluorescence and western blotting. Apoptosis of hepatic cells was examined by the western blot analysis of caspase 3 expression and by DNA ladder analysis. Pathological changes were examined using light and electron microscopy. Serum AST and LDH levels in the PKC-β inhibitor treatment group were diminished compared with those in the untreated group (P<0.01). Serum TNF-α and ICAM-1 (P<0.01) levels were also decreased at different time-points in the PKC-β inhibitor treatment group. The relative expression of NF-κB p65 and caspase 3 in the hepatic tissue was weakened in the PKC-β inhibitor treatment group compared with that in the untreated group (P<0.01). Pathological changes in hepatic tissue were attenuated by the PKC-β inhibitor. In conclusion, PKC-β inhibitor treatment protected against liver I/R injury in diabetic rats. The mechanisms probably

  8. PPARδ agonist attenuates alcohol-induced hepatic insulin resistance and improves liver injury and repair

    PubMed Central

    Pang, Maoyin; de la Monte, Suzanne M.; Longato, Lisa; Tong, Ming; He, Jiman; Chaudhry, Rajeeve; Duan, Kevin; Ouh, Jiyun; Wands, Jack R.

    2009-01-01

    Background/Aims Chronic ethanol exposure impairs liver regeneration due to inhibition of insulin signaling and oxidative injury. PPAR agonists function as insulin sensitizers and anti-inflammatory agents. We investigated whether treatment with a PPARδ agonist could restore hepatic insulin sensitivity, survival signaling, and regenerative responses vis-a-vis chronic ethanol feeding. Methods Adult rats were fed isocaloric liquid diets containing 0% or 37% ethanol, and administered a PPARδ agonist by i.p. injection. We used liver tissue to examine histopathology, gene expression, oxidative stress, insulin signaling, and regenerative responses to 2/3 hepatectomy. Results Chronic ethanol feeding caused insulin resistance, increased oxidative stress, lipid peroxidation, DNA damage, and hepatocellular injury in liver. These effects were associated with reduced insulin receptor binding and affinity, impaired survival signaling through PI3K/Akt/GSK3β, and reduced expression of insulin responsive genes mediating energy metabolism and tissue remodeling. PPARδ agonist treatment reduced ethanol-mediated hepatic injury, oxidative stress, lipid peroxidation, and insulin resistance, increased signaling through PI3K/Akt/GSK3β, and enhanced the regenerative response to partial hepatectomy. Conclusions PPARδ agonist administration may attenuate the severity of chronic ethanol-induced liver injury and ethanol’s adverse effects on the hepatic repair by restoring insulin responsiveness, even in the context of continued high-level ethanol consumption. PMID:19398227

  9. Preventive activity of banana peel polyphenols on CCl4-induced experimental hepatic injury in Kunming mice

    PubMed Central

    WANG, RUI; FENG, XIA; ZHU, KAI; ZHAO, XIN; SUO, HUAYI

    2016-01-01

    The aim of the present study was to evaluate the preventive effects of banana peel polyphenols (BPPs) against hepatic injury. Mice were divide into normal, control, 100 mg/kg and 200 mg/kg banana peel polyphenol and silymarin groups. All the mice except normal mice were induced with hepatic damage using CCl4. The serum and tissue levels of mice were determined by a kit and the tissues were further examined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. BPPs reduced the serum levels of aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase in a CCl4-induced mouse model of hepatic injury. Furthermore, BPPs reduced the levels of malondialdehyde and triglyceride, while increasing glutathione levels in the serum and liver tissues of mice. In addition, the effects of 200 mg/kg treatment were more evident, and these effects were comparable to those of the drug silymarin. Serum levels of the cytokines, interleukin (IL)-6, IL-12, tumor necrosis factor (TNF)-α and interferon-γ, were reduced in the mice treated with BPPs compared with injury control group mice, and these levels were comparable to those of the normal and silymarin-treated groups. Histopathological examination indicated that BPPs were able to reduce the extent of CCl4-induced liver tissue injury and protect the liver cells. Furthermore, the mRNA and protein expression levels of the inflammation-associated factors cyclooxygenase-2, nitric oxide synthase, TNF-α and IL-1β were reduced in mice treated with BPPs compared with the control group mice. Mice that received 200 mg/kg BPP exhibited reduced expression levels of these factors compared with mice that received 100 mg/kg BPP. In conclusion, the results of the present study suggested that BPPs exert a good preventive effect against hepatic injury. PMID:27168833

  10. 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

  11. Salvianolic acid A preconditioning confers protection against concanavalin A-induced liver injury through SIRT1-mediated repression of p66shc in mice

    SciTech Connect

    Xu, Xiaomei; Hu, Yan; Zhai, Xiaohan; Lin, Musen; Chen, Zhao; Tian, Xiaofeng; Zhang, Feng; Gao, Dongyan; Ma, Xiaochi; Lv, Li; Yao, Jihong

    2013-11-15

    Salvianolic acid A (SalA) is a phenolic carboxylic acid derivative extracted from Salvia miltiorrhiza. It has many biological and pharmaceutical activities. The purpose of this study was to investigate the effect of SalA on concanavalin A (ConA)-induced acute hepatic injury in Kunming mice and to explore the role of SIRT1 in such an effect. The results showed that in vivo pretreatment with SalA significantly reduced ConA-induced elevation in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and decreased levels of the hepatotoxic cytokines such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). Moreover, the SalA pretreatment ameliorated the increases in NF-κB and in cleaved caspase-3 caused by ConA exposure. Whereas, the pretreatment completely reversed expression of the B-cell lymphoma-extra large (Bcl-xL). More importantly, the SalA pretreatment significantly increased the expression of SIRT1, a NAD{sup +}-dependent deacetylase, which was known to attenuate acute hypoxia damage and metabolic liver diseases. In our study, the increase in SIRT1 was closely associated with down-regulation of the p66 isoform (p66shc) of growth factor adapter Shc at both protein and mRNA levels. In HepG2 cell culture, SalA pretreatment increased SIRT1 expression in a time and dose-dependent manner and such an increase was abrogated by siRNA knockdown of SIRT1. Additionally, inhibition of SIRT1 significantly reversed the decreased expression of p66shc, and attenuated SalA-induced p66shc down-regulation. Collectively, the present study indicated that SalA may be a potent activator of SIRT and that SalA can alleviate ConA-induced hepatitis through SIRT1-mediated repression of the p66shc pathway. - Highlights: • We report for the first time that SalA protects against ConA-induced hepatitis. • We find that SalA is a potential activator of SIRT1. • SalA's protection against hepatitis involves SIRT1-mediated repression of p66shc.

  12. Fibroblast growth factor 21 deficiency exacerbates chronic alcohol-induced hepatic steatosis and injury

    PubMed Central

    Liu, Yanlong; Zhao, Cuiqing; Xiao, Jian; Liu, Liming; Zhang, Min; Wang, Cuiling; Wu, Guicheng; Zheng, Ming-Hua; Xu, Lan-Man; Chen, Yong-Ping; Mohammadi, Moosa; Chen, Shao-Yu; Cave, Matthew; McClain, Craig; Li, Xiaokun; Feng, Wenke

    2016-01-01

    Fibroblast growth factor 21 (FGF21) is a hepatokine that regulates glucose and lipid metabolism in the liver. We sought to determine the role of FGF21 in hepatic steatosis in mice exposed to chronic alcohol treatment and to discern underlying mechanisms. Male FGF21 knockout (FGF21 KO) and control (WT) mice were divided into groups that were fed either the Lieber DeCarli diet containing 5% alcohol or an isocaloric (control) diet for 4 weeks. One group of WT mice exposed to alcohol received recombinant human FGF21 (rhFGF21) in the last 5 days. Liver steatosis and inflammation were assessed. Primary mouse hepatocytes and AML-12 cells were incubated with metformin or rhFGF21. Hepatic genes and the products involved in in situ lipogenesis and fatty acid β-oxidation were analyzed. Alcohol exposure increased circulating levels and hepatic expression of FGF21. FGF21 depletion exacerbated alcohol-induced hepatic steatosis and liver injury, which was associated with increased activation of genes involved in lipogenesis mediated by SREBP1c and decreased expression of genes involved in fatty acid β-oxidation mediated by PGC1α. rhFGF21 administration reduced alcohol-induced hepatic steatosis and inflammation in WT mice. These results reveal that alcohol-induced FGF21 expression is a hepatic adaptive response to lipid dysregulation. Targeting FGF21 signaling could be a novel treatment approach for alcoholic steatohepatitis. PMID:27498701

  13. Fibroblast growth factor 21 deficiency exacerbates chronic alcohol-induced hepatic steatosis and injury.

    PubMed

    Liu, Yanlong; Zhao, Cuiqing; Xiao, Jian; Liu, Liming; Zhang, Min; Wang, Cuiling; Wu, Guicheng; Zheng, Ming-Hua; Xu, Lan-Man; Chen, Yong-Ping; Mohammadi, Moosa; Chen, Shao-Yu; Cave, Matthew; McClain, Craig; Li, Xiaokun; Feng, Wenke

    2016-01-01

    Fibroblast growth factor 21 (FGF21) is a hepatokine that regulates glucose and lipid metabolism in the liver. We sought to determine the role of FGF21 in hepatic steatosis in mice exposed to chronic alcohol treatment and to discern underlying mechanisms. Male FGF21 knockout (FGF21 KO) and control (WT) mice were divided into groups that were fed either the Lieber DeCarli diet containing 5% alcohol or an isocaloric (control) diet for 4 weeks. One group of WT mice exposed to alcohol received recombinant human FGF21 (rhFGF21) in the last 5 days. Liver steatosis and inflammation were assessed. Primary mouse hepatocytes and AML-12 cells were incubated with metformin or rhFGF21. Hepatic genes and the products involved in in situ lipogenesis and fatty acid β-oxidation were analyzed. Alcohol exposure increased circulating levels and hepatic expression of FGF21. FGF21 depletion exacerbated alcohol-induced hepatic steatosis and liver injury, which was associated with increased activation of genes involved in lipogenesis mediated by SREBP1c and decreased expression of genes involved in fatty acid β-oxidation mediated by PGC1α. rhFGF21 administration reduced alcohol-induced hepatic steatosis and inflammation in WT mice. These results reveal that alcohol-induced FGF21 expression is a hepatic adaptive response to lipid dysregulation. Targeting FGF21 signaling could be a novel treatment approach for alcoholic steatohepatitis. PMID:27498701

  14. Angelica sinensis polysaccharide attenuates concanavalin A-induced liver injury in mice.

    PubMed

    Wang, Kaiping; Song, Zhizhen; Wang, Hongjing; Li, Qiang; Cui, Zheng; Zhang, Yu

    2016-02-01

    Angelica sinensis polysaccharide (ASP), extracted from the roots of A. sinensis (Oliv.) Diels, is a β-D-pyranoid polysaccharide with an average molecular weight of 72,900 Da. In this study, we investigated the protective effects of ASP against concanavalin A-induced liver failure and the underlying mechanisms. Concentrations of ASP ranging from 5 to 125 μg/mL could inhibit concanavalin A (ConA)-induced lymphoproliferative response. The potential hepatoprotective activity of ASP was demonstrated by the significant decrease in serum transaminase (ALT and AST) levels and the attenuation of liver inflammation damage exhibited by H&E stain of the liver. Furthermore, ASP pretreatment significantly decreased proinflammatory cytokines (TNF-α, IFN-γ, IL-2 and IL-6) and alleviated oxidative stress by reducing MDA and ROS levels and by enhancing SOD activity after ConA administration in mice. Results of Western blot analysis indicated that ASP attenuated Caspase-3-dependent apoptosis by Caspase-8 and JNK-mediated pathway and inhibited the activation of IL-6/STAT3 and NF-κB signaling pathways in ConA-induced liver damage in mice. In conclusion, ASP pretreatment could attenuate concanavalin A-induced liver injury through its anti-inflammatory and anti-oxidant actions in mice. PMID:26741264

  15. Simulating Chemical-Induced Injury Using Virtual Hepatic Tissues

    EPA Science Inventory

    Chemical-induced liver injury involves a dynamic sequence of events that span multiple levels of biological organization. Current methods for testing the toxicity of a single chemical can cost millions of dollars, take up to two years and sacrifice thousands of animals. It is dif...

  16. Ischemic Preconditioning Increases the Tolerance of Fatty Liver to Hepatic Ischemia-Reperfusion Injury in the Rat

    PubMed Central

    Serafín, Anna; Roselló-Catafau, Joan; Prats, Neus; Xaus, Carme; Gelpí, Emilio; Peralta, Carmen

    2002-01-01

    Hepatic steatosis is a major risk factor in ischemia-reperfusion. The present study evaluates whether preconditioning, demonstrated to be effective in normal livers, could also confer protection in the presence of steatosis and investigates the potential underlying protective mechanisms. Fatty rats had increased hepatic injury and decreased survival after 60 minutes of ischemia compared with lean rats. Fatty livers showed a degree of neutrophil accumulation and microcirculatory alterations similar to that of normal livers. However, in presence of steatosis, an increased lipid peroxidation that could be reduced with glutathione-ester pretreatment was observed after hepatic reperfusion. Ischemic preconditioning reduced hepatic injury and increased animal survival. Both in normal and fatty livers, this endogenous protective mechanism was found to control lipid peroxidation, hepatic microcirculation failure, and neutrophil accumulation, reducing the subsequent hepatic injury. These beneficial effects could be mediated by nitric oxide, because the inhibition of nitric oxide synthesis and nitric oxide donor pretreatment abolished and simulated, respectively, the benefits of preconditioning. Thus, ischemic preconditioning could be an effective surgical strategy to reduce the hepatic ischemia-reperfusion injury in normal and fatty livers under normothermic conditions, including hepatic resections, and liver transplantation. PMID:12163383

  17. Hepatitis

    MedlinePlus

    ... Got Homework? Here's Help White House Lunch Recipes Hepatitis KidsHealth > For Kids > Hepatitis Print A A A ... an important digestive liquid called bile . What Is Hepatitis? Hepatitis is an inflammation (say: in-fluh-MAY- ...

  18. Toxicogenomics-based prediction of acetaminophen-induced liver injury using human hepatic cell systems.

    PubMed

    Rodrigues, Robim M; Heymans, Anja; De Boe, Veerle; Sachinidis, Agapios; Chaudhari, Umesh; Govaere, Olivier; Roskams, Tania; Vanhaecke, Tamara; Rogiers, Vera; De Kock, Joery

    2016-01-01

    Primary human hepatocytes (hHEP), human HepaRG and HepG2 cell lines are the most used human liver-based in vitro models for hepatotoxicity testing, including screening of drug-induced liver injury (DILI)-inducing compounds. hHEP are the reference hepatic in vitro system, but their availability is limited and the cells available for toxicology studies are often of poor quality. Hepatic cell lines on the other hand are highly proliferative and represent an inexhaustible hepatic cell source. However, these hepatoma-derived cells do not represent the population diversity and display reduced hepatic metabolism. Alternatively, stem cell-derived hepatic cells, which can be produced in high numbers and can differentiate into multiple cell lineages, are also being evaluated as a cell source for in vitro hepatotoxicity studies. Human skin-derived precursors (hSKP) are post-natal stem cells that, after conversion towards hepatic cells (hSKP-HPC), respond to hepatotoxic compounds in a comparable way as hHEP. In the current study, four different human hepatic cell systems (hSKP-HPC, hHEP, HepaRG and HepG2) are evaluated for their capacity to predict hepatic toxicity. Their hepatotoxic response to acetaminophen (APAP) exposure is compared to data obtained from patients suffering from APAP-induced acute liver failure (ALF). The results indicate that hHEP, HepaRG and hSKP-HPC identify comparable APAP-induced hepatotoxic functions and that HepG2 cells show the slightest hepatotoxic response. Pathway analyses further points out that HepaRG cells show the highest predicted activation of the functional genes related to 'damage of liver', followed by hSKP-HPC and hHEP cells that generated similar results. HepG2 did not show any activation of this function. PMID:26497421

  19. Sulfasalazine-induced renal and hepatic injury in rats and the protective role of taurine

    PubMed Central

    Heidari, Reza; Rasti, Maryam; Shirazi Yeganeh, Babak; Niknahad, Hossein; Saeedi, Arastoo; Najibi, Asma

    2016-01-01

    Introduction: Sulfasalazine is a drug commonly administrated against inflammatory-based disorders. On the other hand, kidney and liver injury are serious adverse events accompanied by sulfasalazine administration. No specific therapeutic option is available against this complication. The current investigation was designed to evaluate the potential protective effects of taurine against sulfasalazine-induced kidney and liver injury in rats. Methods: Male Sprague-Dawley rats were administered with sulfasalazine (600 mg/kg, oral) for 14 consecutive days. Animals received different doses of taurine (250, 500 and 1000 mg/ kg, i.p.) every day. Markers of organ injury were evaluated on day 15th, 24 h after the last dose of sulfasalazine. Results: Sulfasalazine caused renal and hepatic injury as judged by an increase in serum level of creatinine (Cr), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and alkaline phosphatase (ALP). The levels of reactive oxygen species (ROS) and lipid peroxidation were raised in kidney and liver of sulfasalazine-treated animals. Moreover, tissue glutathione reservoirs were depleted after sulfasalazine administration. Histopathological changes of kidney and liver also endorsed organ injury. Taurine administration (250, 500 and 1000 mg/kg/day, i.p) alleviated sulfasalazine-induced renal and hepatic damage. Conclusion: Taurine administration could serve as a potential protective agent with therapeutic capabilities against sulfasalazine adverse effects. PMID:27340618

  20. Propranolol Improves Impaired Hepatic Phosphatidylinositol 3-Kinase/Akt Signaling after Burn Injury

    PubMed Central

    Brooks, Natasha C; Song, Juquan; Boehning, Darren; Kraft, Robert; Finnerty, Celeste C; Herndon, David N; Jeschke, Marc G

    2012-01-01

    Severe burn injury is associated with induction of the hepatic endoplasmic reticulum (ER) stress response. ER stress leads to activation of c-Jun N-terminal kinase (JNK), suppression of insulin receptor signaling via phosphorylation of insulin receptor substrate 1 and subsequent insulin resistance. Marked and sustained increases in catecholamines are prominent after a burn. Here, we show that administration of propranolol, a nonselective β1/2 adrenergic receptor antagonist, attenuates ER stress and JNK activation. Attenuation of ER stress by propranolol results in increased insulin sensitivity, as determined by activation of hepatic phosphatidylinositol 3-kinase and Akt. We conclude that catecholamine release is responsible for the ER stress response and impaired insulin receptor signaling after burn injury. PMID:22396018

  1. Ability of IDO to attenuate liver injury in alpha-galactosylceramide-induced hepatitis model.

    PubMed

    Ito, Hiroyasu; Hoshi, Masato; Ohtaki, Hirofumi; Taguchi, Ayako; Ando, Kazuki; Ishikawa, Tetsuya; Osawa, Yosuke; Hara, Akira; Moriwaki, Hisataka; Saito, Kuniaki; Seishima, Mitsuru

    2010-10-15

    IDO converts tryptophan to l-kynurenine, and it is noted as a relevant molecule in promoting tolerance and suppressing adaptive immunity. In this study, we examined the effect of IDO in α-galactosylceramide (α-GalCer)-induced hepatitis. The increase in IDO expression in the liver of wild-type (WT) mice administered α-GalCer was confirmed by real-time PCR, Western blotting, and IDO immunohistochemical analysis. The serum alanine aminotransferase levels in IDO-knockout (KO) mice after α-GalCer injection significantly increased compared with those in WT mice. 1-Methyl-D-tryptophan also exacerbated liver injury in this murine hepatitis model. In α-GalCer-induced hepatitis models, TNF-α is critical in the development of liver injury. The mRNA expression and protein level of TNF-α in the liver from IDO-KO mice were more enhanced compared with those in WT mice. The phenotypes of intrahepatic lymphocytes from WT mice and IDO-KO mice treated with α-GalCer were analyzed by flow cytometry, and the numbers of CD49b(+) and CD11b(+) cells were found to have increased in IDO-KO mice. Moreover, as a result of the increase in the number of NK cells and macrophages in the liver of IDO-KO mice injected with α-GalCer, TNF-α secretion in these mice was greater than that in WT mice. Deficiency of IDO exacerbated liver injury in α-GalCer-induced hepatitis. IDO induced by proinflammatory cytokines may decrease the number of TNF-α-producing immune cells in the liver. Thus, IDO may suppress overactive immune response in the α-GalCer-induced hepatitis model. PMID:20844202

  2. Relationship between the characteristics of immunopathological expression of hepatitis C virus antigen and hepatocytic injury.

    PubMed

    Sun, Y; Gao, S L; Hao, L J; Li, L; Gu, B; Ding, Q Y; Lu, P J; Xiong, H Y; Li, Y X

    1993-10-01

    Biopsied liver tissues from 352 cases were tested for hepatitis C virus (HCVAg) with improved PAP immunohistologic chemical method. Furthermore, corresponding seroantibody to hepatitis C virus was also tested. The total HCVAg positive rate was 9.1%. The HCVAg positive rate in chronic persistent hepatitis (CPH) was 5%. The HCVAg positive rate in chronic active hepatitis (CAH) was 11.2%. The HCVAg positive rate raised gradually along with the severity of hepatocytic injury. HCVAg may be seen in necrotic liver cells exfoliating into the liver sinus, indicating a close relationship between HCVAg and hepatocytic injury. Expression of HCVAg was mostly of the nucleus type in CPH cases and was mostly of the plasma type in CAH cases. The periphery of nucleus type-expressed positive cells generally had no marked inflammatory cell infiltration. The periphery of plasma type-expressed positive cells had a certain amount of inflammatory cell infiltration. Along with the severity of hepatocytic injury, HCVAg expressed itself in a positive correlation according to the nucleus and plasma types. The HCVAg positive cells were located mostly in the lobular peripheral band and rarely located in the venoperipheral band. It was possible that this had some relation with the lobular microcirculation of blood and blood supply. In this study, there was no obvious correlation between the HCVAg positive rate in hepatic tissues and the anti-HCV positive rate in sera. Neither the patients with HCVAg positive liver tissues nor the patients with seropositive anti-HCV had any history of blood transfusion and the use of blood products.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7518373

  3. Biomarkers distinguish apoptotic and necrotic cell death during hepatic ischemia/reperfusion injury in mice.

    PubMed

    Yang, Min; Antoine, Daniel J; Weemhoff, James L; Jenkins, Rosalind E; Farhood, Anwar; Park, B Kevin; Jaeschke, Hartmut

    2014-11-01

    Hepatic ischemia/reperfusion (IRP) injury is a significant clinical problem during tumor-resection surgery (Pringle maneuver) and liver transplantation. However, the relative contribution of necrotic and apoptotic cell death to the overall liver injury is still controversial. To address this important issue with a standard murine model of hepatic IRP injury, plasma biomarkers of necrotic cell death such as micro-RNA 122, full-length cytokeratin 18 (FK18), and high-mobility group box 1 (HMGB1) protein and plasma biomarkers of apoptosis such as plasma caspase-3 activity and caspase-cleaved fragment of cytokeratin 18 (CK18) coupled with markers of inflammation (hyperacetylated HMGB1) were compared by histological features in hematoxylin and eosin-stained and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL)-stained liver sections. After 45 minutes of hepatic ischemia and 1 to 24 hours of reperfusion, all necrosis markers increased dramatically in plasma by 40- to >10,000-fold over the baseline with a time course similar to that of alanine aminotransferase. These data correlated well with histological characteristics of necrosis. Within the area of necrosis, most cells were TUNEL positive; initially (≤3 hours of reperfusion), the staining was restricted to nuclei, but it later spread to the cytosol, and this is characteristic of karyorrhexis during necrotic cell death. In contrast, the lack of morphological evidence of apoptotic cell death and relevant caspase-3 activity in the postischemic liver correlated well with the absence of caspase-3 activity and CK18 (except for a minor increase at 3 hours of reperfusion) in plasma. A quantitative comparison of FK18 (necrosis) and CK18 (apoptosis) release indicated dominant cell death by necrosis during IRP and only a temporary and very minor degree of apoptosis. These data suggest that the focus of future research should be the elucidation of necrotic signaling mechanisms to

  4. BIOMARKERS DISTINGUISH APOPTOTIC AND NECROTIC CELL DEATH DURING HEPATIC ISCHEMIA-REPERFUSION INJURY IN MICE

    PubMed Central

    Yang, Min; Antoine, Daniel J.; Weemhoff, James L.; Jenkins, Rosalind E.; Farhood, Anwar; Park, B. Kevin; Jaeschke, Hartmut

    2014-01-01

    Hepatic ischemia-reperfusion (IRP) injury is a significant clinical problem during tumor resection surgery (Pringle maneuver), and liver transplantation. However, the relative contribution of necrotic and apoptotic cell death to the overall liver injury is still controversial. In order to address this important issue in a standard murine model of hepatic IRP injury, plasma biomarkers of necrotic cell death such as micro-RNA-122, full-length cytokeratin-18 (FK18) and high mobility group box-1 (HMGB1) protein, and apoptosis including plasma caspase-3 activity and caspase-cleaved cytokeratin-18 (CK18), coupled with markers of inflammation (hyper-acetylated HMGB1) were compared with histological features in H&E- and TUNEL-stained liver sections. After 45 min of hepatic ischemia and 1–24h of reperfusion, all necrosis markers increased dramatically in plasma by 40-to->10,000-fold over baseline with a time course similar to ALT. These data correlated well with histological characteristics of necrosis. Within the area of necrosis, most cells were TUNEL-positive; initially (≤ 3h of RP) the staining was restricted to nuclei but later spread to the cytosol characteristic for karyorrhexis during necrotic cell death. In contrast, the lack of morphological evidence of apoptotic cell death and relevant caspase-3 activity in the postischemic liver correlated well with the absence of caspase-3 activity and CK18 (except a minor increase at 3h RP) in plasma. The quantitative comparison of FK18 (necrosis) and CK18 (apoptosis) release indicated the dominant cell death by necrosis during IRP and only a temporary and very minor degree of apoptosis. These data suggest that the focus of future research should be on the elucidation of necrotic signaling mechanisms to identify relevant targets, which may be used to attenuate hepatic IRP injury. PMID:25046819

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

    PubMed Central

    Liu, Tong; Xia, Yujing; Li, Jingjing; Li, Sainan; Feng, Jiao; Wu, Liwei; Zhang, Rong; Xu, Shizan; Cheng, Keran; Zhou, Yuqing; Zhou, Shunfeng; Dai, Weiqi; Chen, Kan; Wang, Fan; Lu, Jie; Zhou, Yingqun; Guo, Chuanyong

    2016-01-01

    Objective. Shikonin possesses anti-inflammatory effects. However, its function in concanavalin A-induced acute liver injury remains uncertain. The aim of the present study was to investigate the functions of shikonin and its mechanism of protection on ConA-induced acute liver injury. Materials and Methods. Balb/C mice were exposed to ConA (20 mg/kg) via tail vein injection to establish acute liver injury; shikonin (7.5 mg/kg and 12.5 mg/kg) was intraperitoneally administered 2 h before the ConA injection. The serum liver enzyme levels and the inflammatory cytokine levels were determined at 3, 6, and 24 h after ConA injection. Results. After the injection of ConA, inflammatory cytokines IL-1β, TNF-α, and IFN-γ were significantly increased. Shikonin significantly ameliorated liver injury and histopathological changes and suppressed the release of inflammatory cytokines. The expressions of Bcl-2 and Bax were markedly affected by shikonin pretreatment. LC3, Beclin-1, and p-JNK expression levels were decreased in the shikonin-pretreated groups compared with the ConA-treated groups. Shikonin attenuated ConA-induced liver injury by reducing apoptosis and autophagy through the inhibition of the JNK pathway. Conclusion. Our results indicated that shikonin pretreatment attenuates ConA-induced acute liver injury by inhibiting apoptosis and autophagy through the suppression of the JNK pathway. PMID:27293314

  6. Pretreatment with Fucoidan from Fucus vesiculosus Protected against ConA-Induced Acute Liver Injury by Inhibiting Both Intrinsic and Extrinsic Apoptosis

    PubMed Central

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

    2016-01-01

    This study aimed to explore the effects of fucoidan from Fucus vesiculosus on concanavalin A (ConA)-induced acute liver injury in mice. Pretreatment with fucoidan protected liver function indicated by ALT, AST and histopathological changes by suppressing inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ). In addition, intrinsic and extrinsic apoptosis mediated by Bax, Bid, Bcl-2, Bcl-xL and Caspase 3, 8, and 9 were inhibited by fucoidan and the action was associated with the TRADD/TRAF2 and JAK2/STAT1 signal pathways. Our results demonstrated that fucoidan from Fucus vesiculosus alleviated ConA-induced acute liver injury via the inhibition of intrinsic and extrinsic apoptosis mediated by the TRADD/TRAF2 and JAK2/STAT1 pathways which were activated by TNF-α and IFN-γ. These findings could provide a potential powerful therapy for T cell-related hepatitis. PMID:27035150

  7. Lactobacillus rhamnosus GG reduces hepatic TNFα production and inflammation in chronic alcohol-induced liver injury.

    PubMed

    Wang, Yuhua; Liu, Yanlong; Kirpich, Irina; Ma, Zhenhua; Wang, Cuiling; Zhang, Min; Suttles, Jill; McClain, Craig; Feng, Wenke

    2013-09-01

    The therapeutic effects of probiotic treatment in alcoholic liver disease (ALD) have been studied in both patients and experimental animal models. Although the precise mechanisms of the pathogenesis of ALD are not fully understood, gut-derived endotoxin has been postulated to play a crucial role in hepatic inflammation. Previous studies have demonstrated that probiotic therapy reduces circulating endotoxin derived from intestinal gram-negative bacteria in ALD. In this study, we investigated the effects of probiotics on hepatic tumor necrosis factor-α (TNFα) production and inflammation in response to chronic alcohol ingestion. Mice were fed Lieber DeCarli liquid diet containing 5% alcohol for 8weeks, and Lactobacillus rhamnosus GG (LGG) was supplemented in the last 2 weeks. Eight-week alcohol feeding caused a significant increase in hepatic inflammation as shown by histological assessment and hepatic tissue myeloperoxidase activity assay. Two weeks of LGG supplementation reduced hepatic inflammation and liver injury and markedly reduced TNFα expression. Alcohol feeding increased hepatic mRNA expression of Toll-like receptors (TLRs) and CYP2E1 and decreased nuclear factor erythroid 2-related factor 2 expression. LGG supplementation attenuated these changes. Using human peripheral blood monocytes-derived macrophages, we also demonstrated that incubation with ethanol primes both lipopolysaccharide- and flagellin-induced TNFα production, and LGG culture supernatant reduced this induction in a dose-dependent manner. In addition, LGG treatment also significantly decreased alcohol-induced phosphorylation of p38 MAP kinase. In conclusion, probiotic LGG treatment reduced alcohol-induced hepatic inflammation by attenuation of TNFα production via inhibition of TLR4- and TLR5-mediated endotoxin activation. PMID:23618528

  8. Activation of α2 adrenoceptor attenuates lipopolysaccharide-induced hepatic injury

    PubMed Central

    Chen, Jing-Hui; Yu, Gao-Feng; Jin, Shang-Yi; Zhang, Wen-Hua; Lei, Dong-Xu; Zhou, Shao-Li; Song, Xing-Rong

    2015-01-01

    Sepsis induces hepatic injury but whether alpha-2 adrenoceptor (α2-AR) modulates the severity of sepsis-induced liver damage remains unclear. The present study used lipopolysaccharide (LPS) to induce hepatic injury and applied α2-AR agonist dexmedetomidine (DEX) and/or antagonist yohimbine to investigate the contribution of α2-AR in LPS-induced liver injury. Our results showed that LPS resulted in histological and functional abnormality of liver tissue (ALT and AST transaminases, lactate), higher mortality, an increase in proinflammatory cytokines (IL-1β, IL-6 & TNF-α), as well as a change in oxidative stress (MDA, SOD). Activation of α2-AR by dexmedetomidine (DEX) attenuated LPS-induced deleterious effects on the liver and block of α2-AR by yohimbine aggravated LPS-induced liver damage. Our data suggest that α2-AR plays an important role in sepsis-induced liver damage and activation of α2-AR with DEX could be a novel therapeutic avenue to protect the liver against sepsis-induced injury. PMID:26617786

  9. Natalizumab-induced hepatic injury: A case report and review of literature.

    PubMed

    Antezana, A; Sigal, S; Herbert, J; Kister, I

    2015-11-01

    Natalizumab is an α4-integrin monoclonal antibody used for treatment of relapsing multiple sclerosis (MS). At least and nearly 30 cases of liver failure in natalizumab-treated patients are listed in the post-marketing FDA adverse event reporting system (FAERS) and twelve patients with severe liver injury, including several after the first infusion, have been reported (Lisotti et al., 2012; Bezabeh et al., 2010; Martinez-Lapiscina et al., 2013; Michael et al., 2007; Hillen et al., 2015). Herein, we describe a case of a young woman with relapsing MS who developed acute liver injury after the second infusion of natalizumab. Liver biopsy demonstrated a mixed pattern of medication-induced injury or partially treated auto-immune hepatitis. Liver function normalized after natalizumab discontinuation and a subsequent liver biopsy showed resolution of hepatitis. The patient's MS has since been successfully treated with rituximab for over a year. We review the published cases of liver injury associated with natalizumab and those in the post-marketing FDA adverse event reporting system (FAERS). PMID:26590653

  10. Huperzine A attenuates hepatic ischemia reperfusion injury via anti-oxidative and anti-apoptotic pathways.

    PubMed

    Xu, Zhe; Wang, Yang

    2014-08-01

    Hepatic ischemia reperfusion (HI/R) injury may occur during liver transplantation and remains a serious concern in clinical practice. Huperzine A (HupA), an alkaloid isolated from the Chinese traditional medicine Huperzia serrata, has been demonstrated to possess anti‑oxidative and anti‑apoptotic properties. In the present study, a rat model of HI/R was established by clamping the hepatic artery, the hepatoportal vein and the bile duct with a vascular clamp for 30 min followed by reperfusion for 6 h under anesthesia. HupA was injected into the tail vein 5 min prior to the induction of HI/R at doses of 167 and 500 µg/kg. The histopathological assessment of the liver was performed using hematoxylin and eosin staining. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were assayed in the serum samples. The tissue levels of superoxide dismutase (SOD), catalase (CAT), malondiadehyde (MDA) and glutathione (GSH) were also measured spectrophotometrically. Furthermore, the protein expression of caspase‑3, Bcl‑2 and Bax in hepatic tissues was detected via western blot analysis. Treatment of Wistar rats with HupA at doses of 167 and 500 µg/kg markedly attenuated HI/R injury as observed histologically. In addition, the significant reductions of serum ALT and AST were observed in HupA‑treated ischemic rats. Furthermore, HupA treatment enhanced the activity of hepatic tissue SOD, CAT and GSH, but decreased the MDA tissue content. Western blot analysis revealed elevated levels of Bcl‑2 expression but decreased Bax and caspase‑3 tissue expression at the protein level in the HupA‑treated group. The present data suggest that HupA attenuates the HI/R injury of rats through its anti‑oxidative and anti‑apoptotic signaling pathways. PMID:24888717

  11. Urinary proteomic profiling reveals diclofenac-induced renal injury and hepatic regeneration in mice

    SciTech Connect

    Swelm, Rachel P.L. van; Laarakkers, Coby M.M.; Pertijs, Jeanne C.L.M.; Verweij, Vivienne; Masereeuw, Rosalinde; Russel, Frans G.M.

    2013-06-01

    Diclofenac (DF) is a widely used non-steroidal anti-inflammatory drug for the treatment of rheumatic disorders, but is often associated with liver injury. We applied urinary proteomic profiling using MALDI-TOF MS to identify biomarkers for DF-induced hepatotoxicity in mice. Female CH3/HeOUJIco mice were treated with 75 mg/kg bw DF by oral gavage and 24 h urine was collected. Proteins identified in urine of DF-treated mice included epidermal growth factor, transthyretin, kallikrein, clusterin, fatty acid binding protein 1 and urokinase, which are related to liver regeneration but also to kidney injury. Both organs showed enhanced levels of oxidative stress (TBARS, p < 0.01). Kidney injury was confirmed by histology and increased Kim1 and Il-6 mRNA expression levels (p < 0.001 and p < 0.01). Liver histology and plasma ALT levels in DF-treated mice were not different from control, but mRNA expression of Stat3 (p < 0.001) and protein expression of PCNA (p < 0.05) were increased, indicating liver regeneration. In conclusion, urinary proteome analysis revealed that DF treatment in mice induced kidney and liver injury. Within 24 h, however, the liver was able to recover by activating tissue regeneration processes. Hence, the proteins found in urine of DF-treated mice represent kidney damage rather than hepatic injury. - Highlights: • The urinary proteome shows biological processes involved in adverse drug reactions. • Urine proteins of DF-treated mice relate to kidney injury rather than liver injury. • Liver regeneration, not liver injury, is apparent 24h after oral DF administration. • Pretreatment with LPS does not enhance DF-induced liver injury in mice.

  12. Pancreatic injury in hepatic alcohol dehydrogenase-deficient deer mice after subchronic exposure to ethanol

    SciTech Connect

    Kaphalia, Bhupendra S.; Bhopale, Kamlesh K.; Kondraganti, Shakuntala; Wu Hai; Boor, Paul J.; Ansari, G.A. Shakeel

    2010-08-01

    Pancreatitis caused by activation of digestive zymogens in the exocrine pancreas is a serious chronic health problem in alcoholic patients. However, mechanism of alcoholic pancreatitis remains obscure due to lack of a suitable animal model. Earlier, we reported pancreatic injury and substantial increases in endogenous formation of fatty acid ethyl esters (FAEEs) in the pancreas of hepatic alcohol dehydrogenase (ADH)-deficient (ADH{sup -}) deer mice fed 4% ethanol. To understand the mechanism of alcoholic pancreatitis, we evaluated dose-dependent metabolism of ethanol and related pancreatic injury in ADH{sup -} and hepatic ADH-normal (ADH{sup +}) deer mice fed 1%, 2% or 3.5% ethanol via Lieber-DeCarli liquid diet daily for 2 months. Blood alcohol concentration (BAC) was remarkably increased and the concentration was {approx} 1.5-fold greater in ADH{sup -} vs. ADH{sup +} deer mice fed 3.5% ethanol. At the end of the experiment, remarkable increases in pancreatic FAEEs and significant pancreatic injury indicated by the presence of prominent perinuclear space, pyknotic nuclei, apoptotic bodies and dilation of glandular ER were found only in ADH{sup -} deer mice fed 3.5% ethanol. This pancreatic injury was further supported by increased plasma lipase and pancreatic cathepsin B (a lysosomal hydrolase capable of activating trypsinogen), trypsinogen activation peptide (by-product of trypsinogen activation process) and glucose-regulated protein 78 (endoplasmic reticulum stress marker). These findings suggest that ADH-deficiency and high alcohol levels in the body are the key factors in ethanol-induced pancreatic injury. Therefore, determining how this early stage of pancreatic injury advances to inflammation stage could be important for understanding the mechanism(s) of alcoholic pancreatitis.

  13. The Mechanisms and Physiological Relevance of Glycocalyx Degradation in Hepatic Ischemia/Reperfusion Injury

    PubMed Central

    van Golen, Rowan F.; Reiniers, Megan J.; Vrisekoop, Nienke; Zuurbier, Coert J.; Olthof, Pim B.; van Rheenen, Jacco; van Gulik, Thomas M.; Parsons, Barry J.

    2014-01-01

    Abstract Significance: Hepatic ischemia/reperfusion (I/R) injury is an inevitable side effect of major liver surgery that can culminate in liver failure. The bulk of I/R-induced liver injury results from an overproduction of reactive oxygen and nitrogen species (ROS/RNS), which inflict both parenchymal and microcirculatory damage. A structure that is particularly prone to oxidative attack and modification is the glycocalyx (GCX), a meshwork of proteoglycans and glycosaminoglycans (GAGs) that covers the lumenal endothelial surface and safeguards microvascular homeostasis. ROS/RNS-mediated degradation of the GCX may exacerbate I/R injury by, for example, inducing vasoconstriction, facilitating leukocyte adherence, and directly activating innate immune cells. Recent Advances: Preliminary experiments revealed that hepatic sinusoids contain a functional GCX that is damaged during murine hepatic I/R and major liver surgery in patients. There are three ROS that mediate GCX degradation: hydroxyl radicals, carbonate radical anions, and hypochlorous acid (HOCl). HOCl converts GAGs in the GCX to GAG chloramides that become site-specific targets for oxidizing and reducing species and are more efficiently fragmented than the parent molecules. In addition to ROS/RNS, the GAG-degrading enzyme heparanase acts at the endothelial surface to shed the GCX. Critical Issues: The GCX seems to be degraded during major liver surgery, but the underlying cause remains ill-defined. Future Directions: The relative contribution of the different ROS and RNS intermediates to GCX degradation in vivo, the immunogenic potential of the shed GCX fragments, and the role of heparanase in liver I/R injury all warrant further investigation. Antioxid. Redox Signal. 21, 1098–1118. PMID:24313895

  14. Caffeine test in predicting flutamide-induced hepatic injury in patients with prostate cancer.

    PubMed

    Ozono, S; Yamaguchi, A; Mochizuki, H; Kawakami, T; Fujimoto, K; Otani, T; Yoshida, K; Ichinei, M; Yamashita, T; Hirao, Y

    2002-01-01

    The caffeine test measures the activity of cytochrome p450 (CYP1A2) which is a major enzyme involved in the activation of flutamide. The usefulness of this test in predicting flutamide-induced hepatic injury in patients with prostate cancer was examined. The subjects were: (1). five patients whose aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level rose to 100 IU/l or higher following the start of flutamide (moderately injured group); (2). four patients whose AST and ALT levels were higher than normal but less than 100 IU/l (mildly injured group); and (3). two patients whose hepatic function remained normal (normal group). The subjects were each given canned coffee to drink. Urinary caffeine (137X), paraxanthine (17X) and 1, 7-dimethyluric acid (17U) levels were measured 4-5 h later. The metabolite ratio, (17U+17X)/137X, was calculated to serve as an indicator of CYP1A2 activity. The metabolite ratio for the moderately injured group (3.98+/-1.56) and the mildly injured group (5.55+/-1.42) were lower than that for the normal group (9.56). The results suggest that a decrease in CYP1A2 activity is involved in the onset of flutamide-induced hepatic injury, and that the caffeine test seems to provide a useful means of its prediction. PMID:12497002

  15. Sustainable inflammation transforms hepatic cells by causing oxidative stress injury and potential epithelial-mesenchymal transition.

    PubMed

    Lu, Kun; Liu, Guoyan; Yang, Ling; Liu, Fan; Gao, Libin; Shi, Jingxian; Deng, Xiaoling; Li, Qifu; Xu, Donghui; Shi, Songlin

    2016-09-01

    The inflammatory microenvironment promotes tumorigenesis. However, the mechanism through which inflammation transforms hepatic cells in precancerous lesions remains unclear. Hepatic cells undergo significant changes in metabolism before carcinogenesis, but the specific alterations in gene expression and cellular functions in response to precancerous inflammation have not been elucidated. In this study, a hepatitis-hepatoma mouse model was successfully established. Label-free quantitative (LFQ) proteomics coupled with bioinformatics analysis was then performed to identify differentially expressed proteins and their functions in hepatic cells with precancerous inflammation. We found that different chemical treatments induced several common changes in the model. Hepatic cells underwent serious oxidative stress injury. Canonical pathway analysis using IPA revealed the activation of signaling pathways, such as integrin signaling, signaling by Rho family GTPases, IL-8 signaling, and ILK signaling, as well as the inhibition of RhoGDI signaling. Analysis of the KEGG pathway indicated alteration in the pathways for focal adhesion and regulation of actin cytoskeleton. Results from western blot analysis demonstrated the upregulation of proteins, including p-STAT3, TWIST, SNAIL, Vimentin, and MMP-9, which are involved in epithelial-mesenchymal transition (EMT). These results indicated that hepatic cells were likely to undergo EMT. Interestingly, the expression of E-cadherin was upregulated, but this observation must be further investigated. In conclusion, the results revealed that notable functional and pathway changes occurred during the precancerous inflammation stage in the liver. Our study contributes to understanding of the roles of inflammation in tumorigenesis and provides a molecular basis for further studies on the tumorigenesis of hepatocellular carcinoma. PMID:27315196

  16. Alleviative effects from boswellic acid on acetaminophen-induced hepatic injury.

    PubMed

    Chen, Lung-Che; Hu, Li-Hong; Yin, Mei-Chin

    2016-06-01

    Protective effects of boswellic acid (BA) against acetaminophen (APAP)-induced hepatotoxicity in Balb/ cA mice were examined. BA, at 0.05 or 0.1%, was supplied for 4 weeks. Acute liver injury was induced by APAP treatment. Results showed that BA intake increased hepatic BA bioavailability. APAP treatment decreased glutathione (GSH) level, increased reactive oxygen species (ROS) and oxidized glutathione (GSSG) production; and lowered activity and protein expression of glutathione reductase (GR) and heme oxygenase (HO)-1 in liver. BA intake at both doses alleviated subsequent APAP-induced oxidative stress by retaining GSH content, decreasing ROS and GSSG formations, reserving activity and expression of GR and HO-1 in liver, and lowering hepatic cytochrome P450 2E1 activity and expression. APAP treatment enhanced hepatic levels of interleukin-6, tumor necrosis factor-alpha and monocyte chemoattractant protein-1. BA pre-intake diminished APAP-induced release of those inflammatory cytokines and chemokines. APAP upregulated hepatic protein expression of toll-like receptor (TLR)-3, TLR-4, MyD88, nuclear factor kappa B (NF-κB) p50, NF-κB p65 and JNK. BA pre-intake at both doses suppressed the expression of NF-κB p65 and p-JNK, and only at 0.1% down-regulated hepatic TLR-3, TLR-4 and MyD88 expression. APAP led to obvious foci of inflammatory cell infiltration in liver, determined by H&E stain. BA intake at both doses attenuated hepatic inflammatory infiltration. These findings support that boswellic acid is a potent hepatoprotective agent. PMID:27161000

  17. Aloe vera attenuated liver injury in mice with acetaminophen-induced hepatitis

    PubMed Central

    2014-01-01

    Background An overdose of the acetaminophen causes liver injury. This study aims to examine the anti-oxidative, anti-inflammatory effects of Aloe vera in mice with acetaminophen induced hepatitis. Methods Male mice were randomly divided into three groups (n = 8 each). Control group were given orally distilled water (DW). APAP group were given orally N-acetyl-P-aminophenol (APAP) 400 mg/kg suspended in DW. Aloe vera-treated group were given orally APAP and Aloe vera (150 mg/kg) suspended in DW. Twenty-four hours later, the liver was removed to determine hepatic malondialdehyde (MDA), hepatic glutathione (GSH), the number of interleukin (IL)-12 and IL-18 positive stained cells (%) by immunohistochemistry method, and histopathological examination. Then, the serum was collected to determine transaminase (ALT). Results In APAP group, ALT, hepatic MDA and the number of IL-12 and IL-18 positive stained cells were significantly increased when compared to control group (1210.50 ± 533.86 vs 85.28 ± 28.27 U/L, 3.60 ± 1.50 vs 1.38 ± 0.15 nmol/mg protein, 12.18 ± 1.10 vs 1.84 ± 1.29%, and 13.26 ± 0.90 vs 2.54 ± 1.29%, P = 0.000, respectively), whereas hepatic GSH was significantly decreased when compared to control group (5.98 ± 0.30 vs 11.65 ± 0.43 nmol/mg protein, P = 0.000). The mean level of ALT, hepatic MDA, the number of IL-12 and IL-18 positive stained cells, and hepatic GSH in Aloe vera-treated group were improved as compared with APAP group (606.38 ± 495.45 vs 1210.50 ± 533.86 U/L, P = 0.024; 1.49 ± 0.64 vs 3.60 ± 1.50 nmol/mg protein, P = 0.001; 5.56 ± 1.25 vs 12.18 ± 1.10%, P = 0.000; 6.23 ± 0.94 vs 13.26 ± 0.90%, P = 0.000; and 10.02 ± 0.20 vs 5.98 ± 0.30 nmol/mg protein, P = 0.000, respectively). Moreover, in the APAP group, the liver showed extensive hemorrhagic hepatic necrosis at all zones while in Aloe vera-treated group, the liver architecture was improved histopathology. Conclusions APAP overdose can cause liver injury. Our result indicate

  18. Minocycline protects against hepatic ischemia/reperfusion injury in a rat model.

    PubMed

    Li, Yining; Li, Tao; Qi, Haizhi; Yuan, Fang

    2015-01-01

    Hepatic ischemia/reperfusion (I/R) injury is a common clinical problem. The present study was conducted to investigate the protective effect and mechanism of minocycline (Mino), a tetracycline with anti-inflammatory and antioxidant properties, on I/R injury of liver in rats. In total, 54 male Sprague-Dawley rats were randomly divided into 3 groups with 18 rats in each: Sham-operated (control group), I/R model (I/R group) and Mino preconditioning groups (Mino group). The rats of the Mino group were administered Mino (45 mg/kg) by gastric irrigation at 36 h before surgery and were subsequently administered with 22.5 mg/kg every 12 h for the 36 h before surgery. The rats were sacrificed at 2, 6 and 24 h after reperfusion, and the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) were measured. Hematoxylin/eosin staining of liver tissues was performed to detect the rat liver histological changes and the grade of liver I/R injury (Suzuki's criteria); the levels of malondialdehyde (MDA) and myeloperoxidase (MPO) were determined by spectrophotometry; hepatic tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) mRNA were measured by quantitative polymerase chain reaction; the Dickkopf-1 (DKK-1) and β-catenin gene products of the liver were detected by western blot analysis. Mino treatment significantly ameliorated the I/R injury of the liver, as shown by decreased Suzuki scores and liver function (ALT, AST and LDH). After 2, 6 and 24 h reperfusion, compared to the I/R group the MDA and MPO levels of the Mino group decreased in the liver tissues and the levels of hepatic TNF-α and IL-1β mRNA were decreased too. The protein expression of hepatic DKK-1 decreased, whereas β-catenin increased, which indicates that the Wnt/β-catenin pathway has been activated. In conclusion, Mino protects the liver from I/R injury mainly through reducing oxidative stress and inhibiting the release of pro

  19. Minocycline protects against hepatic ischemia/reperfusion injury in a rat model

    PubMed Central

    LI, YINING; LI, TAO; QI, HAIZHI; YUAN, FANG

    2015-01-01

    Hepatic ischemia/reperfusion (I/R) injury is a common clinical problem. The present study was conducted to investigate the protective effect and mechanism of minocycline (Mino), a tetracycline with anti-inflammatory and antioxidant properties, on I/R injury of liver in rats. In total, 54 male Sprague-Dawley rats were randomly divided into 3 groups with 18 rats in each: Sham-operated (control group), I/R model (I/R group) and Mino preconditioning groups (Mino group). The rats of the Mino group were administered Mino (45 mg/kg) by gastric irrigation at 36 h before surgery and were subsequently administered with 22.5 mg/kg every 12 h for the 36 h before surgery. The rats were sacrificed at 2, 6 and 24 h after reperfusion, and the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) were measured. Hematoxylin/eosin staining of liver tissues was performed to detect the rat liver histological changes and the grade of liver I/R injury (Suzuki's criteria); the levels of malondialdehyde (MDA) and myeloperoxidase (MPO) were determined by spectrophotometry; hepatic tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) mRNA were measured by quantitative polymerase chain reaction; the Dickkopf-1 (DKK-1) and β-catenin gene products of the liver were detected by western blot analysis. Mino treatment significantly ameliorated the I/R injury of the liver, as shown by decreased Suzuki scores and liver function (ALT, AST and LDH). After 2, 6 and 24 h reperfusion, compared to the I/R group the MDA and MPO levels of the Mino group decreased in the liver tissues and the levels of hepatic TNF-α and IL-1β mRNA were decreased too. The protein expression of hepatic DKK-1 decreased, whereas β-catenin increased, which indicates that the Wnt/β-catenin pathway has been activated. In conclusion, Mino protects the liver from I/R injury mainly through reducing oxidative stress and inhibiting the release of pro

  20. Protective effects of heme-oxygenase expression in cyclosporine A--induced injury.

    PubMed

    Rezzani, Rita; Rodella, Luigi; Bianchi, Rossella; Goodman, Alvin I; Lianos, Elias A

    2005-04-01

    Cyclosporine A (CsA) is the immunosuppressant of first choice in allotransplantation. Its use is associated with side effects of nephrotoxicity and neurotoxicity, which are among the most prominent. This study was undertaken to explore whether expression and activity of heme oxygenase (HO), the rate-limiting enzyme in heme degradation, is altered in a rat model of CsA-induced injury. Male Sprague Dawley rats were divided into four groups and treated for 21 days. Group I (control) was injected with olive oil (vehicle), group II with CsA (15 mg/kg/day), group III with CsA and the HO inhibitor stannous mesoporphyrin (SnMP) (30 micromol/kg/day) and group IV with one dose of the HO inducer cobalt protoporphyrin (CoPP) 5 mg/100 or heme (10 mg/kg body weight), three days after onset of CsA treatment. Renal tissue was processed for light microscopy, and for HO-1 enzyme activity, assay and for Western blot analysis. In CsA-treated rats there was histological evidence of tubulointerstitial scarring. HO-1 was undetectable in CsA-treated rats compared to control while there was no change in HO-2. In animals treated with a combination of CsA and SnMP, HO-1 activity was further reduced. In animals treated with a combination of CsA and CoPP, HO-1 protein levels were partially restored. These observations indicate that downregulation of HO-1 expression by CsA could be one mechanism underlying CsA-induced toxicity. The CsA-induced decrease in HO-1 expression is partial and restorable, and attempts to preserve HO levels may attenuate CsA toxicity. PMID:16181108

  1. Endogenous glucocorticoids released during acute toxic liver injury enhance hepatic IL-10 synthesis and release.

    PubMed

    Swain, M G; Appleyard, C; Wallace, J; Wong, H; Le, T

    1999-01-01

    Endogenous glucocorticoids are known to play a role in the regulation of the inflammatory response possibly by modulating pro- and anti-inflammatory cytokine expression. We examined endogenous glucocorticoid secretion, hepatic damage, tumor necrosis factor-alpha (TNF-alpha), and interleukin-10 (IL-10) mRNA expression and release in rats treated with carbon tetrachloride (CCl4) after treatment with vehicle or a glucocorticoid receptor antagonist (RU-486). Rats treated with CCl4 demonstrated striking elevations of plasma corticosterone levels. Inhibition of endogenous glucocorticoid activity by pretreatment with the glucocorticoid receptor antagonist RU-486 resulted in augmented CCl4-mediated hepatotoxicity, as reflected by histology and serum transaminase levels, which were independent of alterations in serum TNF-alpha levels or hepatic mRNA expression. CCl4 treatment resulted in enhanced hepatic IL-10 mRNA expression and elevated serum IL-10 levels, which were markedly attenuated by glucocorticoid receptor blockade. In summary, significant endogenous glucocorticoid release occurs during acute toxic liver injury in the rat and suppresses the inflammatory response independent of effects on TNF-alpha but possibly by upregulating hepatic IL-10 production. PMID:9886996

  2. Role of matrix metalloproteinases in cholestasis and hepatic ischemia/reperfusion injury: A review

    PubMed Central

    Palladini, Giuseppina; Ferrigno, Andrea; Richelmi, Plinio; Perlini, Stefano; Vairetti, Mariapia

    2015-01-01

    Matrix metalloproteinases (MMPs) are a family of proteases using zinc-dependent catalysis to break down extracellular matrix (ECM) components, allowing cell movement and tissue reorganization. Like many other proteases, MMPs are produced as zymogens, an inactive form, which are activated after their release from cells. Hepatic ischemia/reperfusion (I/R) is associated with MMP activation and release, with profound effects on tissue integrity: their inappropriate, prolonged or excessive expression has harmful consequences for the liver. Kupffer cells and hepatic stellate cells can secrete MMPs though sinusoidal endothelial cells are a further source of MMPs. After liver transplantation, biliary complications are mainly attributable to cholangiocytes, which, compared with hepatocytes, are particularly susceptible to injury and ultimately a major cause of increased graft dysfunction and patient morbidity. This paper focuses on liver I/R injury and cholestasis and reviews factors and mechanisms involved in MMP activation together with synthetic compounds used in their regulation. In this respect, recent data have demonstrated that the role of MMPs during I/R may go beyond the mere destruction of the ECM and may be much more complex than previously thought. We thus discuss the role of MMPs as an important factor in cholestasis associated with I/R injury. PMID:26576096

  3. Magnesium lithospermate B reduces inflammatory response in a mouse model of hepatic ischemia-reperfusion injury.

    PubMed

    Song, Shaohua; Liu, Wenyu; Liu, Fang; Wang, Zhengxin; Ding, Guoshan; Guo, Wenyuan; Fu, Zhiren

    2014-06-01

    It has been well proved that acute inflammatory response and hepatocellular apoptosis contributed to the pathogenesis of liver ischemia reperfusion (IR) injury. A vast amount of research has demonstrated that magnesium lithospermate B (MLB) has potent anti-apoptosis and potential anti-inflammatory pharmacological properties. However, it has not previously been examined whether MLB can attenuate hepatic IR injury. Firstly, the optimal dose of MLB to protect against hepatic IR injury was determined using hepatic IR model in mice. Then, the effect of MLB on IR-induced inflammatory response was detected in detail. We found that MLB exhibited protective effect from the beginning of 50 mg/kg and culminated at the doses of 100 and 200 mg/kg. The alanine aminotransferase and aspartate aminotransferase levels in MLB group were markedly decreased. Severe hepatocellular swelling/necrosis, sinusoidal/vascular congestion and inflammatory cell infiltration were seen and a large number of apoptotic cells were found in the liver samples from Saline group, while minimal damage and very few apoptotic cells were noted in the samples from MLB group. Kuppfer cells infiltration, myeloperoxidase activity and mRNA level of CD11b in MLB group was significantly decreased. Serum TNF-a and IL-6, and mRNA expression of CXCL-10 and ICAM-1 was markedly decreased in the samples from MLB group. Inflammatory signaling pathway activation was largely prevented in MLB group. MLB can significantly attenuate IR-induced hepatocellular damage and hepatocellular apoptosis by preventing inflammatory signaling pathways activation, inflammatory mediators expression and macrophage and neutrophil infiltration. PMID:24385154

  4. Zinc might prevent heat-induced hepatic injury by activating the Nrf2-antioxidant in mice.

    PubMed

    Wang, F; Li, Y; Cao, Y; Li, C

    2015-05-01

    Zinc (Zn) is generally known to be an essential trace element with growth-promoting and antioxidant activities. The present study was performed to clarify the role of Zn in the livers of heat-treated mice. Eight-week-old male mice were divided into control (Con), heat treatment (HT) and heat treatment plus zinc groups (HT + Zn) and were fed diets containing 60, 60, or 300 mg/kg Zn (zinc sulfate), respectively. After 30 days of feeding on their respective diets, the control group was maintained at a controlled temperature (25 °C), whereas the HT and HT + Zn groups were exposed to an elevated ambient temperature (40-42 °C) for 2 h each day. After heat exposure for seven consecutive days, sera and liver tissues were collected. The mice in the HT group exhibited reduced liver weights and lower hepatosomatic indices. Histological findings revealed that the hepatocytes of the HT group were subjected to serious damage and exhibited irregular arrangements and nuclear pyknosis. Moreover, in the HT group, the hepatic malondialdehyde levels were significantly increased, while the serum alkaline phosphatase levels, hepatic copper/zinc-superoxide dismutase (CuZn-SOD) and glutathione peroxidase activities were significantly reduced compared to those of the control group. However, in the HT + Zn group, the histomorphology of the liver was restored, the serum aspartate aminotransferase (AST) level was significantly decreased, and the hepatic CuZn-SOD activity was significantly increased compared to the HT group. Furthermore, expressions of the hepatic Nrf2 protein and Nrf2, Keap1, and NQO1 genes in the HT + Zn group were not only higher than the HT group but also higher than the control group. Zn might alleviate heat-induced hepatic injury as revealed by restored histomorphology and AST level. Our results further suggest that Zn might exert its protective effects via the activation of the Nrf2-antioxidant pathway. PMID:25586622

  5. Glutathione protects against hepatic injury in a murine model of primary Sjögren’s syndrome

    PubMed Central

    Jiang, Shuhua; Hu, Liwei; Ping, Lifeng; Sun, Fengyan; Wang, Xiaolei

    2016-01-01

    Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease which may cause complications such as hepatic dysfunction and injury. As an important antioxidant, reduced glutathione (GSH) has been reported protecting against hepatic injury induced by some diseases, but the role of GSH in pSS is poorly understood. This study aims at investigating the role of GSH in hepatic injury during pSS. A murine model of pSS, non-obese diabetic (NOD) mice, was used for GSH administration via tail intravenous injection. Enzyme-linked immunosorbent assay (ELISA) was performed to detect serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), as well as the levels of GSH, tumor necrosis factor, interleukin (IL) 10, integrin alpha M, IL1B, malondialdehyde, nicotinamide adenine dinucleotide phosphate oxidase 4, and superoxide dismutases in hepatocyte homogenates. Hematoxylin-eosin staining was performed to observe hepatic histology. The results showed that serum AST and ALT levels were up-regulated in the NOD mice (p = 0.0021 and 0.0048), but were significantly recovered after the GSH administration (p = 0.0081 and 0.0263). The NOD mice exhibited disturbed hepatic tissue structure, which was attenuated by GSH. The GSH administration could also promote the production of GSH in the hepatocytes (p = 0.0264), and control the levels of inflammatory factors and oxidative stress-related factors. These results indicate that GSH has significant effects on protecting against the hepatic injury during pSS, which may be associated with its regulation of the inflammatory factors and oxidative stress-related factors. This study suggests that GSH is a promising therapeutic strategy for controlling hepatic injury during pSS and offers valuable information for further research.

  6. Inhibition of nitric oxide synthesis aggravates reperfusion injury after hepatic ischemia and endotoxemia.

    PubMed

    Wang, Y; Mathews, W R; Guido, D M; Farhood, A; Jaeschke, H

    1995-10-01

    The potential role of nitric oxide (NO) was investigated in the pathophysiology of liver injury after priming with 20 min hepatic ischemia-reperfusion and administration of .5 mg/kg Salmonella enteritidis endotoxin. Liver injury during the early reperfusion phase of 4 h was characterized by severe vascular oxidant stress, lipid peroxidation (LPO), neutrophil infiltration, and a 33% reduction of the microvascular blood flow in the liver. Inhibition of NO synthesis with N omega-nitro-L-arginine methyl ester hydrochloride (L-NAME) aggravated liver injury by 90%, reduced LPO, and did not affect liver neutrophils but further impaired microvascular blood flow. Treatment with the NO-donor spermine-NONOate or L-arginine did not affect these parameters in postischemic animals, however, treatment did restore all values of L-NAME-treated animals back to disease control levels. These data suggest that endogenous NO formation is sufficient to limit ischemic liver injury during reperfusion but inhibition of NO synthesis will result in additional ischemic damage. NO may also be involved in scavenging of superoxide in the vasculature and in inducing LPO. PMID:8564557

  7. Reduction of hepatic ischemia/reperfusion injury by a soluble P-selectin glycoprotein ligand-1.

    PubMed Central

    Dulkanchainun, T S; Goss, J A; Imagawa, D K; Shaw, G D; Anselmo, D M; Kaldas, F; Wang, T; Zhao, D; Busuttil, A A; Kato, H; Murray, N G; Kupiec-Weglinski, J W; Busuttil, R W

    1998-01-01

    OBJECTIVE: The authors' goal was to determine the effects of specific binding and blockade of P- and E-selectins by a soluble P-selectin glycoprotein ligand-1 (PSGL-1) in rat models of hepatic in vivo warm ischemia and ex vivo cold ischemia. The authors also sought to determine the effect of selectin blockade on isograft survival in a syngeneic rat orthotopic liver transplant model. SUMMARY BACKGROUND DATA: Ischemia/reperfusion (I/R) injury is a major factor in poor graft function after liver transplantation, which may profoundly influence early graft function and late changes. It is hypothesized that I/R injury leads to the upregulation of P-selectin, which is then rapidly translocated to endothelial cell surfaces within 5 minutes of reperfusion of the liver, initiating steps leading to tethering of polymorphonuclear neutrophil leukocytes to the vascular intima. Local production by leukocytes of interleukin-1, tumor necrosis factor-alpha, or both induces P-selectin expression on the endothelium and continues the cascade of events, which increases cell adherence and infiltration of the organ. METHODS: To examine directly the effects of selectins in a warm hepatic I/R injury model, 100 microg of PSGL-1 or saline was given through the portal vein at the time of total hepatic inflow occlusion. The effects of PSGL-1 in cold ischemia were assessed using an isolated perfused rat liver after 6 hours of 4 degrees C storage in University of Wisconsin (UW) solution, with or without the instillation of PSGL-1 before the storage. To evaluate the effect of selectin blockade on liver transplant survival, syngeneic orthotopic liver transplants were performed between inbred male Sprague-Dawley rats after 24 hours of cold ischemic storage in UW solution. A separate group of animals received two doses of 100 microg of PSGL-1 through the portal vein before storage and before reperfusion of the transplanted liver. Recipient survival was assessed at 7 days, and the Kaplan-Meier product

  8. Gadolinium chloride, a Kupffer cell inhibitor, attenuates hepatic injury in a rat model of chronic cholestasis.

    PubMed

    Zandieh, Ali; Payabvash, Seyedmehedi; Pasalar, Parvin; Morteza, Afsaneh; Zandieh, Basira; Tavangar, Seyed Mohammad; Dehpour, Ahmad Reza

    2011-11-01

    The aim of the current study was to elucidate the effect of Kupffer cells inhibition on hepatic injury induced by chronic cholestasis. Sprague-Dawley rats underwent bile duct ligation (BDL) or sham operation and were treated with either saline solution or gadolinium chloride (GdCl(3), a specific Kupffer cell inhibitor, 20 mg/kg i.p. daily). Serum and liver samples were collected after 28 days. Direct and total bilirubin concentrations and serum enzyme activities of alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and γ-glutamyl transpeptidase (GGT) increased following BDL (p < 0.01). On the contrary to bilirubin concentrations and AST activity, GdCl(3) partially prevented the elevation in ALP, ALT and GGT enzyme activities (p < 0.05). GdCl(3) alleviated lipid peroxidation (reflected by malondialdehyde [MDA] concentration) and increased the activities of antioxidant enzymes (i.e. catalase and glutathione peroxidase) in liver samples after BDL (p < 0.05). Fibrosis, ductular proliferation and portal inflammation were also scored in liver samples. Among morphological changes appeared following BDL (i.e. marked fibrosis, portal inflammation and ductular proliferation); only ductular proliferation was not alleviated by GdCl(3). Therefore, Kupffer cells inhibition has beneficial effects against the development of hepatic injury induced by chronic cholestasis. PMID:21339256

  9. Hepatic Xbp1 Gene Deletion Promotes Endoplasmic Reticulum Stress-induced Liver Injury and Apoptosis.

    PubMed

    Olivares, Shantel; Henkel, Anne S

    2015-12-11

    Endoplasmic reticulum (ER) stress activates the unfolded protein response (UPR), a highly conserved signaling cascade that functions to alleviate stress and promote cell survival. If, however, the cell is unable to adapt and restore homeostasis, then the UPR activates pathways that promote apoptotic cell death. The molecular mechanisms governing the critical transition from adaptation and survival to initiation of apoptosis remain poorly understood. We aim to determine the role of hepatic Xbp1, a key mediator of the UPR, in controlling the adaptive response to ER stress in the liver. Liver-specific Xbp1 knockout mice (Xbp1(LKO)) and Xbp1(fl/fl) control mice were subjected to varying levels and durations of pharmacologic ER stress. Xbp1(LKO) and Xbp1(fl/fl) mice showed robust and equal activation of the UPR acutely after induction of ER stress. By 24 h, Xbp1(fl/fl) controls showed complete resolution of UPR activation and no liver injury, indicating successful adaptation to the stress. Conversely, Xbp1(LKO) mice showed ongoing UPR activation associated with progressive liver injury, apoptosis, and, ultimately, fibrosis by day 7 after induction of ER stress. These data indicate that hepatic XBP1 controls the adaptive response of the UPR and is critical to restoring homeostasis in the liver in response to ER stress. PMID:26504083

  10. Protective effect of berberine chloride on Plasmodium chabaudi-induced hepatic tissue injury in mice

    PubMed Central

    Dkhil, Mohamed A.; Al-Quraishy, Saleh; Al-Shamrany, Ahmed; Alazzouni, Ahmed S.; Lubbad, Mahmoud Y.; Al-Shaebi, Esam M.; Taib, Noory T.

    2014-01-01

    The present study aimed to investigate the protective role of berberine (BER) against Plasmodium chabaudi-induced infection in mice. Animals were divided into three groups. Group I served as a vehicle control. Group II and group III were infected with 1000 P. chabaudi infected erythrocytes. Group III was gavaged with 100 μl of 10 mg/kg berberine chloride for 10 days. All mice were sacrificed at day 10 post-infection. The percentage of parasitemia was significantly reduced more than 30%, after treatment of mice with BER. Infection caused marked hepatic injuries as indicated by histopathological alterations as evidenced by the presence of hepatic lobular inflammatory cellular infiltrations, dilated sinusoids, vacuolated hepatocytes, increased number of Kupffer cells and the malaria pigment, hemozoin. These changes in livers led to the increased histological score. Also, infection induced a significant increase in liver alanine aminotransferase and aspartate aminotransferase and a significant increase in the total leucocytic count. Moreover, mice became anemic as proved by the significant decrease in erythrocyte number and haemoglobin content. BER showed a significant protective potential by improving the above mentioned parameters. Based on these results, it is concluded that berberine could offer protection against hepatic tissue damage. PMID:26288557

  11. Tangeretin Alleviates Cisplatin-Induced Acute Hepatic Injury in Rats: Targeting MAPKs and Apoptosis

    PubMed Central

    Omar, Hany A.; Mohamed, Wafaa R.; Arab, Hany H.; Arafa, El-Shaimaa A.

    2016-01-01

    Despite its broad applications, cisplatin affords considerable nephro- and hepatotoxicity through triggering inflammatory and oxidative stress cascades. The aim of the current investigation was to study the possible protective effects of tangeretin on cisplatin-induced hepatotoxicity. The impact of tangeretin on cisplatin-evoked hepatic dysfunction and histopathologic changes along with oxidative stress, inflammatory and apoptotic biomarkers were investigated compared to silymarin. Tangeretin pre-treatment significantly improved liver function tests (ALT and AST), inhibited cisplatin-induced lipid profile aberrations (total cholesterol and triglycerides) and diminished histopathologic structural damage in liver tissues. Tangeretin also attenuated cisplatin-induced hepatic inflammatory events as indicated by suppression of tumor necrosis factor-α (TNF-α) and enhancement of interleukin-10 (IL-10). Meanwhile, it lowered malondialdehyde (MDA), nitric oxide (NO) and nuclear factor erythroid 2-related factor 2 (NRF-2) levels with restoration of glutathione (GSH), and glutathione peroxidase (GPx). Regarding mitogen-activated protein kinase (MAPK) pathway, tangeretin attenuated cisplatin-induced increase in phospho-p38, phospho-c-Jun N-terminal kinase (p-JNK) and phospho-extracellular signal-regulated kinase (p-ERK1/2) in liver tissues. In addition, tangeretin downregulated Bax expression with augmentation of Bcl-2 promoting liver cell survival. Our results highlight the protective effects of tangeretin against cisplatin-induced acute hepatic injury via the concerted modulation of inflammation, oxidative stress, MAPKs and apoptotic pathways. PMID:27031695

  12. Tangeretin Alleviates Cisplatin-Induced Acute Hepatic Injury in Rats: Targeting MAPKs and Apoptosis.

    PubMed

    Omar, Hany A; Mohamed, Wafaa R; Arab, Hany H; Arafa, El-Shaimaa A

    2016-01-01

    Despite its broad applications, cisplatin affords considerable nephro- and hepatotoxicity through triggering inflammatory and oxidative stress cascades. The aim of the current investigation was to study the possible protective effects of tangeretin on cisplatin-induced hepatotoxicity. The impact of tangeretin on cisplatin-evoked hepatic dysfunction and histopathologic changes along with oxidative stress, inflammatory and apoptotic biomarkers were investigated compared to silymarin. Tangeretin pre-treatment significantly improved liver function tests (ALT and AST), inhibited cisplatin-induced lipid profile aberrations (total cholesterol and triglycerides) and diminished histopathologic structural damage in liver tissues. Tangeretin also attenuated cisplatin-induced hepatic inflammatory events as indicated by suppression of tumor necrosis factor-α (TNF-α) and enhancement of interleukin-10 (IL-10). Meanwhile, it lowered malondialdehyde (MDA), nitric oxide (NO) and nuclear factor erythroid 2-related factor 2 (NRF-2) levels with restoration of glutathione (GSH), and glutathione peroxidase (GPx). Regarding mitogen-activated protein kinase (MAPK) pathway, tangeretin attenuated cisplatin-induced increase in phospho-p38, phospho-c-Jun N-terminal kinase (p-JNK) and phospho-extracellular signal-regulated kinase (p-ERK1/2) in liver tissues. In addition, tangeretin downregulated Bax expression with augmentation of Bcl-2 promoting liver cell survival. Our results highlight the protective effects of tangeretin against cisplatin-induced acute hepatic injury via the concerted modulation of inflammation, oxidative stress, MAPKs and apoptotic pathways. PMID:27031695

  13. Comparative analysis of portal hepatic infiltrating leucocytes in acute drug-induced liver injury, idiopathic autoimmune and viral hepatitis.

    PubMed

    Foureau, D M; Walling, T L; Maddukuri, V; Anderson, W; Culbreath, K; Kleiner, D E; Ahrens, W A; Jacobs, C; Watkins, P B; Fontana, R J; Chalasani, N; Talwalkar, J; Lee, W M; Stolz, A; Serrano, J; Bonkovsky, H L

    2015-04-01

    Drug-induced liver injury (DILI) is often caused by innate and adaptive host immune responses. Characterization of inflammatory infiltrates in the liver may improve understanding of the underlying pathogenesis of DILI. This study aimed to enumerate and characterize leucocytes infiltrating liver tissue from subjects with acute DILI (n = 32) versus non-DILI causes of acute liver injury (n = 25). Immunostains for CD11b/CD4 (Kupffer and T helper cells), CD3/CD20 (T and B cells) and CD8/CD56 [T cytotoxic and natural killer (NK) cells] were evaluated in biopsies from subjects with acute DILI, either immunoallergic (IAD) or autoimmune (AID) and idiopathic autoimmune (AIH) and viral hepatitis (VH) and correlated with clinical and pathological features. All biopsies showed numerous CD8(+) T cells and macrophages. DILI cases had significantly fewer B lymphocytes than AIH and VH and significantly fewer NK cells than VH. Prominent plasma cells were unusual in IAD (three of 10 cases), but were associated strongly with AIH (eight of nine) and also observed in most with AID (six of nine). They were also found in five of 10 cases with VH. Liver biopsies from subjects with DILI were characterized by low counts of mature B cells and NK cells in portal triads in contrast to VH. NK cells were found only in cases of VH, whereas AIH and VH both showed higher counts of B cells than DILI. Plasma cells were associated most strongly with AIH and less so with AID, but were uncommon in IAD. PMID:25418487

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

    PubMed

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

    2016-08-01

    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. PMID:27233607

  15. Hepatitis

    MedlinePlus

    ... has been associated with drinking contaminated water. Hepatitis Viruses Type Transmission Prognosis A Fecal-oral (stool to ... risk for severe disease. Others A variety of viruses can affect the liver Signs and Symptoms Hepatitis ...

  16. Wnt Agonist Attenuates Liver Injury and Improves Survival after Hepatic Ischemia/Reperfusion

    PubMed Central

    Kuncewitch, Michael; Yang, Weng-Lang; Molmenti, Ernesto; Nicastro, Jeffrey; Coppa, Gene F.; Wang, Ping

    2012-01-01

    The Wnt/β-catenin signaling pathway is well characterized in stem cell biology and plays a critical role in liver development, regeneration, and homeostasis. We hypothesized that pharmacological activation of Wnt signaling protects against hepatic ischemia/reperfusion (I/R) injury through its known proliferative and anti-apoptotic properties. Sprague-Dawley rats underwent 70% hepatic ischemia by microvascular clamping of the hilum of the left and median lobes of the liver for 90 min, followed by reperfusion. Wnt agonist (2-amino-4-[3,4-(methylenedioxy)benzylamino]-6-(3-methoxyphenyl)pyrimidine, 5 mg/kg BW) or vehicle (20% DMSO in saline) in 0.5 ml was injected intraperitoneally (i.p.) 1 h prior to ischemia or infused intravenously over 30 min right after ischemia. Blood and tissue samples from the pre-treated groups were collected 24 h after reperfusion, and a survival study was performed. Hepatic expression of β-catenin and its downstream target gene Axin2 were decreased after I/R while Wnt agonist restored their expression to sham levels. Wnt agonist blunted I/R-induced elevations of AST, ALT, and LDH and significantly improved the microarchitecture of the liver. The cell proliferation determined by Ki67 immunostaining significantly increased with Wnt agonist treatment and inflammatory cascades were dampened in Wnt agonist-treated animals, as demonstrated by attenuations in IL-6, myeloperoxdase, iNOS and nitrotyrosine. Wnt agonist also significantly decreased the amount of apoptosis, as evidenced by decreases in both TUNEL staining as well as caspase-3 activity levels. Finally, the 10-day survival rate was increased from 27% in the vehicle group to 73% in the pre-treated Wnt agonist group and 55% in the Wnt agonist post-ischemia treatment group. Thus, we propose that direct Wnt/β-catenin stimulation may represent a novel therapeutic approach in the treatment of hepatic I/R. PMID:23143067

  17. 1-Deoxynojirimycin Alleviates Liver Injury and Improves Hepatic Glucose Metabolism in db/db Mice.

    PubMed

    Liu, Qingpu; Li, Xuan; Li, Cunyu; Zheng, Yunfeng; Wang, Fang; Li, Hongyang; Peng, Guoping

    2016-01-01

    The present study investigated the effect of 1-Deoxynojirimycin (DNJ) on liver injury and hepatic glucose metabolism in db/db mice. Mice were divided into five groups: normal control, db/db control, DNJ-20 (DNJ 20 mg·kg(-1)·day(-1)), DNJ-40 (DNJ 40 mg·kg(-1)·day(-1)) and DNJ-80 (DNJ 80 mg·kg(-1)·day(-1)). All doses were treated intravenously by tail vein for four weeks. DNJ was observed to significantly reduce the levels of serum triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and liver TG, as well as activities of serum alanine aminotransferase (ALT), and aspartate transaminase (AST); DNJ also alleviated macrovesicular steatosis and decreased tumor necrosis factor α (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6) levels in liver tissue. Furthermore, DNJ treatment significantly increased hepatic glycogen content, the activities of hexokinase (HK), pyruvate kinase (PK) in liver tissue, and decreased the activities of glucose-6-phosphatase (G6Pase), glycogen phosphorylase (GP), and phosphoenolpyruvate carboxykinase (PEPCK). Moreover, DNJ increased the phosphorylation of phosphatidylinositol 3 kinase (PI3K) on p85, protein kinase B (PKB) on Ser473, glycogen synthase kinase 3β (GSK-3β) on Ser9, and inhibited phosphorylation of glycogen synthase (GS) on Ser645 in liver tissue of db/db mice. These results demonstrate that DNJ can increase hepatic insulin sensitivity via strengthening of the insulin-stimulated PKB/GSK-3β signal pathway and by modulating glucose metabolic enzymes in db/db mice. Moreover, DNJ also can improve lipid homeostasis and attenuate hepatic steatosis in db/db mice. PMID:26927057

  18. Hepatic expression of serum amyloid A1 is induced by traumatic brain injury and modulated by telmisartan.

    PubMed

    Villapol, Sonia; Kryndushkin, Dmitry; Balarezo, Maria G; Campbell, Ashley M; Saavedra, Juan M; Shewmaker, Frank P; Symes, Aviva J

    2015-10-01

    Traumatic brain injury affects the whole body in addition to the direct impact on the brain. The systemic response to trauma is associated with the hepatic acute-phase response. To further characterize this response, we performed controlled cortical impact injury on male mice and determined the expression of serum amyloid A1 (SAA1), an apolipoprotein, induced at the early stages of the acute-phase response in liver and plasma. After cortical impact injury, induction of SAA1 was detectable in plasma at 6 hours post-injury and in liver at 1 day post-injury, followed by gradual diminution over time. In the liver, cortical impact injury increased neutrophil and macrophage infiltration, apoptosis, and expression of mRNA encoding the chemokines CXCL1 and CXCL10. An increase in angiotensin II AT1 receptor mRNA at 3 days post-injury was also observed. Administration of the AT1 receptor antagonist telmisartan 1 hour post-injury significantly decreased liver SAA1 levels and CXCL10 mRNA expression, but did not affect CXCL1 expression or the number of apoptotic cells or infiltrating leukocytes. To our knowledge, this is the first study to demonstrate that SAA1 is induced in the liver after traumatic brain injury and that telmisartan prevents this response. Elucidating the molecular pathogenesis of the liver after brain injury will assist in understanding the efficacy of therapeutic approaches to brain injury. PMID:26435412

  19. Antioxidant properties of repaglinide and its protections against cyclosporine A-induced renal tubular injury

    PubMed Central

    Li, Dao; Li, Jin; Li, Hui; Wu, Qiong; Li, Qi-Xiong

    2016-01-01

    Objective(s): Repaglinide (RG) is an antihyperglycemic agent used for the treatment of non-insulin-dependent diabetes mellitus. It has a good safety and efficacy profile in diabetic patients with complications in renal impairment and is an appropriate treatment choice, even for individuals with more severe degrees of renal malfunctions. The aim of the present study was to examine the protective effect of RG on cyclosporine A (CsA)-induced rat renal impairment and to evaluate the antioxidant mechanisms by which RG exerts its protective actions. Materials and Methods: Fifty male Sprague-Dawley rats weighing 250–300 g were randomly divided into five groups: administrations of olive oil (control, PO), RG (0.4 mg/kg, PO), CsA (30 mg/kg in olive oil, SC), RG (0.2 or 0.4 mg/kg, PO) plus CsA (30 mg/kg in olive oil SC) every day for 15 days. Results: SC administration of CsA (30 mg/kg) to rats produced marked elevations in the levels of renal impairment parameters such as urinary protein, N-acetyl-beta-D-glucosaminidase (NAG), serum creatinine (SCr), and blood urea nitrogen (BUN). It also caused histologic injury to the kidneys. Oral administration of RG (0.2 and 0.4 mg/kg) markedly decreased all the aforementioned changes. In addition, CsA caused increases in the levels of malondialdehyde (MDA) and decreases in superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), glutathione reductase (GSR), glutathione-S-transferase (GST), and glutathione in kidney homogenate, which were reversed significantly by both doses of RG. Conclusion: The findings of our study indicate that RG may play an important role in protecting the kidney from oxidative insult.

  20. Change in renal heme oxygenase expression in cyclosporine A-induced injury.

    PubMed

    Rezzani, Rita; Rodella, Luigi; Buffoli, Barbara; Goodman, Alvin A; Abraham, Nader G; Lianos, Elias A; Bianchi, Rossella

    2005-01-01

    Cyclosporine A (CsA) is the first immunosuppressant used in allotransplantation. Its use is associated with side effects that include nephrotoxicity. This study explored the anatomic structures involved in CsA nephrotoxicity and the effect of heme oxygenase (HO) in preventing CsA injury. Rats were divided into four groups, which were treated with olive oil, CsA (15 mg/kg/day), CsA plus the HO inhibitor (SnMP; 30 microM/kg/day), and with the HO inducer (CoPP; 5 mg/100 g bw). Renal tissue was treated for morphological, biochemical, and immunohistochemical studies. CsA-treated rats showed degenerative changes with renal fibrosis localized mainly around proximal tubules. Collapsed vessels were sometimes seen in glomeruli. No HO-1 expression and increased expression of endothelin-1 (ET-1) were observed in CsA-treated rats compared with controls. In CsA plus SnMP-treated rats, HO-1 expression was further reduced and the morphology was not changed compared to the CsA group, whereas CsA plus CoPP-treated animals again showed normal morphology and with restoration and an increase in HO-1 levels. HO activity and immunohistochemical data showed similar alterations as HO expression. No changes were observed for HO-2 analysis. The observations indicate that HO-1 downregulation and ET-1 upregulation by CsA might be one mechanism underlying CsA-induced nephrotoxicity. Therefore, attempts to preserve HO levels attenuate CsA nephrotoxicity. PMID:15637343

  1. Acute hepatitis C virus infection in a nurse trainee following a needlestick injury.

    PubMed

    Scaggiante, Renzo; Chemello, Liliana; Rinaldi, Roberto; Bartolucci, Giovanni Battista; Trevisan, Andrea

    2013-01-28

    Hepatitis C virus (HCV) infection after biological accident (needlestick injury) is a rare event. This report describes the first case of acute HCV infection after a needlestick injury in a female nursing student at Padua University Hospital. The student nurse was injured on the second finger of the right hand when recapping a 23-gauge needle after taking a blood sample. The patient who was the source was a 72-year-old female with weakly positive anti-HCV test results. Three months after the injury, at the second step of follow-up, a relevant increase in transaminases with a low viral replication activity (350 IU/mL) was observed in the student, indicating HCV infection. The patient tested positive for the same genotype (1b) of HCV as the injured student. A rapid decline in transaminases, which was not accompanied by viral clearance, and persistently positive HCV-RNA was described 1 mo later. Six months after testing positive for HCV, the student was treated with pegylated interferon plus ribavirin for 24 wk. A rapid virological response was observed after 4 wk of treatment, and a sustained virological response (SVR) was evident 6 mo after therapy withdrawal, confirming that the patient was definitively cured. Despite the favourable IL28B gene (rs12979860) CC- polymorphism observed in the patient, which is usually predictive of a spontaneous clearance and SVR, spontaneous viral clearance did not take place; however, infection with this genotype was promising for a sustained virological response after therapy. PMID:23382640

  2. Inhibition of glutamate carboxypeptidase II (NAALADase) protects against dynorphin A-induced ischemic spinal cord injury in rats.

    PubMed

    Long, Joseph B; Yourick, Debra L; Slusher, Barbara S; Robinson, Michael B; Meyerhoff, James L

    2005-01-31

    Glutamate carboxypeptidase (GCP) II (EC 3.4.17.21), which is also known as N-acetylated-alpha-linked acidic dipeptidase (NAALADase), hydrolyses the endogenous acidic dipeptide N-acetylaspartylglutamate (NAAG), yielding N-acetyl-aspartate and glutamate. Inhibition of this enzyme by 2-(phosphonomethyl) pentanedioic acid (2-PMPA) has been shown to protect against ischemic injury to the brain and hypoxic and metabolic injury to neuronal cells in culture, presumably by increasing and decreasing the extracellular concentrations of NAAG and glutamate, respectively. Since both NAAG and GCP II are found in especially high concentrations in the spinal cord, injuries to the spinal cord involving pathophysiological elevations in extracellular glutamate might be particularly responsive to GCP II inhibition. Lumbar subarachnoid injections of dynorphin A in rats cause ischemic spinal cord injury, elevated extracellular glutamate and a persistent hindlimb paralysis that is mediated through excitatory amino acid receptors. We therefore used this injury model to evaluate the protective effects of 2-PMPA. When coadministered with dynorphin A, 2-PMPA significantly attenuated the dynorphin A-induced elevations in cerebrospinal fluid glutamate levels and by 24 h postinjection caused significant dose-dependent improvements in motor scores that were associated with marked histopathological improvements. These results indicate that 2-PMPA provides effective protection against excitotoxic spinal cord injury. PMID:15680261

  3. Magnetic hydroxyapatite nanoworms for magnetic resonance diagnosis of acute hepatic injury

    NASA Astrophysics Data System (ADS)

    Xu, Yun-Jun; Dong, Liang; Lu, Yang; Zhang, Le-Cheng; An, Duo; Gao, Huai-Ling; Yang, Dong-Mei; Hu, Wen; Sui, Cong; Xu, Wei-Ping; Yu, Shu-Hong

    2016-01-01

    Inorganic non-metallic biomaterials, including the silicon frustule of a unicellular diatom, the carbonate shell of a mollusk and the calcium skeleton of the vertebrate, which are the main constituent part of an organism, serve as the supportive and protective components of soft tissue. Among them, hydroxyapatite, which primarily makes up the enamel and bone, is widely used in tissue engineering. Recently, the inorganic nonmetallic biomaterials, especially the applications of hydroxyapatites have attracted great attention. Herein, we report a novel synthesis method of magnetic functionalized hydroxyapatite nanocomposites. By simply tuning the ratios of reactants, a series of hydroxyapatite-Fe3O4 worm-shaped nanocomposites (HAP-ION nanoworms) are obtained. In addition, layer-by-layer surface modifications with chitosan (CH) and sodium alginate (SA) were employed to improve the solubility and biocompatibility, and low cytotoxicity and no hemolysis were observed. With the increase of iron oxide nanocrystals, the magnetic properties of the magnetic assembled nanoworms were enhanced, which resulted in better performance of magnetic resonance (MR) imaging. Owing to the intravenous injection of HAP-ION nanoworms, the contrast to noise ratio (CNR) of hepatic MR imaging in vivo was enhanced obviously, which should be beneficial for hepatic injury grading and further therapeutic treatment.Inorganic non-metallic biomaterials, including the silicon frustule of a unicellular diatom, the carbonate shell of a mollusk and the calcium skeleton of the vertebrate, which are the main constituent part of an organism, serve as the supportive and protective components of soft tissue. Among them, hydroxyapatite, which primarily makes up the enamel and bone, is widely used in tissue engineering. Recently, the inorganic nonmetallic biomaterials, especially the applications of hydroxyapatites have attracted great attention. Herein, we report a novel synthesis method of magnetic

  4. Comparison of imatinib, nilotinib and silymarin in the treatment of carbon tetrachloride-induced hepatic oxidative stress, injury and fibrosis

    SciTech Connect

    Shaker, Mohamed E.; Zalata, Khaled R.; Mehal, Wajahat Z.; Shiha, Gamal E.; Ibrahim, Tarek M.

    2011-04-15

    Effective and well-tolerated anti-fibrotic drugs are currently lacking. Therefore, this study was carried out to investigate the potential anti-fibrotic effects of imatinib, nilotinib and silymarin on established hepatic fibrosis in the carbon tetrachloride (CCl{sub 4}) rat model. Male Wistar rats received intraperitoneal injections of CCl{sub 4} twice weekly for 8 weeks, as well as daily intraperitoneal treatments of imatinib (10 and 20 mg/kg), nilotinib (10 and 20 mg/kg) and silymarin (100 mg/kg) during the last 4 weeks of CCl{sub 4}-intoxication. At the end of the study, hepatic damage was evaluated by analysis of liver function tests and hepatic oxidative stress parameters. Hepatic fibrosis was evaluated by histopathology and morphometry, as well as collagen and 4-hydroxyproline contents. Nilotinib (20 mg/kg) was the most effective treatment to counteract CCl{sub 4}-induced hepatic injury as indicated by liver function tests and histopathology. Nilotinib (10 mg/kg), nilotinib (20 mg/kg) and silymarin (100 mg/kg) treatments reduced the mean score of hepatic fibrosis by 31%, 68% and 47%, respectively, and hepatic collagen content by 47%, 49% and 18%, respectively in CCl{sub 4}-treated rats. Hepatic morphometric evaluation and 4-hydroxyproline content revealed that CCl{sub 4}-induced fibrosis was ameliorated significantly by nilotinib (20 mg/kg) and imatinib (20 mg/kg). Unlike nilotinib, imatinib (20 mg/kg) showed some sort of hepatic injury evidenced by elevation of serum aminotransferases and total bilirubin levels, and hepatic total nitrate/nitrite content, as well as characteristic anisonucleosis visualized with the hematoxylin-eosin staining. In conclusion, this study provides the evidence that nilotinib exerts anti-fibrotic activity and suggests that it may be valuable in the treatment of hepatic fibrosis in humans. - Graphical abstract: Display Omitted Research Highlights: > The anti-fibrotic effects of imatinib, nilotinib and silymarin were compared

  5. Hepatic ischemia

    MedlinePlus

    Hepatic ischemia is a condition in which the liver does not get enough blood or oxygen, causing injury to ... pressure from any condition can lead to hepatic ischemia. Such conditions may include: Abnormal heart rhythms Dehydration ...

  6. Dimethylacetamide-induced Hepatic Injury in Vitro: Mechanism and Potential Preventive Strategy.

    PubMed

    Liu, Xin; Gong, Wei; Xu, Yan Qiong; Zhu, Bao Li

    2016-02-01

    N,N-Dimethylacetamide (DMAc) is a widely used organic solvent in modern chemical industry with low to moderate hepatotoxicity to occupational health of employees. But so far, there are fewer and less conclusive data concerning its pathogenic mechanism in detail. In current study, the toxicity of DMAc was firstly investigated on human normal hepatocytes (LO-2), using a series of molecular biology measurements to ananlyze the effect and mechanism of DMAc-induced hepatic cell injury and explore effective prophylactic measures. We found that DMAc triggered LO-2 apoptosis in a obviously dose-dependent manner, caused by increased ROS generation and activation of Bcl-2 pathway. Significantly, glutathione (GSH) rather than vitamin C (Vit C) could partially inhibit DMAc-induced apoptosis thus showing potential as a effective precaution for workers. PMID:27003174

  7. Anchoring Hepatic Gene Expression with Development of Fibrosis and Neoplasia in a Toxicant-Induced Fish Model of Liver Injury

    PubMed Central

    Van Wettere, Arnaud J.; Law, J. Mac; Hinton, David E.; Kullman, Seth W.

    2014-01-01

    Fish have been used as laboratory models to study hepatic development and carcinogenesis but not for pathogenesis of hepatic fibrosis. In this study, a dimethylnitrosamine-induced fish model of hepatic injury was developed in Japanese medaka (Oryzias latipes) and gene expression was anchored with the development of hepatic fibrosis and neoplasia. Exposed livers exhibited mild hepatocellular degenerative changes 2 weeks post-exposure. Within six weeks hepatic fibrosis/cirrhosis was evident with development of neoplasia by 10 weeks. Stellate cell activation and development of fibrosis was associated with upregulation of tgfb1,tgfb receptor 2, smad3a, smad3b, ctnnb1, myc, mmp2, mmp14a, mmp14b, timp2a, timp2b, timp3, col1a1a, and col1a1b, and a less pronounced increase in mmp13 and col4a1expression. Tgfb receptor I expression was unchanged. Immunohistochemistry suggested that biliary epithelial cells and stellate cells were the main producers of TGF-β1. This study identified a group of candidate genes likely to be involved in the development of hepatic fibrosis, and demonstrated that the TGF-β pathway likely plays a major role in the pathogenesis. These results support the medaka as a viable fish model of hepatic fibrosis. PMID:23197195

  8. HUMAN ADRENOMEDULLIN AND ITS BINDING PROTEIN ATTENUATE ORGAN INJURY AND REDUCE MORTALITY AFTER HEPATIC ISCHEMIA-REPERFUSION

    PubMed Central

    Yang, Juntao; Wu, Rongqian; Qiang, Xiaoling; Zhou, Mian; Dong, Weifeng; Ji, Youxin; Marini, Corrado P.; Ravikumar, Thanjavur S.; Wang, Ping

    2009-01-01

    Objective To determine whether administration of a vasoactive peptide, human adrenomedullin (AM), in combination with its binding protein (i.e., AMBP-1), prevents or minimizes hepatic ischemia-reperfusion (I/R) injury. Summary Background Data Hepatic I/R injury results from tissue hypoxia and subsequent inflammatory responses. Even though numerous pharmacological modalities and substances have been studied to reduce I/R-induced mortality, none have been entirely successful. We have shown that administration of AM/AMBP-1 produces significant beneficial effects under various pathophysiological conditions. However, it remains unknown if human AM/AMBP-1 has any protective effects on hepatic I/R-induced tissue damage and mortality. Methods 70% hepatic ischemia was induced in male adult rats by placing a microvascular clip across the hilum of the left and median lobes for 90 min. After removing the clip, human AM alone, human AMBP-1 alone, human AM in combination with human AMBP-1 or vehicle was administered intravenously over a period of 30 min. Blood and tissue samples were collected 4 h after reperfusion for various measurements. In additional groups of animals, the non-ischemic liver lobes were resected at the end of 90-min ischemia. The animals were monitored for 7 days and survival was recorded. Results After hepatic I/R, plasma levels of AM were significantly increased while AMBP-1 levels were markedly decreased. Likewise, gene expression of AM in the liver was increased significantly while AMBP-1 expression was markedly decreased. Administration of AM in combination with AMBP-1 immediately after the onset of reperfusion downregulated inflammatory cytokines, decreased hepatic neutrophil infiltration, inhibited liver cell apoptosis and necrosis, and reduced liver injury and mortality in a rat model of hepatic I/R. On the other hand, administration of human AM alone or human AMBP-1 alone after hepatic I/R failed to produce significant protection. Conclusions Human

  9. The protective effect of diosmin on hepatic ischemia reperfusion injury: an experimental study.

    PubMed

    Tanrikulu, Yusuf; Sahin, Mefaret; Kismet, Kemal; Kilicoglu, Sibel Serin; Devrim, Erdinc; Tanrikulu, Ceren Sen; Erdemli, Esra; Erel, Serap; Bayraktar, Kenan; Akkus, Mehmet Ali

    2013-11-01

    Liver ischemia reperfusion injury (IRI) is an important pathologic process leading to bodily systemic effects and liver injury. Our study aimed to investigate the protective effects of diosmin, a phlebotrophic drug with antioxidant and anti-inflammatory effects, in a liver IRI model. Forty rats were divided into 4 groups. Sham group, control group (ischemia-reperfusion), intraoperative treatment group, and preoperative treatment group. Ischemia reperfusion model was formed by clamping hepatic pedicle for a 60 minute of ischemia followed by liver reperfusion for another 90 minutes. Superoxide dismutase (SOD) and catalase (CAT) were measured as antioaxidant enzymes in the liver tissues, and malondialdehyde (MDA) as oxidative stress marker, xanthine oxidase (XO) as an oxidant enzyme and glutathione peroxidase (GSH-Px) as antioaxidant enzyme were measured in the liver tissues and the plasma samples. Hepatic function tests were lower in treatment groups than control group (p<0.001 for ALT and AST). Plasma XO and MDA levels were lower in treatment groups than control group, but plasma GSH-Px levels were higher (p<0.05 for all). Tissue MDA levels were lower in treatment groups than control group, but tissue GSH-Px, SOD, CAT and XO levels were higher (p<0.05 for MDA and p<0.001 for others). Samples in control group histopathologically showed morphologic abnormalities specific to ischemia reperfusion. It has been found that both preoperative and intraoperative diosmin treatment decreases cellular damage and protects cells from toxic effects in liver IRI. As a conclusion, diosmin may be used as a protective agent against IRI in elective and emergent liver surgical operations. PMID:24289756

  10. Acute Liver Injury Induces Nucleocytoplasmic Redistribution of Hepatic Methionine Metabolism Enzymes

    PubMed Central

    Delgado, Miguel; Garrido, Francisco; Pérez-Miguelsanz, Juliana; Pacheco, María; Partearroyo, Teresa; Pérez-Sala, Dolores

    2014-01-01

    Abstract Aims: The discovery of methionine metabolism enzymes in the cell nucleus, together with their association with key nuclear processes, suggested a putative relationship between alterations in their subcellular distribution and disease. Results: Using the rat model of d-galactosamine intoxication, severe changes in hepatic steady-state mRNA levels were found; the largest decreases corresponded to enzymes exhibiting the highest expression in normal tissue. Cytoplasmic protein levels, activities, and metabolite concentrations suffered more moderate changes following a similar trend. Interestingly, galactosamine treatment induced hepatic nuclear accumulation of methionine adenosyltransferase (MAT) α1 and S-adenosylhomocysteine hydrolase tetramers, their active assemblies. In fact, galactosamine-treated livers showed enhanced nuclear MAT activity. Acetaminophen (APAP) intoxication mimicked most galactosamine effects on hepatic MATα1, including accumulation of nuclear tetramers. H35 cells that overexpress tagged-MATα1 reproduced the subcellular distribution observed in liver, and the changes induced by galactosamine and APAP that were also observed upon glutathione depletion by buthionine sulfoximine. The H35 nuclear accumulation of tagged-MATα1 induced by these agents correlated with decreased glutathione reduced form/glutathione oxidized form ratios and was prevented by N-acetylcysteine (NAC) and glutathione ethyl ester. However, the changes in epigenetic modifications associated with tagged-MATα1 nuclear accumulation were only prevented by NAC in galactosamine-treated cells. Innovation: Cytoplasmic and nuclear changes in proteins that regulate the methylation index follow opposite trends in acute liver injury, their nuclear accumulation showing potential as disease marker. Conclusion: Altogether these results demonstrate galactosamine- and APAP-induced nuclear accumulation of methionine metabolism enzymes as active oligomers and unveil the implication of

  11. Chlordecone potentiates hepatic fibrosis in chronic liver injury induced by carbon tetrachloride in mice.

    PubMed

    Tabet, Elise; Genet, Valentine; Tiaho, François; Lucas-Clerc, Catherine; Gelu-Simeon, Moana; Piquet-Pellorce, Claire; Samson, Michel

    2016-07-25

    Chronic liver damage due to viral or chemical agents leads to a repair process resulting in hepatic fibrosis. Fibrosis may lead to cirrhosis, which may progress to liver cancer or a loss of liver function, with an associated risk of liver failure and death. Chlordecone is a chlorinated pesticide used in the 1990s. It is not itself hepatotoxic, but its metabolism in the liver triggers hepatomegaly and potentiates hepatotoxic agents. Chlordecone is now banned, but it persists in soil and water, resulting in an ongoing public health problem in the Caribbean area. We assessed the probable impact of chlordecone on the progression of liver fibrosis in the population of contaminated areas, by developing a mouse model of chronic co-exposure to chlordecone and a hepatotoxic agent, carbon tetrachloride (CCl4). After repeated administrations of chlordecone and CCl4 by gavage over a 12-week period, we checked for liver damage in the exposed mice, by determining serum liver transaminase (AST, ALT) levels, histological examinations of the liver and measuring the expression of genes encoding extracellular matrix components. The co-exposure of mice to CCl4 and chlordecone resulted in significant increases in ALT and AST levels. Chlordecone also increased expression of the Col1A2, MMP-2, TIMP-1 and PAI-1 genes in CCl4-treated mice. Finally, we demonstrated, by quantifying areas of collagen deposition and alpha-SMA gene expression, that chlordecone potentiated the hepatic fibrosis induced by CCl4. In conclusion, our data suggest that chlordecone potentiates hepatic fibrosis in mice with CCl4-induced chronic liver injury. PMID:26853152

  12. Nuciferine Prevents Hepatic Steatosis and Injury Induced by a High-Fat Diet in Hamsters

    PubMed Central

    Li, Xiaoxia; Feng, Rennan; Guan, Chunmei; Wang, Yanwen; Li, Ying; Sun, Changhao

    2013-01-01

    Background Nuciferine is a major active aporphine alkaloid from the leaves of N. nucifera Gaertn that possesses anti-hyperlipidemia, anti-hypotensive, anti-arrhythmic, and insulin secretagogue activities. However, it is currently unknown whether nuciferine can benefit hepatic lipid metabolism. Methodology/Principal Findings In the current study, male golden hamsters were randomly divided into four groups fed a normal diet, a high-fat diet (HFD), or a HFD supplemented with nuciferine (10 and 15 mg/kg·BW/day). After 8 weeks of intervention, HFD-induced increases in liver and visceral adipose tissue weight, dyslipidemia, liver steatosis, and mild necroinflammation in hamsters were analyzed. Nuciferine supplementation protected against HFD-induced changes, alleviated necroinflammation, and reversed serum markers of metabolic syndrome in hamsters fed a HFD. RT-PCR and western blot analyses revealed that hamsters fed a HFD had up-regulated levels of genes related to lipogenesis, increased free fatty acid infiltration, and down-regulated genes involved in lipolysis and very low density lipoprotein secretion. In addition, gene expression of cytochrome P4502E1 and tumor necrosis factor-α were also increased in the HFD group. Nuciferine supplementation clearly suppressed HFD-induced alterations in the expression of genes involved in lipid metabolism. Conclusions/Significance Nuciferine supplementation ameliorated HFD-induced dyslipidemia as well as liver steatosis and injury. The beneficial effects of nuciferine were associated with altered expression of hepatic genes involved in lipid metabolism. PMID:23691094

  13. Magnetic hydroxyapatite nanoworms for magnetic resonance diagnosis of acute hepatic injury.

    PubMed

    Xu, Yun-Jun; Dong, Liang; Lu, Yang; Zhang, Le-Cheng; An, Duo; Gao, Huai-Ling; Yang, Dong-Mei; Hu, Wen; Sui, Cong; Xu, Wei-Ping; Yu, Shu-Hong

    2016-01-21

    Inorganic non-metallic biomaterials, including the silicon frustule of a unicellular diatom, the carbonate shell of a mollusk and the calcium skeleton of the vertebrate, which are the main constituent part of an organism, serve as the supportive and protective components of soft tissue. Among them, hydroxyapatite, which primarily makes up the enamel and bone, is widely used in tissue engineering. Recently, the inorganic nonmetallic biomaterials, especially the applications of hydroxyapatites have attracted great attention. Herein, we report a novel synthesis method of magnetic functionalized hydroxyapatite nanocomposites. By simply tuning the ratios of reactants, a series of hydroxyapatite-Fe3O4 worm-shaped nanocomposites (HAP-ION nanoworms) are obtained. In addition, layer-by-layer surface modifications with chitosan (CH) and sodium alginate (SA) were employed to improve the solubility and biocompatibility, and low cytotoxicity and no hemolysis were observed. With the increase of iron oxide nanocrystals, the magnetic properties of the magnetic assembled nanoworms were enhanced, which resulted in better performance of magnetic resonance (MR) imaging. Owing to the intravenous injection of HAP-ION nanoworms, the contrast to noise ratio (CNR) of hepatic MR imaging in vivo was enhanced obviously, which should be beneficial for hepatic injury grading and further therapeutic treatment. PMID:26694026

  14. ROLE OF CASPASE-1 AND INTERLEUKIN-1β IN ACETAMINOPHEN-INDUCED HEPATIC INFLAMMATION AND LIVER INJURY

    PubMed Central

    Williams, C. David; Farhood, Anwar; Jaeschke, Hartmut

    2010-01-01

    Acetaminophen (APAP) overdose can result in serious liver injury and potentially death. Toxicity is dependent on metabolism of APAP to a reactive metabolite initiating a cascade of intracellular events resulting in hepatocellular necrosis. This early injury triggers a sterile inflammatory response with formation of cytokines and innate immune cell infiltration in the liver. Recently, IL-1β signaling has been implicated in the potentiating of APAP-induced liver injury. To test if IL-1β formation through caspase-1 is critical for the pathophysiology, C57Bl/6 mice were treated with the pan-caspase inhibitor Z-VD-fmk to block the inflammasome-mediated maturation of IL-1β during APAP overdose (300 mg/kg APAP). This intervention did not affect IL-1β gene transcription but prevented the increase in IL-1β plasma levels. However, APAP-induced liver injury and neutrophil infiltration was not affected. Similarly, liver injury and the hepatic neutrophilic inflammation were not attenuated in IL-1-receptor-1 deficient mice compared to wild type animals. To evaluate the potential of IL-1β to increase injury, mice were given pharmacological doses of IL-1β after APAP overdose. Despite increased systemic activation of neutrophils and recruitment into the liver, there was no alteration in injury. We conclude that endogenous IL-1β formation after APAP overdose is insufficient to activate and recruit neutrophils into the liver or cause liver injury. Even high pharmacological doses of IL-1β, which induce hepatic neutrophil accumulation and activation, do not enhance APAP-induced liver injury. Thus, IL-1 signaling is irrelevant for APAP hepatotoxicity. The inflammatory cascade is a less important therapeutic target than intracellular signaling pathways to attenuate APAP-induced liver injury. PMID:20637792

  15. Role of caspase-1 and interleukin-1beta in acetaminophen-induced hepatic inflammation and liver injury.

    PubMed

    Williams, C David; Farhood, Anwar; Jaeschke, Hartmut

    2010-09-15

    Acetaminophen (APAP) overdose can result in serious liver injury and potentially death. Toxicity is dependent on metabolism of APAP to a reactive metabolite initiating a cascade of intracellular events resulting in hepatocellular necrosis. This early injury triggers a sterile inflammatory response with formation of cytokines and innate immune cell infiltration in the liver. Recently, IL-1beta signaling has been implicated in the potentiation of APAP-induced liver injury. To test if IL-1beta formation through caspase-1 is critical for the pathophysiology, C57Bl/6 mice were treated with the pan-caspase inhibitor Z-VD-fmk to block the inflammasome-mediated maturation of IL-1beta during APAP overdose (300 mg/kg APAP). This intervention did not affect IL-1beta gene transcription but prevented the increase in IL-1beta plasma levels. However, APAP-induced liver injury and neutrophil infiltration were not affected. Similarly, liver injury and the hepatic neutrophilic inflammation were not attenuated in IL-1-receptor-1 deficient mice compared to wild-type animals. To evaluate the potential of IL-1beta to increase injury, mice were given pharmacological doses of IL-1beta after APAP overdose. Despite increased systemic activation of neutrophils and recruitment into the liver, there was no alteration in injury. We conclude that endogenous IL-1beta formation after APAP overdose is insufficient to activate and recruit neutrophils into the liver or cause liver injury. Even high pharmacological doses of IL-1beta, which induce hepatic neutrophil accumulation and activation, do not enhance APAP-induced liver injury. Thus, IL-1 signaling is irrelevant for APAP hepatotoxicity. The inflammatory cascade is a less important therapeutic target than intracellular signaling pathways to attenuate APAP-induced liver injury. PMID:20637792

  16. Role of caspase-1 and interleukin-1{beta} in acetaminophen-induced hepatic inflammation and liver injury

    SciTech Connect

    Williams, C. David; Farhood, Anwar; Jaeschke, Hartmut

    2010-09-15

    Acetaminophen (APAP) overdose can result in serious liver injury and potentially death. Toxicity is dependent on metabolism of APAP to a reactive metabolite initiating a cascade of intracellular events resulting in hepatocellular necrosis. This early injury triggers a sterile inflammatory response with formation of cytokines and innate immune cell infiltration in the liver. Recently, IL-1{beta} signaling has been implicated in the potentiation of APAP-induced liver injury. To test if IL-1{beta} formation through caspase-1 is critical for the pathophysiology, C57Bl/6 mice were treated with the pan-caspase inhibitor Z-VD-fmk to block the inflammasome-mediated maturation of IL-1{beta} during APAP overdose (300 mg/kg APAP). This intervention did not affect IL-1{beta} gene transcription but prevented the increase in IL-1{beta} plasma levels. However, APAP-induced liver injury and neutrophil infiltration were not affected. Similarly, liver injury and the hepatic neutrophilic inflammation were not attenuated in IL-1-receptor-1 deficient mice compared to wild-type animals. To evaluate the potential of IL-1{beta} to increase injury, mice were given pharmacological doses of IL-1{beta} after APAP overdose. Despite increased systemic activation of neutrophils and recruitment into the liver, there was no alteration in injury. We conclude that endogenous IL-1{beta} formation after APAP overdose is insufficient to activate and recruit neutrophils into the liver or cause liver injury. Even high pharmacological doses of IL-1{beta}, which induce hepatic neutrophil accumulation and activation, do not enhance APAP-induced liver injury. Thus, IL-1 signaling is irrelevant for APAP hepatotoxicity. The inflammatory cascade is a less important therapeutic target than intracellular signaling pathways to attenuate APAP-induced liver injury.

  17. Hepatoprotective effects of polysaccharide isolated from Agaricus bisporus industrial wastewater against CCl₄-induced hepatic injury in mice.

    PubMed

    Huang, Jiafu; Ou, Yixin; Yew, Tai Wai David; Liu, Jingna; Leng, Bo; Lin, Zhichao; Su, Yi; Zhuang, Yuanhong; Lin, Jiaofen; Li, Xiumin; Xue, Yu; Pan, Yutian

    2016-01-01

    During the industrial production of canned mushroom (Agaricus bisporus), a large quantity of wastewater is produced. In this study, the wastewater generated during the canning of mushroom was analyzed. From this wastewater, four polysaccharide components (Abnp1001, Abnp1002, Abap1001, and Abap1002) with hepatic-protective activity were isolated by ultrafiltration, DEAE cellulose-52 chromatography and Sephadex G-200 size-exclusion chromatography. Results of ultraviolet spectra analysis and molecular weight determination showed that Abnp1001, Abnp1002, Abap1001 and Abap1002 were uniform with average molecular weights of 336, 12.8, 330 and 15.8kDa, respectively. The monosaccharide composition analysis using gas chromatography (GC) showed that the four fractions were heteropolysaccharides and mainly composed of glucose. Fourier transform-infrared (FT-IR) analysis showed that the isolated fractions were all composed of β-glycoside linkages. Additionally, the potential hepatoprotective activities of these polysaccharides against CCl4-induced hepatic injury in mice were studied. Notably, Abnp1002 and Abap1002 could lower the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentrations in serum in a dose dependent manner and reduce the hepatocellular degeneration and necrosis, as well as inflammatory infiltration. These results indicate that these two polysaccharides had protective effects on acute hepatic injury induced by CCl4 in mice and suggest that the polysaccharides extracted from A. bisporus industrial wastewater might have potential in therapeutics of acute hepatic injury. PMID:26454111

  18. Treatment of surgical brain injury by immune tolerance induced by intrathymic and hepatic portal vein injection of brain antigens

    PubMed Central

    Yang, Weijian; Liu, Yong; Liu, Baolong; Tan, Huajun; Lu, Hao; Wang, Hong; Yan, Hua

    2016-01-01

    Surgical brain injury (SBI) defines complications induced by intracranial surgery, such as cerebral edema and other secondary injuries. In our study, intrathymic and hepatic portal vein injection of allogeneic myelin basic protein (MBP) or autogeneic brain cell suspensions were administered to a standard SBI model. Serum pro-inflammatory IL-2, anti-inflammatory IL-4 concentrations and the CD4+T/CD8+T ratio were measured at 1, 3, 7, 14 and 21 d after surgery to verify the establishment of immune tolerance. Furthermore, we confirmed neuroprotective effects by evaluating neurological scores at 1, 3, 7, 14 and 21 d after SBI. Anti-Fas ligand (FasL) immunohistochemistry and TUNEL assays of brain sections were tested at 21 d after surgery. Intrathymic injections of MBP or autogeneic brain cell suspensions functioned by both suppressing secondary inflammatory reactions and improving prognoses, whereas hepatic portal vein injections of autogeneic brain cell suspensions exerted a better effect than MBP. Intrathymic and hepatic portal vein injections of MBP had equal effects on reducing secondary inflammation and improving prognoses. Otherwise, hepatic portal vein injections of autogeneic brain cell suspensions had better outcomes than intrathymic injections of autogeneic brain cell suspensions. Moreover, the benefit of injecting antigens into the thymus was outweighed by hepatic portal vein injections. PMID:27554621

  19. Treatment of surgical brain injury by immune tolerance induced by intrathymic and hepatic portal vein injection of brain antigens.

    PubMed

    Yang, Weijian; Liu, Yong; Liu, Baolong; Tan, Huajun; Lu, Hao; Wang, Hong; Yan, Hua

    2016-01-01

    Surgical brain injury (SBI) defines complications induced by intracranial surgery, such as cerebral edema and other secondary injuries. In our study, intrathymic and hepatic portal vein injection of allogeneic myelin basic protein (MBP) or autogeneic brain cell suspensions were administered to a standard SBI model. Serum pro-inflammatory IL-2, anti-inflammatory IL-4 concentrations and the CD4(+)T/CD8(+)T ratio were measured at 1, 3, 7, 14 and 21 d after surgery to verify the establishment of immune tolerance. Furthermore, we confirmed neuroprotective effects by evaluating neurological scores at 1, 3, 7, 14 and 21 d after SBI. Anti-Fas ligand (FasL) immunohistochemistry and TUNEL assays of brain sections were tested at 21 d after surgery. Intrathymic injections of MBP or autogeneic brain cell suspensions functioned by both suppressing secondary inflammatory reactions and improving prognoses, whereas hepatic portal vein injections of autogeneic brain cell suspensions exerted a better effect than MBP. Intrathymic and hepatic portal vein injections of MBP had equal effects on reducing secondary inflammation and improving prognoses. Otherwise, hepatic portal vein injections of autogeneic brain cell suspensions had better outcomes than intrathymic injections of autogeneic brain cell suspensions. Moreover, the benefit of injecting antigens into the thymus was outweighed by hepatic portal vein injections. PMID:27554621

  20. Protective effects of medical ozone combined with traditional Chinese medicine against chemically-induced hepatic injury in dogs

    PubMed Central

    Li, Li-Jie; Yang, Yun-Gao; Zhang, Zhi-Ling; Nie, Sui-Feng; Li, Ze; Li, Feng; Hua, He-Yu; Hu, Yan-Jun; Zhang, Hong-Shuan; Guo, Ya-Bing

    2007-01-01

    AIM: To investigate the protective effect of medical ozone (O3) combined with Traditional Chinese Medicine (TCM) Yigan Fuzheng Paidu Capsules (YC) against carbon tetrachloride (CCl4)-induced hepatic injury in dogs. METHODS: Thirty healthy dogs were divided randomly into five groups (n = 6 in each group), namely control, oleanolic acid tablet (OAT), O3, YC and O3 + YC, given either no particular pre-treatment, oral OAT, medical ozone rectal insulfflation every other day, oral YC, or oral YC plus medical ozone rectal insulfflation every other day, respectively, for 30 consecutive days. After pre-treatment, acute hepatic injury was induced in all dogs with a single-dose intraperitoneal injection of CCl4. General condition and survival time were recorded. The biochemical and hematological indexes of alanine aminotransferase (ALT), aspartate aminotransferase/alanine aminotransferase (AST/ALT), serum total bilirubin (TBIL), prothrombin time (PT), blood ammonia (AMMO), and blood urea nitrogen (BUN) were measured after CCl4 injection. Hepatic pathological changes were also observed. RESULTS: Compared to the other four groups, the changes of group O3 + YC dogs’ general conditions (motoricity, mental state, eating, urination and defecation) could be better controlled. In group O3 + YC the survival rates were higher (P < 0.05 vs group control). AST/ALT values were kept within a normal level in group O3 + YC. Hepatic histopathology showed that hepatic injury in group O3 + YC was less serious than those in the other four groups. CONCLUSION: Medical ozone combined with TCM YC could exert a protective effect on acute liver injury induced by CCl4. PMID:18023088

  1. WISP1 mediates hepatic warm ischemia reperfusion injury via TLR4 signaling in mice

    PubMed Central

    Tong, Yao; Ding, Xi-Bing; Chen, Zhi-Xia; Jin, Shu-Qing; Zhao, Xiang; Wang, Xin; Mei, Shu-Ya; Jiang, Xi; Wang, Lingyu; Li, Quan

    2016-01-01

    Wnt-induced secreted protein-1 (WISP1) is an extracellular matrix protein that has been reported in cancer researches. Our previous studies on WISP1 implied it could be a harmful mediator in septic mice. However, its role in liver ischemia reperfusion (I/R) injury is unknown. This study investigated the effects of WISP1 on liver I/R damage. Male C57BL/6 wild-type mice were used to undergo 60 min segmental (70%) ischemia. WISP1 expression was measured after indicated time points of reperfusion. Anti-WISP1 antibody was injected intraperitoneally to mice. Toll-like receptor 4 (TLR4) knockout mice and TIR-domain-containing adaptor inducing interferon-β (TRIF) knockout mice were adopted in this study. WISP1 was significantly enhanced after 6 h of reperfusion when compared with sham treated mice and significantly decreased either by TLR4 knockout mice or TRIF knockout mice. Anti-WISP1 antibody significantly decreased serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), pathological changes and pro-inflammatory cytokine levels in the mice following I/R. Furthermore, significantly increased serum transaminase levels were found in C57 wild-type mice treated with recombinant WISP1 protein, but not found in TLR4 knockout or TRIF knockout mice subjected to liver I/R. Taken together, WISP1 might contribute to hepatic ischemia reperfusion injury in mice and possibly depends on TLR4/TRIF signaling. PMID:26821752

  2. Antioxidant effects of proanthocyanidin from grape seed on hepatic tissue injury in diabetic rats

    PubMed Central

    Mansouri, Esrafil; Khorsandi, Layasadat; Abedi, Hassan Ali

    2014-01-01

    Objective(s): Diabetes plays an important role in the induction of the liver injury. Grape seed proanthocyanidin (GSP) have a wide range of medicinal properties against oxidative stress. In this study we evaluated antioxidant effects of GSP on liver in streptozotocin-induced diabetic rats. Materials and Methods: Thirty male Sprague–Dawley rats were divided into three groups: control, untreated diabetic and diabetic rats treated with GSP. Diabetes was induced in rats by intraperitoneal injection of streptozotocin (50 mg/kg). GSP were administered via oral gavage (200 mg/kg) for 4 weeks. Results: GSP produced significant hepatoprotective effects by decreasing activities of serum aminotransferases and alkaline phosphatase, and decreasing liver malondialdehyde and bilirubin (P<0.05) levels. It increased liver superoxide dismutase, catalase and glutathione peroxidase activities and albumin level (P<0.05). Administration of GSP significantly ameliorated structural changes induced in liver of diabetic rats. Conclusion: GSP have protective effects against hepatic tissue injury due to antioxidant properties. PMID:25140209

  3. Hepatitis

    MedlinePlus

    ... be serious. Some can lead to scarring, called cirrhosis, or to liver cancer. Sometimes hepatitis goes away by itself. If it does not, it can be treated with drugs. Sometimes hepatitis lasts a lifetime. Vaccines can help prevent some viral forms.

  4. Development of PEGylated Cysteine-Modified Lysine Dendrimers with Multiple Reduced Thiols To Prevent Hepatic Ischemia/Reperfusion Injury.

    PubMed

    Katsumi, Hidemasa; Nishikawa, Makiya; Hirosaki, Rikiya; Okuda, Tatsuya; Kawakami, Shigeru; Yamashita, Fumiyoshi; Hashida, Mitsuru; Sakane, Toshiyasu; Yamamoto, Akira

    2016-08-01

    To inhibit hepatic ischemia/reperfusion injury, we developed polyethylene glycol (PEG) conjugated (PEGylated) cysteine-modified lysine dendrimers with multiple reduced thiols, which function as scavengers of reactive oxygen species (ROS). Second, third, and fourth generation (K2, K3, and K4) highly branched amino acid spherical lysine dendrimers were synthesized, and cysteine (C) was conjugated to the outer layer of these lysine dendrimers to obtain K2C, K3C, and K4C dendrimers. Subsequently, PEG was reacted with the C residues of the dendrimers to obtain PEGylated dendrimers with multiple reduced thiols (K2C-PEG, K3C-PEG, and K4C-PEG). Radiolabeled K4C-PEG ((111)In-K4C-PEG) exhibited prolonged retention in the plasma, whereas (111)In-K2C-PEG and (111)In-K3C-PEG rapidly disappeared from the plasma. K4C-PEG significantly prevented the elevation of plasma alanine aminotransferase (ALT) activity, an index of hepatocyte injury, in a mouse model of hepatic ischemia/reperfusion injury. In contrast, K2C-PEG, K3C-PEG, l-cysteine, and glutathione, the latter two of which are classical reduced thiols, hardly affected the plasma ALT activity. These findings indicate that K4C-PEG with prolonged circulation time is a promising compound to inhibit hepatic ischemia/reperfusion injury. PMID:27336683

  5. The effects of low-intensity laser therapy on hepatic ischemia-reperfusion injury in a rat model.

    PubMed

    Takhtfooladi, Mohammad Ashrafzadeh; Takhtfooladi, Hamed Ashrafzadeh; Khansari, Mohammadreza

    2014-11-01

    Ischemia-reperfusion (I/R) is a major mechanism of liver injury following hepatic surgery or transplantation. Despite numerous reports on the role and relics of low-intensity laser therapy (LILT) in many organs, the potential effects of LILT on hepatic ischemia-reperfusion have not been explored. This study was aimed to investigate the impresses of LILT applied to the skin following hepatic ischemia and reperfusion. Thirty-six healthy male Wistar rats were allocated into three groups of twelve animals each as follows: Sham, Ischemia-reperfusion (IR), and Ischemia-reperfusion with laser treatment (IR+LILT). Hepatic ischemia was induced by clamping the arterial and portal venous for 45 min. A laser diode (400 mW, 804 nm) was applied to the skin surface at the anatomical site of the liver at a dose of 3 J/cm(2), and the duration of irradiation was selected 120 s with 15-min interval after beginning the reperfusion. Animals were maintained under anesthesia and sacrificed 6 h subsequent reperfusion. Hepatic samples were evaluated for histological assessment and biochemistry analysis. Serum aminotransferase levels, tumor necrosis factor-alpha (TNF-α) levels, malondialdehyde (MDA), and glutathione (GSH) levels were significantly lower (P < 0.05) in the irradiated group compared to the I/R group during the 6 h after reperfusion. The number of histopathological changes in the hepatic tissues was significantly lower in the treated group (P < 0.05). These observations suggest that LILT applied in transcutaneous manner effectively improves hepatic injuries after ischemia-reperfusion period in rats. PMID:24906482

  6. Protection of rat liver against hepatic ischemia-reperfusion injury by a novel selenocysteine-containing 7-mer peptide

    PubMed Central

    Jiang, Qianqian; Pan, Yu; Cheng, Yupeng; Li, Huiling; Li, Hui

    2016-01-01

    Hepatic ischemia-reperfusion (I-R) injury causes acute organ damage or dysfunction, and remains a problem for liver transplantation. In the I-R phase, the generation of reactive oxygen species aggravates the injury. In the current study, a novel selenocysteine-containing 7-mer peptide (H-Arg-Sec-Gly-Arg-Asn-Ala-Gln-OH) was constructed to imitate the active site of an antioxidant enzyme, glutathione peroxidase (GPX). The 7-mer peptide which has a lower molecular weight, and improved water-solubility, higher stability and improved cell membrane permeability compared with other GPX mimics. Its GPX activity reached 13 U/µmol, which was 13 times that of ebselen (a representative GPX mimic). The effect of this GPX mimic on I-R injury of the liver was assessed in rats. The 7-mer peptide significantly inhibited the increase in serum hepatic amino-transferases, tissue malondialdehyde, nitric oxide contents, myeloperoxidase activity and decrease of GPX activity compared with I-R tissue. Following treatment with the 7-mer peptide, the expression of B-cell CLL/lymphoma-2 (Bcl-2) was significantly upregulated at the mRNA and protein level compared with the I-R group, as determined by reverse transcription-polymerase chain reaction and immunohistochemistry, respectively. By contrast, Bcl-2 associated X protein (Bax) was downregulated by the 7-mer peptide compared the I-R group. Histological and ultrastructural changes of the rat liver tissue were also compared among the experimental groups. The results of the current study suggest that the 7-mer peptide protected the liver against hepatic I-R injury via suppression of oxygen-derived free radicals and regulation of Bcl-2 and Bax expression, which are involved in the apoptosis of liver cells. The findings of the present study will further the investigation of the 7-mer peptide as an effective therapeutic agent in hepatic I-R injury. PMID:27431272

  7. Hepatic injury after nonmyeloablative conditioning followed by allogeneic hematopoietic cell transplantation: a study of 193 patients.

    PubMed

    Hogan, William J; Maris, Michael; Storer, Barry; Sandmaier, Brenda M; Maloney, David G; Schoch, H Gary; Woolfrey, Ann E; Shulman, Howard M; Storb, Rainer; McDonald, George B

    2004-01-01

    Liver injury is a frequent, serious complication of allogeneic hematopoietic cell transplantation (HCT) following myeloablative preparative regimens. We sought to determine the frequency and severity of hepatic injury after nonmyeloablative conditioning and its relationship to outcomes. One hundred ninety-three consecutive patients who received 2 Gy total body irradiation with or without fludarabine were evaluated for end points related to liver injury. Patients with diseases treatable by HCT who were ineligible for conventional myeloablative allogeneic HCT because of advanced age and/or comorbid conditions were included. Fifty-one patients (26%) developed hyperbilirubinemia of 68.4 microM (4 mg/dL) or greater, most commonly resulting from cholestasis due to graft-versus-host disease (GVHD) or sepsis. Pretransplantation factors associated with liver dysfunction were a diagnosis of aggressive malignancy (hazard ratio [HR] 1.9; P =.04) and the inclusion of fludarabine in the conditioning regimen (HR 1.8; P =.07). Overall survival at 1 year was superior for patients who had maximal serum bilirubin levels in the normal (78%) or minimally elevated (22.23-66.69 microM [1.3-3.9 mg/dL]) ranges (69%) compared with those in the 68.4 to 117.99 microM (4-6.9 mg/dL; 20%), 119.7 to 169.29 microM (7.0-9.9 mg/dL; 17%), and 171.0 microM (10 mg/dL; 19%) or greater groups. In summary, significant jaundice occurred in 26% of patients and was predominantly due to cholestasis resulting from GVHD and/or sepsis. Aggressive malignancies (mainly advanced disease) and later development of jaundice after transplantation predicted inferior survival. PMID:12969980

  8. Anti-4-1BB monoclonal antibodies attenuate concanavalin A-induced immune-mediated liver injury in mice

    PubMed Central

    Xia, Guangtao; Wu, Sensen; Zhang, Yuanchao

    2016-01-01

    Effective therapies for the treatment of immune-mediated liver disease are currently lacking. As a member of the tumor necrosis factor receptor superfamily, 4-1BB has a key role in T-cell activation and has been implicated in the development of autoimmune disorders. The purpose of the present study was to evaluate the potential therapeutic or preventive function of an anti-4-1BB monoclonal antibody (mAb) in a mouse model of concanavalin (Con) A-induced immune-mediated liver injury. A mouse model of immune-mediated liver injury was established by tail vein injection of Con A (20 mg/kg). 4-1BB mAb (100 µg), with or without methylprednisolone (MEP; 3 mg/kg), was intraperitoneally injected into the tail vein 2 h prior to or 2 h following Con A injection. Con A induced marked hepatocyte necrosis, significantly reduced CD 4+/CD25+ T-cell levels, and increased the serum levels of aspartate transaminase (AST) and alanine transaminase (ALT), in addition to the percentage of 4-1BB+ T-cells, compared with the control (all P<0.05). The administration of 4-1BB mAb prior to or following Con A injection was able to attenuate Con A-induced liver tissue damage and significantly reduce serum AST and ALT levels (P<0.05). A combination of MEP and 4-1BB mAb further reduced serum AST and ALT levels, compared with either treatment alone. In addition, administration of 4-1BB mAb and MEP alone or in combination significantly increased CD4+/CD25+ T-cell levels, compared with the control (P<0.05). These results suggested that 4-1BB mAb was able to attenuate liver injury and preserve liver function in a mouse model of Con A-induced immune-mediated liver injury by promoting the expansion of CD4+/CD25+ T-cells. Furthermore, a combination of 4-1BB mAb with MEP was associated with greater beneficial effects than either treatment alone. The clinical significance of 4-1BB mAb in immune-mediated liver disease remains to be elucidated in future studies. PMID:27588047

  9. The ameliorative effect of thymol against hydrocortisone-induced hepatic oxidative stress injury in adult male rats.

    PubMed

    Aboelwafa, Hanaa R; Yousef, Hany N

    2015-08-01

    The aim of the present study was to investigate whether hydrocortisone induces oxidative stress in hepatocytes and to evaluate the possible ameliorative effect of thymol against such hepatic injury. Twenty-four adult male rats were divided into control, thymol, hydrocortisone, and hydrocortisone+thymol groups. The 4 groups were treated daily for 15 days. Hydrocortisone significantly induced oxidative stress in the liver tissues, marked by increased serum levels of alanine transaminase (ALT), aspartate transaminase (AST), total oxidative capacity (TOC), and tumor necrosis factor-alpha (TNF-α) accompanied by marked decline of serum levels of total protein, albumin, and total antioxidant capacity (TAC). Also, marked elevation in the levels of the thiobarbituric acid reactive substances (TBARS) and TNF-α, beside significant decrease in the level of glutathione (GSH) in hepatic tissues were recorded. These biochemical alterations were accompanied by histopathological changes marked by destruction of the normal hepatic architecture, in addition to ultrastructural alterations represented by degenerative features covering almost all the cytoplasmic organelles of the hepatocytes. Supplementation of hydrocortisone-treated rats with thymol reversed most of the biochemical, histological, and ultrastructural alterations. The results of our study confirm that thymol has strong ameliorative effect against hydrocortisone-induced oxidative stress injury in hepatic tissues. PMID:25821896

  10. 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

  11. Cellular Specific Role of Toll-Like Receptor 4 in Hepatic Ischemia-Reperfusion Injury

    PubMed Central

    Nace, Gary W; Huang, Hai; Klune, John R; Eid, Raymond E; Rosborough, Brian R; Korff, Sebastian; Li, Shen; Shapiro, Richard A; Stolz, Donna B; Sodhi, Chhinder P; Hackam, David J; Geller, David A; Billiar, Timothy R; Tsung, Allan

    2013-01-01

    Ischemia-reperfusion (I/R) injury is a process whereby an initial hypoxic insult and subsequent return of blood flow leads to the propagation of innate immune responses and organ injury. The necessity of the pattern recognition receptor, toll-like receptor (TLR)-4, for this innate immune response has been previously shown. However, TLR4 is present on various cell types of the liver, both immune and non-immune cells. Therefore, we sought to determine the role of TLR4 in individual cell populations, specifically parenchymal hepatocytes, myeloid cells including Kupffer cells, and dendritic cells following hepatic I/R. When hepatocyte specific (Alb-TLR4-/-) and myeloid cell specific (Lyz-TLR4-/-) TLR4 knockout mice were subjected to warm hepatic ischemia there was significant protection in these mice compared to wild-type (WT). However, the protection afforded in these two strains was significantly less than global TLR4 specific TLR4 knockout (TLR4-/-) mice. Dendritic cell specific TLR4-/- (CD11c-TLR4-/-) mice had significantly increased hepatocellular damage compared to WT mice. Circulating levels of high mobility group box-1 (HMGB1) were significantly reduced in the Alb-TLR4-/- mice compared to WT, Lyz-TLR4-/-, CD11c-TLR4-/- mice and equivalent to global TLR4-/- mice, suggesting that TLR4 mediated HMGB1 release from hepatocytes may be a source of HMGB1 after I/R. Hepatocytes exposed to hypoxia responded by rapidly phosphorylating the mitogen-activated protein kinases JNK and p38 in a TLR4-dependent manner; inhibition of JNK decreased the release of HMGB1 after both hypoxia in vitro and I/R in vivo. Conclusion These results provide insight into the individual cellular response of TLR4. It was found that the parenchymal hepatocyte is an active participant in the sterile inflammatory response after I/R through TLR4-mediated activation of pro-inflammatory signaling and release of danger signals such as HMGB1. PMID:23460269

  12. Association between exposures to brominated trihalomethanes, hepatic injury and type II diabetes mellitus.

    PubMed

    Makris, Konstantinos C; Andrianou, Xanthi D; Charisiadis, Pantelis; Burch, James B; Seth, Ratanesh K; Ioannou, Androniki; Picolos, Michael; Christophi, Costas A; Chatterjee, Saurabh

    2016-01-01

    hepatic injury (ALT) and inflammation (leptin) was recognized via the use of selected biomarkers of effect. Our evidence that THM could act as hepatic toxins with a further initiation of diabetogenic effects call for additional studies to help us better understand the disease process of the two co-morbidities (NAFLD and T2DM). PMID:27173514

  13. Tenascin-C: a novel mediator of hepatic ischemia and reperfusion injury.

    PubMed

    Kuriyama, Naohisa; Duarte, Sergio; Hamada, Takashi; Busuttil, Ronald W; Coito, Ana J

    2011-12-01

    Hepatic ischemia/reperfusion (IRI) injury remains a major challenge in clinical orthotopic liver transplantation (OLT). Tenascin-C (Tnc) is an extracellular matrix protein (ECM) involved in various aspects of immunity and tissue injury. Using a Tnc-deficient mouse model, we present data that suggest an active role for Tnc in liver IRI. We show that Tnc-deficient mice have a reduction in liver damage and a significant improvement in liver regeneration after IRI. The inability of Tnc(-/-) mice to express Tnc significantly reduced the levels of active caspase-3/transferase-mediated dUTP nick end-labeling (TUNEL) apoptotic markers and enhanced the expression of the proliferation cell nuclear antigen (PCNA) after liver IRI. The lack of Tnc expression resulted in impaired leukocyte recruitment and decreased expressions of interleukin (IL)-1β, IL-6, and CXCL2 after liver reperfusion. Tnc-deficient livers were characterized by altered expression patterns of vascular adhesion molecules, such as vascular cell adhesion molecule-1 and platelet endothelial cell adhesion molecule-1 post-IRI. Moreover, matrix metalloproteinase-9 (MMP-9) synthesis, which facilitates leukocyte transmigration across vascular barriers in liver IRI, was markedly down-regulated in the absence of Tnc. We also show that Tnc is capable of inducing MMP-9 expression in isolated neutrophils through Toll-like receptor 4. Therefore, our data suggest that Tnc is a relevant mediator of the pathogenic events underlying liver IRI. The data also support the view that studies aimed at further understanding how newly synthesized ECM molecules, such as Tnc, participate in inflammatory responses are needed to improve therapeutic approaches in liver IRI. PMID:21898491

  14. Dialysis-requiring acute kidney injury among hospitalized adults with documented hepatitis C Virus infection: a nationwide inpatient sample analysis.

    PubMed

    Nadkarni, G N; Patel, A; Simoes, P K; Yacoub, R; Annapureddy, N; Kamat, S; Konstantinidis, I; Perumalswami, P; Branch, A; Coca, S G; Wyatt, C M

    2016-01-01

    Chronic hepatitis C virus (HCV) infection may cause kidney injury, particularly in the setting of cryoglobulinemia or cirrhosis; however, few studies have evaluated the epidemiology of acute kidney injury in patients with HCV. We aimed to describe national temporal trends of incidence and impact of severe acute kidney injury (AKI) requiring renal replacement 'dialysis-requiring AKI' in hospitalized adults with HCV. We extracted our study cohort from the Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project using data from 2004 to 2012. We defined HCV and dialysis-requiring acute kidney injury based on previously validated ICD-9-CM codes. We analysed temporal changes in the proportion of hospitalizations complicated by dialysis-requiring AKI and utilized survey multivariable logistic regression models to estimate its impact on in-hospital mortality. We identified a total of 4,603,718 adult hospitalizations with an associated diagnosis of HCV from 2004 to 2012, of which 51,434 (1.12%) were complicated by dialysis-requiring acute kidney injury. The proportion of hospitalizations complicated by dialysis-requiring acute kidney injury increased significantly from 0.86% in 2004 to 1.28% in 2012. In-hospital mortality was significantly higher in hospitalizations complicated by dialysis-requiring acute kidney injury vs those without (27.38% vs 2.95%; adjusted odds ratio: 2.09; 95% confidence interval: 1.74-2.51). The proportion of HCV hospitalizations complicated by dialysis-requiring acute kidney injury increased significantly between 2004 and 2012. Similar to observations in the general population, dialysis-requiring acute kidney injury was associated with a twofold increase in odds of in-hospital mortality in adults with HCV. These results highlight the burden of acute kidney injury in hospitalized adults with HCV infection. PMID:26189719

  15. High Intrinsic Aerobic Capacity Protects against Ethanol-Induced Hepatic Injury and Metabolic Dysfunction: Study Using High Capacity Runner Rat Model.

    PubMed

    Szary, Nicholas; Rector, R Scott; Uptergrove, Grace M; Ridenhour, Suzanne E; Shukla, Shivendra D; Thyfault, John P; Koch, Lauren G; Britton, Steven L; Ibdah, Jamal A

    2015-01-01

    Rats artificially selected over several generations for high intrinsic endurance/aerobic capacity resulting in high capacity runners (HCR) has been developed to study the links between high aerobic fitness and protection from metabolic diseases (Wisloff et al., Science, 2005). We have previously shown that the HCR strain have elevated hepatic mitochondrial content and oxidative capacity. In this study, we tested if the elevated hepatic mitochondrial content in the HCR rat would provide "metabolic protection" from chronic ethanol-induced hepatic steatosis and injury. The Leiber-Decarli liquid diet with ethanol (7% v/v; HCR-E) and without (HCR-C) was given to HCR rats (n = 8 per group) from 14 to 20 weeks of age that were weight matched and pair-fed to assure isocaloric intake. Hepatic triglyceride (TG) content and macro- and microvesicular steatosis were significantly greater in HCR-E compared with HCR-C (p < 0.05). In addition, hepatic superoxide dismutase activity and glutathione levels were significantly (p < 0.05) reduced in the HCR-E rats. This hepatic phenotype also was associated with reduced total hepatic fatty acid oxidation (p = 0.03) and β-hydroxyacyl-CoA dehydrogenase activity (p = 0.01), and reductions in microsomal triglyceride transfer protein and apoB-100 protein content (p = 0.01) in HCR-E animals. However, despite these documented hepatic alterations, ethanol ingestion failed to induce significant hepatic liver injury, including no changes in hepatic inflammation, or serum alanine amino transferase (ALTs), free fatty acids (FFAs), triglycerides (TGs), insulin, or glucose. High intrinsic aerobic fitness did not reduce ethanol-induced hepatic steatosis, but protected against ethanol-induced hepatic injury and systemic metabolic dysfunction in a high aerobic capacity rat model. PMID:26610588

  16. High Intrinsic Aerobic Capacity Protects against Ethanol-Induced Hepatic Injury and Metabolic Dysfunction: Study Using High Capacity Runner Rat Model

    PubMed Central

    Szary, Nicholas; Rector, R. Scott; Uptergrove, Grace M.; Ridenhour, Suzanne E.; Shukla, Shivendra D.; Thyfault, John P.; Koch, Lauren G.; Britton, Steven L.; Ibdah, Jamal A.

    2015-01-01

    Rats artificially selected over several generations for high intrinsic endurance/aerobic capacity resulting in high capacity runners (HCR) has been developed to study the links between high aerobic fitness and protection from metabolic diseases (Wisloff et al., Science, 2005). We have previously shown that the HCR strain have elevated hepatic mitochondrial content and oxidative capacity. In this study, we tested if the elevated hepatic mitochondrial content in the HCR rat would provide “metabolic protection” from chronic ethanol-induced hepatic steatosis and injury. The Leiber-Decarli liquid diet with ethanol (7% v/v; HCR-E) and without (HCR-C) was given to HCR rats (n = 8 per group) from 14 to 20 weeks of age that were weight matched and pair-fed to assure isocaloric intake. Hepatic triglyceride (TG) content and macro- and microvesicular steatosis were significantly greater in HCR-E compared with HCR-C (p < 0.05). In addition, hepatic superoxide dismutase activity and glutathione levels were significantly (p < 0.05) reduced in the HCR-E rats. This hepatic phenotype also was associated with reduced total hepatic fatty acid oxidation (p = 0.03) and β-hydroxyacyl-CoA dehydrogenase activity (p = 0.01), and reductions in microsomal triglyceride transfer protein and apoB-100 protein content (p = 0.01) in HCR-E animals. However, despite these documented hepatic alterations, ethanol ingestion failed to induce significant hepatic liver injury, including no changes in hepatic inflammation, or serum alanine amino transferase (ALTs), free fatty acids (FFAs), triglycerides (TGs), insulin, or glucose. High intrinsic aerobic fitness did not reduce ethanol-induced hepatic steatosis, but protected against ethanol-induced hepatic injury and systemic metabolic dysfunction in a high aerobic capacity rat model. PMID:26610588

  17. 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.

  18. Liquiritigenin Protects Rats from Carbon Tetrachloride Induced Hepatic Injury through PGC-1α Pathway

    PubMed Central

    Zhang, Yiping; He, Yuanqiao; Yu, Hongbo; Ma, Fuying; Wu, Jianguo; Zhang, Xiaoyu

    2015-01-01

    The lack of effective treatment for liver cirrhosis and hepatocellular carcinomas imposes serious challenges to the healthcare system. Here, we investigated the efficacy and mechanism of liquiritigenin involved in preventing or retarding the progression of liver diseases in a rat model with chronic carbon tetrachloride (CCl4) exposure. Sprague Dawley rats were given CCl4 and lliquiritigenin alone or simultaneously for 8 weeks before liver was harvested to check histological changes by Hematoxylin and Eosin (H&E) staining, apoptosis by TUNEL assay, ROS by dihydroethidium staining, antioxidant enzyme activities and malondialdehyde using specific kits, and gene expression by quantitative real-time PCR and western blot. Chronic CCl4 exposure caused profound changes in liver histology with extensive hepatocyte death (necrosis and apoptosis), fat accumulation, and infiltration of inflammatory cells, accompanied by depressed activities of antioxidant enzymes, increased oxidative stress, elevated expression of inflammation and fibrotic genes, and downregulation of PGC-1α, ND1, and Bcl-x in rat liver. All these changes were abolished or alleviated by lliquiritigenin. The results demonstrated that liquiritigenin is effective in protecting liver from injury or treating chronic liver diseases. The modulation of PGC-1α and its downstream genes might play a critical role in relieving CCl4-induced hepatic pathogenesis by liquiritigenin. PMID:26199636

  19. Platycodin D attenuates bile duct ligation-induced hepatic injury and fibrosis in mice.

    PubMed

    Kim, Tae-Won; Lee, Hong-Ki; Song, In-Bae; Lim, Jong-Hwan; Cho, Eun-Sang; Son, Hwa-Young; Jung, Ju-Young; Yun, Hyo-In

    2013-01-01

    Platycodin D (PD) is the major triterpene saponin in the root of Platycodon grandiflorum. The aim of the present study was to evaluate the protective effects of PD on bile duct ligation (BDL)-induced cholestasis in mice. Mice were allocated to five groups: sham, BDL alone, and BDL with PD treatment at 1, 2, and 4mg/kg. PD was administered to the mice for 28 consecutive days after the BDL operation. PD treatment of BDL-operated mice decreased serum alanine aminotransferase, serum aspartate aminotransferase, and total bilirubin levels by up to 37%, 31%, and 41%, respectively, in comparison with the levels in mice that underwent BDL alone. PD treatment attenuated oxidative stress, as evidenced by an increase in anti-oxidative enzyme levels glutathione and superoxide dismutase together with a decrease in lipid peroxidation and oxidative stress indices levels of malondialdehyde and nitric oxide. Histopathological studies further confirmed the protective effects of PD on cholestasis-induced hepatic injury and liver fibrosis in mice. In addition, nuclear factor-kappa B and inducible nitric oxide synthase levels significantly decreased after PD treatment, as did the levels of hepatocyte apoptosis. Taken together, these results suggest that PD treatment might be beneficial in cholestasis-induced hepatotoxicity. PMID:23116642

  20. Agaricoglycerides Protect against Hepatic Ischemia/Reperfusion Injury by Attenuating Inflammatory Response, Oxidative Stress, and Expression of NF-κB

    PubMed Central

    Zhao, Xiang-qian; Liang, Bin; Liu, Yang; Huang, Xiao-qiang

    2015-01-01

    We have investigated the effects of agaricoglycerides (AG) in a mouse model of hepatic I/R injury. I/R triggered increases/changes in markers of liver injury, hepatic oxidative stress, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and nuclear factor κB (NF-κB). AG significantly reduced the extent of liver inflammation and oxidative stress and also attenuated the NF-κB activation as well as TNF-α and IL-1β production. Our results indicate that AG may represent a novel protective strategy against I/R-induced injury and inflammatory diseases. PMID:25960746

  1. Mesothelial cells give rise to hepatic stellate cells and myofibroblasts via mesothelial-mesenchymal transition in liver injury.

    PubMed

    Li, Yuchang; Wang, Jiaohong; Asahina, Kinji

    2013-02-01

    In many organs, myofibroblasts play a major role in the scarring process in response to injury. In liver fibrogenesis, hepatic stellate cells (HSCs) are thought to transdifferentiate into myofibroblasts, but the origins of both HSCs and myofibroblasts remain elusive. In the developing liver, lung, and intestine, mesothelial cells (MCs) differentiate into specific mesenchymal cell types; however, the contribution of this differentiation to organ injury is unknown. In the present study, using mouse models, conditional cell lineage analysis has demonstrated that MCs expressing Wilms tumor 1 give rise to HSCs and myofibroblasts during liver fibrogenesis. Primary MCs, isolated from adult mouse liver using antibodies against glycoprotein M6a, undergo myofibroblastic transdifferentiation. Antagonism of TGF-β signaling suppresses transition of MCs to mesenchymal cells both in vitro and in vivo. These results indicate that MCs undergo mesothelial-mesenchymal transition and participate in liver injury via differentiation to HSCs and myofibroblasts. PMID:23345421

  2. Dietary fat sources differentially modulate intestinal barrier and hepatic inflammation in alcohol-induced liver injury in rats

    PubMed Central

    Zhong, Wei; Li, Qiong; Xie, Guoxiang; Sun, Xiuhua; Tan, Xiaobing; Sun, Xinguo; Jia, Wei

    2013-01-01

    Endotoxemia is a causal factor in the development of alcoholic liver injury. The present study aimed at determining the interactions of ethanol with different fat sources at the gut-liver axis. Male Sprague-Dawley rats were pair fed control or ethanol liquid diet for 8 wk. The liquid diets were based on a modified Lieber-DeCarli formula, with 30% total calories derived from corn oil (rich in polyunsaturated fatty acids). To test the effects of saturated fats, corn oil in the ethanol diet was replaced by either cocoa butter (CB, rich in long-chain saturated fatty acids) or medium-chain triglycerides (MCT, exclusively medium-chain saturated fatty acids). Ethanol feeding increased hepatic lipid accumulation and inflammatory cell infiltration and perturbed hepatic and serum metabolite profiles. Ethanol feeding with CB or MCT alleviated ethanol-induced liver injury and attenuated ethanol-induced metabolic perturbation. Both CB and MCT also normalized ethanol-induced hepatic macrophage activation, cytokine expression, and neutrophil infiltration. Ethanol feeding elevated serum endotoxin level, which was normalized by MCT but not CB. In accordance, ethanol-induced downregulations of intestinal occludin and zonula occludens-1 were normalized by MCT but not CB. However, CB normalized ethanol-increased hepatic endotoxin level in association with upregulation of an endotoxin detoxifying enzyme, argininosuccinate synthase 1 (ASS1). Knockdown ASS1 in H4IIEC3 cells resulted in impaired endotoxin clearance and upregulated cytokine expression. These data demonstrate that the protection of saturated fats against alcohol-induced liver injury occur via different actions at the gut-liver axis and are chain length dependent. PMID:24113767

  3. Hepatic Deficiency of Augmenter of Liver Regeneration Exacerbates Alcohol-Induced Liver Injury and Promotes Fibrosis in Mice.

    PubMed

    Kumar, Sudhir; Wang, Jiang; Rani, Richa; Gandhi, Chandrashekhar R

    2016-01-01

    Why only a subpopulation (about 15%) of humans develops liver cirrhosis due to alcohol is a critical as yet unanswered question. Liver-specific depletion of augmenter of liver regeneration (ALR) protein in mice causes robust steatosis and hepatocyte apoptosis by 2 weeks; these pathologies regress subsequently with return of ALR expression even at lower than control levels, but the mice develop modest steatohepatitis by 8 weeks. We aimed to investigate whether chronic alcohol ingestion promotes excessive hepatic fibrosis in these ALR-deficient mice. Liver-specific ALR-deficient and wild type (WT) female mice (8-10 weeks old) were placed on 4% alcohol-supplemented or isocaloric diet for 4 weeks. Liver sections were examined for histopathology, and parameters of steatosis and fibrosis were quantified. The mRNA expression of alcohol dehydrogenase-1, acetaldehyde dehydrogenase-1 and cytochrome P450-2E1 increased in WT mice but decreased in ALR-deficient mice upon alcohol ingestion. While alcohol induced steatosis and mild inflammation in WT mice, ALR-deficient mice showed minimal steatosis, strong hepatocellular injury and inflammation, prominent ductular proliferation, and robust fibrosis. Compared to the WT mice, alcohol feeding of ALR-deficient mice resulted in significantly greater increase in hepatic TNFα and TGFβ, and oxidative stress; there was also hepatic iron accumulation, robust lipid peroxidation and mitochondrial DNA damage. Importantly, similar to ALR-deficient mice, lower hepatic ALR levels in human alcoholic liver cirrhosis were associated with increased iron content, reduced expression of alcohol dehydrogenase and acetaldehyde dehydrogenase, and elevated fibrogenic markers. We conclude that ALR deficiency or anomaly can play a critical role in alcohol-induced hepatic fibrosis/cirrhosis, mechanisms of which may involve dysregulation of alcohol metabolism and iron homeostasis, mitochondrial damage and oxidative injury. PMID:26808690

  4. Hepatic Deficiency of Augmenter of Liver Regeneration Exacerbates Alcohol-Induced Liver Injury and Promotes Fibrosis in Mice

    PubMed Central

    Kumar, Sudhir; Wang, Jiang; Rani, Richa; Gandhi, Chandrashekhar R.

    2016-01-01

    Why only a subpopulation (about 15%) of humans develops liver cirrhosis due to alcohol is a critical as yet unanswered question. Liver-specific depletion of augmenter of liver regeneration (ALR) protein in mice causes robust steatosis and hepatocyte apoptosis by 2 weeks; these pathologies regress subsequently with return of ALR expression even at lower than control levels, but the mice develop modest steatohepatitis by 8 weeks. We aimed to investigate whether chronic alcohol ingestion promotes excessive hepatic fibrosis in these ALR-deficient mice. Liver-specific ALR-deficient and wild type (WT) female mice (8–10 weeks old) were placed on 4% alcohol-supplemented or isocaloric diet for 4 weeks. Liver sections were examined for histopathology, and parameters of steatosis and fibrosis were quantified. The mRNA expression of alcohol dehydrogenase-1, acetaldehyde dehydrogenase-1 and cytochrome P450-2E1 increased in WT mice but decreased in ALR-deficient mice upon alcohol ingestion. While alcohol induced steatosis and mild inflammation in WT mice, ALR-deficient mice showed minimal steatosis, strong hepatocellular injury and inflammation, prominent ductular proliferation, and robust fibrosis. Compared to the WT mice, alcohol feeding of ALR-deficient mice resulted in significantly greater increase in hepatic TNFα and TGFβ, and oxidative stress; there was also hepatic iron accumulation, robust lipid peroxidation and mitochondrial DNA damage. Importantly, similar to ALR-deficient mice, lower hepatic ALR levels in human alcoholic liver cirrhosis were associated with increased iron content, reduced expression of alcohol dehydrogenase and acetaldehyde dehydrogenase, and elevated fibrogenic markers. We conclude that ALR deficiency or anomaly can play a critical role in alcohol-induced hepatic fibrosis/cirrhosis, mechanisms of which may involve dysregulation of alcohol metabolism and iron homeostasis, mitochondrial damage and oxidative injury. PMID:26808690

  5. Hepatoprotective and anti-hepatitis C viral activity of Platycodon grandiflorum extract on carbon tetrachloride-induced acute hepatic injury in mice.

    PubMed

    Kim, Tae-Won; Lim, Jong-Hwan; Song, In-Bae; Park, Sang-Jin; Yang, Jae-Won; Shin, Jung Cheul; Suh, Joo-Won; Son, Hwa-Young; Cho, Eun-Sang; Kim, Myoung-Seok; Lee, Sang-Wook; Kim, Jong-Woo; Yun, Hyo-In

    2012-01-01

    The present study aims to evaluate the anti-HCV activity of hotwater extract from Platycodon grandiflorum (BC703) with HCV genotype 1b subgenomic replicon system and investigate its hepatoprotective activity on carbon tetrachloride (CCl(4))-induced acute liver damage in mice. BC703 produced significant hepatoprotective effects against CCl(4)-induced acute hepatic injury by decreasing the activities of serum enzymes, nitric oxide and lipid peroxidation. Histopathological studies further substantiated the protective effect of BC703. Furthermore, BC703 inhibited the HCV RNA replication with an EC(50) value and selective index (CC(50)/EC(50)) of 2.82 µg/mL and above 35.46, respectively. However, digested BC703 using a simulated gastric juice showed poor protective effect against CCl(4)-induced hepatotoxicity in mice and decreased anti-HCV activity as compared to the intact BC703. Although further studies are necessary, BC703 may be a beneficial agent for the management of acute hepatic injury and chronic HCV infection. PMID:22878389

  6. Hepatic injury induces contrasting response in liver and kidney to chemicals that are metabolically activated: Role of male sex hormone

    SciTech Connect

    Kim, Young C. Yim, Hye K.; Jung, Young S.; Park, Jae H.; Kim, Sung Y.

    2007-08-15

    Injury to liver, resulting in loss of its normal physiological/biochemical functions, may adversely affect a secondary organ. We examined the response of the liver and kidney to chemical substances that require metabolic activation for their toxicities in mice with a preceding liver injury. Carbon tetrachloride treatment 24 h prior to a challenging dose of carbon tetrachloride or acetaminophen decreased the resulting hepatotoxicity both in male and female mice as determined by histopathological examination and increases in serum enzyme activities. In contrast, the renal toxicity of the challenging toxicants was elevated markedly in male, but not in female mice. Partial hepatectomy also induced similar changes in the hepatotoxicity and nephrotoxicity of a challenging toxicant, suggesting that the contrasting response of male liver and kidney was associated with the reduction of the hepatic metabolizing capacity. Carbon tetrachloride pretreatment or partial hepatectomy decreased the hepatic xenobiotic-metabolizing enzyme activities in both sexes but elevated the renal p-nitrophenol hydroxylase, p-nitroanisole O-demethylase and aminopyrine N-demethylase activities significantly only in male mice. Increases in Cyp2e1 and Cyp2b expression were also evident in male kidney. Castration of males or testosterone administration to females diminished the sex-related differences in the renal response to an acute liver injury. The results indicate that reduction of the hepatic metabolizing capacity induced by liver injury may render secondary target organs susceptible to chemical substances activated in these organs. This effect may be sex-specific. It is also suggested that an integrated approach should be taken for proper assessment of chemical hazards.

  7. Lactobacillus fermentum ZYL0401 Attenuates Lipopolysaccharide-Induced Hepatic TNF-α Expression and Liver Injury via an IL-10- and PGE2-EP4-Dependent Mechanism

    PubMed Central

    Lv, Longxian; Yang, Jianzhuan; Lu, Haifeng; Li, Lanjuan

    2015-01-01

    Lipopolysaccharide (LPS) has essential role in the pathogenesis of D-galactosamine-sensitized animal models and alcoholic liver diseases of humans, by stimulating release of pro-inflammatory mediators that cause hepatic damage and intestinal barrier impairment. Oral pretreatment of probiotics has been shown to attenuate LPS-induced hepatic injury, but it is unclear whether the effect is direct or due to improvement in the intestinal barrier. The present study tested the hypothesis that pretreatment with probiotics enables the liver to withstand directly LPS-induced hepatic injury and inflammation. In a mouse model of LPS-induced hepatic injury, the levels of hepatic tumor necrosis factor-alpha (TNF-α) and serum alanine aminotransferase (ALT) of mice with depleted intestinal commensal bacteria were not significantly different from that of the control models. Pre-feeding mice for 10 days with Lactobacillus fermentum ZYL0401 (LF41), significantly alleviated LPS-induced hepatic TNF-α expression and liver damage. After LF41 pretreatment, mice had dramatically more L.fermentum-specific DNA in the ileum, significantly higher levels of ileal cyclooxygenase (COX)-2 and interleukin 10 (IL-10) and hepatic prostaglandin E2 (PGE2). However, hepatic COX-1, COX-2, and IL-10 protein levels were not changed after the pretreatment. There were also higher hepatic IL-10 protein levels after LPS challenge in LF41-pretreaed mice than in the control mice. Attenuation of hepatic TNF-α was mediated via the PGE2/E prostanoid 4 (EP4) pathway, and serum ALT levels were attenuated in an IL-10-dependent manner. A COX-2 blockade abolished the increase in hepatic PGE2 and IL-10 associated with LF41. In LF41-pretreated mice, a blockade of IL-10 caused COX-2-dependent promotion of hepatic PGE2, without affecting hepatic COX-2levels. In LF41-pretreated mice, COX2 prevented enhancing TNF-α expression in both hepatic mononuclear cells and the ileum, and averted TNF-α-mediated increase in

  8. Hepatitis C virus cures after direct acting antiviral-related drug-induced liver injury: Case report.

    PubMed

    Hasin, Yaakov; Shteingart, Shimon; Dahari, Harel; Gafanovich, Inna; Floru, Sharon; Braun, Marius; Shlomai, Amir; Verstandig, Anthony; Dery, Ilana; Uprichard, Susan L; Cotler, Scott J; Lurie, Yoav

    2016-07-18

    The United States Food and Drug Administration recently warned that the direct acting antiviral (DAA) combination hepatitis C virus (HCV) treatment of Paritaprevir, Ombitasvir, Dasabuvir, Ritonavir, and Ribavirin (PODr + R) can cause severe liver injury in patients with advanced liver disease. Drug induced liver injury was observed in a small number of patients with decompensated cirrhosis treated with other DAAs, but has not been reported in patients with compensated cirrhosis. We report a case of a 74-year-old woman with chronic HCV and Child-Pugh class A cirrhosis (compensated cirrhosis) treated with PODr + R. The patient presented on day 14 of PODr + R therapy with jaundice and new-onset ascites. Her total bilirubin level increased to 23 mg/dL and international normalized ratio rose to 1.65, while aminotransferase levels remained relatively stable. Hepatitis C treatment was discontinued on day 24 and she gradually recovered. Follow-up testing showed that she achieved a sustained virologic response. In conclusion, hepatic decompensation developed within two weeks of starting treatment with PODr + R in a patient with Child-Pugh class A cirrhosis and was characterized by jaundice and ascites with stable aminotransferase levels. Careful monitoring is warranted in patients with HCV-related cirrhosis treated with PODr + R. PMID:27458506

  9. Hepatitis C virus cures after direct acting antiviral-related drug-induced liver injury: Case report

    PubMed Central

    Hasin, Yaakov; Shteingart, Shimon; Dahari, Harel; Gafanovich, Inna; Floru, Sharon; Braun, Marius; Shlomai, Amir; Verstandig, Anthony; Dery, Ilana; Uprichard, Susan L; Cotler, Scott J; Lurie, Yoav

    2016-01-01

    The United States Food and Drug Administration recently warned that the direct acting antiviral (DAA) combination hepatitis C virus (HCV) treatment of Paritaprevir, Ombitasvir, Dasabuvir, Ritonavir, and Ribavirin (PODr + R) can cause severe liver injury in patients with advanced liver disease. Drug induced liver injury was observed in a small number of patients with decompensated cirrhosis treated with other DAAs, but has not been reported in patients with compensated cirrhosis. We report a case of a 74-year-old woman with chronic HCV and Child-Pugh class A cirrhosis (compensated cirrhosis) treated with PODr + R. The patient presented on day 14 of PODr + R therapy with jaundice and new-onset ascites. Her total bilirubin level increased to 23 mg/dL and international normalized ratio rose to 1.65, while aminotransferase levels remained relatively stable. Hepatitis C treatment was discontinued on day 24 and she gradually recovered. Follow-up testing showed that she achieved a sustained virologic response. In conclusion, hepatic decompensation developed within two weeks of starting treatment with PODr + R in a patient with Child-Pugh class A cirrhosis and was characterized by jaundice and ascites with stable aminotransferase levels. Careful monitoring is warranted in patients with HCV-related cirrhosis treated with PODr + R. PMID:27458506

  10. Modulation of carbon tetrachloride-induced hepatic oxidative stress, injury and fibrosis by olmesartan and omega-3.

    PubMed

    Shaaban, Ahmed A; Shaker, Mohamed E; Zalata, Khaled R; El-kashef, Hassan A; Ibrahim, Tarek M

    2014-01-25

    This study was designed to investigate the potential effects of omega-3, olmesartan and their combination on established hepatic fibrosis in the carbon tetrachloride (CCl4) rat model. Male Wistar rats received subcutaneous injections of CCl4 twice weekly for 12weeks, as well as daily oral treatments of olmesartan (1 and 3mg/kg), omega-3 (75 and 150mg/kg) and their combination during the last 4weeks of intoxication. Our results indicated that omega-3 and, to a lesser extent, olmesartan dose-dependently blunted CCl4-induced necroinflammation scoring and elevation of liver injury parameters in serum. Besides, omega-3 and, to a lesser extent, olmesartan treatments in a dose dependent manner attenuated CCl4-induced liver fibrosis, as demonstrated by hepatic histopathology scoring and 4-hydroxyproline content. The mechanisms behind these beneficial effects of both omega-3 and olmesartan were also elucidated. These include (1) counteracting hepatic oxidative stress and augmenting hepatic antioxidants; (2) preventing the activation of hepatic stellate cells (HSCs), as denoted by reducing α-smooth muscle actin (α-SMA) expression in the liver; (3) inhibiting the proliferation and chemotaxis of HSCs, as evidenced by downregulating platelet-derived growth factor receptors-β (PDGFR-β) expression in the liver; and (4) inhibiting the fibrogenesis response of HSCs, as indicated by inhibiting the secretion of transforming growth factor-β1 (TGF-β1). Unexpectedly, when olmesartan was co-administered with omega-3, it interfered with the hepatoprotective and anti-fibrotic activities of omega-3. In conclusion, this study introduces the first evidence regarding the pronounced anti-fibrotic activity of omega-3 and suggests that it may be beneficial in the treatment of hepatic fibrosis in humans. PMID:24144775

  11. Protection of rat liver against hepatic ischemia-reperfusion injury by a novel selenocysteine-containing 7-mer peptide.

    PubMed

    Jiang, Qianqian; Pan, Yu; Cheng, Yupeng; Li, Huiling; Li, Hui

    2016-09-01

    Hepatic ischemia-reperfusion (I-R) injury causes acute organ damage or dysfunction, and remains a problem for liver transplantation. In the I-R phase, the generation of reactive oxygen species aggravates the injury. In the current study, a novel selenocysteine-containing 7‑mer peptide (H-Arg-Sec-Gly-Arg-Asn-Ala-Gln-OH) was constructed to imitate the active site of an antioxidant enzyme, glutathione peroxidase (GPX). The 7‑mer peptide which has a lower molecular weight, and improved water‑solubility, higher stability and improved cell membrane permeability compared with other GPX mimics. Its GPX activity reached 13 U/µmol, which was 13 times that of ebselen (a representative GPX mimic). The effect of this GPX mimic on I‑R injury of the liver was assessed in rats. The 7‑mer peptide significantly inhibited the increase in serum hepatic amino‑transferases, tissue malondialdehyde, nitric oxide contents, myeloperoxidase activity and decrease of GPX activity compared with I‑R tissue. Following treatment with the 7‑mer peptide, the expression of B‑cell CLL/lymphoma‑2 (Bcl‑2) was significantly upregulated at the mRNA and protein level compared with the I‑R group, as determined by reverse transcription‑polymerase chain reaction and immunohistochemistry, respectively. By contrast, Bcl‑2 associated X protein (Bax) was downregulated by the 7‑mer peptide compared the I‑R group. Histological and ultrastructural changes of the rat liver tissue were also compared among the experimental groups. The results of the current study suggest that the 7‑mer peptide protected the liver against hepatic I‑R injury via suppression of oxygen‑derived free radicals and regulation of Bcl‑2 and Bax expression, which are involved in the apoptosis of liver cells. The findings of the present study will further the investigation of the 7-mer peptide as an effective therapeutic agent in hepatic I-R injury. PMID:27431272

  12. Fish Oil Reduces Hepatic Injury by Maintaining Normal Intestinal Permeability and Microbiota in Chronic Ethanol-Fed Rats

    PubMed Central

    Chen, Jiun-Rong; Chen, Ya-Ling; Peng, Hsiang-Chi; Lu, Yu-An; Chuang, Hsiao-Li; Chang, Hsiao-Yun; Wang, Hsiao-Yun; Su, Yu-Ju; Yang, Suh-Ching

    2016-01-01

    The aim of this study was to investigate the ameliorative effects of fish oil on hepatic injury in ethanol-fed rats based on the intestinal permeability and microbiota. Rats were assigned to 6 groups and fed either a control diet or an ethanol diet such as C (control), CF25 (control with 25% fish oil), CF57 (control with 57% fish oil), E (ethanol), EF25 (ethanol with 25% fish oil), and EF57 (ethanol with 57% fish oil) groups. Rats were sacrificed at the end of 8 weeks. Plasma aspartate aminotransferase (AST) and aminotransferase (ALT) activities, hepatic cytokines, and plasma endotoxin levels were significantly higher in the E group. In addition, hepatic histopathological analysis scores in the E group were significantly elevated. Rats in the E group also showed increased intestinal permeability and decreased numbers of fecal Bifidobacterium. However, plasma AST and ALT activities and hepatic cytokine levels were significantly lower in the EF25 and EF57 groups. Histological changes and intestinal permeability were also improved in the EF25 and EF57 groups. The fecal Escherichia coli numbers were significantly lower, but fecal Bifidobacterium numbers were significantly higher in the EF25 and EF57 groups. PMID:27143963

  13. Expression and function of fibroblast growth factor (FGF) 9 in hepatic stellate cells and its role in toxic liver injury

    SciTech Connect

    Antoine, Marianne; Wirz, Werner; Tag, Carmen G.; Gressner, Axel M.; Marvituna, Meltem; Wycislo, Mathias; Hellerbrand, Claus; Kiefer, Paul . E-mail: paul.kiefer@klinik.uni-regensburg.de

    2007-09-21

    Hepatic injury and regeneration of the liver are associated with activation of hepatic stellate cells (HSC). Fibroblast growth factors (FGFs) and their receptors are important regulators of repair in various tissues. HSC express FGFR3IIIc as well as FGFGR4 and different spliced FGFR1IIIc and FGFR2IIIc isoforms which differ in the presence or absence of the acid box and of the first Ig-like domain. Expression of FGF9, known to be capable to activate the HSC FGFR2/3-isoforms, was increased in HSC in liver slice cultures after exposition to carbon tetrachloride, as an acute liver injury model. FGF9 significantly stimulated 3-H thymidine incorporation of hepatocytes, but failed to induce DNA synthesis in HSC despite the fact that FGF9 induced a sustained activation of extracellular signal-related kinases (ERK) 1/2. FGF9 induced an increased phosphorylation of Tyr436 of the fibroblast growth factor receptor substrate (FRS) 2, while phosphorylation of Tyr196 which is required for efficient Grb2 recruitment remained unchanged. Our findings suggest that HSC FGF9 provide a paracrine mitogenic signal to hepatocytes during acute liver injury, while the autocrine FGF9 signaling appears to be not sufficient to induce cell proliferation.

  14. TGF-β-SMAD3 signaling mediates hepatic bile acid and phospholipid metabolism following lithocholic acid-induced liver injury.

    PubMed

    Matsubara, Tsutomu; Tanaka, Naoki; Sato, Misako; Kang, Dong Wook; Krausz, Kristopher W; Flanders, Kathleen C; Ikeda, Kazuo; Luecke, Hans; Wakefield, Lalage M; Gonzalez, Frank J

    2012-12-01

    Transforming growth factor-β (TGFβ) is activated as a result of liver injury, such as cholestasis. However, its influence on endogenous metabolism is not known. This study demonstrated that TGFβ regulates hepatic phospholipid and bile acid homeostasis through MAD homolog 3 (SMAD3) activation as revealed by lithocholic acid-induced experimental intrahepatic cholestasis. Lithocholic acid (LCA) induced expression of TGFB1 and the receptors TGFBR1 and TGFBR2 in the liver. In addition, immunohistochemistry revealed higher TGFβ expression around the portal vein after LCA exposure and diminished SMAD3 phosphorylation in hepatocytes from Smad3-null mice. Serum metabolomics indicated increased bile acids and decreased lysophosphatidylcholine (LPC) after LCA exposure. Interestingly, in Smad3-null mice, the metabolic alteration was attenuated. LCA-induced lysophosphatidylcholine acyltransferase 4 (LPCAT4) and organic solute transporter β (OSTβ) expression were markedly decreased in Smad3-null mice, whereas TGFβ induced LPCAT4 and OSTβ expression in primary mouse hepatocytes. In addition, introduction of SMAD3 enhanced the TGFβ-induced LPCAT4 and OSTβ expression in the human hepatocellular carcinoma cell line HepG2. In conclusion, considering that Smad3-null mice showed attenuated serum ALP activity, a diagnostic indicator of cholangiocyte injury, these results strongly support the view that TGFβ-SMAD3 signaling mediates an alteration in phospholipid and bile acid metabolism following hepatic inflammation with the biliary injury. PMID:23034213

  15. Exercise-Induced Release of Pharmacologically Active Substances and Their Relevance for Therapy of Hepatic Injury

    PubMed Central

    Schon, Hans-Theo; Weiskirchen, Ralf

    2016-01-01

    Chronic liver disease (CLD) features constant parenchymal injury and repair together with an increasing hepatic impairment, finally leading to fibrosis and cirrhosis and a heightened risk of hepatocellular carcinoma (HCC). Closely related to the rise in obesity, the worldwide prevalence of nonalcoholic fatty liver disease, the most common form of CLD, has reached an epidemic dimension and is estimated to afflict up to 46% of the general population, including more than one out of three U.S. citizens. Up to now there is no effective drug treatment available, which is why recommendations encompass both exercise programs and changes in dietary habits. Exercise is well-known for unleashing potent anti-inflammatory effects, which can principally counteract liver inflammation and chronic low-grade inflammation. This review article summarizes the underlying mechanisms responsible for the exercise-mediated anti-inflammatory effects, illustrates the application in animal models as well as in humans, and highlights the therapeutic value when possible. Based on the available results there is no doubt that exercise can even be beneficial in an advanced stage of liver disease and it is the goal of this review article to provide evidence for the therapeutic impact on fibrosis, cirrhosis, and HCC and to assess whether exercise might be of value as adjuvant therapy in the treatment of CLD. In principle, all exercise programs carried out in these high-risk patients should be guided and observed by qualified healthcare professionals to guarantee the patients’ safety. Nevertheless, it is also necessary to additionally determine the optimal amount and intensity of exercise to maximize its value, which is why further studies are essential. PMID:27625607

  16. Exercise-Induced Release of Pharmacologically Active Substances and Their Relevance for Therapy of Hepatic Injury.

    PubMed

    Schon, Hans-Theo; Weiskirchen, Ralf

    2016-01-01

    Chronic liver disease (CLD) features constant parenchymal injury and repair together with an increasing hepatic impairment, finally leading to fibrosis and cirrhosis and a heightened risk of hepatocellular carcinoma (HCC). Closely related to the rise in obesity, the worldwide prevalence of nonalcoholic fatty liver disease, the most common form of CLD, has reached an epidemic dimension and is estimated to afflict up to 46% of the general population, including more than one out of three U.S. citizens. Up to now there is no effective drug treatment available, which is why recommendations encompass both exercise programs and changes in dietary habits. Exercise is well-known for unleashing potent anti-inflammatory effects, which can principally counteract liver inflammation and chronic low-grade inflammation. This review article summarizes the underlying mechanisms responsible for the exercise-mediated anti-inflammatory effects, illustrates the application in animal models as well as in humans, and highlights the therapeutic value when possible. Based on the available results there is no doubt that exercise can even be beneficial in an advanced stage of liver disease and it is the goal of this review article to provide evidence for the therapeutic impact on fibrosis, cirrhosis, and HCC and to assess whether exercise might be of value as adjuvant therapy in the treatment of CLD. In principle, all exercise programs carried out in these high-risk patients should be guided and observed by qualified healthcare professionals to guarantee the patients' safety. Nevertheless, it is also necessary to additionally determine the optimal amount and intensity of exercise to maximize its value, which is why further studies are essential. PMID:27625607

  17. Prospective randomized study of the benefits of preoperative corticosteroid administration on hepatic ischemia-reperfusion injury and cytokine response in patients undergoing hepatic resection1

    PubMed Central

    Aldrighetti, Luca; Arru, Marcella; Finazzi, Renato; Soldini, Laura; Catena, Marco; Ferla, Gianfranco

    2007-01-01

    Background. Hepatic injury secondary to warm ischemia and reperfusion (I/R) remains an important clinical issue following liver surgery. The aim of this prospective, randomized study was to determine whether steroid administration may reduce liver injury and improve short-term outcome. Patients and methods. Forty-three patients undergoing liver resection were randomized to a steroid group or a control group. Patients in the steroid group received 500 mg of methylprednisolone preoperatively. Serum levels of alanine aminotransferase (ALT), aspartate amminotransferase (AST), total bilirubin, anti-thrombin III (AT-III), prothrombin time (PT), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α) were compared between the two groups. Length of stay and type and number of complications were recorded. Results. Postoperative serum levels of ALT, AST, total bilirubin, and inflammatory cytokines were significantly lower in the steroid group than in controls. The postoperative level of AT-III in the control group was significantly lower than in the steroid group (ANOVA p < 0.01). The incidence of postoperative complications in the control group tended to be significantly higher than that in the steroid group. Conclusion. These results suggest that steroid pretreatment represents a potentially important biologic modifier of I/R injury and may contribute to maintenance of coagulant/anticoagulant homeostasis. PMID:18333219

  18. Adenosine preconditioning attenuates hepatic reperfusion injury in the rat by preventing the down-regulation of endothelial nitric oxide synthase

    PubMed Central

    Serracino-Inglott, Ferdinand; Virlos, Ioannis T; Habib, Nagy A; Williamson, Robin CN; Mathie, Robert T

    2002-01-01

    Background Previous work has suggested that in the liver, adenosine preconditioning is mediated by nitric oxide. Whether the endothelial isoform of nitric oxide synthase plays a part in this mechanism has however not yet been investigated. Methods Wistar rats were used (6 in each group) – Groups: (1) sham, (2) ischemia-reperfusion, (3) adenosine + ischemia-reperfusion, (4) endothelial isoform inhibitor + adenosine + ischemia-reperfusion. Results Using immunohistochemistry, this study has revealed a decrease in the expression of endothelial nitric oxide synthase following hepatic ischemia-reperfusion. This was prevented by adenosine pre-treatment. When an inhibitor of endothelial nitric oxide synthase was administered prior to adenosine pre-treatment, pre-conditioning did not occur despite normal expression of endothelial nitric oxide synthase. Conclusions These findings suggest that adenosine attenuates hepatic injury by preventing the downregulation of endothelial nitric oxide synthase that occurs during ischemia-reperfusion. PMID:12241560

  19. Morphology and Molecular Mechanisms of Hepatic Injury in Rats under Simulated Weightlessness and the Protective Effects of Resistance Training.

    PubMed

    Du, Fang; Ding, Ye; Zou, Jun; Li, Zhili; Tian, Jijing; She, Ruiping; Wang, Desheng; Wang, Huijuan; Lv, Dongqiang; Chang, Lingling

    2015-01-01

    This study investigated the effects of long-term simulated weightlessness on liver morphology, enzymes, glycogen, and apoptosis related proteins by using two-month rat-tail suspension model (TS), and liver injury improvement by rat-tail suspension with resistance training model (TS&RT). Microscopically the livers of TS rats showed massive granular degeneration, chronic inflammation, and portal fibrosis. Mitochondrial and endoplasmic reticulum swelling and loss of membrane integrity were observed by transmission electron microscopy (TEM). The similar, but milder, morphological changes were observed in the livers of TS&RT rats. Serum biochemistry analysis revealed that the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were significantly higher (p<0.05) in TS rats than in controls. The levels of ALT and AST in TS&RT rats were slightly lower than in RT rats, but they were insignificantly higher than in controls. However, both TS and TS&RT rats had significantly lower levels (p<0.05) of serum glucose and hepatic glycogen than in controls. Immunohistochemistry demonstrated that the expressions of Bax, Bcl-2, and active caspase-3 were higher in TS rats than in TS&RT and control rats. Real-time polymerase chain reaction (real-time PCR) showed that TS rats had higher mRNA levels (P < 0.05) of glucose-regulated protein 78 (GRP78) and caspase-12 transcription than in control rats; whereas mRNA expressions of C/EBP homologous protein (CHOP) and c-Jun N-terminal kinase (JNK) were slightly higher in TS rats. TS&RT rats showed no significant differences of above 4 mRNAs compared with the control group. Our results demonstrated that long-term weightlessness caused hepatic injury, and may trigger hepatic apoptosis. Resistance training slightly improved hepatic damage. PMID:26000905

  20. Temporary Trans-jejunal Hepatic Duct Stenting in Roux-en-y Hepaticojejunostomy for Reconstruction of Iatrogenic Bile Duct Injuries

    PubMed Central

    Sadegh Fazeli, Mohammad; Kazemeini, Ali Reza; Jafarian, Ali; Bashashati, Mohammad; Keramati, Mohammad Reza

    2016-01-01

    Background Bile Duct Injuries (BDI) during cholecystectomy are now being recognized as major health problems. Objectives Herein, we present our experience with handling major BDIs and report long-term outcome of hepaticojejunostomies followed by trans-jejunal hepatic duct stenting performed to reconstruct extra-hepatic biliary tracts. Materials and Methods In this case series, we prospectively collected data of 22 patients, who underwent first time biliary reconstruction through Roux-en-y hepaticojejunostomy followed by hepatic duct stenting using a trans-jejunal bifurcated 6F tube drain. The long-term outcome was assessed and defined as excellent (asymptomatic, normal liver enzymes and bilirubin levels), good (asymptomatic, mild abnormality in liver enzyme and bilirubin levels), poor (symptomatic, abnormal liver enzymes and bilirubin level) and failure (requiring reoperation). Results A total of 22 patients including four males (18.1%) and 18 females (81.8%) were evaluated. The mean age was 42.71 (range: 23 - 74) years. Twelve patients had undergone open cholecystectomy (54.5%) and the rest had a history of laparoscopic cholecystectomy. The mean interval between the primary operation and reconstruction was 92.71 days. The mean follow-up period after biliary reconstruction was 42.33 (range: 1 - 96) months. No instance of anastomotic leakage or stenosis, biliary sepsis, thromboembolic event, or respiratory infection was noted in the long-term follow-up. The outcome was excellent in all patients. No case with poor or failure of result was noticed. Conclusions Although a devastating complication iatrogenic major bile duct injuries can be corrected surgically with a high rate of success. Temporary trans-jejunal stenting of the hepatic ducts can help in maintaining the integrity of anastomosis without stenosis or biliary sepsis. PMID:27626003

  1. Role of fibroblast growth factor type 1 and 2 in carbon tetrachloride-induced hepatic injury and fibrogenesis.

    PubMed

    Yu, Chundong; Wang, Fen; Jin, Chengliu; Huang, Xinqiang; Miller, David L; Basilico, Claudio; McKeehan, Wallace L

    2003-10-01

    Genomic ablation of hepatocyte-specific fibroblast growth factor receptor (FGFR)4 in mice revealed a role of FGF signaling in cholesterol and bile acid metabolism and hepatolobular restoration in response to injury without effect on liver development or hepatocyte proliferation. Although the potential role of all 23 FGF polypeptides in the liver is still unclear, the most widely studied prototypes, FGF1 and FGF2, are present and have been implicated in liver cell growth and function in vitro. To determine whether FGF1 and FGF2 play a role in response to injury and fibrosis, we examined the impact of both acute and chronic exposure to carbon tetrachloride (CCl(4)) in the livers of FGF1- and FGF2-deficient mice. After acute CCl(4) exposure, FGF1(-/-)FGF2(-/-) mice exhibited an accelerated release of serum alanine aminotransferase similar to FGFR4 deficiency, but no effect on overall hepatolobular restoration or bile acid metabolism. FGF1(-/-)FGF2(-/-) mice exhibited a normal increase in alpha-smooth muscle actin and desmin associated with activation and migration of hepatic stellate cells to damage, but a reduced level of hepatic stellate cell-derived matrix collagen alpha1(I) synthesis. Liver fibrosis resulting from chronic CCl(4) exposure was markedly decreased in the livers of FGF1/FGF2-deficient mice. These results suggest an agonist role for FGF1 and FGF2 in specifically insult-induced liver matrix deposition and hepatic fibrogenesis and a potential target for the prevention of hepatic fibrosis. PMID:14507672

  2. Morphology and Molecular Mechanisms of Hepatic Injury in Rats under Simulated Weightlessness and the Protective Effects of Resistance Training

    PubMed Central

    Zou, Jun; Li, Zhili; Tian, Jijing; She, Ruiping; Wang, Desheng; Wang, Huijuan; Lv, Dongqiang; Chang, Lingling

    2015-01-01

    This study investigated the effects of long-term simulated weightlessness on liver morphology, enzymes, glycogen, and apoptosis related proteins by using two-month rat-tail suspension model (TS), and liver injury improvement by rat-tail suspension with resistance training model (TS&RT). Microscopically the livers of TS rats showed massive granular degeneration, chronic inflammation, and portal fibrosis. Mitochondrial and endoplasmic reticulum swelling and loss of membrane integrity were observed by transmission electron microscopy (TEM). The similar, but milder, morphological changes were observed in the livers of TS&RT rats. Serum biochemistry analysis revealed that the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were significantly higher (p<0.05) in TS rats than in controls. The levels of ALT and AST in TS&RT rats were slightly lower than in RT rats, but they were insignificantly higher than in controls. However, both TS and TS&RT rats had significantly lower levels (p<0.05) of serum glucose and hepatic glycogen than in controls. Immunohistochemistry demonstrated that the expressions of Bax, Bcl-2, and active caspase-3 were higher in TS rats than in TS&RT and control rats. Real-time polymerase chain reaction (real-time PCR) showed that TS rats had higher mRNA levels (P < 0.05) of glucose-regulated protein 78 (GRP78) and caspase-12 transcription than in control rats; whereas mRNA expressions of C/EBP homologous protein (CHOP) and c-Jun N-terminal kinase (JNK) were slightly higher in TS rats. TS&RT rats showed no significant differences of above 4 mRNAs compared with the control group. Our results demonstrated that long-term weightlessness caused hepatic injury, and may trigger hepatic apoptosis. Resistance training slightly improved hepatic damage. PMID:26000905

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

    PubMed Central

    Weber, Susanne Nicole; Bohner, Annika; Dapito, Dianne H.; Schwabe, Robert F.; Lammert, Frank

    2016-01-01

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

  4. Heme Oxygenase-1 Protects Corexit 9500A-Induced Respiratory Epithelial Injury across Species

    PubMed Central

    Oliva, Octavio M.; Karki, Suman; Surolia, Ranu; Wang, Zheng; Watson, R. Douglas; Thannickal, Victor J.; Powell, Mickie; Watts, Stephen; Kulkarni, Tejaswini; Batra, Hitesh; Bolisetty, Subhashini; Agarwal, Anupam; Antony, Veena B.

    2015-01-01

    The effects of Corexit 9500A (CE) on respiratory epithelial surfaces of terrestrial mammals and marine animals are largely unknown. This study investigated the role of CE-induced heme oxygenase-1 (HO-1), a cytoprotective enzyme with anti-apoptotic and antioxidant activity, in human bronchial airway epithelium and the gills of exposed aquatic animals. We evaluated CE-mediated alterations in human airway epithelial cells, mice lungs and gills from zebrafish and blue crabs. Our results demonstrated that CE induced an increase in gill epithelial edema and human epithelial monolayer permeability, suggesting an acute injury caused by CE exposure. CE induced the expression of HO-1 as well as C-reactive protein (CRP) and NADPH oxidase 4 (NOX4), which are associated with ROS production. Importantly, CE induced caspase-3 activation and subsequent apoptosis of epithelial cells. The expression of the intercellular junctional proteins, such as tight junction proteins occludin, zonula occludens (ZO-1), ZO-2 and adherens junctional proteins E-cadherin and Focal Adhesion Kinase (FAK), were remarkably inhibited by CE, suggesting that these proteins are involved in CE-induced increased permeability and subsequent apoptosis. The cytoskeletal protein F-actin was also disrupted by CE. Treatment with carbon monoxide releasing molecule-2 (CORM-2) significantly inhibited CE-induced ROS production, while the addition of HO-1 inhibitor, significantly increased CE-induced ROS production and apoptosis, suggesting a protective role of HO-1 or its reaction product, CO, in CE-induced apoptosis. Using HO-1 knockout mice, we further demonstrated that HO-1 protected against CE-induced inflammation and cellular apoptosis and corrected CE-mediated inhibition of E-cadherin and FAK. These observations suggest that CE activates CRP and NOX4-mediated ROS production, alters permeability by inhibition of junctional proteins, and leads to caspase-3 dependent apoptosis of epithelial cells, while HO-1 and its

  5. Heme oxygenase-1 protects corexit 9500A-induced respiratory epithelial injury across species.

    PubMed

    Li, Fu Jun; Duggal, Ryan N; Oliva, Octavio M; Karki, Suman; Surolia, Ranu; Wang, Zheng; Watson, R Douglas; Thannickal, Victor J; Powell, Mickie; Watts, Stephen; Kulkarni, Tejaswini; Batra, Hitesh; Bolisetty, Subhashini; Agarwal, Anupam; Antony, Veena B

    2015-01-01

    The effects of Corexit 9500A (CE) on respiratory epithelial surfaces of terrestrial mammals and marine animals are largely unknown. This study investigated the role of CE-induced heme oxygenase-1 (HO-1), a cytoprotective enzyme with anti-apoptotic and antioxidant activity, in human bronchial airway epithelium and the gills of exposed aquatic animals. We evaluated CE-mediated alterations in human airway epithelial cells, mice lungs and gills from zebrafish and blue crabs. Our results demonstrated that CE induced an increase in gill epithelial edema and human epithelial monolayer permeability, suggesting an acute injury caused by CE exposure. CE induced the expression of HO-1 as well as C-reactive protein (CRP) and NADPH oxidase 4 (NOX4), which are associated with ROS production. Importantly, CE induced caspase-3 activation and subsequent apoptosis of epithelial cells. The expression of the intercellular junctional proteins, such as tight junction proteins occludin, zonula occludens (ZO-1), ZO-2 and adherens junctional proteins E-cadherin and Focal Adhesion Kinase (FAK), were remarkably inhibited by CE, suggesting that these proteins are involved in CE-induced increased permeability and subsequent apoptosis. The cytoskeletal protein F-actin was also disrupted by CE. Treatment with carbon monoxide releasing molecule-2 (CORM-2) significantly inhibited CE-induced ROS production, while the addition of HO-1 inhibitor, significantly increased CE-induced ROS production and apoptosis, suggesting a protective role of HO-1 or its reaction product, CO, in CE-induced apoptosis. Using HO-1 knockout mice, we further demonstrated that HO-1 protected against CE-induced inflammation and cellular apoptosis and corrected CE-mediated inhibition of E-cadherin and FAK. These observations suggest that CE activates CRP and NOX4-mediated ROS production, alters permeability by inhibition of junctional proteins, and leads to caspase-3 dependent apoptosis of epithelial cells, while HO-1 and its

  6. Interaction of Platelet Activating Factor, Reactive Oxygen Species Generated by Xanthine Oxidase, and Leukocytes in the Generation of Hepatic Injury After Shock/Resuscitation

    PubMed Central

    Yamakawa, Yasuhiko; Takano, Manabu; Patel, Mayur; Tien, Nevin; Takada, Tadahiro; Bulkley, Gregory B.

    2000-01-01

    Objective To evaluate the putative relation of platelet activating factor (PAF), xanthine oxidase, reactive oxidants, and leukocytes in the pathogenesis of hepatic injury after shock/resuscitation (S/R) in vivo. Background Reactive oxygen metabolites generated by xanthine oxidase at reperfusion have been found to trigger postischemic injury in many organs, including the liver. However, the precise linear sequence of the mechanism of consequent hepatic injury after S/R remains to be characterized. Methods Unheparinized male rats were bled to a mean blood pressure of 45 ± 3 mmHg. After 2 hours of shock, they were resuscitated by reinfusion of shed blood (anticoagulated with citrate-phosphate-dextrose) and crystalloid and observed for the next 6 or 24 hours. Results S/R caused the oxidation of hepatic glutathione and generated centrolobular leukocyte accumulation at 6 hours, followed by predominantly centrolobular hepatocellular injury at 24 hours. Each of these components was attenuated by PAF inhibition with WEB 2170, xanthine oxidase inhibition with allopurinol, antioxidant treatment with N-acetylcysteine, or severe leukopenia induced by vinblastine. In each case, the degree of leukocyte accumulation at 6 hours correlated with the hepatocellular injury seen at 24 hours. However, xanthine oxidase inhibition with allopurinol failed to attenuate further the small level of residual hepatocellular injury seen in leukopenic rats. Conclusion These findings suggest that reactive oxidants generated by xanthine oxidase at reperfusion, stimulated by PAF, mediate hepatocellular injury by triggering leukocyte accumulation, primarily within the centrolobular sinusoids. PMID:10714632

  7. Effect of Thiol-reducing Agents and Antioxidants on Sulfasalazine-induced Hepatic Injury in Normotermic Recirculating Isolated Perfused Rat Liver

    PubMed Central

    Heidari, Reza; Esmailie, Neda; Azarpira, Negar; Najibi, Asma; Niknahad, Hossein

    2016-01-01

    Sulfasalzine is a widely administered drug against inflammatory-based disorders in human. However several cases of liver injury are associated with its administration. There is no stabilized safe protective agent against sulfasalazine-induced liver injury. Current investigation was designed to evaluate if N-acetylcysteine (NAC) and dithioteritol (DTT) as thiol reducing agents and/or vitamins C and E as antioxidants have any protective effects against sulfasalazine-induced hepatic injury in an ex vivo model of isolated rat liver. Rat liver was canulated and perfused via portal vein in a closed recirculating system. Different concentrations of sulfasalazine and/or thiol reductants and antioxidants were administered and markers of organ injury were monitored at different time intervals. It was found that 5 mM of sulfasalazine caused marked liver injury as judged by rise in liver perfusate level of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) (p < 0.05). A significant amount of lipid peroxidation and hepatic glutathione depletion were detected in drug-treated livers, accompanied with significant histopathological changes of the organ. Administration of NAC (500 μM), DTT (400 μM), Vitamin C (200 μM), or vitamin E (200 μM) significantly alleviated sulfasalazine-induced hepatic injury in isolated perfused rat liver. The data obtained from current investigation indicate potential therapeutic properties of thiol reductants and antioxidants against sulfasalazine-induced liver injury. PMID:27123164

  8. Effect of Thiol-reducing Agents and Antioxidants on Sulfasalazine-induced Hepatic Injury in Normotermic Recirculating Isolated Perfused Rat Liver.

    PubMed

    Heidari, Reza; Esmailie, Neda; Azarpira, Negar; Najibi, Asma; Niknahad, Hossein

    2016-04-01

    Sulfasalzine is a widely administered drug against inflammatory-based disorders in human. However several cases of liver injury are associated with its administration. There is no stabilized safe protective agent against sulfasalazine-induced liver injury. Current investigation was designed to evaluate if N-acetylcysteine (NAC) and dithioteritol (DTT) as thiol reducing agents and/or vitamins C and E as antioxidants have any protective effects against sulfasalazine-induced hepatic injury in an ex vivo model of isolated rat liver. Rat liver was canulated and perfused via portal vein in a closed recirculating system. Different concentrations of sulfasalazine and/or thiol reductants and antioxidants were administered and markers of organ injury were monitored at different time intervals. It was found that 5 mM of sulfasalazine caused marked liver injury as judged by rise in liver perfusate level of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) (p < 0.05). A significant amount of lipid peroxidation and hepatic glutathione depletion were detected in drug-treated livers, accompanied with significant histopathological changes of the organ. Administration of NAC (500 μM), DTT (400 μM), Vitamin C (200 μM), or vitamin E (200 μM) significantly alleviated sulfasalazine-induced hepatic injury in isolated perfused rat liver. The data obtained from current investigation indicate potential therapeutic properties of thiol reductants and antioxidants against sulfasalazine-induced liver injury. PMID:27123164

  9. Multiphoton microscopy can visualize zonal damage and decreased cellular metabolic activity in hepatic ischemia-reperfusion injury in rats

    NASA Astrophysics Data System (ADS)

    Thorling, Camilla A.; Liu, Xin; Burczynski, Frank J.; Fletcher, Linda M.; Gobe, Glenda C.; Roberts, Michael S.

    2011-11-01

    Ischemia-reperfusion (I/R) injury is a common occurrence in liver surgery. In orthotopic transplantation, the donor liver is exposed to periods of ischemia and when oxygenated blood is reintroduced to the liver, oxidative stress may develop and lead to graft failure. The aim of this project was to investigate whether noninvasive multiphoton and fluorescence lifetime imaging microscopy, without external markers, were useful in detecting early liver damage caused by I/R injury. Localized hepatic ischemia was induced in rats for 1 h followed by 4 h reperfusion. Multiphoton and fluorescence lifetime imaging microscopy was conducted prior to ischemia and up to 4 h of reperfusion and compared to morphological and biochemical assessment of liver damage. Liver function was significantly impaired at 2 and 4 h of reperfusion. Multiphoton microscopy detected liver damage at 1 h of reperfusion, manifested by vacuolated cells and heterogeneous spread of damage over the liver. The damage was mainly localized in the midzonal region of the liver acinus. In addition, fluorescence lifetime imaging showed a decrease in cellular metabolic activity. Multiphoton and fluorescence lifetime imaging microscopy detected evidence of early I/R injury both structurally and functionally. This provides a simple noninvasive technique useful for following progressive liver injury without external markers.

  10. Overactivation of the nuclear factor (erythroid-derived 2)-like 2-antioxidant response element pathway in hepatocytes decreases hepatic ischemia/reperfusion injury in mice.

    PubMed

    Lee, Lung-Yi; Harberg, Calvin; Matkowskyj, Kristina A; Cook, Shelly; Roenneburg, Drew; Werner, Sabine; Johnson, Jeffrey; Foley, David P

    2016-01-01

    Hepatic ischemia/reperfusion injury (IRI) is a critical component of hepatic surgery. Oxidative stress has long been implicated as a key player in IRI. In this study, we examine the cell-specific role of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-antioxidant response element pathway in warm hepatic IRI. Nrf2 knockout (KO) and wild-type (WT) animals and novel transgenic mice expressing a constitutively active nuclear factor (erythroid-derived 2)-like 2 (caNrf2) mutant in hepatocytes (AlbCre+/caNrf2+) and their littermate controls underwent partial hepatic ischemia or sham surgery. The animals were killed 6 hours after reperfusion, and their serum and tissue were collected for analysis. As compared to WT animals after ischemia/reperfusion (IR), Nrf2 KO mice had increased hepatocellular injury with increased serum alanine aminotransferase and aspartate aminotransferase, Suzuki score, apoptosis, an increased inflammatory infiltrate, and enhanced inflammatory cytokine expression. On the other hand, AlbCre+/caNrf2+ that underwent IR had significantly reduced serum transaminases, less necrosis on histology, and a less pronounced inflammatory infiltrate and inflammatory cytokine expression as compared to the littermate controls. However, there were no differences in apoptosis. Taken together, Nrf2 plays a critical role in our murine model of warm hepatic IRI, with Nrf2 deficiency exacerbating hepatic IRI and hepatocyte-specific Nrf2 overactivation providing protection against warm hepatic IRI. PMID:26285140

  11. Hepatocellular protein profiles after hepatic ischemia/reperfusion injury with or without octreotide preconditioning in a rabbit model.

    PubMed

    Yang, J; Sun, H; Guan, R; Liu, W; Xia, Y; Zhao, J; Liu, J

    2014-12-01

    Hepatic ischemic/reperfusion injury (HIRI) is a major complication of liver resection and transplantation. Octreotide, a somatostatin analogue, has been used to treat hepatic fibrosis and portal hypertension; however, its function against HIRI remains unclear. To elucidate the effect of octreotide in HIRI, we investigated the hepatocellular protein profiles in response to octreotide preconditioning in a rabbit model by using proteomic analysis. Twenty-four rabbits were divided into 3 groups: the sham operative group (control), the ischemia/reperfusion group (IR), and the ischemia/reperfusion + octreotide group (IR+Oct). They were subjected to 30 minutes of normothermic ischemia followed by 120 minutes of reperfusion by using Pringle's maneuver method. Proteomic studies were then performed to compare the protein profiles of their left liver lobe. A total of 16 differential proteins were successfully identified. These findings suggest that octreotide might exert an effect against HIRI through up-regulating the expression of the anti-injury substances, such as heat-shock proteins 70 and 27 (confirmed by using Western blot analysis); significantly raising the phosphatidylethanolamine-binding protein that alleviates IR-related apoptosis; and down-regulating mitochondrial metabolic enzymes such as NADH2 dehydrogenase and triosephosphate isomerase. PMID:25498038

  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. Ablation of aldehyde reductase aggravates carbon tetrachloride-induced acute hepatic injury involving oxidative stress and endoplasmic reticulum stress.

    PubMed

    Akihara, Ryusuke; Homma, Takujiro; Lee, Jaeyong; Yamada, Ken-Ichi; Miyata, Satoshi; Fujii, Junichi

    2016-09-16

    Aldehyde reductase (Akr1a) has been reported to be involved in the biosynthesis of ascorbic acid (AsA) in the mouse liver. Because Akr1a is expressed at high levels in the liver, we aimed to investigate the role of Akr1a in liver homeostasis by employing a carbon tetrachloride (CCl4)-induced hepatotoxicity model. Akr1a-deficient (Akr1a(-/-)) and wild-type (WT) mice were injected intraperitoneally with CCl4 and the extent of hepatic injury in the acute phase was assessed. Liver damage was heavier in the Akr1a(-/-) mice than in the WT mice. Furthermore, severe hepatic steatosis was observed in the livers of Akr1a(-/-) mice compared to WT mice and was restored to the levels in WT mice by AsA supplementation. Since the presence or absence of AsA had no effect on the decrease in CYP2E1 activity after the CCl4 treatment, it appears that AsA plays a role in the process after the bioactivation of CCl4. Biomarkers for oxidative stress and ER stress were markedly increased in the livers of Akr1a(-/-) mice and were effectively suppressed by AsA supplementation. Based on these collective results, we conclude that Akr1a exerts a protective effect against CCl4-induced hepatic steatosis by replenishing AsA via its antioxidative properties. PMID:27501753

  14. The calcium-activated potassium channel KCa3.1 is an important modulator of hepatic injury.

    PubMed

    Sevelsted Møller, Linda; Fialla, Annette Dam; Schierwagen, Robert; Biagini, Matteo; Liedtke, Christian; Laleman, Wim; Klein, Sabine; Reul, Winfried; Koch Hansen, Lars; Rabjerg, Maj; Singh, Vikrant; Surra, Joaquin; Osada, Jesus; Reinehr, Roland; de Muckadell, Ove B Schaffalitzky; Köhler, Ralf; Trebicka, Jonel

    2016-01-01

    The calcium-activated potassium channel KCa3.1 controls different cellular processes such as proliferation and volume homeostasis. We investigated the role of KCa3.1 in experimental and human liver fibrosis. KCa3.1 gene expression was investigated in healthy and injured human and rodent liver. Effect of genetic depletion and pharmacological inhibition of KCa3.1 was evaluated in mice during carbon tetrachloride induced hepatic fibrogenesis. Transcription, protein expression and localisation of KCa3.1 was analysed by reverse transcription polymerase chain reaction, Western blot and immunohistochemistry. Hemodynamic effects of KCa3.1 inhibition were investigated in bile duct-ligated and carbon tetrachloride intoxicated rats. In vitro experiments were performed in rat hepatic stellate cells and hepatocytes. KCa3.1 expression was increased in rodent and human liver fibrosis and was predominantly observed in the hepatocytes. Inhibition of KCa3.1 aggravated liver fibrosis during carbon tetrachloride challenge but did not change hemodynamic parameters in portal hypertensive rats. In vitro, KCa3.1 inhibition leads to increased hepatocyte apoptosis and DNA damage, whereas proliferation of hepatic stellate cells was stimulated by KCa3.1 inhibition. Our data identifies KCa3.1 channels as important modulators in hepatocellular homeostasis. In contrast to previous studies in vitro and other tissues this channel appears to be anti-fibrotic and protective during liver injury. PMID:27354175

  15. The calcium-activated potassium channel KCa3.1 is an important modulator of hepatic injury

    PubMed Central

    Sevelsted Møller, Linda; Fialla, Annette Dam; Schierwagen, Robert; Biagini, Matteo; Liedtke, Christian; Laleman, Wim; Klein, Sabine; Reul, Winfried; Koch Hansen, Lars; Rabjerg, Maj; Singh, Vikrant; Surra, Joaquin; Osada, Jesus; Reinehr, Roland; de Muckadell, Ove B. Schaffalitzky; Köhler, Ralf; Trebicka, Jonel

    2016-01-01

    The calcium-activated potassium channel KCa3.1 controls different cellular processes such as proliferation and volume homeostasis. We investigated the role of KCa3.1 in experimental and human liver fibrosis. KCa3.1 gene expression was investigated in healthy and injured human and rodent liver. Effect of genetic depletion and pharmacological inhibition of KCa3.1 was evaluated in mice during carbon tetrachloride induced hepatic fibrogenesis. Transcription, protein expression and localisation of KCa3.1 was analysed by reverse transcription polymerase chain reaction, Western blot and immunohistochemistry. Hemodynamic effects of KCa3.1 inhibition were investigated in bile duct-ligated and carbon tetrachloride intoxicated rats. In vitro experiments were performed in rat hepatic stellate cells and hepatocytes. KCa3.1 expression was increased in rodent and human liver fibrosis and was predominantly observed in the hepatocytes. Inhibition of KCa3.1 aggravated liver fibrosis during carbon tetrachloride challenge but did not change hemodynamic parameters in portal hypertensive rats. In vitro, KCa3.1 inhibition leads to increased hepatocyte apoptosis and DNA damage, whereas proliferation of hepatic stellate cells was stimulated by KCa3.1 inhibition. Our data identifies KCa3.1 channels as important modulators in hepatocellular homeostasis. In contrast to previous studies in vitro and other tissues this channel appears to be anti-fibrotic and protective during liver injury. PMID:27354175

  16. Isocaloric manipulation of macronutrients within a high-carbohydrate/moderate-fat diet induces unique effects on hepatic lipogenesis, steatosis and liver injury.

    PubMed

    Pierce, Andrew A; Duwaerts, Caroline C; Soon, Russell K; Siao, Kevin; Grenert, James P; Fitch, Mark; Hellerstein, Marc K; Beysen, Carine; Turner, Scott M; Maher, Jacquelyn J

    2016-03-01

    Diets containing excess carbohydrate and fat promote hepatic steatosis and steatohepatitis in mice. Little is known, however, about the impact of specific carbohydrate/fat combinations on liver outcome. This study was designed to determine whether high-energy diets with identical caloric density but different carbohydrate and fat composition have unique effects on the liver. Four experimental diets were formulated with 60%kcal carbohydrate and 20%kcal fat, each in nearly pure form from a single source: starch-oleate, starch-palmitate, sucrose-oleate and sucrose-palmitate. The diets were fed to mice for 3 or 12 weeks for analysis of lipid metabolism and liver injury. All mice developed hepatic steatosis over 12 weeks, but mice fed the sucrose-palmitate diet accumulated more hepatic lipid than those in the other three experimental groups. The exaggerated lipid accumulation in sucrose-palmitate-fed mice was attributable to a disproportionate rise in hepatic de novo lipogenesis. These mice accrued more hepatic palmitate and exhibited more evidence of liver injury than any of the other experimental groups. Interestingly, lipogenic gene expression in mice fed the custom diets did not correlate with actual de novo lipogenesis. In addition, de novo lipogenesis rose in all mice between 3 and 12 weeks, without feedback inhibition from hepatic steatosis. The pairing of simple sugar (sucrose) and saturated fat (palmitate) in a high-carbohydrate/moderate-fat diet induces more de novo lipogenesis and liver injury than other carbohydrate/fat combinations. Diet-induced liver injury correlates positively with hepatic de novo lipogenesis and is not predictable by isolated analysis of lipogenic gene expression. PMID:26895660

  17. Paraoxonase-1 (PON1) inhibition by tienilic acid produces hepatic injury: Antioxidant protection by fennel extract and whey protein concentrate.

    PubMed

    Abdel-Wahhab, Khaled G; Fawzi, Heba; Mannaa, Fathia A

    2016-03-01

    This study evaluated the effect of whey protein concentrate (WPC) or fennel seed extract (FSE) on paraoxonase-1 activity (PON1) and oxidative stress in liver of tienilic acid (TA) treated rats. Six groups of rats were treated for six weeks as follows: control; WPC (0.5g/kg/day); FSE (200mg/ kg/day); TA (1g/kg/twice a week); TA (1g/kg/twice a week) plus WPC (0.5g/kg/day); TA (1g/kg/twice a week) plus FSE (200mg/kg/day). TA administration significantly increased ALT and AST besides to total- and direct bilirubin levels. Also, serum tumor necrosis factor-α and nitric oxide levels were significantly increased. Furthermore, serum PON1, and hepatic reduced glutathione, glutathione-S-transferase and Na(+)/K(+)-ATPase values were diminished matched with a significant rise in the level of hepatic lipid peroxidation. Also, triglycerides, total- and LDL-cholesterol levels were significantly elevated while HDL-cholesterol was unchanged. The administration of either WPC or FSE to TA-treated animals significantly protected the liver against the injurious effects of tienilic acid. This appeared from the improvement of hepatic functions, atherogenic markers, Na(+)/K(+) ATPase activity, endogenous antioxidants and hepatic lipid peroxidation level; where WPC showed the strongest protection effect. In conclusion, the present study indicated that WPC and FSE improve PON1 activity and attenuate liver dysfunction induced by TA. This may be attributed to the high content of antioxidant compounds in WPC and fennel extract. PMID:26884099

  18. Comparison of the effect of adenoviral delivery of three superoxide dismutase genes against hepatic ischemia-reperfusion injury.

    PubMed

    Wheeler, M D; Katuna, M; Smutney, O M; Froh, M; Dikalova, A; Mason, R P; Samulski, R J; Thurman, R G

    2001-12-10

    The purpose of this study was to investigate the effectiveness of superoxide dismutase (SOD) overexpression in an acute model of hepatic oxidative stress. Oxidative stress was established using a warm ischemia-reperfusion model, where nearly 70% of the liver was made hypoxic by clamping the hepatic artery and a branch of the portal vein for 1 hr followed by restoration of blood flow. Animals were infected i.v. with 1 x 10(9) plaque-forming units (PFU) of adenovirus containing the transgene for cytosolic Cu/Zn-SOD (Ad.SOD1), mitochondrial Mn-SOD (Ad.SOD2), extracellular Cu/Zn-SOD (Ad.SOD3), or the bacterial reporter gene for beta-galactosidase (Ad.lacZ) 3 days prior to experiments. Ad.SOD1 and Ad.SOD2 caused a three-fold increase in SOD expression and activity in liver compared to Ad.lacZ-treated control animals. Intravenous administration of Ad.SOD3 increased SOD activity slightly in serum but not in liver. Increases in serum transaminases and pathology due to ischemia-reperfusion were blunted by Ad.SOD1 and Ad.SOD2; however, extracellular SOD had no significant effect. Moreover, lipid-derived free radical adducts (a(N) = 15.65 G and a(H)(beta) = 2.78 G) were increased by ischemia-reperfusion. This effect was blunted by about 60% in Ad.SOD1- and Ad.SOD2-infected animals, but was unaffected by Ad.SOD3. However, when high doses of Ad.SOD3 (3 x 10(10) PFU) were administered. serum SOD activity was elevated three-fold and was protective against hepatic ischemia-reperfusion injury under these conditions. These data demonstrate that adenoviral delivery of superoxide dismutase can effectively reduce hepatic oxidative stress. PMID:11779401

  19. Troglitazone-induced hepatic mitochondrial proteome expression dynamics in heterozygous Sod2{sup +/-} mice: Two-stage oxidative injury

    SciTech Connect

    Lee, Y.H. |; Chung, Maxey C.M. | Lin Qingsong; Boelsterli, Urs A. ||

    2008-08-15

    The determinants of susceptibility to troglitazone-induced idiosyncratic liver injury have not yet been determined; however, troglitazone has been shown to target mitochondria and induce mitochondria-mediated hepatocellular injury in vitro. The aim of this study was to use a systems approach to analyze the dynamics of mitochondrial changes at the proteome level and more clearly define the mechanisms and time course of troglitazone hepatotoxicity by using a previously characterized mouse model that is highly sensitized to troglitazone hepatotoxicity. Mice heterozygous in mitochondrial superoxide dismutase-2 (Sod2{sup +/-}) were injected intraperitoneally with troglitazone (30 mg/kg/day) or vehicle daily for 2 or 4 weeks. Hepatic mitochondria were isolated, purified, and subjected to two-dimensional difference gel electrophoresis (2D-DIGE). We found that among the {approx} 1500 resolved hepatic mitochondrial proteins, 70 exhibited significantly altered abundance after troglitazone treatment. MALDI-TOF/TOF MS/MS analysis revealed that early changes (2 weeks) included increased levels of heat shock protein family members (mortalin, HSP7C), Lon protease, and catalase, indicating induction of a mitochondrial stress response. In contrast, after 4 weeks, a number of critical proteins including ATP synthase {beta}-subunit, aconitase-2, and catalase exhibited decreased abundance, and total protein carbonyls were significantly increased, suggesting uncompensated oxidative damage. Aconitase-2 (ACO2) was decreased at both time points, making this protein a potential sensitive and early biomarker for mitochondrial oxidant stress. These results show that, in this murine model of underlying clinically silent mitochondrial stress, superimposed troglitazone induces a two-stage response: an initial adaptive response, followed by a toxic response involving oxidant injury to mitochondrial proteins.

  20. CD248/endosialin critically regulates hepatic stellate cell proliferation during chronic liver injury via a PDGF-regulated mechanism

    PubMed Central

    Wilhelm, Annika; Aldridge, Victoria; Haldar, Debashis; Naylor, Amy J; Weston, Christopher J; Hedegaard, Ditte; Garg, Abhilok; Fear, Janine; Reynolds, Gary M; Croft, Adam P; Henderson, Neil C; Buckley, Christopher D; Newsome, Philip N

    2016-01-01

    Introduction CD248 (endosialin) is a stromal cell marker expressed on fibroblasts and pericytes. During liver injury, myofibroblasts are the main source of fibrotic matrix. Objective To determine the role of CD248 in the development of liver fibrosis in the rodent and human setting. Design CD248 expression was studied by immunostaining and quantitative PCR in both normal and diseased human and murine liver tissue and isolated hepatic stellate cells (HSCs). Hepatic fibrosis was induced in CD248−/− and wild-type controls with carbon tetrachloride (CCl4) treatment. Results Expression of CD248 was seen in normal liver of humans and mice but was significantly increased in liver injury using both immunostaining and gene expression assays. CD248 was co-expressed with a range of fibroblast/HSC markers including desmin, vimentin and α-smooth muscle actin (α-SMA) in murine and human liver sections. CD248 expression was restricted to isolated primary murine and human HSC. Collagen deposition and α-SMA expression, but not inflammation and neoangiogenesis, was reduced in CD248−/− mice compared with wild-type mice after CCl4 treatment. Isolated HSC from wild-type and CD248−/− mice expressed platelet-derived growth factor receptor α (PDGFR-α) and PDGFR-β at similar levels. As expected, PDGF-BB stimulation induced proliferation of wild-type HSC, whereas CD248−/− HSC did not demonstrate a proliferative response to PDGF-BB. Abrogated PDGF signalling in CD248−/− HSC was confirmed by significantly reduced c-fos expression in CD248−/− HSC compared with wild-type HSC. Conclusions Our data show that deletion of CD248 reduces susceptibility to liver fibrosis via an effect on PDGF signalling, making it an attractive clinical target for the treatment of liver injury. PMID:26078290

  1. Hepatic Stellate Cell-Derived Microvesicles Prevent Hepatocytes from Injury Induced by APAP/H2O2

    PubMed Central

    Huang, Renwei; Wang, Yan; Liang, Yaolong; Liao, Xiaorong; Li, Mingyi

    2016-01-01

    Hepatic stellate cells (HSCs), previously described for liver-specific mesenchymal stem cells (MSCs), appear to contribute to liver regeneration. Microvesicles (MVs) are nanoscale membrane fragments, which can regulate target cell function by transferring contents from their parent cells. The aim of this study was to investigate the effect of HSC-derived MVs on xenobiotic-induced liver injury. Rat and human hepatocytes, BRL-3A and HL-7702, were used to build hepatocytes injury models by n-acetyl-p-aminophenol n-(APAP) or H2O2 treatment. MVs were prepared from human and rat HSCs, LX-2, and HST-T6 and, respectively, added to injured BRL-3A and HL-7702 hepatocytes. MTT assay was utilized to determine cell proliferation. Cell apoptosis was analyzed by flow cytometry and hoechst33258 staining. Western blot was used for analyzing the expression of activated caspase-3. Liver injury indicators, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) in culture medium were also assessed. Results showed that (1) HSC-MVs derived from LX-2 and HST-T6 were positive to CD90 and annexin V surface markers; (2) HSC-MVs dose-dependently improved the viability of hepatocytes in both injury models; (3) HSC-MVs dose-dependently inhibited the APAP/H2O2 induced hepatocytes apoptosis and activated caspase-3 expression and leakage of LDH, ALT, and AST. Our results demonstrate that HSC-derived MVs protect hepatocytes from toxicant-induced injury. PMID:27239205

  2. Hepatitis B vaccination. Response of alcoholic with and without liver injury.

    PubMed

    Mendenhall, C; Roselle, G A; Lybecker, L A; Marshall, L E; Grossman, C J; Myre, S A; Weesner, R E; Morgan, D D

    1988-03-01

    Alcoholics are at risk to develop hepatitis B infections, chronic active hepatitis, and even hepatoma. Hence, immunization with hepatitis B vaccine is recommended. However, immune abnormalities may coexist which alter their responsiveness to vaccination. This study compares the immune response to this vaccine in controls (group I), alcoholics without overt liver disease (group II), and alcoholics with clinical liver disease (group III). By the seventh month after the initial vaccination, 89% in group I, 70% in group II, and 18% in group III had a response greater than 36 RIA units. The magnitude of the response was significantly different in groups I, II, and III (19,456 vs 8,326 vs 153 RIA units, respectively; P less than 0.05, group I vs III). In those who did not respond, a significant (P less than 0.02) lower helper/inducer (T4) class of lymphocytes was observed as compared to patients who exhibited an adequate response. These observations suggest: (1) that the response to hepatitis B vaccine is a T-cell-dependent event and (2) that in this population, using the existing vaccine, postvaccination evaluations of antibody concentrations are needed before protection against hepatitis B infection can be assumed. PMID:2856849

  3. Injury mechanism dictates contribution of bone marrow-derived cells to murine hepatic vascular regeneration

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Stem and progenitor cells derived from adult marrow have been shown to regenerate vascular cells in response to injury. However, it is unclear whether the type of injury dictates the contribution of such cells to neovascularization and which subpopulations of cells contribute to vascular regeneratio...

  4. Natural killer cells contribute to hepatic injury and help in viral persistence during progression of hepatitis B e-antigen-negative chronic hepatitis B virus infection.

    PubMed

    Ghosh, S; Nandi, M; Pal, S; Mukhopadhyay, D; Chakraborty, B C; Khatun, M; Bhowmick, D; Mondal, R K; Das, S; Das, K; Ghosh, R; Banerjee, S; Santra, A; Chatterjee, M; Chowdhury, A; Datta, S

    2016-08-01

    Hepatitis B e-antigen negative (e(-)) chronic HBV infection (CHI) encompasses a heterogeneous clinical spectrum ranging from inactive carrier (IC) state to e(-) chronic hepatitis B (CHB), cirrhosis and hepatic decompensation. In the backdrop of dysfunctional virus-specific T cells, natural killer (NK) cells are emerging as innate effectors in CHI. We characterized CD3(-) CD56(+) NK cells in clinically well-defined, treatment-naive e(-) patients in IC, e(-)CHB or decompensated liver cirrhosis (LC) phase to appraise their role in disease progression. The NK cell frequencies increased progressively with disease severity (IC 8.2%, e(-)CHB 13.2% and LC 14.4%). Higher proportion of NK cells from LC/e(-)CHB expressed CD69, NKp46, NKp44, TRAIL and perforin, the last two being prominent features of CD56(bright) and CD56(dim) NK subsets, respectively. The frequencies of CD3(-) CD56(+) NK cells together with TRAIL(+) CD56(bright) and Perforin(+) CD56(dim) NK cells correlated positively with serum alanine transaminase levels in e(-)CHB/LC. K562 cell-stimulated NK cells from e(-)CHB/LC exhibited significantly greater degranulation but diminished interferon-γ production than IC. Further, Perforin(+) NK cell frequency inversely correlated with autologous CD4(+) T-cell count in e(-) patients and ligands of NK receptors were over-expressed in CD4(+) T cells from e(-)CHB/LC relative to IC. Co-culture of sorted CD56(dim) NK cells and CD4(+) T cells from e(-)CHB showed enhanced CD4(+) T-cell apoptosis, which was reduced by perforin inhibitor, concanamycin A, suggesting a possible perforin-dependent NK cell-mediated CD4(+) T-cell depletion. Moreover, greater incidence of perforin-expressing NK cells and decline in CD4(+) T cells were noticed intrahepatically in e(-)CHB than IC. Collectively, NK cells contribute to the progression of e(-)CHI by enhanced TRAIL- and perforin-dependent cytolytic activity and by restraining anti-viral immunity through reduced interferon-γ secretion and

  5. Mechanisms of Liver Injury. II. Mechanisms of neutrophil-induced liver cell injury during hepatic ischemia-reperfusion and other acute inflammatory conditions.

    PubMed

    Jaeschke, Hartmut

    2006-06-01

    Polymorphonuclear leukocytes (neutrophils) are a vital part of the innate immune response to microbial infections and tissue trauma, e.g., ischemia-reperfusion injury, in many organs including the liver. However, an excessive inflammatory response can lead to a dramatic aggravation of the existing injury. To design interventions, which selectively target the detrimental effects of neutrophils, a detailed understanding of the pathophysiology is critical. Systemic or local exposure to proinflammatory mediators causes activation and priming of neutrophils for reactive oxygen formation and recruits them into the vascular beds of the liver without causing tissue injury. However, generation of a chemotactic signal from the parenchyma will trigger extravasation and an attack on target cells (e.g., hepatocytes). Adhesion to the target induces degranulation with release of proteases and formation of reactive oxygen species including hydrogen peroxide and hypochlorous acid, which can diffuse into hepatocytes and induce an intracellular oxidant stress and mitochondrial dysfunction. Various neutrophil-derived proteases are involved in transmigration and cell toxicity but can also promote the inflammatory response by processing of proinflammatory mediators. In addition, necrotic cells release mediators, e.g., high-mobility group box-1, which further promotes neutrophilic hepatitis and tissue damage. On the basis of these evolving insights into the mechanisms of neutrophil-mediated liver damage, the most selective strategies appear not to interfere with the cytotoxic potential of neutrophils, but rather strengthen the target cells' defense mechanisms including enhancement of the intracellular antioxidant defense systems, activation of cell survival pathways, or initiation of cell cycle activation and regeneration. PMID:16687579

  6. The potential role of Punica granatum treatment on murine malaria-induced hepatic injury and oxidative stress.

    PubMed

    Hafiz, Taghreed A; Mubaraki, Murad A; Al-Quraishy, Saleh; Dkhil, Mohamed A

    2016-04-01

    Malaria is a health burden disease where the world harnessed the power of expertise and innovation to understand the biology of the parasite and the pathogenesis of the disease as well as to discover effective drugs. However, the treatment of malaria remains a challenging task and inadequate to address today's perplexing problem, the emergence of resistant strains. Historically, traditional medicine has been a mainstay for remediation and still retains its importance with the presence of potent natural products. Pomegranate has been used as antioxidant and anti-inflammatory against a range of diseases. Therefore, pomegranate peel extract (PPE) was used in this study to examine its effect on Plasmodium chabaudi-induced hepatic inflammation. Animals were allocated into three groups: a vehicle control group, a group infected with 10(6) P. chabaudi-parasitized erythrocytes and a pomegranate-treated group infected with 10(6) P. chabaudi-parasitized erythrocytes. This group received 100 μl of 300 mg/kg PPE after infection. The results showed the effectiveness of PPE on reversing the anaemic signs that have been provoked by P. chabaudi infection through instating the haemoglobin concentration and erythrocyte count back to normal values. Moreover, PPE exhibited hepatoprotective activities upon histopathological examination and liver function tests. These data were further confirmed by the significant reduction of the hepatic oxidative markers, glutathione, nitric oxide and malondialdehyde, in mice infected with P. chabaudi. Based on these outcomes, pomegranate could be used as a hepatoprotective agent against P. chabaudi-induced hepatic injury. However, further studies are needed in order to determine the mode of action of pomegranate upon infection. PMID:26670312

  7. Kolaviron, a Garcinia biflavonoid complex ameliorates hyperglycemia-mediated hepatic injury in rats via suppression of inflammatory responses

    PubMed Central

    2013-01-01

    Background Chronic inflammation plays a crucial role in hyperglycemia-induced liver injury. Kolaviron (KV), a natural biflavonoid from Garcinia kola seeds have been shown to possess anti- inflammatory properties which has not been explored in diabetes. To our knowledge, this is the first study to investigate the effect of KV on pro-inflammatory proteins in the liver of diabetic rats. Methods Diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ) (50 mg/kg) in male Wistar rats. Kolaviron (100 mg/kg) was administered orally five times a week for six weeks. The concentrations of cytokines and chemokine were measured using Bio-plex Pro™ magnetic bead-based assays (Bio-Rad Laboratories, Hercules, USA). Plasma glucose and serum biomarkers of liver dysfunction were analyzed with diagnostic kits in an automated clinical chemistry analyzer. Insulin concentration was estimated by radioimmunoassay (RIA). Result Kolaviron (100mg/kg) treatment significantly ameliorated hyperglycemia and liver dysfunction. Serum levels of hepatic marker enzymes were significantly reduced in kolaviron treated diabetic rats. Kolaviron prevented diabetes induced increase in the hepatic levels of proinflammatory cytokines; interleukin (IL)-1beta, IL-6, tumour necrosis factor (TNF-α) and monocyte chemotactic protein (MCP-1). Conclusion The results of this study demonstrate that the hepatoprotective effects of kolaviron in diabetic rats may be partly associated with its modulating effect on inflammatory responses. PMID:24359406

  8. Resveratrol mitigates hepatic injury in rats by regulating oxidative stress, nuclear factor-kappa B, and apoptosis

    PubMed Central

    Seif el-Din, Sayed Hassan; El-Lakkany, Naglaa Mohamed; Salem, Maha Badr; Hammam, Olfat Ali; Saleh, Samira; Botros, Sanaa Sabet

    2016-01-01

    Resveratrol is a naturally occurring polyphenol, possesses several pharmacological activities including anticancer, antioxidant, antidiabetic, antinociceptive, and antiasthmatic activity. Little is known about its hepatoprotective action mechanisms. This study was conceived to explore the possible protective mechanisms of resveratrol compared with the hepatoprotective silymarin in thioacetamide (TAA)-induced hepatic injury in rats. Thirty-two rats were equally divided into four groups; normal control (i), TAA (100 mg/kg) (ii), TAA + silymarin (50 mg/kg) (iii), and TAA + resveratrol (10 mg/kg) (iv). Liver function and histopathology, pro-inflammatory cytokines, oxidative stress, and apoptotic markers were examined. Data were analyzed using ANOVA test followed by Tukey post hoc test. Compared to TAA-intoxicated group, resveratrol mitigated liver damage, and inflammation as noted by less inflammatory infiltration, hydropic degeneration with decreased levels of tumor necrosis factor-alpha, interleukin-6, and interferon-gamma by 78.83, 18.12, and 64.49%, respectively. Furthermore, it reduced (P < 0.05) alanine and aspartate aminotransferases by 36.64 and 48.09%, respectively, restored hepatic glutathione content and normalized superoxide dismutase and malondialdehyde levels. While it inhibited nuclear factor-kappa B, cytochrome 2E1, and enhanced apoptosis of necrotic hepatocytes via increasing caspase-3 activity. Our findings indicated that the potential hepatoprotective mechanisms of resveratrol are associated with inhibition of inflammation, enhancing the apoptosis of necrotic hepatocytes, and suppression of oxidative stress. PMID:27429929

  9. 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

  10. Xenobiotic Metabolism: The Effect of Acute Kidney Injury on Non-Renal Drug Clearance and Hepatic Drug Metabolism

    PubMed Central

    Dixon, John; Lane, Katie; MacPhee, Iain; Philips, Barbara

    2014-01-01

    Acute kidney injury (AKI) is a common complication of critical illness, and evidence is emerging that suggests AKI disrupts the function of other organs. It is a recognized phenomenon that patients with chronic kidney disease (CKD) have reduced hepatic metabolism of drugs, via the cytochrome P450 (CYP) enzyme group, and drug dosing guidelines in AKI are often extrapolated from data obtained from patients with CKD. This approach, however, is flawed because several confounding factors exist in AKI. The data from animal studies investigating the effects of AKI on CYP activity are conflicting, although the results of the majority do suggest that AKI impairs hepatic CYP activity. More recently, human study data have also demonstrated decreased CYP activity associated with AKI, in particular the CYP3A subtypes. Furthermore, preliminary data suggest that patients expressing the functional allele variant CYP3A5*1 may be protected from the deleterious effects of AKI when compared with patients homozygous for the variant CYP3A5*3, which codes for a non-functional protein. In conclusion, there is a need to individualize drug prescribing, particularly for the more sick and vulnerable patients, but this needs to be explored in greater depth. PMID:24531139

  11. KAP Degradation by Calpain Is Associated with CK2 Phosphorylation and Provides a Novel Mechanism for Cyclosporine A-Induced Proximal Tubule Injury

    PubMed Central

    Pascual, Gloria; Bardaji, Beatriz; Montero, M. Angeles; Salcedo, M. Teresa; Plana, Maria; López-Hellin, Joan; Itarte, Emilio; Meseguer, Anna

    2011-01-01

    The use of cyclosporine A (CsA) is limited by its severe nephrotoxicity that includes reversible vasoconstrictor effects and proximal tubule cell injury, the latter associated whith chronic kidney disease progression. The mechanisms of CsA-induced tubular injury, mainly on the S3 segment, have not been completely elucidated. Kidney androgen-regulated protein (KAP) is exclusively expressed in kidney proximal tubule cells, interacts with the CsA-binding protein cyclophilin B and its expression diminishes in kidneys of CsA-treated mice. Since we reported that KAP protects against CsA toxicity in cultured proximal tubule cells, we hypothesized that low KAP levels found in kidneys of CsA-treated mice might correlate with proximal tubule cell injury. To test this hypothesis, we used KAP Tg mice developed in our laboratory and showed that these mice are more resistant to CsA-induced tubular injury than control littermates. Furthermore, we found that calpain, which was activated by CsA in cell cultures and kidney, is involved in KAP degradation and observed that phosphorylation of serine and threonine residues found in KAP PEST sequences by protein kinase CK2 enhances KAP degradation by calpain. Moreover, we also observed that CK2 inhibition protected against CsA-induced cytotoxicity. These findings point to a novel mechanism for CsA-induced kidney toxicity that might be useful in developing therapeutic strategies aimed at preventing tubular cell damage while maintaining the immunosuppressive effects of CsA. PMID:21980535

  12. Bioinformatics analysis of hepatitis C virus genotype 2a-induced human hepatocellular carcinoma in Huh7 cells

    PubMed Central

    Xu, Ping; Wu, Meiying; Chen, Hui; Xu, Junchi; Wu, Minjuan; Li, Ming; Qian, Feng; Xu, Junhua

    2016-01-01

    Hepatocellular carcinoma (HCC) is a liver cancer that could be induced by hepatitis C virus genotype 2a Japanese fulminant hepatitis-1 (JFH-1) strain. The aim of this study was to investigate the molecular mechanisms of HCC. The microarray data GSE20948 includes 14 JFH-1- and 14 mock (equal volume of medium [control])-infected Huh7 samples. The data were downloaded from the Gene Expression Omnibus. After data processing, soft cluster analyses were performed to identify co-regulated genes with similar temporal expression patterns. Functional and pathway enrichment analyses, as well as functional annotation analysis, were performed. Subsequently, combined networks of protein–protein interaction network, microRNA regulatory network, and transcriptional regulatory network were constructed. Hub nodes, modules, and five clusters of co-regulated genes were also identified. In total, 173 up and 207 down co-regulated genes were separately identified in JFH-1-infected Huh7 cells compared with those of control cells. Functional enrichment analysis indicated that up co-regulated genes were related to skeletal system morphogenesis and neuron differentiation and down co-regulated genes were related to steroid/cholesterol/sterol metabolisms. Hub genes (such as IRF1, GBP1, ICAM1, Foxa1, DHCR7, HMGCS2, and MSMO1) were identified. Transcription factors IRF1 and Foxa1 were the targets of miR-130a, miR-17-5p, and miR-20a. PPARGC1A was targeted by miR-29 family, and MSMO1 was the target of miR-23 family. Hub nodes (such as IRF1, GBP1, ICAM1, Foxa1, DHCR7, HMGCS2, and MSMO1) and microRNAs might be used as candidate biomarkers of JFH-1-infected HCC. PMID:26811688

  13. Bioinformatics analysis of hepatitis C virus genotype 2a-induced human hepatocellular carcinoma in Huh7 cells.

    PubMed

    Xu, Ping; Wu, Meiying; Chen, Hui; Xu, Junchi; Wu, Minjuan; Li, Ming; Qian, Feng; Xu, Junhua

    2016-01-01

    Hepatocellular carcinoma (HCC) is a liver cancer that could be induced by hepatitis C virus genotype 2a Japanese fulminant hepatitis-1 (JFH-1) strain. The aim of this study was to investigate the molecular mechanisms of HCC. The microarray data GSE20948 includes 14 JFH-1- and 14 mock (equal volume of medium [control])-infected Huh7 samples. The data were downloaded from the Gene Expression Omnibus. After data processing, soft cluster analyses were performed to identify co-regulated genes with similar temporal expression patterns. Functional and pathway enrichment analyses, as well as functional annotation analysis, were performed. Subsequently, combined networks of protein-protein interaction network, microRNA regulatory network, and transcriptional regulatory network were constructed. Hub nodes, modules, and five clusters of co-regulated genes were also identified. In total, 173 up and 207 down co-regulated genes were separately identified in JFH-1-infected Huh7 cells compared with those of control cells. Functional enrichment analysis indicated that up co-regulated genes were related to skeletal system morphogenesis and neuron differentiation and down co-regulated genes were related to steroid/cholesterol/sterol metabolisms. Hub genes (such as IRF1, GBP1, ICAM1, Foxa1, DHCR7, HMGCS2, and MSMO1) were identified. Transcription factors IRF1 and Foxa1 were the targets of miR-130a, miR-17-5p, and miR-20a. PPARGC1A was targeted by miR-29 family, and MSMO1 was the target of miR-23 family. Hub nodes (such as IRF1, GBP1, ICAM1, Foxa1, DHCR7, HMGCS2, and MSMO1) and microRNAs might be used as candidate biomarkers of JFH-1-infected HCC. PMID:26811688

  14. Increased hepatic receptor interacting protein kinase 3 expression due to impaired proteasomal functions contributes to alcohol-induced steatosis and liver injury

    PubMed Central

    Wang, Shaogui; Ni, Hong-Min; Dorko, Kenneth; Kumer, Sean C.; Schmitt, Timothy M.; Nawabi, Atta; Komatsu, Masaaki; Huang, Heqing; Ding, Wen-Xing

    2016-01-01

    Chronic alcohol exposure increased hepatic receptor-interacting protein kinase (RIP) 3 expression and necroptosis in the liver but its mechanisms are unclear. In the present study, we demonstrated that chronic alcohol feeding plus binge (Gao-binge) increased RIP3 but not RIP1 protein levels in mouse livers. RIP3 knockout mice had decreased serum alanine amino transferase activity and hepatic steatosis but had no effect on hepatic neutrophil infiltration compared with wild type mice after Gao-binge alcohol treatment. The hepatic mRNA levels of RIP3 did not change between Gao-binge and control mice, suggesting that alcohol-induced hepatic RIP3 proteins are regulated at the posttranslational level. We found that Gao-binge treatment decreased the levels of proteasome subunit alpha type-2 (PSMA2) and proteasome 26S subunit, ATPase 1 (PSMC1) and impaired hepatic proteasome function. Pharmacological or genetic inhibition of proteasome resulted in the accumulation of RIP3 in mouse livers. More importantly, human alcoholics had decreased expression of PSMA2 and PSMC1 but increased protein levels of RIP3 compared with healthy human livers. Moreover, pharmacological inhibition of RIP1 decreased Gao-binge-induced hepatic inflammation, neutrophil infiltration and NF-κB subunit (p65) nuclear translocation but failed to protect against steatosis and liver injury induced by Gao-binge alcohol. In conclusion, results from this study suggest that impaired hepatic proteasome function by alcohol exposure may contribute to hepatic accumulation of RIP3 resulting in necroptosis and steatosis while RIP1 kinase activity is important for alcohol-induced inflammation. PMID:26769846

  15. Correlation of Apgar Score with Asphyxial Hepatic Injury and Mortality in Newborns: A Prospective Observational Study From India

    PubMed Central

    Sharma, Deepak; Choudhary, Mukesh; Lamba, Mamta; Shastri, Sweta

    2016-01-01

    OBJECTIVE The objective of this study is to determine the correlation of Apgar score with asphyxial hepatic injury and neonatal mortality in moderately and severely asphyxiated newborns. MATERIAL AND METHODS This is a secondary analysis of our prospective observational case-controlled study. Sixteen neonates with severe birth asphyxia (five-minute Apgar ≤3) were compared with either 54 moderate asphyxia neonates (five-minute Apgar >3) or 30 normal neonates. Liver function tests were measured on postnatal days 1, 3, and 10 in the study and control groups. Neonatal mortality was observed in the study and control population. RESULTS Correlation of Apgar score in severely asphyxiated neonates compared with normal Apgar score neonates and moderately asphyxiated neonates for deranged hepatic function showed significant correlation (odds ratio [OR] 4.88, 95% CI 3.26–5.84, P = 0.01 and OR 2.46, 95% CI 1.94–3.32, P = 0.02, respectively). There was a significant increase in serum lactate dehydrogenase (LDH) and total bilirubin on day 1 and serum LDH at age of 10th postnatal life in severely asphyxiated neonates when compared to moderately asphyxiated neonates, whereas there was a significant decrease in total bilirubin and serum albumin on day 3 in severely asphyxiated neonates. There was a significant increase in serum alanine transaminase, serum LDH, and total bilirubin on day 1, serum aspartate transaminase, serum LDH, and total bilirubin on day 3, and International Normalized Ratio on day 10 of postnatal life when severely asphyxiated neonates were compared with normal neonates. There was a significant reduction in total protein and serum albumin on day 1 and direct bilirubin on day 3 in severely asphyxiated neonates when compared with normal neonates. There was a significant increase in neonatal mortality in severely asphyxiated neonates when compared to the other two groups. Correlation of Apgar score in severely asphyxiated neonates compared with normal Apgar

  16. Inhibition of Human Hepatic Bile Acid Transporters by Tolvaptan and Metabolites: Contributing Factors to Drug-Induced Liver Injury?

    PubMed

    Slizgi, Jason R; Lu, Yang; Brouwer, Kenneth R; St Claire, Robert L; Freeman, Kimberly M; Pan, Maxwell; Brock, William J; Brouwer, Kim L R

    2016-01-01

    Tolvaptan is a vasopressin V(2)-receptor antagonist that has shown promise in treating Autosomal Dominant Polycystic Kidney Disease (ADPKD). Tolvaptan was, however, associated with liver injury in some ADPKD patients. Inhibition of bile acid transporters may be contributing factors to drug-induced liver injury. In this study, the ability of tolvaptan and two metabolites, DM-4103 and DM-4107, to inhibit human hepatic transporters (NTCP, BSEP, MRP2, MRP3, and MRP4) and bile acid transport in sandwich-cultured human hepatocytes (SCHH) was explored. IC(50) values were determined for tolvaptan, DM-4103 and DM-4107 inhibition of NTCP (∼41.5, 16.3, and 95.6 μM, respectively), BSEP (31.6, 4.15, and 119 μM, respectively), MRP2 (>50, ∼51.0, and >200 μM, respectively), MRP3 (>50, ∼44.6, and 61.2 μM, respectively), and MRP4 (>50, 4.26, and 37.9 μM, respectively). At the therapeutic dose of tolvaptan (90 mg), DM-4103 exhibited a C(max)/IC(50) value >0.1 for NTCP, BSEP, MRP2, MRP3, and MRP4. Tolvaptan accumulation in SCHH was extensive and not sodium-dependent; intracellular concentrations were ∼500 μM after a 10-min incubation duration with tolvaptan (15 μM). The biliary clearance of taurocholic acid (TCA) decreased by 43% when SCHH were co-incubated with tolvaptan (15 μM) and TCA (2.5 μM). When tolvaptan (15 μM) was co-incubated with 2.5 μM of chenodeoxycholic acid, taurochenodeoxycholic acid, or glycochenodeoxycholic acid in separate studies, the cellular accumulation of these bile acids increased by 1.30-, 1.68-, and 2.16-fold, respectively. Based on these data, inhibition of hepatic bile acid transport may be one of the biological mechanisms underlying tolvaptan-associated liver injury in patients with ADPKD. PMID:26507107

  17. 5-lipoxygenase activation is involved in the mechanisms of chronic hepatic injury in a rat model of chronic aluminum overload exposure.

    PubMed

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

    2016-08-15

    We previously confirmed that rats overloaded with aluminum exhibited hepatic function damage and increased susceptibility to hepatic inflammation. However, the mechanism of liver toxicity by chronic aluminum overload is poorly understood. In this study, we investigated changes in the 5-lipoxygenase (5-LO) signaling pathway and its effect on liver injury in aluminum-overloaded rats. A rat hepatic injury model of chronic aluminum injury was established via the intragastric administration of aluminum gluconate (Al(3+) 200mg/kg per day, 5days a week for 20weeks). The 5-LO inhibitor, caffeic acid (10 and 30mg/kg), was intragastrically administered 1h after aluminum administration. Hematoxylin and eosin staining was used to visualize pathological changes in rat liver tissue. A series of biochemical indicators were measured with biochemistry assay or ELISAs. Immunochemistry and RT-PCR methods were used to detect 5-LO protein and mRNA expression in the liver, respectively. Caffeic acid administration protected livers against histopathological injury, decreased plasma ALT, AST, and ALP levels, decreased TNF-α, IL-6, IL-1β and LTs levels, increased the reactive oxygen species content, and down-regulated the mRNA and protein expressions of 5-LO in aluminum overloaded rats. Our results indicate that 5-lipoxygenase activation is mechanistically involved in chronic hepatic injury in a rat model of chronic aluminum overload exposure and that the 5-LO signaling pathway, which associated with inflammation and oxidative stress, is a potential therapeutic target for chronic non-infection liver diseases. PMID:27368151

  18. Total Flavonoids from Rosa laevigata Michx Fruit Ameliorates Hepatic Ischemia/Reperfusion Injury through Inhibition of Oxidative Stress and Inflammation in Rats

    PubMed Central

    Tao, Xufeng; Sun, Xiance; Xu, Lina; Yin, Lianhong; Han, Xu; Qi, Yan; Xu, Youwei; Zhao, Yanyan; Wang, Changyuan; Peng, Jinyong

    2016-01-01

    The effects of total flavonoids (TFs) from Rosa laevigata Michx fruit against liver damage and cerebral ischemia/reperfusion (I/R) injury have been reported, but its action on hepatic I/R injury remains unknown. In this work, the effects and possible mechanisms of TFs against hepatic I/R injury were examined using a 70% partial hepatic warm ischemia rat model. The results demonstrated TFs decreased serum aspartate transaminase (AST), alanine aminotransferase (ALT), myeloperoxidase (MPO), and lactate dehydrogenase (LDH) activities, improved liver histopathology and ultrastructure through hematoxylin-eosin (HE) staining and electron microscope observation. In addition, TFs significantly decreased malondialdehyde (MDA) and increased the levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), which indicated that TFs alleviated oxidative stress caused by I/R injury. RT-PCR results proved that TFs downregulated the gene levels of inflammatory factors including interleukin-1 beta (IL-1β), interleukin-1 (IL-6), and tumor necrosis factor alpha (TNF-α). Further research indicated that TF-induced hepatoprotection was completed through inhibiting TLR4/MyD88 and activating Sirt1/Nrf2 signaling pathways. Blockade of the TLR4 pathway by TFs inhibited NF-κB and AP-1 transcriptional activities and inflammatory reaction. Activation of Sirt1/Nrf2 pathway by TFs increased the protein levels of HO-1 and GST to improve oxidative stress. Collectively, these findingsconfirmed the potent effects of TFs against hepatic I/R injury, which should be developed as a candidate for the prevention of this disease. PMID:27399769

  19. Total Flavonoids from Rosa laevigata Michx Fruit Ameliorates Hepatic Ischemia/Reperfusion Injury through Inhibition of Oxidative Stress and Inflammation in Rats.

    PubMed

    Tao, Xufeng; Sun, Xiance; Xu, Lina; Yin, Lianhong; Han, Xu; Qi, Yan; Xu, Youwei; Zhao, Yanyan; Wang, Changyuan; Peng, Jinyong

    2016-01-01

    The effects of total flavonoids (TFs) from Rosa laevigata Michx fruit against liver damage and cerebral ischemia/reperfusion (I/R) injury have been reported, but its action on hepatic I/R injury remains unknown. In this work, the effects and possible mechanisms of TFs against hepatic I/R injury were examined using a 70% partial hepatic warm ischemia rat model. The results demonstrated TFs decreased serum aspartate transaminase (AST), alanine aminotransferase (ALT), myeloperoxidase (MPO), and lactate dehydrogenase (LDH) activities, improved liver histopathology and ultrastructure through hematoxylin-eosin (HE) staining and electron microscope observation. In addition, TFs significantly decreased malondialdehyde (MDA) and increased the levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), which indicated that TFs alleviated oxidative stress caused by I/R injury. RT-PCR results proved that TFs downregulated the gene levels of inflammatory factors including interleukin-1 beta (IL-1β), interleukin-1 (IL-6), and tumor necrosis factor alpha (TNF-α). Further research indicated that TF-induced hepatoprotection was completed through inhibiting TLR4/MyD88 and activating Sirt1/Nrf2 signaling pathways. Blockade of the TLR4 pathway by TFs inhibited NF-κB and AP-1 transcriptional activities and inflammatory reaction. Activation of Sirt1/Nrf2 pathway by TFs increased the protein levels of HO-1 and GST to improve oxidative stress. Collectively, these findingsconfirmed the potent effects of TFs against hepatic I/R injury, which should be developed as a candidate for the prevention of this disease. PMID:27399769

  20. Differential Regulation of TGF-β/Smad Signaling in Hepatic Stellate Cells between Acute and Chronic Liver Injuries.

    PubMed

    Yoshida, Katsunori; Matsuzaki, Koichi

    2012-01-01

    Current evidence suggests that regulation of extracellular matrix (ECM) accumulation by fibrogenic transforming growth factor (TGF)-β and platelet-derived growth factor (PDGF) signals involves different mechanisms in acute and chronic liver injuries, even though hepatic stellate cells (HSC) are the principal effecter in both cases. As a result of chronic liver damage, HSC undergo progressive activation to become myofibroblasts (MFB)-like cells. Our current review will discuss the differential regulation of TGF-β signaling between HSC and MFB in vitro and in vivo. Smad proteins, which convey signals from TGF-β receptors to the nucleus, have intermediate linker regions between conserved Mad-homology (MH) 1 and MH2 domains. TGF-β type I receptor and Ras-associated kinases differentially phosphorylate Smad2 and Smad3 to create COOH-terminally (C), linker (L), or dually (L/C) phosphorylated (p) isoforms. After acute liver injury, TGF-β and PDGF synergistically promote collagen synthesis in the activated HSC via pSmad2L/C and pSmad3L/C pathways. To avoid unlimited ECM deposition, Smad7 induced by TGF-β negatively regulates the fibrogenic TGF-β signaling. In contrast, TGF-β and PDGF can transmit the fibrogenic pSmad2L/C and mitogenic pSmad3L signals in MFB throughout chronic liver injury, because Smad7 cannot be induced by the pSmad3L pathway. This lack of Smad7 induction might lead to constitutive fibrogenesis in MFB, which eventually develop into accelerated liver fibrosis. PMID:22457652

  1. ACETAMINOPHEN-INDUCED HEPATIC NEUTROPHIL ACCUMULATION AND INFLAMMATORY LIVER INJURY IN CD18-DEFICIENT MICE

    PubMed Central

    Williams, C. David; Bajt, Mary Lynn; Farhood, Anwar; Jaeschke, Hartmut

    2014-01-01

    Background Acetaminophen (APAP) hepatotoxicity is currently the most frequent cause of acute liver failure in the US and many European countries. Although intracellular signaling mechanisms are critical for hepatocellular injury, a contribution of inflammatory cells, especially neutrophils, has been suggested. However, conflicting results were obtained when using immunological intervention strategies. Aims The role of neutrophils was investigated using a CD18-deficient mouse model. Results Treatment of C57Bl/6 wild type mice with 300 mg/kg APAP resulted in severe liver cell necrosis at 12 and 24 h. This injury was accompanied by formation of cytokines and chemokines and accumulation of neutrophils in the liver. However, there was no difference in the inflammatory response or liver injury in CD18-deficient mice compared to wild type animals. In contrast to treatment with endotoxin, no upregulation of CD11b or priming for reactive oxygen was observed on neutrophils isolated from the peripheral blood or the liver after APAP administration. Furthermore, animals treated with endotoxin 3 h after APAP experienced an exaggerated inflammatory response as indicated by substantially higher cytokine and chemokine formation and twice the number of neutrophils in the liver. However, liver injury in the two-hit model was the same as with APAP alone. Conclusions Our data do not support the hypothesis that neutrophils contribute to APAP hepatotoxicity or that a neutrophil-mediated injury phase could be provoked by a second, pro-inflammatory hit. Thus, APAP-induced liver injury in mice is dominated by intracellular mechanisms of cell death rather than by neutrophilic inflammation. PMID:20500806

  2. Protectin D1 reduces concanavalin A-induced liver injury by inhibiting NF-κB-mediated CX3CL1/CX3CR1 axis and NLR family, pyrin domain containing 3 inflammasome activation.

    PubMed

    Ren, Jun; Meng, Shanshan; Yan, Bingdi; Yu, Jinyan; Liu, Jing

    2016-04-01

    Protectin D1 (PD1) is a bioactive product generated from docosahexaenoic acid, which may exert anti-inflammatory effects in various inflammatory diseases. However, the underlying molecular mechanism of its anti‑inflammatory activity on concanavalin A (Con A)-induced hepatitis remains unknown. The aim of the present study was to investigate the protective effects of PD1 against Con A‑induced liver injury and the underlying mechanisms via intravenous injection of PD1 prior to Con A administration. C57BL/6 mice were randomly divided into four experimental groups as follows: Control group, Con A group (30 mg/kg), 20 µg/kg PD1 + Con A (30 mg/kg) group and 10 µg/kg PD1 + Con A (30 mg/kg) group. PD1 pretreatment was demonstrated to significantly inhibit elevated plasma aminotransferase levels, high mobility group box 1 and liver necrosis, which were observed in Con A‑induced hepatitis. Furthermore, compared with the Con A group, PD1 pretreatment prevented the production of pro‑inflammatory cytokines, including tumor necrosis factor‑α, interferon‑γ and interleukin‑2, ‑1β and ‑6. In addition, pretreatment with PD1 markedly downregulated cluster of differentiation (CD)4+, CD8+ and natural killer T (NKT) cell infiltration in the liver. PD1 pretreatment was observed to suppress the messenger RNA and protein expression levels of NLR family, pyrin domain containing 3 and Toll‑like receptor (TLR) 4 in liver tissue samples. Further data indicated that PD1 pretreatment inhibited the activation of the nuclear factor κ‑light‑chain‑enhancer of activated B cells (NF‑κB) signaling pathway and chemokine (C‑X3‑C motif) ligand 1 (CX3CL1)/chemokine (C-X3-C motif) receptor 1 (CX3CR1) axis by preventing phosphorylation of nuclear factor of κ light polypeptide gene enhancer in B-cells inhibitor, α and NF‑κB in Con A‑induced liver injury. Therefore, these results suggest that PD1 administration protects mice against Con

  3. Propofol but not sevoflurane prevents mitochondrial dysfunction and oxidative stress by limiting HIF-1α activation in hepatic ischemia/reperfusion injury.

    PubMed

    Bellanti, Francesco; Mirabella, Lucia; Mitarotonda, Domenica; Blonda, Maria; Tamborra, Rosanna; Cinnella, Gilda; Fersini, Alberto; Ambrosi, Antonio; Dambrosio, Michele; Vendemiale, Gianluigi; Serviddio, Gaetano

    2016-07-01

    Mitochondrial dysfunction, reactive oxygen species (ROS) production and oxidative stress during reperfusion are determinant in hepatic ischemia/reperfusion (I/R) injury but may be impacted by different anesthetic agents. Thus, we aimed at comparing the effects of inhaled sevoflurane or intravenous propofol anesthesia on liver mitochondria in a rodent model of hepatic I/R injury. To this, male Wistar rats underwent I/R surgery using sevoflurane or propofol. In the I/R model, propofol limited the raise in serum aminotransferase levels as compared to sevoflurane. Mitochondrial oxygen uptake, respiratory activity, membrane potential and proton leak were altered in I/R; however, this impairment was significantly prevented by propofol but not sevoflurane. In addition, differently from sevoflurane, propofol limited hepatic I/R-induced mitochondria H2O2 production rate, free radical leak and hydroxynonenal-protein adducts levels. The I/R group anesthetized with propofol also showed a better recovery of hepatic ATP homeostasis and conserved integrity of mitochondrial PTP. Moreover, hypoxia-inducible factor 1 alpha (HIF-1α) expression was limited in such group. By using a cell model of desferoxamine-dependent HIF activation, we demonstrated that propofol was able to inhibit apoptosis and mitochondrial depolarization associated to HIF-1α action. In conclusion, hepatic I/R injury induces mitochondrial dysfunction that is not prevented by inhaled sevoflurane. On the contrary, propofol reduces liver damage and mitochondrial dysfunction by preserving respiratory activity, membrane potential and energy homeostasis, and limiting free radicals production as well as PTP opening. These hepatoprotective effects may involve the inhibition of HIF-1α. PMID:27154980

  4. Cell-specific overactivation of nuclear erythroid 2 p45-related factor 2-mediated gene expression in myeloid cells decreases hepatic ischemia/reperfusion injury.

    PubMed

    Lee, Lung-Yi; Harberg, Calvin; Matkowskyj, Kristina A; Cook, Shelly; Roenneburg, Drew; Werner, Sabine; Johnson, Delinda A; Johnson, Jeffrey A; Foley, David P

    2016-08-01

    Hepatic ischemia/reperfusion injury (IRI) is an unavoidable consequence of liver transplantation that can lead to postoperative hepatic dysfunction. Myeloid cells that include Kupffer cells, monocytes, and neutrophils contribute to the inflammatory response and cellular injury observed during hepatic IRI. We hypothesize that overactivation of the nuclear erythroid 2 p45-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway in myeloid cells leads to decreased cellular damage after hepatic IRI. We constructed transgenic mice with constitutively active nuclear erythroid 2 p45-related factor 2 (caNrf2) that over activates the Nrf2-ARE pathway in myeloid cells (lysozyme M cre recombinase [LysMcre]+/caNrf2+, n = 9), and their littermate controls lacking transgene expression (LysMcre+/caNrf2-, n = 11). The mice underwent either sham or partial hepatic ischemia surgery, with 60 minutes of ischemia followed by 6 hours of reperfusion. After IRI, LysMcre+/caNrf2+ mice demonstrated significantly decreased serum alanine aminotransferase and decreased areas of necrosis. Immunohistochemistry and immunoblot of caspase 3 showed a significantly decreased cleaved to full-length caspase 3 ratio in LysMcre+/caNrf2+ animals. Lymphocyte antigen 6 complex locus G and CD68 staining demonstrated reduced inflammatory cell infiltration. LysMcre+/caNrf2+ animals also had significantly decreased gene expression of proinflammatory cytokines, including interleukin (IL) 1β, IL6, tumor necrosis factor α, chemokine (C-C motif) ligand 2, and chemokine (C-X-C motif) ligand 10, and significantly decreased levels of 8-isoprostanes. In our model, Nrf2 overactivation in myeloid cells leads to decreased hepatocellular damage, necrosis, apoptosis, inflammation, and oxidative stress. Pharmacologic targeting of the Nrf2-ARE pathway in myeloid cells may be a novel strategy to mitigate hepatic IRI. Liver Transplantation 22 1115-1128 2016 AASLD. PMID:27113842

  5. miR-30b inhibits autophagy to alleviate hepatic ischemia-reperfusion injury via decreasing the Atg12-Atg5 conjugate

    PubMed Central

    Li, Shi-Peng; He, Jin-Dan; Wang, Zhen; Yu, Yao; Fu, Shu-Yu; Zhang, Hai-Ming; Zhang, Jian-Jun; Shen, Zhong-Yang

    2016-01-01

    AIM: To explore the role and potential mechanism of miR-30b regulation of autophagy in hepatic ischemia-reperfusion injury (IRI). METHODS: An animal model of hepatic IRI was generated in C57BL/6 mice. For in vitro studies, AML12 cells were immersed in mineral oil for 1 h and then cultured in complete Dulbecco’s Modified Eagle’s Medium (DMEM)/F12 to simulate IRI. Mice and cells were transfected with miR-30b agomir/mimics or antagomir/inhibitor to examine the effect of miR-30b on autophagy to promote hepatic IRI. The expression of miR-30b was measured by real-time polymerase chain reaction. Apoptotic cells were detected by terminal uridine nick-end labeling (TUNEL) staining, and cell viability was detected by methylthiazole tetrazolium assay. The expression of light chain 3, autophagy-related gene (Atg)12, Atg5, P62, and caspase-3 were detected by western blotting analysis. RESULTS: miR-30b levels were significantly downregulated after hepatic IRI, and the numbers of autophagosomes were increased in response to IRI both in vivo and in vitro. These findings demonstrate that low levels of miR-30b could promote hepatic IRI. Furthermore, we found that miR-30b interacted with Atg12-Atg5 conjugate by binding to Atg12. Overexpression of miR-30b diminished Atg12 and Atg12-Atg5 conjugate levels, which promoted autophagy in response to IR. In contrast, downregulation of miR-30b was associated with increased Atg12-Atg5 conjugate levels and increased autophagy. CONCLUSION: miR-30b inhibited autophagy to alleviate hepatic ischemia-reperfusion injury via decreasing the Atg12-Atg5 conjugate. PMID:27182160

  6. Hepatic progenitor cells, stem cells, and AFP expression in models of liver injury

    PubMed Central

    Kuhlmann, Wolf D; Peschke, Peter

    2006-01-01

    Adult hepatocytes and liver-cell progenitors play a role in restoring liver tissue after injury. For the study of progenitor cells in liver repair, experimental models included (a) surgical removal of liver tissue by partial hepatectomy; (b) acute injury by carbontetrachloride; (c) acute injury by d-galactosamine (GalN) and N-nitrosomorpholine (NNM); and (d) chemical hepatocarcinogenesis by feeding NNM in low and high doses. Serological and immunohistological detection of alpha-fetoprotein gene expression served to follow pathways of cellular differentiation. Stem cells were not required in models of surgical removal of parenchyma and in carbon tetrachloride intoxication of adult hepatocytes. In contrast, regeneration of liver occurred through biliary epithelial cells in injuries induced by GalN and NNM. These biliary epithelial cells, collectively called oval cells, are most probably derived from the canals of Hering. Proliferating bile duct cells reached a level of differentiation with reactivation of foetal genes and significant alpha-1-fetoprotein (AFP) synthesis signalling a certain degree of retrodifferentiation with potential stemness. Due to the same embryonic origin of bile ducts and hepatocytes, biliary epithelium and its proliferating progeny (oval cells) have a defined role in liver regeneration as a transit and amplification compartment. In their early proliferation stage, oval cells were heavily engaged in DNA synthesis ([3H]thymidine labelling). Pulse-chase experiments during experimental hepatocarcinogenesis exhibited their development into hepatocytes with high risk for transformation and leading to foci of altered hepatocytes. Hepatocellular carcinomas may arise either from proliferating/differentiating oval cells or from adult hepatocytes; both cell types have stem-like properties. AFP-positive and AFP-negative carcinomas occurred in the same liver. They may represent random clonal origin. The heterogeneity of phenotypic marker (AFP) correlated

  7. Effect of infliximab on acute hepatic ischemia/reperfusion injury in rats

    PubMed Central

    Yucel, Ahmet Fikret; Pergel, Ahmet; Aydin, Ibrahim; Alacam, Hasan; Karabicak, Ilhan; Kesicioglu, Tugrul; Tumkaya, Levent; Kalkan, Yildiray; Ozer, Ender; Arslan, Zakir; Sehitoglu, Ibrahim; Sahin, Dursun Ali

    2015-01-01

    This study aimed to investigate the hepatoprotective and antioxidant effects of infliximab (IFX) against liver ischemia/reperfusion (I/R) injury in rats. A total of 30 male Wistar albino rats were divided into three groups: sham, I/R, and I/R+IFX. IFX was given at a dose of 3 mg/kg for three days before I/R. Rat livers were subjected to 60 min of ischemia followed by 90 h of reperfusion. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), TNF-α, malondialdehyde (MDA), and glutathione peroxidase (GSH-Px) levels were measured in the serum. The liver was removed to evaluate the histopathologic changes. The I/R group had a significant increase in AST, ALT, MDA, and TNF-α levels, and a decrease in GSH-Px activity compared with the sham group. The use of IFX significantly reduced the ALT, AST, MDA and TNF-α levels and significantly increased GSH-Px activity. IFX attenuated the histopathologic changes. IFX has a protective effect on liver I/R injury. This liver protective effect may be related to antioxidant and anti-TNF-α effects. We propose that, for the relief of liver injury subsequent to transplantation, liver resection, trauma, and shock, tentative treatments can be incorporated with IFX, which is already approved for clinical use. PMID:26885068

  8. Protective effect of R. glutinosa oligosaccharides against high l-carnitine diet-induced endothelial dysfunction and hepatic injury in mice.

    PubMed

    Li, Wenfeng; Zhang, Ruijun; Guo, Jianjun; Shao, Hongjun; Yang, Xingbin

    2016-04-01

    Current research for the first time demonstrated that endothelial dysfunction and hepatic injury in mice were induced by ingestion of 3% l-carnitine water for consecutive 10 weeks. Interestingly, oral administration of dietary raffinose family oligosaccharides (RFOs) at 400 and 800mg/kgbw significantly reduced the impact of l-carnitine on the serum total cholesterol, triglycerides, high- and low-density lipoproteins, alanine aminotransferase, aspartate amino-transferase, NO, endothelin-1 and C-reactive protein. Furthermore, l-carnitine-induced elevation of hepatic lipid contents and malonaldehyde formation, and the inhibition of SOD and GSH-Px activities in mice were markedly ameliorated by oral administration of RFOs. Moreover, histopathology of H&E and Oil Red O staining of the liver also confirmed the protective effect of RFOs against hepatic steatosis and oxidative injury induced by high l-carnitine diet in mice. These findings for the first time suggest that RFOs may alleviate endothelial dysfunction and liver injury from ingestion of high l-carnitine diet. PMID:26769087

  9. A One-Two Punch: Hydralazine-Induced Liver Injury in a Recovering Ischemic Hepatitis.

    PubMed

    Alansari, Ahmed; Quiel, Luis; Boma, Noella

    2016-01-01

    A 77-year-old woman presented to the emergency department with a 2-day history of nausea and vomiting. Her medical history included diabetes mellitus, hypertension, atrial fibrillation, dilated cardiomyopathy, and coronary artery disease. Her home medications included aspirin, clopidogrel, warfarin, digoxin, metoprolol, losartan, simvastatin, isosorbide dinitrate, furosemide, and spironolactone. Initial physical examination showed blood pressure of 170/80 mm Hg with a heart rate of 69 beats per minute, otherwise unremarkable. Initial laboratory workup was significant for INR of 3.6, with slightly elevated troponin I and creatinine of 0.06 ng/mL and 1.4 mg/dL, respectively. The patient was admitted to the medicine floor. However, a few hours later, her atrial fibrillation went into rapid ventricular response, associated with hypotension. Cardiac enzymes began to trend up along with worsening of her renal function tests and hepatic enzymes. Her INR remained supratherapeutic despite holding coumadin and giving vitamin K. The patient was transferred to the medical intensive care unit for closer monitoring. During day 1 of the medical intensive care unit stay, losartan, simvastatin, and diuretics were held, whereas aspirin, clopidogrel, and isosorbide dinitrate were continued. In the following 2 days, there was worsening of tissue perfusion, and laboratory workup showed AST 514 IU/L, ALT 391 IU/L, INR >9, creatinine 3.8 mg/dL, and troponin I 0.19 ng/mL; therefore, digoxin was also held. Once the patient achieved hemodynamic stability, she was started on hydralazine. On day 4, renal function, cardiac, and hepatic enzymes improved significantly. However, 24 hours later, transaminases began to trend up again reaching a maximum of AST and ALT of 359 and 525 IU/L, respectively. Other possible causes were ruled out because her viral hepatitis markers, antihistone antibody, antinuclear antibody, and anti-double-stranded DNA were all negative. After thorough review of all

  10. Fumigaclavine C improves concanavalin A-induced liver injury in mice mainly via inhibiting TNF-alpha production and lymphocyte adhesion to extracellular matrices.

    PubMed

    Zhao, Ying; Liu, Junyan; Wang, Jun; Wang, Lei; Yin, Hao; Tan, Renxiang; Xu, Qiang

    2004-06-01

    Fumigaclavine C, an alkaloidal metabolite, was produced by Aspergillus fumigatus (strain No. CY018). This study examined the effect of this compound on concanavalin A (Con A)-induced liver injury in mice, a T cell-dependent model of liver damage. Con A administration resulted in severe liver injury, T lymphocyte activation and a strong increment in spleen cell adhesion, as well as in tumour necrosis factor-alpha (TNF-alpha) production. Against this liver injury, the intraperitoneal administration of fumigaclavine C dose-dependently inhibited the elevation in transaminase activity, TNF-alpha production in serum and the histological changes, including inflammatory infiltration, hepatocyte necrosis and degeneration and Kupffer cell hyperplasia. In addition, this compound in-vitro also inhibited the proliferation of spleen cells induced by Con A, and reduced their IL-2 and TNF-alpha production. Moreover, the intraperitoneal administration of fumigaclavine C inhibited the potential of spleen cells isolated from the liver-injured mice to adhere to fibronectin, laminin and type IV collagen. These results suggest that the improvement of this T cell-mediated liver injury by fumigaclavine C may be related to the inhibition of lymphocyte activation, proliferation and adhesion to extracellular matrices as well as the reduction in TNF-alpha production. PMID:15231043

  11. Myeloid Knockout of HIF-1α Does Not Markedly Affect Hemorrhage/Resuscitation-Induced Inflammation and Hepatic Injury

    PubMed Central

    Wetzel, G.; Relja, B.; Klarner, A.; Henrich, D.; Dehne, N.; Brühne, B.; Lehnert, M.; Marzi, I.

    2014-01-01

    Background. Hypoxia-inducible factor-1α (HIF-1α) and NF-κB play important roles in the inflammatory response after hemorrhagic shock and resuscitation (H/R). Here, the role of myeloid HIF-1α in liver hypoxia, injury, and inflammation after H/R with special regard to NF-κB activation was studied. Methods. Mice with a conditional HIF-1α knockout (KO) in myeloid cell-line and wild-type (WT) controls were hemorrhaged for 90 min (30 ± 2 mm Hg) and resuscitated. Controls underwent only surgical procedures. Results. After six hours, H/R enhanced the expression of HIF-1α-induced genes vascular endothelial growth factor (VEGF) and adrenomedullin (ADM). In KO mice, this was not observed. H/R-induced liver injury in HIF-1α KO was comparable to WT. Elevated plasma interleukin-6 (IL-6) levels after H/R were not reduced by HIF-1α KO. Local hepatic hypoxia was not significantly reduced in HIF-1α KO compared to controls after H/R. H/R-induced NF-κB phosphorylation in liver did not significantly differ between WT and KO. Conclusions. Here, deleting HIF-1α in myeloid cells and thereby in Kupffer cells was not protective after H/R. This data indicates that other factors, such as NF-κB, due to its upregulated phosphorylation in WT and KO mice, contrary to HIF-1α, are rather key modulators of inflammation after H/R in our model. PMID:24991092

  12. Estrogen-related receptor γ controls hepatic CB1 receptor-mediated CYP2E1 expression and oxidative liver injury by alcohol

    PubMed Central

    Jang, Hyun-Hee; Park, Jinyoung; Kim, Jung Ran; Koh, Minseob; Jeong, Won-Il; Koo, Seung-Hoi; Park, Tae-Sik; Yun, Chul-Ho; Park, Seung Bum; Chiang, John Y L; Lee, Chul-Ho; Choi, Hueng-Sik

    2013-01-01

    Background The hepatic endocannabinoid system and cytochrome P450 2E1 (CYP2E1), a key enzyme causing alcohol-induced reactive oxygen species (ROS) generation, are major contributors to the pathogenesis of alcoholic liver disease. The nuclear hormone receptor oestrogen-related receptor γ (ERRγ) is a constitutively active transcriptional activator regulating gene expression. Objective To investigate the role of ERRγ in the alcohol-mediated regulation of CYP2E1 and to examine the possibility to control alcohol-mediated oxidative stress and liver injury through an ERRγ inverse agonist. Design For chronic alcoholic hepatosteatosis study, C57BL/6J wild-type and CB1−/− mice were administered alcohol for 4 weeks. GSK5182 and chlormethiazole (CMZ) were given by oral gavage for the last 2 weeks of alcohol feeding. Gene expression profiles and biochemical assays were performed using the liver or blood of mice. Results Hepatic ERRγ gene expression induced by alcohol-mediated activation of CB1 receptor results in induction of CYP2E1, while liver-specific ablation of ERRγ gene expression blocks alcohol-induced expression of CYP2E1 in mouse liver. An ERRγ inverse agonist significantly ameliorates chronic alcohol-induced liver injury in mice through inhibition of CYP2E1-mediated generation of ROS, while inhibition of CYP2E1 by CMZ abrogates the beneficial effects of the inverse agonist. Finally, chronic alcohol-mediated ERRγ and CYP2E1 gene expression, ROS generation and liver injury in normal mice were nearly abolished in CB1−/− mice. Conclusions ERRγ, as a previously unrecognised transcriptional regulator of hepatic CB1 receptor, controls alcohol-induced oxidative stress and liver injury through CYP2E1 induction, and its inverse agonist could ameliorate oxidative liver injury due to chronic alcohol exposure. PMID:23023167

  13. Potent hepatoprotective effect in CCl4-induced hepatic injury in mice of phloroacetophenone from Myrcia multiflora

    PubMed Central

    Ferreira, Eduardo Antonio; Gris, Eliana Fortes; Felipe, Karina Bettega; Correia, João Francisco Gomes; Cargnin-Ferreira, Eduardo; Wilhelm Filho, Danilo; Pedrosa, Rozangela Curi

    2010-01-01

    Background This study investigated the hepatoprotective effect and antioxidant properties of phloroacetophenone (2′,4′,6′-trihydroxyacetophenone – THA), an acetophenone derived from the plant Myrcia multiflora. Material & Method The free radical scavenging activity in vitro and induction of oxidative hepatic damage by carbon tetrachloride (CCl4) (0.5 ml/kg, i.p.) were tested in male Swiss mice (25±5 g). Results This compound exhibited in vitro antioxidant effects on FeCl2–ascorbate-induced lipid peroxidation (LPO) in mouse liver homogenate, scavenging hydroxyl and superoxide radicals, and 2,2-diphenyl-1-picrylhydrazyl. The in vivo assays showed that THA significantly (p<0.01) prevented the increases of hepatic LPO as measured by the levels of thiobarbituric acid-reactive substances, mitochondrial swelling. It also protected hepatocytes against protein carbonylation and oxidative DNA damage. Consistent with these observations, THA pre-treatment normalized the activities of antioxidant enzymes, such as catalase, glutathione peroxidase, and superoxide dismutase, and increased the levels of reduced glutathione (GSH) in CCl4-treated mice. In addition, THA treatment significantly prevented the elevation of serum enzymatic activities of alanine amino transferase, aspartate amino transferase, and lactate dehydrogenase, as well as histological alterations induced by CCl4. Silymarin (SIL) (24 mg/kg), a known hepatoprotective drug used for comparison, led to a significant decrease (p<0.01) in activities of theses enzymes in way very similar to that observed in pre-treatment with THA. Conclusion These results suggest that the protective effects are due to reduction of oxidative damage induced by CCl4 resulting from the antioxidant properties of THA. PMID:21483585

  14. Prenatal administration of the cytochrome P4501A inducer, {Beta}-naphthoflavone (BNF), attenuates hyperoxic lung injury in newborn mice: Implications for bronchopulmonary dysplasia (BPD) in premature infants

    SciTech Connect

    Couroucli, Xanthi I.; Liang Yanhong Wei; Jiang Weiwu; Wang Lihua; Barrios, Roberto; Yang Peiying; Moorthy, Bhagavatula

    2011-10-15

    Supplemental oxygen contributes to the development of bronchopulmonary dysplasia (BPD) in premature infants. In this investigation, we tested the hypothesis that prenatal treatment of pregnant mice (C57BL/6J) with the cytochrome P450 (CYP)1A1 inducer, ss-napthoflavone (BNF), will lead to attenuation of lung injury in newborns (delivered from these dams) exposed to hyperoxia by mechanisms entailing transplacental induction of hepatic and pulmonary CYP1A enzymes. Pregnant mice were administered the vehicle corn oil (CO) or BNF (40 mg/kg), i.p., once daily for 3 days on gestational days (17-19), and newborns delivered from the mothers were either maintained in room air or exposed to hyperoxia (> 95% O{sub 2}) for 1-5 days. After 3-5 days of hyperoxia, the lungs of CO-treated mice showed neutrophil infiltration, pulmonary edema, and perivascular inflammation. On the other hand, BNF-pretreated neonatal mice showed decreased susceptibility to hyperoxic lung injury. These mice displayed marked induction of ethoxyresorufin O-deethylase (EROD) (CYP1A1) and methoxyresorufin O-demethylase (MROD) (CYP1A2) activities, and levels of the corresponding apoproteins and mRNA levels until PND 3 in liver, while CYP1A1 expression alone was augmented in the lung. Prenatal BNF did not significantly alter gene expression of pulmonary NAD(P)H quinone reductase (NQO1). Hyperoxia for 24-72 h resulted in increased pulmonary levels of the F{sub 2}-isoprostane 8-iso-PGF{sub 2{alpha}}, whose levels were decreased in mice prenatally exposed to BNF. In conclusion, our results suggest that prenatal BNF protects newborns against hyperoxic lung injury, presumably by detoxification of lipid hydroperoxides by CYP1A enzymes, a phenomenon that has implications for prevention of BPD in infants. - Highlights: > Supplemental oxygen is routinely administered to premature infants. > Hyperoxia causes lung injury in experimental animals. > Prenatal treatment of mice with beta-naphthoflavone attenuates oxygen

  15. Red cabbage (Brassica oleracea L.) mediates redox-sensitive amelioration of dyslipidemia and hepatic injury induced by exogenous cholesterol administration.

    PubMed

    Al-Dosari, Mohammed S

    2014-01-01

    The widely used culinary vegetable, red cabbage (Brassica oleracea L. Var. capitata f. rubra), of the Brassicaceae family contains biologically potent anthocyanins and a myriad of antioxidants. Previous studies have shown that the pharmacological effects of red cabbage in vivo are redox-sensitive. The present study explored whether red cabbage modulates various histopathological and biochemical parameters in rats administered with a cholesterol-rich diet (CRD). To this end, prolonged administration of a lyophilized-aqueous extract of red cabbage (250 and 500 mg/kg body weight) significantly blunted the imbalances in lipids, liver enzymes and renal osmolytes induced by the CRD. The effects of red cabbage were compared to simvastatin (30 mg/kg body weight) treated rats. Estimation of malondialdehyde and non-protein sulfhydryls revealed robust antioxidant properties of red cabbage. Histopathological analysis of livers from rats administered with red cabbage showed marked inhibition in inflammatory and necrotic changes triggered by CRD. Similarly, in vitro studies using a 2',7'-Dichlorofluorescein-based assay showed that red cabbage conferred cytoprotective effects in cultured HepG2 cells. In conclusion, the present study discloses the potential therapeutic effects of red cabbage in dyslipidemia as well as hepatic injury, that is at least, partly mediated by its antioxidant properties. PMID:24467544

  16. Purple potato (Solanum tuberosum L.) anthocyanins attenuate alcohol-induced hepatic injury by enhancing antioxidant defense.

    PubMed

    Jiang, Zhihui; Chen, Chen; Wang, Jian; Xie, Wenyan; Wang, Meng; Li, Xinsheng; Zhang, Xiaoying

    2016-01-01

    Alcoholic liver disease (ALD) is a serious and challenging health issue. In the past decade, natural components possessing hepatoprotective properties have gained more attention for ALD intervention. In this study, the phytochemical components of anthocyanins from purple potato were assessed using UPLC-MS/MS, and the hepatoprotective effects of purple potato anthocyanins (PPAs) were investigated in the ALD mouse model. Serum and liver biochemical parameters were determined, along with histopathological changes in liver tissue. In addition, the major contributors to alcohol-induced oxidative stress were assessed. The results indicated that the levels of aspartate transaminase and alanine transaminase were lower in the serum of the PPA-treated group than the alcohol-treated group. PPAs significantly inhibited the reduction of total cholesterol and triglycerides. Higher levels of superoxide dismutase and reduced glutathione enzymes as well as a reduction in the formation of malondialdehyde occurred in mice fed with PPAs. In addition, PPAs protected against increased alcohol-induced levels and activity of cytochrome P450 2E1 (CYP2E1), which demonstrates the effects of PPAs against alcohol-induced oxidative stress and liver injury. This study suggests that PPAs could be an effective therapeutic agent in alcohol-induced liver injuries by inhibiting CYP2E1 expression and thereby strengthening antioxidant defenses. PMID:26481011

  17. Therapeutic Efficacy of Nigella Sativa Linn. against Antituberculosis Drug-Induced Hepatic Injury in Wistar Rats.

    PubMed

    Jaswal, Amita; Sharma, Monika; Raghuvanshi, Suchita; Sharma, Samta; Reshi, Mohd Salim; Uthra, Chhavi; Shukla, Sangeeta

    2016-01-01

    Antituberculosis drug (ATD)-induced hepatotoxicity is a major impediment for the effective treatment of tuberculosis (TB). All first-line anti-TB medications have adverse effects that interrupt the successful completion of TB treatment. This investigation focuses on the evaluation of the protective role of Nigella sativa (NS) against liver injury caused by ATDs. Female rats were treated with ATDs for 8 weeks (3 d/wk) followed by NS for 8 weeks (3 d/wk). The antioxidant activity of NS was estimated with a 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay and by analyzing total phenolic contents. Qualitative characterization of active compounds of the plant was done by high-performance liquid chromotography (HPLC). ATD-induced adverse effects were associated with sharp elevation in levels of serum transaminases, albumin, cholesterol, urea, uric acid, creatinine, and blood urea nitrogen (BUN). ATDs significantly increased lipid peroxidation (LPO) and decreased enzyme activities (superoxide dismutase [SOD], catalase [CAT], adenosine triphosphatase [ATPase], and glucose-6-phosphatase [G6Pase]) in liver, indicating oxidative stress. Conjoint treatment with NS could reverse the serological biochemistry and inhibit oxidative stress by suppressing LPO and augmenting antioxidant enzyme activity toward that of the control. Histological studies support the above biochemical findings. Results indicate that NS exerts excellent hepatoprotective abilities and can be used as a supplement to improve patient adherence and reduce interruptions in treatment due to ATD-related liver injury. PMID:27279584

  18. Xiayuxue decoction reduces renal injury by promoting macrophage apoptosis in hepatic cirrhotic rats.

    PubMed

    Liu, C; Cai, J; Cheng, Z; Dai, X; Tao, L; Zhang, J; Xue, D

    2015-01-01

    Renal pathological changes in cirrhotic rat have not been extensively reported. The aim of this study was to investigate whether Xiayuxue decoction (XYXD) could attenuate renal injury induced by bile duct ligation (BDL), with special focus on the mechanisms promoting renal macrophage apoptosis. The rats were treated with BDL for 5 weeks and administered 0.36 g/kg XYXD intragastrically from day 1 of initiating BDL. Renal tissue was monitored by hematoxylin-eosin and Sirius red staining. Macrophage infiltration and proinflammatory cytokines such as tumor necrosis factor and chemokine ligand 2 were detected by quantitative polymerase chain reaction. Macrophage apoptosis was detected by double immunofluorescence staining. Blood urea nitrogen, creatinine, and glomerulus diameter increased significantly after a 5-week BDL treatment in XYXD (BDL-XYXD) rats. CD68 and pro-inflammatory cytokine mRNA increased in the kidneys of control (BDL-water) rats. Fluorescence microscopy analysis showed that XYXD promoted apoptosis in renal CD68+ macrophages. Collogen1 (Col 1), pro-fibrogenic cytokines, and α-smooth muscle actin in kidneys of BDL-water rats increased significantly compared to the sham group. XYXD inhibited Col 1 and pro-fibrotic factors in BDL-XYXD rats. Our results demonstrated that XYXD significantly reduced renal injury by, at least in part, promoting macrophage apoptosis in rats with damaged renal histopathology due to BDL-induced cirrhosis. PMID:26400305

  19. Hepatitis E Pathogenesis.

    PubMed

    Lhomme, Sébastien; Marion, Olivier; Abravanel, Florence; Chapuy-Regaud, Sabine; Kamar, Nassim; Izopet, Jacques

    2016-01-01

    Although most hepatitis E virus (HEV) infections are asymptomatic, some can be severe, causing fulminant hepatitis and extra-hepatic manifestations, including neurological and kidney injuries. Chronic HEV infections may also occur in immunocompromised patients. This review describes how our understanding of the pathogenesis of HEV infection has progressed in recent years. PMID:27527210

  20. Hepatitis E Pathogenesis

    PubMed Central

    Lhomme, Sébastien; Marion, Olivier; Abravanel, Florence; Chapuy-Regaud, Sabine; Kamar, Nassim; Izopet, Jacques

    2016-01-01

    Although most hepatitis E virus (HEV) infections are asymptomatic, some can be severe, causing fulminant hepatitis and extra-hepatic manifestations, including neurological and kidney injuries. Chronic HEV infections may also occur in immunocompromised patients. This review describes how our understanding of the pathogenesis of HEV infection has progressed in recent years. PMID:27527210

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

    PubMed

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

    2014-01-01

    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. PMID:24269813

  2. The Effect of Etoricoxib on Hepatic Ischemia-Reperfusion Injury in Rats

    PubMed Central

    Kunak, Celalettin Semih; Kukula, Osman; Mutlu, Emre; Genç, Fatma; Güleç Peker, Gülçer; Kuyrukluyıldız, Ufuk; Binici, Orhan; Altuner, Durdu; Alp, Hamit Hakan

    2015-01-01

    Ischemia-reperfusion (I/R) damage is known to be a pathological process which continues with the increase of oxidants and expands with the inflammatory response. There is not any study about protective effect of etoricoxib on the liver I/R damage in literature. Objective. This study investigates the effect of etoricoxib on oxidative stress induced by I/R of the rat liver. Material and Methods. Experimental animals were divided into four groups as liver I/R control (LIRC), 50 mg/kg etoricoxib + liver I/R (ETO-50), 100 mg/kg etoricoxib + liver I/R (ETO-100), and healthy group (HG). ETO-50 and ETO-100 groups were administered etoricoxib, while LIRC and HG groups were orally given distilled water by gavage. Hepatic artery was clamped for one hour to provide ischemia, and then reperfusion was provided for 6 hours. Oxidant, antioxidant, and COX-2 gene expressions were studied in the liver tissues. ALT and AST were measured. Results. Etoricoxib in 50 and 100 mg/kg doses changed the levels of oxidant/antioxidant parameters such as MDA, MPO, tGSH, GSHRd, GST, SOD, NO, and 8-OH/Gua in favour of antioxidants. Furthermore, etoricoxib prevented increase of COX-2 gene expression and ALT and AST levels. This important protective effect of etoricoxib on the rat liver I/R can be tested in the clinical setting. PMID:26236425

  3. The Protective Effects of Trypsin Inhibitor on Hepatic Ischemia-Reperfusion Injury and Liver Graft Survival

    PubMed Central

    Guan, Lianyue; Liu, Hongyu; Fu, Peiyao; Li, Zhuonan; Li, Peidong; Xie, Lijuan; Xin, Mingang; Wang, Zhanpeng

    2016-01-01

    The aim of this study was to explore the protective effects of ulinastatin (urinary trypsin inhibitor, UTI) on liver ischemia-reperfusion injury (IRI) and graft survival. We employed mouse liver cold IRI and orthotopic liver transplantation (OLTx) models. UTI was added to lactated Ringer's (LR) solution for liver perfusion and preservation in vitro or combined with UTI injection intraperitoneally to the liver graft recipient. Our results indicated that UTI supplementation protected the liver from cold IRI in a dose-dependent manner and prolonged liver graft survival from extended cold preserved liver donors significantly. The underlying mechanism of UTI on liver IRI may be mediated by inhibition of proinflammatory cytokine release, increasing the expression of the antiapoptotic gene Bcl-2 and decreasing the expression of the proapoptosis genes of Caspase-3 and Bax, and further protects hepatocytes from apoptotic death and improves liver function. PMID:26783413

  4. HDACi Valproic Acid (VPA) and Suberoylanilide Hydroxamic Acid (SAHA) Delay but Fail to Protect against Warm Hepatic Ischemia-Reperfusion Injury

    PubMed Central

    Ruess, Dietrich A.; Probst, Moriz; Marjanovic, Goran; Wittel, Uwe A.; Hopt, Ulrich T.; Keck, Tobias; Bausch, Dirk

    2016-01-01

    Background Histone deacetylases (HDAC) catalyze N-terminal deacetylation of lysine-residues on histones and multiple nuclear and cytoplasmic proteins. In various animal models, such as trauma/hemorrhagic shock, ischemic stroke or myocardial infarction, HDAC inhibitor (HDACi) application is cyto- and organoprotective and promotes survival. HDACi reduce stress signaling, cell death and inflammation. Hepatic ischemia-reperfusion (I/R) injury during major liver resection or transplantation increases morbidity and mortality. Assuming protective properties, the aim of this study was to investigate the effect of the HDACi VPA and SAHA on warm hepatic I/R. Material and Methods Male Wistar-Kyoto rats (age: 6–8 weeks) were randomized to VPA, SAHA, vehicle control (pre-) treatment or sham-groups and underwent partial no-flow liver ischemia for 90 minutes with subsequent reperfusion for 6, 12, 24 and 60 hours. Injury and regeneration was quantified by serum AST and ALT levels, by macroscopic aspect and (immuno-) histology. HDACi treatment efficiency, impact on MAPK/SAPK-activation and Hippo-YAP signaling was determined by Western blot. Results Treatment with HDACi significantly enhanced hyperacetylation of Histone H3-K9 during I/R, indicative of adequate treatment efficiency. Liver injury, as measured by macroscopic aspect, serum transaminases and histology, was delayed, but not alleviated in VPA and SAHA treated animals. Importantly, tissue destruction was significantly more pronounced with VPA. SAPK-activation (p38 and JNK) was reduced by VPA and SAHA in the early (6h) reperfusion phase, but augmented later on (JNK, 24h). Regeneration appeared enhanced in SAHA and VPA treated animals and was dependent on Hippo-YAP signaling. Conclusions VPA and SAHA delay warm hepatic I/R injury at least in part through modulation of SAPK-activation. However, these HDACi fail to exert organoprotective effects, in this setting. For VPA, belated damage is even aggravated. PMID:27513861

  5. Glutathione peroxidase-deficient mice are more susceptible to neutrophil-mediated hepatic parenchymal cell injury during endotoxemia: importance of an intracellular oxidant stress.

    PubMed

    Jaeschke, H; Ho, Y S; Fisher, M A; Lawson, J A; Farhood, A

    1999-02-01

    Neutrophils contribute to hepatocellular injury in a number of acute inflammatory reactions. However, the molecular mechanism of parenchymal cell injury remains controversial. To address the issue of whether or not reactive oxygen species (ROS) are important in the injury process, we used the galactosamine/endotoxin (Gal/ET) model of acute liver failure, which involves a neutrophil-mediated parenchymal cell injury. In C3Heb/FeJ mice, Gal/ET induced a significant increase of hepatic and plasma levels of glutathione disulfide (GSSG), an indicator of oxidant stress, selectively during the neutrophil-mediated injury phase. In glutathione peroxidase-deficient mice (Gpx1(-/-)), Gal/ET or Gal/tumor necrosis factor alpha (TNF-alpha) caused more severe neutrophil-mediated liver injury compared with wild-type animals. However, there was no significant difference in other critical parameters, e.g., activation of the transcription factor, nuclear factor-kappaB (NF-kappaB), and soluble intercellular adhesion molecule-1 (sICAM-1), parenchymal cell apoptosis, and neutrophil sequestration in the liver. Our results suggest that neutrophil-derived ROS are responsible for an intracellular oxidant stress in hepatocytes after Gal/ET treatment. Because of the higher susceptibility of Gpx1(-/-) mice to a neutrophil-mediated injury, we conclude that peroxides generated by neutrophils diffused into hepatocytes and contributed to parenchymal cell death in vivo. Thus, strengthening defense mechanisms against ROS in target cells can attenuate excessive inflammatory injury without affecting host defense reactions. PMID:9918921

  6. The protective effects of carnosine in alcohol-induced hepatic injury in rats.

    PubMed

    Baykara, B; Micili, S Cilaker; Tugyan, K; Tekmen, I; Bagriyanik, Ha; Sonmez, U; Sonmez, A; Oktay, G; Yener, N; Ozbal, S

    2014-02-01

    Consumption of alcohol leads to oxidative stress in liver by inducing lipid peroxidation. The aim of this study was to investigate the effects of carnosine (CAR) in alcohol-induced liver injury by biochemical and histomorphological evaluations. The rats were divided into four groups, namely, control group, alcohol (AL) group, CAR group and AL + CAR group. Three doses of ethanol (5 g/kg, 25% (v/v) in distilled water) were given by nasogastric catheter for twice-a-day. CAR (100 mg/kg) was given 1 h before the administration of ethanol using the same method. Levels of alanine aminotransferase, aspartate aminotransferase, myeloperoxidase and malondialdehyde were significantly increased in the AL group compared with control, CAR and AL + CAR groups. Glutathione level was significantly decreased in the AL group, while it was increased in the AL + CAR group. Immunoreactivity of caspase-3 and bax increased in the hepatocytes of AL group when compared with control and AL + CAR groups. Expression of bcl-2 was decreased in AL group than AL + CAR group. Under electron microscopy, dense mitochondria, accumulation of lipid, sinusoidal dilatation, vacuolization and decrease in the number of microvilli were observed in AL group, while these findings were markedly less in the AL + CAR group. In conclusion, pretreatment of CAR is effective for recovering biochemical alterations and morphologic damage in the liver of rats treated with ethanol. PMID:22661399

  7. Is montelukast as effective as N-acetylcysteine in hepatic injury due to acetaminophen intoxication in rats?

    PubMed

    İçer, Mustafa; Zengin, Yilmaz; Gunduz, Ercan; Dursun, Recep; Durgun, Hasan Mansur; Turkcu, Gul; Yuksel, Hatice; Üstündağ, Mehmet; Guloglu, Cahfer

    2016-01-01

    This study aims to investigate the acute protective effect of montelukast sodium in hepatic injury secondary to acetaminophen (APAP) intoxication. This study used 60 rats. The rats were grouped into 6 groups. The control group was administered oral distilled water 10 ml/kg, the APAP group oral APAP 1 g/kg, the montelukast sodium (MK) group oral MK 30 mg/kg, the acetaminophen+N-acetylcysteine (APAP+NAC) group oral APAP 1 g/kg, followed by a single dose of intraperitoneal NAC 1.5 g/kg three hours later, the acetaminophen+montelukast sodium (APAP+MK) group oral APAP 1 g/kg, followed by oral MK 30 mg/kg 3 h later, the acetaminophen+N-acetylcysteine+montelukast sodium (APAP+NAC+MK) group oral APAP 1 g/kg, followed by a single intraperitoneal NAC 1.5 g/kg plus oral MK 30 mg/kg 3 h later. Blood and liver tissue samples were taken 24h after drug administration. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and total bilirubin were studied from the blood samples. Liver tissue samples were used for histopathological examination. Compared with the control group, serum AST and ALT activities were higher in the APAP and APAP+NAC groups. APAP+NAC, APAP+MK, and APAP+NAC+MK groups had reduced serum ALT and AST activities than the group administered APAP alone. APAP+MK and APAP+NAC+MK groups had a lower serum ALP activity than the control group. Histopathologically, there was a difference between the group administered APAP alone and the APAP+MK and APAP+NAC+MK groups. MK is as protective as NAC in liver tissue in APAP intoxication in rats. PMID:26462568

  8. Reduced inflammatory response and increased microcirculatory disturbances during hepatic ischemia-reperfusion injury in steatotic livers of ob/ob mice

    PubMed Central

    Hasegawa, Tadashi; Ito, Yoshiya; Wijeweera, Jayanthika; Liu, Jie; Malle, Ernst; Farhood, Anwar; McCuskey, Robert S.; Jaeschke, Hartmut

    2016-01-01

    Steatosis is a major risk factor for complications after liver surgery. Since neutrophil cytotoxicity is critical for ischemia-reperfusion injury in normal livers, the aim of the present study was to evaluate whether an exaggerated inflammatory response could cause the increased injury in steatotic livers. In C57Bl/6 mice, 60 min of warm hepatic ischemia triggered a gradual increase in hepatic neutrophil accumulation during reperfusion with peak levels of 100-fold over baseline at 12 h of reperfusion. Neutrophil extravasation and a specific neutrophil-induced oxidant stress (immunostaining for hypochlorous acid-modified epitopes) started at 6 h of reperfusion and peaked at 12–24 h. Ob/ob mice, which had a severe macrovesicular steatosis, suffered significantly higher injury (alanine transaminase activity: 18,000 ± 2,100 U/l; 65% necrosis) compared with lean littermates (alanine transaminase activity: 4,900 ± 720 U/l; 24% necrosis) at 6 h of reperfusion. However, 62% fewer neutrophils accumulated in steatotic livers. This correlated with an attenuated increase in mRNA levels of several proinflammatory genes in ob/ob mice during reperfusion. In contrast, sham-operated ob/ob mice had a 50% reduction in liver blood flow and 35% fewer functional sinusoids compared with lean littermates. These deficiencies in liver blood flow and the microcirculation were further aggravated only in ob/ob mice during reperfusion. The attenuated inflammatory response and reduced neutrophil-induced oxidant stress observed in steatotic livers during reperfusion cannot be responsible for the dramatically increased injury in ob/ob mice. In contrast, the aggravated injury appears to be mediated by ischemic necrosis due to massive impairment of blood and oxygen supply in the steatotic livers. PMID:17307725

  9. Reduced inflammatory response and increased microcirculatory disturbances during hepatic ischemia-reperfusion injury in steatotic livers of ob/ob mice.

    PubMed

    Hasegawa, Tadashi; Ito, Yoshiya; Wijeweera, Jayanthika; Liu, Jie; Malle, Ernst; Farhood, Anwar; McCuskey, Robert S; Jaeschke, Hartmut

    2007-05-01

    Steatosis is a major risk factor for complications after liver surgery. Since neutrophil cytotoxicity is critical for ischemia-reperfusion injury in normal livers, the aim of the present study was to evaluate whether an exaggerated inflammatory response could cause the increased injury in steatotic livers. In C57Bl/6 mice, 60 min of warm hepatic ischemia triggered a gradual increase in hepatic neutrophil accumulation during reperfusion with peak levels of 100-fold over baseline at 12 h of reperfusion. Neutrophil extravasation and a specific neutrophil-induced oxidant stress (immunostaining for hypochlorous acid-modified epitopes) started at 6 h of reperfusion and peaked at 12-24 h. Ob/ob mice, which had a severe macrovesicular steatosis, suffered significantly higher injury (alanine transaminase activity: 18,000 +/- 2,100 U/l; 65% necrosis) compared with lean littermates (alanine transaminase activity: 4,900 +/- 720 U/l; 24% necrosis) at 6 h of reperfusion. However, 62% fewer neutrophils accumulated in steatotic livers. This correlated with an attenuated increase in mRNA levels of several proinflammatory genes in ob/ob mice during reperfusion. In contrast, sham-operated ob/ob mice had a 50% reduction in liver blood flow and 35% fewer functional sinusoids compared with lean littermates. These deficiencies in liver blood flow and the microcirculation were further aggravated only in ob/ob mice during reperfusion. The attenuated inflammatory response and reduced neutrophil-induced oxidant stress observed in steatotic livers during reperfusion cannot be responsible for the dramatically increased injury in ob/ob mice. In contrast, the aggravated injury appears to be mediated by ischemic necrosis due to massive impairment of blood and oxygen supply in the steatotic livers. PMID:17307725

  10. Regulator of G-Protein Signaling-5 Is a Marker of Hepatic Stellate Cells and Expression Mediates Response to Liver Injury

    PubMed Central

    Bahrami, Arya J.; Gunaje, Jagadambika J.; Hayes, Brian J.; Riehle, Kimberly J.; Kenerson, Heidi L.; Yeung, Raymond S.; Stempien-Otero, April S.; Campbell, Jean S.; Mahoney, William M.

    2014-01-01

    Liver fibrosis is mediated by hepatic stellate cells (HSCs), which respond to a variety of cytokine and growth factors to moderate the response to injury and create extracellular matrix at the site of injury. G-protein coupled receptor (GPCR)-mediated signaling, via endothelin-1 (ET-1) and angiotensin II (AngII), increases HSC contraction, migration and fibrogenesis. Regulator of G-protein signaling-5 (RGS5), an inhibitor of vasoactive GPCR agonists, functions to control GPCR-mediated contraction and hypertrophy in pericytes and smooth muscle cells (SMCs). Therefore we hypothesized that RGS5 controls GPCR signaling in activated HSCs in the context of liver injury. In this study, we localize RGS5 to the HSCs and demonstrate that Rgs5 expression is regulated during carbon tetrachloride (CCl4)-induced acute and chronic liver injury in Rgs5LacZ/LacZ reporter mice. Furthermore, CCl4 treated RGS5-null mice develop increased hepatocyte damage and fibrosis in response to CCl4 and have increased expression of markers of HSC activation. Knockdown of Rgs5 enhances ET-1-mediated signaling in HSCs in vitro. Taken together, we demonstrate that RGS5 is a critical regulator of GPCR signaling in HSCs and regulates HSC activation and fibrogenesis in liver injury. PMID:25290689

  11. Iron overload results in hepatic oxidative stress, immune cell activation, and hepatocellular ballooning injury, leading to nonalcoholic steatohepatitis in genetically obese mice.

    PubMed

    Handa, Priya; Morgan-Stevenson, Vicki; Maliken, Bryan D; Nelson, James E; Washington, Shenna; Westerman, Mark; Yeh, Matthew M; Kowdley, Kris V

    2016-01-15

    The aim of this study was to determine the effect of iron overload in the development of nonalcoholic steatohepatitis (NASH) in a genetically obese mouse model (Lepr(db/db)). Leptin receptor-deficient mice were fed a normal or an iron-supplemented chow for 8 wk and switched to normal chow for 8 wk. All dietary iron (DI)-fed mice developed hepatic iron overload predominantly in the reticuloendothelial system. Hepatocellular ballooning injury was observed in the livers of 85% of DI mice, relative to 20% of chow-fed Lepr(db/db). Hepatic malonyldialdehyde levels and mRNA levels of antioxidant genes (Nrf2, Gpx1, and Hmox1) were significantly increased in the DI mice. Hepatic mRNA levels of mitochondrial biogenesis regulators Pgc1α, Tfam, Cox4, and Nrf1 were diminished in the DI mice. In addition, gene expression levels of cytokines (Il6, Tnfα) and several innate and adaptive immune cell markers such as Tlr4, Inos, CD11c, CD4, CD8, and Ifnγ were significantly increased in livers of the DI group. Strikingly, Nlrp3, a component of the inflammasome and Il18, a cytokine elicited by inflammasome activation, were significantly upregulated in the livers of DI mice. In addition, RAW 264.7 macrophages loaded with exogenous iron showed significantly higher levels of inflammatory markers (Inos, Tnfα, Mcp1, Tlr4). Thus dietary iron excess leads to hepatic oxidative stress, inflammasome activation, induction of inflammatory and immune mediators, hepatocellular ballooning injury, and therefore NASH in this model. Taken together, these studies indicate a multifactorial role for iron overload in the pathogenesis of NASH in the setting of obesity and metabolic syndrome. PMID:26564716

  12. CXC-chemokine regulation and neutrophil trafficking in hepatic ischemia-reperfusion injury in P-selectin/ICAM-1 deficient mice

    PubMed Central

    Monson, Keith M; Dowlatshahi, Shadi; Crockett, Elahé T

    2007-01-01

    Background Neutrophil adhesion and migration are critical in hepatic ischemia and reperfusion injury (I/R). P-selectin and the intercellular adhesion molecule (ICAM)-1 can mediate neutrophil-endothelial cell interactions, neutrophil migration, and the interactions of neutrophils with hepatocytes in the liver. Despite very strong preclinical data, recent clinical trials failed to show a protective effect of anti-adhesion therapy in reperfusion injury, indicating that the length of injury might be a critical factor in neutrophil infiltration. Therefore, the aim of this study was to assess the role of P-selectin and ICAM-1 in neutrophil infiltration and liver injury during early and late phases of liver I/R. Methods Adult male wild-type and P-selectin/ICAM-1-deficient (P/I null) mice underwent 90 minutes of partial liver ischemia followed by various periods of reperfusion (6, 15 h, and a survival study). Liver injury was assessed by plasma level of alanine aminotransferase (ALT) and histopathology. The plasma cytokines, TNF-α, IL-6, MIP-2 and KC, were measured by ELISA. Results Reperfusion caused significant hepatocellular injury in both wild-type and P/I null mice as was determined by plasma ALT levels and liver histopathology. The injury was associated with a marked neutrophil infiltration into the ischemic livers of both wild-type and P/I null mice. Although the levels of ALT and neutrophil infiltration were slightly lower in the P/I null mice compared with the wild-type mice the differences were not statistically significant. The plasma cytokine data of TNF-α and IL-6 followed a similar pattern to ALT data, and no significant difference was found between the wild-type and P/I null groups. In contrast, a significant difference in KC and MIP-2 chemokine levels was observed between the wild-type and P/I null mice. Additionally, the survival study showed a trend towards increased survival in the P/I null group. Conclusion While ICAM-1 and P-selectin does not appear

  13. ASS and SULT2A1 are Novel and Sensitive Biomarkers of Acute Hepatic Injury-A Comparative Study in Animal Models

    PubMed Central

    Prima, Victor; Cao, Mengde; Svetlov, Stanislav I

    2013-01-01

    Liver and kidney damage associated with polytrauma, endotoxic shock/sepsis, and organ transplantation, are among the leading causes of the multiple organ failure. Development of novel sensitive biomarkers that detect early stages of liver and kidney injury is vital for the effective diagnostics and treatment of these life-threatening conditions. Previously, we identified several hepatic proteins, including Argininosuccinate Synthase (ASS) and sulfotransferases which were degraded in the liver and rapidly released into circulation during Ischemia/Reperfusion (I/R) injury. Here we compared sensitivity and specificity of the newly developed sandwich ELISA assays for ASS and the sulfotransferase isoform SULT2A1 with the standard clinical liver and kidney tests Alanine Aminotransferase (ALT) and Aspartate Transaminase (AST) in various pre-clinical models of acute injury. Our data suggest that ASS and SULT2A1 have superior characteristics for liver and kidney health assessment in endotoxemia, Ischemia/Reperfusion (I/R), chemical and drug-induced liver injury and may be of high potential value for clinical applications. PMID:23724364

  14. The hepatocurative effects of Cynara scolymus L. leaf extract on carbon tetrachloride-induced oxidative stress and hepatic injury in rats.

    PubMed

    Colak, Emine; Ustuner, Mehmet Cengiz; Tekin, Neslihan; Colak, Ertugrul; Burukoglu, Dilek; Degirmenci, Irfan; Gunes, Hasan Veysi

    2016-01-01

    Cynara scolymus is a pharmacologically important medicinal plant containing phenolic acids and flavonoids. Experimental studies indicate antioxidant and hepatoprotective effects of C. scolymus but there have been no studies about therapeutic effects of liver diseases yet. In the present study, hepatocurative effects of C. scolymus leaf extract on carbon tetrachloride (CCl4)-induced oxidative stress and hepatic injury in rats were investigated by serum hepatic enzyme levels, oxidative stress indicator (malondialdehyde-MDA), endogenous antioxidants, DNA fragmentation, p53, caspase 3 and histopathology. Animals were divided into six groups: control, olive oil, CCl4, C. scolymus leaf extract, recovery and curative. CCl4 was administered at a dose of 0.2 mL/kg twice daily on CCl4, recovery and curative groups. Cynara scolymus extract was given orally for 2 weeks at a dose of 1.5 g/kg after CCl4 application on the curative group. Significant decrease of serum alanine-aminotransferase (ALT) and aspartate-aminotransferase (AST) levels were determined in the curative group. MDA levels were significantly lower in the curative group. Significant increase of superoxide dismutase (SOD) and catalase (CAT) activity in the curative group was determined. In the curative group, C. scolymus leaf extract application caused the DNA % fragmentation, p53 and caspase 3 levels of liver tissues towards the normal range. Our results indicated that C. scolymus leaf extract has hepatocurative effects of on CCl4-induced oxidative stress and hepatic injury by reducing lipid peroxidation, providing affected antioxidant systems towards the normal range. It also had positive effects on the pathway of the regulatory mechanism allowing repair of DNA damage on CCl4-induced hepatotoxicity. PMID:27026910

  15. Melatonin pretreatment enhances the therapeutic effects of exogenous mitochondria against hepatic ischemia-reperfusion injury in rats through suppression of mitochondrial permeability transition.

    PubMed

    Chen, Hong-Hwa; Chen, Yen-Ta; Yang, Chih-Chao; Chen, Kuan-Hung; Sung, Pei-Hsun; Chiang, Hsin-Ju; Chen, Chih-Hung; Chua, Sarah; Chung, Sheng-Ying; Chen, Yi-Ling; Huang, Tien-Hung; Kao, Gour-Shenq; Chen, Sheng-Yi; Lee, Mel S; Yip, Hon-Kan

    2016-08-01

    We tested the hypothesis that melatonin (Mel) enhances exogenous mitochondria (Mito) treatment against rodent hepatic ischemia-reperfusion (IR) injury. In vitro study utilized three groups of hepatocytes (i.e. nontreatment, menadione, and menadione-melatonin treatment, 4.0 × 10(5) each), while in vivo study used adult male Sprague Dawley rats (n = 40) equally divided into sham-control (SC), IR (60-min left-lobe ischemia + 72-hr reperfusion), IR-Mel (melatonin at 30 min/6/8 hr after reperfusion), IR-Mito (mitochondria 15,000 μg/rat 30 min after reperfusion), and IR-Mel-Mito. Following menadione treatment in vitro, oxidative stress (NOX-1/NOX-2/oxidized protein), apoptotic (cleaved caspase-3/PARP), DNA damage (γ-H2AX/CD90/XRCC1), mitochondria damage (cytosolic cytochrome c) biomarkers, and mitochondrial permeability transition were found to be lower, whereas mitochondrial cytochrome c were found to be higher in hepatocytes with melatonin treatment compared to those without (all P < 0.001). In vivo study demonstrated highest liver injury score and serum AST in IR group, but lowest in SC group and higher in IR-Mito group than that in groups IR-Mel and IR-Mel-Mito, and higher in IR-Mel group than that in IR-Mel-Mito group after 72-hr reperfusion (all P < 0.003). Protein expressions of inflammatory (TNF-α/NF-κB/IL-1β/MMP-9), oxidative stress (NOX-1/NOX-2/oxidized protein), apoptotic (caspase-3/PARP/Bax), and mitochondria damage (cytosolic cytochrome c) biomarkers displayed an identical pattern, whereas mitochondria integrity marker (mitochondrial cytochrome c) showed an opposite pattern compared to that of liver injury score (all P < 0.001) among five groups. Microscopically, expressions of apoptotic nuclei, inflammatory (MPO(+) /CD68(+) /CD14(+) cells), and DNA damage (γ-H2AX(+) cells) biomarkers exhibited an identical pattern compared to that of liver injury score (all P < 0.001) among five groups. Melatonin-supported mitochondria treatment offered an additional

  16. Hepatic encephalopathy.

    PubMed

    Córdoba, Juan; Mínguez, Beatriz

    2008-02-01

    Hepatic encephalopathy is a severe complication of cirrhosis that is related to the effects of ammonia. Analysis of interorgan ammonia trafficking has identified an important role of skeletal muscle in ammonia removal and has highlighted the importance of the nutritional status. Ammonia causes neurotransmitter abnormalities and induces injury to astrocytes that is partially mediated by oxidative stress. These disturbances lead to astrocyte swelling and brain edema, which appear to be involved in the pathogenesis of neurological manifestations. Inflammatory mediators worsen brain disturbances. New methods for assessing hepatic encephalopathy include clinical scales, neuropsychological tests, imaging of portal-systemic circulation, and magnetic resonance of the brain. Reappraisal of current therapy indicates the need for performing placebo-controlled trials and the lack of evidence for administering diets with restricted protein content. Liver transplant should be considered in selected patients with hepatic encephalopathy. Future prospects include new drugs that decrease plasma ammonia, measures to reduce brain edema, and liver-support devices. PMID:18293278

  17. Ischaemia and reperfusion injury of rat liver increases expression of glutathione S-transferase A1/A2 in zone 3 of the hepatic lobule.

    PubMed Central

    Branum, G D; Selim, N; Liu, X; Whalen, R; Boyer, T D

    1998-01-01

    Effects of ischaemia-reperfusion injury (I/R) of liver on expression of rat glutathione S-transferase (rGST) isoenzymes that metabolize products of oxidative stress were examined. Rats underwent lobar liver ischaemia for 30 min followed by reperfusion. In ischaemic lobes, rGSTA1/A2 transcript levels increased significantly 12 h after I/R (2.94-fold) and protein levels increased significantly at 24 h (1.45-fold); increased transcript levels were also observed in nonischaemic lobes (1.78-fold). Superoxide dismutase prevented I/R and the increases in transcript and protein levels in ischaemic and non-ischaemic lobes. By in-situ hybridization, increases in transcript levels at 6 h were present in zones 2 and 3 of the ischaemic lobes and peaked at 12 h (2.5-fold zone 2, 4.5-fold zone 3). Significant increases in transcript levels also were observed at 24 h in zones 2 (2.0-fold) and 3 (2.9-fold) of non-ischaemic lobes. Nuclear run-off assays showed a 1.8-fold increase in rGSTA1/A2 transcription rates in ischaemic lobes at 3 h. We conclude that I/R causes increased rGSTA1/A2 expression in the zone of the hepatic lobule most susceptible to oxidative injury and that this expression may be an important defence against injury. PMID:9461493

  18. How Does the Severity of Injury Vary between Motorcycle and Automobile Accident Victims Who Sustain High-Grade Blunt Hepatic and/or Splenic Injuries? Results of a Retrospective Analysis

    PubMed Central

    Hsieh, Ting-Min; Tsai, Tsung-Cheng; Liu, Yueh-Wei; Hsieh, Ching-Hua

    2016-01-01

    Background: High-grade blunt hepatic and/or splenic injuries (BHSI) remain a great challenge for trauma surgeons. The main aim of this study was to investigate the characteristics, mortality rates, and outcomes of high-grade BHSI in motorcyclists and car occupants hospitalized for treatment of traumatic injuries in a Level I trauma center in southern Taiwan. Methods: High-grade BHSI are defined as grade III-VI blunt hepatic injuries and grade III-V blunt splenic injuries. This retrospective study reviewed the data of 101 motorcyclists and 32 car occupants who experienced a high-grade BHSI from 1 January 2011 to 31 December 2013. Two-sided Fisher’s exact or Pearson’s chi-square tests were used to compare categorical data, unpaired Student’s t-test was used to analyze normally distributed continuous data, and Mann–Whitney’s U test was used to compare non-normally distributed data. Results: In this study, the majority (76%, 101/133) of high-grade BHSI were due to motorcycle crashes. Car occupants had a significantly higher injury severity score (ISS; 26.8 ± 10.9 vs. 20.7 ± 10.4, respectively, p = 0.005) and organ injured score (OIS; 3.8 ± 1.0 vs. 3.4 ± 0.6, respectively, p = 0.033), as well as a significantly longer hospital length of stay (LOS; 21.2 days vs. 14.6 days, respectively, p = 0.038) than did motorcyclists. Car occupants with high-grade BHSI also had worse clinical presentations than their motorcyclist counterparts, including a significantly higher incidence of hypotension, hyperpnea, tube thoracostomy, blood transfusion >4 units, LOS in intensive care unit >5 days, and complications. However, there were no differences in the percentage of angiography or laparotomy performed or mortality rate between these two groups of patients. Conclusions: This study demonstrated that car occupants with high-grade BHSI were injured more severely, had a higher incidence of worse clinical presentation, had a longer hospital LOS, and had a higher incidence of

  19. Protective effect of panax notoginseng saponins on acute ethanol-induced liver injury is associated with ameliorating hepatic lipid accumulation and reducing ethanol-mediated oxidative stress.

    PubMed

    Ding, Ren-Bo; Tian, Ke; Cao, Yi-Wei; Bao, Jiao-Lin; Wang, Meng; He, Chengwei; Hu, Yuanjia; Su, Huanxing; Wan, Jian-Bo

    2015-03-11

    The aim of present study was to evaluate the effects of Panax notoginseng saponins (PNS) against acute ethanol-induced liver injury and further to elucidate its probable mechanisms. Mice were treated with PNS (100 or 300 mg/kg) once daily for seven consecutive days priors to ethanol gavage (4.7 g/kg) every 12 h for a total of three doses. Acute alcohol gavage dramatically significantly increased serum activities of alanine aminotransferase (ALT) (23.4 ± 5.0 IU/L vs 11.7 ± 4.1 IU/L) and aspartate aminotransferase (AST) (52.6 ± 14.9 IU/L vs 31.1 ± 12.9 IU/L), and hepatic triglyceride level (4.04 ± 0.64 mg/g vs 1.92 ± 0.34 mg/g), these elevations were significantly diminished by pretreatment with PNS at dose of 100 mg/kg or 300 mg/kg. Alcohol exposure markedly induced the lipolysis of white adipose tissue (WAT), up-regulated protein expression of the phosphorylated hormone-sensitive lipase (p-HSL, p < 0.01), and total HSL (p < 0.01), and enhanced fatty acid uptake capacity in liver as indicated by increasing hepatic CD36 expression (p < 0.01), these effects were attenuated by PNS treatment. Additionally, PNS suppressed the elevation of reactive oxygen species (ROS) production and malondialdehyde (MDA) content, reduced TNF-α and IL-6 levels, restored glutathione (GSH) level, enhanced the superoxide dismutase (SOD) activity in liver, and abrogated cytochrome P450 2E1 (CYP2E1) induction. These data demonstrated that pretreatment with PNS protected against acute ethanol-induced liver injury, possibly through ameliorating hepatic lipid accumulation and reducing CYP2E1-mediated oxidative stress. Our findings also suggested that PNS may be potential to be developed as an effective agent for acute ethanol-induced liver injury. PMID:25665731

  20. Effect of indole-3-carbinol on ethanol-induced liver injury and acetaldehyde-stimulated hepatic stellate cells activation using precision-cut rat liver slices.

    PubMed

    Guo, Yu; Wu, Xiao-Qian; Zhang, Chun; Liao, Zhang-Xiu; Wu, Yong; Xia, Zheng-Yuan; Wang, Hui

    2010-12-01

    1. Indole-3-carbinol (I3C), a major indole compound found in high levels in cruciferous vegetables, shows a broad spectrum of biological activities. However, few studies have reported the effect of I3C on alcoholic liver injury. In the present study, we investigated the protective effect of I3C on acute ethanol-induced hepatotoxicity and acetaldehyde-stimulated hepatic stellate cells (HSC) activation using precision-cut liver slices (PCLS). 2. Rat PCLS were incubated with 50 mmol/L ethanol or 350 μmol/L acetaldehyde, and different concentrations (100-400 μmol/L) of I3C were added into the culture system of these two liver injury models, respectively. Hepatotoxicity was assessed by measuring enzyme leakage and malondialdehyde (MDA) content in tissue. Activities of alcoholic enzymes were also determined. α-Smooth muscle actin (α-SMA), transforming growth factor (TGF-β(1) ) and hydroxyproline (HYP) were used as indices to evaluate the activation of HSC. In addition, matrix metalloproteinase-1 (MMP-1) and the tissue inhibitor of metalloproteinase (TIMP-1) were observed to estimate collagen degradation. 3. I3C significantly reduced the enzyme leakage in ethanol-treated slices. In I3C groups, cytochrome P450 (CYP) 2E1 activities were inhibited by 40.9-51.8%, whereas alcohol dehydrogenase (ADH) activity was enhanced 1.6-fold compared with the ethanol-treated group. I3C also showed an inhibitory effect against HSC activation and collagen production stimulated by acetaldehyde. After being incubated with I3C (400 μmol/L), the expression of MMP-1 was markedly enhanced, whereas TIMP-1 was decreased. 4. These results showed that I3C protected PCLS against alcoholic liver injury, which might be associated with the regulation of ethanol metabolic enzymes, attenuation of oxidative injury and acceleration of collagen degradation. PMID:20880187

  1. Lactobacillus rhamnosus GG supernatant promotes intestinal barrier function, balances Treg and TH17 cells and ameliorates hepatic injury in a mouse model of chronic-binge alcohol feeding.

    PubMed

    Chen, Rui-Cong; Xu, Lan-Man; Du, Shan-Jie; Huang, Si-Si; Wu, He; Dong, Jia-Jia; Huang, Jian-Rong; Wang, Xiao-Dong; Feng, Wen-Ke; Chen, Yong-Ping

    2016-01-22

    Impaired intestinal barrier function plays a critical role in alcohol-induced hepatic injury, and the subsequent excessive absorbed endotoxin and bacterial translocation activate the immune response that aggravates the liver injury. Lactobacillus rhamnosus GG supernatant (LGG-s) has been suggested to improve intestinal barrier function and alleviate the liver injury induced by chronic and binge alcohol consumption, but the underlying mechanisms are still not clear. In this study, chronic-binge alcohol fed model was used to determine the effects of LGG-s on the prevention of alcoholic liver disease in C57BL/6 mice and investigate underlying mechanisms. Mice were fed Lieber-DeCarli diet containing 5% alcohol for 10 days, and one dose of alcohol was gavaged on Day 11. In one group, LGG-s was supplemented along with alcohol. Control mice were fed isocaloric diet. Nine hours later the mice were sacrificed for analysis. Chronic-binge alcohol exposure induced an elevation in liver enzymes, steatosis and morphology changes, while LGG-s supplementation attenuated these changes. Treatment with LGG-s significantly improved intestinal barrier function reflected by increased mRNA expression of tight junction (TJ) proteins and villus-crypt histology in ileum, and decreased Escherichia coli (E. coli) protein level in liver. Importantly, flow cytometry analysis showed that alcohol reduced Treg cell population while increased TH17 cell population as well as IL-17 secretion, which was reversed by LGG-s administration. In conclusion, our findings indicate that LGG-s is effective in preventing chronic-binge alcohol exposure-induced liver injury and shed a light on the importance of the balance of Treg and TH17 cells in the role of LGG-s application. PMID:26617183

  2. Ebselen pretreatment attenuates ischemia/reperfusion injury and prevents hyperglycemia by improving hepatic insulin signaling and β-cell survival in gerbils.

    PubMed

    Park, S; Kang, S; Kim, D S; Shin, B K; Moon, N R; Daily, J W

    2014-08-01

    Transient carotid artery occlusion causes ischemia/reperfusion (I/R) injury resulting in neuron and pancreatic β-cell death with consequential post-stroke hyperglycemia, which can lead to diabetes and may accelerate the development of Alzheimer's disease. Antioxidants have been shown to protect against the I/R injury and destruction of neurons. However, it is unknown whether the protection against I/R injury extends to the pancreatic β-cells. Therefore, we investigated whether treatment with ebselen, a glutathione peroxidase mimic, prevents neuronal and β-cell death following I/R in gerbils susceptible to stroke. After 28 days post artery occlusion, there was widespread neuronal cell death in the CA1 of the hippocampus and elevated IL-1β and TNF-α levels. Pretreatment with ebselen prevented the death by 56% and attenuated neurological damage (abnormal eyelid drooping, hair bristling, muscle tone, flexor reflex, posture, and walking patterns). Ischemic gerbils also exhibited impaired glucose tolerance and insulin sensitivity which induced post-stroke hyperglycemia associated with decreased β-cell mass due to increased β-cell apoptosis. Ebselen prevented the increased β-cell apoptosis, possibly by decreasing IL-1β and TNF-α in islets. Ischemia also attenuated hepatic insulin signaling, and expression of GLUT2 and glucokinase, whereas ebselen prevented the attenuation and suppressed gluconeogenesis by decreasing PEPCK expression. In conclusion, antioxidant protection by ebselen attenuated I/R injury of neurons and pancreatic β-cells and prevented subsequent impairment of glucose regulation that could lead to diabetes and Alzheimer's disease. PMID:24807533

  3. Hepatic effects of lung-protective pressure-controlled ventilation and a combination of high-frequency oscillatory ventilation and extracorporeal lung assist in experimental lung injury

    PubMed Central

    Kredel, Markus; Muellenbach, Ralf M.; Johannes, Amélie; Brederlau, Joerg; Roewer, Norbert; Wunder, Christian

    2011-01-01

    Summary Background Ventilation with high positive end-expiratory pressure (PEEP) can lead to hepatic dysfunction. The aim of this study was to investigate the hepatic effects of strategies using high airway pressures either in pressure-controlled ventilation (PCV) or in high-frequency oscillatory ventilation (HFOV) combined with an arteriovenous extracorporeal lung assist (ECLA). Material/Methods Pietrain pigs underwent induction of lung injury by saline lavage. Ventilation was continued for 24 hours either as PCV with tidal volumes of 6 ml/kg and PEEP 3 cmH2O above the lower inflection point of the pressure-volume curve or as HFOV (≥12 Hz) with a mean tracheal airway pressure 3 cmH2O above the lower inflection point combined with arteriovenous ECLA (HFOV+ECLA). Fluids and norepinephrine stabilized the circulation. The indocyanine green plasma disappearance rate, serum bilirubin, aspartate aminotransferase, alanine aminotransferase, γ-glutamyltransferase, alkaline phosphatase, glutamate dehydrogenase, lactate dehydrogenase and creatine kinase were determined repeatedly. Finally, liver neutrophils were counted and liver cell apoptosis was assessed by terminal deoxynucleotidyl transferase nick end labeling (TUNEL). Results Aspartate aminotransferase increased in the PCV group about three-fold and in the HFOV+ECLA group five-fold (p<0.001). Correspondingly, creatine kinase increased about two-fold and four-fold, respectively (p<0.001). Lactate dehydrogenase was increased in the HFOV+ECLA group (p<0.028). The number of neutrophils infiltrating the liver tissue and the apoptotic index were low. Conclusions High airway pressure PCV and HFOV with ECLA in the treatment of lavage-induced lung injury in pigs did not cause liver dysfunction or damage. The detected elevation of enzymes might be of extrahepatic origin. PMID:21959601

  4. The role of purinergic signaling in the liver and in transplantation: effects of extracellular nucleotides on hepatic graft vascular injury, rejection and metabolism

    PubMed Central

    Beldi, Guido; Enjyoji, Keiichi; Wu, Yan; Miller, Lindsay; Banz, Yara; Sun, Xiaofeng; Robson, Simon C.

    2010-01-01

    Extracellular nucleotides (e.g. ATP, UTP, ADP) are released by activated endothelium, leukocytes and platelets within the injured vasculature and bind specific cell-surface type-2 purinergic (P2) receptors. This process drives vascular inflammation and thrombosis within grafted organs. Importantly, there are also vascular ectonucleotidases i.e. ectoenzymes that hydrolyze extracellular nucleotides in the blood to generate nucleosides (viz. adenosine). Endothelial cell NTPDase1/CD39 has been shown to critically modulate levels of circulating nucleotides. This process tends to limit the activation of platelet and leukocyte expressed P2 receptors and also generates adenosine to reverse inflammatory events. This vascular protective CD39 activity is rapidly inhibited by oxidative reactions, such as is observed with liver ischemia reperfusion injury. In this review, we chiefly address the impact of these signaling cascades following liver transplantation. Interestingly, the hepatic vasculature, hepatocytes and all non-parenchymal cell types express several components co-ordinating the purinergic signaling response. With hepatic and vascular dysfunction, we note heightened P2- expression and alterations in ectonucleotidase expression and function that may predispose to progression of disease. In addition to documented impacts upon the vasculature during engraftment, extracellular nucleotides also have direct influences upon liver function and bile flow (both under physiological and pathological states). We have recently shown that alterations in purinergic signaling mediated by altered CD39 expression have major impacts upon hepatic metabolism, repair mechanisms, regeneration and associated immune responses. Future clinical applications in transplantation might involve new therapeutic modalities using soluble recombinant forms of CD39, altering expression of this ectonucleotidase by drugs and/or using small molecules to inhibit deleterious P2-mediated signaling while

  5. Resveratrol preconditioning protects hepatocytes against hepatic ischemia reperfusion injury via Toll-like receptor 4/nuclear factor-κB signaling pathway in vitro and in vivo.

    PubMed

    He, Diao; Guo, Zhen; Pu, Jun-Liang; Zheng, Dao-Feng; Wei, Xu-Fu; Liu, Rui; Tang, Cheng-Yong; Wu, Zhong-Jun

    2016-06-01

    The purpose of this study was to investigate the protective effect of resveratrol against hepatic ischemia reperfusion injury (HIRI) and explore the potential underlying mechanism. Resveratrol-pretreated BRL-3A (rat liver) cells and rats underwent hypoxia/reoxygenation and hepatic ischemia/reperfusion, respectively. BRL-3A cell damage was evaluated, and the mRNA and protein expression of related signal molecules was assessed in cell model. The protein expression of related signal molecules was also assessed in rat model. Inflammatory cytokines levels were determined in the cell supernatant and rat serum while rat liver function and hepatocyte apoptosis were assessed. The results revealed that resveratrol significantly enhanced cell viability, inhibited cell apoptosis, and decreased levels of lactate dehydrogenase (LDH) and production of tumor necrosis factor-α (TNF-α) and interleukin-(IL)-1β in the cell supernatant. In addition, resveratrol ameliorated elevated Toll-like receptor 4 (TLR4) and nuclear factor (NF)-κB, and the depressed inhibitor of NF-κB (IκB)-α caused by hypoxia/reoxygenation stimulation in BRL-3A cells. Moreover, resveratrol inhibited the translocation of NF-κB p65 after the stimulation of hypoxia/reoxygenation in BRL-3A cells. In vivo assays revealed that resveratrol reduced levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and liver pathological changes, while it alleviated hepatocyte apoptosis, negatively mediated the production of TNF-α and IL-1β in serum, and reversed TLR4/NF-κB signaling pathway caused by hepatic ischemia/reperfusion stimulation in liver tissues. The results indicate that resveratrol protected hepatocytes against HIRI, which may be mediated in part via the TLR4/NF-κB signaling pathway. PMID:27064547

  6. Epigenetic Alterations of IL-6/STAT3 Signaling by Placental Stem Cells Promote Hepatic Regeneration in a Rat Model with CCl4-induced Liver Injury

    PubMed Central

    Jung, Jieun; Moon, Ji Wook; Choi, Jong-Ho; Lee, Yong Woo; Park, Sun-Hwa; Kim, Gi Jin

    2015-01-01

    Background Human chorionic plate-derived mesenchymal stem cells (CP-MSCs) isolated from the placenta have been reported to demonstrate therapeutic effects in animal models of liver injury; however, the underlying epigenetic mechanism of this effect has not been elucidated. Thus, we investigated whether CP-MSCs influence epigenetic processes during regeneration of the injured liver. Methods CP-MSCs were engrafted into a carbon tetrachloride (CCl4)-injured rat model through direct transplantation into the liver (DTX), intrasplenic transplantation (STX), and intravenous transplantation via the tail vein (TTX). Non-transplanted (NTX) rats were maintained as sham controls. Liver tissues were analyzed after transplantation using immunohistochemistry, western blot analysis, and quantitative methylation-specific polymerase chain reaction. Proliferation and human interleukin-6 (hIL-6) enzyme-linked immunosorbent assays were performed using CCl4-treated hepatic cells that were co-cultured with CP-MSCs. Results The Ki67 labeling index, cell cyclins, albumin, IL-6, and gp130 levels were elevated in the CP-MSC transplantation groups. The concentration of hIL-6 in supernatants and the proliferation of CCl4-treated rat hepatic cells were enhanced by co-culturing with CP-MSCs (p<0.05), while the methylation of IL-6/IL-6R and STAT3 by CP-MSC transplantation decreased. Conclusion These results suggest that administration of CP-MSCs promotes IL-6/STAT3 signaling by decreasing the methylation of the IL-6/SATA3 promoters and thus inducing the proliferation of hepatic cells in a CCl4-injured liver rat model. These data advance our understanding of the therapeutic mechanisms in injured livers, and can facilitate the development of cell-based therapies using placenta-derived stem cells. PMID:26019757

  7. Update on Alcoholic Hepatitis

    PubMed Central

    Torok, Natalie J.

    2015-01-01

    Alcoholic liver disease is one of the most prevalent liver diseases worldwide, and a major cause of morbidity and mortality. Alcoholic hepatitis is a severe form of liver injury in patients with alcohol abuse, can present as an acute on chronic liver failure associated with a rapid decline in liver synthetic function, and consequent increase in mortality. Despite therapy, about 30%–50% of patients with severe alcoholic hepatitis eventually die. The pathogenic pathways that lead to the development of alcoholic hepatitis are complex and involve oxidative stress, gut dysbiosis, and dysregulation of the innate and adaptive immune system with injury to the parenchymal cells and activation of hepatic stellate cells. As accepted treatment approaches are currently limited, a better understanding of the pathophysiology would be required to generate new approaches that improve outcomes. This review focuses on recent advances in the diagnosis, pathogenesis of alcoholic hepatitis and novel treatment strategies. PMID:26540078

  8. Development of a Fatal Noncompressible Truncal Hemorrhage Model with Combined Hepatic and Portal Venous Injury in Normothermic Normovolemic Swine

    PubMed Central

    Yanala, Ujwal R.; Johanning, Jason M.; Pipinos, Iraklis I.; Larsen, Gustavo; Velander, William H.; Carlson, Mark A.

    2014-01-01

    Noncompressible truncal hemorrhage and brain injury currently account for most early mortality of warfighters on the battlefield. There is no effective treatment for noncompressible truncal hemorrhage, other than rapid evacuation to a surgical facility. The availability of an effective field treatment for noncompressible truncal hemorrhage could increase the number of warfighters salvaged from this frequently-lethal scenario. Our intent was to develop a porcine model of noncompressible truncal hemorrhage with a ∼50% one-hour mortality so that we could develop new treatments for this difficult problem. Normovolemic normothermic domestic swine (barrows, 3 months old, 34–36 kg) underwent one of three injury types through a midline incision: 1) central stellate injury (N = 6); 2) excision of a portal vein branch distal to the main PV trunk (N = 6); or 3) hemi-transection of the left lateral lobe of the liver at its base (N = 10). The one-hour mortality of these injuries was 0, 82, and 40%, respectively; the final mean arterial pressure was 65, 24, and 30 mm Hg, respectively; and the final hemoglobin was 8.3, 2.3, and 3.6 g/dL, respectively. Hemi-transection of the left lateral lobe of the liver appeared to target our desired mortality rate better than the other injury mechanisms. PMID:25251401

  9. Carvedilol Improves Inflammatory Response, Oxidative Stress and Fibrosis in the Alcohol-Induced Liver Injury in Rats by Regulating Kuppfer Cells and Hepatic Stellate Cells

    PubMed Central

    Leitão, Renata Ferreira de Carvalho; Brito, Gerly Anne de Castro; Miguel, Emilio de Castro; Guedes, Paulo Marcos Matta; de Araújo, Aurigena Antunes

    2016-01-01

    Aim To evaluate the anti-inflammatory, anti-oxidant and antifibrotic effects of carvedilol (CARV) in rats with ethanol-induced liver injury. Methods Liver injury was induced by gavage administration of alcohol (7 g/kg) for 28 consecutive days. Eighty Wistar rats were pretreated with oral CARV at 1, 3, or 5 mg/kg or with saline 1 h before exposure to alcohol. Liver homogenates were assayed for interleukin (IL)-1β, IL-10, and tumor necrosis factor (TNF)-α level as well as for myeloperoxidase (MPO) activity and malonyldialdehyde (MDA) and glutathione (GSH) levels. Serum aspartate aminotransferase (AST) activity and liver triglyceride (TG) levels were also assayed. Immunohistochemical analyses of cyclooxygenase 2 (COX-2), receptor activator of nuclear factor kappa-B/ligand (RANK/RANKL), suppressor of cytokine signalling (SOCS1), the Kupffer cell marker IBA-1 (ionized calcium-binding adaptor molecule 1), intercellular adhesion molecule 1 (ICAM-1), superoxide dismutase (SOD-1), and glutathione peroxidase (GPx-1) expression were performed. Confocal microscopy analysis of IL-1β and NF-κB expression and real-time quantitative PCR analysis for TNFα, PCI, PCIII, and NF-κB were performed. Results CARV treatment (5 mg/kg) during the alcohol exposure protocol was associated with reduced steatosis, hepatic cord degeneration, fibrosis and necrosis, as well as reduced levels of AST (p < 0.01), ALT (p < 0.01), TG (p < 0.001), MPO (p < 0.001), MDA (p < 0.05), and proinflammatory cytokines (IL-1β and TNF-α, both p < 0.05), and increased levels of the anti-inflammatory cytokine IL-10 (p < 0.001) and GSH (p < 0.05), compared to the alcohol-only group. Treatment with CARV 5 mg/kg also reduced expression levels of COX-2, RANK, RANKL, IBA-1, and ICAM-1 (all p < 0.05), while increasing expression of SOCS1, SOD-1, and GPx-1 (all p < 0.05) and decreasing expression of IL-1β and NF-κB (both, p < 0.05). Real-time quantitative PCR analysis showed that mRNA production of TNF

  10. Attenuation of Experimental Autoimmune Hepatitis by Exogenous and Endogenous Cannabinoids: Involvement of Regulatory T Cells

    PubMed Central

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

    2009-01-01

    Immune-mediated liver diseases including autoimmune and viral hepatitis are a major health problem worldwide. Natural cannabinoids such as Δ9-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. PMID:18388242

  11. Successful use of N-acetylcysteine to treat severe hepatic injury caused by a dietary fitness supplement.

    PubMed

    El Rahi, Cynthia; Thompson-Moore, Nathaniel; Mejia, Patricia; De Hoyos, Patricio

    2015-06-01

    In the absence of adequate premarketing efficacy and safety evaluations, adverse events from over-the-counter supplements are emerging as a public health concern. Specifically, bodybuilding products are being identified as a frequent cause of drug-induced liver injury. We present a case of a 20-year-old Hispanic male who presented with acute nausea and vomiting accompanied by severe right upper quadrant abdominal pain, shivering, and shortness of breath. Laboratory data pointed to mixed cholestatic and hepatocellular damage, and after exclusion of known alternate etiologies, the patient was diagnosed with acute drug-induced liver injury secondary to the use of "Friction," a bodybuilding supplement. Treatment with N-acetylcysteine (NAC) 20% oral solution was initiated empirically at a dose of 4000 mg [DOSAGE ERROR CORRECTED] (70 mg/kg) every 4 hours and was continued once the diagnosis was made. Within 48 hours of admission to our hospital, the patient began to show clinical resolution of right abdominal pain and tolerance to oral diet associated with a significant decline toward normal in his liver function tests and coagulopathy. The WHO-UMC causality assessment system suggested a "certain causality" between exposure to the supplement and the acute liver injury. In the event of suspected drug-induced liver injury, treatment with NAC should be considered given its favorable risk-benefit profile. PMID:25823877

  12. Risk Factors for Development of Cholestatic Drug-Induced Liver Injury: Inhibition of Hepatic Basolateral Bile Acid Transporters Multidrug Resistance-Associated Proteins 3 and 4

    PubMed Central

    Köck, Kathleen; Ferslew, Brian C.; Netterberg, Ida; Yang, Kyunghee; Urban, Thomas J.; Swaan, Peter W.; Stewart, Paul W.

    2014-01-01

    Impaired hepatic bile acid export may contribute to development of cholestatic drug-induced liver injury (DILI). The multidrug resistance-associated proteins (MRP) 3 and 4 are postulated to be compensatory hepatic basolateral bile acid efflux transporters when biliary excretion by the bile salt export pump (BSEP) is impaired. BSEP inhibition is a risk factor for cholestatic DILI. This study aimed to characterize the relationship between MRP3, MRP4, and BSEP inhibition and cholestatic potential of drugs. The inhibitory effect of 88 drugs (100 μM) on MRP3- and MRP4-mediated substrate transport was measured in membrane vesicles. Drugs selected for investigation included 50 BSEP non-inhibitors (24 non-cholestatic; 26 cholestatic) and 38 BSEP inhibitors (16 non-cholestatic; 22 cholestatic). MRP4 inhibition was associated with an increased risk of cholestatic potential among BSEP non-inhibitors. In this group, for each 1% increase in MRP4 inhibition, the odds of the drug being cholestatic increased by 3.1%. Using an inhibition cutoff of 21%, which predicted a 50% chance of cholestasis, 62% of cholestatic drugs inhibited MRP4 (P < 0.05); in contrast, only 17% of non-cholestatic drugs were MRP4 inhibitors. Among BSEP inhibitors, MRP4 inhibition did not provide additional predictive value of cholestatic potential; almost all BSEP inhibitors were also MRP4 inhibitors. Inclusion of pharmacokinetic predictor variables (e.g., maximal unbound concentration in plasma) in addition to percent MRP4 inhibition in logistic regression models did not improve cholestasis prediction. Association of cholestasis with percent MRP3 inhibition was not statistically significant, regardless of BSEP-inhibition status. Inhibition of MRP4, in addition to BSEP, may be a risk factor for the development of cholestatic DILI. PMID:24154606

  13. Enhanced Effectivity of an ALK5-Inhibitor after Cell-Specific Delivery to Hepatic Stellate Cells in Mice with Liver Injury

    PubMed Central

    van Beuge, Marike Marjolijn; Prakash, Jai; Lacombe, Marie; Post, Eduard; Reker-Smit, Catharina; Beljaars, Leonie; Poelstra, Klaas

    2013-01-01

    Transforming growth factor-β (TGF-β) is a major pro-fibrotic cytokine, causing the overproduction of extracellular matrix molecules in many fibrotic diseases. Inhibition of its type-I receptor (ALK5) has been shown to effectively inhibit fibrosis in animal models. However, apart from its pro-fibrotic effects, TGF-β also has a regulatory role in the immune system and influences tumorigenesis, which limits the use of inhibitors. We therefore explored the cell-specific delivery of an ALK5-inhibitor to hepatic stellate cells, a key cell in the development of liver fibrosis. We synthesized a conjugate of the ALK5-inhibitor LY-364947 coupled to mannose-6-phosphate human serum albumin (M6PHSA), which binds to the insulin-like growth factor II receptor on activated HSC. The effectivity of the conjugate was evaluated in primary HSC and in an acute liver injury model in mice. In vitro, the free drug and the conjugate significantly inhibited fibrotic markers in HSC. In hepatocytes, TGF-β-dependent signaling was inhibited by free drug, but not by the conjugate, thus showing its cell-specificity. In vivo, the conjugate localized in desmin-positive cells in the liver and not in hepatocytes or immune cells. In the acute liver injury model in mice, the conjugate reduced fibrogenic markers and collagen deposition more effectively than free drug. We conclude that we can specifically deliver an ALK5-inhibitor to HSC using the M6PHSA carrier and that this targeted drug reduces fibrogenic parameters in vivo, without affecting other cell-types. PMID:23441194

  14. Ginger Essential Oil Ameliorates Hepatic Injury and Lipid Accumulation in High Fat Diet-Induced Nonalcoholic Fatty Liver Disease.

    PubMed

    Lai, Yi-Syuan; Lee, Wan-Ching; Lin, Yu-En; Ho, Chi-Tang; Lu, Kuan-Hung; Lin, Shih-Hang; Panyod, Suraphan; Chu, Yung-Lin; Sheen, Lee-Yan

    2016-03-16

    The objective of this study was to investigate the hepatoprotective efficacy and mechanism of action of ginger essential oil (GEO) against the development of nonalcoholic fatty liver disease (NAFLD). Mice were maintained on either a control diet or high-fat diet (HFD) supplemented with GEO (12.5, 62.5, and 125 mg/kg) or citral (2.5 and 25 mg/kg) for 12 weeks. We demonstrated that GEO and its major component (citral) lowered HFD-induced obesity in a dose-dependent manner, accompanied by anti-hyperlipidemic effects by reducing serum free fatty acid, triglyceride, and total cholesterol levels. Moreover, liver histological results showed that administration of 62.5 and 125 mg/kg GEO and 25 mg/kg citral significantly reduced hepatic lipid accumulation. Further assessment by Western blotting and investigation of the lipid metabolism revealed that hepatic protein expression of sterol regulatory element-binding protein-1c (SREBP-1c), acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), and cytochrome P450 2E1 (CYP2E1) were down-regulated by GEO and citral, indicating that GEO and citral suppressed HFD-stimulated lipid biosynthesis and oxidative stress. Furthermore, GEO and citral effectively enhanced the antioxidant capacities and reduced inflammatory response in mouse liver, which exerted protective effects against steatohepatitis. Collectively, GEO and citral exhibited potent hepatoprotective effects against NAFLD induced by HFD in obese mice. Thus, GEO might be an effective dietary supplement to ameliorate NAFLD-related metabolic diseases, and citral could play a vital role in its management. PMID:26900108

  15. Assessment of hepatoprotective potential of N. indicum leaf on haloalkane xenobiotic induced hepatic injury in Swiss albino mice.

    PubMed

    Dey, Priyankar; Dutta, Somit; Sarkar, Mousumi Poddar; Chaudhuri, Tapas Kumar

    2015-06-25

    CCl4 is a potent environmental toxin which cause liver damage through free radical mediated inflammatory processes. In this study, hepatoprotective capacity of Nerium indicum leaf extract (NILE) was evaluated on CCl4 induced acute hepatotoxicity in murine model. Animals were divided into 5 groups and treated as following: control group (received only normal saline), CCl4 group (received only CCl4), silymarin group (received CCl4 and 100mg/kg silymarin), NILE low group (received CCl4 and 50mg/kg NILE) and NILE high group (received CCl4 and 200mg/kg NILE). After 10 consecutive days of treatment, the levels of hepatic biochemical markers, malondialdehyde (MDA) content, peroxidase and catalase activities were measured as well as histopathological study was performed. Furthermore, liver explant cultures were set up as following: control (no treatment), CCl4 group (contained 25 μl/ml CCl4), silymarin group (contained 25 μl/ml CCl4 and 100 μg/ml silymarin), NILE low group (contained 25 μl/ml CCl4 and 25 μg/ml NILE) and NILE high group (contained 25 μl/ml CCl4 and 100 μg/ml NILE). Hepatic transaminases and phosphatases, tumor necrosis factor-α (TNF-α) expression, nitric oxide (NO) release and cell viability were studied on the explant cultures. Phytochemical fingerprinting of NILE was performed by gas chromatography-mass spectrometry (GC-MS). The results showed that the biochemical parameters were overexpressed due to CCl4 administration, which were significantly normalized by NILE treatment. The findings were further supported by histopathological evidences showing less hepatocellular necrosis, inflammation and fibrosis in NILE and silymarin treated groups, compared to CCl4 group. GC-MS analysis revealed presence of different bioactive phytochemicals with hepatoprotective and antioxidant properties. Therefore, the present study indicate that NILE possesses potent hepatoprotective capacity to ameliorate haloalkane xenobiotic induced injured liver in murine model

  16. Knowledge and beliefs among health care workers regarding hepatitis B infection and needle stick injuries at a tertiary care hospital, karachi.

    PubMed

    Habib, Faiza; Khan, Durreshahwar K; Shan-E-Abbas; Bhatti, Faiza; Zafar, Afia

    2011-05-01

    Hepatitis B virus (HBV) infection is a recognized occupational risk for health care workers (HCWs). This study aimed to assess the knowledge and beliefs of HCWs regarding HBV transmission and needle stick injuries (NSIs). A cross-sectional questionnaire based KAP study was conducted at Civil Hospital, Karachi, during the period of January to September 2006. HCWs were inquired about possible modes of HBV transmission and association with NSIs. Data were entered using EpiInfo 6.04d software. Statistical analysis was performed using SPSS 12.5 software. A total of 343 HCWs participated, and those answered at least 5 correct modes of HBV transmission were considered knowledgeable. Knowledgeable group was more likely to report NSIs (p < 0.006), more vaccinated (p < 0.001) and were also more likely to attend awareness session (p < 0.009). Overall knowledge were inadequate and behaviour and attitude towards clinical practices were found compromised. To reduce the occupational risk, effort should be focused to establish effective infection control program and training of staff. PMID:21575529

  17. Viral Hepatitis

    MedlinePlus

    ... Public Home » For Veterans and the Public Viral Hepatitis Menu Menu Viral Hepatitis Viral Hepatitis Home For ... the Public Veterans and Public Home How is Hepatitis C Treated? Find the facts about the newest ...

  18. Biomarkers of Lung Injury

    EPA Science Inventory

    Unlike the hepatic, cardiovascular, nervous, or excretory organ systems, where there .ls a strong contribution of host factors or extracellular biochemical milieu in causing organ damage, the causes of lung injuries and subsequent diseases are primarily from direct environmental ...

  19. Hepatitis E in Transplantation.

    PubMed

    Marion, Olivier; Abravanel, Florence; Lhomme, Sebastien; Izopet, Jacques; Kamar, Nassim

    2016-03-01

    Hepatitis E virus (HEV) has a worldwide distribution and is known to cause acute and fulminant hepatitis. However, over the last few years, it has been shown to also cause chronic hepatitis and cirrhosis in immunosuppressed patients, especially solid-organ-transplant patients. In immunocompetent and immunosuppressed patients, HEV is also associated with extra-hepatic manifestations, such as neurological symptoms and kidney injury. Unfortunately, a diagnostic assay for HEV infection is still not available in all countries. Reduction of immunosuppression is the first-line therapeutic option for organ-transplant patients with chronic hepatitis. In addition, ribavirin is highly efficient at treating chronic HEV infection. In this comprehensive review, we summarize the current knowledge regarding HEV diagnosis, its natural history, clinical manifestations, and treatments in patients with a solid-organ transplant. PMID:26838163

  20. 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? ...

  1. Effects of four Indian medicinal herbs on Isoniazid-, Rifampicin- and Pyrazinamide-induced hepatic injury and immunosuppression in guinea pigs

    PubMed Central

    Adhvaryu, Meghna R; Reddy, Narsimha; Parabia, Minoo H

    2007-01-01

    AIM: To evaluate and compare the hepatoprotective and immunomodulatory effects of Curcuma longa (CL), Ocimum sanctum (OS), Tinospora cordifolia (TC) and Zizyphus mauritiana (ZM) on liver injury and immunosuppression induced by Isoniazid (INH), Rifampicin (RIF) and Pyrazinamide (PZA). METHODS: Duncan Hartley guinea pigs, weighing 700-1050 g, were treated orally with 50 mg/kg of INH, 100 mg/kg of RIF and 300 mg/Kg of PZA for 21-d. 200 mg/kg (bw) of each herb crude extract was administered to the herb control group and 2-h previous to INH + RIF + PZA (AKT) doses to the Herb + AKT groups. Serum alanine aminotransferase (ALT), aspertate aminotransferase (AST) bilirubin and Alkaline Phosphatase (ALP) were assessed on d 0 and 21 in all the groups. Phagocytic % (P%), Phagocytic Index (PI) and Chemotactic Index (CI) were also measured as immunologic parameters. Histological analysis was carried out to assess injury to the liver. RESULTS: The AKT treated control group showed hepatotoxicity as judged by elevated serum AST 5-fold, AST/ALT ratio 4-fold, ALP 2-fold and hepatological changes, such as focal necrosis, portal triaditis and steatosis. Immune function was suppressed as judged by decreased P% (51.67 ± 1.68 vs 40.61 ± 1.28, P < 0.01), PI (2.0725 ± 0.05 vs 0.61 ± 0.05, P < 0.001) and CI (1.8525 ± 0.04 vs 0.695 ± 0.07, P < 0.001). All four herb treated groups showed normal liver histology, enzyme levels and increased P%, while PI and CI were enhanced in the TC and ZM treated groups, respectively. CL + AKT, TC + AKT and ZM + AKT showed nearly normal histology with minimal inflammation and microvesicular steatosis, while OS + AKT showed partial protection. Hepatotoxicity was prevented by restricting the rise of AST by 2-fold in CL + AKT and TC + AKT groups and by 3-fold in OS + AKT and ZM + AKT groups, AST/ALT by 2-fold and ALP to normal levels in all four groups. All four herb + AKT groups showed normal to enhanced neutrophil function. CONCLUSION: All four herbs

  2. β-Caryophyllene alleviates D-galactosamine and lipopolysaccharide-induced hepatic injury through suppression of the TLR4 and RAGE signaling pathways.

    PubMed

    Cho, Hong-Ik; Hong, Jeong-Min; Choi, Joo-Wan; Choi, Hyo-Sun; Kwak, Jong Hwan; Lee, Dong-Ung; Kook Lee, Sang; Lee, Sun-Mee

    2015-10-01

    Agastache rugosa (A. rugosa, Labiatae), a perennial herb spread throughout Korean fields, is widely consumed as a wild edible vegetable and is used in folk medicine. This study examined the hepatoprotective mechanisms of β-caryophyllene (BCP), a major bicyclic sesquiterpene of A. rugosa, against D-galactosamine (GalN) and lipopolysaccharide (LPS)-induced hepatic failure. Mice were given an intraperitoneal injection of BCP (50, 100 and 200 mg/kg) 1 h before GalN (800 mg/kg)/LPS (40 μg/kg) injection and were killed 1 h or 6 h after GalN/LPS injection. GalN/LPS markedly increased mortality and serum aminotransferase activity, both of which were attenuated by BCP. BCP also attenuated increases in serum tumor necrosis factor-α, interleukin 6, and high-mobility group protein B1 levels by GalN/LPS. GalN/LPS significantly increased toll-like receptor (TLR) 4 and receptor for advanced glycation end products (RAGE) protein expression, extracellular signal-related kinase, p38 and c-Jun N-terminal kinase phosphorylation, nuclear factor κB (NF-κB), early growth response protein-1, and macrophage inflammatory protein-2 protein expression. These increases were attenuated by BCP. Furthermore, BCP suppressed increased TLR4 and RAGE protein expression and proinflammatory cytokines production in LPS-treated isolated Kupffer cells. Our findings suggest that BCP protects against GalN/LPS-induced liver injury through down-regulation of the TLR4 and RAGE signaling. PMID:26254779

  3. The concanavalin A model of acute hepatitis in mice.

    PubMed

    Heymann, F; Hamesch, K; Weiskirchen, R; Tacke, F

    2015-04-01

    The intravenous injection of the plant lectin concanavalin A (ConA) is a widely used model for acute immune-mediated hepatitis in mice. In contrast to several other models for acute hepatic damage, ConA-induced injury is primarily driven by the activation and recruitment of T cells to the liver. Hence, the ConA model has unique features with respect to its pathogenesis and important similarities to immune-mediated hepatitis in humans, such as autoimmune hepatitis, acute viral hepatitis or distinct entities of drug toxicity leading to immune activation. However, the ConA model has considerable variability, depending on the preparation of the compound, genetic background of the mice, sex, age and microbial environment of the animal facility barrier. This standard operating procedure (SOP) comprises a detailed protocol for the ConA application, including preparation of ConA working solution, handling of the animals, choice of the appropriate conditions and endpoints, as well as efficient dose-finding. PMID:25835734

  4. Diosmin protects against ethanol-induced hepatic injury via alleviation of inflammation and regulation of TNF-α and NF-κB activation.

    PubMed

    Tahir, Mir; Rehman, Muneeb U; Lateef, Abdul; Khan, Rehan; Khan, Abdul Quaiyoom; Qamar, Wajhul; Ali, Farrah; O'Hamiza, Oday; Sultana, Sarwat

    2013-03-01

    The present investigation was designed to evaluate the efficacy of diosmin against ethanol-induced hepatotoxicity in rats by modulating various mechanisms including ethanol metabolizing enzymes, generation of free radicals, imbalance in oxidant-antioxidant status, oxidative damage to membrane lipids, activation of transcription factors and elevation in inflammatory markers involved in ethanol-induced hepatic damage. Diosmin is a flavone glycoside, having anti-inflammatory and anti-cancer properties. Thirty female Wistar rats segregated in five groups, each with six animals. Group I as control followed by Group II, III and IV were treated with ethanol for 28 days. While groups III and IV were administered with diosmin at 10 mg/kg b wt (D1) and 20 mg/kg b wt (D2) respectively prior to ethanol administration. Group V was given only higher dose of diosmin. In ethanol-treated group, ethanol metabolizing enzymes viz., CYP 450 2E1 and alcohol dehydrogenase (ADH) significantly increased by 77.82% and 32.32% in liver tissues respectively as compared with control group and this enhancement is significantly normalized with diosmin administration. Diosmin administration (D1 & D2) significantly (p < 0.001) attenuates oxidative stress markers i.e., LPO, GSH, GPx, GR and XO by 90.77 & 137.55%, 17.18 & 25%, 37.3 & 49.86%, 21.63 & 44.9% and 56.14 &77.19% respectively. Serum ALT, AST and LDH significantly increased by 102.03, 116.91 and 45.20% in ethanol-treated group as compared with control group. Group III and IV animals showed significant reduction in the serum toxicity markers. Diosmin further alleviated ethanol-induced NF-κB activation, enhanced expression of TNF-α, COX-2 and iNOS. Findings from the present study permit us to conclude that diosmin alleviates alcoholic liver injury via modulating ethanol metabolizing pathway, inhibition of oxidative stress markers and suppression of inflammatory markers. This may represent a novel protective strategy against ethanol

  5. Hepatitis virus panel

    MedlinePlus

    Hepatitis A antibody test; Hepatitis B antibody test; Hepatitis C antibody test; Hepatitis D antibody test ... or past infection, or immunity to hepatitis A Hepatitis B tests: Hepatitis B surface antigen (HBsAg), you have ...

  6. Hepatitis C and HIV

    MedlinePlus

    ... Problems : Hepatitis C Subscribe Translate Text Size Print Hepatitis C What is Hepatitis? Hepatitis means inflammation of the liver. This condition ... our related pages, Hepatitis A and Hepatitis B . Hepatitis C and HIV About 25% of people living ...

  7. Hepatitis B and HIV

    MedlinePlus

    ... Problems : Hepatitis B Subscribe Translate Text Size Print Hepatitis B What is Hepatitis? Hepatitis means inflammation of the liver. This condition ... our related pages, Hepatitis A and Hepatitis C . Hepatitis B and HIV About 10% of people living ...

  8. Hepatitis Testing

    MedlinePlus

    ... caused by viruses. They include hepatitis A, hepatitis B, and hepatitis C. To diagnose hepatitis, your health care provider will ask you about your medical history and symptoms, do a physical exam, and order blood tests. There are blood tests for each type of ...

  9. Operative treatment of hepatic trauma in Vachira Phuket Hospital.

    PubMed

    Vatanaprasan, Thanong

    2005-03-01

    Descriptive study of an 8-year period, 211 patients with hepatic trauma were studied retrospectively. Most of the patients were male (81.5%). Patients mainly affected were in the third decade of life (46.9%) with an age range of 2 to 65 years old (Mean 26.1 +/- 9.8). Fifty four percent resulted from blunt and 46.4% from penetrating injuries. The most common cause of injuries was motorcycle accidents (41.2%). The injuries were graded by the hepatic injury scale (grades I to VI). There were 22 (10.4%), 62 (29.4%), 70 (33.2%), 27 (12.8%), 28 (13.3%) and 2 (0.9%) patients with grade I, II, III, IV, V and VI hepatic injuries, respectively. Forty seven percent of patients were in shock when they first arrived at the emergency room. One hundred and sixty five patients (78.2%) had 375 associated injuries. Seventy three percent of patients had low grade hepatic injuries (grades I to III), the remainder (27%) had high grade hepatic injuries (grades IV to VI). Operative treatment of hepatic injuries varied according to degree of injury. Low grade hepatic injuries amenable to relatively simple operative treatment. Nineteen deaths (12.3%) occurring in this group were attributed to the commonly encountered associated injuries inside and outside the abdomen, which were more frequently seen after blunt trauma (89.5%). High-grade hepatic injuries required major techniques. Thirty four of these patients died (59.6%), death was related to the injury itself (91.2%), which were more frequently seen after blunt trauma (85%). During operation, suture ligature of the bleeding point, or hepatorrhaphy stopped the bleeding in most circumstances. Perihepatic packing was a useful procedure when termination of the operation was considered necessary in order to prevent the development of hypothermia, acidosis and coagulopathy. Perihepatic packing was used for treatment of 73% of high grade hepatic injuries and yielded 65.5% survival rate. The results were 59 patients had complication (morbidity

  10. Hepatitis B and Hepatitis C in Pregnancy

    MedlinePlus

    ... infected with the hepatitis B virus, can I breastfeed? • If I am infected with the hepatitis B ... infected with the hepatitis C virus, can I breastfeed? • Glossary What are hepatitis B and hepatitis C ...

  11. Hepatic Enzyme Decline after Pediatric Blunt Trauma: A Tool for Timing Child Abuse?

    ERIC Educational Resources Information Center

    Baxter, Amy L.; Lindberg, Daniel M.; Burke, Bonnie L.; Shults, Justine; Holmes, James F.

    2008-01-01

    Objectives: Previous research in adult patients with blunt hepatic injuries has suggested a pattern of serum hepatic transaminase concentration decline. Evaluating this decline after pediatric blunt hepatic trauma could establish parameters for estimating the time of inflicted injuries. Deviation from a consistent transaminase resolution pattern…

  12. Experimental design of complement component 5a-induced acute lung injury (C5a-ALI): a role of CC-chemokine receptor type 5 during immune activation by anaphylatoxin

    PubMed Central

    Russkamp, Norman F.; Ruemmler, Robert; Roewe, Julian; Moore, Bethany B.; Ward, Peter A.; Bosmann, Markus

    2015-01-01

    Excessive activation of the complement system is detrimental in acute inflammatory disorders. In this study, we analyzed the role of complement-derived anaphylatoxins in the pathogenesis of experimental acute lung injury/acute respiratory distress syndrome (ALI/ARDS) in C57BL/6J mice. Intratracheal administration of recombinant mouse complement component (C5a) caused alveolar inflammation with abundant recruitment of Ly6-G+CD11b+ leukocytes to the alveolar spaces and severe alveolar-capillary barrier dysfunction (C5a-ALI; EC50[C5a] = 20 ng/g body weight). Equimolar concentrations of C3a or desarginated C5a (C5adesArg) did not induce alveolar inflammation. The severity of C5a-ALI was aggravated in C5-deficient mice. Depletion of Ly6-G+ cells and use of C5aR1−/− bone marrow chimeras suggested an essential role of C5aR1+ hematopoietic cells in C5a-ALI. Blockade of PI3K/Akt and MEK1/2 kinase pathways completely abrogated lung injury. The mechanistic description is that C5a altered the alveolar cytokine milieu and caused significant release of CC-chemokines. Mice with genetic deficiency of CC-chemokine receptor (CCR) type 5, the common receptor of chemokine (C-C motif) ligand (CCL) 3, CCL4, and CCL5, displayed reduced lung damage. Moreover, treatment with a CCR5 antagonist, maraviroc, was protective against C5a-ALI. In summary, our results suggest that the detrimental effects of C5a in this model are partly mediated through CCR5 activation downstream of C5aR1, which may be evaluated for potential therapeutic exploitation in ALI/ARDS.—Russkamp, N. F., Ruemmler, R., Roewe, J., Moore, B. B., Ward, P. A., Bosmann, M. Experimental design of complement component 5a-induced acute lung injury (C5a-ALI): a role of CC-chemokine receptor type 5 during immune activation by anaphylatoxin. PMID:25999468

  13. Hepatitis virus panel

    MedlinePlus

    Hepatitis A antibody test; Hepatitis B antibody test; Hepatitis C antibody test; Hepatitis D antibody test ... There are different tests for hepatitis A and B. A positive test is ... may mean: You currently have a hepatitis infection. This may ...

  14. Hepatitis C and Incarceration

    MedlinePlus

    HEPATITIS C & INCARCERATION What is hepatitis? “Hepatitis” means inflammation or swelling of the liver. The liver is an important ... viral hepatitis: Hepatitis A, Hepatitis B, and Hepatitis C. They are all different from each other and ...

  15. Hepatitis C: Treatment

    MedlinePlus

    ... Public Home » Hepatitis C » Hepatitis C Treatment Viral Hepatitis Menu Menu Viral Hepatitis Viral Hepatitis Home For ... Enter ZIP code here Enter ZIP code here Hepatitis C Treatment for Veterans and the Public Treatment ...

  16. Hepatic Encephalopathy

    MedlinePlus Videos and Cool Tools

    ... is Hepatic Encephalopathy? Hepatic Encephalopathy, sometimes referred to as portosystemic encephalopathy or PSE, is a condition that ... medical care is an important factor in staying as healthy as possible. The American Liver Foundation is ...

  17. Hepatitis D

    MedlinePlus

    ... if the hepatitis B virus is also present. Transmission Hepatitis D can be found in the blood, ... other body fluids of people who are infected. Transmission happens when infected body fluid enters another person’s ...

  18. Autoimmune hepatitis

    MedlinePlus

    Lupoid hepatitis; Chronic acute liver disease ... This form of hepatitis is an autoimmune disease . The body's immune system cannot tell the difference between healthy body tissue and harmful, outside ...

  19. Hepatitis C

    MedlinePlus

    ... 2014 Select a Language: Fact Sheet 507 Hepatitis C WHAT IS HEPATITIS C? HOW IS IT DIAGNOSED? ... treatment may be less likely to work. Hep C treatment is less effective for coinfected people. Cure ...

  20. 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 ...

  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 A

    MedlinePlus

    ... is an inflammation of the liver. One type, hepatitis A, is caused by the hepatitis A virus (HAV). The disease spreads through contact with ... suggest medicines to help relieve your symptoms. The hepatitis A vaccine can prevent HAV. Good hygiene can also ...

  3. 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 ...

  4. Hepatitis A

    MedlinePlus

    ... Organizations ​​ (PDF, 341 KB)​​​​​ Alternate Language URL Español Hepatitis A Page Content On this page: What is ... Nutrition Points to Remember Clinical Trials What is hepatitis A? Hepatitis * A is a virus , or infection, ...

  5. Autoimmune Hepatitis

    MedlinePlus

    ... Organizations ​​ (PDF, 341 KB)​​​​​ Alternate Language URL Autoimmune Hepatitis Page Content On this page: What is autoimmune ... Points to Remember Clinical Trials What is autoimmune hepatitis? Autoimmune hepatitis is a chronic—or long lasting— ...

  6. Khat-induced liver injuries: A report of two cases.

    PubMed

    Alhaddad, Omkolsoum M; Elsabaawy, Maha M; Rewisha, Eman A; Salman, Tary A; Kohla, Mohamed A S; Ehsan, Nermine A; Waked, Imam A

    2016-03-01

    Khat is consumed for recreational purposes in many countries, including Yemen, where >50% of adults chew khat leaves regularly. A wide spectrum of khat-induced liver injuries has been reported in the literature. Herein, we report two patients with khat-induced liver injury. Both patients clinically presented with acute hepatitis, one of whom showed radiological evidence of hepatic outflow obstruction. Based on the histological tests, both patients had acute hepatitis, which indicated drug-induced liver injury (DILI) on a background of chronic hepatitis and portal fibrosis; of the two, one presented with symptoms of immune-mediated liver injury. PMID:27049456

  7. Robotic suture of a large caval injury caused by endo-GIA stapler malfunction during laparoscopic wedge resection of liver segments VII and VIII en-bloc with the right hepatic vein.

    PubMed

    Boggi, Ugo; Moretto, Carlo; Vistoli, Fabio; D'Imporzano, Simone; Mosca, Franco

    2009-01-01

    Primary endo-GIA stapler malfunction occurred during robotic wedge resection of liver segments VII and VIII en-bloc with the right hepatic vein, in an obese woman diagnosed with single liver metastasis from a previous carcinoid tumour. Haemorrhage was soon controlled by clamping the vena cava below the injury using two wristed forceps angled at 90 degrees . With the two instruments locked in the holding position the ensuing operative strategy was discussed between surgeon and anaesthesia teams. Using the third robotic arm the caval injury was repaired laparoscopically with interrupted polypropylene sutures. The patient was transfused with two units of packed red blood cells, recovered uneventfully, and was discharged on post-operative day five. We conclude that even the most advanced technologies can fail and that surgeons should be fully aware of the consequences of these malfunctions and be prepared for repair. From this point of view, the da Vinci surgical system seems to have some advantages over classical laparoscopic methods including the ability to lock the wristed instruments in the holding position, the use of three arms by the same operating surgeon, and the extreme facilitation of intracorporeal suturing and knot-tying in deep and narrow spaces, extremely difficult if not impossible with conventional laparoscopic instruments. PMID:19707931

  8. Hepatic drug metabolism and adverse hepatic drug reactions.

    PubMed

    Schaffner, F

    1975-01-01

    Drugs and other chemicals are usually metabolized in the liver in the drug-metabolizing enzyme system. The metabolites sometimes bind with cellular macromolecules and injure the cell directly or serve as new antigens to create immunologic injury in a delayed fashion. The immediate or toxic injury is dose-dependent, predictable and zonal in the liver lobule, usually in the central region. Carbon tetrachloride intoxication and acetaminophen overdose are examples of injury resulting from microsomal metabolism. Other injuries related to microsomal metabolism are those produced by vinyl chloride in polymerization plant workers and by methotrexate in psoriatics or leukemic children. Most adverse drug reactions affecting the liver and producing jaundice are unpredictable, delayed in onset, and only hypothetically related to microsomal metabolism in some instances. The two main types are cholestasis and viral-hepatitis-like. The former may be in a pure form, in which case it may be partly dose-dependent, or in a form mixed with hepatitis. Many drugs produce cholestasis in a small percentage of persons, and because the reaction is benign, albeit prolonged at times, such drugs continue to be used. The viral-hepatitis-like reaction involves few drugs and affects few persons, but can be fatal. The recognition that chronic hepatitis can be caused by drugs such as oxyphenisatin, alpha-methyldopa, and isoniazid has added a new dimension to the clinical problem of adverse drug reactions, which may extend to widely used and commonly available agents like aspirin. PMID:171822

  9. Gene regulation in hepatic stellate cell.

    PubMed

    Lang, A; Brenner, D A

    1999-03-01

    Hepatic stellate cells are now recognized as the major source of extracellular matrix in hepatic fibrosis. Following liver injury the hepatic stellate cell changes from a quiescent to an activated cell. The activation process includes an increased proliferation rate, a phenotypic change to a myofibroblast-like cell, loss of vitamin A stores, increased extra-cellular matrix protein synthesis and contractility. Furthermore, hepatic stellate cells have been implicated in hepatic inflammation through their ability to secrete cytokines and chemokines. Here, we review the literature on the molecular pathogenesis of hepatic stellate cells activation with emphasis on the most recent findings. The reviewed topics include transcriptional and post-transcriptional regulation of the genes encoding type I collagen in hepatic stellate cells; the role of the transcription factor nuclear factor Kappa B in the hepatic stellate cell activation; focal adhesion kinase and integrin-mediated signal transduction in hepatic stellate cell, and apoptosis in hepatic stellate cells. New insight into hepatic stellate cell activation and death may lead to the development of novel therapies for hepatic fibrosis. PMID:10363203

  10. Myeloid STAT3 inhibits T-cell–mediated hepatitis by regulating T helper 1 cytokine and interleukin-17 production

    PubMed Central

    Lafdil, Fouad; Wang, Hua; Park, Ogyi; Zhang, Weici; Moritoki, Yuki; Yin, Shi; Fu, Xin Yuan; Gershwin, M. Eric; Lian, Zhe-Xiong; Gao, Bin

    2009-01-01

    Background & Aims T-cell–mediated hepatitis is a leading cause of acute liver failure; there is no effective treatment and the mechanisms underlying its pathogenesis are obscure. The aim of this study was to investigate the immune-cell signaling pathways involved—specifically the role of signal transducer and activator of transcription 3 (STAT3)—in T-cell–mediated hepatitis in mice. Methods T-cell–mediated hepatitis was induced in mice by injection of concanavalin A (Con A). Mice with myeloid cell-specific and T-cell–specific deletion of STAT3 were generated. Results STAT3 was activated in myeloid and T cells following Con A injection. Deletion of STAT3 specifically from myeloid cells exacerbated T-cell hepatitis and induced STAT1-dependent production of a Th1 cytokine (IFN-γ), and to a lesser extent of Th17 cytokines (IL-17 and IL-22), in a STAT1-independent manner. In contrast, deletion of STAT3 in T cells reduced T-cell mediated hepatitis and IL-17 production. Furthermore, deletion of IFN-γ completely abolished Con A-induced T-cell hepatitis whereas deletion of IL-17 slightly but significantly reduced such injury. In vitro experiments indicated that IL-17 promoted liver inflammation but inhibited hepatocyte apoptosis. Conclusion Myeloid STAT3 activation inhibits T-cell–mediated hepatitis via suppression of a Th1 cytokine (IFN-γ) in a STAT1-dependent manner whereas STAT3 activation in T cells promotes T-cell hepatitis to a lesser extent, via induction of IL-17. Therefore, activation of STAT3 in myeloid cells could be a novel therapeutic strategy for patients with T-cell hepatitis. PMID:19686746

  11. [Role of multislice computed tomography in the diagnosis of acute rupture of the thoracic aorta and hepatic artery in a patient with severe concomitant injury].

    PubMed

    Muslimov, R Sh; Sharifullin, F A; Chernaia, N R; Novruzbekov, M S; Kokov, L S

    2015-01-01

    Acute traumatic aortic rupture is associated with extremely high mortality rates and requires emergency diagnosis and treatment. This clinical example shows the role of multislice spiral computed tomography in the emergency diagnosis of rupture of two large arterial vessels in severe concomitant injury. It presents the benefits of this rapid and noninvasive imaging technique, an algorithm of the study and the semiotics of injuries in patients with suspected traumatic aortic rupture. The paper also shows the importance of this method in defining treatment policy and then in the assessment of the results of the performed correction. PMID:25864362

  12. Chronic hepatitis E: A brief review

    PubMed Central

    Murali, Arvind R; Kotwal, Vikram; Chawla, Saurabh

    2015-01-01

    Hepatitis E viral infection has traditionally been considered an acute, self-limited, water borne disease similar to hepatitis A, endemic to developing countries. However, over the past decade, zoonotic transmission and progression to chronicity in human patients has been identified, resulting in persistently elevated transaminase levels, progressive liver injury and cirrhosis. In addition to liver injury, neurological, renal and rheumatological manifestations have also been reported. Chronic hepatitis E occurs mainly in immunosuppressed individuals such as transplant recipients, human immunodeficiency virus patients with low CD4 counts and in patients with hematological malignancies receiving chemotherapy. Diagnosis is established by persistent elevation of hepatitis E virus RNA in the stool or serum. This population often requires treatment with antiviral agents, particularly ribavirin, as spontaneous clearance with reduction in immunosuppression occurs only in about a third of the patients. The purpose of this review, is to further discuss the clinical presentation, and recent advances in diagnosis, treatment and prophylaxis of chronic hepatitis E. PMID:26380044

  13. 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

  14. Hepatitis Vaccines.

    PubMed

    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. Protective Role of Dietary Curcumin in the Prevention of the Oxidative Stress Induced by Chronic Alcohol with respect to Hepatic Injury and Antiatherogenic Markers

    PubMed Central

    Varatharajalu, Ravi; Garige, Mamatha; Leckey, Leslie C.; Reyes-Gordillo, Karina; Shah, Ruchi; Lakshman, M. Raj

    2016-01-01

    Curcumin, an antioxidant compound found in Asian spices, was evaluated for its protective effects against ethanol-induced hepatosteatosis, liver injury, antiatherogenic markers, and antioxidant status in rats fed with Lieber-deCarli low menhaden (2.7% of total calories from ω-3 polyunsaturated fatty acids (PUFA)) and Lieber-deCarli high menhaden (13.8% of total calories from ω-3 PUFA) alcohol-liquid (5%) diets supplemented with or without curcumin (150 mg/kg/day) for 8 weeks. Treatment with curcumin protected against high ω-3 PUFA and ethanol-induced hepatosteatosis and increase in liver injury markers, alanine aminotransferase, and aspartate aminotransferase. Curcumin upregulated paraoxonase 1 (PON1) mRNA and caused significant increase in serum PON1 and homocysteine thiolactonase activities as compared to high ω-3 PUFA and ethanol group. Moreover, treatment with curcumin protected against ethanol-induced oxidative stress by increasing the antioxidant glutathione and decreasing the lipid peroxidation adduct 4-hydroxynonenal. These results strongly suggest that chronic ethanol in combination with high ω-3 PUFA exacerbated hepatosteatosis and liver injury and adversely decreases antiatherogenic markers due to increased oxidative stress and depletion of glutathione. Curcumin supplementation significantly prevented these deleterious actions of chronic ethanol and high ω-3 PUFA. Therefore, we conclude that curcumin may have therapeutic potential to protect against chronic alcohol-induced liver injury and atherosclerosis. PMID:26881029

  16. Gasoline immersion injury

    SciTech Connect

    Simpson, L.A.; Cruse, C.W.

    1981-01-01

    Chemical burns and pulmonary complications are the most common problems encountered in the patient immersed in gasoline. Our patient demonstrated a 46-percent total-body-surface area, partial-thickness chemical burn. Although he did not develop bronchitis or pneumonitis, he did display persistent atelectasis, laryngeal edema, and subsequent upper airway obstruction. This had not previously been reported in gasoline inhalation injuries. Hydrocarbon hepatitis secondary to the vascular endothelial damage is apparently a reversible lesion with no reported long-term sequelae. Gasoline immersion injuries may be a series multisystem injury and require the burn surgeon to take a multisystem approach to its diagnosis and treatment.

  17. Hepatitis B Vaccine

    MedlinePlus

    ... as a combination product containing Hepatitis A Vaccine, Hepatitis B Vaccine) ... What is hepatitis B?Hepatitis B is a serious infection that affects the liver. It is caused by the hepatitis B virus. ...

  18. Hepatitis A Vaccine

    MedlinePlus

    Twinrix® (as a combination product containing Hepatitis A Vaccine, Hepatitis B Vaccine) ... What is hepatitis A?Hepatitis A is a serious liver disease caused by the hepatitis A virus (HAV). HAV is found in ...

  19. Hepatitis C: Clinical Trials

    MedlinePlus

    ... and Public Home » Hepatitis C » Treatment Decisions Viral Hepatitis Menu Menu Viral Hepatitis Viral Hepatitis Home For ... can I find out about participating in a hepatitis C clinical trial? Many trials are being conducted ...

  20. Autoimmune hepatitis

    MedlinePlus

    ... diseases. These include: Graves disease Inflammatory bowel disease Rheumatoid arthritis Scleroderma Sjogren syndrome Systemic lupus erythematosus Thyroiditis Type 1 diabetes Ulcerative colitis Autoimmune hepatitis may occur in family ...

  1. Hepatitis B

    MedlinePlus

    ... A Hepatitis B HPV (Human Papillomavirus) Influenza (Flu) Measles Meningococcal Disease Mumps Pertussis (Whooping Cough) Pneumococcal Disease Rubella (German Measles) Shingles (Herpes Zoster) Tetanus (Lockjaw) Professional Resources Adult ...

  2. Dietary tomato powder inhibits alcohol-induced hepatic injury by suppressing cytochrome p450 2E1 induction in rodent models.

    PubMed

    Stice, Camilla P; Liu, Chun; Aizawa, Koichi; Greenberg, Andrew S; Ausman, Lynne M; Wang, Xiang-Dong

    2015-04-15

    Chronic and excessive alcohol consumption leads to the development of alcoholic liver disease (ALD) and greatly increases the risk of liver cancer. Induction of the cytochrome p450 2E1 (CYP2E1) enzyme by chronic and excessive alcohol intake is known to play a role in the pathogenesis of ALD. High intake of tomatoes, rich in the carotenoid lycopene, is associated with a decreased risk of chronic disease. We investigated the effects of whole tomato (tomato powder, TP), partial tomato (tomato extract, TE), and purified lycopene (LYC) against ALD development in rats. Of the three supplements, only TP reduced the severity of alcohol-induced steatosis, hepatic inflammatory foci, and CYP2E1 protein levels. TE had no effect on these outcomes and LYC greatly increased inflammatory foci in alcohol-fed rats. To further support the protective effect of TP against ALD, TP was supplemented in a carcinogen (diethylnitrosamine, DEN)-initiated alcohol-promoted mouse model. In addition to reduced steatosis and inflammatory foci, TP abolished the presence of preneoplastic foci of altered hepatocytes in DEN-injected mice fed alcohol. These reductions were associated with decreased hepatic CYP2E1 protein levels, restored levels of peroxisome proliferator-activated receptor-α and downstream gene expression, decreased inflammatory gene expression, and reduced endoplasmic reticulum stress markers. These data provide strong evidence for TP as an effective whole food prevention strategy against ALD. PMID:25592162

  3. Role of mitogen-activated protein kinases and nuclear factor-kappa B in 1,3-dichloro-2-propanol-induced hepatic injury

    PubMed Central

    Lee, In-Chul; Lee, Sang-Min; Ko, Je-Won; Park, Sung-Hyeuk; Shin, In-Sik; Moon, Changjong; Kim, Sung-Ho

    2016-01-01

    In this study, the potential hepatotoxicity of 1,3-dichloro-2-propanol and its hepatotoxic mechanisms in rats was investigated. The test chemical was administered orally to male rats at 0, 27.5, 55, and 110 mg/kg body weight. 1,3-Dichloro-2-propanol administration caused acute hepatotoxicity, as evidenced by an increase in serum aminotransferases, total cholesterol, and total bilirubin levels and a decrease in serum glucose concentration in a dose-dependent manner with corresponding histopathological changes in the hepatic tissues. The significant increase in malondialdehyde content and the significant decrease in glutathione content and antioxidant enzyme activities indicated that 1,3-dichloro-2-propanol-induced hepatic damage was mediated through oxidative stress, which caused a dose-dependent increase of hepatocellular apoptotic changes in the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay and immunohistochemical analysis for caspase-3. The phosphorylation of mitogen-activated protein kinases caused by 1,3-dichloro-2-propanol possibly involved in hepatocellular apoptotic changes in rat liver. Furthermore, 1,3-dichloro-2-propanol induced an inflammatory response through activation of nuclear factor-kappa B signaling that coincided with the induction of pro-inflammatory mediators or cytokines in a dose-dependent manner. Taken together, these results demonstrate that hepatotoxicity may be related to oxidative stress-mediated activation of mitogen-activated protein kinases and nuclear factor-kappa B-mediated inflammatory response. PMID:27051440

  4. Transforming growth factor-beta and platelet-derived growth factor signal via c-Jun N-terminal kinase-dependent Smad2/3 phosphorylation in rat hepatic stellate cells after acute liver injury.

    PubMed

    Yoshida, Katsunori; Matsuzaki, Koichi; Mori, Shigeo; Tahashi, Yoshiya; Yamagata, Hideo; Furukawa, Fukiko; Seki, Toshihito; Nishizawa, Mikio; Fujisawa, Junichi; Okazaki, Kazuichi

    2005-04-01

    After liver injury, transforming growth factor-beta (TGF-beta) and platelet-derived growth factor (PDGF) regulate the activation of hepatic stellate cells (HSCs) and tissue remodeling. Mechanisms of PDGF signaling in the TGF-beta-triggered cascade are not completely understood. TGF-beta signaling involves phosphorylation of Smad2 and Smad3 at linker and C-terminal regions. Using antibodies to distinguish Smad2/3 phosphorylated at linker regions from those phosphorylated at C-terminal regions, we investigated Smad2/3-mediated signaling in rat liver injured by CCl(4) administration and in cultured HSCs. In acute liver injury, Smad2/3 were transiently phosphorylated at both regions. Although linker-phosphorylated Smad2 remained in the cytoplasm of alpha-smooth muscle actin-immunoreactive mesenchymal cells adjacent to necrotic hepatocytes in centrilobular areas, linker-phosphorylated Smad3 accumulated in the nuclei. c-Jun N-terminal kinase (JNK) in the activated HSCs directly phosphorylated Smad2/3 at linker regions. Co-treatment of primary cultured HSCs with TGF-beta and PDGF activated the JNK pathway, subsequently inducing endogenous linker phosphorylation of Smad2/3. The JNK pathway may be involved in migration of resident HSCs within the space of Disse to the sites of tissue damage because the JNK inhibitor SP600125 inhibited HSC migration induced by TGF-beta and PDGF signals. Moreover, treatment of HSCs with both TGF-beta and PDGF increased transcriptional activity of plasminogen activator inhibitor-1 through linker phosphorylation of Smad3. In conclusion, TGF-beta and PDGF activate HSCs by transmitting their signals through JNK-mediated Smad2/3 phosphorylation at linker regions, both in vivo and in vitro. PMID:15793284

  5. Cholestatic phenotypes of autoimmune hepatitis.

    PubMed

    Czaja, Albert J

    2014-09-01

    Autoimmune hepatitis can have cholestatic features that are outside the codified diagnostic criteria. These features have uncertain effects on the clinical presentation and progression of disease. Patients with autoimmune hepatitis can have antimitochondrial antibodies and coincidental bile duct injury or loss (2%-13% of patients), focal biliary strictures and dilations based on cholangiography (2%-11%), or histologic changes of bile duct injury or loss in the absence of other features (5%-11%). These findings probably represent atypical manifestations of autoimmune hepatitis or variants of primary biliary cirrhosis or primary sclerosing cholangitis, depending on the predominant findings. Serum levels of alkaline phosphatase and γ-glutamyl transferase, histologic features of bile duct injury, and findings from cholangiography are associated with responsiveness to corticosteroid therapy and individualized alternative treatments. Corticosteroid therapy, in combination with low-dose ursodeoxycholic acid, has been promulgated by international societies, but these recommendations are not based on strong evidence. The frequency, variable outcomes, and uncertainties in diagnosis and management of the cholestatic phenotypes must be addressed by a collaborative investigational network. This network should define the genetic and pathologic features of these disorders, standardize their nomenclature, and establish a treatment algorithm. In this review, the different cholestatic phenotypes of autoimmune hepatitis, mechanisms of pathogenesis, current management strategies and outcomes, and opportunities for improving understanding and therapy are presented. PMID:24013108

  6. Pretreatment With TCDD Exacerbates Liver Injury From Concanavalin A: Critical Role for NK Cells

    PubMed Central

    Ganey, Patricia E.

    2013-01-01

    For many liver diseases, including viral and autoimmune hepatitis, immune cells play an important role in the development and progression of liver injury. Concanavalin A (Con A) administration to rodents has been used as a model of immune-mediated liver injury resembling human autoimmune hepatitis. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been demonstrated to alter the development of immune-mediated diseases. Mice pretreated with TCDD developed exacerbated liver injury in response to administration of a mild dose (6mg/kg) of Con A. In the present study, we tested the hypothesis that TCDD pretreatment exacerbates Con A-induced liver injury by enhancing the activation and recruitment of accessory cell types including neutrophils, macrophages, and natural killer (NK) cells. Mice were treated with 0, 0.3, 3, or 30 μg/kg TCDD and 4 days later with Con A or saline. TCDD pretreatment with doses of 3 and 30 μg/kg significantly increased liver injury from Con A administration. The plasma concentrations of neutrophil chemokines were significantly increased in TCDD-pretreated mice after Con A administration. NKT cell-deficient (CD1d KO) mice were used to examine whether NKT cells were required for TCDD/Con A-induced liver injury. CD1d KO mice were completely protected from liver injury induced by treatment with Con A alone, whereas the injury from TCDD/Con A treatment was reduced but not eliminated. However, T-cell deficient (RAG1 KO) mice were protected from liver injury induced by Con A irrespective of pretreatment with TCDD. TCDD/Con A treatment increased the percentage of NK cells expressing the activation marker CD69. Depletion of NK cells prior to treatment resulted in significant reductions in plasma interferon-γ and liver injury from TCDD/Con A treatment. In summary, exposure to TCDD exacerbated the immune-mediated liver injury induced by Con A, and our findings suggest that NK cells play a critical role in this response. PMID:23970800

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

    PubMed

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

    2013-11-01

    For many liver diseases, including viral and autoimmune hepatitis, immune cells play an important role in the development and progression of liver injury. Concanavalin A (Con A) administration to rodents has been used as a model of immune-mediated liver injury resembling human autoimmune hepatitis. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been demonstrated to alter the development of immune-mediated diseases. Mice pretreated with TCDD developed exacerbated liver injury in response to administration of a mild dose (6 mg/kg) of Con A. In the present study, we tested the hypothesis that TCDD pretreatment exacerbates Con A-induced liver injury by enhancing the activation and recruitment of accessory cell types including neutrophils, macrophages, and natural killer (NK) cells. Mice were treated with 0, 0.3, 3, or 30 μg/kg TCDD and 4 days later with Con A or saline. TCDD pretreatment with doses of 3 and 30 μg/kg significantly increased liver injury from Con A administration. The plasma concentrations of neutrophil chemokines were significantly increased in TCDD-pretreated mice after Con A administration. NKT cell-deficient (CD1d KO) mice were used to examine whether NKT cells were required for TCDD/Con A-induced liver injury. CD1d KO mice were completely protected from liver injury induced by treatment with Con A alone, whereas the injury from TCDD/Con A treatment was reduced but not eliminated. However, T-cell deficient (RAG1 KO) mice were protected from liver injury induced by Con A irrespective of pretreatment with TCDD. TCDD/Con A treatment increased the percentage of NK cells expressing the activation marker CD69. Depletion of NK cells prior to treatment resulted in significant reductions in plasma interferon-γ and liver injury from TCDD/Con A treatment. In summary, exposure to TCDD exacerbated the immune-mediated liver injury induced by Con A, and our findings suggest that NK cells play a critical role in this response. PMID:23970800

  8. Urethral Injuries

    MedlinePlus

    ... Injuries Ureteral Injuries Urethral Injuries Injuries to the Penis and Scrotum Most urethral injuries occur in men. ... leakage of urine into the tissues of the penis, scrotum, abdominal wall, or perineum (the area between ...

  9. Hepatic Encephalopathy

    PubMed Central

    Bleibel, Wissam; Al-Osaimi, Abdullah M. S.

    2012-01-01

    Chronic liver disease and cirrhosis affect hundreds of millions of patients all over the world. The majority of patients with cirrhosis will eventually develop complications related to portal hypertension. One of these recurrent and difficult to treat complications is hepatic encephalopathy. Studies have indicated that overt hepatic encephalopathy affects 30 to 45% of patients with cirrhosis and a higher percentage may be affected by minimal degree of encephalopathy. All of these factors add to the impact of hepatic encephalopathy on the healthcare system and presents a major challenge to the gastroenterologist, hospitalist and primary care physician. PMID:23006457

  10. Mutations in core nucleotide sequence of hepatitis B virus correlate with fulminant and severe hepatitis.

    PubMed Central

    Ehata, T; Omata, M; Chuang, W L; Yokosuka, O; Ito, Y; Hosoda, K; Ohto, M

    1993-01-01

    Infection with hepatitis B virus leads to a wide spectrum of liver injury, including self-limited acute hepatitis, fulminant hepatitis, and chronic hepatitis with progression to cirrhosis or acute exacerbation to liver failure, as well as an asymptomatic chronic carrier state. Several studies have suggested that the hepatitis B core antigen could be an immunological target of cytotoxic T lymphocytes. To investigate the reason why the extreme immunological attack occurred in fulminant hepatitis and severe exacerbation patients, the entire precore and core region of hepatitis B virus DNA was sequenced in 24 subjects (5 fulminant, 10 severe fatal exacerbation, and 9 self-limited acute hepatitis patients). No significant change in the nucleotide sequence and deduced amino acid residue was noted in the nine self-limited acute hepatitis patients. In contrast, clustering changes in a small segment of 16 amino acids (codon 84-99 from the start of the core gene) in all seven adr subtype infected fulminant and severe exacerbation patients was found. A different segment with clustering substitutions (codon 48-60) was also found in seven of eight adw subtype infected fulminant and severe exacerbation patients. Of the 15 patients, 2 lacked precore stop mutation which was previously reported to be associated with fulminant hepatitis. These data suggest that these core regions with mutations may play an important role in the pathogenesis of hepatitis B viral disease, and such mutations are related to severe liver damage. Images PMID:8450049

  11. Effects of Consumption of Rooibos (Aspalathus linearis) and a Rooibos-Derived Commercial Supplement on Hepatic Tissue Injury by tert-Butyl Hydroperoxide in Wistar Rats

    PubMed Central

    Canda, B. D.; Oguntibeju, O. O.; Marnewick, J. L.

    2014-01-01

    This study investigated the antioxidative effect of rooibos herbal tea and a rooibos-derived commercial supplement on tert-butyl hydroperoxide- (t-BHP-) induced oxidative stress in the liver. Forty male Wistar rats consumed fermented rooibos, unfermented rooibos, a rooibos-derived commercial supplement, or water for 10 weeks, while oxidative stress was induced during the last 2 weeks via intraperitoneal injection of 30 µmole of t-BHP per 100 g body weight. None of the beverages impaired the body weight gain of the respective animals. Rats consuming the rooibos-derived commercial supplement had the highest (P < 0.05) daily total polyphenol intake (169 mg/day) followed by rats consuming the unfermented rooibos (93.4 mg/day) and fermented rooibos (73.1 mg/day). Intake of both the derived supplement and unfermented rooibos restored the t-BHP-induced reduction and increased (P < 0.05) the antioxidant capacity status of the liver, while not impacting on lipid peroxidation. The rooibos herbal tea did not affect the hepatic antioxidant enzymes, except fermented rooibos that caused a decrease (P < 0.05) in superoxide dismutase activity. This study confirms rooibos herbal tea as good dietary antioxidant sources and, in conjunction with its many other components, offers a significantly enhanced antioxidant status of the liver in an induced oxidative stress situation. PMID:24738022

  12. Enrichment and purification of total flavonoids from Cortex Juglandis Mandshuricae extracts and their suppressive effect on carbon tetrachloride-induced hepatic injury in Mice.

    PubMed

    Zhao, Pan; Qi, Chao; Wang, Gang; Dai, Xinpeng; Hou, Xiaohong

    2015-12-15

    In the present work, a simple and efficient chromatographic separation method was developed for preparative separation and enrichment of total flavonoids (TFs) from Cortex Juglandis Mandshuricae (CJM) extracts and then the protective effect of TFs against CCl4-induced acute liver injury in mice was investigated. Enrichment and purification of TFs from CJM extracts were studied using six macroporous resins and HPD-750 resin was selected as the best resin according to its adsorption and desorption properties. The operating parameters of resin column chromatography were optimized. Under the optimal conditions, TFs from CJM with purity larger than 50% were produced and their antioxidant activity was further evaluated in vitro. The mice were orally administrated with the purified TFs for seven days and then given CCl4 (0.3%, 10mL/kg i.p.). The results showed that TFs of CJM significantly attenuated the activities of serum aspartate transaminase (AST) and alanine transaminase (ALT) compared with model group, as well as the relative liver weight. Histopathological observation also revealed that TFs reduced the incidence of liver lesions and improved hepatocyte abnormality. Moreover, oral administration of TFs significantly enhanced antioxidant enzyme activities (superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px)) and decreased the content of malondialdehyde (MDA). Histopathological and biochemical results elicited that TFs of CJM had significant hepatoprotective activity comparable to the standard silymarin. This is the first time to reveal the protective actions of the TFs from CJM against CCl4-induced liver damage in mice and this natural product should be developed as a new drug for treatment of live injury in future. PMID:26562802

  13. An analytical review of vasculobiliary injury in laparoscopic and open cholecystectomy

    PubMed Central

    Strasberg, Steven M; Helton, W Scott

    2011-01-01

    Objectives Biliary injuries are frequently accompanied by vascular injuries, which may worsen the bile duct injury and cause liver ischemia. We performed an analytical review with the aim of defining vasculobiliary injury and setting out the important issues in this area. Methods A literature search of relevant terms was peformed using OvidSP. Bibliographies of papers were also searched to obtain older literature. Results Vasculobiliary injury was defined as: an injury to both a bile duct and a hepatic artery and/or portal vein; the bile duct injury may be caused by operative trauma, be ischaemic in origin or both, and may or may not be accompanied by various degrees of hepatic ischaemia. Right hepatic artery (RHA) vasculobiliary injury (VBI) is the most common variant. Injury to the RHA likely extends the biliary injury to a higher level than the gross observed mechanical injury. VBI results in slow hepatic infarction in about 10% of patients. Repair of the artery is rarely possible and the overall benefit unclear. Injuries involving the portal vein or common or proper hepatic arteries are much less common, but have more serious effects including rapid infarction of the liver. Conclusions Routine arteriography is recommended in patients with a biliary injury if early repair is contemplated. Consideration should be given to delaying repair of a biliary injury in patients with occlusion of the RHA. Patients with injuries to the portal vein or proper or common hepatic should be emergently referred to tertiary care centers. PMID:21159098

  14. Hepatitis B

    MedlinePlus

    ... and Change Plan Wallet card for patients to record their alcohol use over a 4-week period as a way to monitor and reduce their drinking behavior. Glossary Definitions of terms commonly used with viral hepatitis and ...

  15. Hepatitis B

    MedlinePlus

    ... U.S. Preventive Services Task Force recommendation statement. Ann Intern Med . 2014;161(1):58-66. PMID 24863637 ... Development Conference Statement: Management of hepatitis B. Ann Intern Med . 2009;150:104-10. PMID: 19124811 www. ...

  16. Phase II Study of Chemoembolization With Drug-Eluting Beads in Patients With Hepatic Neuroendocrine Metastases: High Incidence of Biliary Injury

    SciTech Connect

    Bhagat, Nikhil Reyes, Diane K.; Lin, Mingde; Kamel, Ihab; Pawlik, Timothy M.; Frangakis, Constantine; Geschwind, J. F.

    2013-04-15

    To evaluate safety in an interim analysis of transarterial chemoembolization (TACE) with doxorubicin-eluting beads (DEB) in 13 patients with hepatic metastases from neuroendocrine tumors (NETs) as part of a phase II trial. Institutional Review Board approval and informed consent were obtained. Thirteen patients completed preliminary safety analysis. Their mean age was 65 years, Eastern Cooperative Oncology Group status was 0/1, tumor burden range was 4-75 %, and mean targeted tumor size was 5.9 cm. Up to four DEB-TACE sessions (100-300 {mu}m beads loaded with {<=}100 mg doxorubicin) within 6 months were allowed. Tumor response was assessed by magnetic resonance imaging 1 month after treatment using contrast-enhancement [European Association for the Study of the Liver (EASL) and size Response Evaluation Criteria in Solid Tumors (RECIST)] criteria. Safety was assessed by National Cancer Institute Common Terminology Criteria. DEB-TACE was successfully performed in all 13 patients. At 1 month follow-up, there was a mean 12 % decrease in tumor size (p < 0.0003) and a 56 % decrease in tumor enhancement (p < 0.0001). By EASL criteria, the targeted lesion objective response rate was 78 %. Grade 3 to 4 toxicities were fatigue (23 %), increased alanine amino transferase (15 %), hyperglycemia (15 %), and abdominal pain (8 %). Seven patients developed bilomas (54 %); all of these patients had multiple small (<4 cm) lesions. Subsequently, four underwent percutaneous drainage, three for abscess formation and one for symptoms related to mass effect. Although biloma and liver abscess are known risks after TACE, the high incidence in our study population was unexpected and forced interruption of the trial. Although this occurred in a small group of patients, we have changed our technique and patient selection as a result of these findings, thus allowing resumption of the trial.

  17. Hepatitis E Virus Infection

    PubMed Central

    Dalton, Harry R.; Abravanel, Florence; Izopet, Jacques

    2014-01-01

    SUMMARY Hepatitis E virus (HEV) infection is a worldwide disease. An improved understanding of the natural history of HEV infection has been achieved within the last decade. Several reservoirs and transmission modes have been identified. Hepatitis E is an underdiagnosed disease, in part due to the use of serological assays with low sensitivity. However, diagnostic tools, including nucleic acid-based tests, have been improved. The epidemiology and clinical features of hepatitis E differ between developing and developed countries. HEV infection is usually an acute self-limiting disease, but in developed countries it causes chronic infection with rapidly progressive cirrhosis in organ transplant recipients, patients with hematological malignancy requiring chemotherapy, and individuals with HIV. HEV also causes extrahepatic manifestations, including a number of neurological syndromes and renal injury. Acute infection usually requires no treatment, but chronic infection should be treated by reducing immunosuppression in transplant patients and/or the use of antiviral therapy. In this comprehensive review, we summarize the current knowledge about the virus itself, as well as the epidemiology, diagnostics, natural history, and management of HEV infection in developing and developed countries. PMID:24396139

  18. Insulin Protects against Hepatic Damage Postburn

    PubMed Central

    Jeschke, Marc G; Kraft, Robert; Song, Juquan; Gauglitz, Gerd G; Cox, Robert A; Brooks, Natasha C; Finnerty, Celeste C; Kulp, Gabriela A; Herndon, David N; Boehning, Darren

    2011-01-01

    Burn injury causes hepatic dysfunction associated with endoplasmic reticulum (ER) stress and induction of the unfolded protein response (UPR). ER stress/UPR leads to hepatic apoptosis and activation of the Jun-N-terminal kinase (JNK) signaling pathway, leading to vast metabolic alterations. Insulin has been shown to attenuate hepatic damage and to improve liver function. We therefore hypothesized that insulin administration exerts its effects by attenuating postburn hepatic ER stress and subsequent apoptosis. Male Sprague Dawley rats received a 60% total body surface area (TBSA) burn injury. Animals were randomized to receive saline (controls) or insulin (2.5 IU/kg q. 24 h) and euthanized at 24 and 48 h postburn. Burn injury induced dramatic changes in liver structure and function, including induction of the ER stress response, mitochondrial dysfunction, hepatocyte apoptosis, and up-regulation of inflammatory mediators. Insulin decreased hepatocyte caspase-3 activation and apoptosis significantly at 24 and 48 h postburn. Furthermore, insulin administration decreased ER stress significantly and reversed structural and functional changes in hepatocyte mitochondria. Finally, insulin attenuated the expression of inflammatory mediators IL-6, MCP-1, and CINC-1. Insulin alleviates burn-induced ER stress, hepatocyte apoptosis, mitochondrial abnormalities, and inflammation leading to improved hepatic structure and function significantly. These results support the use of insulin therapy after traumatic injury to improve patient outcomes. PMID:21267509

  19. 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 10 Other Languages . Resource Video See ...

  20. Hepatitis C - children

    MedlinePlus

    ... virus (HCV). Other common hepatitis virus infections include hepatitis A and hepatitis B . ... Elisofon SA, Jonas MMF. Viral hepatitis in children. In: Boyer TD, Manns MP, Sanyal AJ, eds. Zakim & Boyer's Hepatology: A Textbook of Liver Disease. 6th ed. ...

  1. Hepatitis A FAQs

    MedlinePlus

    ... of Viral Hepatitis Contact Us Quick Links to Hepatitis ... A | B | C | D | E Viral Hepatitis Home ... Outbreaks State and Local Partners & Grantees Resource Center Hepatitis A FAQs for the Public Recommend on Facebook ...

  2. Delta agent (Hepatitis D)

    MedlinePlus

    Hepatitis D virus ... Hepatitis D virus (HDV) is found only in people who carry the hepatitis B virus. HDV may make liver ... B virus but who never had symptoms. Hepatitis D infects about 15 million people worldwide. It occurs ...

  3. Hepatitis C FAQs

    MedlinePlus

    ... of Viral Hepatitis Contact Us Quick Links to Hepatitis ... A | B | C | D | E Viral Hepatitis Home ... Outbreaks State and Local Partners & Grantees Resource Center Hepatitis C FAQs for the Public Recommend on Facebook ...

  4. Hepatitis B FAQs

    MedlinePlus

    ... of Viral Hepatitis Contact Us Quick Links to Hepatitis ... A | B | C | D | E Viral Hepatitis Home ... Outbreaks State and Local Partners & Grantees Resource Center Hepatitis B FAQs for the Public Recommend on Facebook ...

  5. Hepatitis A Test

    MedlinePlus

    ... be limited. Home Visit Global Sites Search Help? 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 ...

  6. IL-18, TNF, and IFN-γ alleles and genotypes are associated with susceptibility to chronic hepatitis B infection and severity of liver injury.

    PubMed

    Ferreira, Sandro da Costa; Chachá, Silvana Gama Florêncio; Souza, Fernanda Fernandes; Teixeira, Andreza Corrêa; Santana, Rodrigo de Carvalho; Deghaide, Neifi Hassan Saloun; Rodrigues, Sandra; Marano, Leonardo Arduíno; Mendes-Junior, Celso Teixeira; Zucoloto, Sérgio; Donadi, Eduardo Antônio; Martinelli, Ana de Lourdes Candolo

    2015-10-01

    This study evaluated the association of polymorphisms in the IL-18 (-607C/A and -137C/G), IFNγ (+874 A/T), and TNF (-238 A/G and -308 A/G) genes with susceptibility to HBV infection and severity of liver injury. A total of 259 chronic HBV-infected patients followed at the University Hospital, Faculty of Medicine of Ribeirão Preto, São Paulo, Brazil, and 202 healthy individuals were studied. Four Single Nucleotide Polymorphisms (SNPs) were amplified by Polymerase Chain Reaction (PCR). Liver biopsy was performed in 212 HBV-infected patients and classified according to severity of liver fibrosis (scores 0-4) and necroinflammatory activity (HAI scores 0-18). TNF-308*A allele (P < 0.001; OR = 2.16) and TNF -308 AA genotype (P = 0.026; OR = 5.43) were associated with susceptibility to HBV infection. An association was found between severe liver fibrosis when compared to mild fibrosis and the following polymorphisms: Alleles IL-18 -137*G (P = 0.004; OR = 3.45), TNF -308*A (P < 0.001; OR = 3.39), and IFNγ +874*T (P = 0.029; OR = 1.85) and IL-18 -137 GG genotype (P = 0.009; OR = 3.70). No significant association was found between IL-18 (-607 A/C) polymorphism and severity of liver fibrosis. Alleles IL-18 -137*G (P = 0.028; OR = 2.64) and TNF-308*A (P = 0.002; OR = 3.06) and IL-18 -137 GG genotype (P = 0.011; OR = 4.20) were associated with severe necroinflammatory activity (HAI>12) when compared to mild necroinflammatory activity (HAI 1-8). The results suggest that IL-18 -137C/G, TNF-308 G/A and IFNγ +874 A/T SNPs were associated to more severe liver injury in chronic HBV infection. TNF -308*A allele and TNF -308 AA genotype could play a role in the susceptibility to HBV infection. PMID:25952099

  7. Feature Hepatitis: Hepatitis Symptoms, Diagnosis, Treatment & Prevention

    MedlinePlus

    ... Current Issue Past Issues Feature Hepatitis Hepatitis: Symptoms, Diagnosis, Treatment & Prevention Past Issues / Spring 2009 Table of ... Stomach ache Nausea Diarrhea No appetite Fever Headaches Diagnosis To check for hepatitis viruses, your doctor will ...

  8. Pathophysiological Significance of Hepatic Apoptosis

    PubMed Central

    Wang, Kewei; Lin, Bingliang

    2013-01-01

    Apoptosis is a classical pathological feature in liver diseases caused by various etiological factors such as drugs, viruses, alcohol, and cholestasis. Hepatic apoptosis and its deleterious effects exacerbate liver function as well as involvement in fibrosis/cirrhosis and carcinogenesis. An imbalance between apoptotic and antiapoptotic capabilities is a prominent characteristic of liver injury. The regulation of apoptosis and antiapoptosis can be a pivotal step in the treatment of liver diseases. PMID:27335822

  9. Evaluation and Management of Hepatic Encephalopathy: Current Status and Future Directions.

    PubMed

    Suraweera, Duminda; Sundaram, Vinay; Saab, Sammy

    2016-07-15

    Hepatic encephalopathy is a spectrum of neurocognitive manifestations often seen in patients with liver injury or rarely in patients with portosystemic shunting without liver injury. It can be divided into minimal (covert) hepatic encephalopathy and overt hepatic encephalopathy, depending on the severity. Patients with hepatic encephalopathy have compromised clinical outcomes, decreased quality of life, and increased healthcare utilization, often resulting in a heavy financial and personal burden on caregivers. The diagnosis remains largely clinical, with the exclusion of possible other causes for the altered mental status. Current treatment strategies include nonabsorbable disaccharides and antibiotics. This review will focus on the diagnosis, management and clinical impact of hepatic encephalopathy. PMID:27377741

  10. Evaluation and Management of Hepatic Encephalopathy: Current Status and Future Directions

    PubMed Central

    Suraweera, Duminda; Sundaram, Vinay; Saab, Sammy

    2016-01-01

    Hepatic encephalopathy is a spectrum of neurocognitive manifestations often seen in patients with liver injury or rarely in patients with portosystemic shunting without liver injury. It can be divided into minimal (covert) hepatic encephalopathy and overt hepatic encephalopathy, depending on the severity. Patients with hepatic encephalopathy have compromised clinical outcomes, decreased quality of life, and increased healthcare utilization, often resulting in a heavy financial and personal burden on caregivers. The diagnosis remains largely clinical, with the exclusion of possible other causes for the altered mental status. Current treatment strategies include nonabsorbable disaccharides and antibiotics. This review will focus on the diagnosis, management and clinical impact of hepatic encephalopathy. PMID:27377741

  11. Hepatitis C: Sex and Sexuality

    MedlinePlus

    ... with Hepatitis » Sex and Sexuality: Entire Lesson Viral Hepatitis Menu Menu Viral Hepatitis Viral Hepatitis Home For ... hepatitis C virus through sex. Can you pass hepatitis C to a sex partner? Yes, but it ...

  12. Hepatitis C

    PubMed Central

    Mehta, Bharti; Kumar Dharma, Vijay; Chawla, Sumit; Jindal, Harashish; Bhatt, Bhumika

    2014-01-01

    Hepatitis C Virus (HCV) infection is a major cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Following acute infection, 20% of people eliminate the virus over weeks or months and are often asymptomatic. The remaining 80% of people will develop chronic disease, of which approximately 20% will eventually develop liver cirrhosis and 1–5% will develop liver cancer. About 150 million people are chronically infected with HCV, and more than 350 000 people die every year from hepatitis C related liver diseases. The economic cost of hepatitis C is significant both to the individual and to the society. In the United States the average lifetime cost of the disease was estimated at $33 407 USD with the cost of a liver transplant approximately $200 000 USD. PEG-IFN and ribavirin treatment is also expensive and, at an average cost of approximately GB £7000 in the UK for a treatment course, is unaffordable in developing countries. Hepatitis C, not only brings down the quality of the life of individuals but also affect progress of the nation by adding financial burden. If we prevent the disease from occurring or find a perfect cure of the disease, in form of a prophylactic or therapeutic vaccine, it will be a boon to not only to the individual but to the nation as a whole. PMID:24165512

  13. Head Injuries

    MedlinePlus

    ... before. Often, the injury is minor because your skull is hard and it protects your brain. But ... injuries can be more severe, such as a skull fracture, concussion, or traumatic brain injury. Head injuries ...

  14. Head Injuries

    MedlinePlus

    ... before. Usually, the injury is minor because your skull is hard and it protects your brain. But ... injuries can be more severe, such as a skull fracture, concussion, or traumatic brain injury. Head injuries ...

  15. Back Injuries

    MedlinePlus

    ... extending from your neck to your pelvis. Back injuries can result from sports injuries, work around the house or in the garden, ... back is the most common site of back injuries and back pain. Common back injuries include Sprains ...

  16. Head Injuries

    MedlinePlus

    ... of head injuries include bicycle or motorcycle wrecks, sports injuries, falls from windows (especially among children who live ... to watch for? When can I start playing sports again after a head injury? How can brain damage from a head injury ...

  17. [Hepatic encephalopathy].

    PubMed

    Córdoba, Juan; Mur, Rafael Esteban

    2014-07-01

    Hepatic encephalopathy (EH) is a severe complication of hepatic cirrhosis that is characterized by multiple neuropsychiatric manifestations. EH is usually triggered by a precipitating factor and occurs in patients with severely impaired hepatic function. Minimal EH is characterized by minor cognitive impairments that are difficult to specify but represent a risk for the patients. The primary pathophysiological mechanism of EH is considered to be an increase in blood ammonia with an impairment in the patency of the blood-brainbarrier and its metabolism to glutamine in astrocytes. The diagnosis is clinical and neuroimaging techniques can be complementary. The diagnosis of minimal EH requires specific neurocognitive tests. The clinical evaluation should be directed towards identifying the trigger. Nonabsorbable disaccharides and rifaximin constitute the treatment of choice, along with prophylaxis for new episodes. PMID:25087716

  18. Hepatitis A

    MedlinePlus

    ... Low-grade fever Nausea and vomiting Pale or clay-colored stools Yellow skin (jaundice) ... The virus does not remain in the body after the infection is gone. Most people with hepatitis A recover within 3 months. Nearly all people get better within 6 months. There ...

  19. Autoimmune Hepatitis

    MedlinePlus

    ... provider will closely monitor and manage any side effects that may occur, as high doses of prednisone are often prescribed to treat autoimmune hepatitis. Immune system suppressors. Medications that suppress the immune system prevent the body from making autoantibodies and block the immune reaction ...

  20. Hepatitis A

    MedlinePlus

    ... Advisory Board Sponsors Sponsorship Opporunities Spread the Word Shop AAP Find a Pediatrician ... Body Hepatitis means “inflammation of the liver.” This inflammation can be caused by a wide variety of toxins, drugs, and metabolic diseases, as well as infection. There ...

  1. Blockade of Retinol Metabolism Protects T Cell-Induced Hepatitis by Increasing Migration of Regulatory T Cells.

    PubMed

    Lee, Young-Sun; Yi, Hyon-Seung; Suh, Yang-Gun; Byun, Jin-Seok; Eun, Hyuk Soo; Kim, So Yeon; Seo, Wonhyo; Jeong, Jong-Min; Choi, Won-Mook; Kim, Myung-Ho; Kim, Ji Hoon; Park, Keun-Gyu; Jeong, Won-Il

    2015-11-01

    Retinols are metabolized into retinoic acids by alcohol dehydrogenase (ADH) and retinaldehyde dehydrogenase (Raldh). However, their roles have yet to be clarified in hepatitis despite enriched retinols in hepatic stellate cells (HSCs). Therefore, we investigated the effects of retinols on Concanavalin A (Con A)-mediated hepatitis. Con A was injected into wild type (WT), Raldh1 knock-out (Raldh1(-/-)), CCL2(-/-) and CCR2(-/-) mice. For migration study of regulatory T cells (Tregs), we used in vivo and ex vivo adoptive transfer systems. Blockade of retinol metabolism in mice given 4-methylpyrazole, an inhibitor of ADH, and ablated Raldh1 gene manifested increased migration of Tregs, eventually protected against Con A-mediated hepatitis by decreasing interferon-γ in T cells. Moreover, interferon-γ treatment increased the expression of ADH3 and Raldh1, but it suppressed that of CCL2 and IL-6 in HSCs. However, the expression of CCL2 and IL-6 was inversely increased upon the pharmacologic or genetic ablation of ADH3 and Raldh1 in HSCs. Indeed, IL-6 treatment increased CCR2 expression of Tregs. In migration assay, ablated CCR2 in Tregs showed reduced migration to HSCs. In adoptive transfer of Tregs in vivo and ex vivo, Raldh1-deficient mice showed more increased migration of Tregs than WT mice. Furthermore, inhibited retinol metabolism increased survival rate (75%) compared with that of the controls (25%) in Con A-induced hepatitis. These results suggest that blockade of retinol metabolism protects against acute liver injury by increased Treg migration, and it may represent a novel therapeutic strategy to control T cell-mediated acute hepatitis. PMID:26537191

  2. 76 FR 36367 - National Vaccine Injury Compensation Program: Revisions to the Vaccine Injury Table

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-06-22

    ...On September 13, 2010, the Secretary of Health and Human Services (the Secretary) published in the Federal Register a Notice of Proposed Rulemaking (NPRM) proposing changes to the regulations governing the National Vaccine Injury Compensation Program (VICP). Specifically, the Secretary proposed revisions to the Vaccine Injury Table (Table) to create distinct listings for hepatitis A, trivalent......

  3. Hemostatic methods for the management of spleen and liver injuries.

    PubMed

    Uranüs, S; Mischinger, H J; Pfeifer, J; Kronberger, L; Rabl, H; Werkgartner, G; Steindorfer, P; Kraft-Kirz, J

    1996-10-01

    The spleen and liver are the most frequently injured organs during blunt and penetrating abdominal trauma. Emergency laparotomy is crucial for early control of bleeding and to prevent "secondary" injury as a result of physiologic splanchnic vasoconstriction and free oxygen radicals. Altogether 98 patients with spleen and liver injuries were treated over an 8-year period. Primary orthotopic spleen preservation could be achieved in 46 of 63 patients. In 58 patients with hepatic trauma, hemostatic treatment was chosen based on the severity of the injury. Nonoperative management was used for four splenic and seven hepatic trauma patients. The most commonly used techniques were fibrin sealing, suturing, and débridement for hepatic injury and mesh splenorrhaphy, fibrin glue, and partial resection with a TA stapler for splenic injury. The death of patients with complex injuries was mainly due to preclinical massive blood loss and multiple organ failure. PMID:8798373

  4. Complement activation in discordant hepatic xenotransplantation.

    PubMed

    Tector, A J; Chen, X; Soderland, C; Tchervenkov, J I

    1998-11-01

    Little is known about hyperacute rejection in hepatic xenotransplantation. Information from clinical xenoperfusions suggests that the liver may be rejected by a mechanism less vigorous than either kidney or heart xenografts. We used the in vitro model of porcine hepatic sinusoidal endothelial cells (PHEC) incubated with either complement replete or deficient human serum to determine the relative roles of the classical and alternate pathways of complement in the immediate response to hepatic xenotransplantation. Our results suggest that either the classical or alternate pathways are capable of independently activating the complement cascade upon exposure to the porcine hepatic sinusoidal endothelium. Our results also imply that either pathway alone is capable of initiating similar degrees of injury as the entire cascade. PMID:9915253

  5. Chronic Hepatitis E Virus Infection and Treatment

    PubMed Central

    Kamar, Nassim; Izopet, Jacques; Dalton, Harry R.

    2013-01-01

    It is now well accepted that hepatitis E virus (HEV) infection can induce chronic hepatitis and cirrhosis in immunosuppressed patients. Chronic genotype-3 HEV infections were first reported in patients with a solid-organ transplant. Thereafter, cases of chronic HEV infection have been reported in patients with hematological disease and in those who are human immunodeficiency virus (HIV)-positive. HEV-associated extra-hepatic manifestations, including neurological symptoms, kidney injuries, and hematological disorders, have been also reported. In transplant patients, reducing the dosage of immunosuppressive drugs allows the virus to be cleared in some patients. In the remaining patients, as well as hematological patients and patients who are HIV-positive, anti-viral therapies, such as pegylated interferon and ribavirin, have been found to be efficient in eradicating HEV infection. This review summarizes our current knowledge of chronic HEV infection, its treatment, and the extra-hepatic manifestations induced by HEV. PMID:25755487

  6. [Hepatic encephalopathy].

    PubMed

    Jacques, Jérémie; Carrier, Paul; Debette-Gratien, Marilyne; Sobesky, Rodolphe; Loustaud-Ratti, Véronique

    2016-01-01

    Hepatic encephalopathy is a severe complication of liver cirrhosis and is an important therapeutic challenge, with a social and economic issue. If, now, the pathophysiology is not totally understood (main role of ammonia, but a better understanding of cerebral mechanisms), the clinical presentation is well-known. Some treatments are useful (disaccharides, treatment of the trigger) but their efficiency is limited. Nevertheless, the emergence of new treatments, such as non-absorbable antibiotics (rifaximin essentially), is an interesting therapeutic tool. PMID:26597584

  7. Drug-induced hepatitis

    MedlinePlus

    Toxic hepatitis ... to get liver damage. Some drugs can cause hepatitis with small doses, even if the liver breakdown ... liver. Many different drugs can cause drug-induced hepatitis. Painkillers and fever reducers that contain acetaminophen are ...

  8. Hepatitis A - children

    MedlinePlus

    ... have the virus and do not practice good hygiene. Other common hepatitis virus infections include hepatitis B ... where diapers are changed to ensure that proper hygiene is followed. If your child gets hepatitis A, ...

  9. Hepatitis B virus (image)

    MedlinePlus

    Hepatitis B is also known as serum hepatitis and is spread through blood and sexual contact. It is ... population. This photograph is an electronmicroscopic image of hepatitis B virus particles. (Image courtesy of the Centers for ...

  10. Preventing hepatitis A

    MedlinePlus

    Hepatitis A is inflammation (irritation and swelling) of the liver caused by the hepatitis A virus. You can take several steps to ... reduce your risk of spreading or catching the hepatitis A virus: Always wash your hands thoroughly after ...

  11. What Is Hepatitis?

    MedlinePlus

    ... Twitter Facebook Google + iTunes Play Store What is hepatitis? Online Q&A Reviewed July 2016 Q: What ... Question and answer archives Submit a question World Hepatitis Day Know hepatitis - Act now Event notice Key ...

  12. Eye Injuries

    MedlinePlus

    The structure of your face helps protect your eyes from injury. Still, injuries can damage your eye, sometimes severely enough that you could lose your vision. Most eye injuries are preventable. If you play sports or ...

  13. Head Injuries

    MedlinePlus

    ... injuries internal head injuries, which may involve the skull, the blood vessels within the skull, or the brain Fortunately, most childhood falls or ... knock the brain into the side of the skull or tear blood vessels. Some internal head injuries ...

  14. Back Injuries

    MedlinePlus

    ... the most common site of back injuries and back pain. Common back injuries include Sprains and strains Herniated disks Fractured vertebrae These injuries can cause pain and limit your movement. Treatments vary but might ...

  15. Eye Injuries

    MedlinePlus

    ... of your face helps protect your eyes from injury. Still, injuries can damage your eye, sometimes severely enough that you could lose your vision. Most eye injuries are preventable. If you play sports or work ...

  16. Blast Injuries

    MedlinePlus

    ... Service Members & Veterans Family & Caregivers Medical Providers Blast Injuries U.S. Army photo by Sgt. Gustavo Olgiati How ... tertiary injury Does a blast cause different brain injuries than blunt trauma? There currently is no evidence ...

  17. Ocular Injury

    MedlinePlus

    ... usually occur from blunt trauma, such as a sports injury or a fall with injury to the nose ... of protective goggles at all times. Even in sports like baseball, eye injuries can be prevented by using batting helmets that ...

  18. Sports Injuries

    MedlinePlus

    ... sometimes you can injure yourself when you play sports or exercise. Accidents, poor training practices, or improper ... can also lead to injuries. The most common sports injuries are Sprains and strains Knee injuries Swollen ...

  19. Hepatology after Hepatitis C.

    PubMed

    Fitz, J Gregory

    2016-01-01

    The ∼90% probability of curing individual patients with hepatitis C virus (HCV)using direct-acting antivirals represents one of the most dramatic medical success stories of the modern era, and the journey from viral discovery to treatment occurred over just ∼25 years. The realities of the global burden of disease (2-3% of the world's population is infected), limited access to care and cost of treatment mean that HCV will continue to be a major problem for the next 25 years. But what if HCV (and hepatitis B) could be eradicated? Since liver transplantation and HCV management have been the mainstays of academic hepatology practice, where do we go from here? Unfortunately, we are in an era where the incidence and prevalence of liver diseases around the globe is increasing, and death from complications of cirrhosis is now among the top 10 causes in most countries; so hepatologists are expected to play a major role in the future. Despite remarkable progress, success at the population level is limited by the resource-intensive nature of caring for patients with end-stage disease. Accordingly, the major advances in the next decade are likely to focus on (i) the earlier identification of individuals and populations at higher risk for liver diseases, and (ii) initiation in high-risk populations of specific strategies for early detection and treatment of fibrosis, cancer and cirrhosis. The answers will lie in large part in the further exploration of the human genome in carefully phenotyped patients. Risk variants in the PNPLA3 gene represent the best example to date. The risk variants are common and are enriched in certain populations around the globe; and individuals that possess risk variants are more likely to have liver injury from fatty liver disease (even as children), alcohol and viral hepatitis. Further, those with liver injury are more likely to progress to cirrhosis and hepatoma. Similarly, in those with established liver disease, use of biomarkers and other

  20. Hepatic Shock Differential Diagnosis and Risk Factors: A Review Article

    PubMed Central

    Soleimanpour, Hassan; Safari, Saeid; Rahmani, Farzad; Nejabatian, Arezu; Alavian, Seyed Moayed

    2015-01-01

    Context: Liver as an important organ has a vital role in physiological processes in the body. Different causes can disrupt normal function of liver. Factors such as hypo-perfusion, hypoxemia, infections and some others can cause hepatic injury and hepatic shock. Evidence Acquisition: Published research resources from 2002 to May 2015 in some databases (PubMed, Scopus, Index Copernicus, DOAJ, EBSCO-CINAHL, Science direct, Cochrane library and Google scholar and Iranian search database like SID and Iranmedex) were investigated for the present study. Results: Different causes can lead to hepatic shock. Most of these causes can be prevented by early resuscitation and treatment of underlying factors. Conclusions: Hepatic shock is detected in ill patients, especially those with hemodynamic disorders. It can be prevented by early treatment of underlying disease. There is no definite treatment for hepatic shock and should be managed conservatively. Hepatic shock in patients can increase the mortality rate. PMID:26587034

  1. Management of blunt hepatic trauma.

    PubMed

    Letoublon, C; Amariutei, A; Taton, N; Lacaze, L; Abba, J; Risse, O; Arvieux, C

    2016-08-01

    For the last 20 years, nonoperative management (NOM) of blunt hepatic trauma (BHT) has been the initial policy whenever this is possible (80% of cases), i.e., in all cases where the hemodynamic status does not demand emergency laparotomy. NOM relies upon the coexistence of three highly effective treatment modalities: radiology with contrast-enhanced computerized tomography (CT) and hepatic arterial embolization, intensive care surveillance, and finally delayed surgery (DS). DS is not a failure of NOM management but rather an integral part of the surgical strategy. When imposed by hemodynamic instability, the immediate surgical option has seen its effectiveness transformed by development of the concept of abbreviated (damage control) laparotomy and wide application of the method of perihepatic packing (PHP). The effectiveness of these two conservative and cautious strategies for initial management is evidenced by current experience, but the management of secondary events that may arise with the most severe grades of injury must be both rapid and effective. PMID:27519150

  2. Molecular mechanisms of hepatic apoptosis

    PubMed Central

    Wang, K

    2014-01-01

    Apoptosis is a prominent feature of liver diseases. Causative factors such as alcohol, viruses, toxic bile acids, fatty acids, drugs, and immune response, can induce apoptotic cell death via membrane receptors and intracellular stress. Apoptotic signaling network, including membrane death receptor-mediated cascade, reactive oxygen species (ROS) generation, endoplasmic reticulum (ER) stress, lysosomal permeabilization, and mitochondrial dysfunction, is intermixed each other, but one mechanism may dominate at a particular stage. Mechanisms of hepatic apoptosis are complicated by multiple signaling pathways. The progression of liver disease is affected by the balance between apoptotic and antiapoptotic capabilities. Therapeutic options of liver injury are impacted by the clear understanding toward mechanisms of hepatic apoptosis. PMID:24434519

  3. Feature Hepatitis: Hepatitis Symptoms, Diagnosis, Treatment & Prevention

    MedlinePlus

    ... of chronic liver disease, cirrhosis, viral hepatitis, and liver cancer make liver disease one of the 10 leading ... disease are decreasing, those for viral hepatitis and liver cancer are on the rise, both in the U.S. ...

  4. Hepatic glutathione content in patients with alcoholic and non alcoholic liver diseases

    SciTech Connect

    Altomare, E.; Vendemiale, G.; Albano, O.

    1988-01-01

    Reduced and oxidized hepatic glutathione was evaluated during alcoholic and non alcoholic liver injury. We studied 35 chronic alcoholics, 20 patients with non alcoholic liver diseases, 15 control subjects. Hepatic glutathione was measured in liver biopsies and correlated with histology and laboratory tests. Alcoholic and non alcoholic patients exhibited a significant decrease of hepatic glutathione compared to control subjects. Oxidized glutathione was significantly higher in the two groups of patients compared to controls. The decreased hepatic glutathione level in patients with alcoholic and non alcoholic liver diseases may represent a contributing factor of liver injury and may enhance the risk of toxicity in these patients.

  5. Protect Yourself from Hepatitis

    MedlinePlus

    ... develop yellowish eyes and skin. All the hepatitis viruses can cause acute, or short-term, hepatitis. Some can also cause chronic hepatitis, in which the infection lasts a long time, sometimes for your whole life. Chronic hepatitis can eventually lead to scarring of ...

  6. Hepatic osteodystrophy.

    PubMed

    Gatta, Angelo; Verardo, Alberto; Di Pascoli, Marco; Giannini, Sandro; Bolognesi, Massimo

    2014-09-01

    Metabolic disturbances of bone are frequent in patients with chronic liver disease. The prevalence of osteoporosis among patients with advanced chronic liver disease is reported between 12% and 55%; it is higher in primary biliary cirrhosis. All patients with advanced liver disease should be screened for osteoporosis with a densitometry, especially if the etiology is cholestatic and in the presence of other risk factors. Clinical relevance of hepatic osteodystrophy increases after liver transplantation. After liver transplant, a rapid loss of bone mineral density can be detected in the first 6 months, followed by stabilization and slight improvement of the values. At the time of transplantation, bone density values are very important prognostic factors. Therapy of hepatic osteodystrophy is based primarily on the control of risk factors: cessation of tobacco and alcohol assumption, reduction of caffeine ingestion, exercise, supplementation of calcium and vitamin D, limitation of drugs such as loop diuretics, corticosteroids, cholestyramine. Bisphosphonates have been proposed for the therapy of osteoporosis in patients with liver disease, particularly after liver transplantation. The possible side effects of oral administration of bisphosphonates, such as the occurrence of esophageal ulcerations, are of particular concern in patients with liver cirrhosis and portal hypertension, due to the risk of gastrointestinal hemorrhage from ruptured esophageal varices, although this risk is probably overestimated. PMID:25568651

  7. [Hepatic encephalopathy].

    PubMed

    Festi, Davide; Marasco, Giovanni; Ravaioli, Federico; Colecchia, Antonio

    2016-07-01

    Hepatic encephalopathy (HE) is a common complication of liver cirrhosis and it can manifest with a broad spectrum of neuropsychiatric abnormalities of varying severity, acuity and time course with important clinical implications. According to recent guidelines, HE has been classified into different types, depending on the severity of hepatic dysfunction, the presence of porto-systemic shunts and the number of previous episodes or persistent manifestations. From a clinical point of view, HE can be recognized as unimpaired, covert (that deals with minimal and grade 1 according to the grading of mental state), and overt (that is categorized from grade 2 to grade 4). Different and only partially known pathogenic mechanisms have been identified, comprising ammonia, inflammatory cytokines, benzodiazepine-like compounds and manganese deposition. Different therapeutic strategies are available for treating HE, in particular the overt HE, since covert HE needs to be managed case by case. Recognition and treatment of precipitating factors represent fundamental part of the management. The more effective treatments, which can be performed separately or combined, are represented by non-absorbable disaccharides (lactulose and lactitol) and the topic antibiotic rifaximin; other possible therapies, mainly used in patients non responders to previous treatments, are represented by branched chain amino acids and metabolic ammonia scavengers. PMID:27571468

  8. Lisfranc injuries.

    PubMed

    Welck, M J; Zinchenko, R; Rudge, B

    2015-04-01

    Lisfranc injuries are commonly asked about in FRCS Orthopaedic trauma vivas. The term "Lisfranc injury" strictly refers to an injury where one or more of the metatarsals are displaced from the tarsus. The term is more commonly used to describe an injury to the midfoot centred on the 2nd tarsometatarsal joint. The injury is named after Jacques Lisfranc de St. Martin (1790-1847), a French surgeon and gynaecologist who first described the injury in 1815. 'Lisfranc injury' encompasses a broad spectrum of injuries, which can be purely ligamentous or involve the osseous and articular structures. They are often difficult to diagnose and treat, but if not detected and appropriately managed they can cause long-term disability. This review outlines the anatomy, epidemiology, classification, investigation and current evidence on management of this injury. PMID:25543185

  9. Pancreatic injury.

    PubMed

    Ahmed, Nasim; Vernick, Jerome J

    2009-12-01

    Injury to the pancreas, because of its retroperitoneal location, is a rare occurrence, most commonly seen with penetrating injuries (gun shot or stab wounds). Blunt trauma to the pancreas accounts for only 25% of the cases. Pancreatic injuries are associated with high morbidity and mortality due to accompanying vascular and duodenal injuries. Pancreatic injuries are not always easy to diagnose resulting in life threatening complications. Physical examination as well as serum amylase is not diagnostic following blunt trauma. Computed tomography (CT) scan can delineate the injury or transaction of the pancreas. Endoscopic retrograde pancreaticography (ERCP) is the main diagnostic modality for evaluation of the main pancreatic duct. Unrecognized ductal injury leads to pancreatic pseudocyst, fistula, abscess, and other complications. Management depends upon the severity of the pancreatic injury as well as associated injuries. Damage control surgery in hemodynamic unstable patients reduces morbidity and mortality. PMID:20016434

  10. Basketball injuries.

    PubMed

    Newman, Joel S; Newberg, Arthur H

    2010-11-01

    Basketball injuries are most prevalent in the lower extremity, especially at the ankle and knee. Most basketball injuries are orthopedic in nature and commonly include ligament sprains, musculotendinous strains, and overuse injuries including stress fractures. By virtue of its excellent contrast resolution and depiction of the soft tissues and trabecular bone, magnetic resonance imaging has become the principal modality for evaluating many basketball injuries. In this article, commonly encountered basketball injuries and their imaging appearances are described. The epidemiology of basketball injuries across various age groups and levels of competition and between genders are reviewed. PMID:21094400

  11. Viral hepatitis: Indian scenario.

    PubMed

    Satsangi, Sandeep; Chawla, Yogesh K

    2016-07-01

    Viral hepatitis is a cause for major health care burden in India and is now equated as a threat comparable to the "big three" communicable diseases - HIV/AIDS, malaria and tuberculosis. Hepatitis A virus and Hepatitis E virus are predominantly enterically transmitted pathogens and are responsible to cause both sporadic infections and epidemics of acute viral hepatitis. Hepatitis B virus and Hepatitis C virus are predominantly spread via parenteral route and are notorious to cause chronic hepatitis which can lead to grave complications including cirrhosis of liver and hepatocellular carcinoma. Around 400 million people all over the world suffer from chronic hepatitis and the Asia-Pacific region constitutes the epicentre of this epidemic. The present article would aim to cover the basic virologic aspects of these viruses and highlight the present scenario of viral hepatitis in India. PMID:27546957

  12. A rat model of concurrent combined injuries (polytrauma)

    PubMed Central

    Akscyn, Robert M; Franklin, J Lee; Gavrikova, Tatyana A; Schwacha, Martin G; Messina, Joseph L

    2015-01-01

    Polytrauma, a combination of injuries to more than one body part or organ system, is common in modern warfare and in automobile and industrial accidents. The combination of injuries can include burn injury, fracture, hemorrhage, trauma to the extremities, and trauma to specific organ systems. To investigate the effects of combined injuries, we have developed a new and highly reproducible model of polytrauma. This model combines burn injury with soft tissue and gastrointestinal (GI) tract trauma. Male Sprague Dawley rats were subjected to a 15-20% total body surface area scald burn, or a single puncture of the cecum with a G30 needle, or the combination of both injuries (polytrauma). Unlike many ‘double hit’ models, the injuries in our model were performed simultaneously. We asked whether multiple minor injuries, when combined, would result in a distinct phenotype, different from single minor injuries or a more severe single injury. There were differences between the single injuries and polytrauma in the maintenance of blood glucose, body temperature, body weight, hepatic mRNA and circulating levels of TNF-α, IL-1β and IL-6, and hepatic ER-stress. It has been suggested that models utilizing combinatorial injuries may be needed to more accurately model the human condition. We believe our model is ideal for studying the complex sequelae of polytrauma, which differs from single injuries. Insights gained from this model may suggest better treatment options to improve patient outcomes. PMID:26884923

  13. Diabetes and Hepatitis B Vaccination

    MedlinePlus

    Diabetes and Hepatitis B Vaccination Information for Diabetes Educators What is hepatitis B? Hepatitis B is a contagious liver disease that results from infection with the hepatitis B virus. When first infected, a person can develop ...

  14. Hepatitis B Blood Tests: FAQ

    MedlinePlus

    ... 2 Billion People have been infected with Hepatitis B Worldwide The Hepatitis B Foundation is working on ... people living with hepatitis B. Learn About Hepatitis B in 10 Other Languages . Resource Video See More ...

  15. Hepatitis Information for the Public

    MedlinePlus

    ... of Viral Hepatitis Contact Us Quick Links to Hepatitis ... A | B | C | D | E Viral Hepatitis Home ... Outbreaks State and Local Partners & Grantees Resource Center Hepatitis Information for the Public Recommend on Facebook Tweet ...

  16. Hepatic venous outflow obstruction: Three similar syndromes

    PubMed Central

    Bayraktar, Ulas Darda; Seren, Soley; Bayraktar, Yusuf

    2007-01-01

    Our goal is to provide a detailed review of veno-occlusive disease (VOD), Budd-Chiari syndrome (BCS), and congestive hepatopathy (CH), all of which results in hepatic venous outflow obstruction. This is the first article in which all three syndromes have been reviewed, enabling the reader to compare the characteristics of these disorders. The histological findings in VOD, BCS, and CH are almost identical: sinusoidal congestion and cell necrosis mostly in perivenular areas of hepatic acini which eventually leads to bridging fibrosis between adjacent central veins. Tender hepatomegaly with jaundice and ascites is common to all three conditions. However, the clinical presentation depends mostly on the extent and rapidity of the outflow obstruction. Although the etiology and treatment are completely different in VOD, BCS, and CH; the similarities in clinical manifestations and liver histology may suggest a common mechanism of hepatic injury and adaptation in response to increased sinusoidal pressure. PMID:17461490

  17. Direct evidence for cytotoxicity associated with expression of hepatitis delta virus antigen.

    PubMed

    Cole, S M; Gowans, E J; Macnaughton, T B; Hall, P D; Burrell, C J

    1991-05-01

    It has been postulated that hepatocyte injury resulting from infection with hepatitis D virus may be caused by a direct virus cytotoxicity in contrast to immune-mediated injury associated with hepatitis B virus. We have transfected HeLa and HepG2 continuous cell lines with a recombinant plasmid containing the hepatitis D antigen gene under the inducible control of the human metallothionein promoter. The addition of zinc to the cell culture medium then led to the expression of hepatitis D antigen associated with, in the short term, a significant reduction in the rate of RNA but not DNA synthesis and, in the longer term, cell death. The necrotic cells had pyknotic nuclei and shrunken eosinophilic cytoplasm; these necrotic cells resembled the apoptotic bodies seen in hepatitis D virus-related hepatitis. The level of hepatitis D antigen in individual cells that produced these changes was similar to the level of hepatitis D antigen in hepatocytes from a chimpanzee with acute hepatitis D virus infection. We conclude that the expression of hepatitis D antigen resulted in significant cytotoxic changes in these cells, providing strong support for the view that hepatitis D antigen may be specifically cytotoxic to infected hepatocytes in vivo. PMID:1709411

  18. Gastrointestinal bleeding and obstructive jaundice: Think of hepatic artery aneurysm

    PubMed Central

    Vultaggio, Fabrice; Morère, Pierre-Henri; Constantin, Christophe; Christodoulou, Michel; Roulin, Didier

    2016-01-01

    Hemobilia is an uncommon and potential life-threatening condition mainly due to hepato-biliary tree traumatic or iatrogenic injuries. Spontaneously ruptured aneurysm of the hepatic artery is seldom described. We report the case of an 89-year-old woman presenting with abdominal pain, jaundice and gastrointestinal bleeding, whose ultrasound and computed tomography revealed a non-traumatic, spontaneous aneurysm of the right hepatic artery. The oeso-gastro-duodenoscopy and colonoscopy did not reveal any bleeding at the ampulla of Vater, nor anywhere else. Selective angiography confirmed the diagnosis of hepatic artery aneurysm and revealed a full hepatic artery originating from the superior mesenteric artery. The patient was successfully treated by selective embolization of microcoils. We discuss the etiologies of hemobilia and its treatment with selective embolization, which remains favored over surgical treatment. Although aneurysm of the hepatic artery is rare, especially without trauma, a high index of suspicion is needed in order to ensure appropriate treatment. PMID:27358680

  19. Gastrointestinal bleeding and obstructive jaundice: Think of hepatic artery aneurysm.

    PubMed

    Vultaggio, Fabrice; Morère, Pierre-Henri; Constantin, Christophe; Christodoulou, Michel; Roulin, Didier

    2016-06-27

    Hemobilia is an uncommon and potential life-threatening condition mainly due to hepato-biliary tree traumatic or iatrogenic injuries. Spontaneously ruptured aneurysm of the hepatic artery is seldom described. We report the case of an 89-year-old woman presenting with abdominal pain, jaundice and gastrointestinal bleeding, whose ultrasound and computed tomography revealed a non-traumatic, spontaneous aneurysm of the right hepatic artery. The oeso-gastro-duodenoscopy and colonoscopy did not reveal any bleeding at the ampulla of Vater, nor anywhere else. Selective angiography confirmed the diagnosis of hepatic artery aneurysm and revealed a full hepatic artery originating from the superior mesenteric artery. The patient was successfully treated by selective embolization of microcoils. We discuss the etiologies of hemobilia and its treatment with selective embolization, which remains favored over surgical treatment. Although aneurysm of the hepatic artery is rare, especially without trauma, a high index of suspicion is needed in order to ensure appropriate treatment. PMID:27358680

  20. First report of hepatic hematoma after presumed Bothrops envenomation.

    PubMed

    Cunha, Fernanda Cristina; Heerdt, Maike; Torrez, Pasesa Pascuala Quispe; França, Francisco Oscar de Siqueira; Molin, Graziela Zibetti Dal; Battisti, Rúbia; Zannin, Marlene

    2015-01-01

    In Latin America, Bothrops envenomation is responsible for the majority of accidents caused by venomous snakes. Patients usually present local edema, bleeding and coagulopathy. Visceral hemorrhage is extremely rare and considered a challenge for diagnosis and management. We report the first case of hepatic hematoma owing to the bothropic envenomation in a 66-year-old man who was bitten in the left leg. He presented local edema, coagulopathy, and acute kidney injury. Radiological findings suggested hepatic hematoma, with a volume of almost 3 liters. The hepatic hematoma was gradually absorbed without the need for surgical intervention with complete resolution in 8 months. PMID:26516980

  1. Emerging therapeutic targets for the treatment of hepatic fibrosis.

    PubMed

    Fagone, Paolo; Mangano, Katia; Pesce, Antonio; Portale, Teresa Rosanna; Puleo, Stefano; Nicoletti, Ferdinando

    2016-02-01

    Fibrosis represents a response to chronic injury, aimed at maintaining organ integrity. Hepatic fibrosis is mainly related to chronic viral hepatitis B or C (HBV or HCV), alcoholic and nonalcoholic steatohepatitis (NASH), and biliary diseases. A deep understanding of the cellular and molecular mechanisms underlying liver fibrosis has enabled the development of 'pathogenetic tailored' therapeutic interventions. However, effective drugs to prevent or revert hepatic fibrosis are still lacking. In this review, we discuss the cellular populations and the molecular pathways involved in liver fibrogenesis as well as the novel approaches currently being tested in clinical trials. PMID:26523773

  2. Spinal injury

    MedlinePlus

    ... head. Alternative Names Spinal cord injury; SCI Images Skeletal spine Vertebra, cervical (neck) Vertebra, lumbar (low back) Vertebra, thoracic (mid back) Vertebral column Central nervous system Spinal cord injury Spinal anatomy Two person roll - ...

  3. Corneal injury

    MedlinePlus

    ... as sand or dust Ultraviolet injuries: Caused by sunlight, sun lamps, snow or water reflections, or arc- ... a corneal injury if you: Are exposed to sunlight or artificial ultraviolet light for long periods of ...

  4. Inhalation Injuries

    MedlinePlus

    ... you can inhale that can cause acute internal injuries. Particles in the air from fires and toxic ... and lung diseases worse. Symptoms of acute inhalation injuries may include Coughing and phlegm A scratchy throat ...

  5. Cycling injuries.

    PubMed Central

    Cohen, G. C.

    1993-01-01

    Bicycle-related injuries have increased as cycling has become more popular. Most injuries to recreational riders are associated with overuse or improper fit of the bicycle. Injuries to racers often result from high speeds, which predispose riders to muscle strains, collisions, and falls. Cyclists contact bicycles at the pedals, seat, and handlebars. Each is associated with particular cycling injuries. Images Figure 1 Figure 3 Figure 4 Figure 5 PMID:8471908

  6. Warning: fatal reaction to the use of fibrin glue in deep hepatic wounds. Case reports.

    PubMed

    Berguer, R; Staerkel, R L; Moore, E E; Moore, F A; Galloway, W B; Mockus, M B

    1991-03-01

    Two cases of severe hypotension following the use of fibrin glue for hemostasis in hepatic injuries are reported. A systemic reaction to bovine thrombin via large venous lacerations is suspected. A preliminary animal study supports this hypothesis. Caution is advised in the use of fibrin glue for hemostasis in deep hepatic wounds. PMID:2002531

  7. [Viral hepatitis in travellers].

    PubMed

    Abreu, Cândida

    2007-01-01

    Considering the geographical asymmetric distribution of viral hepatitis A, B and E, having a much higher prevalence in the less developed world, travellers from developed countries are exposed to a considerable and often underestimated risk of hepatitis infection. In fact a significant percentage of viral hepatitis occurring in developed countries is travel related. This results from globalization and increased mobility from tourism, international work, humanitarian and religious missions or other travel related activities. Several studies published in Europe and North America shown that more than 50% of reported cases of hepatitis A are travel related. On the other hand frequent outbreaks of hepatitis A and E in specific geographic areas raise the risk of infection in these restricted zones and that should be clearly identified. Selected aspects related with the distribution of hepatitis A, B and E are reviewed, particularly the situation in Portugal according to the published studies, as well as relevant clinical manifestations and differential diagnosis of viral hepatitis. Basic prevention rules considering enteric transmitted hepatitis (hepatitis A and hepatitis E) and parenteral transmitted (hepatitis B) are reviewed as well as hepatitis A and B immunoprophylaxis. Common clinical situations and daily practice "pre travel" advice issues are discussed according to WHO/CDC recommendations and the Portuguese National Vaccination Program. Implications from near future availability of a hepatitis E vaccine, a currently in phase 2 trial, are highlighted. Potential indications for travellers to endemic countries like India, Nepal and some regions of China, where up to 30% of sporadic cases of acute viral hepatitis are caused by hepatitis E virus, are considered. Continued epidemiological surveillance for viral hepatitis is essential to recognize and control possible outbreaks, but also to identify new viral hepatitis agents that may emerge as important global health

  8. Orienteering injuries

    PubMed Central

    Folan, Jean M.

    1982-01-01

    At the Irish National Orienteering Championships in 1981 a survey of the injuries occurring over the two days of competition was carried out. Of 285 individual competitors there was a percentage injury rate of 5.26%. The article discusses the injuries and aspects of safety in orienteering. Imagesp236-ap237-ap237-bp238-ap239-ap240-a PMID:7159815

  9. Hepatic abscesses

    PubMed Central

    Rajagopalan, S.; Langer, V.

    2012-01-01

    Hepatic abscesses are potentially lethal diseases if early diagnosis and treatment are not instituted. They are prevalent all over the globe and pyogenic abscesses are predominant over amoebic. With better control of intra abdominal and systemic infections by a spectrum of antibiotics, aetiology of pyogenic abscesses are secondary to interventions and diseases in the biliary tree to a large extent today. The common organisms isolated are the Gram negative group. Amoebic abscesses continue to plague some regions of the world where hygiene and sanitation are questionable. Over the years, diagnosis, treatment and prognosis have evolved remarkably. Imaging modalities like ultrasonography and CT scan have become the cornerstone of diagnosis. The absence of ionizing radiation makes MRI an attractive alternative in patients who require multiple follow up scans. Serological testing in amoebic abscesses has become more reliable. Though antibiotics have remained the principal modality of management, percutaneous drainage of abscesses have vastly improved the chances of cure and bring down the morbidity drastically in pyogenic abscesses. Amoebic abscesses respond well to medical treatment with nitroimidazoles, and minimally invasive surgical drainage is an option in cases where open surgery is indicated. PMID:24532886

  10. Paneth cell-mediated multiorgan dysfunction after acute kidney injury

    PubMed Central

    Park, Sang Won; Kim, Mihwa; Kim, Joo Yun; Ham, Ahrom; Brown, Kevin M.; Mori-Akiyama, Yuko; Ouellette, André J.; D’Agati, Vivette D.; Lee, H. Thomas

    2012-01-01

    Acute kidney injury (AKI) is frequently complicated by extra-renal multi-organ injury including intestinal and hepatic dysfunction. In this study, we hypothesized that a discrete intestinal source of pro-inflammatory mediators drives multi-organ injury in response to AKI. After induction of AKI in mice by renal ischemia-reperfusion or bilateral nephrectomy, small intestinal Paneth cells increased the synthesis and release of IL-17A in conjunction with severe intestinal apoptosis and inflammation. We also detected significantly increased IL-17A in portal and systemic circulation after AKI. Intestinal macrophages appear to transport released Paneth cell granule constituents induced by AKI, away from the base of the crypts into the liver. Genetic or pharmacologic depletion of Paneth cells decreased small intestinal IL-17A secretion and plasma IL-17A levels significantly and attenuated intestinal, hepatic, and renal injury after AKI. Similarly, portal delivery of IL-17A in macrophage depleted mice decreased markedly, and intestinal, hepatic, and renal injury following AKI was attenuated without affecting intestinal IL-17A generation. In conclusion, AKI induces IL-17A synthesis and secretion by Paneth cells to initiate intestinal and hepatic injury by hepatic and systemic delivery of IL-17A by macrophages. Modulation of Paneth cell dysregulation may have therapeutic implications by reducing systemic complications arising from AKI. PMID:23109723

  11. Hepatitis B Test

    MedlinePlus

    ... IgM; anti-HBe; Hepatitis B e Antibody; HBV DNA Formal name: Hepatitis B Virus Testing Related tests: ... produced by the virus, and others detect viral DNA . The main uses for HBV tests include: To ...

  12. Hepatitis Foundation International

    MedlinePlus

    ... partner – it's your best friend. Welcome. The Hepatitis Foundation International (HFI) is a 501 (c) 3 non- ... and cures is your participation in the Hepatitis Foundation International Registry. Whether you are affected, a caregiver, ...

  13. Hepatitis A - children

    MedlinePlus

    ... hepatitis A. Children can get hepatitis A at day care center from other children or from child care ... treatment with immunoglobulin therapy. If your child attends day care: Make sure the children and staff at the ...

  14. Hepatitis C (image)

    MedlinePlus

    Hepatitis C is a virus-caused liver inflammation which may cause jaundice, fever and cirrhosis. Persons who are most at risk for contracting and spreading hepatitis C are those who share needles for injecting drugs ...

  15. Head injury.

    PubMed

    Hureibi, K A; McLatchie, G R

    2010-05-01

    Head injury is one of the commonest injuries in sport. Most are mild but some can have serious outcomes. Sports medicine doctors should be able to recognise the clinical features and evaluate athletes with head injury. It is necessary during field assessment to recognise signs and symptoms that help in assessing the severity of injury and making a decision to return-to-play. Prevention of primary head injury should be the aim. This includes protective equipment like helmets and possible rule changes. PMID:20533694

  16. Sensitization to autoimmune hepatitis in group VIA calcium-independent phospholipase A2-null mice led to duodenal villous atrophy with apoptosis, goblet cell hyperplasia and leaked bile acids.

    PubMed

    Jiao, Li; Gan-Schreier, Hongying; Tuma-Kellner, Sabine; Stremmel, Wolfgang; Chamulitrat, Walee

    2015-08-01

    Chronic bowel disease can co-exist with severe autoimmune hepatitis (AIH) in an absence of primary sclerosing cholangitis. Genetic background may contribute to this overlap syndrome. We previously have shown that the deficiency of iPLA2β causes an accumulation of hepatocyte apoptosis, and renders susceptibility for acute liver injury. We here tested whether AIH induction in iPLA2β-null mice could result in intestinal injury, and whether bile acid metabolism was altered. Control wild-type (WT) and female iPLA2β-null (iPLA2β(-/-)) mice were intravenously injected with 10mg/kg concanavalinA (ConA) or saline for 24h. ConA treatment of iPLA2β(-/-) mice caused massive liver injury with increased liver enzymes, fibrosis, and necrosis. While not affecting WT mice, ConA treatment of iPLA2β(-/-) mice caused severe duodenal villous atrophy concomitant with increased apoptosis, cell proliferation, globlet cell hyperplasia, and endotoxin leakage into portal vein indicating a disruption of intestinal barrier. With the greater extent than in WT mice, ConA treatment of iPLA2β(-/-) mice increased jejunal expression of innate response cytokines CD14, TNF-α, IL-6, and SOCS3 as well as chemokines CCL2 and the CCL3 receptor CCR5. iPLA2β deficiency in response to ConA-induced AIH caused a significant decrease in hepatic and biliary bile acids, and this was associated with suppression of hepatic Cyp7A1, Ntcp and ABCB11/Bsep and upregulation of intestinal FXR/FGF15 mRNA expression. The suppression of hepatic Ntcp expression together with the loss of intestinal barrier could account for the observed bile acid leakage into peripheral blood. Thus, enteropathy may result from acute AIH in a susceptible host such as iPLA2β deficiency. PMID:25957555

  17. FACTORS IN THE PATHOPHYSIOLOGY OF THE LIVER ISCHEMIA-REPERFUSION INJURY

    PubMed Central

    Montalvo-Jave, Eduardo E.; Escalante-Tattersfield, Tomas; Ortega-Salgado, Jose A.; Piña, Enrique; Geller, David A.

    2008-01-01

    Hepatic ischemia-reperfusion injury is commonplace in liver surgery, particularly in hepatic transplantation, hepatic resection, and trauma. The signaling events contributing to local hepatocellular damage are diverse and complex, and involve the interaction between hepatocytes, sinusoidal endothelial cells, Kupffer cells, as well as infiltrating neutrophils, macrophages, and platelets. Signaling mediators include cytokines, reactive oxygen and nitrogen species, calcium, complement, and several transcription factors. The purpose of this review article is to summarize the factors that contribute to the pathophysiology of hepatic ischemia-reperfusion injury. PMID:17707862

  18. Treating hepatitis C.

    PubMed

    Hanson, Karmen

    2014-10-01

    (1) New treatments for hepatitis C are curing more people than before. (2) Baby boomers make up an estimated 75 percent of all cases of hepatitis C. (3) Medicare and some insurance plans cover screening for hepatitis C as a preventive service without a copayment. PMID:25514812

  19. Hepatitis B (HBV)

    MedlinePlus

    ... How Can I Help a Friend Who Cuts? Hepatitis B (HBV) KidsHealth > For Teens > Hepatitis B (HBV) Print A A A Text Size ... Prevented? How Is It Treated? What Is It? Hepatitis (pronounced: hep-uh-TIE-tiss) is a disease ...

  20. Personal experience with 411 hepatic resections.

    PubMed Central

    Iwatsuki, S; Starzl, T E

    1988-01-01

    Over a 24-year period, 411 partial hepatic resections were performed: 142 right or left trisegmentectomies, 158 lobectomies, 25 segmentectomies, and 86 local excisions. The operations were performed for benign lesions in 182 patients, for primary hepatic malignancies in 106, and for hepatic metastases in 123, including 90 from colorectal cancers. The 30-day (operative) mortality rate was 3.2%, and there were an additional six late deaths (1.5%) due to hepatic failure caused by the resection. The highest operative mortality rate (6.3%) resulted from the trisegmentectomies, but this merely reflected the extent of the disease being treated. A mortality rate of 8.5% for patients with primary hepatic malignancy was associated not only with the extensiveness of lesions, but also with cirrhosis in the remaining liver fragment. There was no mortality for 123 patients with metastatic disease, 100 patients with cavernous hemangioma, 22 with liver cell adenoma, 17 with focal nodular hyperplasia, 16 with congenital cystic disease, and five with hydatid cysts. Trauma, pre-existing iatrogenic injury, and cirrhosis were the only conditions that had lethal portent in patients with benign disease. Furthermore, patients with benign disease who survived operation had minimal liability from recurrence of their original disease and none from the resection per se. By contrast, tumor recurrence dominated the actuarial survival rates for cancer patients, which at 1 and 5 years were 68.5% and 31.9%, respectively, after resection for primary hepatic malignancy, and 84.2% and 29.5%, respectively, for hepatic metastases. In this report, the expanding role of partial hepatectomy in the treatment of liver disease was emphasized, as well as the need for considering, in some cases, the alternative of total hepatectomy and liver replacement. Images Fig. 1. Fig. 2. Fig. 3. Fig. 4. Fig. 5. Fig. 9. PMID:3178330

  1. Tulipalin A induced phytotoxicity

    PubMed Central

    McCluskey, James; Bourgeois, Marie; Harbison, Raymond

    2014-01-01

    Tulipalin A induced phytotoxicity is a persistent allergic contact dermatitides documented in floral workers exposed to Alstroemeria and its cultivars.[1] The causative allergen is tulipalin A, a toxic glycoside named for the tulip bulbs from which it was first isolated.[2] The condition is characterized by fissured acropulpitis, often accompanied by hyperpigmentation, onychorrhexis, and paronychia. More of the volar surface may be affected in sensitized florists. Dermatitis and paronychia are extremely common conditions and diagnostic errors may occur. A thorough patient history, in conjunction with confirmatory patch testing with a bulb sliver and tuliposide A exposure, can prevent misdiagnosis. We report a case of Tulipalin A induced phytotoxicity misdiagnosed as an unresolved tinea manuum infection in a patient evaluated for occupational exposure. PMID:25024947

  2. Tulipalin A induced phytotoxicity.

    PubMed

    McCluskey, James; Bourgeois, Marie; Harbison, Raymond

    2014-04-01

    Tulipalin A induced phytotoxicity is a persistent allergic contact dermatitides documented in floral workers exposed to Alstroemeria and its cultivars.[1] The causative allergen is tulipalin A, a toxic glycoside named for the tulip bulbs from which it was first isolated.[2] The condition is characterized by fissured acropulpitis, often accompanied by hyperpigmentation, onychorrhexis, and paronychia. More of the volar surface may be affected in sensitized florists. Dermatitis and paronychia are extremely common conditions and diagnostic errors may occur. A thorough patient history, in conjunction with confirmatory patch testing with a bulb sliver and tuliposide A exposure, can prevent misdiagnosis. We report a case of Tulipalin A induced phytotoxicity misdiagnosed as an unresolved tinea manuum infection in a patient evaluated for occupational exposure. PMID:25024947

  3. Pathogenesis of Hepatic Encephalopathy

    PubMed Central

    Ciećko-Michalska, Irena; Szczepanek, Małgorzata; Słowik, Agnieszka; Mach, Tomasz

    2012-01-01

    Hepatic encephalopathy can be a serious complication of acute liver failure and chronic liver diseases, predominantly liver cirrhosis. Hyperammonemia plays the most important role in the pathogenesis of hepatic encephalopathy. The brain-blood barrier disturbances, changes in neurotransmission, neuroinflammation, oxidative stress, GABA-ergic or benzodiazepine pathway abnormalities, manganese neurotoxicity, brain energetic disturbances, and brain blood flow abnormalities are considered to be involved in the development of hepatic encephalopathy. The influence of small intestine bacterial overgrowth (SIBO) on the induction of minimal hepatic encephalopathy is recently emphasized. The aim of this paper is to present the current views on the pathogenesis of hepatic encephalopathy. PMID:23316223

  4. Hepatitis: protecting BMETs & CEs.

    PubMed

    Baker, S A

    1994-01-01

    Hepatitis is the primary occupational hazard for healthcare workers. Not until the 1970s were hepatitis viruses isolated and identified as types A and B. In the late 1970s, hepatitis D was discovered as a major cause of fulminant hepatitis. Soon, it was evident that another type was also at work. Because testing was only available for types A and B, the new category was referred to as non-A, non-B. In the 1980s, scientists identified two more viruses from this non-A, non-B group, namely hepatitis E and hepatitis C. These five types of hepatitis have different modes of transmission. The fecal-to-oral route is the mode of transmission for hepatitis types A and E. But, types B and D are bloodborne pathogens. With the advent of a safe vaccine for hepatitis B, this category is declining. To date, hepatitis C appears to have multiple routes of transmission, with half the cases being posttransfusion. In the United States, 85,000 people per year develop chronic hepatitis C, which ultimately leads to severe liver damage. This paper addresses each of the five viruses that have been grouped by routes of transmission, prevention techniques for BMETs and CEs, and statistics of reported cases to the Centers for Disease Control and Prevention (CDCP) over the last 20 years. PMID:10139739

  5. Skiing Injuries

    PubMed Central

    Bartlett, L. H.

    1975-01-01

    In the broad spectrum of orthopedic skiing injuries, ‘second aid’ on the mountain and at the base by the physician is very important. All skiing physicians should carry minimal medical supplies, including narcotic medication. Diagnosis and treatment of injuries at the hospital are outlined. Most ski fractures of the tibia can be treated by conservative methods. A more aggressive approach to diagnosis and treatment of ligamentous injuries of the knee is recommended. PMID:20469236

  6. Gunshot injuries.

    PubMed

    Hinkle, J; Betz, S

    1995-05-01

    If current trends for this nation continue, by the year 2003 the number of people killed by firearms will exceed the number of people killed in motor vehicle accidents. Critical care practitioners must understand the mechanism of injury associated with firearm injuries to provide optimal care. This article reviews internal, exterior, and terminal ballistics, bullet design, wound classification, and initial assessment and treatment of firearm injuries. PMID:7743422

  7. Transitioning from Idiopathic to Explainable Autoimmune Hepatitis.

    PubMed

    Czaja, Albert J

    2015-10-01

    Autoimmune hepatitis lacks an identifiable cause, and its diagnosis requires the exclusion of etiologically defined diseases that resemble it. Insights into its pathogenesis are moving autoimmune hepatitis from an idiopathic to explainable disease, and the goal of this review is to describe the insights that are hastening this transition. Two types of autoimmune hepatitis are justified by serological markers, but they also have distinctive genetic associations (DRB1 and DQB1 genes) and autoantigens. DRB1 alleles are the principal susceptibility factors in white adults, and a six amino acid sequence encoded in the antigen-binding groove of class II molecules of the major histocompatibility complex can influence the selection of autoantigens. Polymorphisms, including variants of SH2B3 and CARD10 genes, may affect immune reactivity and disease severity. The cytochrome mono-oxygenase, CYP2D6, is the autoantigen associated with type 2 autoimmune hepatitis, and it shares homologies with multiple viruses that might promote self-intolerance by molecular mimicry. Chemokines, especially CXCL9 and CXCL10, orchestrate the migration of effector cells to sites of injury and are associated with disease severity. Cells of the innate and adaptive immune responses promote tissue damage, and possible deficiencies in the number and function of regulatory T cells may facilitate the injurious process. Receptor-mediated apoptosis is the principal mechanism of hepatocyte loss, and cell-mediated and antibody-dependent mechanisms of cytotoxicity also contribute. Insights that explain autoimmune hepatitis will allow triggering exogenous antigens to be characterized, risk management to be improved, prognostic indices to be refined, and site-specific therapeutic interventions to emerge. PMID:25999246

  8. Chemokine Receptor Ccr6 Deficiency Alters Hepatic Inflammatory Cell Recruitment and Promotes Liver Inflammation and Fibrosis

    PubMed Central

    Blaya, Delia; Morales-Ibanez, Oriol; Coll, Mar; Millán, Cristina; Altamirano, José; Arroyo, Vicente; Caballería, Joan; Bataller, Ramón; Ginès, Pere; Sancho-Bru, Pau

    2015-01-01

    Chronic liver diseases are characterized by a sustained inflammatory response in which chemokines and chemokine-receptors orchestrate inflammatory cell recruitment. In this study we investigated the role of the chemokine receptor CCR6 in acute and chronic liver injury. In the absence of liver injury Ccr6-/- mice presented a higher number of hepatic macrophages and increased expression of pro-inflammatory cytokines and M1 markers Tnf-α, Il6 and Mcp1. Inflammation and cell recruitment were increased after carbon tetrachloride-induced acute liver injury in Ccr6-/- mice. Moreover, chronic liver injury by carbon tetrachloride in Ccr6-/- mice was associated with enhanced inflammation and fibrosis, altered macrophage recruitment, enhanced CD4+ cells and a reduction in Th17 (CD4+IL17+) and mature dendritic (MHCII+CD11c+) cells recruitment. Clodronate depletion of macrophages in Ccr6-/- mice resulted in a reduction of hepatic pro-inflammatory and pro-fibrogenic markers in the absence and after liver injury. Finally, increased CCR6 hepatic expression in patients with alcoholic hepatitis was found to correlate with liver expression of CCL20 and severity of liver disease. In conclusion, CCR6 deficiency affects hepatic inflammatory cell recruitment resulting in the promotion of hepatic inflammation and fibrosis. PMID:26691857

  9. Alcoholic hepatitis.

    PubMed

    Damgaard Sandahl, Thomas

    2014-10-01

    Alcoholic hepatitis (AH) is an acute inflammatory syndrome causing significant morbidity and mortality. The prognosis is strongly dependent on disease severity, as assessed by clinical scoring systems. Reliable epidemiological data as well as knowledge of the clinical course of AH are essential for planning and resource allocation within the health care system. Likewise, individual evaluation of risk is desirable in the clinical handling of patients with AH as it can guide treatment, improve patient information, and serve as strata in clinical trials. The present PhD thesis is based on three studies using a cohort of nearly 2000 patients diagnosed with AH in Denmark from 1999 to 2008 as a cohort, in a population-based study design. The aims of this thesis were as follows. (1) To describe the incidence and short- and long-term mortality, of AH in Denmark (Study I). (2) To validate and compare the ability of the currently available prognostic scores to predict mortality in AH (Study II). (3) To investigate the short- and long-term causes of death of patients with AH (Study III). During the study decade, the annual incidence rate in the Danish population rose from 37 to 46 per 106 for men and from 24 to 34 per 106 for women. Both short- and long-term mortality rose for men and women, and the increase in short-term mortality was attributable to increasing patient age and prevalence of cirrhosis. Our evaluation of the most commonly used prognostic scores for predicting the mortality of patients with AH showed that all scores performed similarly, with Area under the Receiver Operator Characteristics curves giving values between 0.74 and 0.78 for 28-day mortality assessed on admission. Our study on causes of death showed that in the short-term (< 84 days after diagnosis), patients with AH were likely to die from liver-related events and infections. In the long-term (≥ 84 days after diagnosis), those who developed cirrhosis mainly died from liver-related causes, and

  10. Autoimmune-like hepatitis during masitinib therapy in an amyotrophic lateral sclerosis patient

    PubMed Central

    Salvado, Maria; Vargas, Victor; Vidal, Marta; Simon-Talero, Macarena; Camacho, Jessica; Gamez, Josep

    2015-01-01

    We report a case of acute severe hepatitis resulting from masitinib in a young amyotrophic lateral sclerosis patient. Hepatotoxicity induced by masitinib, a tyrosine kinase inhibitor, is usually transient with mild elevation of transaminases, although acute hepatitis has been not reported to date. The hepatitis was resolved after masitinib was discontinued and a combination of prednisone and azathioprine was started. The transaminases returned to baseline normal values five months later. This is the first case in the hepatitis literature associated with masitinib. The autoimmune role of this drug-induced liver injury is discussed. Physicians should be aware of this potential complication. PMID:26420975

  11. Rowing injuries.

    PubMed

    Rumball, Jane S; Lebrun, Constance M; Di Ciacca, Stephen R; Orlando, Karen

    2005-01-01

    Participation in the sport of rowing has been steadily increasing in recent decades, yet few studies address the specific injuries incurred. This article reviews the most common injuries described in the literature, including musculoskeletal problems in the lower back, ribs, shoulder, wrist and knee. A review of basic rowing physiology and equipment is included, along with a description of the mechanics of the rowing stroke. This information is necessary in order to make an accurate diagnosis and treatment protocol for these injuries, which are mainly chronic in nature. The most frequently injured region is the low back, mainly due to excessive hyperflexion and twisting, and can include specific injuries such as spondylolysis, sacroiliac joint dysfunction and disc herniation. Rib stress fractures account for the most time lost from on-water training and competition. Although theories abound for the mechanism of injury, the exact aetiology of rib stress fractures remains unknown. Other injuries discussed within, which are specific to ribs, include costochondritis, costovertebral joint subluxation and intercostal muscle strains. Shoulder pain is quite common in rowers and can be the result of overuse, poor technique, or tension in the upper body. Injuries concerning the forearm and wrist are also common, and can include exertional compartment syndrome, lateral epicondylitis, deQuervain's and intersection syndrome, and tenosynovitis of the wrist extensors. In the lower body, the major injuries reported include generalised patellofemoral pain due to abnormal patellar tracking, and iliotibial band friction syndrome. Lastly, dermatological issues, such as blisters and abrasions, and miscellaneous issues, such as environmental concerns and the female athlete triad, are also included in this article.Pathophysiology, mechanism of injury, assessment and management strategies are outlined in the text for each injury, with special attention given to ways to correct

  12. Hepatic encephalopathy: a review.

    PubMed

    Lizardi-Cervera, Javier; Almeda, Paloma; Guevara, Luis; Uribe, Misael

    2003-01-01

    Hepatic encephalopathy (HE) is a complication that presents in as many as 28% of patients with cirrhosis, and reported up to ten years after the diagnosis of cirrhosis. Commonly, it is observed in patients with severe hepatic failure and is characterized by neuropsychiatric manifestations that can range in severity from a mild alteration in mental state to a coma; additionally, some neuromuscular symptoms can be observed. This complication of either acute or chronic hepatic disease is the result of a diminished hepatic reservoir and inability to detoxify some toxins that originate in the bowel. Today, the role of astrocytes, specifically the Alzheimer type II cells, is known to be very important in the pathogenesis of the hepatic encephalopathy, and will be reviewed later. In conclusion, the objectives of this review are: To understand the pathogenesis of hepatic encephalopathy, To recognize the precipitating factors, as well as preventive measures for the development of the hepatic encephalopathy, To describe the new classification of hepatic encephalopathy and its clinical implications, To recognize the clinical manifestations and stages of the disease, To understand the main diagnostic tests used to detect the hepatic encephalopathy, To describe the main therapeutic treatments of hepatic encephalopathy. PMID:15115963

  13. Inflammatory Mediators of Hepatic Steatosis

    PubMed Central

    Hijona, Elizabeth; Hijona, Lander; Arenas, Juan I.; Bujanda, Luis

    2010-01-01

    Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming a world-wide public health problem. NAFLD represents a spectrum of disease ranging from “simple steatosis”, which is considered relatively benign, to nonalcoholic steatohepatitis and to NAFLD-associated cirrhosis and end-stage liver disease. The etiology of NAFLD and its progression is complex and remains incompletely understood. The progression of the disease involves many factors. Apart from the two hits, the accumulation of TG and the development of fibrosis and necroinflammatory processes, exit numerous molecules associated with these two hits. Among them we can highlight the pro-inflammatory molecules and adiponectins. This review focuses on the growing evidence from both experimental and human studies suggesting a central role of cytokines in the pathogenesis of NAFLD. We review the role of cytokines as key regulators of insulin sensitivity and hepatic lipid overloading, liver injury and inflammation, and fibrosis with an emphasis on potential therapeutic implications. PMID:20300479

  14. Feature Hepatitis: Hepatitis Can Strike Anyone

    MedlinePlus

    ... please turn Javascript on. From Hollywood's "Walk of Stars" to Main Street, USA, people from all walks ... that includes many well-known names: Legendary television star Larry Hagman was diagnosed with advanced hepatitis C ...

  15. Sports Injuries

    MedlinePlus

    ... sometimes you can injure yourself when you play sports or exercise. Accidents, poor training practices, or improper gear can cause them. Some people get hurt because they are not in shape. Not warming up or stretching enough can also ... injuries are Sprains and strains Knee injuries Swollen ...

  16. Rowing Injuries

    PubMed Central

    Hosea, Timothy M.; Hannafin, Jo A.

    2012-01-01

    Context: Rowing is one of the original modern Olympic sports and was one of the most popular spectator sports in the United States. Its popularity has been increasing since the enactment of Title IX. The injury patterns in this sport are unique because of the stress applied during the rowing stroke. Evidence Acquisition: This review summarizes the existing literature describing the biomechanics of the rowing stroke and rowing-related injury patterns. Data were obtained from previously published peer-reviewed literature through a search of the entire PubMed database (up to December, 2011) as well as from textbook chapters and rowing coaching manuals. Results: Rowing injuries are primarily overuse related. The knee, lumbar spine, and ribs are most commonly affected. The injury incidence is directly related to the volume of training and technique. Conclusion: Familiarity of the injury patterns and the biomechanical forces affecting the rowing athlete will aid in prompt diagnosis and appropriate management. PMID:23016093

  17. Volleyball injuries.

    PubMed

    Eerkes, Kevin

    2012-01-01

    There has been a significant increase in the numbers of people playing indoor and beach volleyball since the early 1980s and, consequently, an increase in injuries. Most injuries are related to repetitive jumping and hitting the ball overhead. The ankle is the most commonly injured joint, but the knee, shoulder, low back, and fingers also are vulnerable. The shoulder in particular is subject to extreme torque when hitting and jump serving the ball. Some injuries have a predilection for those playing on sand versus those playing in an indoor court. The clinician caring for volleyball players should be aware of the types of injuries these players sustain and how to help them return to play promptly and appropriately. This article reviews the specific injuries that are most common as a result of participating in the sport of volleyball. PMID:22965348

  18. Role of Hepatic Drug Transporters in Drug Development.

    PubMed

    Liu, Houfu; Sahi, Jasminder

    2016-07-01

    Hepatic drug transporters can play an important role in pharmacokinetics and the disposition of therapeutic drugs and endogenous substances. Altered function of hepatic drug transporters due to drug-drug interactions (DDIs), genetic polymorphisms, and disease states can often result in a change in systemic and/or tissue exposure and subsequent pharmacological/toxicological effects of their substrates. Regulatory agencies including the US Food and Drug Administration, European Medicines Agency, and Japan Pharmaceuticals and Medical Devices Agency have issued guidance for industry on drug interaction studies, which contain comprehensive recommendations on in vitro and in vivo study tools and cutoff values to evaluate the DDI potential of new molecular entities mediated by hepatic drug transporters. In this report we summarize the latest regulatory and scientific progress of hepatic drug transporters in clinical DDIs, pharmacogenetics, drug-induced liver injury (DILI), as well as methods for predicting transporter-mediated pharmacokinetics and DDIs. PMID:27385168

  19. Preventing hepatitis B or C

    MedlinePlus

    ... page: //medlineplus.gov/ency/patientinstructions/000401.htm Preventing hepatitis B or C To use the sharing features on this page, please enable JavaScript. Hepatitis B and hepatitis C infections cause irritation and ...

  20. Hepatitis B in Pregnancy.

    PubMed

    Tran, Tram T

    2016-06-01

    Chronic hepatitis B virus (HBV) infection is estimated to affect >350 million people worldwide and represents a significant cause of morbidity and mortality related to cirrhosis and hepatocellular carcinoma. Mother-to-child transmission (MTCT) of HBV remains an important source of incident cases of HBV. Current barriers to eradication of incident HBV infections via MTCT include underutilization of immunoprophylaxis with hepatitis B vaccination and hepatitis B immune globulin in certain endemic regions as well as failure of immunoprophylaxis. PMID:27190321

  1. Head injury - first aid

    MedlinePlus

    ... is shaken, is the most common type of traumatic brain injury. Scalp wounds. Skull fractures. Head injuries may cause ... of people who suffer head injuries are children. Traumatic brain injury (TBI) accounts for over 1 in 6 injury- ...

  2. Hepatitis C: Information on Testing and Diagnosis

    MedlinePlus

    HEPATITIS C Information on Testing & Diagnosis What is Hepatitis C? Hepatitis C is a serious liver disease that results from infection with the Hepatitis C virus. Hepatitis C has been called a silent ...

  3. [Treatment for hepatic osteodystrophy].

    PubMed

    Kaji, Hiroshi

    2015-11-01

    Chronic liver diseases, including liver cirrhosis, are caused by various pathogenesis, such as viral hepatitis, primary biliary cirrhosis, autoimmune hepatitis and steatohepatitis. There have not been enough clinical evidence about the treatment of hepatic osteodystrophy at the present time. Several reports suggested that bisphosphonates, such as alendronate, are effective for an increase in bone mineral density in patients with chronic liver disease. Vitamin D treatment might be useful for the frequent prevalence of vitamin D deficiency in the pathogenesis of hepatic oseodystrophy. The use of estrogens will be limited for the risk of liver dysfunction and hepatocellular carcinoma. PMID:26503875

  4. Unintended hepatic adverse events associated with cancer chemotherapy.

    PubMed

    Senior, John R

    2010-01-01

    Chemotherapy is meant to be toxic, but it is particularly aimed at the tumor cells. Collateral damage may occur to normal cells and tissues, especially if they are fairly rapidly regenerating, as is the case for bone marrow cells, intestinal epithelial cells, and liver cells after hepatic injury. The liver has a great capacity to resist injury, overcome it, and to regenerate, even after quite massive injury (resection of 50%-65%, for example). This capacity may make it susceptible to chemotherapeutic toxicity, and a struggle between injury and adaptation, leading to recovery and tolerance or to failure and death. If the chemotherapy is aimed just at delaying progression of the cancer for a few weeks or months, it may not be worth the risk of irreversible liver injury developing in that time. Close clinical observation and sound clinical judgment are required. PMID:19858501

  5. CCR1 and CCR5 promote hepatic fibrosis in mice

    PubMed Central

    Seki, Ekihiro; De Minicis, Samuele; Gwak, Geum-Youn; Kluwe, Johannes; Inokuchi, Sayaka; Bursill, Christina A.; Llovet, Josep M.; Brenner, David A.; Schwabe, Robert F.

    2009-01-01

    Hepatic fibrosis develops as a response to chronic liver injury and almost exclusively occurs in a proinflammatory environment. However, the role of inflammatory mediators in fibrogenic responses of the liver is only poorly understood. We therefore investigated the role of CC chemokines and their receptors in hepatic fibrogenesis. The CC chemokines MIP-1α, MIP-1β, and RANTES and their receptors CCR1 and CCR5 were strongly upregulated in 2 experimental mouse models of fibrogenesis. Neutralization of CC chemokines by the broad-spectrum CC chemokine inhibitor 35k efficiently reduced hepatic fibrosis, and CCR1- and CCR5-deficient mice displayed substantially reduced hepatic fibrosis and macrophage infiltration. Analysis of fibrogenesis in CCR1- and CCR5-chimeric mice revealed that CCR1 mediates its profibrogenic effects in BM-derived cells, whereas CCR5 mediates its profibrogenic effects in resident liver cells. CCR5 promoted hepatic stellate cell (HSC) migration through a redox-sensitive, PI3K-dependent pathway. Both CCR5-deficient HSCs and CCR1- and CCR5-deficient Kupffer cells displayed strong suppression of CC chemokine–induced migration. Finally, we detected marked upregulation of RANTES, CCR1, and CCR5 in patients with hepatic cirrhosis, confirming activation of the CC chemokine system in human fibrogenesis. Our data therefore support a role for the CC chemokine system in hepatic fibrogenesis and suggest distinct roles for CCR1 and CCR5 in Kupffer cells and HSCs. PMID:19603542

  6. Experimental models of hepatic encephalopathy: ISHEN guidelines.

    PubMed

    Butterworth, Roger F; Norenberg, Michael D; Felipo, Vicente; Ferenci, Peter; Albrecht, Jan; Blei, Andres T

    2009-07-01

    Objectives of the International Society for Hepatic Encephalopathy and Nitrogen Metabolism Commission were to identify well-characterized animal models of hepatic encephalopathy (HE) and to highlight areas of animal modelling of the disorder that are in need of development. Features essential to HE modelling were identified. The best-characterized animal models of HE in acute liver failure, the so-called Type A HE, were found to be the hepatic devascularized rat and the rat with thioacetamide-induced toxic liver injury. In case of chronic liver failure, surgical models in the rat involving end-to-side portacaval anastomosis or bile duct ligation were considered to best model minimal/mild (Type B) HE. Unfortunately, at this time, there are no satisfactory animal models of Type C HE resulting from end-stage alcoholic liver disease or viral hepatitis, the most common aetiologies encountered in patients. The commission highlighted the urgent need for such models and of improved models of HE in chronic liver failure in general as well as a need for models of post-transplant neuropsychiatric disorders. Studies of HE pathophysiology at the cellular and molecular level continue to benefit from in vitro and or ex vivo models involving brain slices or exposure of cultured cells (principally cultured astrocytes) to toxins such as ammonia, manganese and pro-inflammatory cytokines. More attention could be paid in the future to in vitro models involving the neurovascular unit, microglia and neuronal co-cultures in relation to HE pathogenesis. PMID:19638106

  7. [Plasma cholinesterase activity in hepatic diseases].

    PubMed

    Araoud, Manel; Mhenni, Hamida; Hellara, Ilhem; Hellara, Olfa; Neffati, Fadoua; Douki, Wahiba; Mili, Marwa; Saffar, Hammouda; Najjar, Mohamed Fadhel

    2013-01-01

    Plasma cholinesterase activity (ChE) may vary in some pathological circumstances. We studied the changes in activity of this enzyme according to the type of liver injury, to assess the interest of this parameter in the diagnosis of liver diseases. Our study was performed on 102 patients with different liver diseases and 53 healthy controls. The ChE activity was lower in patients compared to control group (p < 0.0001), and more pronounced in cirrhotic patients compared to those suffering from hepatitis. Elevated activities of AST, ALT, GGT and ALP and bilirubinemia, and decreased albuminemia were noted in patients compared to controls (p < 0.001). Hypoalbuminemia was significantly important in cirrhotic patients compared to those suffering from cholestasis or hepatitis. A correlation between ChE and bilirubin, albumin and serum protein was found in patients with cirrhosis or those with chronic hepatitis. A significantly lower activity of ChE was found in patients with hepatic insufficiency (HI). In case of suspicion of HI, the prescription of ChE activity could guide or confirm the diagnosis of the impairment. PMID:23747666

  8. Expression of SPARC by activated hepatic stellate cells and its correlation with the stages of fibrogenesis in human chronic hepatitis.

    PubMed

    Nakatani, Kazuki; Seki, Shuichi; Kawada, Norifumi; Kitada, Takuya; Yamada, Takao; Sakaguchi, Hiroki; Kadoya, Hirokazu; Ikeda, Kazuo; Kaneda, Kenji

    2002-11-01

    Secreted protein, acidic and rich in cysteine (SPARC), which functions in tissue remodeling, has been reported to be expressed by myofibroblasts in liver cirrhosis and hepatocellular carcinoma. This study aimed to reveal its expression in chronic hepatitis. Immuno-light and electron microscopy demonstrated that SPARC was expressed by nerve fibers and hepatic stellate cells (HSCs) in the liver parenchyma and myofibroblasts in the fibrous septa. Reaction products were localized in the rough endoplasmic reticulum and nuclear envelope. Serial section analysis demonstrated that SPARC, platelet-derived growth factor receptor-beta, and alpha-smooth muscle actin were co-expressed by HSCs. Quantitative analysis demonstrated that, while SPARC-positive HSCs were sparse in control livers, they significantly increased in number in the livers with chronic hepatitis. There were, however, no significant differences in number among the grades of activity, the stages of fibrosis, or etiology (virus-infected or autoimmune, hepatitis B virus or hepatitis C virus). In liver cirrhosis, however, they significantly decreased in number. The present results indicate that SPARC is expressed by activated HSCs in chronic hepatitis, suggesting the involvement of SPARC in hepatic fibrogenesis after chronic injuries. PMID:12447677

  9. Erythropoietic and hepatic porphyrias.

    PubMed

    Gross, U; Hoffmann, G F; Doss, M O

    2000-11-01

    Porphyrias are divided into erythropoietic and hepatic manifestations. Erythropoietic porphyrias are characterized by cutaneous symptoms and appear in early childhood. Erythropoietic protoporphyria is complicated by cholestatic liver cirrhosis and progressive hepatic failure in 10%, of patients. Acute hepatic porphyrias (delta-aminolaevulinic acid dehydratase deficiency porphyria, acute intermittent porphyria, hereditary coproporphyria and variegate porphyria) are characterized by variable extrahepatic gastrointestinal, neurological-psychiatric and cardiovascular manifestations requiring early diagnosis to avoid life-threatening complications. Acute hepatic porphyrias are pharmacogenetic and molecular regulatory diseases (without porphyrin accumulation) mainly induced by drugs, sex hormones, fasting or alcohol. The disease process depends on the derepression of hepatic delta-aminolaevulinic acid synthase following haem depletion. In contrast to the acute porphyrias, nonacute, chronic hepatic porphyrias such as porphyria cutanea tarda are porphyrin accumulation disorders leading to cutaneous symptoms associated with liver disease, especially caused by alcohol or viral hepatitis. Alcohol, oestrogens, haemodialysis, hepatitis C and AIDS are triggering factors. Porphyria cutanea tarda is the most common porphyria, followed by acute intermittent porphyria and erythropoietic protoporphyria. The molecular genetics of the porphyrias is very heterogenous. Nearly every family has its own mutation. The mutations identified account for the corresponding enzymatic deficiencies, which may remain clinically silent throughout life. Thus, the recognition of the overt disorder with extrahepatic manifestations depends on the demonstration of biochemical abnormalities due to these primary defects and compensatory hepatic overexpression of hepatic delta-aminolaevulinic acid synthase in the acute porphyrias. Consequently, haem precursors are synthesized in excess. The increased

  10. Liver injury and complications in the postoperative trauma patient: CT evaluation

    SciTech Connect

    Haney, P.J.; Whitley, N.O.; Brotman, S.; Cunat, J.S.; Whitley, J.

    1982-08-01

    Twenty-eight patients with surgically documented and classified hepatic injury were studied by computed tomography (CT) in the postoperative period.CT demonstrated no abnormalities in 12 of these patients, most of whom has sustained simple lacerations of the liver. Of the 16 patients with abnormal scans, perihepatic fluid collections were present in six, five of whom had simple lacerations at surgery. The other 10 patients had CT evidence of parenchymal abnormalities, and all of these had sustained major hepatic injuries. CT is usful in depicting the postoperative anatomy, and in many cases demonstrates the nature and extent of damage; the likelihood of finding an abnormality varies with the severity of the injury, even though repair has been attempted. The frequent problem of postoperative sepsis is also amenable to CT evaluation, but the changes demonstrated are often nonspecific and the possibility of residual hepatic injury has to be considered. Finally, CT can document healing of parenchymal injury.

  11. Electrical injury

    MedlinePlus

    ... damage, especially to the heart, muscles, or brain. Electric current can cause injury in three ways: Cardiac arrest ... How long you were in contact with the electricity How the electricity moved through your body Your ...

  12. Sports Injuries

    MedlinePlus

    ... heart, to help decrease swelling. The Body’s Healing Process From the moment a bone breaks or a ... what happens at each stage of the healing process: At the moment of injury: Chemicals are released ...

  13. Corneal injury

    MedlinePlus

    ... at all times when using hand or power tools or chemicals, during high impact sports, or during other activities where you may get an eye injury. Wear sunglasses that screen ultraviolet light when you are ...

  14. Celiac Axis, Common Hepatic and Hepatic Artery Variants as Evidenced on MDCT Angiography in South Indian Population

    PubMed Central

    Parthasarathy, Ramesh

    2016-01-01

    Introduction With the increase in the hepatobiliary, pancreatic surgeries and liver transplantation, being aware of the anatomic variations of the celiac axis and the hepatic arteries is of paramount importance. Aim To illustrate the normal anatomy and variants of the celiac axis and the hepatic arteries with multidetector computed tomographic (MDCT) angiography in South Indian population and determine the potential variations in the celiac axis anatomy and the hepatic arteries, thus assisting the hepatobiliary surgeon and the interventional radiologist in avoiding iatrogenic injury to the arteries. Materials and Methods Two hundred patients undergoing abdominal CT angiography from July 2014 till July 2015 were retrospectively studied for hepatic arterial and celiac axis anatomical variation. The anatomic variations in our study were correlated with other studies. Results The celiac axis (CA) and the hepatic artery (HA) variations were analysed as per criteria laid by Song et al., and Michel. Out of 15 possible CA variations, 5 types of celiac artery variations were seen in 14 patients. A normal CA was seen in 179(89.5%) patients of the 200 patients. In the remaining 7 patients, the CA anatomy was classified as ambiguous since there was separate origin of the right and left hepatic arteries from the CA with absent common hepatic artery (CHA). The CHA originated normally from the celiac axis in 94% of the cases. Variation of CHA origin was seen in 5 patients. Normal HA anatomy was seen in 114 (57%) patients. Variation in HA anatomy was seen in 86 (43%) patients. Origin of the right hepatic artery (RHA) from the hepatic artery proper was seen in 182 (91%) patients and replaced origin of RHA from the superior mesenteric artery (SMA) was seen in 18 (9%) of the cases. Accessory RHA was seen in 7(3.5%) patients. The left hepatic artery (LHA) originated from the hepatic artery proper in 186 (93%) patients and replaced origin of LHA from the left gastric artery (LGA) was

  15. Evolution in the Management of Hepatic Trauma: A 25-Year Perspective

    PubMed Central

    David Richardson, J.; Franklin, Glen A.; Lukan, James K.; Carrillo, Eddy H.; Spain, David A.; Miller, Frank B.; Wilson, Mark A.; Polk, Hiram C.; Flint, Lewis M.

    2000-01-01

    Objective To define the changes in demographics of liver injury during the past 25 years and to document the impact of treatment changes on death rates. Summary Background Data No study has presented a long-term review of a large series of hepatic injuries, documenting the effect of treatment changes on outcome. A 25-year review from a concurrently collected database of liver injuries documented changes in treatment and outcome. Methods A database of hepatic injuries from 1975 to 1999 was studied for changes in demographics, treatment patterns, and outcome. Factors potentially responsible for outcome differences were examined. Results A total of 1,842 liver injuries were treated. Blunt injuries have dramatically increased; the proportion of major injuries is approximately 16% annually. Nonsurgical therapy is now used in more than 80% of blunt injuries. The death rates from both blunt and penetrating trauma have improved significantly through each successive decade of the study. The improved death rates are due to decreased death from hemorrhage. Factors responsible include fewer major venous injuries requiring surgery, improved outcome with vein injuries, better results with packing, and effective arterial hemorrhage control with arteriographic embolization. Conclusions The treatment and outcome of liver injuries have changed dramatically in 25 years. Multiple modes of therapy are available for hemorrhage control, which has improved outcome. PMID:10973382

  16. Hepatitis (For Parents)

    MedlinePlus

    ... people at risk for contracting hepatitis. But frequent hand washing and good hygiene practices can reduce this risk. All kids in ... to prevent viral hepatitis you should: Follow good hygiene and avoid crowded, ... their hands thoroughly after using the toilet and before eating. ...

  17. Hepatitis and activity

    PubMed Central

    Krikler, Dennis M.

    1971-01-01

    The effects of physical activity during an attack of infectious hepatitis are discussed. There is no evidence that activity during convalescence produces any ill-effects. On the other hand, strenuous physical activity in the acute stage may be dangerous, possibly because hepatic blood-flow is reduced. PMID:5560143

  18. Renal disease in patients infected with hepatitis B virus.

    PubMed

    Jaryal, Ajay; Kumar, Vivek; Sharma, Vishal

    2015-01-01

    Infection with hepatitis B virus (HBV) can result in hepatic diseases which may include an asymptomatic non-replicative carrier state, immunotolerant phase characterized by high DNA levels without significant hepatic injury, immune-reactive phase characterized by occurrence of chronic hepatitis and fibrosis in the liver, or complications like cirrhosis or hepatocellular carcinoma. Extrahepatic manifestations may also accompany HBV infection. These may include serum sickness syndrome, polyarthralgia, polyarthritis, dermatologic manifestations like pitted keratolysis, urticaria, purpura, oral lichen planus or Gianotti-Crosti syndrome-a childhood papular eruption. Renal involvement may occur with HBV infection and usually involves glomerular or vascular injury. Various morphologic forms of renal injury have been reported with HBV infection, the commonest being membranous glomerulonephritis. The manifestations may include swelling over face and body, pedal edema, and urinary abnormalities. Evaluation may detect proteinuria, hematuria and reduction in estimated glomerular filtration rate (GFR). The management options include use of antiviral drugs targeting HBV infection with or without concomitant immunosuppressive medication. With availability of newer drugs like entecavir and tenofovir, these have become the first line agents as they have a high barrier to resistance. Sole use of immunosuppression is not recommended for lack of clear benefit and the possible risk of HBV reactivation or flare. PMID:27509699

  19. Electric injury, Part II: Specific injuries.

    PubMed

    Fish, R M

    2000-01-01

    Electric injury can cause disruption of cardiac rhythm and breathing, burns, fractures, dislocations, rhabdomyolysis, eye and ear injury, oral and gastrointestinal injury, vascular damage, disseminated intravascular coagulation, peripheral and spinal cord injury, and Reflex Sympathetic Dystrophy. Secondary trauma from falls, fires, flying debris, and inhalation injury can complicate the clinical picture. Diagnostic and treatment considerations for electric injuries are described in this article, which is the second part of a three-part series on electric injuries. PMID:10645833

  20. [Update chronic viral hepatitis].

    PubMed

    Ziegenhagen, D J

    2016-03-01

    More than 500,000 people in Germany have chronic viral hepatitis. The interferon-based treatments formerly used in hepatitis B have been widely replaced by life-long oral medication with nucleoside or nucleotide analogues. Treatment for chronic hepatitis C has been improved substantially by the development of new and very expensive drug combinations. Up to 90% of patients can now be cured with certainty, and one to two years after successful treatment there is no relevant risk of recurrence. These individuals expect to receive insurance cover under appropriate conditions. Vaccination programmes are very efficient at decreasing the incidence of hepatitis B, but no vaccine against hepatitis C is likely to become available in the next decade. PMID:27111951

  1. Transcriptional regulation of hepatic stellate cells.

    PubMed

    Mann, Jelena; Mann, Derek A

    2009-07-01

    Hepatic stellate cell (HSC) activation is a process of cellular transdifferentiation in which, upon liver injury, the quiescent vitamin A storing perisinusoidal HSC is converted into a wound-healing myofibroblast and acquires potent pro-inflammatory and pro-fibrogenic activities. This remarkable phenotypic transformation is underpinned by changes in the expression of a vast number of genes. In this review we survey current knowledge of the transcription factors that either control HSC activation or which regulate specific fibrogenic functions of the activated HSC such as collagen expression, proliferation and resistance to apoptosis. PMID:19393271

  2. Replacement of Diseased Mouse Liver by Hepatic Cell Transplantation

    NASA Astrophysics Data System (ADS)

    Rhim, Jonathan A.; Sandgren, Eric P.; Degen, Jay L.; Palmiter, Richard D.; Brinster, Ralph L.

    1994-02-01

    Adult liver has the unusual ability to fully regenerate after injury. Although regeneration is accomplished by the division of mature hepatocytes, the replicative potential of these cells is unknown. Here, the replicative capacity of adult liver cells and their medical usefulness as donor cells for transplantation were investigated by transfer of adult mouse liver cells into transgenic mice that display an endogenous defect in hepatic growth potential and function. The transplanted liver cell populations replaced up to 80 percent of the diseased recipient liver. These findings demonstrate the enormous growth potential of adult hepatocytes, indicating the feasibility of liver cell transplantation as a method to replace lost or diseased hepatic parenchyma.

  3. Hepatitis C virus. A review.

    PubMed Central

    Tang, E.

    1991-01-01

    Hepatitis C virus has been shown to be responsible for most cases of posttransfusion hepatitis, as well as for sporadic non-A, non-B viral hepatitis. Hepatitis C virus has also been implicated in the development of primary hepatocellular carcinoma, autoimmune hepatitis, and fulminant viral hepatitis. Although the role of the parenteral transmission of hepatitis C virus is well established, its route of transmission in cases of sporadic infection remains unclear. Sexual transmission is suspected but not confirmed. Recent work regarding treatment has shown interferon alfa to be effective, but the discontinuation of therapy is associated with a 50% relapse rate. PMID:1656611

  4. Cold injuries.

    PubMed

    Long, William B; Edlich, Richard F; Winters, Kathryne L; Britt, L D

    2005-01-01

    Exposure to cold can produce a variety of injuries that occur as a result of man's inability to adapt to cold. These injuries can be divided into localized injury to a body part, systemic hypothermia, or a combination of both. Body temperature may fall as a result of heat loss by radiation, evaporation, conduction, and convection. Hypothermia or systemic cold injury occurs when the core body temperature has decreased to 35 degrees C (95 degrees F) or less. The causes of hypothermia are either primary or secondary. Primary, or accidental, hypothermia occurs in healthy individuals inadequately clothed and exposed to severe cooling. In secondary hypothermia, another illness predisposes the individual to accidental hypothermia. Hypothermia affects multiple organs with symptoms of hypothermia that vary according to the severity of cold injury. The diagnosis of hypothermia is easy if the patient is a mountaineer who is stranded in cold weather. However, it may be more difficult in an elderly patient who has been exposed to a cold environment. In either case, the rectal temperature should be checked with a low-reading thermometer. The general principals of prehospital management are to (1) prevent further heat loss, (2) rewarm the body core temperature in advance of the shell, and (3) avoid precipitating ventricular fibrillation. There are two general techniques of rewarming--passive and active. The mechanisms of peripheral cold injury can be divided into phenomena that affect cells and extracellular fluids (direct effects) and those that disrupt the function of the organized tissue and the integrity of the circulation (indirect effects). Generally, no serious damage is seen until tissue freezing occurs. The mildest form of peripheral cold injury is frostnip. Chilblains represent a more severe form of cold injury than frostnip and occur after exposure to nonfreezing temperatures and damp conditions. Immersion (trench) foot, a disease of the sympathetic nerves and blood

  5. Extra-hepatic manifestations associated with hepatitis E virus infection: a comprehensive review of the literature

    PubMed Central

    Bazerbachi, Fateh; Haffar, Samir; Garg, Sushil K; Lake, John R

    2016-01-01

    Background and aims: Hepatitis E virus (HEV) infection is a significant public health problem that afflicts almost 20 million individuals annually and causes acute liver injury in 3.5 million, with approximately 56 000 deaths. As with other viral hepatitides, extra-hepatic manifestations could represent an important aspect of this infection. The spectrum of these manifestations is still emerging. Acute pancreatitis and neurological, musculoskeletal, hematological, renal, and other immune-mediated manifestations have been described. The aim of this article is to comprehensively review the published literature of extra-hepatic manifestations associated with HEV infection. Data sources: We searched the PubMed database using the MeSH term “hepatitis E” and each of the extra-hepatic manifestations associated with HEV infection. No language or date restrictions were set in these searches. Searches retrieving articles with non-A, non-B hepatitis were excluded. Additional articles were identified through the reference lists of included articles. Results: Several extra-hepatic manifestations associated with HEV infection have been published. The temporal association between some extra-hepatic manifestations and HEV infection and the exclusion of other possible etiologies suggests that HEV infection could have caused some of them. According to the available data, HEV infection appears to be strongly associated with acute pancreatitis, neurological disorders (with primarily dominant peripheral nerve involvement, most commonly manifested as Guillain-Barré syndrome, followed by neuralgic amyotrophy), hematological diseases (hemolytic anemia due to glucose phosphate dehydrogenase deficiency, and severe thrombocytopenia), glomerulonephritis, and mixed cryoglobulinemia. More data are needed to clarify whether an association exists with musculoskeletal or other immune-mediated manifestations. Conclusions: HEV infection should be considered in patients with acute pancreatitis

  6. Acute hepatitis induced by a Chinese herbal product Qibao Meiran Wan: a case study

    PubMed Central

    Li, Xiaoyan; Qu, Caihong; He, Qiong; Chen, Wenying; Zhang, Xiaojuan; Liu, Xiaoqi; Liu, Yuxing; Tang, Yongbo

    2015-01-01

    Qibao Meiran Wan is a Chinese herbal product sold as a therapy for tonifying the liver and kidney, dizziness, premature graying of hair, backache, constipation, and night sweats. It is widely available in Chinese pharmacies and drugstores and is sold without prescription. We describe a case of acute liver injury in a 26-year-old Chinese man who developed symptomatic hepatitis 1 month after starting Qibao Meiran Wan. There was no evidence of viral hepatitis, Epstein-Barr virus, cytomegalovirus, autoimmune hepatitis, or Budd-Chiari syndrome. The liver injury slowly resolved over 20 days after discontinuing the herbal product. Herbal toxicity was later confirmed by a liver biopsy. Qibao Meiran Wan contains a mixture of several plants including Polygonum multiflorum, which was previously associated with hepatotoxicity. To our knowledge, this is the first report of hepatotoxicity by Qibao Meiran Wan. Clinicians treating patients with acute hepatitis of unclear etiology should pay attention to the consumption of Qibao Meiran Wan. PMID:26379995

  7. Blast injury.

    PubMed

    de Candole, C A

    1967-01-28

    The shock wave generated by an explosion ("blast wave") may cause injury in any or all of the following: (1) direct impact on the tissues of variations in environmental pressure; (2) flying glass and other debris set in motion by it; (3) propulsion of the body. Injuries in the first category affect gas-containing organs (ears, lungs and intestines), and acute death is attributed to air forced into the coronary vessels via damaged pulmonary alveoli. It is estimated that overpressure sufficient to cause lung injury may occur up to five miles from a 20-megaton nuclear explosion. The greatest single hazard from blast is, however, flying glass, and serious wounding from this cause is possible up to 12 miles from an explosion of this magnitude. PMID:6015742

  8. Blast Injury

    PubMed Central

    de Candole, C. A.

    1967-01-01

    The shock wave generated by an explosion (“blast wave”) may cause injury in any or all of the following: (1) direct impact on the tissues of variations in environmental pressure; (2) flying glass and other debris set in motion by it; (3) propulsion of the body. Injuries in the first category affect gas-containing organs (ears, lungs and intestines), and acute death is attributed to air forced into the coronary vessels via damaged pulmonary alveoli. It is estimated that overpressure sufficient to cause lung injury may occur up to five miles from a 20-megaton nuclear explosion. The greatest single hazard from blast is, however, flying glass, and serious wounding from this cause is possible up to 12 miles from an explosion of this magnitude. PMID:6015742

  9. Heparin modulation on hepatic nitric oxide synthase in experimental steatohepatitis

    PubMed Central

    HASSANIN, AMAL; MALEK, HALA ABDEL; SALEH, DALIA

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) is considered to be a hepatic manifestation of metabolic syndrome, and has been etiologically associated with insulin resistance (IR). The histopathology of NAFLD ranges between simple steatosis and nonalcoholic steatohepatitis (NASH), with or without fibrosis. The aim of the present study was to examine the effect of heparin on steatohepatitis and hepatic-induced nitric oxide synthase (iNOS) expression in mice. Male mice were divided into four groups, which included the normal basal diet (control), high fat (HF) diet, HF diet + heparin (treatment group) and heparin control groups. After eight weeks from the initiation of the experiment, blood was collected and livers were harvested for biochemical analysis and histological studies. Serum levels of aspartate aminotransferase, alanine aminotransferase, hepatic triglyceride (TG) and hydroxyproline, as well as the IR, superoxide anion generation and mRNA expression of the hepatic iNOS enzyme were evaluated. Liver specimens were processed for histopathological and immunohistopathological evaluation. Heparin administration decreased the levels of the liver enzymes, IR, superoxide generation, hepatic TG, hydroxyproline and iNOS expression when compared with the HF diet group. These changes were associated with an improvement in inflammation and fibrosis observed via histopathological examination. Therefore, heparin treatment attenuates hepatic injury in steatohepatitis. PMID:25289058

  10. Risk factors for peri-anaesthetic dental injury.

    PubMed

    Ham, S Y; Kim, J; Oh, Y J; Lee, B; Shin, Y-S; Na, S

    2016-09-01

    In this retrospective case-control study, we evaluated peri-operative dental injury risk factors following tracheal intubation. Ninety-four of 290,415 patients experienced dental injury following tracheal intubation over a 10-y period. A control group was matched for surgery type and intubating anaesthetist. The incidence of dental injury was 0.03%. Univariate analysis revealed that previous and current difficult intubation, male gender, hepatitis, neurological disease, anticonvulsant use, pre-existing poor dentition and the use of airway devices (other than a laryngoscope) were associated with dental injury. Multivariate analysis revealed that predictors of dental injury were: history of hepatitis, odds ratio (95% CI) 10.1 (1.02-100.3); poor dentition, 8.8 (3.9-20.0); alternative airway device use, 3.1 (1.2-8.0); and intubation difficulty, 3.7 (1.0-13.3). As well as confirming previously reported risk factors for dental injury during tracheal intubation, this study also suggests hepatitis and the use of alternative airway devices as additional risk factors. PMID:27440234

  11. Feature Hepatitis: The Dangers of Hepatitis: What you should know from A to E

    MedlinePlus

    ... Hepatitis: What you should know from A to E Past Issues / Spring 2009 Table of Contents For ... condition is called chronic hepatitis. Hepatitis A and E do not cause chronic hepatitis. Hepatitis viruses B, ...

  12. Spinal Cord Injury Map

    MedlinePlus

    ... on the severity of the injury. Tap this spinal column to see how the level of injury affects loss of function and control. Learn more about spinal cord injuries. A spinal cord injury affects the ...

  13. Eye Injuries at Home

    MedlinePlus

    ... Patient Stories Español Eye Health / Tips & Prevention Eye Injuries Sections Preventing Eye Injuries Recognizing and Treating Eye ... Sports Eye Injuries by the Numbers — Infographic Eye Injuries at Home Reviewed by: Brenda Pagan-Duran MD ...

  14. Viral hepatitis and hepatitis B antigen: recent advances

    PubMed Central

    Krugman, Saul

    1974-01-01

    Recent advances in hepatitis research have shed new light on the etiology, pathogenesis, epidemiology and prevention of type B hepatitis infection. The so-called ‘Dane’ particle is probably the complete hepatitis B virion; its outer coat is the hepatitis B (Australia) antigen (HB Ag) and its inner core is an immunologically distinct particle. Subtypes of HB Ag (a, d, y, w and r) are useful indices for epidemiological surveys. Concepts of epidemiology have changed: type B hepatitis is transmissible by contact as well as by inoculation. The presence of HB Ag in blood is indicative of the presence of hepatitis B virus. Tests to detect antigen and use of voluntary blood donors have played a major role in the decreased incidence of post transfusion hepatitis. A special hepatitis B gammaglobulin preparation and a heat-inactivated hepatitis B vaccine have proved to be effective in preliminary studies. PMID:4219230

  15. Extra-hepatic replication and infection of hepatitis E virus in neuronal-derived cells.

    PubMed

    Drave, S A; Debing, Y; Walter, S; Todt, D; Engelmann, M; Friesland, M; Wedemeyer, H; Neyts, J; Behrendt, P; Steinmann, E

    2016-07-01

    Hepatitis E virus (HEV) is the causative agent of hepatitis E in humans and a member of the genus Orthohepevirus in the family Hepeviridae. Infection usually leads to acute hepatitis that can become fulminant, particularly among pregnant women and in patients with preexisting liver disease, or may evolve to a chronic state, especially in immunosuppressed individuals. HEV has been shown to produce a range of extra-hepatic manifestations including aplastic anaemia, acute thyroiditis, glomerulonephritis as well as neurological disorders such as Guillain-Barré syndrome, neuralgic amyotrophy and encephalitis. The pathogenesis of these neurological injuries remains largely unknown, and it is also uncertain whether or not HEV can directly infect neuronal cells. In this study, we investigated whether HEV is capable of completing the viral life cycle in human neuronal-derived cell lines such as neuroepithelioma (SK-N-MC), desmoplastic cerebellar medulloblastoma (DAOY), glioblastoma multiforme (DBTRG), glioblastoma astrocytoma (U-373 MG) and oligodendrocytic (M03.13) cells. Following transfection of these cells with HEV Gaussia luciferase reporter virus, all tested cell lines supported HEV RNA replication. Furthermore, extra- and intracellular viral capsid was detected by an HEV antigen ELISA as a marker for virus assembly and release. Permissiveness for HEV cell entry could be demonstrated for the oligodendrocytic cell line M03.13. In conclusion, these results indicate that HEV tropism is not restricted to the liver and HEV can potentially complete the full viral life cycle in neuronal-derived tissues explaining neurologic disorders during HEV infection. PMID:26891712

  16. Oxidative stress and hepatic Nox proteins in chronic hepatitis C and hepatocellular carcinoma

    PubMed Central

    Choi, Jinah; Corder, Nicole L. B.; Koduru, Bhargav; Wang, Yiyan

    2014-01-01

    Hepatocellular carcinoma (HCC) is the most common liver cancer and a leading cause of cancer-related mortality in the world. Hepatitis C virus (HCV) is a major etiologic agent of HCC. A majority of HCV infections lead to chronic infection that can progress to cirrhosis and eventually, HCC and liver failure. A common pathogenic feature present in HCV infection, and other conditions leading to HCC, is oxidative stress. HCV directly increases superoxide and H2O2 formation in hepatocytes by elevating Nox protein expression and sensitizing mitochondria to reactive oxygen species generation while decreasing glutathione. Nitric oxide synthesis and hepatic iron are also elevated. Furthermore, activation of phagocytic NADPH oxidase 2 (Nox2) of host immune cells is likely to exacerbate oxidative stress in HCV-infected patients. Key mechanisms of HCC include: genome instability, epigenetic regulation, inflammation with chronic tissue injury and sustained cell proliferation, and modulation of cell growth and death. Oxidative stress, or Nox proteins, plays various roles in these mechanisms. Nox proteins also function in hepatic fibrosis, which commonly precedes HCC, and Nox4 elevation by HCV was mediated by transforming growth factor beta. This review summarizes mechanisms of oncogenesis by HCV, highlighting the role of oxidative stress and hepatic Nox enzymes in HCC. PMID:24816297

  17. CD40 dependent exacerbation of immune mediated hepatitis by hepatic CD11b+ Gr-1+ myeloid derived suppressor cells in tumor bearing mice

    PubMed Central

    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.

    2015-01-01

    Immunosuppressive CD11b+Gr-1+ myeloid-derived suppressor cells (MDSC) accumulate in the livers of tumor-bearing mice. We studied hepatic MDSC in two murine models of immune mediated hepatitis. Unexpectedly, treatment of tumor bearing mice with Concanavalin A or α-Galactosylceramide resulted in increased ALT and AST serum levels in comparison to tumor free mice. Adoptive transfer of hepatic MDSC into naïve mice exacerbated Concanavalin A induced liver damage. Hepatic CD11b+Gr-1+ cells revealed a polarized pro-inflammatory gene signature after Concanavalin A treatment. An interferon gamma- dependent up-regulation of CD40 on hepatic CD11b+Gr-1+ cells along with an up-regulation of CD80, CD86, and CD1d after Concanavalin A treatment was observed. Concanavalin A treatment resulted in a loss of suppressor function by tumor-induced CD11b+Gr-1+ MDSC as well as enhanced reactive oxygen species-mediated hepatotoxicity. CD40 knockdown in hepatic MDSC led to increased arginase activity upon Concanavalin 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 reactive oxygen species production in vivo. Our findings indicate that in a setting of acute hepatitis, tumor-induced hepatic MDSC act as pro-inflammatory immune effector cells capable of killing hepatocytes in a CD40-dependent manner. PMID:25616156

  18. A Case Report of Supplement-Induced Hepatitis in an Active Duty Service Member.

    PubMed

    Brazeau, Michael J; Castaneda, Joni L; Huitron, Sonny S; Wang, James

    2015-07-01

    The incidence of drug-induced hepatic injury has been increasing as a result of more widespread use of workout supplements containing anabolic steroids to increase muscle mass. Synthetic androgenic steroids are shown to cause cholestatic liver injury, but the exact mechanism of injury is not completely understood. We present a case of a healthy, young, active duty Army male soldier who developed pruritis and jaundice shortly after starting to take a body-building supplement containing anabolic steroids, and was subsequently found to have significant biopsy proven drug-induced liver injury. PMID:26126259

  19. Drug-induced hepatitis

    MedlinePlus

    ... induced hepatitis. Painkillers and fever reducers that contain acetaminophen are a common cause of liver inflammation. These ... problem. However, if you took high doses of acetaminophen , treatment should be started as soon as possible ...

  20. Hepatitis C and sex.

    PubMed

    Page, Emma E; Nelson, Mark

    2016-04-01

    An outbreak of acute hepatitis C among HIV-positive men who have sex with men (MSM) in the last decade has been shown to be sexually transmitted. Initially recreational drug use, in particular drug injection, was not prevalent among those becoming infected with hepatitis C. However more recently chemsex (the use of drugs to enhance sexual experience) and its associated drugs, which are not uncommonly injected, have become more frequently reported among those diagnosed with hepatitis C. It is hoped that the widespread -introduction of direct-acting antivirals and upscaling of numbers treated may have a positive impact on this epidemic. However their introduction may negatively impact on the perceived risk of acquiring hepatitis C and in conjunction with the introduction of HIV transmission prevention strategies may result in increased transmissions and spread to the HIV-negative MSM population. PMID:27037392

  1. Hepatitis C - children

    MedlinePlus

    ... chap 358. Jhaveri R. Hepatitis C virus. In: Cherry JD, Harrison GJ, Kaplan SL, Steinbach WJ, Hotez PJ, eds. Feigin and Cherry's Textbook of Pediatric Infectious Diseases. 7th ed. Philadelphia, ...

  2. Hepatitis Risk Assessment

    MedlinePlus

    ... About the Division of Viral Hepatitis Contact Us File Formats Help: How do I view different file formats (PDF, DOC, PPT, MPEG) on this site? Adobe PDF file Microsoft PowerPoint file Microsoft Word file Microsoft Excel ...

  3. [Patient education of hepatitis].

    PubMed

    Boyer, Dominique; Faillebin, Françoise; de la Brière, Aice

    2013-11-01

    The therapeutic education of patients with hepatitis C helps to improve their health and quality of life. The aim is to encourage compliance with the treatment and the fight against side effects, through to the patient's recovery. PMID:24409616

  4. Hepatitis B - children

    MedlinePlus

    ... kissing, coughing, or sneezing. Breast-feeding by a mother with hepatitis B is safe if the child is treated properly at the time of birth. Teenagers who are not vaccinated can get HBV during unprotected sex or drug use.

  5. Hepatitis B - children

    MedlinePlus

    ... tests detect liver damage and the risk for liver cancer from chronic hepatitis B: Albumin level Liver function tests Prothrombin time Liver biopsy Abdominal ultrasound Liver cancer tumor markers such as alpha fetoprotein The provider ...

  6. HIV and Viral Hepatitis

    MedlinePlus

    ... prevalent among blacks as among whites. Viral Hepatitis Transmission People can be infected with the three most ... risk for HAV. • • New data suggest that sexual transmission of HCV among MSM with HIV occurs more ...

  7. Hepatitis A FAQs

    MedlinePlus

    ... 185°F (85°C), kill the virus, although freezing temperatures do not. Symptoms Does Hepatitis A cause ... food, such as drinking beverages (with or without ice) of unknown purity, eating uncooked shellfish, and eating ...

  8. Chemoembolization of hepatic malignancy.

    PubMed

    Gonsalves, Carin F; Brown, Daniel B

    2009-01-01

    Treatment of primary and secondary hepatic malignancies with transarterial chemoembolization represents an essential component of interventional oncology. This article discusses patient selection, procedure technique, results, and complications associated with transarterial chemoembolization. PMID:18668189

  9. Imaging of hepatic infections.

    PubMed

    Doyle, D J; Hanbidge, A E; O'Malley, M E

    2006-09-01

    Imaging plays a significant role in the detection, characterization and treatment of hepatic infections. Infectious diseases of the liver include pyogenic and amoebic abscesses and parasitic, fungal, viral and granulomatous infections. With increases in worldwide travel, immunosuppression and changing population demographics, identification of cases of hepatic infection is becoming more common in daily practice. Knowledge of the imaging features seen with hepatic infections can assist in early diagnosis and timely initiation of appropriate therapy. This review presents the imaging appearances of hepatic infections, emphasizing specific features that may contribute to the diagnosis. Examples of the imaging findings seen with pyogenic and amoebic abscesses, infection with Echinococcus granulosus (Hydatid), schistosomiasis, candidiasis and tuberculosis (TB) are presented. PMID:16905380

  10. Human hereditary hepatic porphyrias.

    PubMed

    Nordmann, Yves; Puy, Hervé

    2002-11-01

    The human hereditary hepatic porphyrias are diseases due to marked deficiencies of enzymes in the heme biosynthetic pathway. Porphyrias can be classified as either hepatic or erythroid, depending on the major production site of porphyrins or their precursors. The pathogenesis of inherited hepatic porphyrias has now been defined at the molecular level. Some gene carriers are vulnerable to a range of exogenous and endogenous factors, which may trigger neuropsychiatric and/or cutaneous symptoms. Early diagnosis is of prime importance since it makes way for counselling. In this article we present an overview of recent advances on hepatic porphyrias: 5-aminolevulinic acid dehydratase deficiency porphyria, acute intermittent porphyria (AIP), porphyria cutanea tarda (PCT), hereditary coproporphyria (HC), and variegate porphyria (VP). PMID:12367763

  11. Hepatitis D Virus Replication.

    PubMed

    Taylor, John M

    2015-11-01

    This work reviews specific related aspects of hepatitis delta virus (HDV) reproduction, including virion structure, the RNA genome, the mode of genome replication, the delta antigens, and the assembly of HDV using the envelope proteins of its helper virus, hepatitis B virus (HBV). These topics are considered with perspectives ranging from a history of discovery through to still-unsolved problems. HDV evolution, virus entry, and associated pathogenic potential and treatment of infections are considered in other articles in this collection. PMID:26525452

  12. Electrical Injuries

    MedlinePlus

    ... your injuries are depends on how strong the electric current was, what type of current it was, how it moved through your body, and how long you were exposed. Other factors include how ... you should see a doctor. You may have internal damage and not realize it.

  13. Inhalation Injuries

    MedlinePlus

    ... increase mortality 30% to 40% when patients with cutaneous burns and inhalation injury are compared with patients ... nasal hairs • Facial burns • Burns around the mouth • Mineral spirits – 104º F – paint thinner, brush cleaner. • Redness, ...

  14. Multimodal brain monitoring in fulminant hepatic failure

    PubMed Central

    Paschoal Jr, Fernando Mendes; Nogueira, Ricardo Carvalho; Ronconi, Karla De Almeida Lins; de Lima Oliveira, Marcelo; Teixeira, Manoel Jacobsen; Bor-Seng-Shu, Edson

    2016-01-01

    Acute liver failure, also known as fulminant hepatic failure (FHF), embraces a spectrum of clinical entities characterized by acute liver injury, severe hepatocellular dysfunction, and hepatic encephalopathy. Cerebral edema and intracranial hypertension are common causes of mortality in patients with FHF. The management of patients who present acute liver failure starts with determining the cause and an initial evaluation of prognosis. Regardless of whether or not patients are listed for liver transplantation, they should still be monitored for recovery, death, or transplantation. In the past, neuromonitoring was restricted to serial clinical neurologic examination and, in some cases, intracranial pressure monitoring. Over the years, this monitoring has proven insufficient, as brain abnormalities were detected at late and irreversible stages. The need for real-time monitoring of brain functions to favor prompt treatment and avert irreversible brain injuries led to the concepts of multimodal monitoring and neurophysiological decision support. New monitoring techniques, such as brain tissue oxygen tension, continuous electroencephalogram, transcranial Doppler, and cerebral microdialysis, have been developed. These techniques enable early diagnosis of brain hemodynamic, electrical, and biochemical changes, allow brain anatomical and physiological monitoring-guided therapy, and have improved patient survival rates. The purpose of this review is to discuss the multimodality methods available for monitoring patients with FHF in the neurocritical care setting. PMID:27574545

  15. Multimodal brain monitoring in fulminant hepatic failure.

    PubMed

    Paschoal, Fernando Mendes; Nogueira, Ricardo Carvalho; Ronconi, Karla De Almeida Lins; de Lima Oliveira, Marcelo; Teixeira, Manoel Jacobsen; Bor-Seng-Shu, Edson

    2016-08-01

    Acute liver failure, also known as fulminant hepatic failure (FHF), embraces a spectrum of clinical entities characterized by acute liver injury, severe hepatocellular dysfunction, and hepatic encephalopathy. Cerebral edema and intracranial hypertension are common causes of mortality in patients with FHF. The management of patients who present acute liver failure starts with determining the cause and an initial evaluation of prognosis. Regardless of whether or not patients are listed for liver transplantation, they should still be monitored for recovery, death, or transplantation. In the past, neuromonitoring was restricted to serial clinical neurologic examination and, in some cases, intracranial pressure monitoring. Over the years, this monitoring has proven insufficient, as brain abnormalities were detected at late and irreversible stages. The need for real-time monitoring of brain functions to favor prompt treatment and avert irreversible brain injuries led to the concepts of multimodal monitoring and neurophysiological decision support. New monitoring techniques, such as brain tissue oxygen tension, continuous electroencephalogram, transcranial Doppler, and cerebral microdialysis, have been developed. These techniques enable early diagnosis of brain hemodynamic, electrical, and biochemical changes, allow brain anatomical and physiological monitoring-guided therapy, and have improved patient survival rates. The purpose of this review is to discuss the multimodality methods available for monitoring patients with FHF in the neurocritical care setting. PMID:27574545

  16. Immigration and viral hepatitis.

    PubMed

    Sharma, Suraj; Carballo, Manuel; Feld, Jordan J; Janssen, Harry L A

    2015-08-01

    WHO estimates reveal that the global prevalence of viral hepatitis may be as high as 500 million, with an annual mortality rate of up to 1.3 million individuals. The majority of this global burden of disease is borne by nations of the developing world with high rates of vertical and iatrogenic transmission of HBV and HCV, as well as poor access to healthcare. In 2013, 3.2% of the global population (231 million individuals) migrated into a new host nation. Migrants predominantly originate from the developing countries of the south, into the developed economies of North America and Western Europe. This mass migration of individuals from areas of high-prevalence of viral hepatitis poses a unique challenge to the healthcare systems of the host nations. Due to a lack of universal standards for screening, vaccination and treatment of viral hepatitis, the burden of chronic liver disease and hepatocellular carcinoma continues to increase among migrant populations globally. Efforts to increase case identification and treatment among migrants have largely been limited to small outreach programs in urban centers, such that the majority of migrants with viral hepatitis continue to remain unaware of their infection. This review summarizes the data on prevalence of viral hepatitis and burden of chronic liver disease among migrants, current standards for screening and treatment of immigrants and refugees, and efforts to improve the identification and treatment of viral hepatitis among migrants. PMID:25962882

  17. Delta hepatitis in Malaysia.

    PubMed

    Sinniah, M; Dimitrakakis, M; Tan, D S

    1986-06-01

    Sera from one hundred and fifty nine Malaysian individuals were screened for the prevalence of delta markers. These included 15 HBsAg positive homosexuals, 16 acute hepatitis B cases, 9 chronic hepatitis B patients, 13 healthy HBsAg carriers and 106 intravenous (i.v.) drug abusers, of whom 27 were positive for HBsAg only and the rest were anti-HBc IgG positive but HBsAg negative. The prevalence of delta markers in the homosexuals was found to be 6.7%, in the HBsAg positive drug abusers 17.8%, in acute hepatitis B cases 12.5%. No evidence of delta infection was detected in healthy HBsAg carriers, chronic hepatitis B cases and HBsAg negative i.v. drug abusers. With reference to i.v. drug abusers, the prevalence of delta markers was higher in Malays (23%) than in Chinese (7%) although the latter had a higher HBsAg carrier rate. Although the HBsAg carrier rate in the homosexuals was high, their delta prevalence rate was low as compared to drug abusers. In Malaysia, as in other non-endemic regions, hepatitis delta virus transmission appeared to occur mainly via the parenteral and sexual routes. This is the first time in Malaysia that a reservoir of delta infection has been demonstrated in certain groups of the population at high risk for hepatitis B. PMID:3787309

  18. Euforia-induced acute hepatitis in a patient with scleroderma.

    PubMed

    Jiménez-Encarnación, Esther; Ríos, Grissel; Muñoz-Mirabal, Angel; Vilá, Luis M

    2012-01-01

    Euforia, a supplement containing a variety of natural ingredients, is widely used as an antioxidant and anti-inflammatory formula. It is not approved by the US Food and Drug Administration and its side effects are unknown. We report a 45-year-old woman with limited systemic sclerosis who presented with jaundice and marked elevation of serum transaminases. One month before, she started taking Euforia juice. A liver biopsy disclosed submassive hepatocellular necrosis with histopathological changes consistent with toxic hepatitis. The patient's symptoms resolved with cessation of Euforia. Six months later, she persisted with abnormal liver function tests, but these resolved 18 months after discontinuation of Euforia. The mechanism by which Euforia causes liver injury is unknown. Some ingredients contained in this supplement (green tea, Aloe vera, noni and goji) are linked to hepatic injury. To our knowledge, this is the first report of hepatotoxicity associated with Euforia. PMID:23257938

  19. Hepatitis after the use of germander, a herbal remedy.

    PubMed Central

    Laliberté, L; Villeneuve, J P

    1996-01-01

    The authors report two cases of hepatic injury associated with the ingestion of germander, a herbal medicine used to facilitate weight loss. In both patients, hepatitis characterized by asthenia, jaundice and a marked increase in serum amino-transferase levels occurred after 5 to 6 months of germander use. The jaundice disappeared within 8 weeks after germander use was stopped, and the overall outcome was favourable. The subsequent resumption of germander therapy by one patient was soon followed by the recurrence of hepatitis. Similar reports from France have led to the banning of germander in that country. Like several other herbal remedies, germander may be hepatotoxic, and many herbal medicines may not be as safe as the public generally assumes. Images Fig. 1 PMID:8646656

  20. Sphingolipid Therapy in Myocardial Ischemia-Reperfusion Injury

    PubMed Central

    Gundewar, Susheel; Lefer, David J.

    2009-01-01

    Sphingolipids are known to play a significant physiological role in cell growth, cell differentiation, and critical signal transduction pathways. Recent studies have demonstrated a significant role of sphingolipids and their metabolites in the pathogenesis of myocardial ischemia-reperfusion injury. Our laboratory has investigated the cytoprotective effects of N,N,N-Trimethylsphingosine chloride (TMS), a stable N-methylated synthetic sphingolipid analogue on myocardial and hepatic ischemia reperfusion injury in clinically relevant in vivo murine models of ischemia-reperfusion injury. TMS administered intravenously at the onset of ischemia reduced myocardial infarct size in the wild-type and obese (ob/ob) mice. Following myocardial I/R, there was an improvement in cardiac function in the wild-type mice. Additionally, TMS also decreased serum liver enzymes following hepatic I/R in wild-type mice. The cytoprotective effects did not extend to the ob/ob mice following hepatic I/R or to the db/db mice following both myocardial and hepatic I/R. Our data suggests that although TMS is cytoprotective following I/R in normal animals, the cytoprotective actions of TMS are largely attenuated in obese and diabetic animals which may be due to altered signaling mechanisms in these animal models. Here we review the therapeutic role of TMS and other sphingolipids in the pathogenesis of myocardial ischemia reperfusion injury and their possible mechanisms of cardioprotection. PMID:17928150