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Sample records for hepatic cell injury

  1. NKT cells are important mediators of hepatic ischemia-reperfusion injury.

    Richards, James A; Wigmore, Stephen J; Anderton, Stephen M; Howie, Sarah E M

    2017-12-01

    IRI results from the interruption then reinstatement of an organ's blood supply, and this poses a significant problem in liver transplantation and resectional surgery. In this paper, we explore the role T cells play in the pathogenesis of this injury. We used an in vivo murine model of warm partial hepatic IRI, genetically-modified mice, in vivo antibody depletion, adoptive cell transfer and flow cytometry to determine which lymphocyte subsets contribute to pathology. Injury was assessed by measuring serum alanine aminotransfersase (ALT) and by histological examination of liver tissue sections. The absence of T cells (CD3εKO) is associated with significant protection from injury (p=0.010). Through a strategy of antibody depletion it appears that NKT cells (p=0.0025), rather than conventional T (CD4+ or CD8+) (p=0.11) cells that are the key mediators of injury. Our results indicate that tissue-resident NKT cells, but not other lymphocyte populations are responsible for the injury in hepatic IRI. Targeting the activation of NKT cells and/or their effector apparatus would be a novel approach in protecting the liver during transplantation and resection surgery; this may allow us to expand our current criteria for surgery. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  2. Transplantation of autologous bone marrow stem cells via hepatic artery for the treatment of acute hepatic injury: an experimental study in rabbits

    Zhu Yinghe; Han Jinling; Liu Yanping; Gao Jue; Xu Ke; Zhang Xitong; Ding Guomin

    2009-01-01

    Objective: To evaluate the transplantation of autologous bone marrow stem cells via hepatic artery in treating acute hepatic injury in experimental rabbit models and to clarify the synergistic effect of hepatocyte growth-promoting factor (pHGF) in stem cell transplantation therapy for liver injury. Methods Acute hepatic injury models were established in 15 experimental rabbits by daily subcutaneous injection of CCl 4 olive oil solution with the dose of 0.8 ml/kg for 4 days in succession. The experimental rabbits were randomly and equally divided into three groups: study group A (stem cell transplant, n = 5), study group B (stem cell transplant + pFHG, n = 5), and control group (n = 5). Bone marrow of 5 ml was drawn from the tibia in all rabbits of both study groups, from which bone marrow stem cells were isolated by using density gradient centrifugation, and 5 ml cellular suspension was prepared. Under fluoroscopic guidance, catheterization through the femoral artery was performed and the cellular suspension was infused into the liver via the hepatic artery. Only injection of saline was carried out in the rabbits of control group. For the rabbits in group B, pFHG (2.0 mg/kg) was administered intravenously every other day for 20 days. At 2, 4 and 8 weeks after stem cell transplantation, hepatic function was determined. Eight weeks after the transplantation all the rabbits were sacrificed and the liver specimens were collected and sent for pathological examination. Results After stem cell transplantation, the hepatic function was gradually improved.Eight weeks after the transplantation, the activity of AST, ALT and the content of ALB, TBIL were significantly lower than that before the procedure, while the content of GOLB was markedly increased in all rabbits. In addition, the difference in the above parameters between three groups was statistically significant (P < 0.05). Pathologically, the hepatocyte degeneration and the fiberous hyperplasia in the study groups

  3. Influence of Kupffer cell inactivation on cycloheximide-induced hepatic injury

    Kumagai, Kazuyoshi; Kiyosawa, Naoki; Ito, Kazumi; Yamoto, Takashi; Teranishi, Munehiro; Nakayama, Hiroyuki; Manabe, Sunao

    2007-01-01

    In our previous study, we found that cycloheximide (CHX) induces hepatocellular necrosis as well as hepatocellular apoptosis. This article evaluates the role of Kupffer cells on cycloheximide-induced hepatic injury using gadolinium chloride (GdCl 3 ) for the inhibition of Kupffer cells. One group of rats was treated with CHX (CHX group), and another was treated with GdCl 3 before being treated with the same dose of CHX (GdCl 3 /CHX group). The necrotic change in the GdCl 3 /CHX group was exacerbated under the induction of hepatocellular apoptosis by the CHX treatment. A substantial diminution of the number of ED1- or ED2-positive cells was demonstrated in the GdCl 3 /CHX group compared to the CHX group. In addition, the degree of decrease in ED2-positive cells was more apparent than that in ED1-positive cells. Increases in the mRNA levels of IL-10 and Stat3 were observed in the CHX group, but not in the GdCl 3 /CHX group. On the other hand, the hepatic mRNA levels of chemokines and adhesion molecules such as Ccl20, LOX-1, and E-selectin were significantly increased only in the GdCl 3 /CHX group. Thus, Kupffer cell inactivation by the GdCl 3 treatment leads to a loss of the capacity to produce IL-10, supposedly resulting in the enhancement of pro-inflammatory cytokine activities such as tumor necrosis factor (TNF) signaling. These events are suggested to be a factor of the inflammatory exacerbation in the livers of the GdCl 3 /CHX group. In conclusion, Kupffer cells may play a role in protecting hepatic necroinflammatory changes by releasing anti-inflammatory cytokines following the hepatocellular apoptosis resulting from CHX treatment

  4. The let-7/Lin28 axis regulates activation of hepatic stellate cells in alcoholic liver injury.

    McDaniel, Kelly; Huang, Li; Sato, Keisaku; Wu, Nan; Annable, Tami; Zhou, Tianhao; Ramos-Lorenzo, Sugeily; Wan, Ying; Huang, Qiaobing; Francis, Heather; Glaser, Shannon; Tsukamoto, Hidekazu; Alpini, Gianfranco; Meng, Fanyin

    2017-07-07

    The let-7/Lin28 axis is associated with the regulation of key cellular regulatory genes known as microRNAs in various human disorders and cancer development. This study evaluated the role of the let-7/Lin28 axis in regulating a mesenchymal phenotype of hepatic stellate cells in alcoholic liver injury. We identified that ethanol feeding significantly down-regulated several members of the let-7 family in mouse liver, including let-7a and let-7b. Similarly, the treatment of human hepatic stellate cells (HSCs) with lipopolysaccharide (LPS) and transforming growth factor-β (TGF-β) significantly decreased the expressions of let-7a and let-7b. Conversely, overexpression of let-7a and let-7b suppressed the myofibroblastic activation of cultured human HSCs induced by LPS and TGF-β, as evidenced by repressed ACTA2 (α-actin 2), COL1A1 (collagen 1A1), TIMP1 (TIMP metallopeptidase inhibitor 1), and FN1 (fibronectin 1); this supports the notion that HSC activation is controlled by let-7. A combination of bioinformatics, dual-luciferase reporter assay, and Western blot analysis revealed that Lin28B and high-mobility group AT-hook (HMGA2) were the direct targets of let-7a and let-7b. Furthermore, Lin28B deficiency increased the expression of let-7a/let-7b as well as reduced HSC activation and liver fibrosis in mice with alcoholic liver injury. This feedback regulation of let-7 by Lin28B is verified in hepatic stellate cells isolated by laser capture microdissection from the model. The identification of the let-7/Lin28 axis as an important regulator of HSC activation as well as its upstream modulators and down-stream targets will provide insights into the involvement of altered microRNA expression in contributing to the pathogenesis of alcoholic liver fibrosis and novel therapeutic approaches for human alcoholic liver diseases. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  5. Drug-induced hepatic injury

    Friis, Henrik; Andreasen, P B

    1992-01-01

    The Danish Committee on Adverse Drug Reactions received 1100 reports of suspected drug-induced hepatic injury during the decade 1978-1987. The causal relationship between drug and hepatic injury was classified as definite in 57 (5.2%) reports, probable in 989 (89.9%) reports, possible in 50 (4.......5%) reports and unclassifiable in four (0.4%) reports. Hepatic injuries accounted for 5.9% of all adverse drug reactions reported, and 14.7% of the lethal adverse drug reactions. A total of 47.2% were classified as acute cytotoxic, 16.2% as acute cholestatic and 26.9% as abnormal hepatic function. In 52 (4.......7%) cases the hepatic injury was lethal; only 14 (1.3%) cases were chronic. Halothane accounted for 25% of the cases. The incidence of halothane-induced hepatic injury is decreasing, and only one lethal case has been reported since 1981. Next to halothane, sulfasalazine was the drug most often suspected...

  6. Arctigenin protects against liver injury from acute hepatitis by suppressing immune cells in mice.

    Cheng, Xixi; Wang, Huafeng; Yang, Jinlai; Cheng, Yingnan; Wang, Dan; Yang, Fengrui; Li, Yan; Zhou, Dongmei; Wang, Yanxia; Xue, Zhenyi; Zhang, Lijuan; Zhang, Qi; Yang, Luhong; Zhang, Rongxin; Da, Yurong

    2018-06-01

    As a phenylpropanoid and dibenzylbutyrolactone lignan present in medical plants, such as those used in traditional Chinese herbal medicine, including Arctium lappa (Niubang), arctigenin exhibits antimicrobial, anti-inflammatory, and anticancer activities. In this study, we investigated the protective role of arctigenin in Concanavalin A (ConA)-induced acute hepatitis in mice. Arctigenin remarkably reduced the congestion and necroinflammation of livers, and improved hepatic function (ALT and AST) in ConA-induced acute hepatitis in vivo. The infiltration of CD4 T, NKT and macrophages into the livers was found to be reduced with arctigenin treatment. Arctigenin suppressed ConA-induced T lymphocyte proliferations that might have resulted from enhanced IL-10 production by macrophages and CD4 T cells. These results suggested that arctigenin could be a powerful drug candidate for acute hepatitis through immune suppression. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  7. Hepatic Sinusoidal-obstruction Syndrome and Busulfan-induced Lung Injury in a Post-autologous Stem Cell Transplant Recipient.

    Jain, Richa; Gupta, Kirti; Bhatia, Anmol; Bansal, Arun; Bansal, Deepak

    2017-09-15

    Veno-occlusive disease of the liver is mostly encountered as a complication of hematopoietic stem cell transplantation with myeloablative regimens with an incidence estimated to be 13.7%. It is clinically characterized by tender hepatomegaly, jaundice, weight gain and ascites. Strong clinical suspicion and an early recognition of clinical signs are essential to establish the diagnosis and institute effective regimen. Another complication of cytotoxic drugs given for cancers, is development of busulfan-induced lung injury. A strong index of suspicion is needed for its diagnosis, especially in setting where opportunistic fungal and viral infections manifest similarly. We illustrate the clinical and autopsy finings in a 2½-year-old boy who received autologous stem-cell transplantation following resection of stage IV neuroblastoma. He subsequently developed both hepatic veno-occlusive disease and busulfan-induced lung injury. The autopsy findings are remarkable for their rarity.

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

    Renwei Huang

    2016-01-01

    Full Text Available 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.

  9. Hepatic ischemia and reperfusion injury in the absence of myeloid cell-derived COX-2 in mice.

    Sergio Duarte

    Full Text Available Cyclooxygenase-2 (COX-2 is a mediator of hepatic ischemia and reperfusion injury (IRI. While both global COX-2 deletion and pharmacologic COX-2 inhibition ameliorate liver IRI, the clinical use of COX-2 inhibitors has been linked to increased risks of heart attack and stroke. Therefore, a better understanding of the role of COX-2 in different cell types may lead to improved therapeutic strategies for hepatic IRI. Macrophages of myeloid origin are currently considered to be important sources of the COX-2 in damaged livers. Here, we used a Cox-2flox conditional knockout mouse (COX-2-M/-M to examine the function of COX-2 expression in myeloid cells during liver IRI. COX-2-M/-M mice and their WT control littermates were subjected to partial liver ischemia followed by reperfusion. COX-2-M/-M macrophages did not express COX-2 upon lipopolysaccharide stimulation and COX-2-M/-M livers showed reduced levels of COX-2 protein post-IRI. Nevertheless, selective deletion of myeloid cell-derived COX-2 failed to ameliorate liver IRI; serum transaminases and histology were comparable in both COX-2-M/-M and WT mice. COX-2-M/-M livers, like WT livers, developed extensive necrosis, vascular congestion, leukocyte infiltration and matrix metalloproteinase-9 (MMP-9 expression post-reperfusion. In addition, myeloid COX-2 deletion led to a transient increase in IL-6 levels after hepatic reperfusion, when compared to controls. Administration of celecoxib, a selective COX-2 inhibitor, resulted in significantly improved liver function and histology in both COX-2-M/-M and WT mice post-reperfusion, providing evidence that COX-2-mediated liver IRI is caused by COX-2 derived from a source(s other than myeloid cells. In conclusion, these results support the view that myeloid COX-2, including myeloid-macrophage COX-2, is not responsible for the hepatic IRI phenotype.

  10. Role of CT in blunt hepatic injury

    Park, Hyun Joo; Yang, Dal Mo; Kang, Sook Wook; Kim, Hyung Sik; Chung, Hyo Sun; Lee, Young Seok

    1994-01-01

    The aim of this study was to determine the role of the CT scan in blunt hepatic injury and the significance of CT degree of hepatic injury in the decision making of treatment plan. We retrospectively analyzed the CT findings of 22 patients with hepatic injury. We graded hepatic injury on CT scan into five according to the severity. Clinical records, type of management and clinical outcome of the patients were also reviewed. Of the 22 patients, 17 had conservative treatment and five had surgery. The numbers of patients treated conservatively were 0, 4, 11, 2 and 0 in the grade 1, 2, 3, 4, and 5, retrospectively and the numbers of surgically treated cases were 0, 0, 3, 2 and 0 respectively. There was no significant statistical difference between surgically and conservatively treated groups(p-value > 0.05). All patients with conservatively treated group were hemodynamically stable and had no complication during hospitalization. Hemoperitoneum was observed in 11 of 22 patients. In blunt hepatic injury, CT plays an important role in the demonstration of location and extent of the hepatic injury, size of hemoperitoneum and the post operative course. However, we believe that physiologic status of the patients may be more important than the extent of CT based hepatic injury for determining a mode of treatment

  11. Characterization of Microparticles after Hepatic Ischemia-Reperfusion Injury

    Freeman, Christopher M.; Quillin, Ralph C.; Wilson, Gregory C.; Nojima, Hiroyuki; Johnson, Bobby L.; Sutton, Jeffrey M.; Schuster, Rebecca M.; Blanchard, John; Edwards, Michael J.; Caldwell, Charles C.; Lentsch, Alex B.

    2014-01-01

    Background Hepatic ischemia-reperfusion (I/R) is a well-studied model of liver injury and has demonstrated a biphasic injury followed by recovery and regeneration. Microparticles (MPs) are a developing field of study and these small membrane bound vesicles have been shown to have effector function in other physiologic and pathologic states. This study was designed to quantify the levels of MPs from various cell origins–platelets, neutrophils, and endolethial cells–following hepatic ischemia-reperfusion injury. Methods A murine model was used with mice undergoing 90 minutes of partial hepatic ischemia followed by various times of reperfusion. Following reperfusion, plasma samples were taken and MPs of various cell origins were labeled and levels were measured using flow cytometry. Additionally, cell specific MPs were further assessed by Annexin V, which stains for the presence of phosphatidylserine, a cell surface marker linked to apoptosis. Statistical analysis was performed using one-way analysis of variance with subsequent Student-Newman-Keuls test with data presented as the mean and standard error of the mean. Results MPs from varying sources show an increase in circulating levels following hepatic I/R injury. However, the timing of the appearance of different MP subtypes differs for each cell type. Platelet and neutrophil-derived MP levels demonstrated an acute elevation following injury whereas endothelial-derived MP levels demonstrated a delayed elevation. Conclusion This is the first study to characterize circulating levels of cell-specific MPs after hepatic I/R injury and suggests that MPs derived from platelets and neutrophils serve as markers of inflammatory injury and may be active participants in this process. In contrast, MPs derived from endothelial cells increase after the injury response during the reparative phase and may be important in angiogenesis that occurs in the regenerating liver. PMID:24879335

  12. GSK-3β Inhibition Attenuates CLP-Induced Liver Injury by Reducing Inflammation and Hepatic Cell Apoptosis

    Hui Zhang

    2014-01-01

    Full Text Available Liver dysfunction has been known to occur frequently in cases of sepsis. Excessive inflammation and apoptosis are pathological features of acute liver failure. Recent studies suggest that activation of glycogen synthase kinase- (GSK- 3β is involved in inflammation and apoptosis. We aimed to investigate the protective effects of GSK-3β inhibition on polymicrobial sepsis-induced liver injury and to explore the possible mechanisms. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP, and SB216763 was used to inhibit GSK-3β in C57BL/6 mice. GSK-3β was activated following CLP. Administration of SB216763 decreased mortality, ameliorated liver injury, and reduced hepatic apoptosis. The inhibition of GSK-3β also reduced leukocyte infiltration and hepatic inflammatory cytokine expression and release. Moreover, GSK-3β inhibition suppressed the transcriptional activity of nuclear factor-kappa B (NF-κB but enhanced the transcriptional activity of cAMP response element binding protein (CREB in the liver. In in vitro studies, GSK-3β inhibition reduced inflammatory cytokine production via modulation of NF-κB and CREB signaling pathways in lipopolysaccharide-stimulated macrophages. In conclusion, these findings suggest that GSK-3β blockade protects against CLP-induced liver via inhibition of inflammation by modulating NF-κB and CREB activity and suppression of hepatic apoptosis.

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

    Raimundo Fernandes de Araújo Júnior

    Full Text Available To evaluate the anti-inflammatory, anti-oxidant and antifibrotic effects of carvedilol (CARV in rats with ethanol-induced liver injury.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.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-α, procollagen type I (PCI, procollagen

  14. Continuous cell injury promotes hepatic tumorigenesis in cdc42-deficient mouse liver

    van Hengel, Jolanda; D'Hooge, Petra; Hooghe, Bart

    2008-01-01

    be required for liver function. METHODS: Mice in which Cdc42 was ablated in hepatocytes and bile duct cells were generated by Cre-loxP technology. Livers were examined by histologic, immunohistochemical, ultrastructural, and serum analysis to define the effect of loss of Cdc42 on liver structure. RESULTS...... of 2 months, the canaliculi between hepatocytes were greatly enlarged, although the tight junctions flanking the canaliculi appeared normal. Regular liver plates were absent. E-cadherin expression pattern and gap junction localization were distorted. Analysis of serum samples indicated cholestasis...

  15. Regulator of G-protein signaling-5 is a marker of hepatic stellate cells and expression mediates response to liver injury.

    Arya J Bahrami

    Full Text Available 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.

  16. Bone Marrow-Derived Mesenchymal Stem Cells Attenuate Immune-Mediated Liver Injury and Compromise Virus Control During Acute Hepatitis B Virus Infection in Mice.

    Qu, Mengmeng; Yuan, Xu; Liu, Dan; Ma, Yuhong; Zhu, Jun; Cui, Jun; Yu, Mengxue; Li, Changyong; Guo, Deyin

    2017-06-01

    Mesenchymal stem cells (MSCs) have been used as therapeutic tools not only for their ability to differentiate toward different cells, but also for their unique immunomodulatory properties. However, it is still unknown how MSCs may affect immunity during hepatitis B virus (HBV) infection. This study was designed to explore the effect of bone marrow-derived MSCs (BM-MSCs) on hepatic natural killer (NK) cells in a mouse model of acute HBV infection. Mice were injected with 1 × 10 6 BM-MSCs, which stained with chloromethyl derivatives of fluorescein diacetate fluorescent probe, 24 h before hydrodynamic injection of viral DNA (pHBV1.3) through the tail vein. In vivo imaging system revealed that BM-MSCs were accumulated in the injured liver, and they attenuated immune-mediated liver injury during HBV infection, as shown by lower alanine aminotransferase levels, reduced proinflammatory cytokine production, and decreased inflammatory cell infiltration in the liver. Importantly, administration of BM-MSCs restrained the increased expression of natural-killer group 2, member D (NKG2D), an important receptor required for NK cell activation in the liver from HBV-infected mice. BM-MSCs also reduced NKG2D expression on NK cells and suppressed the cytotoxicity of NK cells in vitro. Furthermore, BM-MSC-derived transforming growth factor-β1 suppressed NKG2D expression on NK cells. As a consequence, BM-MSC treatment enhanced HBV gene expression and replication in vivo. These results demonstrate that adoptive transfer of BM-MSCs influences innate immunity and limits immune-mediated liver injury during acute HBV infection by suppressing NK cell activity. Meanwhile, the effect of BM-MSCs on prolonging virus clearance needs to be considered in the future.

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

    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.

  18. Nuclear imaging of hepatic impact injury on rabbits

    Jin Rongbing; Wen Jianliang; Tang Weijia; Ma Xiaolin

    2002-01-01

    Objective: To investigate the effect and clinic application value of nuclear imaging on hepatic impact experiment. Methods: Experimental rabbits were impact injured on liver with BIM-IV bio-impact machine. Liver imaging was performed with sodium phytate labeled by 99m Tc. Liver blood pool imaging was performed with labeled red blood cells. The results of imaging were similar with the results of anatomy. Results: There were significant difference between normal liver and injured liver. Radio diminution and defect were showed on injured liver areas in labeled hepatic cells. Many types of abnormal radioactivity distribution were observed in liver pool imaging. The results of liver imaging and liver blood pool imaging were corresponded to the results of anatomy. Conclusion: Changes of hepatic cell structures and function after injury could be showed by nuclear imaging. Nuclear imaging was valuable in determining injured liver position or injured degree

  19. Tumor Necrosis Factor-producing T-regulatory Cells Are Associated With Severe Liver Injury in Patients With Acute Hepatitis A.

    Choi, Yoon Seok; Jung, Min Kyung; Lee, Jeewon; Choi, Seong Jin; Choi, Sung Hoon; Lee, Hyun Woong; Lee, Jong-Joo; Kim, Hyung Joon; Ahn, Sang Hoon; Lee, Dong Hyeon; Kim, Won; Park, Su-Hyung; Huh, Jun R; Kim, Hyoung-Pyo; Park, Jun Yong; Shin, Eui-Cheol

    2018-03-01

    CD4 + CD25 + Foxp3 + T-regulatory (Treg) cells control immune responses and maintain immune homeostasis. However, under inflammatory conditions, Treg cells produce cytokines that promote inflammation. We investigated production of tumor necrosis factor (TNF) by Treg cells in patients with acute hepatitis A (AHA), and examined the characteristics of these cells and association with clinical factors. We analyzed blood samples collected from 63 patients with AHA at the time of hospitalization (and some at later time points) and 19 healthy donors in South Korea. Liver tissues were collected from patients with fulminant AHA during liver transplantation. Peripheral blood mononuclear cells were isolated from whole blood and lymphocytes were isolated from liver tissues and analyzed by flow cytometry. Cytokine production from Treg cells (CD4 + CD25 + Foxp3 + ) was measured by immunofluorescence levels following stimulation with anti-CD3 and anti-CD28. Epigenetic stability of Treg cells was determined based on DNA methylation patterns. Phenotypes of Treg cells were analyzed by flow cytometry and an RORγt inhibitor, ML-209, was used to inhibit TNF production. Treg cell suppression assay was performed by co-culture of Treg-depleted peripheral blood mononuclear cells s and isolated Treg cells. A higher proportion of CD4 + CD25 + Foxp3 + Treg cells from patients with AHA compared with controls produced TNF upon stimulation with anti-CD3 and anti-CD28 (11.2% vs 2.8%). DNA methylation analysis confirmed the identity of the Treg cells. TNF-producing Treg cells had features of T-helper 17 cells, including up-regulation of RORγt, which was required for TNF production. The Treg cells had reduced suppressive functions compared with Treg cells from controls. The frequency of TNF-producing Treg cells in AHA patients' blood correlated with their serum level of alanine aminotransferase. Treg cells from patients with AHA have altered functions compared with Treg cells from healthy

  20. Coagulation defects in experimental hepatic injury in the dog.

    Osbaldiston, G W; Hoffman, M W

    1971-04-01

    Alteration in activity of blood coagulation factors in dogs with acute hepatic injury caused by oral carbon tetrachloride dosing was studied. Coagulation Factors II, VII and IX were dramatically reduced within 48 hours but recovered to normal in the next five days. Because surgery is rarely performed on dogs with hepatic necrosis, the use of fresh whole blood tranfusion to improve the coagulation defect in hepatic injury was also studied. Transfusion was found to have only a temporary beneficial effect.

  1. CT and MRI diagnosis of acute hepatic injury

    Wang Rengui; Fumio Yamamoto; Pu Yonglin; Gao Yujie.

    1997-01-01

    To evaluate and compare MR and CT in diagnosis of acute traumatic hepatic laceration, ten patients with acute hepatic rupture underwent CT scan and/or MRI in the first 24 hours after injury. The injury was graded as mild ( 50% of one lobe). In the first 24 hours after injury, 33.3% (3/9) and 28.6%(2/7) of the hepatic injury demonstrated isodensity and isointensity on plain CT scan and T 1 -weighted images. All the lesions (100%) were clearly identified as marked hyperintensity on T 2 -weighted images. On T 2 WI, T 1 WI and non-contrast CT, 100%, 57.1% and 55.6% of the acute hepatic injuries could be graded respectively. Delayed complications occurred in four patients with deep hepatic injury about 1 to 3 weeks after injury. T 2 -weighted MR imaging is more sensitive and useful for detection of the type and severity of acute hepatic rupture. Follow-up MRI or CT within the first few weeks after injury is needed in patients with deep hepatic injury for detection of delayed complications

  2. Dynamic movement of cytochrome c from mitochondria into cytosol and peripheral circulation in massive hepatic cell injury.

    Kobayashi, Yoshinori; Mori, Masaaki; Naruto, Takuya; Kobayashi, Naoki; Sugai, Toshiyuki; Imagawa, Tomoyuki; Yokota, Shumpei

    2004-12-01

    In the process of apoptosis, it is known that the transition of cytochrome c from mitochondria into the cytosol occurs, and tumor necrosis factor (TNF)-alpha is one of the molecules responsible for this event. But in the state of hypercytokine induced by D-galactosamine (D-GaIN)/Lipopolysaccharide (LPS), the localization of cytochrome c is little known. Rats were administrated with D-GaIN(700 mg/kg)/LPS(200 microg/kg). Blood and tissue samples were collected and examined for levels of pro-inflammatory cytokines, the apoptosis of liver cells, and the localization of cytochrome c. Before administration of D-GaIN/LPS, cytochrome c was definitely localized in the mitochondria. At 2 h after simultaneous administration of D-GaIN/LPS, cytochrome c had accumulated in the cytosol following abrupt increases of plasma TNF-alpha. Massive cell destruction due to apoptosis proved by Terminal deoxynucleo-tidyl transferase-mediated dUTP nick end labeling staining was observed in liver tissue 4 h later and markedly increased levels of cytochrome c were detected in the plasma 12 h after D-GaIN/LPS administration. Liver injury induced by simultaneous administration of D-GaIN/LPS was closely associated with the production of TNF-alpha, and also with the dynamic movement of cytochrome c from the mitochondria into the cytosol, and then into the systemic circulation. The detection of plasma cytochrome c levels may be a useful clinical tool for the detection of apoptosis in vivo.

  3. The role of computed tomography in blunt hepatic injury

    Kaji, Tatsumi

    1988-01-01

    Computed tomography (CT) images and medical records of 283 patients with blunt abdominal trauma were reviewed. There were 67 patients with hepatic injury. Liver was the most frequently injured organ in blunt abdominal trauma. Most hepatic injuries occurred in the right lobe of the liver. Of the 67 patients with hepatic injury, 60 patients had associated other injuries. There was a high incidence of associated lung injuries (35.8 %). Of importance is the high incidence of associated head injuries (22.4 %), because, in some patients such as those with concomitant head trauma, abdominal symptom is not obvious. The associated hemoperitoneum were correlated with the mode of therapy used in each case (operative vs. nonoperative). 32 patients with hepatic injury but no hemoperitoneum were managed nonoperatively. 9 patients with hepatic injury and little hemoperitoneum were also managed conservatively. 22 patients with high density hemoperitoneum were surgically treated. By combining information on the clinical state of the patient and CT finding, therapy of hepatic injury can be individualized and the incidence of nontherapeutic laparotomies decreased. (author)

  4. Exosomes from Human-Induced Pluripotent Stem Cell-Derived Mesenchymal Stromal Cells (hiPSC-MSCs) Protect Liver against Hepatic Ischemia/ Reperfusion Injury via Activating Sphingosine Kinase and Sphingosine-1-Phosphate Signaling Pathway.

    Du, Yingdong; Li, Dawei; Han, Conghui; Wu, Haoyu; Xu, Longmei; Zhang, Ming; Zhang, Jianjun; Chen, Xiaosong

    2017-01-01

    This study aimed to evaluate the effects of exosomes produced by human-induced pluripotent stem cell-derived mesenchymal stromal cells (hiPSC-MSCs-Exo) on hepatic ischemia-reperfusion (I/R) injury, as well as the underlying mechanisms. Exosomes derived from hiPSC-MSCs were isolated and characterized both biochemically and biophysically. hiPSC-MSCs-Exo were injected systemically into a murine ischemia/reperfusion injury model via the inferior vena cava, and then the therapeutic effects were evaluated. The serum levels of transaminases (aspartate aminotransferase (AST) and alanine aminotransferase (ALT), as well as histological changes were examined. Primary hepatocytes and human hepatocyte cell line HL7702 were used to test whether exosomes could induce hepatocytes proliferation in vitro. In addition, the expression levels of proliferation markers (proliferation cell nuclear antigen, PCNA; Phosphohistone-H3, PHH3) were measured by immunohistochemistry and Western blot. Moreover, SK inhibitor (SKI-II) and S1P1 receptor antagonist (VPC23019) were used to investigate the role of sphingosine kinase and sphingosine-1-phosphate-dependent pathway in the effects of hiPSC-MSCs-Exo on hepatocytes. hiPSCs were efficiently induced into hiPSC-MSCs that had typical MSC characteristics. hiPSC-MSCs-Exo had diameters ranging from 100 to 200 nm and expressed exosome markers (Alix, CD63 and CD81). After hiPSC-MSCs-Exo administration, hepatocyte necrosis and sinusoidal congestion were markedly suppressed in the ischemia/reperfusion injury model, with lower histopathological scores. The levels of hepatocyte injury markers AST and ALT were significantly lower in the treatment group compared to control, and the expression levels of proliferation markers (PCNA and PHH3) were greatly induced after hiPSC-MSCs-Exo administration. Moreover, hiPSC-MSCs-Exo also induced primary hepatocytes and HL7702 cells proliferation in vitro in a dose-dependent manner. We found that hiPSC-MSCs-Exo could

  5. Syncytial giant-cell hepatitis due to autoimmune hepatitis type II (LKM1+) presenting as subfulminant hepatitis.

    Ben-Ari, Z; Broida, E; Monselise, Y; Kazatsker, A; Baruch, J; Pappo, O; Skappa, E; Tur-Kaspa, R

    2000-03-01

    Giant cell hepatitis (GCH) in adults is a rare event. The diagnosis of GCH is based on findings of syncytial giant hepatocytes. It is commonly associated with either viral infection or autoimmune hepatitis type I. A patient with GCH due to autoimmune hepatitis type II (LKM1+) is described, a combination that has not been previously reported. Corticosteroid therapy was effective in decreasing serum liver enzymes; however, the patient deteriorated rapidly and developed subfulminant hepatic failure. Although an emergency orthotopic liver transplantation was performed, the patient died because of reperfusion injury. Interestingly, only a few giant hepatocytes were noted in the explanted liver. This case stresses the association of GCH with autoimmune disorders, the possible immune mechanism involved in the formation of giant cell hepatocytes, and illustrates the rapidly progressive course and unfavorable prognosis that these patients can develop.

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

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

    2016-05-01

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

  7. Application of radionuclide imaging to hepatic impact injury in rabbits

    金榕兵; 麻晓林; 温建良; 唐维佳

    2004-01-01

    Objective: To investigate the role and clinical value of radionuclide imaging in hepatic impact injuries in rabbits.Methods: Rabbits were experimentally impacted on the liver with BIM-IV bio-impact machine. Liver imaging was performed with 99mTc labeled sodium phytate. Liver blood pool imaging was performed with 99mTc -stannous pyrophosphate labeled red blood cells. The results of radionuclide imaging were compared with the anatomic results.Results: There was significant difference between the images of the injured liver and the control. Radio diminution and defect were shown in the injured liver areas. Various sorts of abnormal radioactivity distribution were observed with hepatic blood pool imaging. The results of the liver imaging and liver blood pool imaging were accorded with the results of the anatomic findings.Conclusions: Radionuclide imaging may well display the changes of hepatocellular structures and functions after injury, which is valuable in locating the concrete injured position and differentiating the injured degrees of liver.

  8. Hepatic enzymes have a role in the diagnosis of hepatic injury after blunt abdominal trauma.

    Tan, Ker-Kan; Bang, Shieh-Ling; Vijayan, Appasamy; Chiu, Ming-Terk

    2009-09-01

    Delayed diagnosis of patients with severe liver injuries is associated with an adverse outcome. As computed tomographic (CT) scan is not always available in the management of blunt abdominal trauma worldwide, the present study was undertaken to determine the accuracy of selected haematological markers in predicting the presence of hepatic injury and its severity after blunt abdominal trauma. A retrospective review of all patients with blunt abdominal trauma presented to our institution over a 3-year period was performed. Patients were excluded if they suffered penetrating injuries, died in the emergency department or if the required blood tests were not performed within 24h of the accident. The grading of the hepatic injury was verified using CT scans or surgical findings. Ninety-nine patients with blunt abdominal trauma had the required blood tests performed and were included in the study. The median injury severity score was 24 (range 4-75). Fifty-five patients had hepatic injuries, of which 47.3% were minor (Grades I and II) while 52.7% had major hepatic injuries (Grades III-V). There were no patients with Grade VI injuries. A raised ALT was strongly associated with presence of hepatic injuries (OR, 109.8; 95% CI, 25.81-466.9). This relation was also seen in patients with raised AST>2 times (OR, 21.33; 95% CI, 7.27-62.65). This difference was not seen in both bilirubin and ALP. ALT>2 times normal was associated with major hepatic injuries (OR, 7.15; 95% CI, 1.38-37.14; p=0.012) while patients with simultaneous raised AST>2 times and ALT>2 times had a stronger association for major hepatic injuries (OR, 8.44; 95% CI, 1.64-43.47). Abnormal transaminases levels are associated with hepatic injuries after blunt abdominal trauma. Patients with ALT and AST>2 times normal should be assumed to possess major hepatic trauma and managed accordingly. Patients with normal ALT, AST and LDH are unlikely to have major liver injuries.

  9. Two clinically relevant pressures of carbon dioxide pneumoperitoneum cause hepatic injury in a rabbit model

    Li, Jun; Liu, Ying-Hai; Ye, Zhan-Yong; Liu, He-Nian; Ou, Shan; Tian, Fu-Zhou

    2011-01-01

    AIM: To observe the hepatic injury induced by carbon dioxide pneumoperitoneum (CDP) in rabbits, compare the effects of low- and high-pressure pneumoperitoneum, and to determine the degree of hepatic injury induced by these two clinically relevant CDP pressures.

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

    Rendong Zheng

    2015-01-01

    Full Text Available 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.

  11. Hepatic drug clearance following traumatic injury.

    Slaughter, R L; Hassett, J M

    1985-11-01

    Trauma is a complex disease state associated with physiologic changes that have the potential to alter hepatic drug clearance mechanisms. These responses include alterations in hepatic blood flow, reduction in hepatic microsomal activity, reduction in hepatic excretion processes, and changes in protein binding. Hepatic blood flow is influenced by sympathomimetic activity. Both animal and human studies demonstrate an initial reduction and subsequent increase in hepatic blood flow, which coincides with an observed increase and subsequent return to normal in serum catecholamine concentrations. Unfortunately, there are no human studies that address the importance these findings may have to the clearance processes of high intrinsic clearance compounds. Animal studies of trauma indicate that hepatic microsomal activity is depressed during the post-traumatic period. Reduction in the hepatic clearance of antipyrine, a model low intrinsic compound, has also been demonstrated in animal models of trauma. In addition to these effects, hepatic excretion of substances such as indocyanine green and bilirubin have been demonstrated to be impaired in both traumatized animals and humans. Finally, substantial increases in the serum concentration of the binding protein alpha 1-acid glycoprotein occur in trauma patients. This has been reported to be associated with subsequent decreases in the free fraction of lidocaine and quinidine. In addition to changing serum drug concentration/response relationships, the pharmacokinetic behavior of drugs bound to alpha 1-acid glycoprotein should also change. Preliminary observations in our laboratory in a dog model of surgically-induced trauma have shown a reduction in the total clearance of lidocaine and reduction in free lidocaine concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

  12. Hepatic macrophage complement receptor clearance function following injury.

    Cuddy, B G; Loegering, D J; Blumenstock, F A; Shah, D M

    1986-03-01

    Previous work has demonstrated that in vivo hepatic macrophage complement receptor clearance function is depressed following thermal injury. The present study was carried out to determine if complement receptor function depression is associated with other states of depressed host defense. Hepatic complement receptor clearance function was determined from the hepatic uptake of rat erythrocytes coated with antierythrocyte IgM (EIgM) in rats. Receptor function was determined following cannulation of a carotid artery, laparotomy plus enterotomy, hemorrhagic shock, trauma, thermal injury, acute bacteremia, acute endotoxemia, and injection of erythrocyte stroma, gelatinized lipid emulsion, or colloidal carbon. Hepatic uptake of EIgM was depressed following each of these experimental interventions except arterial cannulation. This effect was shown not to be due to a decrease in hepatic blood flow or depletion of complement and was therefore due to a depression in hepatic macrophage complement receptor clearance function. Thus, impairment of hepatic macrophage complement receptor function is associated with several states of depressed host defense.

  13. Mesh wrapping for severe hepatic injury: a beneficial option in the trauma surgeon's armamentarium.

    Kennedy, Ryan; Brevard, Sidney B; Bosarge, Patrick; Simmons, Jon D; Frotan, Mohammed A; Baker, Jeremy A; Tuart, Lynda; Pritchett, Cindy; Gonzalez, Richard P

    2015-03-01

    The purpose of this study was to assess the efficacy of absorbable mesh wrapping (MW) versus perihepatic packing (HP) for severe hepatic injury. From January 2001 to December 2012, data were collected for MW patients with hepatic injury. Patients who underwent HP were matched with MW patients by injury mechanism, liver injury grade, Injury Severity Score, and age. Twenty-six MW and twenty-six HP patients were matched. Eighteen blunt and 8 penetrating injuries were present in each group. There were 9 (35%) mortalities in the MW group and 16 (62%) in the HP groups (P = .03). Average transfusions were 12.0 and 24.5 (P = .03) packed red blood cells in the MW and HP groups, respectively. Average laparotomies per survivors were 1.3 for the MW and 3.1 for the HP groups (P = .01). Average length of stay for survivors was 19 and 47 (P = .04) days in the MW and HP groups, respectively. MW for hepatic injuries can significantly decrease mortality, transfusions, laparotomies, and length of stay. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Modulation of hepatic stellate cells and reversibility of hepatic fibrosis

    Huang, Yu, E-mail: 1293363632@QQ.com [Faculty of Graduate Studies of Guangxi University of Chinese Medicine, Nanning 530001, Guangxi Zhuang Autonomous Region (China); Deng, Xin, E-mail: Hendly@163.com [Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, 10 East China Road, Nanning 530011, Guangxi Zhuang Autonomous Region (China); Liang, Jian, E-mail: lj99669@163.com [Guangxi University of Chinese Medicine, Nanning 530001, Guangxi Zhuang Autonomous Region (China)

    2017-03-15

    Hepatic fibrosis (HF) is the pathological component of a variety of chronic liver diseases. Hepatic stellate cells (HSC) are the main collagen-producing cells in the liver and their activation promotes HF. If HSC activation and proliferation can be inhibited, HF occurrence and development can theoretically be reduced and even reversed. Over the past ten years, a number of studies have addressed this process, and here we present a review of HSC modulation and HF reversal. - Highlights: • We present a review of the modulation of hepatic stellate cells (HSC) and reversibility of hepatic fibrosis (HF). • HSC are the foci of HF occurrence and development, HF could be prevented and treated by modulating HSC. • If HSC activation and proliferation can be inhibited, HF could theoretically be inhibited and even reversed. • Prevention or reversal of HSC activation, or promotion of HSC apoptosis, immune elimination, and senescence may prevent, inhibit or reverse HF.

  15. Serum sphingomyelin has potential to reflect hepatic injury in chronic hepatitis B virus infection

    Su-Jun Zheng; Feng Qu; Jun-Feng Li; Jing Zhao; Jing-Yun Zhang; Mei Liu; Feng Ren; Yu Chen; Jin-Lan Zhang; Zhong-Ping Duan

    2015-01-01

    Objective: To explore the relation between serum sphingolipids and hepatic injury in chronic HBV infection. Methods: A cohort of participants including 48 healthy persons, 103 chronic HBV-infected patients containing chronic hepatitis B (CHB) and HBV-related cirrhosis were included. High performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) was performed to detect serum sphingolipids. The serological indicators were detected and quantified. The valid liver biop...

  16. Glutathione and antioxidant enzymes serve complementary roles in protecting activated hepatic stellate cells against hydrogen peroxide-induced cell death

    Dunning, Sandra; Rehman, Atta Ur; Tiebosch, Marjolein H.; Hannivoort, Rebekka A.; Haijer, Floris W.; Woudenberg, Jannes; van den Heuvel, Fiona A. J.; Buist-Homan, Manon; Faber, Klaas Nico; Moshage, Han

    2013-01-01

    Background: In chronic liver disease, hepatic stellate cells (HSCs) are activated, highly proliferative and produce excessive amounts of extracellular matrix, leading to liver fibrosis. Elevated levels of toxic reactive oxygen species (ROS) produced during chronic liver injury have been implicated

  17. Maraviroc attenuates trauma-hemorrhage-induced hepatic injury through PPAR gamma-dependent pathway in rats.

    Fu-Chao Liu

    Full Text Available Maraviroc is a CC-chemokine receptor 5 (CCR5 antagonist with potent antiviral and cancer preventive effects. Recent evidence suggests that the co-existence of CCR5 in various cell types is involved in inflammation. However, the effects that CCR5 antagonists produce in trauma-hemorrhage remain unknown. The peroxisome proliferator-activated receptor gamma (PPAR(γ pathway exerts anti-inflammatory effects in injury. In this study, we hypothesized that maraviroc administration in male rats, after trauma-hemorrhage, decreases cytokine production and protects against hepatic injury through a PPAR(γ-dependent pathway. 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 maraviroc (3 mg/kg, intravenously with and without a PPAR(γ antagonist GW9662 (1 mg/kg, intravenously, GW9662 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 maraviroc-treated rats subjected to trauma-hemorrhage. Maraviroc treatment also increased hepatic PPAR(γ expression compared with vehicle-treated trauma-hemorrhaged rats. Co-administration of GW9662 with maraviroc abolished the maraviroc-induced beneficial effects on the above parameters and hepatic injury. These results suggest that the protective effect of maraviroc administration on alleviation of hepatic injury after trauma-hemorrhage, which is, at least in part, through PPAR(γ-dependent pathway.

  18. Ethyl Pyruvate Ameliorates Hepatic Ischemia-Reperfusion Injury by Inhibiting Intrinsic Pathway of Apoptosis and Autophagy

    Miao Shen

    2013-01-01

    Full Text Available Background. Hepatic ischemia-reperfusion (I/R injury is a pivotal clinical problem occurring in many clinical conditions such as transplantation, trauma, and hepatic failure after hemorrhagic shock. Apoptosis and autophagy have been shown to contribute to cell death in hepatic I/R injury. Ethyl pyruvate, a stable and simple lipophilic ester, has been shown to have anti-inflammatory properties. In this study, the purpose is to explore both the effect of ethyl pyruvate on hepatic I/R injury and regulation of intrinsic pathway of apoptosis and autophagy. Methods. Three doses of ethyl pyruvate (20 mg/kg, 40 mg/kg, and 80 mg/kg were administered 1 h before a model of segmental (70% hepatic warm ischemia was established in Balb/c mice. All serum and liver tissues were obtained at three different time points (4 h, 8 h, and 16 h. Results. Alanine aminotransferase (ALT, aspartate aminotransferase (AST, and pathological features were significantly ameliorated by ethyl pyruvate (80 mg/kg. The expression of Bcl-2, Bax, Beclin-1, and LC3, which play an important role in the regulation of intrinsic pathway of apoptosis and autophagy, was also obviously decreased by ethyl pyruvate (80 mg/kg. Furthermore, ethyl pyruvate inhibited the HMGB1/TLR4/ NF-κb axis and the release of cytokines (TNF-α and IL-6. Conclusion. Our results showed that ethyl pyruvate might attenuate to hepatic I/R injury by inhibiting intrinsic pathway of apoptosis and autophagy, mediated partly through downregulation of HMGB1/TLR4/ NF-κb axis and the competitive interaction with Beclin-1 of HMGB1.

  19. Edaravone prevents lung injury induced by hepatic ischemia-reperfusion.

    Uchiyama, Munehito; Tojo, Kentaro; Yazawa, Takuya; Ota, Shuhei; Goto, Takahisa; Kurahashi, Kiyoyasu

    2015-04-01

    Lung injury is a major clinical concern after hepatic ischemia-reperfusion (I/R), due to the production of reactive oxygen species in the reperfused liver. We investigated the efficacy of edaravone, a potent free-radical scavenger, for attenuating lung injury after hepatic I/R. Adult male Sprague-Dawley rats were assigned to sham + normal saline (NS), I/R + NS, or I/R + edaravone group. Rats in the I/R groups were subjected to 90 min of partial hepatic I/R. Five minutes before reperfusion, 3 mg/kg edaravone was administered to the I/R + edaravone group. After 6 h of reperfusion, we evaluated lung histopathology and wet-to-dry ratio. We also measured malondialdehyde (MDA), an indicator of oxidative stress, in the liver and the lung, as well as cytokine messenger RNA expressions in the reperfused liver and plasma cytokine concentrations. Histopathology revealed lung damages after 6 h reperfusion of partial ischemic liver. Moreover, a significant increase in lung wet-to-dry ratio was observed. MDA concentration increased in the reperfused liver, but not in the lungs. Edaravone administration attenuated the lung injury and the increase of MDA in the reperfused liver. Edaravone also suppressed the reperfusion-induced increase of interleukin-6 messenger RNA expressions in the liver and plasma interleukin-6 concentrations. Edaravone administration before reperfusion of the ischemic liver attenuates oxidative stress in the reperfused liver and the subsequent lung injury. Edaravone may be beneficial for preventing lung injury induced by hepatic I/R. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. Renalase as a Novel Biomarker for Evaluating the Severity of Hepatic Ischemia-Reperfusion Injury

    Huili Li

    2016-01-01

    Full Text Available Hepatic ischemia-reperfusion (I/R injury is a serious complication in clinical practice. However, no efficient biomarkers are available for the evaluation of the severity of I/R injury. Recently, renalase has been reported to be implicated in the I/R injury of various organs. This protein is secreted into the blood in response to increased oxidative stress. To investigate the responsiveness of renalase to oxidative stress, we examined the changes of renalase in cell and mouse models. We observed a significant increase of renalase expression in HepG2 cells in a time- and dose-dependent manner when treated with H2O2. Renalase expression also increased significantly in liver tissues that underwent the hepatic I/R process. The increased renalase levels could be efficiently suppressed by antioxidants in vitro and in vivo. Furthermore, serum renalase levels were significantly increased in the mouse models and also efficiently suppressed by antioxidants treatment. The variation trends are consistent between renalase and liver enzymes in the mouse models. In conclusion, renalase is highly sensitive and responsive to oxidative stress in vitro and in vivo. Moreover, renalase can be detected in the blood. These properties make renalase a highly promising biomarker for the evaluation of the severity of hepatic I/R injury.

  1. Development and molecular composition of the hepatic progenitor cell niche.

    Vestentoft, Peter Siig

    2013-05-01

    End-stage liver diseases represent major health problems that are currently treated by liver transplantation. However, given the world-wide shortage of donor livers novel strategies are needed for therapeutic treatment. Adult stem cells have the ability to self-renew and differentiate into the more specialized cell types of a given organ and are found in tissues throughout the body. These cells, whose progeny are termed progenitor cells in human liver and oval cells in rodents, have the potential to treat patients through the generation of hepatic parenchymal cells, even from the patient's own tissue. Little is known regarding the nature of the hepatic progenitor cells. Though they are suggested to reside in the most distal part of the biliary tree, the canal of Hering, the lack of unique surface markers for these cells has hindered their isolation and characterization. Upon activation, they proliferate and form ductular structures, termed "ductular reactions", which radiate into the hepatic parenchyma. The ductular reactions contain activated progenitor cells that not only acquire a phenotype resembling that observed in developing liver but also display markers of differentiation shared with the cholangiocytic or hepatocytic lineages, the two parenchymal hepatic cell types. Interactions between the putative progenitor cells, the surrounding support cells and the extracellular matrix scaffold, all constituting the progenitor cell niche, are likely to be important for regulating progenitor cell activity and differentiation. Therefore, identifying novel progenitor cell markers and deciphering their microenvironment could facilitate clinical use. The aims of the present PhD thesis were to expand knowledge of the hepatic progenitor cell niche and characterize it both during development and in disease. Several animal models of hepatic injury are known to induce activation of the progenitor cells. In order to identify possible progenitor cell markers and niche components

  2. Prophylactic Treatment with Cerium Oxide Nanoparticles Attenuate Hepatic Ischemia Reperfusion Injury in Sprague Dawley Rats

    Nandini D.P.K. Manne

    2017-07-01

    Full Text Available Background: Hepatic ischemia reperfusion is one the main causes for graft failure following transplantation. Although, the molecular events that lead to hepatic failure following ischemia reperfusion (IR are diverse and complex, previous studies have shown that excessive formation of reactive oxygen species (ROS are responsible for hepatic IR injury. Cerium oxide (CeO2 nanoparticles have been previously shown to act as an anti-oxidant and anti-inflammatory agent. Here, we evaluated the protective effects of CeO2 nanoparticles on hepatic ischemia reperfusion injury. Methods: Male Sprague Dawley rats were randomly assigned to one of the four groups: Control, CeO2 nanoparticle only, hepatic ischemia reperfusion (IR group and hepatic ischemia reperfusion (IR plus CeO2 nanoparticle group (IR+ CeO2. Partial warm hepatic ischemia was induced in left lateral and median lobes for 1h, followed by 6h of reperfusion. Animals were sacrificed after 6h of reperfusion and blood and tissue samples were collected and processed for various biochemical experiments. Results: Prophylactic treatment with CeO2 nanoparticles (0.5mg/kg i.v (IR+CeO2 group 1 hour prior to hepatic ischemia and subsequent reperfusion injury lead to a decrease in serum levels of alanine aminotransaminase and lactate dehydrogenase at 6 hours after reperfusion. These changes were accompanied by significant decrease in hepatocyte necrosis along with reduction in several serum inflammatory markers such as macrophage derived chemokine, macrophage inflammatory protein-2, KC/GRO, myoglobin and plasminogen activator inhibitor-1. However, immunoblotting demonstrated no significant changes in the levels of apoptosis related protein markers such as bax, bcl2 and caspase 3 in IR and IR+ CeO2 groups at 6 hours suggesting necrosis as the main pathway for hepatocyte death. Conclusion: Taken together, these data suggest that CeO2 nanoparticles attenuate IR induced cell death and can be used as a prophylactic

  3. Hyperglycemia Aggravates Hepatic Ischemia Reperfusion Injury by Inducing Chronic Oxidative Stress and Inflammation

    Yihan Zhang

    2016-01-01

    Full Text Available Aim. To investigate whether hyperglycemia will aggravate hepatic ischemia reperfusion injury (HIRI and the underlying mechanisms. Methods. Control and streptozotocin-induced diabetic Sprague-Dawley rats were subjected to partial hepatic ischemia reperfusion. Liver histology, transferase, inflammatory cytokines, and oxidative stress were assessed accordingly. Similarly, BRL-3A hepatocytes were subjected to hypoxia/reoxygenation (H/R after high (25 mM or low (5.5 mM glucose culture. Cell viability, reactive oxygen species (ROS, and activation of nuclear factor-erythroid 2-related factor 2 (Nrf2 and nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-κB were determined. Results. Compared with control, diabetic rats presented more severe hepatic injury and increased hepatic inflammatory cytokines and oxidative stress. HIRI in diabetic rats could be ameliorated by pretreatment of N-acetyl-L-cysteine (NAC or apocynin. Excessive ROS generation and consequent Nrf2 and NF-κB translocation were determined after high glucose exposure. NF-κB translocation and its downstream cytokines were further increased in high glucose cultured group after H/R. While proper regulation of Nrf2 to its downstream antioxidases was observed in low glucose cultured group, no further induction of Nrf2 pathway by H/R after high glucose culture was identified. Conclusion. Hyperglycemia aggravates HIRI, which might be attributed to chronic oxidative stress and inflammation and potential malfunction of antioxidative system.

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

    Wang, Rui; Feng, Xia; Zhu, Kai; Zhao, Xin; Suo, Huayi

    2016-05-01

    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 CCl 4 . 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 CCl 4 -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 CCl 4 -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.

  5. Severe Juxtahepatic Venous Injury: Survival after Prolonged Hepatic Vascular Isolation Without Shunting

    J. E. J. Krige

    1990-01-01

    Full Text Available Survival following major juxtahepatic venous injury is rare in blunt liver trauma despite the use of intracaval shunting. Prolonged liver arterial inflow control, total hepatic venous isolation and lobectomy without shunting was used in a patient to repair a combined vena caval and hepatic venous injury after blunt liver injury. An extended period of normothermic hepatic ischemia was tolerated. Early recognition of retrohepatic venous injury and temporary liver packing to control bleeding and correct hypovolemia are essential before caval occlusion. Hepatic vascular isolation without shunting is an effective simple alternative technique allowing major venous repair in complex liver trauma.

  6. Effect of selective hepatic inflow occlusion during liver cancer resection on liver ischemia-reperfusion injury

    Yin-Tian Deng

    2016-11-01

    Full Text Available Objective: To study the effect of selective hepatic inflow occlusion during liver cancer resection on liver ischemia-reperfusion injury. Methods: A total of 68 patients with primary liver cancer who underwent left liver resection in our hospital between May 2012 and August 2015 were selected for study and divided into group A (selective hepatic inflow occlusion of left liver and group B (Prignle hepatic inflow occlusion according to different intraoperative blood occlusion methods, serum was collected before and after operation to determine liver enzyme content, the removed liver tissue was collected to determine energy metabolism indexes, inflammation indexes and oxidative stress indexes. Results: 1 d, 3 d and 5 d after operation, GPT, GOT, GGT, LDH and ALP content in serum of both groups were significantly higher than those before operation, and GPT, GOT, GGT, LDH and ALP content in serum of group A 1 d, 3 d and 5 d after operation were significantly lower than those of group B; ATP, ADP, AMP, PI3K, AKT, GSK3β, T-AOC, PrxI and Trx content in liver tissue of group A were significantly higher than those of group B while PTEN, IL-12p40, MDA and MPO content were significantly lower than those of group B. Conclusions: Selective hepatic inflow occlusion during liver cancer resection can reduce the liver ischemia-reperfusion injury, improve the energy metabolism of liver cells and inhibit inflammation and oxidative stress in liver tissue.

  7. Integrative Metabolic Signatures for Hepatic Radiation Injury.

    Irwin Jack Kurland

    Full Text Available 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.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.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.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.

  8. CT of hepatic and splenic injury in children: Role in the decision for laparotomy

    Brick, S.H.; Taylor, G.A.; Potter, B.M.; Eichelberger, M.R.

    1987-01-01

    Two hundred seventy-four children were examined with CT after incurring blunt trauma to the abdomen. Hepatic and/or splenic injuries were detected in 36 patients. Of 12 children with moderate to severe hepatic injuries, only one required operative intervention. Of 13 children with moderate to sever splenic injuries, only one required splenorrhaphy. Only two of 16 patients with a moderate to large hemoperitoneum required surgery for hepatic or splenic injury. The authors conclude that the decision for laparotomy should not be based on the extent of injury as seen on CT, but on the physiologic condition of the child

  9. The isolation and in vitro expansion of hepatic Sca-1 progenitor cells

    Clayton, Elizabeth; Forbes, Stuart J.

    2009-01-01

    The intra-hepatic population of liver progenitor cells expands during liver injury when hepatocyte proliferation is inhibited. These cells can be purified by density gradient centrifugation and cultured. Separated by size only this population contains small cells of hematopoietic, epithelial and endothelial lineages and is thought to contain liver stem cells. The identity of liver stem cells remains unknown although there is some evidence that tissue Sca1 + CD45 - cells display progenitor cell characteristics. We identified both intra-hepatic and gall bladder Sca1 + cells following liver injury and expanded ex vivo Sca1 cells as part of heterogenous cell culture or as a purified population. We found significant difference between the proliferation of Sca-1 cells when plated on laminin or collagen I while proliferation of heterogenous population was not affected by the extracellular matrix indicating the necessity for culture of Sca1 + cells with laminin matrix or laminin producing cells in long term liver progenitor cell cultures.

  10. Isolated Right Segmental Hepatic Duct Injury Following Laparoscopic Cholecystectomy

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

    2005-01-01

    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

  11. Concomitant hollow viscus injuries in patients with blunt hepatic and splenic injuries: an analysis of a National Trauma Registry database.

    Swaid, Forat; Peleg, Kobi; Alfici, Ricardo; Matter, Ibrahim; Olsha, Oded; Ashkenazi, Itamar; Givon, Adi; Kessel, Boris

    2014-09-01

    Non-operative management has become the standard approach for treating stable patients sustaining blunt hepatic or splenic injuries in the absence of other indications for laparotomy. The liberal use of computed tomography (CT) has reduced the rate of unnecessary immediate laparotomies; however, due to its limited sensitivity in the diagnosis of hollow viscus injuries (HVI), this may be at the expense of a rise in the incidence of missed HVI. The aim of this study was to assess the incidence of concomitant HVI in blunt trauma patients diagnosed with hepatic and/or splenic injuries, and to evaluate whether a correlation exists between this incidence and the severity of hepatic or splenic injuries. A retrospective cohort study involving blunt trauma patients with splenic and/or liver injuries, between the years 1998 and 2012 registered in the Israel National Trauma Registry. The association between the presence and severity of splenic and/or liver injuries and the incidence of HVI was examined. Of the 57,130 trauma victims identified as suffering from blunt torso injuries, 2335 (4%) sustained hepatic injuries without splenic injuries (H group), 3127 (5.4%) had splenic injuries without hepatic injuries (S group), and 564 (1%) suffered from both hepatic and splenic injuries (H+S group). Overall, 957 patients sustained 1063 HVI. The incidence of HVI among blunt torso trauma victims who sustained neither splenic nor hepatic injuries was 1.5% which is significantly lower than in the S (3.1%), H (3.1%), and H+S (6.7%) groups. In the S group, there was a clear correlation between the severity of the splenic injury and the incidence of HVI. This correlation was not found in the H group. The presence of blunt splenic and/or hepatic injuries predicts a higher incidence of HVI, especially if combined. While in blunt splenic injury patients there is a clear correlation between the incidence of HVI and the severity of splenic injury, such a correlation does not exist in patients

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

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

    2016-08-24

    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.

  13. Bilirubin nanoparticle preconditioning protects against hepatic ischemia-reperfusion injury.

    Kim, Jin Yong; Lee, Dong Yun; Kang, Sukmo; Miao, Wenjun; Kim, Hyungjun; Lee, Yonghyun; Jon, Sangyong

    2017-07-01

    Hepatic ischemia-reperfusion injury (IRI) remains a major concern in liver transplantation and resection, despite continuing efforts to prevent it. Accumulating evidence suggests that bilirubin possesses antioxidant, anti-inflammatory and anti-apoptotic properties. However, despite obvious potential health benefits of bilirubin, its clinical applications are limited by its poor solubility. We recently developed bilirubin nanoparticles (BRNPs) consisting of polyethylene glycol (PEG)-conjugated bilirubin. Here, we sought to investigate whether BRNPs protect against IRI in the liver by preventing oxidative stress. BRNPs exerted potent antioxidant and anti-apoptotic activity in primary hepatocytes exposed to hydrogen peroxide, a precursor of reactive oxygen species (ROS). In a model of hepatic IRI in mice, BRNP preconditioning exerted profound protective effects against hepatocellular injury by reducing oxidative stress, pro-inflammatory cytokine production, and recruitment of neutrophils. They also preferentially accumulated in IRI-induced inflammatory lesions. Collectively, our findings indicate that BRNP preconditioning provides a simple and safe approach that can be easily monitored in the blood like endogenous bilirubin, and could be a promising strategy to protect against IRI in a clinical setting. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Hepatic Giant Cell Arteritis and Polymyalgia Rheumatica

    Donald R Duerksen

    1994-01-01

    Full Text Available Polymyalgia rheumatica (PMR is a clinical syndrome of the elderly characterized by malaise, proximal muscle aching and stiffness, low grade fever, elevated erythrocyte sedimentation rare and the frequent association with temporal giant cell arteritis. The authors describe a case of PMR associated with hepatic giant cell arteritis. This lesion has been described in two other clinical reports. The distribution of the arteritis may be patchy; in this report, diagnosis was made with a wedge biopsy performed after an initial nonspecific percutaneous liver biopsy. The authors review the spectrum of liver involvement in PMR and giant cell arteritis. Hepatic abnormalities respond to systemic corticosteroids, and patients with hepatic arteritis have a good prognosis.

  15. Melatonin suppresses activation of hepatic stellate cells through ROR alpha-mediated inhibition of 5-lipoxygenase

    Shajari, Shiva; Laliena, Almudena; Heegsma, Janette; Jesus Tunon, Maria; Moshage, Han; Faber, Klaas Nico

    2015-01-01

    Liver fibrosis is scar tissue resulting from an uncontrolled wound-healing process in response to chronic liver injury. Liver damage generates an inflammatory reaction that activates hepatic stellate cells (HSC) that transdifferentiate from quiescent cells that control retinol metabolism to

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

    Werawatganon, Duangporn; Linlawan, Sittikorn; Thanapirom, Kessarin; Somanawat, Kanjana; Klaikeaw, Naruemon; Rerknimitr, Rungsun; Siriviriyakul, Prasong

    2014-07-08

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

  17. [Management of hepatic injuries with multiple trauma in the emergency unit. Report of three cases].

    Qamouss, Y; Belyamani, L; Azendour, H; Balkhi, H; Haimeur, C; Atmani, M

    2006-01-01

    The problems put by the blunt hepatic injuries at the multiple traumas are discussed after the exposition of three observations. 60% of the blunt hepatic injuries are due to the accidents of the public way. The strategy diagnosis and therapeutic facing a hepatic lesion remains guided by the patient's state haemodynamic. The exam essential to the arrival in the sieve of the emergencies is the abdominal scan that searches for one extrusion intra and possibly retroperitoneal and analyze the hepatic parenchyrma. However, it depends extensively on the experience of the echographist. The city scan stood to the first plan of the medical imagery: it permits a precise diagnosis of the parenchymateuses hepatic lesions, specify the abundance of the hemoperitoine, facilitate the therapeutic conduct in presence of associated lesions and the surveillance of the blunt hepatic injuries.

  18. Complications of nonoperative management of high-grade blunt hepatic injuries.

    Kozar, Rosemary A; Moore, John B; Niles, Sarah E; Holcomb, John B; Moore, Ernest E; Cothren, C Clay; Hartwell, Elizabeth; Moore, Frederick A

    2005-11-01

    Nonoperative management of blunt hepatic injuries is highly successful. Complications associated with high-grade injuries, however, have not been well characterized. The purpose of the present study was therefore to define hepatic-related complications and associated treatment modalities in patients undergoing nonoperative management of high-grade blunt hepatic injuries. Three hundred thirty-seven patients from two regional Level I trauma centers with grade 3 to 5 blunt hepatic injuries during a 40-month period were reviewed. Complications and treatment of hepatic-related complications in patients not requiring laparotomy in the first 24 hours were identified. Of 337 patients with a grade 3 to 5 injury, 230 (68%) were managed nonoperatively. There were 37 hepatic-related complications in 25 patients (11%); 63% (5 of 8) of patients with grade 5 injuries developed complications, 21% (19 of 92) of patients with grade 4 injuries, but only 1% (1 of 130) of patients with grade 3 injuries. Complications included bleeding in 13 patients managed by angioembolization (n = 12) and laparotomy (n = 1), liver abscesses in 2 patients managed with computed tomography-guided drainage (n = 2) and subsequent laparotomy (n = 1). In one patient with bleeding, hepatic necrosis followed surgical ligation of the right hepatic artery and required delayed hepatic lobectomy. Sixteen biliary complications were managed with endoscopic retrograde cholangiopancreatography and stenting (n = 7), drainage (n = 5), and laparoscopy (n = 4). Three patients had suspected abdominal sepsis and underwent a negative laparotomy, whereas an additional three patients underwent laparotomy for abdominal compartment syndrome. Nonoperative management of high-grade liver injuries can be safely accomplished. Mortality is low; however, complications in grade 4 and 5 injuries should be anticipated and may require a combination of operative and nonoperative management strategies.

  19. Tumor induced hepatic myeloid derived suppressor cells can cause moderate liver damage.

    Tobias Eggert

    Full Text Available Subcutaneous tumors induce the accumulation of myeloid derived suppressor cells (MDSC not only in blood and spleens, but also in livers of these animals. Unexpectedly, we observed a moderate increase in serum transaminases in mice with EL4 subcutaneous tumors, which prompted us to study the relationship of hepatic MDSC accumulation and liver injury. MDSC were the predominant immune cell population expanding in livers of all subcutaneous tumor models investigated (RIL175, B16, EL4, CT26 and BNL, while liver injury was only observed in EL4 and B16 tumor-bearing mice. Elimination of hepatic MDSC in EL4 tumor-bearing mice using low dose 5-fluorouracil (5-FU treatment reversed transaminase elevation and adoptive transfer of hepatic MDSC from B16 tumor-bearing mice caused transaminase elevation indicating a direct MDSC mediated effect. Surprisingly, hepatic MDSC from B16 tumor-bearing mice partially lost their damage-inducing potency when transferred into mice bearing non damage-inducing RIL175 tumors. Furthermore, MDSC expansion and MDSC-mediated liver injury further increased with growing tumor burden and was associated with different cytokines including GM-CSF, VEGF, interleukin-6, CCL2 and KC, depending on the tumor model used. In contrast to previous findings, which have implicated MDSC only in protection from T cell-mediated hepatitis, we show that tumor-induced hepatic MDSC themselves can cause moderate liver damage.

  20. Tumor induced hepatic myeloid derived suppressor cells can cause moderate liver damage.

    Eggert, Tobias; Medina-Echeverz, José; Kapanadze, Tamar; Kruhlak, Michael J; Korangy, Firouzeh; Greten, Tim F

    2014-01-01

    Subcutaneous tumors induce the accumulation of myeloid derived suppressor cells (MDSC) not only in blood and spleens, but also in livers of these animals. Unexpectedly, we observed a moderate increase in serum transaminases in mice with EL4 subcutaneous tumors, which prompted us to study the relationship of hepatic MDSC accumulation and liver injury. MDSC were the predominant immune cell population expanding in livers of all subcutaneous tumor models investigated (RIL175, B16, EL4, CT26 and BNL), while liver injury was only observed in EL4 and B16 tumor-bearing mice. Elimination of hepatic MDSC in EL4 tumor-bearing mice using low dose 5-fluorouracil (5-FU) treatment reversed transaminase elevation and adoptive transfer of hepatic MDSC from B16 tumor-bearing mice caused transaminase elevation indicating a direct MDSC mediated effect. Surprisingly, hepatic MDSC from B16 tumor-bearing mice partially lost their damage-inducing potency when transferred into mice bearing non damage-inducing RIL175 tumors. Furthermore, MDSC expansion and MDSC-mediated liver injury further increased with growing tumor burden and was associated with different cytokines including GM-CSF, VEGF, interleukin-6, CCL2 and KC, depending on the tumor model used. In contrast to previous findings, which have implicated MDSC only in protection from T cell-mediated hepatitis, we show that tumor-induced hepatic MDSC themselves can cause moderate liver damage.

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

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

    1985-01-01

    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 [ 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

  2. Hepatitis C virus host cell interactions uncovered

    Gottwein, Judith; Bukh, Jens

    2007-01-01

      Insights into virus-host cell interactions as uncovered by Randall et al. (1) in a recent issue of PNAS further our understanding of the hepatitis C virus (HCV) life cycle, persistence, and pathogenesis and might lead to the identification of new therapeutic targets. HCV persistently infects 180...... million individuals worldwide, causing chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. The only approved treatment, combination therapy with IFN- and ribavirin, targets cellular pathways (2); however, a sustained virologic response is achieved only in approximately half of the patients...... treated. Therefore, there is a pressing need for the identification of novel drugs against hepatitis C. Although most research focuses on the development of HCV-specific antivirals, such as protease and polymerase inhibitors (3), cellular targets could be pursued and might allow the development of broad...

  3. Alternative Cell Sources to Adult Hepatocytes for Hepatic Cell Therapy.

    Pareja, Eugenia; Gómez-Lechón, María José; Tolosa, Laia

    2017-01-01

    Adult hepatocyte transplantation is limited by scarce availability of suitable donor liver tissue for hepatocyte isolation. New cell-based therapies are being developed to supplement whole-organ liver transplantation, to reduce the waiting-list mortality rate, and to obtain more sustained and significant metabolic correction. Fetal livers and unsuitable neonatal livers for organ transplantation have been proposed as potential useful sources of hepatic cells for cell therapy. However, the major challenge is to use alternative cell sources for transplantation that can be derived from reproducible methods. Different types of stem cells with hepatic differentiation potential are eligible for generating large numbers of functional hepatocytes for liver cell therapy to treat degenerative disorders, inborn hepatic metabolic diseases, and organ failure. Clinical trials are designed to fully establish the safety profile of such therapies and to define target patient groups and standardized protocols.

  4. Cell membranes in radiation injury

    Koeteles, G.J.

    1986-01-01

    Cell membrane-related phenomena caused by low linear energy transfer radiation with doses lower than those producing cell killing are outlined. Micromorphological alterations as well as functional activities appearing with the receptors and in binding sites render it possible to reveal early and temporary changes. The cell injuries are suggested to transfer damaging conditions to surviving cells and to contribute to further development of non-stochastic effects in tissues

  5. Penetrating Cardiac and Hepatic Injury; Polytrauma of a Child After Bombing

    Baris Akca

    2013-10-01

    Full Text Available After a bombing attack, patients were brought into hospital suffering from a combination of injuries caused by the blast, penetrating injuries and burns which as a case of polytrauma. In penetrating thoracoabdominal injuries due to bombing possibility of cardiac injury should be kept in mind. Penetrating cardiac injuries in children are rare but has a high mortality and morbidity. In some cases there may be difficulty in diagnosis of penetrating cardiac injury. In this case we want to share the diagnosis, treatment and follow-up processes of penetrating cardiac and hepatic injury with burns of a politrauma child due to bombing.

  6. Immunodetection of hepatic stellate cells in dogs with visceral leishmaniasis.

    Marques, Natália Cassaro; Mo Reira, Pamela Rodrigues Reina; Bertolo, Paulo Henrique Leal; Gava, Fábio Nelson; Vasconcelos, Rosemeri de Oliveira

    2018-06-01

    Hepatic stellate cells (HSC), or Ito cells, store vitamin A when at rest but undergo phenotypic changes in situations of liver injury, which may induce fibrosis, and they may participate in the immune response in the liver. The objective of the present study was to investigate the role of HSC in the livers of dogs with visceral leishmaniasis (VL). Twenty-eight livers from dogs infected with VL that were living in an area endemic for the disease were evaluated, among which 13 were asymptomatic (A) and 15 were symptomatic (S). A control group (C) was formed by five dogs from an area that was not endemic for VL. These organs were subjected to histopathological analysis (Masson's trichrome for fibrosis) and immunohistochemical analysis (Leishmania, smooth-muscle α-actin and TGF-β). In the livers from the symptomatic dogs, a moderate to severe granulomatous inflammatory reaction was observed in the capsule and in the portal, centrilobular and intralobular regions. In the asymptomatic dogs, there was slight to moderate presence of granulomas, and these were even absent in some dogs. The intensity of hepatic fibrosis was predominantly low in the infected dogs (A and S), and fibrosis was absent in the control group. The immunomarking of HSC in the infected groups (A and S) differed significantly (P = 0.0153) from that of the control group. The symptomatic dogs presented the largest number of positive cells. This group also presented a larger number of parasitized macrophages, but did not differ statistically from the asymptomatic group (P > 0.05). The cytokine TGF-β was only detected at low levels, and only in the infected animals, but this did not differ from the control group. Immunomarking for HSC was observed mainly in the nuclei of cells present in the hepatic granulomas of symptomatic dogs and in the sinusoids of the asymptomatic dogs. It was concluded that in the livers of dogs with VL, the HSC are activated and participate in the hepatic response to the

  7. Hepatic progenitor cell resistance to TGF-β1's proliferative and apoptotic effects

    Clark, J. Brian; Rice, Lisa; Sadiq, Tim; Brittain, Evan; Song, Lujun; Wang Jian; Gerber, David A.

    2005-01-01

    The success of hepatocellular therapies using stem or progenitor cell populations is dependent upon multiple factors including the donor cell, microenvironment, and etiology of the liver injury. The following experiments investigated the impact of TGF-β1 on a previously described population of hepatic progenitor cells (HPC). The majority of the hepatic progenitor cells were resistant to endogenously produced TGF-β1's proapoptotic and anti-proliferative effects unlike more well-differentiated cellular populations (e.g., mature hepatocytes). Surprisingly, in vitro TGF-β1 supplementation significantly inhibited de novo hepatic progenitor cell colony formation possibly via an indirect mechanism(s). Therefore despite the HPC's direct resistance to supplemental TGF-β1, this cytokine's inhibitory effect on colony formation could have a potential negative impact on the use of these cells as a therapy for patients with liver disease

  8. Non-operative management versus operative management in high-grade blunt hepatic injury.

    Cirocchi, Roberto; Trastulli, Stefano; Pressi, Eleonora; Farinella, Eriberto; Avenia, Stefano; Morales Uribe, Carlos Hernando; Botero, Ana Maria; Barrera, Luis M

    2015-08-24

    Surgery used to be the treatment of choice in cases of blunt hepatic injury, but this approach gradually changed over the last two decades as increasing non-operative management (NOM) of splenic injury led to its use for hepatic injury. The improvement in critical care monitoring and computed tomographic scanning, as well as the more frequent use of interventional radiology techniques, has helped to bring about this change to non-operative management. Liver trauma ranges from a small capsular tear, without parenchymal laceration, to massive parenchymal injury with major hepatic vein/retrohepatic vena cava lesions. In 1994, the Organ Injury Scaling Committee of the American Association for the Surgery of Trauma (AAST) revised the Hepatic Injury Scale to have a range from grade I to VI. Minor injuries (grade I or II) are the most frequent liver injuries (80% to 90% of all cases); severe injuries are grade III-V lesions; grade VI lesions are frequently incompatible with survival. In the medical literature, the majority of patients who have undergone NOM have low-grade liver injuries. The safety of NOM in high-grade liver lesions, AAST grade IV and V, remains a subject of debate as a high incidence of liver and collateral extra-abdominal complications are still described. To assess the effects of non-operative management compared to operative management in high-grade (grade III-V) blunt hepatic injury. The search for studies was run on 14 April 2014. We searched the Cochrane Injuries Group's Specialised Register, The Cochrane Library, Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R), Embase Classic+Embase (Ovid), PubMed, ISI WOS (SCI-EXPANDED, SSCI, CPCI-S & CPSI-SSH), clinical trials registries, conference proceedings, and we screened reference lists. All randomised trials that compare non-operative management versus operative management in high-grade blunt hepatic injury. Two authors independently

  9. Pretreatment with soluble ST2 reduces warm hepatic ischemia/reperfusion injury

    Yin Hui; Huang Baojun; Yang Heng; Huang Yafei; Xiong Ping; Zheng Fang; Chen Xiaoping; Chen Yifa; Gong Feili

    2006-01-01

    The interleukin-1 receptor-like protein ST2 exists in both membrane-bound (ST2L) and soluble form (sST2). ST2L has been found to play an important regulatory role in Th2-type immune response, but the function of soluble form of ST2 remains to be elucidated. In this study, we report the protective effect of soluble ST2 on warm hepatic ischemia/reperfusion injury. We constructed a eukaryotic expression plasmid, psST2-Fc, which expresses functional murine soluble ST2-human IgG1 Fc (sST2-Fc) fusion protein. The liver damage after ischemia/reperfusion was significantly attenuated by the expression of this plasmid in vivo. sST2-Fc remarkably inhibited the activation of Kupffer cells and the production of proinflammatory mediators TNF-α and IL-6. Furthermore, the levels of TLR4 mRNA and the nuclear translocation of NF-κB were also suppressed by pretreatment with sST2-Fc. These results thus identified soluble ST2 as a negative regulator in hepatic I/R injury, possibly via ST2-TLR4 pathway

  10. Comparison of isolated and concomitant liver injuries: is hepatic trauma entirely responsible for the outcome?

    Yazici, P; Aydin, U; Sozbilen, M

    2010-01-01

    This study was undertaken to examine both isolated and concomitant liver injuries to clarify the role of liver trauma on outcome. This retrospective study was a review of all abdominal trauma patients who presented with liver injuries, with or without concomitant injury at Ege University School of Medicine over a 3-year period. Presentation, injury grade, management, and outcomes were analyzed. Patients with isolated hepatic injury (Group A) were compared with patients who had concomitant hepatic injury (liver and spleen/small bowel) (Group B). Significance was set at 95% confidence intervals. Of 368 patients, 80 (21%) presented with liver injury. Of these, the aetiology was as follows: 53 (66.2%) blunt injury, 19 (23%) penetrating injury, and 8 (10%) gun shot trauma. There were 38 patients in Group A and 42 in Group B. Of these 42 patients, 19 were diagnosed with serious types of injury ; eight thoracic, three open long bone fracture, one intra-cardiac, one intracranial. Six additional patients were observed with injuries to large abdominal vessels. Eleven patients (28.9%) with isolated hepatic injury were managed non-operatively. Mortality, intensive care unit and hospital length of stay, and transfusion requirements were significantly higher in Group B. Only the number of transfused blood units and the grade of liver injury were found to be effective on outcome whereas stepwise regression analysis revealed that injury type (penetrating) and blood transfusion were predictive for mortality. This study highlighted that although isolated liver injury results in good outcome with non-operative management, concomitant injuries to the liver lead to a higher failure and mortality rate. However, liver injury itself is rarely responsible for death.

  11. Apamin suppresses biliary fibrosis and activation of hepatic stellate cells.

    Kim, Jung-Yeon; An, Hyun-Jin; Kim, Woon-Hae; Park, Yoon-Yub; Park, Kyung Duck; Park, Kwan-Kyu

    2017-05-01

    Cholestatic liver disease is characterized by the progressive destruction of biliary epithelial cells (BECs) followed by fibrosis, cirrhosis and liver failure. Activated hepatic stellate cells (HSCs) and portal fibroblasts are the major cellular effectors of enhanced collagen deposition in biliary fibrosis. Apamin, an 18 amino acid peptide neurotoxin found in apitoxin (bee venom), is known to block Ca2+-activated K+ channels and prevent carbon tetrachloride-induced liver fibrosis. In the present study, we aimed to ascertain whether apamin inhibits biliary fibrosis and the proliferation of HSCs. Cholestatic liver fibrosis was established in mouse models with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) feeding. Cellular assays were performed on HSC-T6 cells (rat immortalized HSCs). DDC feeding led to increased hepatic damage and proinflammtory cytokine levels. Notably, apamin treatment resulted in decreased liver injury and proinflammatory cytokine levels. Moreover, apamin suppressed the deposition of collagen, proliferation of BECs and expression of fibrogenic genes in the DDC-fed mice. In HSCs, apamin suppressed activation of HSCs by inhibiting the Smad signaling pathway. These data suggest that apamin may be a potential therapeutic target in cholestatic liver disease.

  12. Carbon monoxide-Releasing Molecule-2 (CORM-2 attenuates acute hepatic ischemia reperfusion injury in rats

    Zhang Weihui

    2010-05-01

    Full Text Available Abstract Background Hepatic ischemia-reperfusion injury (I/Ri is a serious complication occurring during liver surgery that may lead to liver failure. Hepatic I/Ri induces formation of reactive oxygen species, hepatocyte apoptosis, and release of pro-inflammatory cytokines, which together causes liver damage and organ dysfunction. A potential strategy to alleviate hepatic I/Ri is to exploit the potent anti-inflammatory and cytoprotective effects of carbon monoxide (CO by application of so-called CO-releasing molecules (CORMs. Here, we assessed whether CO released from CORM-2 protects against hepatic I/Ri in a rat model. Methods Forty male Wistar rats were randomly assigned into four groups (n = 10. Sham group underwent a sham operation and received saline. I/R group underwent hepatic I/R procedure by partial clamping of portal structures to the left and median lobes with a microvascular clip for 60 minutes, yielding ~70% hepatic ischemia and subsequently received saline. CORM-2 group underwent the same procedure and received 8 mg/kg of CORM-2 at time of reperfusion. iCORM-2 group underwent the same procedure and received iCORM-2 (8 mg/kg, which does not release CO. Therapeutic effects of CORM-2 on hepatic I/Ri was assessed by measuring serum damage markers AST and ALT, liver histology score, TUNEL-scoring of apoptotic cells, NFkB-activity in nuclear liver extracts, serum levels of pro-inflammatory cytokines TNF-α and IL-6, and hepatic neutrophil infiltration. Results A single systemic infusion with CORM-2 protected the liver from I/Ri as evidenced by a reduction in serum AST/ALT levels and an improved liver histology score. Treatment with CORM-2 also up-regulated expression of the anti-apoptotic protein Bcl-2, down-regulated caspase-3 activation, and significantly reduced the levels of apoptosis after I/Ri. Furthermore, treatment with CORM-2 significantly inhibited the activity of the pro-inflammatory transcription factor NF-κB as measured in

  13. Cell entry of hepatitis C virus

    Bartosch, Birke; Cosset, Francois-Loic

    2006-01-01

    Hepatitis C virus (HCV), an important human pathogen, is an enveloped, positive-stranded RNA virus classified in the hepacivirus genus of the Flaviviridae family. Cell attachment of flaviviruses generally leads to endocytosis of bound virions. Systems that support HCV replication and particle formation in vitro are emerging only now, 16 years after the discovery of the virus. Albeit this limitation, the route of HCV cell entry as well as 'capture' molecules involved in low-affinity interactions for the initial contact of HCV with target cells and potential high-affinity receptor candidates that may mediate HCV trafficking and fusion has been described. The objective of this review is to summarize the contribution of different HCV model systems to our current knowledge about structure of the HCV GPs E1 and E2 and their roles in cell entry comprising cell attachment, interactions with cellular receptors, endocytosis, and fusion

  14. Concomitant injuries are an important determinant of outcome of high-grade blunt hepatic trauma.

    Schnüriger, B; Inderbitzin, D; Schafer, M; Kickuth, R; Exadaktylos, A; Candinas, D

    2009-01-01

    Little is known about the clinical importance of concomitant injuries in polytraumatized patients with high-grade blunt liver injury. A retrospective single-centre study was performed to investigate the safety of non-operative management of liver injury and the impact of concomitant intra- and extra-abdominal injuries on clinical outcome. Some 183 patients with blunt liver injury were admitted to Berne University Hospital, Switzerland, between January 2000 and December 2006. Grade 3-5 injuries were considered to be high grade. Immediate laparotomy was required by 35 patients (19.1 per cent), owing to extrahepatic intra-abdominal injury (splenic and vascular injuries, perforations) in 21 cases. The mortality rate was 16.9 per cent; 22 of the 31 deaths were due to concomitant lesions. Of 81 patients with high-grade liver injury, 63 (78 per cent) were managed without surgery; liver-related and extra-abdominal complication rates in these patients were 11 and 17 per cent respectively. Grades 4 and 5 liver injury were associated with hepatic-related and extra-abdominal complications. Concomitant injuries are a major determinant of outcome in patients with blunt hepatic injury and should be given high priority by trauma surgeons. An algorithm for the management of blunt liver injury is proposed. Copyright (c) 2008 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

  15. [Hepatic cell transplantation. Technical and methodological aspects].

    Pareja, Eugenia; Martínez, Amparo; Cortés, Miriam; Bonora, Ana; Moya, Angel; Sanjuán, Fernando; Gómez-Lechón, M José; Mir, José

    2010-03-01

    Hepatic cell transplantation consists of grafting already differentiated cells such as hepatocytes. Human hepatocytes are viable and functionally active. Liver cell transplantation is carried out by means of a 3-step method: isolation of hepatocytes from donor liver rejected for orthotopic transplantation, preparing a cell suspension for infusion and, finally, hepatocytes are implanted into the recipient. There are established protocols for the isolation of human hepatocytes from unused segments of donor livers, based on collagenase digestion of cannulated liver tissue at 37 degrees C. The hepatocytes can be used fresh or cryopreserved. Cryopreservation of isolated human hepatocytes would then be available for planned use. In cell transplant, the important aspects are: infusion route, number of cells, number of infusions and viability of the cells. The cells are infused into the patient through a catheter inserted via portal vein or splenic artery. Liver cell transplantation allows liver tissue to be used that would, otherwise, be discarded, enabling multiple patients to be treated with hepatocytes from a single tissue donor. Copyright 2009 AEC. Published by Elsevier Espana. All rights reserved.

  16. Research on Protective Effect and Mechanism of Idazoxan on lps Attacked Acute Hepatic Injury

    Zhu, Junyu; Ying, Shangqi; Kang, Wenyuan; Huang, Wenjuan; Liang, Huaping

    2018-01-01

    Objective: To observe the protection effect of Idazoxan (IDA) on LPS induced acute hepatic injury, and to explore its action mechanism. Methods: 60 adult C57BL/6 mice were divided into a control group (20 mice, intraperitoneal injection of phosphate buffer), a model group (20 mice, intraperitoneal injection of LPS 10 mg/kg) and a agmatine group (20 mice, intraperitoneal injection of LPS 10 mg/kg and agmatine 200 mg/kg) according to random number table method. Blood and liver tissue were collected for preparation of tissue homogenate. Enzyme-linked immunosorbent assay (ELISA) was adopted for detecting tumor necrosis factor-α (TNF-α) and interleukin (IL- 1β and IL - 6) contents in the serum and liver tissue at 24h after molding. Automatic biochemical analyzer is used for determining alanine transaminase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) level at 24h after molding; The liver tissue pathology changes were observed at 24h after molding. Macrophage RAW264.7 cells were stimulated by 10 μg/mL LPS and with or without IDA (100 μmol/L). 2’, 7’-dichlorofluoresce in diacetate (DCFH-DA) was used as a fluorescent probe for detection of intracellular reactive oxygen species (ROS) level; qRT - PCR method was used for detecting antioxidant enzymes HO-1 and NQO-1 mRNA expression level at 2h, 4h and 8 h. Results: mice in the model group suffered from depression, curling and food water forbidding at 6h after molding. Mice in the Idazoxan group have obviously better spirit and activity than that of model group. The serum ALT, AST and LDH level of LPS attacked acute hepatic injury mice can be effectively alleviated after Idazoxan treatment. The expression of proinflammatory factor TNF-α and IL-6 in the liver can be reduced. The liver showed obvious pathological changes at 24 h after injection, such as liver cell swelling, necrosis, congestion, inflammatory cell infiltration, etc.; The liver cell injury was prominently alleviated in IDA

  17. Severe Aplastic Anemia following Acute Hepatitis from Toxic Liver Injury: Literature Review and Case Report of a Successful Outcome

    Kamran Qureshi

    2014-01-01

    Full Text Available Hepatitis associated aplastic anemia (HAAA is a rare syndrome in which severe aplastic anemia (SAA complicates the recovery of acute hepatitis (AH. HAAA is described to occur with AH caused by viral infections and also with idiopathic cases of AH and no clear etiology of liver injury. Clinically, AH can be mild to fulminant and transient to persistent and precedes the onset SAA. It is assumed that immunologic dysregulation following AH leads to the development of SAA. Several observations have been made to elucidate the immune mediated injury mechanisms, ensuing from liver injury and progressing to trigger bone marrow failure with the involvement of activated lymphocytes and severe T-cell imbalance. HAAA has a very poor outcome and often requires bone marrow transplant (BMT. The findings of immune related myeloid injury implied the use of immunosuppressive therapy (IST and led to improved survival from HAAA. We report a case of young male who presented with AH resulting from the intake of muscle building protein supplements and anabolic steroids. The liver injury slowly resolved with supportive care and after 4 months of attack of AH, he developed SAA. He was treated with IST with successful outcome without the need for a BMT.

  18. Augmented hepatic injury followed by impaired regeneration in metallothionein-I/II knockout mice after treatment with thioacetamide

    Oliver, Jordan R.; Jiang, Sean; Cherian, M. George

    2006-01-01

    of MT in both nucleus and cytoplasm of hepatocytes at 24-72 h after TAA injection. Cell proliferation, as assessed by immunohistochemical staining for proliferating cell nuclear antigen, was detected mainly in the livers of WT mice at 48-72 h after TAA treatment. Hepatic proliferation index in MT-null mice was very low as compared to WT mice during liver regeneration after injection of TAA. These results show that the liver cells of MT-null mice with no functional MT are unable to regenerate after TAA-induced hepatic injury, demonstrating an important role for MT in cellular regeneration

  19. Treatment of penetrating hepatic injuries: a retrospective analysis of 50 patients.

    Gonullu, D; Koksoy, F N; Ilgun, S; Demiray, O; Yucel, O; Yucel, T

    2009-01-01

    The aim of this study was to determine the possibility of non-operative treatment via retrospective analysis of our patients. Fifty patients with penetrating hepatic injuries were examined retrospectively with respect to trauma scores, associated injuries, complications, and mortality parameters. Thirteen injuries were caused by firearms, whereas 37 injuries were caused by stab wounds. Forty-three patients (86%) underwent laparotomy and 7 patients (14%) were monitored by CT and clinical findings (nonoperative group, NO group). The laparotomies were evaluated as non-therapeutic in 11 patients (22%) (NTL group) and therapeutic in 32 patients (64%) (TL group). The morbidity and mortality rates were 40 and 10%, respectively. RTS and ISS scores of the nonsurviving and the surviving patients were significantly different. The rates of major venous, grade IV-V hepatic injuries, and gunshot wounds were significantly higher in the nonsurviving patients when compared to the surviving patients. Major venous and grade IV-V hepatic injuries were the primary factors determining mortality and these injuries generally occurred as a result of firearm injuries. NTL occurring at a rate of 22% would decrease to 2% if 'RTS <7' criteria was added to the hemodynamic instability and/or peritoneal irritation findings determining surgical candidacy. Copyright 2009 S. Karger AG, Basel.

  20. Blunt hepatic and splenic trauma in children: correlation of a CT injury severity scale with clinical outcome

    Ruess, L. [Dept. of Diagnostic Imaging and Radiology, Children`s National Medical Center, and George Washington Univ. School of Medicine and Health Sciences, Washington, DC (United States); Sivit, C.J. [Dept. of Diagnostic Imaging and Radiology, Children`s National Medical Center, and George Washington Univ. School of Medicine and Health Sciences, Washington, DC (United States)]|[Dept. of Pediatrics, Children`s National Medical Center, and George Washington Univ. School of Medicine and Health Sciences, Washington, DC (United States); Eichelberger, M.R. [Dept. of Pediatrics, Children`s National Medical Center, and George Washington Univ. School of Medicine and Health Sciences, Washington, DC (United States)]|[Dept. of Surgery, Children`s National Medical Center, and George Washington Univ. School of Medicine and Health Sciences Washington, DC (United States); Taylor, G.A. [Dept. of Diagnostic Imaging and Radiology, Children`s National Medical Center, and George Washington Univ. School of Medicine and Health Sciences, Washington, DC (United States); Bond, S.J. [Dept. of Surgery, Children`s National Medical Center, and George Washington Univ. School of Medicine and Health Sciences Washington, DC (United States)

    1995-07-01

    The purpose of this report is to compare a computed tomography (CT) injury severity scale for hepatic and splenic injury with the following outcome measures: requirement for surgical hemostasis, requirement for blood transfusion and late complications. Sixty-nine children with isolated hepatic injury and 53 with isolated splenic injury were prospectively classified at CT according to extent of parenchymal involvement. Clinical records were reviewed to determine clinical outcome. Ninety-seven children (80%) were managed non-operatively without transfusion. One child with hepatic injury required surgical hemostasis, and 17 (25%) required transfusion of blood. Increasing severity of hepatic injury at CT was associated with progressively greater frequency of transfusion (P = 0.002 by {chi}{sup 2}-test). One child with splenic injury underwent surgery and eight (15%) required transfusion of blood. Splenic injury grade at CT did not correlate with frequency (P = 0.41 by {chi}{sup 2}-test) or amount (P = 0.35 by factorial analysis of variance) of transfusion. There was one late complication in the nonsurgical group. A majority of children with hepatic and splenic injury were managed non-operatively without requiring blood transfusion. The severity of injury by CT scan did not correlate with need for surgery. Increasing grade of hepatic injury at CT was associated with increasing frequency of blood transfusion. CT staging was not discriminatory in predicting transfusion requirement in splenic injury. (orig.)

  1. Blunt hepatic and splenic trauma in children: correlation of a CT injury severity scale with clinical outcome

    Ruess, L.; Sivit, C.J.; Eichelberger, M.R.; Taylor, G.A.; Bond, S.J.

    1995-01-01

    The purpose of this report is to compare a computed tomography (CT) injury severity scale for hepatic and splenic injury with the following outcome measures: requirement for surgical hemostasis, requirement for blood transfusion and late complications. Sixty-nine children with isolated hepatic injury and 53 with isolated splenic injury were prospectively classified at CT according to extent of parenchymal involvement. Clinical records were reviewed to determine clinical outcome. Ninety-seven children (80%) were managed non-operatively without transfusion. One child with hepatic injury required surgical hemostasis, and 17 (25%) required transfusion of blood. Increasing severity of hepatic injury at CT was associated with progressively greater frequency of transfusion (P = 0.002 by χ 2 -test). One child with splenic injury underwent surgery and eight (15%) required transfusion of blood. Splenic injury grade at CT did not correlate with frequency (P = 0.41 by χ 2 -test) or amount (P = 0.35 by factorial analysis of variance) of transfusion. There was one late complication in the nonsurgical group. A majority of children with hepatic and splenic injury were managed non-operatively without requiring blood transfusion. The severity of injury by CT scan did not correlate with need for surgery. Increasing grade of hepatic injury at CT was associated with increasing frequency of blood transfusion. CT staging was not discriminatory in predicting transfusion requirement in splenic injury. (orig.)

  2. Kupffer cells hasten resolution of liver immunopathology in mouse models of viral hepatitis.

    Giovanni Sitia

    2011-06-01

    Full Text Available Kupffer cells (KCs are widely considered important contributors to liver injury during viral hepatitis due to their pro-inflammatory activity. Herein we utilized hepatitis B virus (HBV-replication competent transgenic mice and wild-type mice infected with a hepatotropic adenovirus to demonstrate that KCs do not directly induce hepatocellular injury nor do they affect the pathogenic potential of virus-specific CD8 T cells. Instead, KCs limit the severity of liver immunopathology. Mechanistically, our results are most compatible with the hypothesis that KCs contain liver immunopathology by removing apoptotic hepatocytes in a manner largely dependent on scavenger receptors. Apoptotic hepatocytes not readily removed by KCs become secondarily necrotic and release high-mobility group box 1 (HMGB-1 protein, promoting organ infiltration by inflammatory cells, particularly neutrophils. Overall, these results indicate that KCs resolve rather than worsen liver immunopathology.

  3. Hepatic differentiation potential of commercially available human mesenchymal stem cells.

    Ong, Shin-Yeu; Dai, Hui; Leong, Kam W

    2006-12-01

    The ready availability and low immunogenicity of commercially available mesenchymal stem cells (MSC) render them a potential cell source for the development of therapeutic products. With cell source a major bottleneck in hepatic tissue engineering, we investigated whether commercially available human MSC (hMSC) can transdifferentiate into the hepatic lineage. Based on previous studies that find rapid gain of hepatic genes in bone marrow-derived stem cells cocultured with liver tissue, we used a similar approach to drive hepatic differentiation by coculturing the hMSC with rat livers treated or untreated with gadolinium chloride (GdCl(3)). After a 24-hour coculture period with liver tissue injured by GdCl(3) in a Transwell configuration, approximately 34% of the cells differentiated into albumin-expressing cells. Cocultured cells were subsequently maintained with growth factors to complete the hepatic differentiation. Cocultured cells expressed more hepatic gene markers, and had higher metabolic functions and P450 activity than cells that were only differentiated with growth factors. In conclusion, commercially available hMSC do show hepatic differentiation potential, and a liver microenvironment in culture can provide potent cues to accelerate and deepen the differentiation. The ability to generate hepatocyte-like cells from a commercially available cell source would find interesting applications in liver tissue engineering.

  4. Protective Effect of Urtica dioica on Liver Injury Induced By Hepatic Ischemia Reperfusion Injury in Rats

    Alpaslan TERZİ

    2010-05-01

    Full Text Available Background: This study was designed to investigate the effects of Urtica dioica on liverischemia reperfusion injury in rats. Methods: Thirty male Wistar-albino rats were used in this experimental study. Animals weredivided into three groups as sham operated (group 1, control (group 2, and Urtica dioicatreatment group (group 3. Urtica dioica 2ml/kg were administered intraperitoneally beforeischemia and immediately after the reperfusion. The levels of total antioxidant capacity, totalfree sulfidril group, Total oxidant status, Oxidative stress index, and myeloperoxidase in livertissues were measured. The serum levels of ALT, AST and LDH were also measuredResults: Total antioxidant capacity and total free sulfidril group in liver tissue were significantlyhigher in group 3 than in group 2. Oxidative stress index and myeloperoxidase in liver tissuewere significantly lower in group 3 than the group 2. The levels of liver enzymes in treatmentgroup were significantly lower than those in the control group. Histological tissue damage wasmilder in the treatment group than that in the control group.Conclusion: It is concluded that Urtica dioica increase the antioxidant capacity and decreaseoxidative stress and liver enzymes in the hepatic ischemi reperfusion injury of rats.

  5. Relation between blood clearance and hepatic uptake of sup 99m Tc-phytate in rats with hepatic injury

    Shibata, Hiroshi; Hisano, Tomoyuki; Kohno, Masahiro (Yamaguchi University, Ube (Japan). Faculty of Agriculture)

    1989-10-01

    The relation among the blood clearance of {sup 99m}Tc-phytake ({sup 99m}Tc-P), the hepatic uptake of {sup 99m}Tc-P and the severity of hepatic injury was investigated by using the rats with carbon tetrachloride (CCL{sub 4}), D-galactosamine (Gal N), alpha-naphthylisothiocyanate (ANIT) or DL-ethionine (EthN) induced hepatic injury. After the administration of CCL{sub 4}, GalN or ANIT, serum GPT activity increased significantly with the increase of dose level, and the degree of this increase was in the order: GalN>CCl{sub 4}>ANIT. However, the mild increase in serum GPT activity was observed after EthN administration. The blood clearance rate of {sup 99m}Tc-P and the hepatic uptake ratio of {sup 99m}Tc-P decreased with the increase of dose level after CCl{sub 4}, GalN or ANIT administration, but significant changes were not found after EthN administration. The degree of decrease in the blood clearance rate of {sup 99m}Tc-P was in the order: GalNapproxCCl{sub 4}>ANIT, and the degree of decrease in the hepatic uptake ratio of {sup 99m}Tc-P was in the order: GalNapproxCCl{sub 4}>ANIT. These results suggest that the disorder in the hepatocytes may be one of causes for inducing the decrease in the hepatic uptake of {sup 99m}Tc-P, and the consequence of this decrease may induce the decrease in the blood clearance of {sup 99m}Tc-P. (author).

  6. Interleukin 17-producing γδT cells promote hepatic regeneration in mice.

    Rao, Raghavendra; Graffeo, Christopher S; Gulati, Rishabh; Jamal, Mohsin; Narayan, Suchithra; Zambirinis, Constantinos P; Barilla, Rocky; Deutsch, Michael; Greco, Stephanie H; Ochi, Atsuo; Tomkötter, Lena; Blobstein, Reuven; Avanzi, Antonina; Tippens, Daniel M; Gelbstein, Yisroel; Van Heerden, Eliza; Miller, George

    2014-08-01

    Subsets of leukocytes synergize with regenerative growth factors to promote hepatic regeneration. γδT cells are early responders to inflammation-induced injury in a number of contexts. We investigated the role of γδT cells in hepatic regeneration using mice with disruptions in Tcrd (encodes the T-cell receptor δ chain) and Clec7a (encodes C-type lectin domain family 7 member a, also known as DECTIN1). We performed partial hepatectomies on wild-type C57BL/6, CD45.1, Tcrd(-/-), or Clec7a(-/-) mice. Cells were isolated from livers of patients and mice via mechanical and enzymatic digestion. γδT cells were purified by fluorescence-activated cell sorting. In mice, partial hepatectomy up-regulated expression of CCL20 and ligands of Dectin-1, which was associated with recruitment and activation of γδT cells and their increased production of interleukin (IL)-17 family cytokines. Recruited γδT cells induced production of IL-6 by antigen-presenting cells and suppressed expression of interferon gamma by natural killer T cells, promoting hepatocyte proliferation. Absence of IL-17-producing γδT cells or deletion of Dectin-1 prevented development of regenerative phenotypes in subsets of innate immune cells. This slowed liver regeneration and was associated with reduced expression of regenerative growth factors and cell cycle regulators. Conversely, exogenous administration of IL-17 family cytokines or Dectin-1 ligands promoted regeneration. More broadly, we found that γδT cells are required for inflammatory responses mediated by IL-17 and Dectin-1. γδT cells regulate hepatic regeneration by producing IL-22 and IL-17, which have direct mitogenic effects on hepatocytes and promote a regenerative phenotype in hepatic leukocytes, respectively. Dectin-1 ligation is required for γδT cells to promote hepatic regeneration. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

  7. Superoxide produced by Kupffer cells is an essential effector in concanavalin A-induced hepatitis in mice.

    Nakashima, Hiroyuki; Kinoshita, Manabu; Nakashima, Masahiro; Habu, Yoshiko; Shono, Satoshi; Uchida, Takefumi; Shinomiya, Nariyoshi; Seki, Shuhji

    2008-12-01

    Although concanavalin A (Con-A)-induced experimental hepatitis is thought to be induced by activated T cells, natural killer T (NKT) cells, and cytokines, precise mechanisms are still unknown. In the current study, we investigated the roles of Kupffer cells, NKT cells, FasL, tumor necrosis factor (TNF), and superoxide in Con-A hepatitis in C57BL/6 mice. Removal of Kupffer cells using gadolinium chloride (GdCl(3)) from the liver completely inhibited Con-A hepatitis, whereas increased serum TNF and IFN-gamma levels were not inhibited at all. Unexpectedly, anti-FasL antibody pretreatment did not inhibit Con-A hepatitis, whereas it inhibited hepatic injury induced by a synthetic ligand of NKT cells, alpha-galactosylceramide. Furthermore, GdCl(3) pretreatment changed neither the activation-induced down-regulation of NK1.1 antigens as well as T cell receptors of NKT cells nor the increased expression of the CD69 activation antigen of hepatic T cells. CD68(+) Kupffer cells greatly increased in proportion in the early phase after Con-A injection; this increase was abrogated by GdCl(3) pretreatment. Anti-TNF antibody (Ab) pretreatment did not inhibit the increase of Kupffer cells, but it effectively suppressed superoxide/reactive oxygen production from Kupffer cells and the resulting hepatic injury. Conversely, depletion of NKT cells in mice by NK1.1 Ab pretreatment did suppress both the increase of CD68(+) Kupffer cells and Con-A hepatitis. Consistently, the diminution of oxygen radicals produced by Kupffer cells by use of free radical scavengers greatly inhibited Con-A hepatitis without suppressing cytokine production. However, adoptive transfer experiments also indicate that a close interaction/cooperation of Kupffer cells with NKT cells is essential for Con-A hepatitis. Superoxide produced by Kupffer cells may be the essential effector in Con-A hepatitis, and TNF and NKT cells support their activation and superoxide production.

  8. Limitations of nonoperative management of type IIIb blunt hepatic injuries in hemodynamically stable patients after fluid resuscitation

    Sekine, Kazuhiko; Kitano, Mitsuhide; Shimizu, Masayuki; Matsumoto, Shokei; Yoshii, Hiroshi; Yamazaki, Motoyasu; Aikawa, Naoki

    2007-01-01

    Nonoperative management (NOM) of hepatic injuries caused by blunt trauma in hemodynamically stable patients is widely accepted, but the feasibility of NOM for severe hepatic injuries has not been fully evaluated. Among all patients with blunt severe hepatic injury (type IIIb) admitted to Saiseikai Kanagawa-ken Hospital and Keio University Hospital from 1988 to 2004, those who had been hemodynamically stable after fluid resuscitation at the emergency department were initially managed nonoperatively. We reviewed demographic, physiological, and laboratory data; computed tomography (CT) findings; 80-day cumulative laparotomy rate; and complications. The anatomical severity of the hepatic injuries was evaluated based on the CT findings, such as hepatic vein injuries and area lacerated according to the Couinaud liver segment. In patients who underwent surgery after admission, the surgical indications and operative findings were reviewed. Overall, 34 consecutive patients were enrolled in this study. Five patients underwent surgery, and all of their surgical indications were attributable to liver-related complications after injury. The indication for surgery was hemodynamic instability in 3 patients with hepatic vein injures in the early phase (<15 hours after estrogen receptor (ER) arrival) and intra-abdominal septic complications in 2 patients in the late phase (hospital days 14 and 64). The cumulative 80-day laparotomy rate in the early phase was significantly higher (p<0.0001) in the patients suspected of having hepatic vein injury, and in the late phase it was higher (p=0.002) in those with injuries in 4 or more segments of hepatic injuries. For the successful NOM of blunt hepatic injury type IIIb in patients who are hemodynamically stable after fluid resuscitation, a strong suspicion of concurrent hepatic vein injury is critical in the early phase, and laceration in 4 or more segments should be noted in the late phase. (author)

  9. Effects of model traumatic injury on hepatic drug metabolism in the rat. IV. Glucuronidation.

    Griffeth, L K; Rosen, G M; Rauckman, E J

    1985-01-01

    A previously validated small mammal trauma model, hind-limb ischemia secondary to infrarenal aortic ligation in the rat, was utilized to investigate the effects of traumatic injury on hepatic glucuronidation activity. As was previously observed with hepatic oxidative drug metabolism, model trauma resulted in a significant decrease in the in vivo glucuronidation of chloramphenicol, with a 23% drop in clearance of this drug. The effect on in vivo pharmacokinetics appeared to result from a complex interaction between trauma's differential influences on conjugating enzyme(s), deconjugating enzyme(s), and hepatic UDP-glucuronic acid levels, as well as the relative physiological importance of these variables. Hepatic UDP-glucuronyltransferase activities towards both p-nitrophenol and chloramphenicol were elevated (44-54%) after model injury when measured in native hepatic microsomes. However, microsomes which had been "activated" by treatment with Triton X-100 showed no significant difference between control and traumatized animals. Serum beta-glucuronidase activities were elevated by 58%, while hepatic beta-glucuronidase rose by about 16%. Nevertheless, in vivo deconjugation showed no significant change. Model trauma also resulted in a 46% decrease in hepatic UDP-glucuronic acid content. Thus, the observed post-traumatic depression of in vivo chloramphenicol glucuronidation could be due either to a diminished availability of a necessary cofactor (UDP-glucuronic acid) or to an alteration in enzyme kinetics or function in vivo.

  10. Endogenous n-3 polyunsaturated fatty acids attenuate T cell-mediated hepatitis via autophagy activation

    Yanli Li

    2016-09-01

    Full Text Available Omega-3 polyunsaturated fatty acids (n-3 PUFAs exert anti-inflammatory effects in several liver disorders, including cirrhosis, acute liver failure, and fatty liver disease. To date, little is known about their role in immune-mediated liver diseases. In this study, we used fat-1 transgenic mice rich in endogenous n-3 PUFAs to examine the role of n-3 PUFAs in immune-mediated liver injury. Concanavalin A (Con A was administered intravenously to wild-type (WT and fat-1 transgenic mice to induce T cell-mediated hepatitis. Reduced liver damage was shown in Con A-administrated fat-1 transgenic mice, as evidenced by decreased mortality, attenuated hepatic necrosis, lessened serum alanine aminotransferase (ALT activity, and inhibited production of pro-inflammatory cytokines (e.g. TNF-α, IL-6, IL-17A and IFN-γ. In vivo and in vitro studies demonstrated that n-3 PUFAs significantly inhibited the activation of hepatic T cells and the differentiation of Th1 cells after Con A challenge. Further studies showed that n-3 PUFAs markedly increased autophagy level in Con A-treated fat-1 T cells compared with the WT counterparts. Blocking hepatic autophagy activity with chloroquine diminished the differences in T cell activation and liver injury between Con A-injected WT and fat-1 transgenic mice. We conclude that n-3 PUFAs limit Con A-induced hepatitis via an autophagy-dependent mechanism, and could be exploited as a new therapeutic approach for autoimmune hepatitis.

  11. Bile ductal injury and ductular reaction are frequent phenomena with different significance in autoimmune hepatitis.

    Verdonk, Robert C; Lozano, Mallaki F; van den Berg, Aad P; Gouw, Annette S H

    2016-09-01

    The significance of bile duct injury and ductular reaction in biopsies from autoimmune hepatitis patients is not clear. We aim to establish the prevalence and clinical relevance of both phenomena in autoimmune hepatitis. Cases of newly diagnosed, untreated autoimmune hepatitis without overlap syndrome were selected. Pretreatment and follow up biopsies were scored for inflammation, fibrosis, bile ductal injury and ductular reaction. Thirty-five cases were studied of whom 14 cases had follow up biopsies. Bile duct injury was present in 29 cases (83%), mostly in a PBC-like pattern and was not correlated with demographical or laboratory findings. Ductular reaction, observed in 25 of 35 cases (71%) using conventional histology and in 30 of 32 cases (94%) using immunohistochemistry, was correlated with portal and lobular inflammation, interface hepatitis and centrilobular necrosis as well as bile duct injury and fibrosis. In 11 of 14 cases (79%) ductular reaction remained present on post-treatment biopsy whereas bile duct injury persisted in six of 14 (43%) of cases. Bile duct injury and ductular reaction are very common in newly diagnosed autoimmune hepatitis and cannot be predicted biochemically. Bile duct injury may subside in the majority of treated AIH cases while DR tends to persist during follow up. These findings show that the two phenomena are part of the spectrum of AIH with dissimilar responses to treatment and do not necessarily point towards an overlap syndrome. Persistence of ductular reaction after treatment supports the notion that it represents a regenerative response. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  12. Promoting effect of adipocytokine, apelin, on hepatic injury in ...

    Marwa N. Emam

    2015-12-14

    Dec 14, 2015 ... and inflammatory markers, pancreatic and hepatic MPO activity with ..... ment, and possibly mediated by an apelin-induced reduction ... So targeting the ape- .... Adenoviral delivery of human and viral IL-10 in murine sepsis.

  13. Hepatic vascular injury: Clinical profile, endovascular management and outcomes

    Bishav Mohan

    2013-01-01

    Conclusion: Prompt endovascular management is the modality of choice in comparison to NOM without AE in both pediatric and adult patients with hemodynamically compromised inaccessible intra hepatic vascular trauma.

  14. Acute Liver Injury Is Independent of B Cells or Immunoglobulin M.

    James A Richards

    Full Text Available Acute liver injury is a clinically important pathology and results in the release of Danger Associated Molecular Patterns, which initiate an immune response. Withdrawal of the injurious agent and curtailing any pathogenic secondary immune response may allow spontaneous resolution of injury. The role B cells and Immunoglobulin M (IgM play in acute liver injury is largely unknown and it was proposed that B cells and/or IgM would play a significant role in its pathogenesis.Tissue from 3 models of experimental liver injury (ischemia-reperfusion injury, concanavalin A hepatitis and paracetamol-induced liver injury and patients transplanted following paracetamol overdose were stained for evidence of IgM deposition. Mice deficient in B cells (and IgM were used to dissect out the role B cells and/or IgM played in the development or resolution of injury. Serum transfer into mice lacking IgM was used to establish the role IgM plays in injury.Significant deposition of IgM was seen in the explanted livers of patients transplanted following paracetamol overdose as well as in 3 experimental models of acute liver injury (ischemia-reperfusion injury, concanavalin A hepatitis and paracetamol-induced liver injury. Serum transfer into IgM-deficient mice failed to reconstitute injury (p = 0.66, despite successful engraftment of IgM. Mice deficient in both T and B cells (RAG1-/- mice (p<0.001, but not B cell deficient (μMT mice (p = 0.93, were significantly protected from injury. Further interrogation with T cell deficient (CD3εKO mice confirmed that the T cell component is a key mediator of sterile liver injury. Mice deficient in B cells and IgM mice did not have a significant delay in resolution following acute liver injury.IgM deposition appears to be common feature of both human and murine sterile liver injury. However, neither IgM nor B cells, play a significant role in the development of or resolution from acute liver injury. T cells appear to be key

  15. Association Between MC-2 Peptide and Hepatic Perfusion and Liver Injury Following Resuscitated Hemorrhagic Shock.

    Matheson, Paul J; Fernandez-Botran, Rafael; Smith, Jason W; Matheson, Samuel A; Downard, Cynthia D; McClain, Craig J; Garrison, Richard N

    2016-03-01

    Hemorrhagic shock (HS) due to trauma remains a major cause of morbidity and mortality in the United States, despite continuing progression of advanced life support and treatment. Trauma is the third most common cause of death worldwide and is the leading cause of death in the 1- to 44-year-old age group. Hemorrhagic shock often progresses to multiple organ failure despite conventional resuscitation (CR) that restores central hemodynamics. To examine whether MC-2 would bind glycosaminoglycans to decrease proinflammatory cytokines' influence in the liver, minimize organ edema, prevent liver injury, and improve hepatic perfusion. MC-2, a synthetic octapeptide derived from the heparin-binding domain of murine interferon gamma (IFN-γ), binds glycosaminoglycans to modulate serum and interstitial cytokine levels and activity. A controlled laboratory study of 3y male Sprague-Dawley rats that were randomized to 4 groups of 8 each: sham, sham+MC-2 (50 mg/kg), HS/CR, or HS/CR+MC-2 (HS = 40% of baseline mean arterial pressure for 60 minutes; CR = return of shed blood and 2 volumes of saline). The study began in March, 2013. Effective hepatic blood flow (EHBF) by galactose clearance, wet-dry weights, cytokines, histopathology, complete metabolic panel, and complete blood cell count were performed at 4 hours after CR. MC-2 partially reversed the HS/CR-induced hepatic hypoperfusion at 3 and 4 hours postresuscitation compared with HS/CR alone. Effective hepatic blood flow decreased during the HS period from a mean (SD) of 7.4 (0.3) mL/min/100 g and 7.5 (0.5) mL/min/100g at baseline to 3.7 (0.4) mL/min/100g and 5.9 (0.5) mL/min/100g for the HS/CR and HS/CR+MC-2 groups, respectively (P hepatic blood flow remained constant in the sham groups throughout the experimental protocol. Organ edema was increased in the ileum and liver in the HS/CR vs sham group, and MC-2 decreased edema in the ileum vs the HS/CR group. MC-2 in HS also decreased levels of alanine aminotransferase

  16. Characterization of two distinct liver progenitor cell subpopulations of hematopoietic and hepatic origins

    Corcelle, V.; Stieger, B.; Gjinovci, A.; Wollheim, C.B.; Gauthier, B.R.

    2006-01-01

    Despite extensive studies, the hematopoietic versus hepatic origin of liver progenitor oval cells remains controversial. The aim of this study was to determine the origin of such cells after liver injury and to establish an oval cell line. Rat liver injury was induced by subcutaneous insertion of 2-AAF pellets for 7 days with subsequent injection of CCl 4 . Livers were removed 9 to 13 days post-CCl 4 treatment. Immunohistochemistry was performed using anti-c-kit, OV6, Thy1, CK19, AFP, vWF and Rab3b. Isolated non-parenchymal cells were grown on mouse embryonic fibroblast, and their gene expression profile was characterized by RT-PCR. We identified a subpopulation of OV6/CK19/Rab3b-expressing cells that was activated in the periportal region of traumatized livers. We also characterized a second subpopulation that expressed the HSCs marker c-kit but not Thy1. Although we successfully isolated both cell types, OV6/CK19/Rab3b + cells fail to propagate while c-kit + -HSCs appeared to proliferate for up to 7 weeks. Cells formed clusters which expressed c-kit, Thy1 and albumin. Our results indicate that a bona fide oval progenitor cell population resides within the liver and is distinct from c-kit + -HSCs. Oval cells require the hepatic niche to proliferate, while cells mobilized from the circulation proliferate and transdifferentiate into hepatocytes without evidence of cell fusion

  17. An Hepatic Abscess in a Patient With Sickle Cell Anemia.

    Marolf, Marissa D; Chaudhary, Manu; Kaplan, Sheldon L

    2016-11-01

    We present a case of hepatic abscess in a transfusion-dependent 16-year-old patient with sickle cell disease. There have been 10 such cases in sickle cell disease patients reported, with the last report published greater than a decade ago. The diagnosis of hepatic abscess merits consideration in sickle cell disease patients presenting with fever without a source and/or abdominal pain.

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

    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

    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. 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. 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). 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.

  19. Selective inhibition of iNOS attenuates trauma-hemorrhage/resuscitation-induced hepatic injury.

    Kan, Wen-Hong; Hsu, Jun-Te; Schwacha, Martin G; Choudhry, Mashkoor A; Raju, Raghavan; Bland, Kirby I; Chaudry, Irshad H

    2008-10-01

    Although trauma-hemorrhage produces tissue hypoxia, systemic inflammatory response and organ dysfunction, the mechanisms responsible for these alterations are not clear. Using a potent selective inducible nitric oxide (NO) synthase inhibitor, N-[3-(aminomethyl) benzyl]acetamidine (1400W), and a nonselective NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), we investigated whether inducible NO synthase plays any role in producing hepatic injury, inflammation, and changes of protein expression following trauma-hemorrhage. To investigate this, male Sprague-Dawley rats were subjected to midline laparotomy and hemorrhagic shock (mean blood pressure 35-40 mmHg for approximately 90 min) followed by fluid resuscitation. Animals were treated with either vehicle (DMSO) or 1400W (10 mg/kg body wt ip), or L-NAME (30 mg/kg iv), 30 min before resuscitation and killed 2 h after resuscitation. Trauma-hemorrhage/resuscitation induced a marked hypotension and increase in markers of hepatic injury (i.e., plasma alpha-glutathione S-transferase, tissue myeloperoxidase activity, and nitrotyrosine formation). Hepatic expression of iNOS, hypoxia-inducible factor-1alpha, ICAM-1, IL-6, TNF-alpha, and neutrophil chemoattractant (cytokine-induced neutrophil chemoattractant-1 and macrophage inflammatory protein-2) protein levels were also markedly increased following trauma-hemorrhage/resuscitation. Administration of the iNOS inhibitor 1400W significantly attenuated hypotension and expression of these mediators of hepatic injury induced by trauma-hemorrhage/resuscitation. However, administration of L-NAME could not attenuate hepatic dysfunction and tissue injury mediated by trauma-hemorrhage, although it improved mean blood pressure as did 1400W. These results indicate that increased expression of iNOS following trauma-hemorrhage plays an important role in the induction of hepatic damage under such conditions.

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

    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.

  1. Bee's honey attenuates non-alcoholic steatohepatitis-induced hepatic injury through the regulation of thioredoxin-interacting protein-NLRP3 inflammasome pathway.

    Xiao, Jia; Liu, Yingxia; Xing, Feiyue; Leung, Tung Ming; Liong, Emily C; Tipoe, George L

    2016-06-01

    We aim to examine whether honey ameliorates hepatic injury in non-alcoholic steatohepatitis (NASH) animal and cell line steatosis models. NASH was induced in female Sprague-Dawley rat by 8-week feeding with a high-fat diet. During the experiment, 5 g/kg honey was intragastrically fed daily. Rat normal hepatocyte BRL-3A cell was treated with sodium palmitate (SP) to induce steatosis in the absence or presence of honey pre-treatment or specific siRNA/overexpress plasmid of thioredoxin-interacting protein (TXNIP) or antagonist/agonist of Nod-like receptor protein 3 (NLRP3). Honey significantly improved the high-fat-diet-induced hepatic injury, steatosis, fibrosis, oxidative stress, and inflammation in rats. Honey also inhibited the overexpression of TXNIP and the activation of NLRP3 inflammasome. These effects were replicated in BRL-3A cell line which showed that the down-regulation of TXNIP or inhibition of NLRP3 contributed to the suppression of NLRP3 inflammasome activation, inflammation, and re-balanced lipid metabolism. In contrast, overexpression of TXNIP or agonism of NLRP3 exacerbated the cellular damage induced by SP. Suppression of the TXNIP-NLRP3 inflammasome pathway may partly contribute to the amelioration of hepatic injury during the progression of NASH by honey. Targeting hepatic TXNIP-NLRP3 inflammasome pathway is a potential therapeutic way for the prevention and treatment of NASH.

  2. Efficacy of 131I treatment for 840 cases of Graves' disease combined with hepatic function injury

    Yin Liang; Tan Jian; Wang Renfei

    2012-01-01

    Objective: To assess the efficacy of 131 I treatment for Graves' disease (GD) complicated with hepatic function injury in order to provide guidance for clinical practice. Methods: A total of 840 GD cases complicated with hepatic function injury were retrospectively reviewed after 131 I treatment. Analysis of variance and Dunnett t test were used to compare serum FT 3 , FT 4 , and TSH levels before and 1, 3, and 6 months after 131 I therapy. R × C table χ 2 test was used to compare therapeutic efficacies among cases with different degrees and types of hepatic function injuries. Analysis of variance and Dunnett t test were used to evaluate recovery time of different degrees of hepatic function injuries. Cross classification 2 × 2 table correlation analysis was adopted to assess the correlation between 131 I therapeutic efficacies of GD and recovery efficacies of hepatic function. Results: The curative rate for GD was 76.8% (645/840). There were significant changes of FT 3 ((25.74 ± 5.81), (15.54 ± 4.12), (12.76 ± 2.35) and (7.95 ± 1.64) pmol/L, respectively; F=5007.958, t=54.455, 69.297 and 94.976, all P<0.05), FT 4 ((75.84 ± 16.78), (45.69 ±8.96), (36.81 ± 5.03) and (25.17 ±.4.46) pmol/L, respectively; F=3876.410, t=513.602, 664.871 and 863.157, all P<0.05) and TSH ((0.01 ±0.02), (0.02±0.08), (0.85 ±0.36) and (1.26 ± 0.54) mU/L, respectively; F=3050.430, t=2.627, 46.989 and 78.315, all P<0.05) before and 1,3,and 6 months after 131 I treatment. The curative rate of hepatic function abnormality was 79.2% (665/840). For mild, medium and severe hepatic function injury patients, curative rates were 88.4% (420/475), 68.8% (214/311) and 57.4% (31/54), respectively. The curative rate of patients with mild hepatic function injury was significantly higher than those with medium and severe hepatic function injury (χ 2 =46.338, 37.100, respectively, both P<0.01), and the recovery time was significantly shorter in patients with mild hepatic function injury

  3. Study on pretreatment of FPS-1 in rats with hepatic ischemia-reperfusion injury.

    Lin, Shiqing; Liu, Kexuan; Wu, Weikang; Chen, Chao; Wang, Zhi; Zhang, Xuanhong

    2009-01-01

    This study was designed to determine whether FPS-1, the water-soluble polysaccharide isolated from fuzi, protected against hepatic damage in hepatic ischemia-reperfusion injury in rats, and its mechanism. SD rats were subjected to 60 min of hepatic ischemia, followed by 120 min reperfusion. FPS-1 (160 mg/kg/day) was administered orally for 5 days before ischemia-reperfusion injury in treatment group. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and albumin (ALB) were assayed to evaluate liver functions. Liver samples were taken for histological examination and determination of malondialdehyde (MDA), superoxide dismutase (SOD), that catalase (CAT) in liver. Na(+)-K(+)-ATPase and Ca(2+)-ATPase in mitochondria were measured with colorimetry method. Morphological changes were also investigated by using both light microscopy and electron microscopy (EM). In addition, apoptosis and oncosis were detected by Annexin V-FITC/PI immunofluorescent flow cytometry analysis. Serum AST and ALT levels were elevated in groups exposed to ischemia-reperfusion (p FPS-1 reversed all these biochemical parameters as well as histological alterations, evidently by increased SOD, CAT, reduced MDA and histological scores compared to the model group (p FPS-1 could attenuate the necrotic states by the detection of immunofluorescent flow cytometry analysis. Pretreatment with FPS-1 reduced hepatic ischemia-reperfusion injury through its potent antioxidative effects and attenuation of necrotic states.

  4. Natural Killer Cells in Viral HepatitisSummary

    Barbara Rehermann

    2015-11-01

    Full Text Available Natural killer (NK cells are traditionally regarded as first-line effectors of the innate immune response, but they also have a distinct role in chronic infection. Here, we review the role of NK cells against hepatitis C virus (HCV and hepatitis B virus (HBV, two agents that cause acute and chronic hepatitis in humans. Interest in NK cells was initially sparked by genetic studies that demonstrated an association between NK cell–related genes and the outcome of HCV infection. Viral hepatitis also provides a model to study the NK cell response to both endogenous and exogenous type I interferon (IFN. Levels of IFN-stimulated genes increase in both acute and chronic HCV infection and pegylated IFNα has been the mainstay of HCV and HBV treatment for decades. In chronic viral hepatitis, NK cells display decreased production of antiviral cytokines. This phenotype is found in both HCV and HBV infection but is induced by different mechanisms. Potent antivirals now provide the opportunity to study the reversibility of the suppressed cytokine production of NK cells in comparison with the antigen-induced defect in IFNγ and tumor necrosis factor-α production of virus-specific T cells. This has implications for immune reconstitution in other conditions of chronic inflammation and immune exhaustion, such as human immunodeficiency virus infection and cancer. Keywords: HBV, HCV, Infection, Interferon, T Cell

  5. Branched Chain Amino Acids Cause Liver Injury in Obese/Diabetic Mice by Promoting Adipocyte Lipolysis and Inhibiting Hepatic Autophagy.

    Zhang, Fuyang; Zhao, Shihao; Yan, Wenjun; Xia, Yunlong; Chen, Xiyao; Wang, Wei; Zhang, Jinglong; Gao, Chao; Peng, Cheng; Yan, Feng; Zhao, Huishou; Lian, Kun; Lee, Yan; Zhang, Ling; Lau, Wayne Bond; Ma, Xinliang; Tao, Ling

    2016-11-01

    The Western meat-rich diet is both high in protein and fat. Although the hazardous effect of a high fat diet (HFD) upon liver structure and function is well recognized, whether the co-presence of high protein intake contributes to, or protects against, HF-induced hepatic injury remains unclear. Increased intake of branched chain amino acids (BCAA, essential amino acids compromising 20% of total protein intake) reduces body weight. However, elevated circulating BCAA is associated with non-alcoholic fatty liver disease and injury. The mechanisms responsible for this quandary remain unknown; the role of BCAA in HF-induced liver injury is unclear. Utilizing HFD or HFD+BCAA models, we demonstrated BCAA supplementation attenuated HFD-induced weight gain, decreased fat mass, activated mammalian target of rapamycin (mTOR), inhibited hepatic lipogenic enzymes, and reduced hepatic triglyceride content. However, BCAA caused significant hepatic damage in HFD mice, evidenced by exacerbated hepatic oxidative stress, increased hepatic apoptosis, and elevated circulation hepatic enzymes. Compared to solely HFD-fed animals, plasma levels of free fatty acids (FFA) in the HFD+BCAA group are significantly further increased, due largely to AMPKα2-mediated adipocyte lipolysis. Lipolysis inhibition normalized plasma FFA levels, and improved insulin sensitivity. Surprisingly, blocking lipolysis failed to abolish BCAA-induced liver injury. Mechanistically, hepatic mTOR activation by BCAA inhibited lipid-induced hepatic autophagy, increased hepatic apoptosis, blocked hepatic FFA/triglyceride conversion, and increased hepatocyte susceptibility to FFA-mediated lipotoxicity. These data demonstrated that BCAA reduces HFD-induced body weight, at the expense of abnormal lipolysis and hyperlipidemia, causing hepatic lipotoxicity. Furthermore, BCAA directly exacerbate hepatic lipotoxicity by reducing lipogenesis and inhibiting autophagy in the hepatocyte. Copyright © 2016. Published by Elsevier

  6. Branched Chain Amino Acids Cause Liver Injury in Obese/Diabetic Mice by Promoting Adipocyte Lipolysis and Inhibiting Hepatic Autophagy

    Fuyang Zhang

    2016-11-01

    Full Text Available The Western meat-rich diet is both high in protein and fat. Although the hazardous effect of a high fat diet (HFD upon liver structure and function is well recognized, whether the co-presence of high protein intake contributes to, or protects against, HF-induced hepatic injury remains unclear. Increased intake of branched chain amino acids (BCAA, essential amino acids compromising 20% of total protein intake reduces body weight. However, elevated circulating BCAA is associated with non-alcoholic fatty liver disease and injury. The mechanisms responsible for this quandary remain unknown; the role of BCAA in HF-induced liver injury is unclear. Utilizing HFD or HFD + BCAA models, we demonstrated BCAA supplementation attenuated HFD-induced weight gain, decreased fat mass, activated mammalian target of rapamycin (mTOR, inhibited hepatic lipogenic enzymes, and reduced hepatic triglyceride content. However, BCAA caused significant hepatic damage in HFD mice, evidenced by exacerbated hepatic oxidative stress, increased hepatic apoptosis, and elevated circulation hepatic enzymes. Compared to solely HFD-fed animals, plasma levels of free fatty acids (FFA in the HFD + BCAA group are significantly further increased, due largely to AMPKα2-mediated adipocyte lipolysis. Lipolysis inhibition normalized plasma FFA levels, and improved insulin sensitivity. Surprisingly, blocking lipolysis failed to abolish BCAA-induced liver injury. Mechanistically, hepatic mTOR activation by BCAA inhibited lipid-induced hepatic autophagy, increased hepatic apoptosis, blocked hepatic FFA/triglyceride conversion, and increased hepatocyte susceptibility to FFA-mediated lipotoxicity. These data demonstrated that BCAA reduces HFD-induced body weight, at the expense of abnormal lipolysis and hyperlipidemia, causing hepatic lipotoxicity. Furthermore, BCAA directly exacerbate hepatic lipotoxicity by reducing lipogenesis and inhibiting autophagy in the hepatocyte.

  7. Hepatitis

    ... most common types of viral hepatitis. What Is Hepatitis A? For kids, hep A is the most common ... they recover, it does not come back. Can Hepatitis A Be Prevented? The following will help keep people ...

  8. Hedgehog-mediated paracrine interaction between hepatic stellate cells and marrow-derived mesenchymal stem cells

    Lin Nan; Tang Zhaofeng; Deng Meihai; Zhong Yuesi; Lin Jizong; Yang Xuhui; Xiang Peng; Xu Ruiyun

    2008-01-01

    During liver injury, bone marrow-derived mesenchymal stem cells (MSCs) can migrate and differentiate into hepatocytes. Hepatic stellate cell (SC) activation is a pivotal event in the development of liver fibrosis. Therefore, we hypothesized that SCs may play an important role in regulating MSC proliferation and differentiation through the paracrine signaling pathway. We demonstrate that MSCs and SCs both express hedgehog (Hh) pathway components, including its ligands, receptors, and target genes. Transwell co-cultures of SCs and MSCs showed that the SCs produced sonic hedgehog (Shh), which enhanced the proliferation and differentiation of MSCs. These findings demonstrate that SCs indirectly modulate the activity of MSCs in vitro via the Hh pathway, and provide a plausible explanation for the mechanisms of transplanted MSCs in the treatment of liver fibrosis

  9. Epigenetic Changes during Hepatic Stellate Cell Activation.

    Silke Götze

    Full Text Available Hepatic stellate cells (HSC, which can participate in liver regeneration and fibrogenesis, have recently been identified as liver-resident mesenchymal stem cells. During their activation HSC adopt a myofibroblast-like phenotype accompanied by profound changes in the gene expression profile. DNA methylation changes at single genes have been reported during HSC activation and may participate in the regulation of this process, but comprehensive DNA methylation analyses are still missing. The aim of the present study was to elucidate the role of DNA methylation during in vitro activation of HSC.The analysis of DNA methylation changes by antibody-based assays revealed a strong decrease in the global DNA methylation level during culture-induced activation of HSC. To identify genes which may be regulated by DNA methylation, we performed a genome-wide Methyl-MiniSeq EpiQuest sequencing comparing quiescent and early culture-activated HSC. Approximately 400 differentially methylated regions with a methylation change of at least 20% were identified, showing either hypo- or hypermethylation during activation. Further analysis of selected genes for DNA methylation and expression were performed revealing a good correlation between DNA methylation changes and gene expression. Furthermore, global DNA demethylation during HSC activation was investigated by 5-bromo-2-deoxyuridine assay and L-mimosine treatment showing that demethylation was independent of DNA synthesis and thereby excluding a passive DNA demethylation mechanism.In summary, in vitro activation of HSC initiated strong DNA methylation changes, which were associated with gene regulation. These results indicate that epigenetic mechanisms are important for the control of early HSC activation. Furthermore, the data show that global DNA demethylation during activation is based on an active DNA demethylation mechanism.

  10. Pharmacological inhibition of the chemokine CXCL16 diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury.

    Alexander Wehr

    Full Text Available Non-alcoholic fatty liver disease (NAFLD is a major cause of morbidity and mortality in developed countries, resulting in steatohepatitis (NASH, fibrosis and eventually cirrhosis. Modulating inflammatory mediators such as chemokines may represent a novel therapeutic strategy for NAFLD. We recently demonstrated that the chemokine receptor CXCR6 promotes hepatic NKT cell accumulation, thereby controlling inflammation in experimental NAFLD. In this study, we first investigated human biopsies (n = 20, confirming that accumulation of inflammatory cells such as macrophages is a hallmark of progressive NAFLD. Moreover, CXCR6 gene expression correlated with the inflammatory activity (ALT levels in human NAFLD. We then tested the hypothesis that pharmacological inhibition of CXCL16 might hold therapeutic potential in NAFLD, using mouse models of acute carbon tetrachloride (CCl4- and chronic methionine-choline-deficient (MCD diet-induced hepatic injury. Neutralizing CXCL16 by i.p. injection of anti-CXCL16 antibody inhibited the early intrahepatic NKT cell accumulation upon acute toxic injury in vivo. Weekly therapeutic anti-CXCL16 administrations during the last 3 weeks of 6 weeks MCD diet significantly decreased the infiltration of inflammatory macrophages into the liver and intrahepatic levels of inflammatory cytokines like TNF or MCP-1. Importantly, anti-CXCL16 treatment significantly reduced fatty liver degeneration upon MCD diet, as assessed by hepatic triglyceride levels, histological steatosis scoring and quantification of lipid droplets. Moreover, injured hepatocytes up-regulated CXCL16 expression, indicating that scavenging functions of CXCL16 might be additionally involved in the pathogenesis of NAFLD. Targeting CXCL16 might therefore represent a promising novel therapeutic approach for liver inflammation and steatohepatitis.

  11. Folic acid and melatonin ameliorate carbon tetrachloride-induced hepatic injury, oxidative stress and inflammation in rats

    Ebaid Hossam

    2013-02-01

    Full Text Available Abstract This study investigated the protective effects of melatonin and folic acid against carbon tetrachloride (CCl4-induced hepatic injury in rats. Oxidative stress, liver function, liver histopathology and serum lipid levels were evaluated. The levels of protein kinase B (Akt1, interferon gamma (IFN-γ, programmed cell death-receptor (Fas and Tumor necrosis factor-alpha (TNF-α mRNA expression were analyzed. CCl4 significantly elevated the levels of lipid peroxidation (MDA, cholesterol, LDL, triglycerides, bilirubin and urea. In addition, CCl4 was found to significantly suppress the activity of both catalase and glutathione (GSH and decrease the levels of serum total protein and HDL-cholesterol. All of these parameters were restored to their normal levels by treatment with melatonin, folic acid or their combination. An improvement of the general hepatic architecture was observed in rats that were treated with the combination of melatonin and folic acid along with CCl4. Furthermore, the CCl4-induced upregulation of TNF-α and Fas mRNA expression was significantly restored by the three treatments. Melatonin, folic acid or their combination also restored the baseline levels of IFN-γ and Akt1 mRNA expression. The combination of melatonin and folic acid exhibited ability to reduce the markers of liver injury induced by CCl4 and restore the oxidative stability, the level of inflammatory cytokines, the lipid profile and the cell survival Akt1 signals.

  12. Hepatitis C virus in sickle cell disease.

    Hassan, Mohamed; Hasan, Syed; Giday, Samuel; Alamgir, Laila; Banks, Alpha; Frederick, Winston; Smoot, Duane; Castro, Oswaldo

    2003-01-01

    PURPOSE: To determine the prevalence of hepatitis C virus antibodies (anti-HCV) in patients with sickle cell disease. PATIENTS AND METHODS: Between 1983 and 2001, 150 patients from the Howard University Hospital Center for Sickle Cell Disease were screened for HCV antibody (52% women, 48% men, mean age 34 years). Frozen serum samples from 56 adult sickle cell patients who had participated in previous surveys (1983-92) of HIV and HTLV-1 serology and who were tested in 1992 for anti-HCV antibody--when commercial ELISA test (Ortho) became available--were included in this paper. Of the 150 patients in the study, 132 had sickle cell anemia genotype (SS), 15 had sickle cell hemoglobin-C disease (SC) and three had sickle beta thalassemia. Clinical charts were reviewed for history of blood transfusion, IV drug abuse, homosexuality, tattooing, iron overload, and alcohol abuse. RESULTS: Antibodies to HCV were detected in 53 patients (35.3%). Of the 55 patients who had frozen serum samples tested in 1992, 32 (58%) were reactive for anti-HCV, while only 21 of the 95 patients (22%) tested after 1992 were positive for HCV antibodies (P<0.001). Thirty-nine of 77 patients (51%) who received more than 10 units of packed red blood cells were positive for HCV antibody, and only 14 of 61 patients (23%) who received less than 10 units of packed red blood cells transfusion were positive for HCV antibodies (P<0.001). None of the 12 patients who never received transfusion were positive for HCV antibody. In the 53 anti-HCV positive patients, the mean alanine amino-transferase (ALT) value was 98- and 81 U/L, respectively, for males and females. These values were normal for the HCV-antibody negative patients. The aspartate amino-transferase (AST) and the total bilirubin were also higher in the anti-HCV positive patients compared to patients in the anti-HCV negative group. Forty-four patients (57.1%) who were transfused more than 10 units developed iron overload defined by a serum ferritin

  13. Multidisciplinary approach for the management of complex hepatic injuries AAST-OIS grades IV-V: a prospective study.

    Asensio, J A; Petrone, P; García-Núñez, L; Kimbrell, B; Kuncir, E

    2007-01-01

    Complex hepatic injuries grades IV-V are highly lethal. The objective of this study is to assess the multidisciplinary approach for their management and to evaluate if survival could be improved with this approach. Prospective 54-month study of all patients sustaining hepatic injuries grades IV-V managed operatively at a Level I Trauma Center. survival. univariate and stepwise logistic regression. Seventy-five patients sustained penetrating (47/63%) and blunt (28/37%) injuries. Seven (9%) patients underwent emergency department thoracotomy with a mortality of 100%. Out of the 75 patients, 52 (69%) sustained grade IV, and 23 (31%) grade V. The estimated blood loss was 3,539+/-3,040 ml. The overall survival was 69%, adjusted survival excluding patients requiring emergency department thoracotomy was 76%. Survival stratified to injury grade: grade IV 42/52-81%, grade V 10/23-43%. Mortality grade IV versus V injuries (p < 0.002; RR 2.94; 95% CI 1.52-5.70). Risk factors for mortality: packed red blood cells transfused in operating room (p=0.024), estimated blood loss (p < 0.001), dysryhthmia (p < 0.0001), acidosis (p = 0.051), hypothermia (p = 0.04). The benefit of angiography and angioembolization indicated: 12% mortality (2/17) among those that received it versus a 36% mortality (21/58) among those that did not (p = 0.074; RR 0.32; 95% CI 0.08-1.25). Stepwise logistic regression identified as significant independent predictors of outcome: estimated blood loss (p= 0.0017; RR 1.24; 95% CI 1.08-1.41) and number of packed red blood cells transfused in the operating room (p = 0.0358; RR 1.16; 95% CI 1.01-1.34). The multidisciplinary approach to the management of these severe grades of injuries appears to improve survival in these highly lethal injuries. A prospective multi-institutional study is needed to validate this approach.

  14. Partial Portal Vein Arterialization Attenuates Acute Bile Duct Injury Induced by Hepatic Dearterialization in a Rat Model.

    Jiang, Jun; Wei, Jishu; Wu, Junli; Gao, Wentao; Li, Qiang; Jiang, Kuirong; Miao, Yi

    2016-01-01

    Hepatic infarcts or abscesses occur after hepatic artery interruption. We explored the mechanisms of hepatic deprivation-induced acute liver injury and determine whether partial portal vein arterialization attenuated this injury in rats. Male Sprague-Dawley rats underwent either complete hepatic arterial deprivation or partial portal vein arterialization, or both. Hepatic ischemia was evaluated using biochemical analysis, light microscopy, and transmission electron microscopy. Hepatic ATP levels, the expression of hypoxia- and inflammation-associated genes and proteins, and the expression of bile transporter genes were assessed. Complete dearterialization of the liver induced acute liver injury, as evidenced by the histological changes, significantly increased serum biochemical markers, decreased ATP content, increased expression of hypoxia- and inflammation-associated genes and proteins, and decreased expression of bile transporter genes. These detrimental changes were extenuated but not fully reversed by partial portal vein arterialization, which also attenuated ductular reaction and fibrosis in completely dearterialized rat livers. Collectively, complete hepatic deprivation causes severe liver injury, including bile infarcts and biloma formation. Partial portal vein arterialization seems to protect against acute ischemia-hypoxia-induced liver injury.

  15. Partial Portal Vein Arterialization Attenuates Acute Bile Duct Injury Induced by Hepatic Dearterialization in a Rat Model

    Jun Jiang

    2016-01-01

    Full Text Available Hepatic infarcts or abscesses occur after hepatic artery interruption. We explored the mechanisms of hepatic deprivation-induced acute liver injury and determine whether partial portal vein arterialization attenuated this injury in rats. Male Sprague-Dawley rats underwent either complete hepatic arterial deprivation or partial portal vein arterialization, or both. Hepatic ischemia was evaluated using biochemical analysis, light microscopy, and transmission electron microscopy. Hepatic ATP levels, the expression of hypoxia- and inflammation-associated genes and proteins, and the expression of bile transporter genes were assessed. Complete dearterialization of the liver induced acute liver injury, as evidenced by the histological changes, significantly increased serum biochemical markers, decreased ATP content, increased expression of hypoxia- and inflammation-associated genes and proteins, and decreased expression of bile transporter genes. These detrimental changes were extenuated but not fully reversed by partial portal vein arterialization, which also attenuated ductular reaction and fibrosis in completely dearterialized rat livers. Collectively, complete hepatic deprivation causes severe liver injury, including bile infarcts and biloma formation. Partial portal vein arterialization seems to protect against acute ischemia-hypoxia-induced liver injury.

  16. Replacement of Retinyl Esters by Polyunsaturated Triacylglycerol Species in Lipid Droplets of Hepatic Stellate Cells during Activation

    Testerink, Nicole; Ajat, Mokrish; Houweling, Martin; Brouwers, Jos F.; Pully, Vishnu V.; van Manen, Henk-Jan; Otto, Cees; Helms, J. Bernd; Vaandrager, Arie B.

    2012-01-01

    Activation of hepatic stellate cells has been recognized as one of the first steps in liver injury and repair. During activation, hepatic stellate cells transform into myofibroblasts with concomitant loss of their lipid droplets (LDs) and production of excessive extracellular matrix. Here we aimed to obtain more insight in the dynamics and mechanism of LD loss. We have investigated the LD degradation processes in rat hepatic stellate cells in vitro with a combined approach of confocal Raman microspectroscopy and mass spectrometric analysis of lipids (lipidomics). Upon activation of the hepatic stellate cells, LDs reduce in size, but increase in number during the first 7 days, but the total volume of neutral lipids did not decrease. The LDs also migrate to cellular extensions in the first 7 days, before they disappear. In individual hepatic stellate cells. all LDs have a similar Raman spectrum, suggesting a similar lipid profile. However, Raman studies also showed that the retinyl esters are degraded more rapidly than the triacylglycerols upon activation. Lipidomic analyses confirmed that after 7 days in culture hepatic stellate cells have lost most of their retinyl esters, but not their triacylglycerols and cholesterol esters. Furthermore, we specifically observed a large increase in triacylglycerol-species containing polyunsaturated fatty acids, partly caused by an enhanced incorporation of exogenous arachidonic acid. These results reveal that lipid droplet degradation in activated hepatic stellate cells is a highly dynamic and regulated process. The rapid replacement of retinyl esters by polyunsaturated fatty acids in LDs suggests a role for both lipids or their derivatives like eicosanoids during hepatic stellate cell activation. PMID:22536341

  17. Replacement of retinyl esters by polyunsaturated triacylglycerol species in lipid droplets of hepatic stellate cells during activation.

    Nicole Testerink

    Full Text Available Activation of hepatic stellate cells has been recognized as one of the first steps in liver injury and repair. During activation, hepatic stellate cells transform into myofibroblasts with concomitant loss of their lipid droplets (LDs and production of excessive extracellular matrix. Here we aimed to obtain more insight in the dynamics and mechanism of LD loss. We have investigated the LD degradation processes in rat hepatic stellate cells in vitro with a combined approach of confocal Raman microspectroscopy and mass spectrometric analysis of lipids (lipidomics. Upon activation of the hepatic stellate cells, LDs reduce in size, but increase in number during the first 7 days, but the total volume of neutral lipids did not decrease. The LDs also migrate to cellular extensions in the first 7 days, before they disappear. In individual hepatic stellate cells. all LDs have a similar Raman spectrum, suggesting a similar lipid profile. However, Raman studies also showed that the retinyl esters are degraded more rapidly than the triacylglycerols upon activation. Lipidomic analyses confirmed that after 7 days in culture hepatic stellate cells have lost most of their retinyl esters, but not their triacylglycerols and cholesterol esters. Furthermore, we specifically observed a large increase in triacylglycerol-species containing polyunsaturated fatty acids, partly caused by an enhanced incorporation of exogenous arachidonic acid. These results reveal that lipid droplet degradation in activated hepatic stellate cells is a highly dynamic and regulated process. The rapid replacement of retinyl esters by polyunsaturated fatty acids in LDs suggests a role for both lipids or their derivatives like eicosanoids during hepatic stellate cell activation.

  18. Hepatitis B Vaccination Status and Needle stick Injuries among ...

    Background: Hepatits B virus (HBV) is the most common blood borne pathogen that poses an occupational risk to Health-care workers. The incidence of infection following needle stick injury has been reported to be high among medical students. Effective vaccines against HBV are available. The aim of this study was to ...

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

    Østerballe, Lene; Helgstrand, Frederik; Axelsen, Thomas

    2014-01-01

    INTRODUCTION: Hepatic pseudoaneurysm (HPA) is a rare complication after liver trauma, yet it is potentially fatal, as it can lead to sudden severe haemorrhage. The risk of developing posttraumatic HPA is one of the arguments for performing follow-up CT of patients with liver injuries. The aim...... no treatment failures. There was no correlation between the severity of the liver injury and development of HPA. 5 out of 7 patients were asymptomatic and would have been discharged without treatment if the protocol did not include a default follow-up CT. CONCLUSIONS: In conclusion, this study shows that HPA...

  20. Amniotic-fluid-derived mesenchymal stem cells overexpressing interleukin-1 receptor antagonist improve fulminant hepatic failure.

    Yu-Bao Zheng

    Full Text Available Uncontrolled hepatic immunoactivation is regarded as the primary pathological mechanism of fulminant hepatic failure (FHF. The major acute-phase mediators associated with FHF, including IL-1β, IL-6, and TNF-α, impair the regeneration of liver cells and stem cell grafts. Amniotic-fluid-derived mesenchymal stem cells (AF-MSCs have the capacity, under specific conditions, to differentiate into hepatocytes. Interleukin-1-receptor antagonist (IL-1Ra plays an anti-inflammatory and anti-apoptotic role in acute and chronic inflammation, and has been used in many experimental and clinical applications. In the present study, we implanted IL-1Ra-expressing AF-MSCs into injured liver via the portal vein, using D-galactosamine-induced FHF in a rat model. IL-1Ra expression, hepatic injury, liver regeneration, cytokines (IL-1β, IL-6, and animal survival were assessed after cell transplantation. Our results showed that AF-MSCs over-expressing IL-1Ra prevented liver failure and reduced mortality in rats with FHF. These animals also exhibited improved liver function and increased survival rates after injection with these cells. Using green fluorescent protein as a marker, we demonstrated that the engrafted cells and their progeny were incorporated into injured livers and produced albumin. This study suggests that AF-MSCs genetically modified to over-express IL-1Ra can be implanted into the injured liver to provide a novel therapeutic approach to the treatment of FHF.

  1. Saccharomyces boulardii prevention of the hepatic injury induced by Salmonella Enteritidis infection.

    Wu, Daichao; Teng, Da; Wang, Xiumin; Dai, Changsong; Wang, Jianhua

    2014-10-01

    Salmonella enterica subsp. enterica serovar Enteritidis (Salmonella Enteritidis) is the predominant cause of serovar-associated food-borne outbreaks in many countries and causes significant clinical symptoms of liver injury, enteritis, and diarrheal diseases. Saccharomyces boulardii is used in clinical application for prophylaxis and the treatment of a variety of diseases caused by bacterial infection. We used a mouse model of Salmonella Enteritidis infection, which included pretreatment with S. boulardii, to reveal the protection mechanisms of S. boulardii against Salmonella Enteritidis infection, including the translocation of Salmonella Enteritidis to the liver 10 days after Salmonella Enteritidis challenge, and the colonisation of Salmonella Enteritidis and the formation of hepatic tissue lesions in mice after Salmonella Enteritidis challenge on the 10th day. Compared with Salmonella Enteritidis infection in mice, S. boulardii decreased Salmonella Enteritidis translocation to the liver by 96%, and 99% of Salmonella Enteritidis colonised the cecum on the 10th day. Saccharomyces boulardii also abated hepatic tissue injury caused by the infiltration of neutrophilic granulocytes, lymphocytes, and plasmocytes by decreasing the translocation of Salmonella to the liver. These findings demonstrated that S. boulardii is an effective agent in the prevention of the hepatic injury induced by Salmonella Enteritidis infection in a mouse model.

  2. Differential Effects of Three Techniques for Hepatic Vascular Exclusion during Resection for Liver Cirrhosis on Hepatic Ischemia-Reperfusion Injury in Rats

    Changjun Jia

    2018-01-01

    Full Text Available Background/Aims. Hepatic ischemia-reperfusion (I/R injury is a serious concern during hepatic vascular occlusion. The objectives of this study were to assess effects of three techniques for hepatic vascular occlusion on I/R injury and to explore the underlying mechanisms. Methods. Liver cirrhotic rats had undertaken Pringle maneuver (PR, hemihepatic vascular occlusion (HH, or hepatic blood inflow occlusion without hemihepatic artery control (WH. Levels of tumor necrosis factor alpha (TNF-α, nuclear factor kappa B (NF-κB, toll-like receptor 4 (TLR4, TIR-domain-containing adapter-inducing interferon-β (TRIF, and hemeoxygenase 1 (HMOX1 were assayed. Results. The histopathologic analysis displayed that liver harm was more prominent in the PR group, but similar in the HH and WH groups. The HH and WH groups responded to hepatic I/R inflammation similarly but better than the PR group. Mechanical studies suggested that TNF-α/NF-κB signaling and TLR4/TRIF transduction pathways were associated with the differential effects. In addition, the HH and WH groups had significantly higher levels of hepatic HMOX1 (P<0.05 than the PR group. Conclusions. HH and WH confer better preservation of liver function and protection than the Pringle maneuver in combating I/R injury. Upregulation of HMOX1 may lead to better protection and clinical outcomes after liver resection.

  3. Hepatitis B Virus Infection In Patients With Homozygous Sickle Cell ...

    Nnebe-Agumadu U H, and Abiodun P O. Hepatitis B Virus Infection in Patients with Homozygous Sickle Cell Disease (HbSS): Need for Intervention. Annals Biomedical Sciences 2002; 1:79-87. This is a prospective study of 213 patients with sickle cell anaemia (SCA) (112 males and 101 females) aged 6 months to 18 years ...

  4. Synthetic Polymer with a Structure-Driven Hepatic Deposition and Curative Pharmacological Activity in Hepatic Cells

    Riber, Camilla Frich; Halling Folkmar Andersen, Anna; Anegaard Rolskov, Lærke

    2017-01-01

    Synthetic polymers make strong contributions as tools for delivery of biological drugs and chemotherapeutics. The most praised characteristic of polymers in these applications is complete lack of pharmacological function such as to minimize the side effects within the human body. In contrast......, synthetic polymers with curative pharmacological activity are truly rare. Moreover, such activity is typically nonspecific rather than structure-defined. In this work, we present the discovery of poly(ethylacrylic acid) (PEAA) as a polymer with a suit of structure-defined, unexpected, pharmacological......, and pharmacokinetic properties not observed in close structural analogues. Specifically, PEAA reveals capacity to bind to albumin with ensuing natural hepatic deposition in vivo and exhibits concurrent inhibitory activity against the hepatitis C virus and inflammation in hepatic cells. Our findings provide a view...

  5. Hepatic parenchymal atrophy induction for intractable segmental bile duct injury after liver resection.

    Hwang, Shin; Park, Gil-Chun; Ha, Tae-Yong; Ko, Gi-Young; Gwon, Dong-Il; Choi, Young-Il; Song, Gi-Won; Lee, Sung-Gyu

    2012-05-01

    Liver resection can result in various types of bile duct injuries but their treatment is usually difficult and often leads to intractable clinical course. We present an unusual case of hepatic segment III duct (B3) injury, which occurred after left medial sectionectomy for large hepatocellular carcinoma and was incidentally detected 1 week later due to bile leak. Since the pattern of this B3 injury was not adequate for operative biliary reconstruction, atrophy induction of the involved hepatic parenchyma was attempted. This treatment consisted of embolization of the segment III portal branch to inhibit bile production, induction of heavy adhesion at the bile leak site and clamping of the percutaneous transhepatic biliary drainage (PTBD) tube to accelerate segment III atrophy. This entire procedure, from liver resection to PTBD tube removal took 4 months. This patient has shown no other complication or tumor recurrence for 4 years to date. These findings suggest that percutaneous segmental portal vein embolization, followed by intentional clamping of external biliary drainage, can effectively control intractable bile leak from segmental bile duct injury.

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

    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.

  7. Effect of selective versus non-selective cyclooxygenase inhibitors on ischemia-reperfusion-induced hepatic injury in rats.

    Abdel-Gaber, Seham A; Ibrahim, Mohamed A; Amin, Entesar F; Ibrahim, Salwa A; Mohammed, Rehab K; Abdelrahman, Aly M

    2015-08-01

    Ischemia-reperfusion (IR) injury represents an important pathological process of liver injury during major hepatic surgery. The role of cyclooxygenase (COX) enzymes in the pathogenesis of ischemia-reperfusion (IR)-induced liver injury is not clear. This study investigated the effect of a selective COX-2 inhibitor, celecoxib, versus non-selective, indomethacin, on hepatic IR injury in rats. Hepatic IR was induced in adult male rats. The animals were divided into 4 groups: normal control (sham group), IR non-treated group; IR-indomethacin-treated group; and IR-celecoxib-treated group. Liver injury was evaluated by serum alanine aminotransferase (ALT) and a histopathological examination of liver tissues. Hepatic tissue content of oxidative stress parameters glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase, malondialdehyde (MDA), nitric oxide (NO) and the inflammatory marker, tumor necrosis factor-alpha, (TNF-α) were measured. Moreover, the immunohistochemical detection of endothelial NO synthase (eNOS), inducible NO synthase (iNOS), and caspase-3 in the hepatic tissue was performed. Celecoxib, but not indomethacin, significantly attenuated hepatic IR injury as evidenced by reduction in serum ALT as well as by improvement in the histopathological scoring. Such effect was associated with attenuation in oxidative stress and TNF-α, along with modulation of immunohistochemical expression of eNOS, iNOS and caspase-3 in the hepatic tissue. The present study concluded that selective COX-2 inhibition (but not non-selective), is hepatoprotective against liver IR injury; indicating a differential role of COX-1 versus COX-2. Modulation of iNOS, eNOS and caspase-3 might participate in the protective effect of selective COX-2-inhibitors. Copyright © 2015 Elsevier Inc. All rights reserved.

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

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

    2010-01-01

    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 - ) 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 - and hepatic ADH-normal (ADH + ) 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 ∼ 1.5-fold greater in ADH - vs. ADH + 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 - 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.

  9. Fibronectin and Kupffer cell function in fulminant hepatic failure

    Imawari, M.; Hughes, R.D.; Gove, C.D.; Williams, R.

    1985-01-01

    The relationship between plasma fibronectin, in vitro plasma opsonic activity, which measures the biological activity of fibronectin, and in vivo Kupffer cell function, as assessed by the systemic clearance of microaggregated [ 125 I]albumin, were determined simultaneously in 15 patients with fulminant hepatic failure and 12 normal subjects. Both the plasma fibronectin and plasma opsonic activity were significantly reduced in patients with fulminant hepatic failure, while the systemic clearance of microaggregated albumin was decreased. There was a significant correlation between plasma fibronectin and the plasma opsonic activity on admission, but no correlation could be detected between either parameter and the clearance of microaggregated albumin. A gelatin-derived plasma expander was shown to block the plasma opsonic activity both in vitro and in vivo. The low plasma fibronectin and decreased clearance of microaggregated albumin in fulminant hepatic failure reflect different aspects of the overall impairment of Kupffer cell function

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

    Swelm, Rachel P.L. van [Department of Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen (Netherlands); Laarakkers, Coby M.M. [Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen (Netherlands); Pertijs, Jeanne C.L.M.; Verweij, Vivienne; Masereeuw, Rosalinde [Department of Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen (Netherlands); Russel, Frans G.M., E-mail: F.Russel@pharmtox.umcn.nl [Department of Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen (Netherlands)

    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.

  11. NATURAL KILLER T CELLS IN HEPATIC LEUCOCYTE INFILTRATES IN PATIENTS WITH MALIGNANT PROCESS AND VIRAL HEPATITIS

    O. V. Lebedinskaya

    2010-01-01

    Full Text Available Morphology, topography, and immunohistochemical features of leukocyte infiltrates were studied in various sites of the liver samples from the patients with metastatic disease, been affected by hepatitis B and C viruses at different degree of activity. Liver of СВА mice with implanted САО-1 tumour was also under study. Histochemical, and functional features, as well as immune phenotype of these cells were investigated. It has been shown that the major fraction of leukocyte infiltrates, mostly associated with implanted tumours in experimental mice, and in the areas adjacent to the tumor in humans, like as on the peak of viral hepatitis activity, is composed of lymphocytes. They are presented by large numvers of activated proliferating and differentiating cells bearing specific antigens, as well as natural killers and T-lymphocytes, possessing high-level killer activity towards NK-sensitive, and autologous lines of cancer cells. Hence, the results of our study, generally, confirm the data from literature reporting on existence of a special lymphocyte subpopulation, NKT cells, in human or murine liver affected by hepatitis virus or malignant tumors. The data concerning functional properties of these cells may be used for development of immunotherapy methods of viral diseases and oncological conditions complicated by liver metastases.

  12. Extracellular adenosine controls NKT-cell-dependent hepatitis induction.

    Subramanian, Meenakshi; Kini, Radhika; Madasu, Manasa; Ohta, Akiko; Nowak, Michael; Exley, Mark; Sitkovsky, Michail; Ohta, Akio

    2014-04-01

    Extracellular adenosine regulates inflammatory responses via the A2A adenosine receptor (A2AR). A2AR deficiency results in much exaggerated acute hepatitis, indicating nonredundancy of adenosine-A2AR pathway in inhibiting immune activation. To identify a critical target of immunoregulatory effect of extracellular adenosine, we focused on NKT cells, which play an indispensable role in hepatitis. An A2AR agonist abolished NKT-cell-dependent induction of acute hepatitis by concanavalin A (Con A) or α-galactosylceramide in mice, corresponding to downregulation of activation markers and cytokines in NKT cells and of NK-cell co-activation. These results show that A2AR signaling can downregulate NKT-cell activation and suppress NKT-cell-triggered inflammatory responses. Next, we hypothesized that NKT cells might be under physiological control of the adenosine-A2AR pathway. Indeed, both Con A and α-galactosylceramide induced more severe hepatitis in A2AR-deficient mice than in WT controls. Transfer of A2AR-deficient NKT cells into A2AR-expressing recipients resulted in exaggeration of Con A-induced liver damage, suggesting that NKT-cell activation is controlled by endogenous adenosine via A2AR, and this physiological regulatory mechanism of NKT cells is critical in the control of tissue-damaging inflammation. The current study suggests the possibility to manipulate NKT-cell activity in inflammatory disorders through intervention to the adenosine-A2AR pathway. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. Methimazole protects lungs during hepatic ischemia-reperfusion injury in rats: an effect not induced by hypothyroidism.

    Tütüncü, Tanju; Demirci, Cagatay; Gözalan, Ugur; Yüksek, Yunus Nadi; Bilgihan, Ayse; Kama, Nuri Aydin

    2007-05-01

    Hepatic ischemia-reperfusion injury may lead to remote organ failure with mortal respiratory dysfunction. The aim of the present study was to analyze the possible protective effects of methimazole on lungs after hepatic ischemia-reperfusion injury. Forty male Wistar albino rats were randomized into five groups: a control group, in which bilateral pulmonary lobectomy was done; a hepatic ischemia-reperfusion group, in which bilateral pulmonary lobectomy was done after hepatic ischemia-reperfusion; a thyroidectomy-ischemia-reperfusion group (total thyroidectomy followed by, 7 days later, bilateral pulmonary lobectomy after hepatic ischemia-reperfusion); a methimazole-ischemia-reperfusion group (following methimazole administration for 7 days, bilateral pulmonary lobectomy was done after hepatic ischemia-reperfusion); and a methimazole +L-thyroxine-ischemia-reperfusion group (following methimazole and L-thyroxine administration for 7 days, bilateral pulmonary lobectomy was performed after hepatic ischemia-reperfusion). Pulmonary tissue specimens were evaluated histopathologically and for myeloperoxidase and malondialdehyde levels. All of the ischemia-reperfusion intervention groups had higher pulmonary injury scoring indices than the control group (P < 0.001). Pulmonary injury index of the ischemia-reperfusion group was higher than that of both the methimazole-supplemented hypothyroid and euthyroid groups (P = 0028; P = 0,038, respectively) and was similar to that of the thyroidectomized group. Pulmonary tissue myeloperoxidase and malondialdehyde levels in the ischemia-reperfusion group were similar with that in the thyroidectomized rats but were significantly higher than that in the control, and both the methimazole-supplemented hypothyroid and euthyroid groups. Methimazole exerts a protective role on lungs during hepatic ischemia-reperfusion injury, which can be attributed to its anti-inflammatory and anti-oxidant effects rather than hypothyroidism alone.

  14. Cocktail of chemical compounds robustly promoting cell reprogramming protects liver against acute injury

    Yuewen Tang

    2017-02-01

    Full Text Available Abstract Tissue damage induces cells into reprogramming-like cellular state, which contributes to tissue regeneration. However, whether factors promoting the cell reprogramming favor tissue regeneration remains elusive. Here we identified combination of small chemical compounds including drug cocktails robustly promoting in vitro cell reprogramming. We then administrated the drug cocktails to mice with acute liver injuries induced by partial hepatectomy or toxic treatment. Our results demonstrated that the drug cocktails which promoted cell reprogramming in vitro improved liver regeneration and hepatic function in vivo after acute injuries. The underlying mechanism could be that expression of pluripotent genes activated after injury is further upregulated by drug cocktails. Thus our study offers proof-of-concept evidence that cocktail of clinical compounds improving cell reprogramming favors tissue recovery after acute damages, which is an attractive strategy for regenerative purpose.

  15. Transfusion Related Hepatitis C Virus (HCV) Infection in Sickle Cell ...

    Rev Olaleye

    ABSTRACT: This study aimed to determine retrospectively, the prevalence of hepatitis C virus infection in relation to a background history of blood transfusion; through anti HCV antibody screening test, amongst adult sickle cell disease patients. Anti HCV antibody was tested for in the serum of 92 consecutively selected ...

  16. Transfusion associated hepatitis B virus infection among sickle cell ...

    Background: Transfusion of blood products is a recognised way of transmitting infections particularly viruses. The extent to which blood transfusion contributes to hepatitis B virus (HBV) infections in transfused patients with sickle cell anaemia (SCA) has been found to be 20% in Lagos, Nigeria. Mamman in Zaria however ...

  17. Hepatic Metastases of Granulosa Cell Tumour of the Ovary

    José I. Rodríguez García

    1996-01-01

    Full Text Available A case of metastatic granulosa cell tumour of the ovary is reported. Investigations revealed a secondary tumour in segment VI and VII of the liver. Right hepatic resection was performed. Microscopic findings revealed a tumour with histological features identical to that removed eleven years before.

  18. A rare case of hepatic duct injury from blunt abdominal trauma.

    Hasaniya, Nahidh W; Premaratne, Shyamal; Premaratne, Ishani D; McNamara, J Judson

    2013-01-01

    A 25 year-old male was brought to the emergency room following an apparent suicide attempt by jumping from the fourth floor. Patient had a large abdominal laceration in the right upper quadrant (RUQ). CT scan showed a sub-scapular hematoma of the liver. Due to the repeated episodes of hypotension, a laporotomy was performed and the left hepatic artery was ligated while the ductal injury was managed with a Roux-en-Y left hepatic jejunostomy and stent. Bile leakage was resolved post-operatively by day 5 and the patient was discharged home on day 13 after clearance from psychiatry. While non-iatrogenic extrahepatic biliary trauma is rare, a high degree of suspicion is essential, especially in cases like the one discussed in this report. Diagnosis can be difficult in patients undergoing observation.

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

    Tokiko Ishida

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

  20. Matrix metalloproteinase-14 mediates formation of bile ducts and hepatic maturation of fetal hepatic progenitor cells

    Otani, Satoshi [Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo (Japan); Kakinuma, Sei, E-mail: skakinuma.gast@tmd.ac.jp [Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo (Japan); Department for Liver Disease Control, Tokyo Medical and Dental University, Tokyo (Japan); Kamiya, Akihide [Institute of Innovative Science and Technology, Tokai University, Isehara (Japan); Goto, Fumio; Kaneko, Shun; Miyoshi, Masato; Tsunoda, Tomoyuki; Asano, Yu; Kawai-Kitahata, Fukiko; Nitta, Sayuri; Nakata, Toru; Okamoto, Ryuichi; Itsui, Yasuhiro; Nakagawa, Mina; Azuma, Seishin [Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo (Japan); Asahina, Yasuhiro [Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo (Japan); Department for Liver Disease Control, Tokyo Medical and Dental University, Tokyo (Japan); Yamaguchi, Tomoyuki [Division of Stem Cell Therapy, Institute of Medical Science, The University of Tokyo, Tokyo (Japan); Koshikawa, Naohiko [Division of Cancer Cell Research, Institute of Medical Science, The University of Tokyo, Tokyo (Japan); Seiki, Motoharu [Medical School, Kanazawa University, Kanazawa (Japan); Nakauchi, Hiromitsu [Division of Stem Cell Therapy, Institute of Medical Science, The University of Tokyo, Tokyo (Japan); and others

    2016-01-22

    Fetal hepatic stem/progenitor cells, called hepatoblasts, play central roles in liver development; however, the molecular mechanisms regulating the phenotype of these cells have not been completely elucidated. Matrix metalloproteinase (MMP)-14 is a type I transmembrane proteinase regulating pericellular proteolysis of the extracellular matrix and is essential for the activation of several MMPs and cytokines. However, the physiological functions of MMP-14 in liver development are unknown. Here we describe a functional role for MMP-14 in hepatic and biliary differentiation of mouse hepatoblasts. MMP-14 was upregulated in cells around the portal vein in perinatal stage liver. Formation of bile duct-like structures in MMP-14–deficient livers was significantly delayed compared with wild-type livers in vivo. In vitro biliary differentiation assays showed that formation of cholangiocytic cysts derived from MMP-14–deficient hepatoblasts was completely impaired, and that overexpression of MMP-14 in hepatoblasts promoted the formation of bile duct-like cysts. In contrast, the expression of molecules associated with metabolic functions in hepatocytes, including hepatic nuclear factor 4α and tryptophan 2,3-dioxygenase, were significantly increased in MMP-14–deficient livers. Expression of the epidermal growth factor receptor and phosphorylation of mitogen-activated protein kinases were significantly upregulated in MMP-14–deficient livers. We demonstrate that MMP-14–mediated signaling in fetal hepatic progenitor cells promotes biliary luminal formation around the portal vein and negatively controls the maturation of hepatocytes. - Highlights: • Loss of MMP-14 delayed formation of bile duct-like structures in perinatal liver. • Overexpression of MMP-14 in hepatobalsts promoted the biliary formation in vitro. • Loss of MMP-14 promoted hepatocyte maturation of hepatoblasts in vivo. • MMP-14–mediated signaling regulates terminal differentiation of

  1. Hepatitis B virus e antigen induces activation of rat hepatic stellate cells

    Zan, Yanlu [Center for Molecular Virology, CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101 (China); University of Chinese Academy of Sciences, Beijing 100049 (China); Zhang, Yuxia, E-mail: yzhang@wehi.edu.au [Center for Molecular Virology, CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101 (China); Tien, Po, E-mail: tienpo@sun.im.ac.cn [Center for Molecular Virology, CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101 (China)

    2013-06-07

    Highlights: •HBeAg expression in HSCs induced production of ECM protein and liver fibrotic markers. •The activation and proliferation of HSCs were mediated by TGF-β. •HBeAg protein purified from cell medium directly activated HSCs. -- Abstract: Chronic hepatitis B virus infection is a major cause of hepatic fibrosis, leading to liver cirrhosis and hepatocellular carcinoma. Hepatitis B virus e antigen (HBeAg) is an accessory protein of HBV, not required for viral replication but important for natural infection in vivo. Hepatic stellate cells (HSCs) are the major producers of excessive extracellular matrix during liver fibrogenesis. Therefore, we examined the influence of HBeAg on HSCs. The rat HSC line HSC-T6 was transfected with HBeAg plasmids, and expression of α-smooth muscle actin, collagen I, transforming growth factor-β1 (TGF-β), and tissue inhibitors of metalloproteinase 1 (TIMP-1) was investigated by quantitative real-time PCR. The proliferation of HSCs was determined by MTS analysis. HBeAg transduction induced up-regulation of these fibrogenic genes and proliferation of HSCs. We found that HBeAg induced TGF-β secretion in HSCs, and the activation of HSCs was prevented by a neutralizing anti-TGF-β antibody. Depletion and addition of HBeAg protein in conditioned medium from HSC-T6 cells transduced with HBeAg indicated that HBeAg directly induced the activation and proliferation of rat primary HSCs. Taken together, HBeAg induces the activation and proliferation of HSCs, mainly mediated by TGF-β, and HBeAg protein purified from cell medium can directly activate HSCs.

  2. Hepatitis B virus e antigen induces activation of rat hepatic stellate cells

    Zan, Yanlu; Zhang, Yuxia; Tien, Po

    2013-01-01

    Highlights: •HBeAg expression in HSCs induced production of ECM protein and liver fibrotic markers. •The activation and proliferation of HSCs were mediated by TGF-β. •HBeAg protein purified from cell medium directly activated HSCs. -- Abstract: Chronic hepatitis B virus infection is a major cause of hepatic fibrosis, leading to liver cirrhosis and hepatocellular carcinoma. Hepatitis B virus e antigen (HBeAg) is an accessory protein of HBV, not required for viral replication but important for natural infection in vivo. Hepatic stellate cells (HSCs) are the major producers of excessive extracellular matrix during liver fibrogenesis. Therefore, we examined the influence of HBeAg on HSCs. The rat HSC line HSC-T6 was transfected with HBeAg plasmids, and expression of α-smooth muscle actin, collagen I, transforming growth factor-β1 (TGF-β), and tissue inhibitors of metalloproteinase 1 (TIMP-1) was investigated by quantitative real-time PCR. The proliferation of HSCs was determined by MTS analysis. HBeAg transduction induced up-regulation of these fibrogenic genes and proliferation of HSCs. We found that HBeAg induced TGF-β secretion in HSCs, and the activation of HSCs was prevented by a neutralizing anti-TGF-β antibody. Depletion and addition of HBeAg protein in conditioned medium from HSC-T6 cells transduced with HBeAg indicated that HBeAg directly induced the activation and proliferation of rat primary HSCs. Taken together, HBeAg induces the activation and proliferation of HSCs, mainly mediated by TGF-β, and HBeAg protein purified from cell medium can directly activate HSCs

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

    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(4)) rat model. Male Wistar rats received intraperitoneal injections of CCl(4) twice weekly for 8weeks, as well as daily intraperitoneal treatments of imatinib (10 and 20mg/kg), nilotinib (10 and 20mg/kg) and silymarin (100mg/kg) during the last 4weeks of CCl(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 (20mg/kg) was the most effective treatment to counteract CCl(4)-induced hepatic injury as indicated by liver function tests and histopathology. Nilotinib (10mg/kg), nilotinib (20mg/kg) and silymarin (100mg/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(4)-treated rats. Hepatic morphometric evaluation and 4-hydroxyproline content revealed that CCl(4)-induced fibrosis was ameliorated significantly by nilotinib (20mg/kg) and imatinib (20mg/kg). Unlike nilotinib, imatinib (20mg/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. Copyright © 2011 Elsevier Inc. All rights reserved.

  4. Amelioration of carbon tetrachloride-induced hepatic injury by emulsified Antrodia extract

    Wei-Chih Chang

    2018-03-01

    Full Text Available Objective(s: Antrodia cinnamomea (AC is found with anti-inflammatory and immunomodulatory biological activities. In this study, we investigated the anti-hepatitis effect of the emulsified AC extract from RO water or supercritical fluid CO2 with ethanol co-solvent extract methods of AC preparations. Materials and Methods: Five groups of eight to ten weeks male rats with a count of ten for each group were studied to evaluate the protection of two kinds of AC extract from hepatic injury. Acute liver injury of rats was induced by injecting 40% carbon tetrachloride (CCl4 1 mg/kg intraperitoneally. Positive and negative control groups rats were perfused with CCl4 or isotonic saline, respectively. Experimental groups received oral administration once/day of AC preparations before CCl4 treatment: water AC extract (WAE group, or emulsified AC extract from supercritical fluid extraction (EAE group for 5 days, and sacrificed on the 6th day and the blood and liver samples were collected under chloral hydrate anesthesia. The anti-inflammatory, antioxidant markers, and relevant signaling pathways were measured (AST, ALT, ROS, IL-1, IL-6, NO, and COX-2, MAPKs, and caspase-3. Results: EAE at 50 mg/kg significantly decreased the serum AST, ALT, IL-1, IL-6, NO, and ROS levels. Both extracts reduced the activation of p-ERK in the liver samples, but EAE inhibited COX-2 and caspase-3 protein expression better than WAE. The EAE ameliorated CCl4-induced hepatic injury significantly; as compared with WAE and the positive control. Conclusion: The hepatoprotection of EAE could be attributed to the antioxidant and anti-inflammatory effects of Antrodia.

  5. The protective effect of huperzine A against hepatic ischemia reperfusion injury in mice.

    Yang, Y; Yang, J; Jiang, Q

    2014-06-01

    Nowadays, hepatic ischemia reperfusion (HI/R) injury is regarded as a serious concern in clinical practices. Huperzine A (HupA) is an alkaloid isolated from the Chinese folk medicine huperzia serrate, which has possessed diverse pharmacological actions. A mouse model of HI/R was caused by clamping the hepatic artery, the hepatoportal vein, and the bile duct with a vascular clamp for 30 minutes followed by reperfusion for 6 hours under anesthesia. The sham group experienced the identical procedure without hepatic ischemia. The HupA group received an injection into the tail vein 5 minutes prior to HI/R at the doses of 167 and 500 μg/kg. The vehicle group was injected with physiological saline instead of HupA. The liver function was assessed by determinations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities. Tissue levels of superoxide dismutase (SOD), catalase (CAT), malondiadehyde (MDA), and glutathione (GSH) were also measured spectrophotometrically. In addition, the activities of hepatic inflammatory mediators such as nuclear factor kappa B (NF-κB) p65, tumor necrosis factors-α (TNF-α, interleukin-1β (IL-1β) and IL-6 were also measured. Furthermore, the apoptotic damage was evaluated by measuring caspase-3 activity in hepatic tissues. Treatment with HupA in mice at the doses of 167 and 500 μg/kg remarkably reduced serum ALT and AST activities in HupA-treated ischemic mice. Furthermore, HupA treatment could enhance the activities of hepatic tissue SOD, CAT, and GSH but decrease MDA tissue content. The activities of inflammatory cytokines including NF-κB p65, TNF-α, IL-1β and IL-6 were all decreased in ischemic mice treated with HupA. Colorimetric test results illustrated that a marked reduction of caspase-3 activity was found in the HupA-treated group compared with the vehicle group. Our present data suggest that HupA has a protective role against HI/R injury of mice and antioxidative, anti-inflammatory, and antiapoptotic

  6. Immunohistochemical characterisation of the hepatic stem cell niche in feline hepatic lipidosis: a preliminary morphological study.

    Valtolina, Chiara; Robben, Joris H; Favier, Robert P; Rothuizen, Jan; Grinwis, Guy Cm; Schotanus, Baukje A; Penning, Louis C

    2018-05-01

    Objectives The aim of this study was to describe the cellular and stromal components of the hepatic progenitor cell niche in feline hepatic lipidosis (FHL). Methods Immunohistochemical staining for the progenitor/bile duct marker (K19), activated Kupffer cells (MAC387), myofibroblasts (alpha-smooth muscle actin [α-SMA]) and the extracellular matrix component laminin were used on seven liver biopsies of cats with FHL and three healthy cats. Double immunofluorescence stainings were performed to investigate co-localisation of different cell types in the hepatic progenitor cell (HPC) niche. Results HPCs, Kupffer cells, myofibroblasts and laminin deposition were observed in the liver samples of FHL, although with variability in the expression and positivity of the different immunostainings between different samples. When compared with the unaffected cats where K19 positivity and minimal α-SMA and laminin positivity were seen mainly in the portal area, in the majority of FHL samples K19 and α-SMA-positive cells and laminin positivity were seen also in the periportal and parenchymatous area. MAC387-positive cells were present throughout the parenchyma. Conclusions and relevance This is a preliminary morphological study to describe the activation and co-localisation of components of the HPC niche in FHL. Although the HPC niche in FHL resembles that described in hepatopathies in dogs and in feline lymphocytic cholangitis, the expression of K19, α-SMA, MAC387 and lamin is more variable in FHL, and a common pattern of activation could not be established. Nevertheless, when HPCs were activated, a spatial association between HPCs and their niche could be demonstrated.

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

    Xinzhi eWang

    2016-04-01

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

  8. Ultrasound appearance of radiation-induced hepatic injury. Correlation with computed tomography and magnetic resonance imaging

    Garra, B.S.; Shawker, T.H.; Chang, R.; Kaplan, K.; White, R.D.

    1988-01-01

    The ultrasound findings in three cases of radiation-induced hepatic injury are described and compared with computed tomography and magnetic resonance imaging findings. Fatty infiltration of the liver was present in two of the cases in which concurrent chemotherapy was being administered. On ultrasound B-scans, the regions of radiation injury were hypoechoic relative to the remainder of the liver. This finding was more obvious in the patients with fatty livers. CT scans on the patients with fatty infiltrated livers showed higher attenuation in the irradiated region than in unexposed liver. In the patient where no fatty infiltration was present, the radiated section of liver had lower attenuation consistent with previous reports. Magnetic resonance imaging showed decreased signal in the exposed areas on T1 weighted images

  9. Protection of the Extracts of Lentinus edodes Mycelia against Carbon-Tetrachloride-Induced Hepatic Injury in Rats

    Mei-Fen Chen

    2012-01-01

    Full Text Available Lentinus edodes is the medicinal macrofungus showing potential for therapeutic applications in infectious disorders including hepatitis. In an attempt to develop the agent for handling hepatic injury, we used the extracts of Lentinus edodes mycelia (LEM to screen the effect on hepatic injury in rats induced by carbon tetrachloride (CCl4. Intraperitoneal administration of CCl4 not only increased plasma glutamic oxaloacetic transaminase (GOT and glutamic pyruvic transaminase (GPT but also decreased hepatic superoxide dismutase (SOD and glutathione peroxidase (GPx levels in rats. Similar to the positive control silymarin, oral administration (three times daily of this product (LEM for 8 weeks significantly reduced plasma GOT and GPT. Also, the activities of antioxidant enzymes of SOD and GPx were elevated by LEM. in liver from CCl4-treated rats, indicating that mycelium can increase antioxidant-like activity. Moreover, the hepatic mRNA and protein levels of SOD and GPx were both markedly raised by LEM. The obtained results suggest that oral administration of the extracts of Lentinus edodes mycelia (LEM has the protective effect against CCl4-induced hepatic injury in rats, mainly due to an increase in antioxidant-like action.

  10. Evaluation of hepatic hemangioma by Tc-99 m red blood cell hepatic blood pool scan

    Sohn, Myung Hee

    2005-01-01

    Hemangioma is the most common benign tumor of the liver, with a prevalence estimated as high as 7%. Tc-99m red blood cell (RBC) hepatic blood pool scan with single photon emission computed tomography (SPECT) imaging is extremely useful for the confirmation or exclusion of hepatic hemangiomas. The classic finding of absent or decreased perfusion and increased blood pooling ('perfusion/blood pool mismatch') is the key diagnostic element in the diagnosis of hemangiomas. The combination of early arterial flow and delayed blood pooling ('perfusion/blood pool match') is shown uncommonly. In giant hemangioma, filling with radioactivity appears first in the periphery, with progressive central fill-in on sequential RBC blood pool scan. However, the reverse filling pattern, which begins first in the center with progressive peripheral filling, is also rarely seen. Studies with false-positive blood pooling have been reported infrequently in nonhemangiomas, including hemangiosarcoma, hepatocellular carcinoma, hepatic adenoma, and metastatic carcinomas (adenocarcinma of the colon, small cell carcinoma of the lung, neruroendocrine carcinoma). False-negative results have been also reported rarely except for small hemagniomas that are below the limits of spatial resolution of gamma camera

  11. Predictive factors for early failure of transarterial embolization in blunt hepatic injury patients

    Lee, Y.-H.; Wu, C.-H.; Wang, L.-J.; Wong, Y.-C.; Chen, H.-W.; Wang, C.-J.; Lin, B.-C.; Hsu, Y.-P.

    2014-01-01

    Aim: To evaluate the early success of transarterial embolization (TAE) in patients with traumatic liver haemorrhage and to determine independent factors for its failure. Materials and methods: From January 2009 to December 2012, TAE was performed in 48 patients for traumatic liver haemorrhage. Their medical charts were reviewed for demographic information, pre-TAE vital signs and laboratory data, injury grade, type of contrast medium extravasation (CME) at CT, angiography findings, and early failure. “Early failure” was defined as the need for repeated TAE or a laparotomy for hepatic haemorrhage within 4 days after TAE. Variables were compared between the early success and early failure groups. Variables with univariate significance were also analysed using multivariate logistic regression for predictors of early failure. Results: Among 48 liver TAE cases, nine (18.8%) were early failures due to liver haemorrhage. Early failure was associated with injury grade (p = 0.039), major liver injury (grades 4 and 5; p = 0.007), multiple CMEs at angiography (p = 0.031), incomplete TAE (p = 0.002), and elevated heart rate (p = 0.026). Incomplete embolization (OR = 8; p = 0.042), and heart rate >110 beats/min (bpm; OR = 8; p = 0.05) were independent factors for early failure of TAE in the group with major liver injuries. Conclusion: Major hepatic injury is an important factor in early failure. Patients with a heart rate >110 bpm and incomplete embolization in the major injury group have an increased rate of early failure. The success rate of proximal TAE was comparable to that of the more time-consuming, superselective, distal TAE. - Highlights: • Early failure of TAE is associated with a higher grade of liver injury. • Incomplete embolization is more likely to suffer early failure of TAE. • A heart rate greater than 110 bpm is more likely to suffer early failure of TAE. • We recommend proximal embolization to prevent early failure of TAE

  12. The improving effects on hepatic fibrosis of interferon-γ liposomes targeted to hepatic stellate cells

    Li, Qinghua; Yan, Zhiqiang; Li, Feng; Lu, Weiyue; Wang, Jiyao; Guo, Chuanyong

    2012-07-01

    No satisfactory anti-fibrotic therapies have yet been applied clinically. One of the main reasons is the inability to specifically target the responsible cells to produce an available drug concentration and the side-effects. Exploiting the key role of the activated hepatic stellate cells (HSCs) in both hepatic fibrogenesis and over-expression of platelet-derived growth factor receptor-β (PDGFR-β), we constructed targeted sterically stable liposomes (SSLs) modified by a cyclic peptide (pPB) with affinity for the PDGFR-β to deliver interferon (IFN)-γ to HSCs. The pPB-SSL-IFN-γ showed satisfactory size distribution. In vitro pPB-SSL could be taken up by activated HSCs. The study of tissue distribution via living-body animal imaging showed that the pPB-SSL-IFN-γ mostly accumulated in the liver until 24 h. Furthermore, the pPB-SSL-IFN-γ showed more significant remission of hepatic fibrosis. In vivo the histological Ishak stage, the semiquantitative score for collagen in fibrotic liver and the serum levels of collagen type IV-C in fibrotic rats treated with pPB-SSL-IFN-γ were less than those treated with SSL-IFN-γ, IFN-γ and the control group. In vitro pPB-SSL-IFN-γ was also more effective in suppressing activated HSC proliferation and inducing apoptosis of activated HSCs. Thus the data suggest that pPB-SSL-IFN-γ might be a more effective anti-fibrotic agent and a new opportunity for clinical therapy of hepatic fibrosis.

  13. Effects of Urtica dioica on hepatic ischemia‐reperfusion injury in rats

    Kandis, Hayati; Karapolat, Sami; Yildirim, Umran; Saritas, Ayhan; Gezer, Suat; Memisogullari, Ramazan

    2010-01-01

    OBJECTIVES: To evaluate the effects of Urtica dioica on hepatic ischemia‐reperfusion injury. METHODS: Thirty adult male Wistar albino rats were divided into three groups: sham group (group 1), control group (group 2), and Urtica dioica group (group 3). All the rats were exposed to hepatic ischemia for 60 min, followed by 60 min of reperfusion. In group 2, a total of 2 ml/kg 0.9% saline solution was given intraperitoneally. In group 3, a total of 2 ml/kg Urtica dioica was given intraperitoneally. At the end of the procedure, liver tissue and blood samples were taken from all rats. Serum aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, ceruloplasmin, catalase, paraoxonase, arylesterase, and lipid hydroperoxide levels were measured. Liver tissue histopathologies were also evaluated by light microscopy. RESULTS: Serum aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase levels were significantly higher in group 2 than in group 1, and significantly lower in group 3 than in group 2. Also, group 2 had higher serum lipid hydroperoxides and ceruloplasmin levels but lower catalase, paraoxonase, and arylesterase levels than group 1. In group 3, serum lipid hydroperoxides and ceruloplasmin levels were significantly lower, and catalase, paraoxonase, and arylesterase levels were higher than those in group 2. Histopathological examination showed that liver tissue damage was significantly decreased in group 3 compared with group 2. CONCLUSIONS: Urtica dioica has a protective effect on the liver in hepatic ischemia‐reperfusion‐injured rats. PMID:21340227

  14. Effects of Urtica dioica on hepatic ischemia-reperfusion injury in rats.

    Kandis, Hayati; Karapolat, Sami; Yildirim, Umran; Saritas, Ayhan; Gezer, Suat; Memisogullari, Ramazan

    2010-01-01

    To evaluate the effects of Urtica dioica on hepatic ischemia-reperfusion injury. Thirty adult male Wistar albino rats were divided into three groups: sham group (group 1), control group (group 2), and Urtica dioica group (group 3). All the rats were exposed to hepatic ischemia for 60 min, followed by 60 min of reperfusion. In group 2, a total of 2 ml/kg 0.9% saline solution was given intraperitoneally. In group 3, a total of 2 ml/kg Urtica dioica was given intraperitoneally. At the end of the procedure, liver tissue and blood samples were taken from all rats. Serum aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, ceruloplasmin, catalase, paraoxonase, arylesterase, and lipid hydroperoxide levels were measured. Liver tissue histopathologies were also evaluated by light microscopy. Serum aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase levels were significantly higher in group 2 than in group 1, and significantly lower in group 3 than in group 2. Also, group 2 had higher serum lipid hydroperoxides and ceruloplasmin levels but lower catalase, paraoxonase, and arylesterase levels than group 1. In group 3, serum lipid hydroperoxides and ceruloplasmin levels were significantly lower, and catalase, paraoxonase, and arylesterase levels were higher than those in group 2. Histopathological examination showed that liver tissue damage was significantly decreased in group 3 compared with group 2. Urtica dioica has a protective effect on the liver in hepatic ischemia-reperfusion-injured rats.

  15. Right hepatic vein injury after blunt abdominal trauma in a 12-year-old boy- case report

    Roik, D.; Konecka, A.; Brzewski, M.; Marcinski, A.; Kaminski, A.; Piotrowska, A.; Jasinska, A.

    2008-01-01

    Blunt abdominal trauma in children is one of the most frequent causes of hospitalization. We present a rare case of traumatic liver injury. A 12-year-old boy was admitted to the Surgery Department after a bicycle fall and handlebar impact injury to the right infracostal area. At admission he was stable, with no abnormalities except for a subcutaneous hepatoma found in the injured area. Abdominal ultrasound examination revealed free intraperitoneal fluid. Computed tomography (CT) revealed irregular branching laceration of the right superior hepatic segments with extension into the hepatic veins. No active extravasation of contrast material was seen. On the next day, cause of the deterioration of the patient's condition, CT examination was repeated and revealed focal extravasation of contrast material in the portal hilum posterior to the gallbladder. An injury of the right hepatic vein was found on laparotomy. Hepatic vein injury is a rare but very serious complication after blunt liver trauma and it is an indication for surgical treatment. Diagnostic imaging is essential for therapeutic decisions, but its value is sometimes limited.The precise analysis of injury mechanism and localization may be very helpful.CT is currently the modality of choice for the evaluation of blunt liver trauma. If an active bleeding is suspected the delayed scans seem to be recommended. (author)

  16. Protective effect of Mangifera indica L. extract (Vimang) on the injury associated with hepatic ischaemia reperfusion.

    Sánchez, Gregorio Martínez; Rodríguez H, María A; Giuliani, Attilia; Núñez Sellés, Alberto J; Rodríguez, Niurka Pons; León Fernández, Olga Sonia; Re, L

    2003-03-01

    The effect of Mangifera indica L. extract (Vimang) on treatment of injury associated with hepatic ischaemia/reperfusion was tested. Vimang protects from the oxidative damage induced by oxygen-based free radicals as shown in several in vitro test systems conducted. The ability of Vimang to reduce liver damage was investigated in rats undergoing right-lobe blood fl ow occlusion for 45 min followed by 45 min of reperfusion. The ischaemia/reperfusion model leads to an increase of transaminase (ALT and AST), membrane lipid peroxidation, tissue neutrophil in filtration, DNA fragmentation, loss of protein -SH groups, cytosolic Ca2+ overload and a decrease of catalase activity. Oral administration of Vimang (50, 110 and 250 mg/kg, b.w.) 7 days before reperfusion, reduced transaminase levels and DNA fragmentation in a dose dependent manner (p Vimang also restored the cytosolic Ca2+ levels and inhibited polymorphonuclear migration at a dose of 250 mg/kg b.w., improved the oxidation of total and non protein sulfhydryl groups and prevented modification in catalase activity, uric acid and lipid peroxidation markers (p Vimang could be a useful new natural drug for preventing oxidative damage during hepatic injury associated with free radical generation. Copyright 2003 John Wiley & Sons, Ltd.

  17. Nonoperative management of blunt hepatic injury: an Eastern Association for the Surgery of Trauma practice management guideline.

    Stassen, Nicole A; Bhullar, Indermeet; Cheng, Julius D; Crandall, Marie; Friese, Randall; Guillamondegui, Oscar; Jawa, Randeep; Maung, Adrian; Rohs, Thomas J; Sangosanya, Ayodele; Schuster, Kevin; Seamon, Mark; Tchorz, Kathryn M; Zarzuar, Ben L; Kerwin, Andrew

    2012-11-01

    During the last century, the management of blunt force trauma to the liver has changed from observation and expectant management in the early part of the 1900s to mainly operative intervention, to the current practice of selective operative and nonoperative management. These issues were first addressed by the Eastern Association for the Surgery of Trauma in the Practice Management Guidelines for Nonoperative Management of Blunt Injury to the Liver and Spleen published online in 2003. Since that time, a large volume of literature on these topics has been published requiring a reevaluation of the previous Eastern Association for the Surgery of Trauma guideline. The National Library of Medicine and the National Institutes of Health MEDLINE database were searched using PubMed (http://www.pubmed.gov). The search was designed to identify English-language citations published after 1996 (the last year included in the previous guideline) using the keywords liver injury and blunt abdominal trauma. One hundred seventy-six articles were reviewed, of which 94 were used to create the current practice management guideline for the selective nonoperative management of blunt hepatic injury. Most original hepatic guidelines remained valid and were incorporated into the greatly expanded current guidelines as appropriate. Nonoperative management of blunt hepatic injuries currently is the treatment modality of choice in hemodynamically stable patients, irrespective of the grade of injury or patient age. Nonoperative management of blunt hepatic injuries should only be considered in an environment that provides capabilities for monitoring, serial clinical evaluations, and an operating room available for urgent laparotomy. Patients presenting with hemodynamic instability and peritonitis still warrant emergent operative intervention. Intravenous contrast enhanced computed tomographic scan is the diagnostic modality of choice for evaluating blunt hepatic injuries. Repeated imaging should be

  18. Gal-3 regulates the capacity of dendritic cells to promote NKT-cell-induced liver injury.

    Volarevic, Vladislav; Markovic, Bojana Simovic; Bojic, Sanja; Stojanovic, Maja; Nilsson, Ulf; Leffler, Hakon; Besra, Gurdyal S; Arsenijevic, Nebojsa; Paunovic, Verica; Trajkovic, Vladimir; Lukic, Miodrag L

    2015-02-01

    Galectin-3 (Gal-3), an endogenous lectin, exhibits pro- and anti-inflammatory effects in various disease conditions. In order to explore the role of Gal-3 in NKT-cell-dependent pathology, we induced hepatitis in C57BL/6 WT and Gal-3-deficient mice by using specific ligand for NKT cells: α-galactosylceramide, glycolipid Ag presented by CD1d. The injection of α-galactosylceramide significantly enhanced expression of Gal-3 in liver NKT and dendritic cells (DCs). Genetic deletion or selective inhibition of Gal-3 (induced by Gal-3-inhibitor TD139) abrogated the susceptibility to NKT-cell-dependent hepatitis. Blood levels of pro-inflammatory cytokines (TNF-α, IFN-γ, IL-12) and their production by liver DCs and NKT cells were also downregulated. Genetic deletion or selective inhibition of Gal-3 alleviated influx of inflammatory CD11c(+) CD11b(+) DCs in the liver and favored tolerogenic phenotype and IL-10 production of liver NKT and DCs. Deletion of Gal-3 attenuated the capacity of DCs to support liver damage in the passive transfer experiments and to produce pro-inflammatory cytokines in vitro. Gal-3-deficient DCs failed to optimally stimulate production of pro-inflammatory cytokines in NKT cells, in vitro and in vivo. In conclusion, Gal-3 regulates the capacity of DCs to support NKT-cell-mediated liver injury, playing an important pro-inflammatory role in acute liver injury. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  19. Mesenchymal stem cell-conditioned medium prevents radiation-induced liver injury by inhibiting inflammation and protecting sinusoidal endothelial cells

    Chen Yixing; Zeng Zhaochong; Sun Jing; Huang Yan; Zhang Zhenyu; Zeng Haiying

    2015-01-01

    Current management of radiation-induced liver injury is limited. Sinusoidal endothelial cell (SEC) apoptosis and inflammation are considered to be initiating events in hepatic damage. We hypothesized that mesenchymal stem cells (MSCs) possess anti-apoptotic and anti-inflammatory actions during hepatic irradiation, acting via paracrine mechanisms. This study aims to examine whether MSC-derived bioactive components are protective against radiation-induced liver injury in rats. MSC-conditioned medium (MSC-CM) was generated from rat bone marrow–derived MSCs. The effect of MSC-CM on the viability of irradiated SECs was examined by flow cytometric analysis. Activation of the Akt and ERK pathways was analyzed by western blot. MSC-CM was also delivered to Sprague–Dawley rats immediately before receiving liver irradiation, followed by testing for pathological features, changes in serum hyaluronic acid, ALT, and inflammatory cytokine levels, and liver cell apoptosis. MSC-CM enhanced the viability of irradiated SECs in vitro and induced Akt and ERK phosphorylation in these cells. Infusion of MSC-CM immediately before liver irradiation provided a significant anti-apoptotic effect on SECs and improved the histopathological features of injury in the irradiated liver. MSC-CM also reduced the secretion and expression of inflammatory cytokines and increased the expression of anti-inflammatory cytokines. MSC-derived bioactive components could be a novel therapeutic approach for treating radiation-induced liver injury. (author)

  20. Saccharomyces boulardii ameliorates clarithromycin- and methotrexate-induced intestinal and hepatic injury in rats.

    Duman, Deniz Güney; Kumral, Zarife Nigâr Özdemir; Ercan, Feriha; Deniz, Mustafa; Can, Güray; Cağlayan Yeğen, Berrak

    2013-08-28

    Saccharomyces boulardii is a probiotic used for the prevention of antibiotic-associated diarrhoea. We aimed to investigate whether S. boulardii could alter the effects of clarithromycin (CLA) and methotrexate (MTX) on oro-caecal intestinal transit and oxidative damage in rats. Rats were divided into two groups receiving a single dose of MTX (20 mg/kg) or CLA (20 mg/kg per d) for 1 week. Groups were treated with either saline or S. boulardii (500 mg/kg) twice per d throughout the experiment. The control group was administered only saline. Following decapitation, intestinal transit and inflammation markers of glutathione (GSH), malondialdehyde and myeloperoxidase were measured in intestinal and hepatic tissues. CLA and MTX increased intestinal transit, while S. boulardii treatment slowed down CLA-facilitated transit back to control level. Both MTX and CLA increased lipid peroxidation while depleting the antioxidant GSH content in the hepatic and ileal tissues. Conversely, lipid peroxidation was depressed and GSH levels were increased in the ileal and hepatic tissues of S. boulardii-treated rats. Increased ileal neutrophil infiltration due to MTX and CLA treatments was also reduced by S. boulardii treatment. Histological analysis supported that S. boulardii protected intestinal tissues against the inflammatory effects of both agents. These findings suggest that S. boulardii ameliorates intestinal injury and the accompanying hepatic inflammation by supporting the antioxidant state of the tissues and by inhibiting the recruitment of neutrophils. Moreover, a preventive effect on MTXinduced toxicity is a novel finding of S. boulardii, proposing it as an adjunct to chemotherapy regimens.

  1. Histones activate the NLRP3 Inflammasome in Kupffer Cells during Sterile Inflammatory Liver Injury

    Huang, Hai; Chen, Hui-Wei; Evankovich, John; Yan, Wei; Rosborough, Brian R.; Nace, Gary W.; Ding, Qing; Loughran, Patricia; Beer-Stolz, Donna; Billiar, Timothy R.; Esmon, Charles T.; Tsung, Allan

    2013-01-01

    Cellular processes that drive sterile inflammatory injury after hepatic ischemia/reperfusion (I/R) injury are not completely understood. Activation of the inflammasome plays a key role in response to invading intracellular pathogens, but mounting evidence suggests it also plays a role in inflammation driven by endogenous danger-associate molecular pattern (DAMP) molecules released after ischemic injury. The nucleotide-binding domain, leucine-rich repeat containing protein 3 (NLRP3) inflammasome is one such process, and the mechanism by which its activation results in damage and inflammatory responses following liver I/R is unknown. Here we report that both NLRP3 and its downstream target Caspase-1 are activated I/R and are essential for hepatic I/R injury as both NLRP3 and Caspase-1 KO mice are protected from injury. Furthermore, inflammasome-mediated injury is dependent on Caspase-1 expression in liver non-parenchymal cells. While upstream signals that activate the inflammasome during ischemic injury are not well characterized, we show that endogenous extracellular histones activate the NLRP3 inflammasome during liver I/R through Toll-like Receptor-9 (TLR9). This occurs through TLR9-dependent generation of reactive oxygen species. This mechanism is operant in resident liver Kupffer cells, which drive innate immune responses after I/R injury by recruiting additional cell types, including neutrophils and inflammatory monocytes. These novel findings illustrate a new mechanism by which extracellular histones and activation of NLRP3 inflammasome contribute to liver damage and activation of innate immunity during sterile inflammation. PMID:23904166

  2. Alleviation of lipopolysaccharide/d-galactosamine-induced liver injury in leukocyte cell-derived chemotaxin 2 deficient mice

    Akinori Okumura

    2017-12-01

    Full Text Available Leukocyte cell-derived chemotaxin 2 (LECT2 is a secreted pleiotropic protein that is mainly produced by the liver. We have previously shown that LECT2 plays an important role in the pathogenesis of inflammatory liver diseases. Lipopolysaccharide/d-galactosamine (LPS/d-GalN-induced acute liver injury is a known animal model of fulminant hepatic failure. Here we found that this hepatic injury was alleviated in LECT2-deficient mice. The levels of TNF-α and IFN-γ, which mediate this hepatitis, had significantly decreased in these mice, with the decrease in IFN-γ production notably greater than that in TNF-α. We therefore analyzed IFN-γ-producing cells in liver mononuclear cells. Flow cytometric analysis showed significantly reduced IFN-γ production in hepatic NK and NKT cells in LECT2-deficient mice compared with in wild-type mice. We also demonstrated a decrease in IFN-γ production in LECT2-deficient mice after systemic administration of recombinant IL-12, which is known to induce IFN-γ in NK and NKT cells. These results indicate that a decrease of IFN-γ production in NK and NKT cells was involved in the alleviation of LPS/d-GalN-induced liver injury in LECT2-deficient mice.

  3. Epirubicin-adsorbed nanodiamonds kill chemoresistant hepatic cancer stem cells.

    Wang, Xin; Low, Xinyi Casuarine; Hou, Weixin; Abdullah, Lissa Nurrul; Toh, Tan Boon; Mohd Abdul Rashid, Masturah; Ho, Dean; Chow, Edward Kai-Hua

    2014-12-23

    Chemoresistance is a primary cause of treatment failure in cancer and a common property of tumor-initiating cancer stem cells. Overcoming mechanisms of chemoresistance, particularly in cancer stem cells, can markedly enhance cancer therapy and prevent recurrence and metastasis. This study demonstrates that the delivery of Epirubicin by nanodiamonds is a highly effective nanomedicine-based approach to overcoming chemoresistance in hepatic cancer stem cells. The potent physical adsorption of Epirubicin to nanodiamonds creates a rapidly synthesized and stable nanodiamond-drug complex that promotes endocytic uptake and enhanced tumor cell retention. These attributes mediate the effective killing of both cancer stem cells and noncancer stem cells in vitro and in vivo. Enhanced treatment of both tumor cell populations results in an improved impairment of secondary tumor formation in vivo compared with treatment by unmodified chemotherapeutics. On the basis of these results, nanodiamond-mediated drug delivery may serve as a powerful method for overcoming chemoresistance in cancer stem cells and markedly improving overall treatment against hepatic cancers.

  4. Inhibitory effect of tanshinone IIA on rat hepatic stellate cells.

    Ya-Wei Liu

    Full Text Available Anti-inflammation via inhibition of NF-κB pathways in hepatic stellate cells (HSCs is one therapeutic approach to hepatic fibrosis. Tanshinone IIA (C19H18O3, Tan IIA is a lipophilic diterpene isolated from Salvia miltiorrhiza Bunge, with reported anti-inflammatory activity. We tested whether Tan IIA could inhibit HSC activation.The cell line of rat hepatic stellate cells (HSC-T6 was stimulated with lipopolysaccharide (LPS (100 ng/ml. Cytotoxicity was assessed by MTT assay. HSC-T6 cells were pretreated with Tan IIA (1, 3 and 10 µM, then induced by LPS (100 ng/ml. NF-κB activity was evaluated by the luciferase reporter gene assay. Western blotting analysis was performed to measure NF-κB-p65, and phosphorylations of MAPKs (ERK, JNK, p38. Cell chemotaxis was assessed by both wound-healing assay and trans-well invasion assay. Quantitative real-time PCR was used to detect gene expression in HSC-T6 cells.All concentrations of drugs showed no cytotoxicity against HSC-T6 cells. LPS stimulated NF-κB luciferase activities, nuclear translocation of NF-κB-p65, and phosphorylations of ERK, JNK and p38, all of which were suppressed by Tan IIA. In addition, Tan IIA significantly inhibited LPS-induced HSCs chemotaxis, in both wound-healing and trans-well invasion assays. Moreover, Tan IIA attenuated LPS-induced mRNA expressions of CCL2, CCL3, CCL5, IL-1β, TNF-α, IL-6, ICAM-1, iNOS, and α-SMA in HSC-T6 cells.Our results demonstrated that Tan IIA decreased LPS-induced HSC activation.

  5. Stem cells and repair of lung injuries

    Randell Scott H

    2004-07-01

    Full Text Available Abstract Fueled by the promise of regenerative medicine, currently there is unprecedented interest in stem cells. Furthermore, there have been revolutionary, but somewhat controversial, advances in our understanding of stem cell biology. Stem cells likely play key roles in the repair of diverse lung injuries. However, due to very low rates of cellular proliferation in vivo in the normal steady state, cellular and architectural complexity of the respiratory tract, and the lack of an intensive research effort, lung stem cells remain poorly understood compared to those in other major organ systems. In the present review, we concisely explore the conceptual framework of stem cell biology and recent advances pertinent to the lungs. We illustrate lung diseases in which manipulation of stem cells may be physiologically significant and highlight the challenges facing stem cell-related therapy in the lung.

  6. PTP1B confers liver fibrosis by regulating the activation of hepatic stellate cells

    Chen, Pei-Jie; Cai, Shuang-Peng; Yang, Yang; Li, Wan-Xia; Huang, Cheng; Meng, Xiao-Ming; Li, Jun, E-mail: lj@ahmu.edu.cn

    2016-02-01

    Liver fibrosis is a reversible wound-healing response to chronic hepatic injuries. Activation of hepatic stellate cells (HSCs) plays a pivotal role in the development of hepatic fibrosis. The currently accepted mechanism for the resolution of liver fibrosis is the apoptosis and inactivation of activated HSCs. Protein tyrosine phosphatase 1B (PTP1B), a prototype of non-receptor protein tyrosine phosphatase, is proved to be a vital modulator in cardiac fibrogenesis. However, the precise role of PTP1B on liver fibrosis and HSC activation is still unclear. Our study showed that the expression of PTP1B was elevated in fibrotic liver but reduced after spontaneous recovery. Moreover, stimulation of HSC-T6 cells with transforming growth factor-β1 (TGF-β1) resulted in a dose/time-dependent increase of PTP1B mRNA and protein. Co-incubation of HSC-T6 cells with PTP1B-siRNA inhibited the cell proliferation and activation induced by TGF-β1. Additionally, both mRNA and protein of PTP1B were dramatically decreased in inactivated HSCs after treated with adipogenic differentiation mixture (MDI). Over-expression of PTP1B hindered the inactivation of HSC-T6 cells induced by MDI. These observations revealed a regulatory role of PTP1B in liver fibrosis and implied PTP1B as a potential therapeutic target. - Highlights: • The expression of PTP1B in the fibrotic livers and recovery livers • The expression of PTP1B in activated and inactivated HSCs • Blockade of PTP1B inhibited the TGF-β1-induced proliferation and activation of HSCs. • Over-expression of PTP1B abolished the inactivation of HSCs induced by MDI.

  7. PTP1B confers liver fibrosis by regulating the activation of hepatic stellate cells

    Chen, Pei-Jie; Cai, Shuang-Peng; Yang, Yang; Li, Wan-Xia; Huang, Cheng; Meng, Xiao-Ming; Li, Jun

    2016-01-01

    Liver fibrosis is a reversible wound-healing response to chronic hepatic injuries. Activation of hepatic stellate cells (HSCs) plays a pivotal role in the development of hepatic fibrosis. The currently accepted mechanism for the resolution of liver fibrosis is the apoptosis and inactivation of activated HSCs. Protein tyrosine phosphatase 1B (PTP1B), a prototype of non-receptor protein tyrosine phosphatase, is proved to be a vital modulator in cardiac fibrogenesis. However, the precise role of PTP1B on liver fibrosis and HSC activation is still unclear. Our study showed that the expression of PTP1B was elevated in fibrotic liver but reduced after spontaneous recovery. Moreover, stimulation of HSC-T6 cells with transforming growth factor-β1 (TGF-β1) resulted in a dose/time-dependent increase of PTP1B mRNA and protein. Co-incubation of HSC-T6 cells with PTP1B-siRNA inhibited the cell proliferation and activation induced by TGF-β1. Additionally, both mRNA and protein of PTP1B were dramatically decreased in inactivated HSCs after treated with adipogenic differentiation mixture (MDI). Over-expression of PTP1B hindered the inactivation of HSC-T6 cells induced by MDI. These observations revealed a regulatory role of PTP1B in liver fibrosis and implied PTP1B as a potential therapeutic target. - Highlights: • The expression of PTP1B in the fibrotic livers and recovery livers • The expression of PTP1B in activated and inactivated HSCs • Blockade of PTP1B inhibited the TGF-β1-induced proliferation and activation of HSCs. • Over-expression of PTP1B abolished the inactivation of HSCs induced by MDI.

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

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

    2011-01-01

    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 4 ) rat model. Male Wistar rats received intraperitoneal injections of CCl 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 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 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 4 -treated rats. Hepatic morphometric evaluation and 4-hydroxyproline content revealed that CCl 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. → These effects were

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

    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

  10. Imaging of hepatic toxicity of systemic therapy in a tertiary cancer centre: chemotherapy, haematopoietic stem cell transplantation, molecular targeted therapies, and immune checkpoint inhibitors.

    Alessandrino, F; Tirumani, S H; Krajewski, K M; Shinagare, A B; Jagannathan, J P; Ramaiya, N H; Di Salvo, D N

    2017-07-01

    The purpose of this review is to familiarise radiologists with the spectrum of hepatic toxicity seen in the oncology setting, in view of the different systemic therapies used in cancer patients. Drug-induced liver injury can manifest in various forms, and anti-neoplastic agents are associated with different types of hepatotoxicity. Although chemotherapy-induced liver injury can present as hepatitis, steatosis, sinusoidal obstruction syndrome, and chronic parenchymal damages, molecular targeted therapy-associated liver toxicity ranges from mild liver function test elevation to fulminant life-threatening acute liver failure. The recent arrival of immune checkpoint inhibitors in oncology has introduced a new range of immune-related adverse events, with differing mechanisms of liver toxicity and varied imaging presentation of liver injury. High-dose chemotherapy regimens for haematopoietic stem cell transplantation are associated with sinusoidal obstruction syndrome. Management of hepatic toxicity depends on the clinical scenario, the drug in use, and the severity of the findings. In this article, we will (1) present the most common types of oncological drugs associated with hepatic toxicity and associated liver injuries; (2) illustrate imaging findings of hepatic toxicities and the possible differential diagnosis; and (3) provide a guide for management of these conditions. Copyright © 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

  11. Molecular basis of hepatic fibrosis and current status of its diagnosis and treatment

    LI Yan

    2018-01-01

    Full Text Available During the process of acute or chronic liver injury, hepatic stellate cells interact with various types of cells such as hepatic parenchymal cells, Kupffer cells, and liver sinusoidal endothelial cells to mediate extracellular matrix deposition and sinusoid capillarization and thus initiate the process of hepatic fibrosis. The nature of hepatic fibrosis is repair response after liver injury. Liver biopsy is regarded as the gold standard for the diagnosis of hepatic fibrosis; however, it is generally associated with the risk of bleeding and even death. Noninvasive diagnostic methods for liver fibrosis mainly include serum biomarkers, imaging techniques, and predictive statistical model, but such methods cannot completely replace liver biopsy. At present, the treatment of hepatic fibrosis focuses on the research and development of new drugs targeting primary disease, hepatic stellate cells, or balance of extracellular matrix synthesis/degradation. The research on the molecular mechanism of hepatic fibrosis provides a solid theoretical basis for exploring the treatment of hepatic fibrosis.

  12. Fulminant Hepatic Failure Attributed to Ackee Fruit Ingestion in a Patient with Sickle Cell Trait

    Dianne E. Grunes

    2012-01-01

    Full Text Available We report a case of fulminant liver failure resulting in emergent liver transplantation following 3 weeks of nausea, vomiting, and malaise from Jamaican Vomiting Sickness. Jamaican Vomiting Sickness is caused by ingestion of the unripe arils of the Ackee fruit, its seeds and husks. It is characterized by acute gastrointestinal illness and hypoglycemia. In severe cases, central nervous system depression can occur. In previous studies, histologic sections taken from patients with Jamaican Vomiting Sickness have shown hepatotoxicity similar to that seen in Reye syndrome and/or acetaminophen toxicity. We highlight macroscopic and microscopic changes in the liver secondary to hepatoxicity of Ackee fruit versus those caused by a previously unknown sickle cell trait. We discuss the clinical variables and the synergistic hepatotoxic effect of Ackee fruit and ischemic injury from sickled red blood cells, causing massive hepatic necrosis in this patient.

  13. Flurbiprofen, a Cyclooxygenase Inhibitor, Protects Mice from Hepatic Ischemia/Reperfusion Injury by Inhibiting GSK-3β Signaling and Mitochondrial Permeability Transition

    Fu, Hailong; Chen, Huan; Wang, Chengcai; Xu, Haitao; Liu, Fang; Guo, Meng; Wang, Quanxing; Shi, Xueyin

    2012-01-01

    Flurbiprofen acts as a nonselective inhibitor for cyclooxygenases (COX-1 and COX-2), but its impact on hepatic ischemia/reperfusion (I/R) injury remains unclear. Mice were randomized into sham, I/R and flurbiprofen (Flurb) groups. The hepatic artery and portal vein to the left and median liver lobes were occluded for 90 min and unclamped for reperfusion to establish a model of segmental (70%) warm hepatic ischemia. Pretreatment of animals with flurbiprofen prior to I/R insult significantly decreased serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH), and prevented hepatocytes from I/R-induced apoptosis/necrosis. Moreover, flurbiprofen dramatically inhibited mitochondrial permeability transition (MPT) pore opening, and thus prevented mitochondrial-related cell death and apoptosis. Mechanistic studies revealed that flurbiprofen markedly inhibited glycogen synthase kinase (GSK)-3β activity and increased phosphorylation of GSK-3β at Ser9, which, consequently, could modulate the adenine nucleotide translocase (ANT)–cyclophilin D (CyP-D) complex and the susceptibility to MPT induction. Therefore, administration of flurbiprofen prior to hepatic I/R ameliorates mitochondrial and hepatocellular damage through inhibition of MPT and inactivation of GSK-3β, and provides experimental evidence for clinical use of flurbiprofen to protect liver function in surgical settings in addition to its conventional use for pain relief. PMID:22714712

  14. The hepatic stellate cell in sight : targeting antiproliferative drugs to the fibrotic liver

    Greupink, Albert Hendrikus

    2006-01-01

    Liver fibrosis is characterized by the accumulation of excessive amounts of scar tissue in response to chronic liver injury. Important causes of chronic liver injury are viral hepatitis, metabolic disorders such as Wilson’s disease, autoimmune diseases and chronic exposure to certain chemicals,

  15. Bioenergetic Changes during Differentiation of Human Embryonic Stem Cells along the Hepatic Lineage

    Hopkinson, Branden M; Madsen, Claus Desler; Kalisz, Mark

    2017-01-01

    Mitochondrial dysfunction has been demonstrated to result in premature aging due to its effects on stem cells. Nevertheless, a full understanding of the role of mitochondrial bioenergetics through differentiation is still lacking. Here we show the bioenergetics profile of human stem cells...... of embryonic origin differentiating along the hepatic lineage. Our study reveals especially the transition between hepatic specification and hepatic maturation as dependent on mitochondrial respiration and demonstrates that even though differentiating cells are primarily dependent on glycolysis until induction...

  16. Left hepatic vein injury during laparoscopic antireflux surgery for large para-oesophageal hiatus hernia

    Nagpal Anish

    2009-01-01

    Full Text Available Although the advent of laparoscopic fundoplication has increased both patient and physician acceptance of antireflux surgery, it has become apparent that the laparoscopic approach is associated with an increased risk of some complications and as well as the occurrence of new complications specific to this approach. One such complication occurred in our patient who had intra-operative left hepatic vein injury during laparoscopic floppy Nissen fundoplication for large para-oesophageal rolling hernia. With timely conversion to open procedure, the bleeding was controlled and the antireflux and the procedure were completed uneventfully. However, this suggests that even with an experience in advanced laparoscopy surgery, complications can occur. Clear understanding of the normal and pathologic anatomy and its variations facilitates laparoscopic surgery and should help the surgeon avoid complications. The incidence of some of these complications decreases as surgeons gain experience; however, new complications can arise due to the increase in such procedures.

  17. Clear cell HCC: an imitator of hepatic adenoma

    Incedayi, M.; Sivrioglu, A.

    2012-01-01

    Full text: A 60-year old male patient was complaining of a postprandial heartburn and of abdominal distension. Physical examination was normal except for nodular, painless hepatomegaly. Ultrasonographic examination of the liver showed diffuse increased echogenicity and coarse echotexture. A large mixed echogenic mass is seen in the right hepatic lobe. Computerized tomography showed heterogeneously hypodense mass lesions with fatty change on non-contrast scans and enhance heterogeneously on both arterial phase and venous phase postcontrast scans. Following true-cut biopsy, it was ascertained to be a clear cell HCC. Clear cell HCC may include large fatty areas and this is often misdiagnosed to be an adenoma. Clear cell HCC is characterized by high female prevalence, high rate of association with liver cirrhosis and has no significant difference in prognosis compared with non-clear cell HCC

  18. The impact of a massive transfusion protocol (1:1:1) on major hepatic injuries: does it increase abdominal wall closure rates?

    Ball, Chad G; Dente, Christopher J; Shaz, Beth; Wyrzykowski, Amy D; Nicholas, Jeffrey M; Kirkpatrick, Andrew W; Feliciano, David V

    2013-10-01

    Massive transfusion protocols (MTPs) using high plasma and platelet ratios for exsanguinating trauma patients are increasingly popular. Major liver injuries often require massive resuscitations and immediate hemorrhage control. Current published literature describes outcomes among patients with mixed patterns of injury. We sought to identify the effects of an MTP on patients with major liver trauma. Patients with grade 3, 4 or 5 liver injuries who required a massive blood component transfusion were analyzed. We compared patients with high plasma:red blood cell:platelet ratio (1:1:1) transfusions (2007-2009) with patients injured before the creation of an institutional MTP (2005-2007). Among 60 patients with major hepatic injuries, 35 (58%) underwent resuscitation after the implementation of an MTP. Patient and injury characteristics were similar between cohorts. Implementation of the MTP significantly improved plasma: red blood cell:platelet ratios and decreased crystalloid fluid resuscitation (p = 0.026). Rapid improvement in early acidosis and coagulopathy was superior with an MTP (p = 0.009). More patients in the MTP group also underwent primary abdominal fascial closure during their hospital stay (p = 0.021). This was most evident with grade 4 injuries (89% vs. 14%). The mean time to fascial closure was 4.2 days. The overall survival rate for all major liver injuries was not affected by an MTP (p = 0.61). The implementation of a formal MTP using high plasma and platelet ratios resulted in a substantial increase in abdominal wall approximation. This occurred concurrently to a decrease in the delivered volume of crystalloid fluid.

  19. Combining Vγ9Vδ2 T Cells with a Lipophilic Bisphosphonate Efficiently Kills Activated Hepatic Stellate Cells

    Xiaoying Zhou

    2017-10-01

    Full Text Available Activated hepatic stellate cells (aHSCs are now established as a central driver of fibrosis in human liver injury. In the presence of chronic or repeated injury, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC can occur, so there is interest in down-regulating aHSCs activity in order to treat these diseases. Here, we report that Vγ9Vδ2 T cells are reduced in patients with liver cirrhosis, stimulating us to investigate possible interactions between Vγ9Vδ2 T cells and aHSCs. We find that Vγ9Vδ2 T cells kill aHSCs and killing is enhanced when aHSCs are pretreated with BPH-1236, a lipophilic analog of the bone resorption drug zoledronate. Cytotoxicity is mediated by direct cell-to-cell contact as shown by Transwell experiments and atomic force microscopy, with BPH-1236 increasing the adhesion between aHSCs and Vγ9Vδ2 T cells. Mechanistically, BPH-1236 functions by inhibiting farnesyl diphosphate synthase, leading to accumulation of the phosphoantigen isopentenyl diphosphate and recognition by Vγ9Vδ2 T cells. The cytolytic process is largely dependent on the perforin/granzyme B pathway. In a Rag2−/−γc−/− immune-deficient mouse model, we find that Vγ9Vδ2 T cells home-in to the liver, and when accompanied by BPH-1236, kill not only orthotopic aHSCs but also orthotopic HCC tumors. Collectively, our results provide the first proof-of-concept of a novel immunotherapeutic strategy for the treatment of fibrosis–cirrhosis–HCC diseases using adoptively transferred Vγ9Vδ2 T cells, combined with a lipophilic bisphosphonate.

  20. [The effect of portal blood stasis on lung and renal injury induced by hepatic ischemia reperfusion in a rabbit model].

    Wang, Ye; Yang, Jia-mei; Hou, Yuan-kai; Li, Dian-qi; Hu, Ming-hua; Liu, Peng

    2008-04-15

    To investigate the effect and mechanism of portal blood stasis on lung and renal injury induced by hepatic ischemia reperfusion. A rabbit hepatic ischemia reperfusion injury model was established by hepatic portal occlusion and in situ hypothermic irrigation for 30 min. Twenty-four New Zealand white rabbits were employed and randomly divided into 3 groups equally by different dosage of portal blood stasis removal: group A5 (5 ml blood removal), group A10 (10 ml blood removal),and group B (no blood removal). Eight rabbits were served as controls with no hepatic portal occlusion and hypothermic irrigation. After reperfusion 4 h serum endotoxin content, tumor necrosis factor-alpha (TNF-alpha), urea nitrogen (BUN), and creatinine (Cr) were examined respectively, meantime lung and kidney tissues were sampled to determine the content of malondialdehyde (MDA), superoxide dismutase (SOD), the pathology, and wet to dry weight ratio, broncho-alveolar lavage fluid protein content in lung tissues. Removing portal blood stasis ameliorated lung and renal injury as shown by decreasing the level of serum endotoxin, TNF-alpha, BUN, Cr, wet to dry weight ratio, broncho-alveolar lavage fluid protein content, MDA, SOD. TNF-alpha, Cr, broncho-alveolar lavage fluid protein content in lung tissues and MDA in kidney tissue in group A5 were significantly reduced compared with those in group B (P portal blood stasis before the resume of splanchnic circulation may ameliorate the lung and renal injury induced by hepatic ischemia reperfusion. The possible mechanism may be that portal blood stasis removal reduces endotoxin absorption, and further decreases production of serum TNF-alpha.

  1. Lactobacillus paracasei GMNL-32, Lactobacillus reuteri GMNL-89 and L. reuteri GMNL-263 ameliorate hepatic injuries in lupus-prone mice.

    Hsu, Tsai-Ching; Huang, Chih-Yang; Liu, Chung-Hsien; Hsu, Kuo-Ching; Chen, Yi-Hsing; Tzang, Bor-Show

    2017-04-01

    Probiotics are known to regulate host immunity by interacting with systemic and mucosal immune cells as well as intestinal epithelial cells. Supplementation with certain probiotics has been reported to be effective against various disorders, including immune-related diseases. However, little is known about the effectiveness of Lactobacillus paracasei GMNL-32 (GMNL-32), Lactobacillus reuteri GMNL-89 (GMNL-89) and L. reuteri GMNL-263 (GMNL-263) in the management of autoimmune diseases, especially systemic lupus erythematosus (SLE). NZB/W F1 mice, which are a lupus-prone animal model, were orally gavaged with GMNL-32, GMNL-89 or GMNL-263 to investigate the effects of these Lactobacillus strains on liver injuries in NZB/W F1 mice. The results thus obtained reveal that supplementary GMNL-32, GMNL-89 or GMNL-263 in NZB/W F1 mice ameliorates hepatic apoptosis and inflammatory indicators, such as matrix metalloproteinase-9 activity and C-reactive protein and inducible nitric oxide synthase expressions. In addition, supplementation with GMNL-32, GMNL-89 or GMNL-263 in NZB/W F1 mice reduced the expressions of hepatic IL-1β, IL-6 and TNF-α proteins by suppressing the mitogen-activated protein kinase and NF-κB signalling pathways. These findings, presented here for the first time, reveal that GMNL-32, GMNL-89 and GMNL-263 mitigate hepatic inflammation and apoptosis in lupus-prone mice and may support an alternative remedy for liver disorders in cases of SLE.

  2. Immune checkpoint inhibitor-induced gastrointestinal and hepatic injury: pathologists' perspective.

    Karamchandani, Dipti M; Chetty, Runjan

    2018-04-27

    Immune checkpoint inhibitors (CPIs) are a relatively new class of 'miracle' dugs that have revolutionised the treatment and prognosis of some advanced-stage malignancies, and have increased the survival rates significantly. This class of drugs includes cytotoxic T lymphocyte antigen-4 inhibitors such as ipilimumab; programmed cell death protein-1 inhibitors such as nivolumab, pembrolizumab and avelumab; and programmed cell death protein ligand-1 inhibitors such as atezolizumab. These drugs stimulate the immune system by blocking the coinhibitory receptors on the T cells and lead to antitumoural response. However, a flip side of these novel drugs is immune-related adverse events (irAEs), secondary to immune-mediated process due to disrupted self-tolerance. The irAEs in the gastrointestinal (GI) tract/liver may result in diarrhoea, colitis or hepatitis. An accurate diagnosis of CPI-induced colitis and/or hepatitis is essential for optimal patient management. As we anticipate greater use of these drugs in the future given the significant clinical response, pathologists need to be aware of the spectrum of histological findings that may be encountered in GI and/or liver biopsies received from these patients, as well as differentiate them from its histopathological mimics. This present review discusses the clinical features, detailed histopathological features, management and the differential diagnosis of the luminal GI and hepatic irAEs that may be encountered secondary to CPI therapy. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  3. Recent Advances in Hepatitis C Virus Cell Entry

    Jean Dubuisson

    2010-03-01

    Full Text Available More than 170 million patients worldwide are chronically infected with hepatitis C virus (HCV. Prevalence rates range from 0.5% in Northern European countries to 28% in some areas of Egypt. HCV is hepatotropic, and in many countries chronic hepatitis C is a leading cause of liver disease including fibrosis, cirrhosis and hepatocellular carcinoma. HCV persists in 50–85% of infected patients, and once chronic infection is established, spontaneous clearance is rare. HCV is a member of the Flaviviridae family, in which it forms its own genus. Many lines of evidence suggest that the HCV life cycle displays many differences to that of other Flaviviridae family members. Some of these differences may be due to the close interaction of HCV with its host’s lipid and particular triglyceride metabolism in the liver, which may explain why the virus can be found in association with lipoproteins in serum of infected patients. This review focuses on the molecular events underlying the HCV cell entry process and the respective roles of cellular co-factors that have been implied in these events. These include, among others, the lipoprotein receptors low density lipoprotein receptor and scavenger receptor BI, the tight junction factors occludin and claudin-1 as well as the tetraspanin CD81. We discuss the roles of these cellular factors in HCV cell entry and how association of HCV with lipoproteins may modulate the cell entry process.

  4. Pro-inflammatory activated Kupffer cells by lipids induce hepatic NKT cells deficiency through activation-induced cell death.

    Tongfang Tang

    Full Text Available BACKGROUND: Dietary lipids play an important role in the progression of non-alcoholic fatty liver disease (NAFLD through alternation of liver innate immune response. AIMS: The present study was to investigate the effect of lipid on Kupffer cells phenotype and function in vivo and in vitro. And further to investigate the impact of lipid on ability of Kupffer cell lipid antigen presentation to activate NKT cells. METHODS: Wild type male C57BL/6 mice were fed either normal or high-fat diet. Hepatic steatosis, Kupffer cell abundance, NKT cell number and cytokine gene expression were evaluated. Antigen presentation assay was performed with Kupffer cells treated with certain fatty acids in vitro and co-cultured with NKT cells. RESULTS: High-fat diet induced hepatosteatosis, significantly increased Kupffer cells and decreased hepatic NKT cells. Lipid treatment in vivo or in vitro induced increase of pro-inflammatory cytokines gene expression and toll-like receptor 4 (TLR4 expression in Kupffer cells. Kupffer cells expressed high levels of CD1d on cell surface and only presented exogenous lipid antigen to activate NKT cells. Ability of Kupffer cells to present antigen and activate NKT cells was enhanced after lipid treatment. In addition, pro-inflammatory activated Kupffer cells by lipid treatment induced hepatic NKT cells activation-induced apoptosis and necrosis. CONCLUSION: High-fat diet increase Kupffer cells number and induce their pro-inflammatory status. Pro-inflammatory activated Kupfffer cells by lipid promote hepatic NKT cell over-activation and cell death, which lead to further hepatic NKT cell deficiency in the development of NAFLD.

  5. Pro-inflammatory activated Kupffer cells by lipids induce hepatic NKT cells deficiency through activation-induced cell death.

    Tang, Tongfang; Sui, Yongheng; Lian, Min; Li, Zhiping; Hua, Jing

    2013-01-01

    Dietary lipids play an important role in the progression of non-alcoholic fatty liver disease (NAFLD) through alternation of liver innate immune response. The present study was to investigate the effect of lipid on Kupffer cells phenotype and function in vivo and in vitro. And further to investigate the impact of lipid on ability of Kupffer cell lipid antigen presentation to activate NKT cells. Wild type male C57BL/6 mice were fed either normal or high-fat diet. Hepatic steatosis, Kupffer cell abundance, NKT cell number and cytokine gene expression were evaluated. Antigen presentation assay was performed with Kupffer cells treated with certain fatty acids in vitro and co-cultured with NKT cells. High-fat diet induced hepatosteatosis, significantly increased Kupffer cells and decreased hepatic NKT cells. Lipid treatment in vivo or in vitro induced increase of pro-inflammatory cytokines gene expression and toll-like receptor 4 (TLR4) expression in Kupffer cells. Kupffer cells expressed high levels of CD1d on cell surface and only presented exogenous lipid antigen to activate NKT cells. Ability of Kupffer cells to present antigen and activate NKT cells was enhanced after lipid treatment. In addition, pro-inflammatory activated Kupffer cells by lipid treatment induced hepatic NKT cells activation-induced apoptosis and necrosis. High-fat diet increase Kupffer cells number and induce their pro-inflammatory status. Pro-inflammatory activated Kupfffer cells by lipid promote hepatic NKT cell over-activation and cell death, which lead to further hepatic NKT cell deficiency in the development of NAFLD.

  6. Freezing Injury in Onion Bulb Cells

    Palta, Jiwan P.; Levitt, Jacob; Stadelmann, Eduard J.

    1977-01-01

    Onion (Allium cepa L.) bulbs were frozen to −4 and −11 C and kept frozen for up to 12 days. After slow thawing, a 2.5-cm square from a bulb scale was transferred to 25 ml deionized H2O. After shaking for standard times, measurements were made on the effusate and on the effused cells. The results obtained were as follows. Even when the scale tissue was completely infiltrated, and when up to 85% of the ions had diffused out, all of the cells were still alive, as revealed by cytoplasmic streaming and ability to plasmolyze. The osmotic concentration of the cell sap, as measured plasmolytically, decreased in parallel to the rise in conductivity of the effusate. The K+ content of the effusate, plus its assumed counterion, accounted for only 20% of the total solutes, but for 100% of the conductivity. A large part of the nonelectrolytes in the remaining 80% of the solutes was sugars. The increased cell injury and infiltration in the −11 C treatment, relative to the −4 C and control (unfrozen) treatments, were paralleled by increases in conductivity, K+ content, sugar content, and pH of the effusate. In spite of the 100% infiltration of the tissue and the large increase in conductivity of the effusate following freezing, no increase in permeability of the cells to water could be detected. The above observations may indicate that freezing or thawing involves a disruption of the active transport system before the cells reveal any injury microscopically. PMID:16660100

  7. Hepatitis C virus cell-cell transmission and resistance to direct-acting antiviral agents

    Xiao, Fei; Fofana, Isabel; Heydmann, Laura

    2014-01-01

    Hepatitis C virus (HCV) is transmitted between hepatocytes via classical cell entry but also uses direct cell-cell transfer to infect neighboring hepatocytes. Viral cell-cell transmission has been shown to play an important role in viral persistence allowing evasion from neutralizing antibodies....... In contrast, the role of HCV cell-cell transmission for antiviral resistance is unknown. Aiming to address this question we investigated the phenotype of HCV strains exhibiting resistance to direct-acting antivirals (DAAs) in state-of-the-art model systems for cell-cell transmission and spread. Using HCV...... genotype 2 as a model virus, we show that cell-cell transmission is the main route of viral spread of DAA-resistant HCV. Cell-cell transmission of DAA-resistant viruses results in viral persistence and thus hampers viral eradication. We also show that blocking cell-cell transmission using host...

  8. Protective effect of tropisetron on rodent hepatic injury after trauma-hemorrhagic shock through P38 MAPK-dependent hemeoxygenase-1 expression.

    Fu-Chao Liu

    Full Text Available Tropisetron can decrease inflammatory cell responses and alleviate organ damage caused by trauma-hemorrhage, but the mechanism of these effects remains unknown. The p38 mitogen-activated protein kinase/hemeoxygenase-1 (p38 MAPK/HO-1 pathway exerts anti-inflammatory effects on different tissues. The aim of this study was to investigate whether p38 MAPK/HO-1 plays any role in the tropisetron-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 min, followed by fluid resuscitation. During resuscitation, several treatment regimens were administered: four doses of tropisetron alone (0.1, 0.3, 1, 3 mg/kg body weight, or a single dose of tropisetron (1 mg/kg body weight with and without a p38 MAPK inhibitor (SB-203580, 2 mg/kg body weight or HO antagonist (chromium-mesoporphyrin, 2.5 mg/kg body weight. Various parameters were measured, and the animals were sacrificed at 24 h post-resuscitation. The results showed that trauma-hemorrhage increased the following parameters: plasma concentrations of aspartate (AST and alanine aminotransferases (ALT, hepatic myeloperoxidase (MPO activity, and levels of cytokine-induced neutrophil chemoattractant-1 and -3 (CINC-1 and CINC-3, intercellular adhesion molecule-1 (ICAM-1, interleukin-6 (IL-6, tumor necrosis factor-α (TNF-α, and macrophage inflammatory protein-1α (MIP-1α. These parameters were significantly improved in the tropisetron-treated rats subjected to trauma-hemorrhage. Tropisetron treatment also increased hepatic p38 MAPK and HO-1 expression compared with vehicle-treated trauma-hemorrhaged rats. Co-administration of SB-203580 or chromium-mesoporphyrin with tropisetron abolished the tropisetron-induced beneficial effects on the above parameters and hepatic injury. These results suggest that the protective effect of tropisetron administration on alleviation of hepatic

  9. Protective effect of tropisetron on rodent hepatic injury after trauma-hemorrhagic shock through P38 MAPK-dependent hemeoxygenase-1 expression.

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

    2012-01-01

    Tropisetron can decrease inflammatory cell responses and alleviate organ damage caused by trauma-hemorrhage, but the mechanism of these effects remains unknown. The p38 mitogen-activated protein kinase/hemeoxygenase-1 (p38 MAPK/HO-1) pathway exerts anti-inflammatory effects on different tissues. The aim of this study was to investigate whether p38 MAPK/HO-1 plays any role in the tropisetron-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 min), followed by fluid resuscitation. During resuscitation, several treatment regimens were administered: four doses of tropisetron alone (0.1, 0.3, 1, 3 mg/kg body weight), or a single dose of tropisetron (1 mg/kg body weight) with and without a p38 MAPK inhibitor (SB-203580, 2 mg/kg body weight) or HO antagonist (chromium-mesoporphyrin, 2.5 mg/kg body weight). Various parameters were measured, and the animals were sacrificed at 24 h post-resuscitation. The results showed that trauma-hemorrhage increased the following parameters: plasma concentrations of aspartate (AST) and alanine aminotransferases (ALT), hepatic myeloperoxidase (MPO) activity, and levels of cytokine-induced neutrophil chemoattractant-1 and -3 (CINC-1 and CINC-3), intercellular adhesion molecule-1 (ICAM-1), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and macrophage inflammatory protein-1α (MIP-1α). These parameters were significantly improved in the tropisetron-treated rats subjected to trauma-hemorrhage. Tropisetron treatment also increased hepatic p38 MAPK and HO-1 expression compared with vehicle-treated trauma-hemorrhaged rats. Co-administration of SB-203580 or chromium-mesoporphyrin with tropisetron abolished the tropisetron-induced beneficial effects on the above parameters and hepatic injury. These results suggest that the protective effect of tropisetron administration on alleviation of hepatic injury

  10. Coinfection of Hepatic Cell Lines with Human Immunodeficiency Virus and Hepatitis B Virus Leads to an Increase in Intracellular Hepatitis B Surface Antigen▿

    Iser, David M.; Warner, Nadia; Revill, Peter A.; Solomon, Ajantha; Wightman, Fiona; Saleh, Suha; Crane, Megan; Cameron, Paul U.; Bowden, Scott; Nguyen, Tin; Pereira, Cândida F.; Desmond, Paul V.; Locarnini, Stephen A.; Lewin, Sharon R.

    2010-01-01

    Liver-related mortality is increased in the setting of HIV-hepatitis B virus (HBV) coinfection. However, interactions between HIV and HBV to explain this observation have not been described. We hypothesized that HIV infection of hepatocytes directly affects the life cycle of HBV. We infected human hepatic cell lines expressing HBV (Hep3B and AD38 cells) or not expressing HBV (Huh7, HepG2, and AD43 cells) with laboratory strains of HIV (NL4-3 and AD8), as well as a vesicular stomatitis virus (VSV)-pseudotyped HIV expressing enhanced green fluorescent protein (EGFP). Following HIV infection with NL4-3 or AD8 in hepatic cell lines, we observed a significant increase in HIV reverse transcriptase activity which was infectious. Despite no detection of surface CD4, CCR5, and CXCR4 by flow cytometry, AD8 infection of AD38 cells was inhibited by maraviroc and NL4-3 was inhibited by AMD3100, demonstrating that HIV enters AD38 hepatic cell lines via CCR5 or CXCR4. High-level infection of AD38 cells (50%) was achieved using VSV-pseudotyped HIV. Coinfection of the AD38 cell line with HIV did not alter the HBV DNA amount or species as determined by Southern blotting or nucleic acid signal amplification. However, coinfection with HIV was associated with a significant increase in intracellular HBsAg when measured by Western blotting, quantitative HBsAg, and fluorescence microscopy. We conclude that HIV infection of HBV-infected hepatic cell lines significantly increased intracellular HBsAg but not HBV DNA synthesis and that increased intrahepatic HBsAg secondary to direct infection by HIV may contribute to accelerated liver disease in HIV-HBV-coinfected individuals. PMID:20357083

  11. Coinfection of hepatic cell lines with human immunodeficiency virus and hepatitis B virus leads to an increase in intracellular hepatitis B surface antigen.

    Iser, David M; Warner, Nadia; Revill, Peter A; Solomon, Ajantha; Wightman, Fiona; Saleh, Suha; Crane, Megan; Cameron, Paul U; Bowden, Scott; Nguyen, Tin; Pereira, Cândida F; Desmond, Paul V; Locarnini, Stephen A; Lewin, Sharon R

    2010-06-01

    Liver-related mortality is increased in the setting of HIV-hepatitis B virus (HBV) coinfection. However, interactions between HIV and HBV to explain this observation have not been described. We hypothesized that HIV infection of hepatocytes directly affects the life cycle of HBV. We infected human hepatic cell lines expressing HBV (Hep3B and AD38 cells) or not expressing HBV (Huh7, HepG2, and AD43 cells) with laboratory strains of HIV (NL4-3 and AD8), as well as a vesicular stomatitis virus (VSV)-pseudotyped HIV expressing enhanced green fluorescent protein (EGFP). Following HIV infection with NL4-3 or AD8 in hepatic cell lines, we observed a significant increase in HIV reverse transcriptase activity which was infectious. Despite no detection of surface CD4, CCR5, and CXCR4 by flow cytometry, AD8 infection of AD38 cells was inhibited by maraviroc and NL4-3 was inhibited by AMD3100, demonstrating that HIV enters AD38 hepatic cell lines via CCR5 or CXCR4. High-level infection of AD38 cells (50%) was achieved using VSV-pseudotyped HIV. Coinfection of the AD38 cell line with HIV did not alter the HBV DNA amount or species as determined by Southern blotting or nucleic acid signal amplification. However, coinfection with HIV was associated with a significant increase in intracellular HBsAg when measured by Western blotting, quantitative HBsAg, and fluorescence microscopy. We conclude that HIV infection of HBV-infected hepatic cell lines significantly increased intracellular HBsAg but not HBV DNA synthesis and that increased intrahepatic HBsAg secondary to direct infection by HIV may contribute to accelerated liver disease in HIV-HBV-coinfected individuals.

  12. [Hepatic cell transplantation: a new therapy in liver diseases].

    Pareja, Eugenia; Cortés, Miriam; Martínez, Amparo; Vila, Juan José; López, Rafael; Montalvá, Eva; Calzado, Angeles; Mir, José

    2010-07-01

    Liver transplantation has been remarkably effective in the treatment in patients with end-stage liver disease. However, disparity between solid-organ supply and increased demand is the greatest limitation, resulting in longer waiting times and increase in mortality of transplant recipients. This situation creates the need to seek alternatives to orthotopic liver transplantation.Hepatocyte transplantation or liver cell transplantation has been proposed as the best method to support patients. The procedure consists of transplanting individual cells to a recipient organ in sufficient quantity to survive and restore the function. The capacity of hepatic regeneration is the biological basis of hepatocyte transplantation. This therapeutic option is an experimental procedure in some patients with inborn errors of metabolism, fulminant hepatic failure and acute and chronic liver failure, as a bridge to orthotopic liver transplantation. In the Hospital La Fe of Valencia, we performed the first hepatocyte transplantation in Spain creating a new research work on transplant program. Copyright 2009 AEC. Published by Elsevier Espana. All rights reserved.

  13. Interferon gamma peptidomimetic targeted to hepatic stellate cells ameliorates acute and chronic liver fibrosis in vivo

    Bansal, Ruchi; Prakash, Jai; De Ruiter, Marieke; Poelstra, Klaas

    2014-01-01

    Hepatic stellate cells play a crucial role in the pathogenesis of hepatic fibrosis. Thus, pharmacological inhibition of pro-fibrotic activities of these cells might lead to an effective therapy for this disease. Among the potent antifibrotics, interferon gamma (IFN gamma), a proinflammatory

  14. Docking of B-cell epitope antigen to specific hepatitis B antibody

    The interaction of pres1 region of hepatitis B virus B-cell epitope antigen with specific hepatitis B neutralizing monoclonal antibody was examined by docking study. We modelled the 3D complex structure of B-cell epitope antigen residues CTTPAQGNSMFPSCCCTKPTDGNCY by homology modelling and docked it with the ...

  15. Interferon gamma peptidomimetic targeted to hepatic stellate cells ameliorates acute and chronic liver fibrosis in vivo

    Bansal, Ruchi; Prakash, Jai; de Ruiter, Marieke; Poelstra, Klaas

    2014-01-01

    Hepatic stellate cells play a crucial role in the pathogenesis of hepatic fibrosis. Thus, pharmacological inhibition of pro-fibrotic activities of these cells might lead to an effective therapy for this disease. Among the potent anti-fibrotics, interferon gamma (IFNγ), a proinflammatory cytokine, is

  16. Cardiopulmonary bypass after severe blunt hepatic injury: management of multi-system blunt trauma in an adolescent.

    Streit, Stephanie; Kavarana, Minoo; Scheurer, Mark A; Cina, Robert A

    2013-06-01

    A 16-year-old adolescent male sustained combined injuries to the tricuspid valve and liver. This injury is exceptional due to the mechanism and the circumstances in which it took place: a flying pumpkin thrown from a sport utility vehicle. An echocardiogram demonstrated a flail chordal apparatus associated with the posterior leaflet of the tricuspid valve, creating substrate for severe tricuspid regurgitation with preserved right heart function. He was treated with non-operative management for the liver injury; he remained hemodynamically stable and was discharged home. He underwent successful repair of the tricuspid valve 17 days following the initial injury necessitating systemic anticoagulation and was discharged home two days later. The patient recovered fully without residual valvular pathology or hepatic sequelae. Copyright © 2013 Elsevier Inc. All rights reserved.

  17. Antioxidant effects of Spirulina supplement against lead acetate-induced hepatic injury in rats

    Walid Hamdy El-Tantawy

    2016-10-01

    Full Text Available Lead is a toxic metal that induces a wide range of behavioral, biochemical and physiological effects in humans. Oxidative damage has been proposed as a possible mechanism involved in lead toxicity. The current study was carried out to evaluate the antioxidant activities of Spirulina supplement against lead acetate -induced hepatic injury in rats. Five groups of rats were used in this study, Control, Lead acetate (100 mg/kg, Lead acetate (100 mg/kg + 0.5 g/kg Spirulina, Lead acetate (100 mg/kg + 1 g/kg Spirulina and Lead acetate + 25 mg/100 g Vitamin C (reference drug. All experimental groups received the oral treatment by stomach tube once daily for 4 weeks. Lead intoxication resulted in a significant increase in serum alanine transaminae (ALT, aspartate transaminae (AST activities, liver homogenate tumor necrosis factor-α (TNF-α, caspase-3, malondialdehyde (MDA, nitric oxide (NO levels and a significant decline of total serum protein, liver homogenate reduced glutathione (GSH level and superoxide dismutase (SOD activity. Both doses of Spirulina supplement as well as Vitamin C succeeded to improve the biochemical parameters of serum and liver and prevented the lead acetate-induced significant changes on plasma and antioxidant status of the liver. Both doses of Spirulina supplement had the same anti-apoptotic activity and high dose exhibited more antioxidant activity than that of low dose. In conclusion, the results of the present work revealed that Spirulina supplement had protective, antioxidant and anti-apoptotic effects on lead acetate-induced hepatic damage.

  18. Efficient generation of hepatic cells from mesenchymal stromal cells by an innovative bio-microfluidic cell culture device.

    Yen, Meng-Hua; Wu, Yuan-Yi; Liu, Yi-Shiuan; Rimando, Marilyn; Ho, Jennifer Hui-Chun; Lee, Oscar Kuang-Sheng

    2016-08-19

    Mesenchymal stromal cells (MSCs) are multipotent and have great potential in cell therapy. Previously we reported the differentiation potential of human MSCs into hepatocytes in vitro and that these cells can rescue fulminant hepatic failure. However, the conventional static culture method neither maintains growth factors at an optimal level constantly nor removes cellular waste efficiently. In addition, not only is the duration of differentiating hepatocyte lineage cells from MSCs required to improve, but also the need for a large number of hepatocytes for cell therapy has not to date been addressed fully. The purpose of this study is to design and develop an innovative microfluidic device to overcome these shortcomings. We designed and fabricated a microfluidic device and a culture system for hepatic differentiation of MSCs using our protocol reported previously. The microfluidic device contains a large culture chamber with a stable uniform flow to allow homogeneous distribution and expansion as well as efficient induction of hepatic differentiation for MSCs. The device enables real-time observation under light microscopy and exhibits a better differentiation efficiency for MSCs compared with conventional static culture. MSCs grown in the microfluidic device showed a higher level of hepatocyte marker gene expression under hepatic induction. Functional analysis of hepatic differentiation demonstrated significantly higher urea production in the microfluidic device after 21 days of hepatic differentiation. The microfluidic device allows the generation of a large number of MSCs and induces hepatic differentiation of MSCs efficiently. The device can be adapted for scale-up production of hepatic cells from MSCs for cellular therapy.

  19. Tracking virus-specific CD4+ T cells during and after acute hepatitis C virus infection.

    Michaela Lucas

    2007-07-01

    Full Text Available CD4+ T cell help is critical in maintaining antiviral immune responses and such help has been shown to be sustained in acute resolving hepatitis C. In contrast, in evolving chronic hepatitis C CD4+ T cell helper responses appear to be absent or short-lived, using functional assays.Here we used a novel HLA-DR1 tetramer containing a highly targeted CD4+ T cell epitope from the hepatitis C virus non-structural protein 4 to track number and phenotype of hepatitis C virus specific CD4+ T cells in a cohort of seven HLA-DR1 positive patients with acute hepatitis C in comparison to patients with chronic or resolved hepatitis C. We observed peptide-specific T cells in all seven patients with acute hepatitis C regardless of outcome at frequencies up to 0.65% of CD4+ T cells. Among patients who transiently controlled virus replication we observed loss of function, and/or physical deletion of tetramer+ CD4+ T cells before viral recrudescence. In some patients with chronic hepatitis C very low numbers of tetramer+ cells were detectable in peripheral blood, compared to robust responses detected in spontaneous resolvers. Importantly we did not observe escape mutations in this key CD4+ T cell epitope in patients with evolving chronic hepatitis C.During acute hepatitis C a CD4+ T cell response against this epitope is readily induced in most, if not all, HLA-DR1+ patients. This antiviral T cell population becomes functionally impaired or is deleted early in the course of disease in those where viremia persists.

  20. Gastrointestinal and hepatic complications of sickle cell disease.

    Ebert, Ellen C; Nagar, Michael; Hagspiel, Klaus D

    2010-06-01

    Sickle cell disease (SCD) is an autosomal recessive abnormality of the beta-globin chain of hemoglobin (Hb), resulting in poorly deformable sickled cells that cause microvascular occlusion and hemolytic anemia. The spleen is almost always affected by SCD, with microinfarcts within the first 36 months of life resulting in splenic atrophy. Acute liver disorders causing right-sided abdominal pain include acute vaso-occlusive crisis, liver infarction, and acute hepatic crisis. Chronic liver disease might be due to hemosiderosis and hepatitis and possibly to SCD itself if small, clinically silent microvascular occlusions occur chronically. Black pigment gallstones caused by elevated bilirubin excretion are common. Their small size permits them to travel into the common bile duct but cause only low-grade obstruction, so hyperbilirubinemia rather than bile duct dilatation is typical. Whether cholecystectomy should be done in asymptomatic individuals is controversial. The most common laboratory abnormality is an elevation of unconjugated bilirubin level. Bilirubin and lactate dehydrogenase levels correlate with one another, suggesting that chronic hemolysis and ineffective erythropoiesis, rather than liver disease, are the sources of hyperbilirubinemia. Abdominal pain is very common in SCD and is usually due to sickling, which resolves with supportive care. Computed tomography scans might be ordered for severe or unremitting pain. The liver typically shows sickled erythrocytes and Kupffer cell enlargement acutely and hemosiderosis chronically. The safety of liver biopsies has been questioned, particularly during acute sickling crisis. Treatments include blood transfusions, exchange transfusions, iron-chelating agents, hydroxyurea, and allogeneic stem-cell transplantation. Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

  1. Imaging of Human Hepatic Stem Cells In Vivo

    Hsu, E.W.

    2006-01-01

    Report on progress in MRI and PET of stem cell tracking. Human hepatic stem cell imaging for both MRI and PET have been accomplished within SCID/nod mice, and succeeded in cell specificity labeling with in vitro, ex vivo, and in vivo image tracking. For MRI, stem cell labeling was accomplished by two methods: (1) in vitro labeling the stem cells just prior to in vivo transplantation, and/or (2) transplanting the stem cells into SCID/nod mice and in vivo specificity labeling the cells just prior to MRI. For labeling techniques 1 and 2, multiple image controls were utilized and include: (A) stem cells(-) and contrast label(-), (B) stem cells(+) and contrast label(-), and (C) stem cells(-) and contrast label(+) help to confirm signal noise background interference, which is a result of slight nonspecific cell labeling. Contrast labeled stem cells are directly transplanted into liver tissues, the tissues excised, and immediately MR imaged to determine cell dispersion dynamics. In this method, the contrast labeled cells appear as void foci throughout the organs. The images are imported into Metamorph imaging software and analyzed for foci radii, diameter, and to discern spheroid volumes. Then, cell numbers are extrapolated to understand ''imaged'' cell aggregate requirements using this technique. For this ex vivo method, a cell aggregate of ∼100 stem cells is required to MRI monitor signal activities. For in vivo imaging, contrast labeled human stem cells within SCID/nod mice are also confirmed as small foci voids and are evident within liver tissues. Initially, these short-term studies where accomplished by in vitro labeling stem cells, transplanting the cells, then in vivo imaging the tissues between days 3-15. Next and to avoid imaged time limitations of detaching contrast agents, the proliferative stem cells were labeled after transplantation, and before MR imaging. This was accomplished to confirm the ability to specifically label unique cell subsets after the

  2. Cell kinetics and acute lung injury

    Witschi, H.P.; Whitaker, M.S.

    1987-01-01

    In order to estimate whether acute lung injury is followed by a stereotype pattern of cell proliferation in the lungs, mice were treated with three cytostatic drugs: cyclophosphamide, busulfan, or 1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU). The alveolar labeling index was measured following drug administration with a pulse of 3 H-labeled thymidine and autoradiography. In cyclophosphamide treated animals, peak alveolar cell proliferation was seen 5 days after injection of the drug. In animals treated with busulfan or BCNU, proliferation was even more delayed (occurring 2 to 3 wks after administration). In contrast, with oleic acid, the highest alveolar cell labeling was found 2 days after intravenous administration. In animals exposed to a cytostatic drug, proliferation of type II alveolar cells was never a prominent feature; whereas, in animals treated with oleic acid there was an initial burst of type II cell proliferation. It was concluded that the patterns of pulmonary repair vary between chemical designed to interfere with DNA replication as compared to agents which produce acute lung damage such as oleic acid

  3. Operative management and outcomes in 103 AAST-OIS grades IV and V complex hepatic injuries: trauma surgeons still need to operate, but angioembolization helps.

    Asensio, Juan A; Roldán, Gustavo; Petrone, Patrizio; Rojo, Esther; Tillou, Areti; Kuncir, Eric; Demetriades, Demetrios; Velmahos, George; Murray, James; Shoemaker, William C; Berne, Thomas V; Chan, Linda

    2003-04-01

    American Association for the Surgery of Trauma (AAST) Organ Injury Scale (OIS) grades IV and V complex hepatic injuries are highly lethal. Our objectives were to review experience and identify predictors of outcome and to evaluate the role of angioembolization in decreasing mortality. This was a retrospective 8-year study of all patients sustaining AAST-OIS grades IV and V hepatic injuries managed operatively. Statistical analysis was performed using univariate and multivariate logistic regression. The main outcome measure was survival. The study included 103 patients, with a mean Revised Trauma Score of 5.61 +/- 2.55 and a mean Injury Severity Score of 33 +/- 9.5. Mechanism of injury was penetrating in 80 (79%) and blunt in 23 (21%). Emergency department thoracotomy was performed in 21 (25%). AAST grade IV injuries occurred in 51 (47%) and grade V injuries occurred in 52 (53%). Mean estimated blood loss was 9,414 mL. Overall survival was 43%. Adjusted overall survival rate after emergency department thoracotomy patients were excluded was 58%. Results stratified to AAST-OIS injury grade were as follows: grade IV, 32 of 51 (63%); grade V, 12 of 52 (23%); grade IV versus grade V (p Trauma Score (adjusted p hepatic veins (adjusted p hepatic injuries.

  4. 18F-FAC PET selectively images hepatic infiltrating CD4 and CD8 T cells in a mouse model of autoimmune hepatitis.

    Salas, Jessica R; Chen, Bao Ying; Wong, Alicia; Cheng, Donghui; Van Arnam, John S; Witte, Owen N; Clark, Peter M

    2018-04-26

    Immune cell-mediated attack on the liver is a defining feature of autoimmune hepatitis and hepatic allograft rejection. Despite an assortment of diagnostic tools, invasive biopsies remain the only method for identifying immune cells in the liver. We evaluated whether PET imaging with radiotracers that quantify immune activation ( 18 F-FDG and 18 F-FAC) and hepatocyte biology ( 18 F-DFA) can visualize and quantify hepatic infiltrating immune cells and hepatocyte inflammation, respectively, in a preclinical model of autoimmune hepatitis. Methods: Mice treated with Concanavalin A (ConA) to induce a model of autoimmune hepatitis or vehicle were imaged with 18 F-FDG, 18 F-FAC, and 18 F-DFA PET. Immunohistochemistry, digital autoradiography, and ex vivo accumulation assays were used to localize areas of altered radiotracer accumulation in the liver. For comparison, mice treated with an adenovirus to induce a viral hepatitis or vehicle were imaged with 18 F-FDG, 18 F-FAC, and 18 F-DFA PET. 18 F-FAC PET was performed on mice treated with ConA, and vehicle or dexamethasone. Biopsy samples of patients suffering from autoimmune hepatitis were immunostained for deoxycytidine kinase (dCK). Results: Hepatic accumulation of 18 F-FDG and 18 F-FAC was 173% and 61% higher, respectively, and hepatic accumulation of 18 F-DFA was 41% lower in a mouse model of autoimmune hepatitis compared to control mice. Increased hepatic 18 F-FDG accumulation was localized to infiltrating leukocytes and inflamed sinusoidal endothelial cells, increased hepatic 18 F-FAC accumulation was concentrated in infiltrating CD4 and CD8 cells, and decreased hepatic 18 F-DFA accumulation was apparent in hepatocytes throughout the liver. In contrast, viral hepatitis increased hepatic 18 F-FDG accumulation by 109% and decreased hepatic 18 F-DFA accumulation by 20% but had no effect on hepatic 18 F-FAC accumulation (non-significant 2% decrease). 18 F-FAC PET provided a non-invasive biomarker of the efficacy of

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

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

    2014-01-01

    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

  6. Role of berberine in ameliorating Schistosoma mansoni-induced hepatic injury in mice

    Mohamed A Dkhi

    2014-01-01

    Full Text Available BACKGROUND: Schistosomiasis is caused by helminth parasites of the genus Schistosoma. Berberine chloride (BER, an isoquinoline alkaloid, has been used in vivo for its antiparasitic, antioxidant and hepatoprotective properties. In this study, the protective effect of BER and praziquantel has been compared for the extent of schistosomiasis-induced oxidative stress in hepatic tissue of mice. RESULTS: S. mansoni was able to induce inflammation and injury to the liver, evidenced (i by an increase in inflammatory cellular infiltrations, dilated sinusoids and vacuolated hepatocytes, (ii by decreased levels of alanine and aspartate aminotransferases and increased levels of alkaline phosphatase, γ-glutamyl transferase in the liver homogenate, (iii by increased production of nitric oxide and thiobarbituric acid reactive substances, and (iv by lowered glutathione levels and decreased activities of catalase and superoxide dismutase, respectively. All these infection-induced parameters were significantly altered during BER treatment. In particular, berberine counteracted the S. mansoni-induced loss of glutathione and the activities of catalase and superoxide dismutase. CONCLUSION: Based on these results, it is concluded that berberine could ameliorate pre-existing liver damage and oxidative stress conditions due to schistosomiasis.

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

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

    2014-01-03

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

  8. Rat Strain Differences in Susceptibility to Alcohol-Induced Chronic Liver Injury and Hepatic Insulin Resistance

    Sarah M. DeNucci

    2010-01-01

    Full Text Available The finding of more severe steatohepatitis in alcohol fed Long Evans (LE compared with Sprague Dawley (SD and Fisher 344 (FS rats prompted us to determine whether host factors related to alcohol metabolism, inflammation, and insulin/IGF signaling predict proneness to alcohol-mediated liver injury. Adult FS, SD, and LE rats were fed liquid diets containing 0% or 37% (calories ethanol for 8 weeks. Among controls, LE rats had significantly higher ALT and reduced GAPDH relative to SD and FS rats. Among ethanol-fed rats, despite similar blood alcohol levels, LE rats had more pronounced steatohepatitis and fibrosis, higher levels of ALT, DNA damage, pro-inflammatory cytokines, ADH, ALDH, catalase, GFAP, desmin, and collagen expression, and reduced insulin receptor binding relative to FS rats. Ethanol-exposed SD rats had intermediate degrees of steatohepatitis, increased ALT, ADH and profibrogenesis gene expression, and suppressed insulin receptor binding and GAPDH expression, while pro-inflammatory cytokines were similarly increased as in LE rats. Ethanol feeding in FS rats only reduced IL-6, ALDH1–3, CYP2E1, and GAPDH expression in liver. In conclusion, susceptibility to chronic steatohepatitis may be driven by factors related to efficiency of ethanol metabolism and degree to which ethanol exposure causes hepatic insulin resistance and cytokine activation.

  9. Relations between CT perfusion parameters and degree of hepatic ischemia reperfusion injury in a rabbit model

    Guo Chengwei; Shen Sandi; Yi Xianlin; Zhang Zhonglin; Liu Zaiyi; Liang Changhong

    2011-01-01

    Objective: To observe the changes of hepatic CT perfusion parameters and their correlation with serum aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP) in a rabbit hepatic ischemia reperfusion injury (IRI) model. Methods: Hepatic IRI was produced in rabbits by inducing left liver lobe ischemia (60 min) followed by 6 h, 12 h and 24 h reperfusion (6 rabbits were used for each reperfusion interval). Additional 6 rabbits were served as sham-operated controls. All the rabbits were scanned with a dynamic iCT protocol. Blood samples were taken from the superior mesenteric vein to measure the levels of serum amylase (ALT, AST, and ALP) in various groups, and liver samples were taken for histological examinations after scanning. One-way analysis of variance (ANOVA) was used to determine differences between groups. The correlations of CT perfusion parameters with serum levels were analyzed using Pearson correlation coefficient. Results: Heterogeneity of CT perfusion patterns appeared in the 6 h groups, which presented as low enhanced area [(25.1±9.3) ml · min -1 · 100 mg -1 ]. In reduced perfusion regions of IRI group, HAP of 12 h IRI group [(19.5± 13.6) ml · min -1 · 100 mg -1 ], 24 h IRI group (8.0±2.7) ml · min -1 · 100 mg -1 ], HPP of 6 h IRI group [(10.8±5.5) ml · min -1 · 100 mg -1 ], 12 h IRI group [(14.4±5.2) ml · min -1 · 100 mg -1 ] , 24 h IRI group [(7.8±3.3) ml · min -1 · 100 mg -1 ] and TLP of 6 h IRI group [(35.9±14.0) ml · min -1 · 100 mg -1 ], 12 h IRI group [(33.9±16.1) ml · min -1 · 100 mg -1 ], 24 h IRI group [(16.0± 5.5) ml · min -1 · 100 mg -1 ] were lower than those of sham group [HAP (21.2±10.5) ml · min -1 · 100 mg -1 , HPP (63.5±24.0) ml · min -1 · 100 mg -1 , TLP (81.4±24.8) ml · min -1 · 100 mg -1 ] (F=8.376, 25.950, 16.925, P<0.01). However, HPI of 6 h IRI group [(65.9±3.9)%], 12 h IRI group [(54.2±16.7)%], and 24 h IRI group [(48.9±10.0)%] were higher compared to sham

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

    Crockett Elahé T

    2007-05-01

    Full Text Available Abstract 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

  11. Spinal cord injury reveals multilineage differentiation of ependymal cells.

    Konstantinos Meletis

    2008-07-01

    Full Text Available Spinal cord injury often results in permanent functional impairment. Neural stem cells present in the adult spinal cord can be expanded in vitro and improve recovery when transplanted to the injured spinal cord, demonstrating the presence of cells that can promote regeneration but that normally fail to do so efficiently. Using genetic fate mapping, we show that close to all in vitro neural stem cell potential in the adult spinal cord resides within the population of ependymal cells lining the central canal. These cells are recruited by spinal cord injury and produce not only scar-forming glial cells, but also, to a lesser degree, oligodendrocytes. Modulating the fate of ependymal progeny after spinal cord injury may offer an alternative to cell transplantation for cell replacement therapies in spinal cord injury.

  12. Only Moderate Intra- and Inter-observer Agreement between Radiologists and Surgeons when Grading Blunt Paediatric Hepatic Injury on CT Scan

    Nellensteijn, D. R.; ten Duis, H. J.; Oldenziel, J.; Polak, W. G.; Hulscher, J. B. F.

    2009-01-01

    Introduction: The American Pediatric Surgical Association developed guidelines for the management of haemodynamically stable children with hepatic or splenic injury, based on grade of injury on CF scan. This study investigated the intra- and inter-observer agreement of radiologists, paediatric

  13. Profile of Inflammation-associated genes during Hepatic Differentiation of Human Pluripotent Stem Cells

    Joseph Ignatius Irudayam

    2015-12-01

    Full Text Available Expression of genes associated with inflammation was analyzed during differentiation of human pluripotent stem cells (PSCs to hepatic cells. Messenger RNA transcript profiles of differentiated endoderm (day 5, hepatoblast (day 15 and hepatocyte-like cells (day 21 were obtained by RNA sequencing analysis. When compared to endoderm cells an immature cell type, the hepatic cells (days 15 and 21 had significantly higher expression of acute phase protein genes including complement factors, coagulation factors, serum amyloid A and serpins. Furthermore, hepatic phase of cells expressed proinflammatory cytokines IL18 and IL32 as well as cytokine receptors IL18R1, IL1R1, IL1RAP, IL2RG, IL6R, IL6ST and IL10RB. These cells also produced CCL14, CCL15, and CXCL- 1, 2, 3, 16 and 17 chemokines. Endoderm cells had higher levels of chemokine receptors, CXCR4 and CXCR7, than that of hepatic cells. Sirtuin family of genes involved in aging, inflammation and metabolism were differentially regulated in endoderm and hepatic phase cells. Ligands and receptors of the tumor necrosis factor (TNF family as well as downstream signaling factors TRAF2, TRAF4, FADD, NFKB1 and NFKBIB were differentially expressed during hepatic differentiation.

  14. Interleukin-1 inhibition facilitates recovery from liver injury and promotes regeneration of hepatocytes in alcoholic hepatitis in mice.

    Iracheta-Vellve, Arvin; Petrasek, Jan; Gyogyosi, Benedek; Bala, Shashi; Csak, Timea; Kodys, Karen; Szabo, Gyongyi

    2017-07-01

    Inflammation and impaired hepatocyte regeneration contribute to liver failure in alcoholic hepatitis (AH). Interleukin (IL)-1 is a key inflammatory cytokine in the pathobiology of AH. The role of IL-1 in liver regeneration in the recovery phase of alcohol-induced liver injury is unknown. In this study, we tested IL-1 receptor antagonist to block IL-1 signalling in a mouse model of acute-on-chronic liver injury on liver inflammation and hepatocyte regeneration in AH. We observed that inhibition of IL-1 signalling decreased liver inflammation and neutrophil infiltration, and resulted in enhanced regeneration of hepatocytes and increased rate of recovery from liver injury in AH. Our novel findings suggest that IL-1 drives sustained liver inflammation and impaired hepatocyte regeneration even after cessation of ethanol exposure. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  15. Intra-Hepatic Depletion of Mucosal-Associated Invariant T Cells in Hepatitis C Virus-Induced Liver Inflammation.

    Bolte, Fabian J; O'Keefe, Ashley C; Webb, Lauren M; Serti, Elisavet; Rivera, Elenita; Liang, T Jake; Ghany, Marc; Rehermann, Barbara

    2017-11-01

    Chronic hepatitis affects phenotypes of innate and adaptive immune cells. Mucosal-associated invariant T (MAIT) cells are enriched in the liver as compared with the blood, respond to intra-hepatic cytokines, and (via the semi-invariant T-cell receptor) to bacteria translocated from the gut. Little is known about the role of MAIT cells in livers of patients with chronic hepatitis C virus (HCV) infection and their fate after antiviral therapy. We collected blood samples from 42 patients with chronic HCV infection who achieved a sustained virologic response after 12 weeks of treatment with sofosbuvir and velpatasvir. Mononuclear cells were isolated from blood before treatment, at weeks 4 and 12 during treatment, and 24 weeks after the end of treatment. Liver biopsies were collected from 37 of the patients prior to and at week 4 of treatment. Mononuclear cells from 56 blood donors and 10 livers that were not suitable for transplantation were used as controls. Liver samples were assessed histologically for inflammation and fibrosis. Mononuclear cells from liver and blood were studied by flow cytometry and analyzed for responses to cytokine and bacterial stimulation. The frequency of MAIT cells among T cells was significantly lower in blood and liver samples of patients with HCV infection than of controls (median, 1.31% vs 2.32% for blood samples, P = .0048; and median, 4.34% vs 13.40% for liver samples, P = .001). There was an inverse correlation between the frequency of MAIT cells in the liver and histologically determined levels of liver inflammation (r = -.5437, P = .0006) and fibrosis (r = -.5829, P = .0002). MAIT cells from the liver had higher levels of activation and cytotoxicity than MAIT cells from blood (P liver inflammation and MAIT cell activation and cytotoxicity, and increased the MAIT cell frequency among intra-hepatic but not blood T cells. The MAIT cell response to T-cell receptor-mediated stimulation did not change during the 12 weeks of

  16. CD40 dependent exacerbation of immune mediated hepatitis by hepatic CD11b+ Gr-1+ myeloid derived suppressor cells in tumor bearing mice

    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

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

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

    2007-01-01

    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

  18. The accumulation of regulatory T cells in the hepatic hilar lymph nodes in biliary atresia.

    Sakamoto, Naoya; Muraji, Toshihiro; Ohtani, Haruo; Masumoto, Kouji

    2017-10-01

    A proposed etiopathogenesis of biliary atresia (BA) involves T-cell-mediated inflammatory bile duct damage and progressive hepatic fibrosis. Pediatric surgeons often observe swelling of the hepatic hilar lymph nodes during the Kasai procedure. Given the importance of regulatory mechanisms in immune responses, the present study was designed to analyze the quantitative changes of regulatory T cells (T reg cells) in the hepatic hilar lymph nodes (hepatic hilar LNs) and peripheral blood (PB) in BA. The hepatic hilar LNs and PB obtained during the Kasai procedure were analyzed by flow cytometry. The ratios of total and active Tregs to the total CD4 + cells in the PB and the hepatic hilar LNs were compared. In patients with BA, the ratios of both the total and active T reg cells in the hepatic hilar LNs were higher than those in the PB (total T reg cells: PB vs. LN; P hilar lymph nodes of BA patients. This finding could shed light on the pathogenesis of BA.

  19. Contrasting effects of cord injury on intravenous and oral pharmacokinetics of diclofenac: a drug with intermediate hepatic extraction.

    Cruz-Antonio, L; Arauz, J; Franco-Bourland, R E; Guízar-Sahagún, G; Castañeda-Hernández, G

    2012-08-01

    Laboratory investigation in rats submitted to experimental spinal cord injury (SCI). To determine the effect of acute SCI on the pharmacokinetics of diclofenac, a marker drug of intermediate hepatic extraction, administered by the intravenous and the oral routes. Female Wistar rats were submitted to complete section of the spinal cord at the T8 level. SCI and sham-injured rats received 3.2 mg kg(-1) of diclofenac sodium either intravenously or orally, diclofenac concentration was measured in whole blood samples and pharmacokinetic parameters were estimated. Diclofenac was not selected as test drug because of its therapeutic properties, but because to its biopharmaceutical properties, that is, intermediate hepatic extraction. Diclofenac bioavailability after intravenous administration was increased in injured rats compared with controls due to a reduced clearance. In contrast, oral diclofenac bioavailability was diminished in SCI animals due to a reduction in drug absorption, which overrides the effect on clearance. Acute SCI induces significant pharmacokinetic changes for diclofenac, a marker drug with intermediate hepatic extraction. SCI-induced pharmacokinetic changes are not only determined by injury characteristics, but also by the route of administration and the biopharmaceutical properties of the studied drug.

  20. Diosmin Attenuates Methotrexate-Induced Hepatic, Renal, and Cardiac Injury: A Biochemical and Histopathological Study in Mice

    Khalifa, Hesham A.; Al-Quraishy, Saleh A.

    2017-01-01

    The current study was designed to investigate the beneficial role of diosmin, a biologically active flavonoid, against methotrexate- (MTX-) induced hepatic, renal, and cardiac injuries in mice. Male Swiss albino mice received a single intraperitoneal injection of MTX (at 20 mg/kg, body weight) either alone or in combination with oral diosmin (at 50 or 100 mg/kg body weight, for 10 days). Serum was used to evaluate tissue injury markers, while hepatic, renal, and cardiac tissue samples were obtained for determination of antioxidant activity as well as histopathological examination. Diosmin treatment ameliorated the MTX-induced elevation of serum alkaline phosphatase, aminotransferases, urea, creatinine, lactate dehydrogenase, and creatine kinases as well as plasma proinflammatory cytokines (interleukin-1-beta, interleukin-6, and tumor necrosis factor-alpha). Additionally, both diosmin doses significantly reduced tissue levels of malondialdehyde and nitric oxide and increased those of glutathione, glutathione peroxidase, glutathione reductase, glutathione S-transferase, superoxide dismutase, and catalase, compared to the MTX-intoxicated group. Histopathological examination showed that diosmin significantly minimized the MTX-induced histological alterations and nearly restored the normal architecture of hepatic, renal, and cardiac tissues. Based on these findings, diosmin may be a promising agent for protection against MTX-induced cytotoxicity in patients with cancer and autoimmune diseases. PMID:28819543

  1. In vitro proliferation and differentiation of hepatic oval cells and their potential capacity for intrahepatic transplantation

    Li, Z.; Chen, J. [Liaocheng People' s Hospital, Department of Hepatobiliary Surgery, Liaocheng, Shandong, China, Department of Hepatobiliary Surgery, Liaocheng People’s Hospital, Liaocheng, Shandong (China); Li, L.; Ran, J.H.; Liu, J. [The First People' s Hospital of Kunming, Kunming, Yunnan, China, The First People’s Hospital of Kunming, Kunming, Yunnan (China); Gao, T.X.; Guo, B.Y. [Dongchangfu Hospital of Women and Child Health Care, Liaocheng, Shandong (China); Li, X.H.; Liu, Z.H.; Liu, G.J.; Gao, Y.C.; Zhang, X.L. [Liaocheng People' s Hospital, Department of Hepatobiliary Surgery, Liaocheng, Shandong, China, Department of Hepatobiliary Surgery, Liaocheng People’s Hospital, Liaocheng, Shandong (China)

    2013-07-30

    Hepatic oval cells (HOCs) are recognized as facultative liver progenitor cells that play a role in liver regeneration after acute liver injury. Here, we investigated the in vitro proliferation and differentiation characteristics of HOCs in order to explore their potential capacity for intrahepatic transplantation. Clusters or scattered HOCs were detected in the portal area and interlobular bile duct in the liver of rats subjected to the modified 2-acetylaminofluorene and partial hepatectomy method. Isolated HOCs were positive for c-kit and CD90 staining (99.8% and 88.8%, respectively), and negative for CD34 staining (3.6%) as shown by immunostaining and flow cytometric analysis. In addition, HOCs could be differentiated into hepatocytes and bile duct epithelial cells after leukemia inhibitory factor deprivation. A two-cuff technique was used for orthotopic liver transplantation, and HOCs were subsequently transplanted into recipients. Biochemical indicators of liver function were assessed 4 weeks after transplantation. HOC transplantation significantly prolonged the median survival time and improved the liver function of rats receiving HOCs compared to controls (P=0.003, Student t-test). Administration of HOCs to rats also receiving liver transplantation significantly reduced acute allograft rejection compared to control liver transplant rats 3 weeks following transplantation (rejection activity index score: control=6.3±0.9; HOC=3.5±1.5; P=0.005). These results indicate that HOCs may be useful in therapeutic liver regeneration after orthotopic liver transplantation.

  2. In vitro proliferation and differentiation of hepatic oval cells and their potential capacity for intrahepatic transplantation

    Li, Z.; Chen, J.; Li, L.; Ran, J.H.; Liu, J.; Gao, T.X.; Guo, B.Y.; Li, X.H.; Liu, Z.H.; Liu, G.J.; Gao, Y.C.; Zhang, X.L.

    2013-01-01

    Hepatic oval cells (HOCs) are recognized as facultative liver progenitor cells that play a role in liver regeneration after acute liver injury. Here, we investigated the in vitro proliferation and differentiation characteristics of HOCs in order to explore their potential capacity for intrahepatic transplantation. Clusters or scattered HOCs were detected in the portal area and interlobular bile duct in the liver of rats subjected to the modified 2-acetylaminofluorene and partial hepatectomy method. Isolated HOCs were positive for c-kit and CD90 staining (99.8% and 88.8%, respectively), and negative for CD34 staining (3.6%) as shown by immunostaining and flow cytometric analysis. In addition, HOCs could be differentiated into hepatocytes and bile duct epithelial cells after leukemia inhibitory factor deprivation. A two-cuff technique was used for orthotopic liver transplantation, and HOCs were subsequently transplanted into recipients. Biochemical indicators of liver function were assessed 4 weeks after transplantation. HOC transplantation significantly prolonged the median survival time and improved the liver function of rats receiving HOCs compared to controls (P=0.003, Student t-test). Administration of HOCs to rats also receiving liver transplantation significantly reduced acute allograft rejection compared to control liver transplant rats 3 weeks following transplantation (rejection activity index score: control=6.3±0.9; HOC=3.5±1.5; P=0.005). These results indicate that HOCs may be useful in therapeutic liver regeneration after orthotopic liver transplantation

  3. A TLR4/MD2 fusion protein inhibits LPS-induced pro-inflammatory signaling in hepatic stellate cells

    Schnabl, Bernd; Brandl, Katharina; Fink, Marina; Gross, Philipp; Taura, Kojiro; Gaebele, Erwin; Hellerbrand, Claus; Falk, Werner

    2008-01-01

    Activated hepatic stellate cells (HSCs) play a key role in hepatic fibrogenesis. In injured liver they are the main extracellular matrix protein producing cell type and further perpetuate hepatic injury by secretion of pro-inflammatory mediators. Since LPS-mediated signaling through toll-like receptor 4 (TLR4) has been identified as key fibrogenic signal in HSCs we aimed to test TLR4 as potential target of therapy via ligand-binding soluble receptors. Incubation of human HSCs with a fusion protein between the extracellular domain of TLR4 and MD2 which binds LPS inhibited LPS-induced NFκB and JNK activation. TLR4/MD2 abolished LPS-induced secretion of IL-6, IL-8, MCP1, and RANTES in HSCs. In addition, TLR4/MD2 fused to human IgG-Fc neutralized LPS activity. Since TLR4 mutant mice are resistant to liver fibrosis, the TLR4/MD2 soluble receptor might represent a new therapeutic molecule for liver fibrogenesis in vivo

  4. Role of myeloid-derived suppressor cells in amelioration of experimental autoimmune hepatitis following activation of TRPV1 receptors by cannabidiol.

    Venkatesh L Hegde

    2011-04-01

    Full Text Available Myeloid-derived suppressor cells (MDSCs are getting increased attention as one of the main regulatory cells of the immune system. They are induced at sites of inflammation and can potently suppress T cell functions. In the current study, we demonstrate how activation of TRPV1 vanilloid receptors can trigger MDSCs, which in turn, can inhibit inflammation and hepatitis.Polyclonal activation of T cells, following injection of concanavalin A (ConA, in C57BL/6 mice caused acute hepatitis, characterized by significant increase in aspartate transaminase (AST, induction of inflammatory cytokines, and infiltration of mononuclear cells in the liver, leading to severe liver injury. Administration of cannabidiol (CBD, a natural non-psychoactive cannabinoid, after ConA challenge, inhibited hepatitis in a dose-dependent manner, along with all of the associated inflammation markers. Phenotypic analysis of liver infiltrating cells showed that CBD-mediated suppression of hepatitis was associated with increased induction of arginase-expressing CD11b(+Gr-1(+ MDSCs. Purified CBD-induced MDSCs could effectively suppress T cell proliferation in vitro in arginase-dependent manner. Furthermore, adoptive transfer of purified MDSCs into naïve mice conferred significant protection from ConA-induced hepatitis. CBD failed to induce MDSCs and suppress hepatitis in the livers of vanilloid receptor-deficient mice (TRPV1(-/- thereby suggesting that CBD primarily acted via this receptor to induce MDSCs and suppress hepatitis. While MDSCs induced by CBD in liver consisted of granulocytic and monocytic subsets at a ratio of ∼2∶1, the monocytic MDSCs were more immunosuppressive compared to granulocytic MDSCs. The ability of CBD to induce MDSCs and suppress hepatitis was also demonstrable in Staphylococcal enterotoxin B-induced liver injury.This study demonstrates for the first time that MDSCs play a critical role in attenuating acute inflammation in the liver, and that agents

  5. Hypoksisk hepatitis

    Amadid, Hanan; Schiødt, Frank Vinholt

    2014-01-01

    Hypoxic hepatitis (HH), also known as ischaemic hepatitis or shock liver, is an acute liver injury caused by hepatic hypoxia. Cardiac failure, respiratory failure and septic shock are the main underlying conditions. In each of these conditions, several haemodynamic mechanisms lead to hepatic...... hypoxia. A shock state is observed in only 50% of cases. Thus, shock liver and ischaemic hepatitis are misnomers. HH can be a diagnostic pitfall but the diagnosis can be established when three criteria are met. Prognosis is poor and prompt identification and treatment of the underlying conditions...

  6. Elevated Levels of Endocannabinoids in Chronic Hepatitis C May Modulate Cellular Immune Response and Hepatic Stellate Cell Activation

    Eleonora Patsenker

    2015-03-01

    Full Text Available The endocannabinoid (EC system is implicated in many chronic liver diseases, including hepatitis C viral (HCV infection. Cannabis consumption is associated with fibrosis progression in patients with chronic hepatitis C (CHC, however, the role of ECs in the development of CHC has never been explored. To study this question, anandamide (AEA and 2-arachidonoyl glycerol (2-AG were quantified in samples of HCV patients and healthy controls by gas and liquid chromatography mass spectrometry. Fatty acid amide hydrolase (FAAH and monoaclyglycerol lipase (MAGL activity was assessed by [3H]AEA and [3H]2-AG hydrolysis, respectively. Gene expression and cytokine release were assayed by TaqMan PCR and ELISpot, respectively. AEA and 2-AG levels were increased in plasma of HCV patients, but not in liver tissues. Hepatic FAAH and MAGL activity was not changed. In peripheral blood mononuclear cells (PBMC, ECs inhibited IFN-γ, TNF-α, and IL-2 secretion. Inhibition of IL-2 by endogenous AEA was stronger in PBMC from HCV patients. In hepatocytes, 2-AG induced the expression of IL-6, -17A, -32 and COX-2, and enhanced activation of hepatic stellate cells (HSC co-cultivated with PBMC from subjects with CHC. In conclusion, ECs are increased in plasma of patients with CHC and might reveal immunosuppressive and profibrogenic effects.

  7. Osteopontin-enhanced hepatic metastasis of colorectal cancer cells.

    Jianjin Huang

    Full Text Available Liver metastasis is a major cause of mortality from colorectal cancer (CRC. However, mechanisms underlying this process are largely unknown. Osteopontin (OPN is a secreted phosphorylated glycoprotein that is involved in tumor migration and metastasis. The role of OPN in cancer is currently unclear. In this study, OPN mRNA was examined in tissues from CRC, adjacent normal mucosa, and liver metastatic lesions using quantitative real-time PCR analysis. The protein expression of OPN and its receptors (integrin αv and CD44 v6 was detected by using an immunohistochemical (IHC method. The role of OPN in liver metastasis was studied in established colon cancer Colo-205 and SW-480 cell lines transfected with sense- or antisense-OPN eukaryotic expression plasmids by flow cytometry and cell adhesion assay. Fluorescence redistribution after photobleaching (FRAP was used to study gap functional intercellular communication (GJIC among OPN-transfected cells. It was found that OPN was highly expressed in metastatic hepatic lesions from CRC compared to primary CRC tissue and adjacent normal mucosa. The expression of OPN mRNA in tumor tissues was significantly related with the CRC stages. OPN expression was also detected in normal hepatocytes surrounding CRC metastatic lesions. Two known receptors of OPN, integrin αv and CD44v6 proteins, were strongly expressed in hepatocytes from normal liver. CRC cells with forced OPN expression exhibited increased heterotypic adhesion with endothelial cells and weakened intercellular communication. OPN plays a significant role in CRC metastasis to liver through interaction with its receptors in hepatocytes, decreased homotypic adhesion, and enhanced heterotypic adhesion.

  8. Substance P increases liver fibrosis by differential changes in senescence of cholangiocytes and hepatic stellate cells.

    Wan, Ying; Meng, Fanyin; Wu, Nan; Zhou, Tianhao; Venter, Julie; Francis, Heather; Kennedy, Lindsey; Glaser, Trenton; Bernuzzi, Francesca; Invernizzi, Pietro; Glaser, Shannon; Huang, Qiaobing; Alpini, Gianfranco

    2017-08-01

    Substance P (SP) is involved in the proliferation of cholangiocytes in bile duct-ligated (BDL) mice and human cholangiocarcinoma growth by interacting with the neurokinin-1 receptor (NK-1R). To identify whether SP regulates liver fibrosis during cholestasis, wild-type or NK-1R knockout (NK-1R -/- ) mice that received BDL or sham surgery and multidrug resistance protein 2 knockout (Mdr2 -/- ) mice treated with either an NK-1R antagonist (L-733,060) or saline were used. Additionally, wild-type mice were treated with SP or saline intraperitoneally. In vivo, there was increased expression of tachykinin precursor 1 (coding SP) and NK-1R in both BDL and Mdr2 -/- mice compared to wild-type mice. Expression of tachykinin precursor 1 and NK-1R was significantly higher in liver samples from primary sclerosing cholangitis patients compared to healthy controls. Knockout of NK-1R decreased BDL-induced liver fibrosis, and treatment with L-733,060 resulted in decreased liver fibrosis in Mdr2 -/- mice, which was shown by decreased sirius red staining, fibrosis gene and protein expression, and reduced transforming growth factor-β1 levels in serum and cholangiocyte supernatants. Furthermore, we observed that reduced liver fibrosis in NK-1R -/- mice with BDL surgery or Mdr2 -/- mice treated with L-733,060 was associated with enhanced cellular senescence of hepatic stellate cells and decreased senescence of cholangiocytes. In vitro, L-733,060 inhibited SP-induced expression of fibrotic genes in hepatic stellate cells and cholangiocytes; treatment with L-733,060 partially reversed the SP-induced decrease of senescence gene expression in cultured hepatic stellate cells and the SP-induced increase of senescence-related gene expression in cultured cholangiocytes. Collectively, our results demonstrate the regulatory effects of the SP/NK-1R axis on liver fibrosis through changes in cellular senescence during cholestatic liver injury. (Hepatology 2017;66:528-541). © 2017 by the American

  9. NK1.1+ cells promote sustained tissue injury and inflammation after trauma with hemorrhagic shock.

    Chen, Shuhua; Hoffman, Rosemary A; Scott, Melanie; Manson, Joanna; Loughran, Patricia; Ramadan, Mostafa; Demetris, Anthony J; Billiar, Timothy R

    2017-07-01

    Various cell populations expressing NK1.1 contribute to innate host defense and systemic inflammatory responses, but their role in hemorrhagic shock and trauma remains uncertain. NK1.1 + cells were depleted by i.p. administration of anti-NK1.1 (or isotype control) on two consecutive days, followed by hemorrhagic shock with resuscitation and peripheral tissue trauma (HS/T). The plasma levels of IL-6, MCP-1, alanine transaminase (ALT), and aspartate aminotransferase (AST) were measured at 6 and 24 h. Histology in liver and gut were examined at 6 and 24 h. The number of NK cells, NKT cells, neutrophils, and macrophages in liver, as well as intracellular staining for TNF-α, IFN-γ, and MCP-1 in liver cell populations were determined by flow cytometry. Control mice subjected to HS/T exhibited end organ damage manifested by marked increases in circulating ALT, AST, and MCP-1 levels, as well as histologic evidence of hepatic necrosis and gut injury. Although NK1.1 + cell-depleted mice exhibited a similar degree of organ damage as nondepleted animals at 6 h, NK1.1 + cell depletion resulted in marked suppression of both liver and gut injury by 24 h after HS/T. These findings indicate that NK1.1 + cells contribute to the persistence of inflammation leading to end organ damage in the liver and gut. © Society for Leukocyte Biology.

  10. Deciduous and permanent dental pulp mesenchymal cells acquire hepatic morphologic and functional features in vitro.

    Ishkitiev, Nikolay; Yaegaki, Ken; Calenic, Bogdan; Nakahara, Taka; Ishikawa, Hiroshi; Mitiev, Vanyo; Haapasalo, Markus

    2010-03-01

    Mesenchymal stem cells display extensive proliferative capacity of multilineage differentiation. The stromal compartment of mesenchymal tissues is considered to harbor stem cells. We assessed the endodermal differentiation of mesenchymal cells from deciduous and wisdom tooth pulp. Dental mesenchymal cells were isolated and expanded in vitro. After cell cultures had been established, cells were characterized using known stem cell markers. For hepatic differentiation the media was supplemented with hepatic growth factor, dexamethasone, Insulin-Transferrin-Selenium-X, and oncostatin. Both cultures showed a number of cells positive for specific hepatic markers including alpha-fetoprotein, albumin, and hepatic nuclear factor 4alpha after differentiation. Also, small clusters of cells positive for insulin-like growth factor 1 were found. The concentration of urea increased significantly in the media. Moreover, a significant amount of glycogen was found in the cells. Because the cells proved to produce specific hepatic proteins and to start functions specific for hepatocytes, such as storing glycogen and urea production, we may state that the mesenchymal cell cultures from wisdom and deciduous tooth pulp acquired morphologic and functional characteristics of hepatocytes. Copyright (c) 2010 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

  11. Ethanol exacerbates T cell dysfunction after thermal injury.

    Choudhry, M A; Messingham, K A; Namak, S; Colantoni, A; Fontanilla, C V; Duffner, L A; Sayeed, M M; Kovacs, E J

    2000-07-01

    To understand the mechanism of suppressed immunity following alcohol consumption and thermal injury, we analyzed T cell functions in a mouse model of acute alcohol exposure and burn injury. Mice with blood alcohol levels at approximately 100 mg/dl were given a 15% scald or sham injury. Mice were sacrificed 48 h after injury. Our data demonstrated a 20-25% decrease in Con A-mediated splenic T cell proliferation (p<0.01) and 45-50% decrease in interleukin-2 (IL-2) production (p<0.01) following burn injury compared to the T cells from sham animals. A further decrease in the proliferation (25-30%) and IL-2 production (40-45%) was detected in T cells derived from burned animals receiving alcohol as compared to burn alone. No significant change in the proliferation and IL-2 production was observed in splenic T cells derived from sham-injured mice regardless of alcohol exposure. Additionally, there was no demonstrable difference in splenocyte apoptosis in any treatment group. These results suggest that alcohol consumption prior to burn injury causes a greater decrease in T cell proliferation and IL-2 production compared to either burn or alcohol injury alone that may further attenuate the cell-mediated immunity and thus enhance susceptibility to infection.

  12. Isolation and characterization of portal branch ligation-stimulated Hmga2-positive bipotent hepatic progenitor cells

    Sakai, Hiroshi; Tagawa, Yoh-ichi; Tamai, Miho; Motoyama, Hiroaki; Ogawa, Shinichiro; Soeda, Junpei; Nakata, Takenari; Miyagawa, Shinichi

    2010-01-01

    Research highlights: → Hepatic progenitor cells were isolated from the portal branch-ligated liver of mice. → Portal branch ligation-stimulated hepatic progenitor cells (PBLHCs) express Hmga2. → PBLHCs have bidirectional differentiation capability in vitro. -- Abstract: Hepatic stem/progenitor cells are one of several cell sources that show promise for restoration of liver mass and function. Although hepatic progenitor cells (HPCs), including oval cells, are induced by administration of certain hepatotoxins in experimental animals, such a strategy would be inappropriate in a clinical setting. Here, we investigated the possibility of isolating HPCs in a portal branch-ligated liver model without administration of any chemical agents. A non-parenchymal cell fraction was prepared from the portal branch-ligated or non-ligated lobe, and seeded onto plates coated with laminin. Most of the cells died, but a small number were able to proliferate. These proliferating cells were cloned as portal branch ligation-stimulated hepatic cells (PBLHCs) by the limiting dilution method. The PBLHCs expressed cytokeratin19, albumin, and Hmga2. The PBLHCs exhibited metabolic functions such as detoxification of ammonium ions and synthesis of urea on Matrigel-coated plates in the presence of oncostatin M. In Matrigel mixed with type I collagen, the PBLHCs became rearranged into cystic and tubular structures. Immunohistochemical staining demonstrated the presence of Hmga2-positive cells around the interlobular bile ducts in the portal branch-ligated liver lobes. In conclusion, successful isolation of bipotent hepatic progenitor cell clones, PBLHCs, from the portal branch-ligated liver lobes of mice provides the possibility of future clinical application of portal vein ligation to induce hepatic progenitor cells.

  13. Apigenin inhibits d-galactosamine/LPS-induced liver injury through upregulation of hepatic Nrf-2 and PPARγ expressions in mice.

    Zhou, Rui-Jun; Ye, Hua; Wang, Feng; Wang, Jun-Long; Xie, Mei-Lin

    2017-11-04

    Apigenin is a natural flavonoid compound widely distributed in a variety of vegetables, medicinal plants and health foods. This study aimed to examine the protective effect of apigenin against d-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced mouse liver injury and to investigate the potential biochemical mechanisms. The results showed that after oral administration of apigenin 100-200 mg/kg for 7 days, the levels of serum alanine aminotransferase and aspartate aminotransferase were decreased, and the severity of liver injury was alleviated. Importantly, apigenin pretreatment increased the levels of hepatic nuclear factor erythroid 2-related factor 2 (Nrf-2) and peroxisome proliferator-activated receptor γ (PPARγ) protein expressions as well as superoxide dismutase, catalase, glutathione S-transferase and glutathione reductase activities, decreased the levels of hepatic nuclear factor-κB (NF-κB) protein expression and tumor necrosis factor-α. These findings demonstrated that apigenin could prevent the D-GalN/LPS-induced liver injury in mice, and its mechanisms might be associated with the increments of Nrf-2-mediated antioxidative enzymes and modulation of PPARγ/NF-κB-mediated inflammation. Copyright © 2017 Elsevier Inc. All rights reserved.

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

    Fang Du

    Full Text Available 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.

  15. Biochemical metabolic changes assessed by 31P magnetic resonance spectroscopy after radiation-induced hepatic injury in rabbits

    Yu, Ri-Sheng; Hao, Liang; Dong, Fei; Mao, Jian-Shan; Sun, Jian-Zhong; Chen, Ying; Lin, Min; Wang, Zhi-Kang; Ding, Wen-Hong

    2009-01-01

    AIM: To compare the features of biochemical metabolic changes detected by hepatic phosphorus-31 magnetic resonance spectroscopy (31P MRS) with the liver damage score (LDS) and pathologic changes in rabbits and to investigate the diagnostic value of 31P MRS in acute hepatic radiation injury. METHODS: A total of 30 rabbits received different radiation doses (ranging 5-20 Gy) to establish acute hepatic injury models. Blood biochemical tests, 31P MRS and pathological examinations were carried out 24 h after irradiation. The degree of injury was evaluated according to LDS and pathology. Ten healthy rabbits served as controls. The MR examination was performed on a 1.5 T imager using a 1H/31P surface coil by the 2D chemical shift imaging technique. The relative quantities of phosphomonoesters (PME), phosphodiesters (PDE), inorganic phosphate (Pi) and adenosine triphosphate (ATP) were measured. The data were statistically analyzed. RESULTS: (1) Relative quantification of phosphorus metabolites: (a) ATP: there were significant differences (P < 0.05) (LDS-groups: control group vs mild group vs moderate group vs severe group, 1.83 ± 0.33 vs 1.55 ± 0.24 vs 1.27 ± 0.09 vs 0.98 ± 0.18; pathological groups: control group vs mild group vs moderate group vs severe group, 1.83 ± 0.33 vs 1.58 ± 0.25 vs 1.32 ± 0.07 vs 1.02 ± 0.18) of ATP relative quantification among control group, mild injured group, moderate injured group, and severe injured group according to both LDS grading and pathological grading, respectively, and it decreased progressively with the increased degree of injury (r = -0.723, P = 0.000). (b) PME and Pi; the relative quantification of PME and Pi decreased significantly in the severe injured group, and the difference between the control group and severe injured group was significant (P < 0.05) (PME: LDS-control group vs LDS-severe group, 0.86 ± 0.23 vs 0.58 ± 0.22, P = 0.031; pathological control group vs pathological severe group, 0.86 ± 0.23 vs 0.60

  16. Multidrug resistance-associated proteins are crucial for the viability of activated rat hepatic stellate cells

    Hannivoort, Rebekka A.; Dunning, Sandra; Borght, Sara Vander; Schroyen, Ben; Woudenberg, Jannes; Oakley, Fiona; Buist-Homan, Manon; van den Heuvel, Fiona A. J.; Geuken, Mariska; Geerts, Albert; Roskams, Tania; Faber, Klaas Nico; Moshage, Han

    Hepatic stellate cells (HSCs) survive and proliferate in the chronically injured liver. ATP-binding cassette (ABC) transporters play a crucial role in cell viability by transporting toxic metabolites or xenobiotics out of the cell. ABC transporter expression in HSCs and its relevance to cell

  17. miR-494 up-regulates the PI3K/Akt pathway via targetting PTEN and attenuates hepatic ischemia/reperfusion injury in a rat model.

    Su, Song; Luo, De; Liu, Xiangdong; Liu, Jiang; Peng, Fangyi; Fang, Cheng; Li, Bo

    2017-10-31

    A rat HIRI model was constructed and treated with an intraperitoneal injection of agomir- miR-494 or agomir-NC (negative control) for 7 days after the surgery. The pathophysiological changes in sham-operated rats, HIRI, HIRI + agomir- miR-494 , and HIRI + agomir-NC were compared. The effect of miR-494 was also assessed in an H 2 O 2 -induced apoptosis model. Hepatic AML12 cells were transfected with mimics NC or miR-494 mimics, followed by 6-h H 2 O 2 treatment. Cell proliferation and apoptosis were detected by CCK8 assay and flow cytometry, respectively. Further, the miR-494 target gene was identified by luciferase reporter assay, and verified both in vitro and in vivo experiments. The activity of AKT pathway was further analyzed in vivo by Western blot. HIRI + agomir- miR-494 rats exhibited significantly higher miR-494 expression, lower serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and glutamate dehydrogenase (GLDH) level, lower hepatic MDA, TOA, and OSI, alleviated hepatic necrosis, reduced hepatocyte apoptosis, and decreased expression of apoptosis-related proteins, when compared with HIRI + agomir-NC rats ( P <0.05 or 0.01). After H 2 O 2 treatment, AML-12 cells transfected with miR-494 mimics had significantly higher proliferation and lower apoptosis rate compared with mimics NC group ( P <0.01). PTEN was identified as an miR-494 target gene. PTEN expression was significantly down-regulated in AML12 cells transfected with miR-494 mimics, and was up-regulated by treatment of miR-494 inhibitor ( P <0.01). Moreover, HIRI + agomir- miR-494 rats exhibited significantly lower PTEN expression, and higher p-AKT, p-mTOR, and p-p70S6K levels compared with HIRI + agomir-NC rats. Therefore, miR-494 protected rats against hepatic ischemia/reperfusion (I/R) injury through down-regulating its downstream target gene PTEN , leading to the activation of PI3K/AKT signaling pathway. © 2017 The Author(s).

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

    Møller, Linda Maria Sevelsted; Fialla, Annette Dam; Schierwagen, Robert

    2016-01-01

    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...

  19. Complete replication of hepatitis B virus and hepatitis C virus in a newly developed hepatoma cell line.

    Yang, Darong; Zuo, Chaohui; Wang, Xiaohong; Meng, Xianghe; Xue, Binbin; Liu, Nianli; Yu, Rong; Qin, Yuwen; Gao, Yimin; Wang, Qiuping; Hu, Jun; Wang, Ling; Zhou, Zebin; Liu, Bing; Tan, Deming; Guan, Yang; Zhu, Haizhen

    2014-04-01

    The absence of a robust cell culture system for hepatitis B virus (HBV) and hepatitis C virus (HCV) infection has limited the analysis of the virus lifecycle and drug discovery. We have established a hepatoma cell line, HLCZ01, the first cell line, to the authors' knowledge, supporting the entire lifecycle of both HBV and HCV. HBV surface antigen (HBsAg)-positive particles can be observed in the supernatant and the lumen of the endoplasmic reticulum of the cells via electron microscopy. Interestingly, HBV and HCV clinical isolates propagate in HLCZ01 cells. Both viruses replicate in the cells without evidence of overt interference. HBV and HCV entry are blocked by antibodies against HBsAg and human CD81, respectively, and the replication of HBV and HCV is inhibited by antivirals. HLCZ01 cells mount an innate immune response to virus infection. The cell line provides a powerful tool for exploring the mechanisms of virus entry and replication and the interaction between host and virus, facilitating the development of novel antiviral agents and vaccines.

  20. Suppression of immune-mediated liver injury after vaccination with attenuated pathogenic cells.

    Mei, Yunhua; Wang, Ying; Xu, Lingyun

    2007-05-15

    Cell vaccination via immunization with attenuated pathogenic cells is an effective preventive method that has been successfully applied in several animal models of inflammatory or autoimmune diseases. Concanavalin A (Con A)-induced hepatitis (CIH) is a commonly used experimental model to study immune-mediated liver injury. Multiple cell types including T lymphocytes, macrophages and neutrophils have been found to be involved in the pathogenesis of CIH. In this study, we used attenuated spleen lymphocytes or peripheral blood lymphocytes as vaccines to investigate whether they could induce protective immune responses to prevent mice from developing CIH. We found that mice receiving such vaccination before CIH induction developed much milder diseases, exhibited a lower level of alanine aminotransferase (ALT) released into their plasma and had less inflammatory lesions in their livers. Such CIH-suppression is dose- and frequency-dependent. The suppressive effect was associated with inhibition of several major inflammatory mediators, pro-inflammatory cytokines and chemokines.

  1. TIM-1 Promotes Hepatitis C Virus Cell Attachment and Infection.

    Wang, Jing; Qiao, Luhua; Hou, Zhouhua; Luo, Guangxiang

    2017-01-15

    Human TIM and TAM family proteins were recently found to serve as phosphatidylserine (PS) receptors which promote infections by many different viruses, including dengue virus, West Nile virus, Ebola virus, Marburg virus, and Zika virus. In the present study, we provide substantial evidence demonstrating that TIM-1 is important for efficient infection by hepatitis C virus (HCV). The knockdown of TIM-1 expression significantly reduced HCV infection but not HCV RNA replication. Likewise, TIM-1 knockout in Huh-7.5 cells remarkably lowered HCV cell attachment and subsequent HCV infection. More significantly, the impairment of HCV infection in the TIM-1 knockout cells could be restored completely by ectopic expression of TIM-1 but not TIM-3 or TIM-4. Additionally, HCV infection and cell attachment were inhibited by PS but not by phosphatidylcholine (PC), demonstrating that TIM-1-mediated enhancement of HCV infection is PS dependent. The exposure of PS on the HCV envelope was confirmed by immunoprecipitation of HCV particles with a PS-specific monoclonal antibody. Collectively, these findings demonstrate that TIM-1 promotes HCV infection by serving as an attachment receptor for binding to PS exposed on the HCV envelope. TIM family proteins were recently found to enhance infections by many different viruses, including several members of the Flaviviridae family. However, their importance in HCV infection has not previously been examined experimentally. The TIM family proteins include three members in humans: TIM-1, TIM-3, and TIM-4. The findings derived from our studies demonstrate that TIM-1, but not TIM-3 or TIM-4, promotes HCV infection by functioning as an HCV attachment factor. Knockout of the TIM-1 gene resulted in a remarkable reduction of HCV cell attachment and infection. PS-containing liposomes blocked HCV cell attachment and subsequent HCV infection. HCV particles could also be precipitated with a PS-specific monoclonal antibody. These findings suggest that TIM-1

  2. Liver cell-derived microparticles activate hedgehog signaling and alter gene expression in hepatic endothelial cells.

    Witek, Rafal P; Yang, Liu; Liu, Renshui; Jung, Youngmi; Omenetti, Alessia; Syn, Wing-Kin; Choi, Steve S; Cheong, Yeiwon; Fearing, Caitlin M; Agboola, Kolade M; Chen, Wei; Diehl, Anna Mae

    2009-01-01

    Angiogenesis contributes to vascular remodeling during cirrhosis. In cirrhotic livers, cholangiocytes, and myofibroblastic hepatic stellate cells (MF-HSC) produce Hedgehog (Hh) ligands. During embryogenesis Hh ligands are released from ligand-producing cells in microparticles and activate Hh signaling in endothelial cells. We studied whether adult liver cell-derived microparticles contain Hh ligands that alter hepatic sinusoidal endothelial cells (SEC). MF-HSC and cholangiocytes were exposed to platelet-derived growth factor to induce Hh ligands; microparticles were isolated from medium, analyzed by transmission electron microscopy and immunoblots, and applied to Hh-reporter-containing cells. Microparticles were obtained from serum and bile of rats after bile duct ligation (BDL) or sham surgery and applied to normal primary liver SEC with or without cyclopamine, an Hh signaling inhibitor. Effects on SEC gene expression were evaluated by quantitative reverse-transcription polymerase chain reaction and immunoblotting. Hh target gene expression and SEC activation markers were compared in primary SEC and in liver sections from healthy and BDL rats. Platelet-derived growth factor-treated MF-HSC and cholangiocytes released exosome-enriched microparticles containing biologically-active Hh ligands. BDL increased release of Hh-containing exosome-enriched microparticles into plasma and bile. Transmission electron microscopy and immunoblots revealed similarities among microparticles from all sources; all microparticles induced similar Hh-dependent changes in SEC gene expression. SEC from healthy livers did not express Hh target genes or activation markers, but both were up-regulated in SEC after BDL. Hh-containing exosome-enriched microparticles released from liver cells alter hepatic SEC gene expression, suggesting a novel mechanism for cirrhotic vasculopathy.

  3. Dihydroartemisinin counteracts fibrotic portal hypertension via farnesoid X receptor-dependent inhibition of hepatic stellate cell contraction.

    Xu, Wenxuan; Lu, Chunfeng; Zhang, Feng; Shao, Jiangjuan; Yao, Shunyu; Zheng, Shizhong

    2017-01-01

    Portal hypertension is a frequent pathological symptom occurring especially in hepatic fibrosis and cirrhosis. Current paradigms indicate that inhibition of hepatic stellate cell (HSC) activation and contraction is anticipated to be an attractive therapeutic strategy, because activated HSC dominantly facilitates an increase in intrahepatic vein pressure through secreting extracellular matrix and contracting. Our previous in vitro study indicated that dihydroartemisinin (DHA) inhibited contractility of cultured HSC by activating intracellular farnesoid X receptor (FXR). However, the effect of DHA on fibrosis-related portal hypertension still requires clarification. In this study, gain- and loss-of-function models of FXR in HSC were established to investigate the mechanisms underlying DHA protection against chronic CCl 4 -caused hepatic fibrosis and portal hypertension. Immunofluorescence staining visually showed a decrease in FXR expression in CCl 4 -administrated rat HSC but an increase in that in DHA-treated rat HSC. Serum diagnostics and morphological analyses consistently indicated that DHA exhibited hepatoprotective effects on CCl 4 -induced liver injury. DHA also reduced CCl 4 -caused inflammatory mediator expression and inflammatory cell infiltration. These improvements were further enhanced by INT-747 but weakened by Z-guggulsterone. Noteworthily, DHA, analogous to INT-747, significantly lowered portal vein pressure and suppressed fibrogenesis. Experiments on mice using FXR shRNA lentivirus consolidated the results above. Mechanistically, inhibition of HSC activation and contraction was found as a cellular basis for DHA to relieve portal hypertension. These findings demonstrated that DHA attenuated portal hypertension in fibrotic rodents possibly by targeting HSC contraction via a FXR activation-dependent mechanism. FXR could be a target molecule for reducing portal hypertension during hepatic fibrosis. © 2016 Federation of European Biochemical Societies.

  4. Modulation of extracellular matrix proteins and hepatate stellate cell activation following gadolinium chloride induced Kuffer cell blockade in an experimental model of liver fibrosis/cirrhosis

    Nilgün Tekkesin

    2013-06-01

    Full Text Available Hepatic fibrosis is now regarded as a common response to chronic liver injury; regardless of its nature (viral infections, alcohol abuse and metal overload. It is also characterized by excessive deposition of extracellular matrix (ECM components. The ECM is a dynamic complex of macromolecules that includes collagens, glycoproteins, and proteoglycans, such as laminin and fibronectin; it has been shown that it does not only support the tissue structure, but also plays a major role in cell adhesion, proliferation, and differentiation. Remodelling of the ECM may be the signal that facilitates lobular reorganization during liver regeneration after a liver injury. Much work has been done concerning the ECM synthesis and protein contents.

  5. Nonlinear Dynamic Theory of Acute Cell Injuries and Brain Ischemia

    Taha, Doaa; Anggraini, Fika; Degracia, Donald; Huang, Zhi-Feng

    2015-03-01

    Cerebral ischemia in the form of stroke and cardiac arrest brain damage affect over 1 million people per year in the USA alone. In spite of close to 200 clinical trials and decades of research, there are no treatments to stop post-ischemic neuron death. We have argued that a major weakness of current brain ischemia research is lack of a deductive theoretical framework of acute cell injury to guide empirical studies. A previously published autonomous model based on the concept of nonlinear dynamic network was shown to capture important facets of cell injury, linking the concept of therapeutic to bistable dynamics. Here we present an improved, non-autonomous formulation of the nonlinear dynamic model of cell injury that allows multiple acute injuries over time, thereby allowing simulations of both therapeutic treatment and preconditioning. Our results are connected to the experimental data of gene expression and proteomics of neuron cells. Importantly, this new model may be construed as a novel approach to pharmacodynamics of acute cell injury. The model makes explicit that any pro-survival therapy is always a form of sub-lethal injury. This insight is expected to widely influence treatment of acute injury conditions that have defied successful treatment to date. This work is supported by NIH NINDS (NS081347) and Wayne State University President's Research Enhancement Award.

  6. Physicochemical properties, antioxidant activities and protective effect against acute ethanol-induced hepatic injury in mice of foxtail millet (Setaria italica) bran oil.

    Pang, Min; He, Shujian; Wang, Lu; Cao, Xinmin; Cao, Lili; Jiang, Shaotong

    2014-08-01

    This study was designed to investigate physicochemical characterization of the oil extracted from foxtail millet bran (FMBO), and the antioxidant and hepatoprotective effects against acute ethanol-induced hepatic injury in mice. GC-MS analysis revealed that unsaturated fatty acids (UFAs) account for 83.76% of the total fatty acids; in particular, the linoleic acid (C18:2) is the predominant polyunsaturated fatty acid (PUFA), and the compounds of squalene and six phytosterols (or phytostanols) were identified in unsaponifiable matter of FMBO. The antioxidant activity examination of FMBO in vitro showed highly ferric-reducing antioxidant power and scavenging effects against DPPH· and HO· radicals. Furthermore, the protective effect of FMBO against acute hepatic injuries induced by ethanol was verified in mice. In this, intragastric administration with different dosages of FMBO in mice ahead of acute ethanol administration could observably antagonize the ethanol-induced increases in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), and the hepatic malondialdehyde (MDA) levels, respectively, along with enhanced hepatic superoxide dismutase (SOD) levels relative to the control. Hepatic histological changes were also observed and confirmed that FMBO is capable of attenuating ethanol-induced hepatic injury.

  7. Inhibition of tumor necrosis factor alpha reduces the outgrowth of hepatic micrometastasis of colorectal tumors in a mouse model of liver ischemia-reperfusion injury.

    Jiao, Shu-Fan; Sun, Kai; Chen, Xiao-Jing; Zhao, Xue; Cai, Ning; Liu, Yan-Jun; Xu, Long-Mei; Kong, Xian-Ming; Wei, Li-Xin

    2014-01-08

    Patients with colorectal cancer (CRC) often develop liver metastases, in which case surgery is considered the only potentially curative treatment option. However, liver surgery is associated with a risk of ischemia-reperfusion (IR) injury, which is thought to promote the growth of colorectal liver metastases. The influence of IR-induced tumor necrosis factor alpha (TNF-α) elevation in the process still is unknown. To investigate the role of TNF-α in the growth of pre-existing micrometastases in the liver following IR, we used a mouse model of colorectal liver metastases. In this model, mice received IR treatment seven days after intrasplenic injections of colorectal CT26 cells. Prior to IR treatment, either TNF-α blocker Enbrel or low-dose TNF-α, which could inhibit IR-induced TNF-α elevation, was administered by intraperitoneal injection. Hepatic IR treatment significantly promoted CT26 tumor growth in the liver, but either Enbrel or low-dose TNF-α pretreatment reversed this trend. Further studies showed that the CT26 + IR group prominently increased the levels of ALT and AST, liver necrosis, inflammatory infiltration and the expressions of hepatic IL-6, MMP9 and E-selectin compared to those of CT26 group. Inhibition of TNF-α elevation remarkably attenuated the increases of these liver inflammatory damage indicators and tumor-promoting factors. These findings suggested that inhibition of TNF-α elevation delayed the IR-enhanced outgrowth of colorectal liver metastases by reducing IR-induced inflammatory damage and the formation of tumor-promoting microenvironments. Both Enbrel and low-dose TNF-α represented the potential therapeutic approaches for the protection of colorectal liver metastatic patients against IR injury-induced growth of liver micrometastases foci.

  8. Hepatic natural killer cells exclusively kill splenic/blood natural killer-resistant tumor cells by the perforin/granzyme pathway

    Vermijlen, David; Luo, Dianzhong; Froelich, Christopher J.; Medema, Jan Paul; Kummer, Jean Alain; Willems, Erik; Braet, Filip; Wisse, Eddie

    2002-01-01

    Hepatic natural killer (NK) cells are located in the liver sinusoids adherent to the endothelium. Human and rat hepatic NK cells induce cytolysis in tumor cells that are resistant to splenic or blood NK cells. To investigate the mechanism of cell death, we examined the capacity of isolated, pure

  9. A novel method of mouse ex utero transplantation of hepatic progenitor cells into the fetal liver

    Shikanai, Mima; Asahina, Kinji; Iseki, Sachiko; Teramoto, Kenichi; Nishida, Tomohiro; Shimizu-Saito, Keiko; Ota, Masato; Eto, Kazuhiro; Teraoka, Hirobumi

    2009-01-01

    Avoiding the limitations of the adult liver niche, transplantation of hepatic stem/progenitor cells into fetal liver is desirable to analyze immature cells in a hepatic developmental environment. Here, we established a new monitor tool for cell fate of hepatic progenitor cells transplanted into the mouse fetal liver by using ex utero surgery. When embryonic day (ED) 14.5 hepatoblasts were injected into the ED14.5 fetal liver, the transplanted cells expressed albumin abundantly or α-fetoprotein weakly, and contained glycogen in the neonatal liver, indicating that transplanted hepatoblasts can proliferate and differentiate in concord with surrounding recipient parenchymal cells. The transplanted cells became mature in the liver of 6-week-old mice. Furthermore, this method was applicable to transplantation of hepatoblast-like cells derived from mouse embryonic stem cells. These data indicate that this unique technique will provide a new in vivo experimental system for studying cell fate of hepatic stem/progenitor cells and liver organogenesis.

  10. Mechanism of estrogen-mediated attenuation of hepatic injury following trauma-hemorrhage: Akt-dependent HO-1 up-regulation.

    Hsu, Jun-Te; Kan, Wen-Hong; Hsieh, Chi-Hsun; Choudhry, Mashkoor A; Schwacha, Martin G; Bland, Kirby I; Chaudry, Irshad H

    2007-10-01

    Protein kinase B (Akt) is known to be involved in proinflammatory and chemotactic events in response to injury. Akt activation also leads to the induction of heme oxygenase (HO)-1. Up-regulation of HO-1 mediates potent, anti-inflammatory effects and attenuates organ injury. Although studies have shown that 17beta-estradiol (E2) prevents organ damage following trauma-hemorrhage, it remains unknown whether Akt/HO-1 plays any role in E2-mediated attenuation of hepatic injury following trauma-hemorrhage. To study this, male rats underwent trauma-hemorrhage (mean blood pressure, approximately 40 mmHg for 90 min), followed by fluid resuscitation. At the onset of resuscitation, rats were treated with vehicle, E2 (1 mg/kg body weight), E2 plus the PI-3K inhibitor (Wortmannin), or the estrogen receptor (ER) antagonist (ICI 182,780). At 2 h after sham operation or trauma-hemorrhage, plasma alpha-GST and hepatic tissue myeloperoxidase (MPO) activity, IL-6, TNF-alpha, ICAM-1, cytokine-induced neutrophil chemoattractant-1, and MIP-2 levels were measured. Hepatic Akt and HO-1 protein levels were also determined. Trauma-hemorrhage increased hepatic injury markers (alpha-GST and MPO activity), cytokines, ICAM-1, and chemokine levels. These parameters were markedly improved in the E2-treated rats following trauma-hemorrhage. E2 treatment also increased hepatic Akt activation and HO-1 expression compared with vehicle-treated, trauma-hemorrhage rats, which were abolished by coadministration of Wortmannin or ICI 182,780. These results suggest that the salutary effects of E2 on hepatic injury following trauma-hemorrhage are in part mediated via an ER-related, Akt-dependent up-regulation of HO-1.

  11. Amelioration of High Cholesterol Diet Caused Lipids Accumulation in Hepatic Cells by Rutin and Ascorbic Acid

    Abdulaziz M. Aleisa

    2013-01-01

    Non Alcoholic Fatty Liver Disease (NAFLD) has become a very common metabolic disorder. It refers to a group of conditions where excess fats are deposited in hepatic cells. Several approaches have been considered for the management of NAFLD including dietary changes, which were reported to suppress hepatic lipids accumulation in previous studies. The present study was designed to investigate the possible synergistic effects of Rutin (RT) and Ascorbic Acid (AA) against lipids accumulation in he...

  12. As bases experimentais da lesão por isquemia e reperfusão do fígado: revisão The experimental basis of hepatic ischemia-reperfusion injury: review

    Luiz Eduardo C. Miranda

    2004-01-01

    Full Text Available O transplante hepático tornou-se o procedimento de escolha para o tratamento da doença hepática terminal. Não obstante o sucesso da cirurgia, a disfunção pós-operatória do fígado enxertado ainda representa importante causa de morbidade e mortalidade. O restabelecimento do fluxo sangüíneo ao fígado recém transplantado impõe a ele nova agressão, agravando a lesão causada pelo período de isquemia. Este fenômeno pouco compreendido é conhecido como lesão por isquemia e reperfusão e envolve disfunção endotelial, seqüestro de leucócitos e agregação de plaquetas, lesão por radicais livre de oxigênio, e distúrbios da microcirculação hepática. Essa revisão discute os vários aspectos fisiopatológicos que estão envolvidos na lesão por isquemia e reperfusão do fígado.Hepatic transplantation has become the main treatment for patients with terminal hepatic disease. Whatever the success of such surgery, the hepatic dysfunction associated with liver transplantation is an important cause of morbidity and mortality. Paradoxically, on restoring the blood supply, the liver is subjected to a further insult, aggravating the injury already caused by ischemia. This complex phenomenon is termed ischemia-reperfusion injury and involves endothelial cell dysfunction, leukocyte entrapment, platelet aggregation, oxidant stress and hepatic microcirculatory perfusion failure. This review discusses the physiopathlogicals mechanisms of liver ischemia-reperfusion injury.

  13. Breath pentane as a potential biomarker for survival in hepatic ischemia and reperfusion injury--a pilot study.

    Changsong Wang

    Full Text Available BACKGROUND: Exhaled pentane, which is produced as a consequence of reactive oxygen species-mediated lipid peroxidation, is a marker of oxidative stress. Propofol is widely used as a hypnotic agent in intensive care units and the operating room. Moreover, this agent has been reported to inhibit lipid peroxidation by directly scavenging reactive oxygen species. In this study, using a porcine liver ischemia-reperfusion injury model, we have evaluated the hypothesis that high concentrations of breath pentane are related to adverse outcome and that propofol could reduce breath pentane and improve liver injury and outcome in swine in this situation. METHODOLOGY/PRINCIPAL FINDINGS: Twenty male swine were assigned to two groups: propofol (n = 10 and chloral hydrate groups (n = 10. Hepatic ischemia was induced by occluding the portal inflow vessels. Ischemia lasted for 30 min, followed by reperfusion for 360 min. Exhaled and blood pentane concentrations in the chloral hydrate group markedly increased 1 min after reperfusion and then decreased to baseline. Breath and blood pentane concentrations in the propofol group increased 1 min after reperfusion but were significantly lower than in the chloral hydrate group. A negative correlation was found between breath pentane levels and survival in the chloral hydrate group. The median overall survival was 251 min after reperfusion (range 150-360 min in the chloral hydrate group. All of the swine were alive in the propofol group. CONCLUSIONS: Monitoring of exhaled pentane may be useful for evaluating the severity of hepatic ischemia-reperfusion injury and aid in predicting the outcome; propofol may improve the outcome in this situation.

  14. Recovery of Corneal Endothelial Cells from Periphery after Injury.

    Sang Ouk Choi

    Full Text Available Wound healing of the endothelium occurs through cell enlargement and migration. However, the peripheral corneal endothelium may act as a cell resource for the recovery of corneal endothelium in endothelial injury.To investigate the recovery process of corneal endothelial cells (CECs from corneal endothelial injury.Three patients with unilateral chemical eye injuries, and 15 rabbit eyes with corneal endothelial chemical injuries were studied. Slit lamp examination, specular microscopy, and ultrasound pachymetry were performed immediately after chemical injury and 1, 3, 6, and 9 months later. The anterior chambers of eyes from New Zealand white rabbits were injected with 0.1 mL of 0.05 N NaOH for 10 min (NaOH group. Corneal edema was evaluated at day 1, 7, and 14. Vital staining was performed using alizarin red and trypan blue.Specular microscopy did not reveal any corneal endothelial cells immediately after injury. Corneal edema subsided from the periphery to the center, CEC density increased, and central corneal thickness decreased over time. In the animal study, corneal edema was greater in the NaOH group compared to the control at both day 1 and day 7. At day 1, no CECs were detected at the center and periphery of the corneas in the NaOH group. Two weeks after injury, small, hexagonal CECs were detected in peripheral cornea, while CECs in mid-periphery were large and non-hexagonal.CECs migrated from the periphery to the center of the cornea after endothelial injury. The peripheral corneal endothelium may act as a cell resource for the recovery of corneal endothelium.

  15. Hepatic overproduction of 13-HODE due to ALOX15 upregulation contributes to alcohol-induced liver injury in mice

    Zhang, Wenliang; Zhong, Wei; Sun, Qian; Sun, Xinguo; Zhou, Zhanxiang

    2017-01-01

    Chronic alcohol feeding causes lipid accumulation and apoptosis in the liver. This study investigated the role of bioactive lipid metabolites in alcohol-induced liver damage and tested the potential of targeting arachidonate 15-lipoxygenase (ALOX15) in treating alcoholic liver disease (ALD). Results showed that chronic alcohol exposure induced hepatocyte apoptosis in association with increased hepatic 13-HODE. Exposure of 13-HODE to Hepa-1c1c7 cells induced oxidative stress, ER stress and apo...

  16. Evolving Role of Endoscopic Retrograde Cholangiopancreatography in Management of Extrahepatic Hepatic Ductal Injuries due to Blunt Trauma: Diagnostic and Treatment Algorithms

    Nikhil P. Jaik

    2008-01-01

    Full Text Available Extrahepatic hepatic ductal injuries (EHDIs due to blunt abdominal trauma are rare. Given the rarity of these injuries and the insidious onset of symptoms, EHDI are commonly missed during the initial trauma evaluation, making their diagnosis difficult and frequently delayed. Diagnostic modalities useful in the setting of EHDI include computed tomography (CT, abdominal ultrasonography (AUS, nuclear imaging (HIDA scan, and cholangiography. Traditional options in management of EHDI include primary ductal repair with or without a T-tube, biliary-enteric anastomosis, ductal ligation, stenting, and drainage. Simple drainage and biliary decompression is often the most appropriate treatment in unstable patients. More recently, endoscopic retrograde cholangiopancreatography (ERCP allowed for diagnosis and potential treatment of these injuries via stenting and/or papillotomy. Our review of 53 cases of EHDI reported in the English-language literature has focused on the evolving role of ERCP in diagnosis and treatment of these injuries. Diagnostic and treatment algorithms incorporating ERCP have been designed to help systematize and simplify the management of EHDI. An illustrative case is reported of blunt traumatic injury involving both the extrahepatic portion of the left hepatic duct and its confluence with the right hepatic duct. This injury was successfully diagnosed and treated using ERCP.

  17. Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increases human hepatic stellate cell activation

    Harvey, Wendy A.; Jurgensen, Kimberly; Pu, Xinzhu; Lamb, Cheri L.; Cornell, Kenneth A.; Clark, Reilly J.; Klocke, Carolyn; Mitchell, Kristen A.

    2016-01-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a halogenated aromatic hydrocarbon that elicits toxicity through the aryl hydrocarbon receptor (AhR). In the liver, gross markers of TCDD toxicity are attributed to AhR activation in parenchymal hepatocytes. However, less is known regarding the consequences of TCDD treatment on non-parenchymal cells in the liver. Hepatic stellate cells (HSCs) are non-parenchymal cells that store vitamin A when quiescent. Upon liver injury, activated HSCs lose this storage ability and instead function in the development and maintenance of inflammation and fibrosis through the production of pro-inflammatory mediators and collagen type I. Reports that TCDD exposure disrupts hepatic retinoid homeostasis and dysregulates extracellular matrix remodeling in the liver led us to speculate that TCDD treatment may disrupt HSC activity. The human HSC line LX-2 was used to test the hypothesis that TCDD treatment directly activates HSCs. Results indicate that exposure to 10 nM TCDD almost Completely inhibited lipid droplet storage in LX-2 cells cultured with retinol and palmitic acid. TCDD treatment also increased LX-2 cell proliferation, expression of α-smooth muscle actin, and production of monocyte chemoattractant protein-1 (MCP-1), all of which are characteristics of activated HSCs. However, TCDD treatment had no effect on Col1a1 mRNA levels in LX-2 cells stimulated with the potent profibrogenic mediator, transforming growth factor-β. The TCDD-mediated increase in LX-2 cell proliferation, but not MCP-1 production, was abolished when phosphoinositide 3-kinase was inhibited. These results indicate that HSCs are susceptible to direct modulation by TCDD and that TCDD likely increases HSC activation through a multi-faceted mechanism.

  18. The epigenetic regulation of stem cell factors in hepatic stellate cells.

    Reister, Sven; Kordes, Claus; Sawitza, Iris; Häussinger, Dieter

    2011-10-01

    The epigenetic regulation by DNA methylation is an important mechanism to control the expression of stem cell factors as demonstrated in tumor cells. It was recently shown that hepatic stellate cells (HSC) express stem/progenitor cell factors and have a differentiation potential. The aim of this work was to investigate if the expression of stem cell markers is regulated by DNA methylation during activation of rat HSC. It was found that CD133, Notch1, and Notch3 are regulated via DNA methylation in HSC, whereas Nestin shows no DNA methylation in HSC and other undifferentiated cells such as embryonic stem cells and umbilical cord blood stem cells from rats. In contrast to this, DNA methylation controls Nestin expression in differentiated cells like hepatocytes and the hepatoma cell line H4IIE. Demethylation by 5-Aza-2-deoxycytidine was sufficient to induce Nestin in H4IIE cells. In quiescent stellate cells and embryonic stem cells, the Nestin expression was suppressed by histone H3 methylation at lysine 9, which is another epigenetic mechanism. Apart from the known induction of Nestin in cultured HSC, this intermediate filament protein was also induced after partial hepatectomy, indicating activation of HSC during liver regeneration. Taken together, this study demonstrates for the first time that the expression of stem cell-associated factors such as CD133, Notch1, and Notch3 is controlled by DNA methylation in HSC. The regulation of Nestin by DNA methylation seems to be restricted to differentiated cells, whereas undifferentiated cells use different epigenetic mechanisms such as histone H3 methylation to control Nestin expression.

  19. Hepatic perivascular epithelioid cell tumor (PEComa: a case report with a review of literatures

    Hyun-Jin Son

    2017-03-01

    Full Text Available Hepatic perivascular epithelioid cell tumors (PEComas are very rare. We report a primary hepatic PEComa with a review of the literature. A 56-year-old women presented with a nodular mass detected during the management of chronic renal failure and chronic hepatitis C. Diagnostic imaging studies suggested a nodular hepatocellular carcinoma in segment 5 of the liver. The patient underwent partial hepatectomy. A brown-colored expansile mass measuring 3.2×3.0 cm was relatively demarcated from the surrounding liver parenchyma. The tumor was mainly composed of epithelioid cells that were arranged in a trabecular growth pattern. Adipose tissue and thick-walled blood vessels were minimally identified. A small amount of extramedullary hematopoiesis was observed in the sinusoidal spaces between tumor cells. Tumor cells were diffusely immunoreactive for human melanoma black 45 (HMB45 and Melan A, focally immunoreactive for smooth muscle actin, but not for hepatocyte specific antigen (HSA.

  20. Back to the drawing board: Understanding the complexity of hepatic innate lymphoid cells.

    Marotel, Marie; Hasan, Uzma; Viel, Sébastien; Marçais, Antoine; Walzer, Thierry

    2016-09-01

    Recent studies of immune populations in nonlymphoid organs have highlighted the great diversity of the innate lymphoid system. It has also become apparent that mouse and human innate lymphoid cells (ILCs) have distinct phenotypes and properties. In this issue of the European Journal of Immunology, Harmon et al. [Eur. J. Immunol. 2016. 46: 2111-2120] characterized human hepatic NK-cell subsets. The authors report that hepatic CD56(bright) NK cells resemble mouse liver ILC1s in that they express CXCR6 and have an immature phenotype. However, unlike mouse ILC1s, they express high levels of Eomes and low levels of T-bet, and upon stimulation with tumor cells, secrete low amounts of cytokines. These unexpected findings further support the differences between human and mouse immune populations and prompt the study of the role of hepatic ILC subsets in immune responses. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Cell therapy for spinal cord injury informed by electromagnetic waves.

    Finnegan, Jack; Ye, Hui

    2016-10-01

    Spinal cord injury devastates the CNS, besetting patients with symptoms including but not limited to: paralysis, autonomic nervous dysfunction, pain disorders and depression. Despite the identification of several molecular and genetic factors, a reliable regenerative therapy has yet to be produced for this terminal disease. Perhaps the missing piece of this puzzle will be discovered within endogenous electrotactic cellular behaviors. Neurons and stem cells both show mediated responses (growth rate, migration, differentiation) to electromagnetic waves, including direct current electric fields. This review analyzes the pathophysiology of spinal cord injury, the rationale for regenerative cell therapy and the evidence for directing cell therapy via electromagnetic waves shown by in vitro experiments.

  2. Carbon Monoxide Protects against Hepatic Ischemia/Reperfusion Injury via ROS-Dependent Akt Signaling and Inhibition of Glycogen Synthase Kinase 3β

    Hyo Jeong Kim

    2013-01-01

    Full Text Available Carbon monoxide (CO may exert important roles in physiological and pathophysiological states through the regulation of cellular signaling pathways. CO can protect organ tissues from ischemia/reperfusion (I/R injury by modulating intracellular redox status and by inhibiting inflammatory, apoptotic, and proliferative responses. However, the cellular mechanisms underlying the protective effects of CO in organ I/R injury remain incompletely understood. In this study, a murine model of hepatic warm I/R injury was employed to assess the role of glycogen synthase kinase-3 (GSK3 and phosphatidylinositol 3-kinase (PI3K-dependent signaling pathways in the protective effects of CO against inflammation and injury. Inhibition of GSK3 through the PI3K/Akt pathway played a crucial role in CO-mediated protection. CO treatment increased the phosphorylation of Akt and GSK3-beta (GSK3β in the liver after I/R injury. Furthermore, administration of LY294002, an inhibitor of PI3K, compromised the protective effect of CO and decreased the level of phospho-GSK3β after I/R injury. These results suggest that CO protects against liver damage by maintaining GSK3β phosphorylation, which may be mediated by the PI3K/Akt signaling pathway. Our study provides additional support for the therapeutic potential of CO in organ injury and identifies GSK3β as a therapeutic target for CO in the amelioration of hepatic injury.

  3. Carbon monoxide protects against hepatic ischemia/reperfusion injury via ROS-dependent Akt signaling and inhibition of glycogen synthase kinase 3β.

    Kim, Hyo Jeong; Joe, Yeonsoo; Kong, Jin Sun; Jeong, Sun-Oh; Cho, Gyeong Jae; Ryter, Stefan W; Chung, Hun Taeg

    2013-01-01

    Carbon monoxide (CO) may exert important roles in physiological and pathophysiological states through the regulation of cellular signaling pathways. CO can protect organ tissues from ischemia/reperfusion (I/R) injury by modulating intracellular redox status and by inhibiting inflammatory, apoptotic, and proliferative responses. However, the cellular mechanisms underlying the protective effects of CO in organ I/R injury remain incompletely understood. In this study, a murine model of hepatic warm I/R injury was employed to assess the role of glycogen synthase kinase-3 (GSK3) and phosphatidylinositol 3-kinase (PI3K)-dependent signaling pathways in the protective effects of CO against inflammation and injury. Inhibition of GSK3 through the PI3K/Akt pathway played a crucial role in CO-mediated protection. CO treatment increased the phosphorylation of Akt and GSK3-beta (GSK3β) in the liver after I/R injury. Furthermore, administration of LY294002, an inhibitor of PI3K, compromised the protective effect of CO and decreased the level of phospho-GSK3β after I/R injury. These results suggest that CO protects against liver damage by maintaining GSK3β phosphorylation, which may be mediated by the PI3K/Akt signaling pathway. Our study provides additional support for the therapeutic potential of CO in organ injury and identifies GSK3β as a therapeutic target for CO in the amelioration of hepatic injury.

  4. Cellular therapy after spinal cord injury using neural progenitor cells

    Vroemen, Maurice

    2006-01-01

    In this thesis, the possibilities and limitations of cell-based therapies after spinal cord injury are explored. Particularly, the potential of adult derived neural progenitor cell (NPC) grafts to function as a permissive substrate for axonal regeneration was investigated. It was found that syngenic

  5. Bone morphogenetic protein 9 as a key regulator of liver progenitor cells in DDC-induced cholestatic liver injury.

    Addante, Annalisa; Roncero, Cesáreo; Almalé, Laura; Lazcanoiturburu, Nerea; García-Álvaro, María; Fernández, Margarita; Sanz, Julián; Hammad, Seddik; Nwosu, Zeribe C; Lee, Se-Jin; Fabregat, Isabel; Dooley, Steven; Ten Dijke, Peter; Herrera, Blanca; Sánchez, Aránzazu

    2018-05-11

    Bone morphogenetic protein 9 (BMP9) interferes with liver regeneration upon acute injury, while promoting fibrosis upon carbon tetrachloride-induced chronic injury. We have now addressed the role of BMP9 in 3,5 diethoxicarbonyl-1,4 dihydrocollidine (DDC)-induced cholestatic liver injury, a model of liver regeneration mediated by hepatic progenitor cell (known as oval cell), exemplified as ductular reaction and oval cell expansion. WT and BMP9KO mice were submitted to DDC diet. Livers were examined for liver injury, fibrosis, inflammation and oval cell expansion by serum biochemistry, histology, RT-qPCR and western blot. BMP9 signalling and effects in oval cells were studied in vitro using western blot and transcriptional assays, plus functional assays of DNA synthesis, cell viability and apoptosis. Crosslinking assays and short hairpin RNA approaches were used to identify the receptors mediating BMP9 effects. Deletion of BMP9 reduces liver damage and fibrosis, but enhances inflammation upon DDC feeding. Molecularly, absence of BMP9 results in overactivation of PI3K/AKT, ERK-MAPKs and c-Met signalling pathways, which together with an enhanced ductular reaction and oval cell expansion evidence an improved regenerative response and decreased damage in response to DDC feeding. Importantly, BMP9 directly targets oval cells, it activates SMAD1,5,8, decreases cell growth and promotes apoptosis, effects that are mediated by Activin Receptor-Like Kinase 2 (ALK2) type I receptor. We identify BMP9 as a negative regulator of oval cell expansion in cholestatic injury, its deletion enhancing liver regeneration. Likewise, our work further supports BMP9 as an attractive therapeutic target for chronic liver diseases. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  6. [Surgical management, prognostic factors, and outcome in hepatic trauma].

    Ott, R; Schön, M R; Seidel, S; Schuster, E; Josten, C; Hauss, J

    2005-02-01

    Hepatic trauma is a rare surgical emergency with significant morbidity and mortality. Extensive experience in liver surgery is a prerequisite for the management of these injuries. The medical records of 68 consecutive patients with hepatic trauma were retrospectively reviewed for the severity of liver injury, management, morbidity, mortality, and risk factors. Of the patients, 14 were treated conservatively and 52 surgically (24 suture/fibrin glue, 16 perihepatic packing, 11 resections, 1 liver transplantation). Two patients died just before emergency surgery could be performed. Overall mortality was 21% (14/68), and 13, 14, 6, 27, and 50% for types I, II, III, IV, and V injuries, respectively. Only nine deaths (all type IV and V) were liver related, while four were caused by extrahepatic injuries and one by concomitant liver cirrhosis. With respect to treatment, conservative management, suture, and resection had a low mortality of 0, 4, and 9%, respectively. In contrast, mortality was 47% in patients in whom only packing was performed (in severe injuries). Stepwise multivariate regression analysis proved prothrombin values 30, and transfusion requirements of more than 10 red packed cells to be significant risk factors for post-traumatic death. Type I-III hepatic injuries can safely be treated by conservative or simple surgical means. However, complex hepatic injuries (types IV and V) carry a significant mortality and may require hepatic surgery, including liver resection or even transplantation. Therefore, patients with severe hepatic injuries should be treated in a specialized institution.

  7. DYRK1A is a regulator of S phase entry in hepatic progenitor cells

    Kruitwagen, Hedwig Suzanne; Westendorp, Bart; Viebahn, Cornelia S; Post, Krista; van Wolferen, Monique E; Oosterhoff, Loes A; Egan, David A; Delabar, Jean-Maurice; Toussaint, Mathilda Jm; Schotanus, Baukje A; de Bruin, Alain; Rothuizen, Jan; Penning, Louis C; Spee, Bart

    Hepatic progenitor cells (HPCs) are adult liver stem cells that act as second line of defense in liver regeneration. They are normally quiescent, but in case of severe liver damage HPC proliferation is triggered by external activation mechanisms from their niche. Although several important

  8. Sofosbuvir and Simeprevir Treatment of a Stem Cell Transplanted Teenager With Chronic Hepatitis C Infection.

    Fischler, Björn; Priftakis, Peter; Sundin, Mikael

    2016-06-01

    There have been no previous reports on the use of interferon-free combinations in pediatric patients with chronic hepatitis C infection. An infected adolescent with severe sickle cell disease underwent stem cell transplantation and subsequent treatment with sofosbuvir and simeprevir during ongoing immunosuppression. Despite the emergence of peripheral edema as a side effect, treatment was continued with sustained antiviral response.

  9. Alleviative effects from boswellic acid on acetaminophen-induced hepatic injury - Corrected and republished from: Biomedicine (Taipei). 2016 Jun; 6 (2): 9. doi: 10.7603/s40681-016-0009-1PMCID: PMC4864770.

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

    2017-06-01

    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 up-regulated 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 hepato-protective agent. © Author(s) 2017. This article is published with open access by China Medical University.

  10. Hepatocellular carcinoma with extensive hepatic artery injury: transcatheter arterial chemoembolization through collaterals after coil embolizatoin of gastric arteries

    Kim, Gab Choul; Yoon, Hyun Ki; Hwang, Jae Cheol; Lee, Duck Hee; Song, Ho Young; Suh, Dong Jin; Lee, Yung Sang; Chung, Young Hwa; Sung, Gyu Bo; Ko, Ki Young

    1999-01-01

    To evaluate the efficacy and safety of transcatheter arterial chemoembolization(TACE) after coil embolization of the gastroduodenal artery in hepatocellular carcinoma cases with multiple collateral arteries caused by proper hepatic artery injury. Between March 1997 and November 1998, a prospective trial of transcatheter arterial chemoembolization (TACE) was performed through collaterals from the gastroduodenal artery of 31 hepatocellular carcinoma patients with extensive proper hepatic artery injury due to repeated TACE. Among this number, 16 (group A) underwent TACE after coil embolization of the right gastric and gastroduodenal artery. The other 15 patients (group B) underwent TACE without coil embolization. The two groups had the same TNM stage and Clild-Pugh status. During the follow-up period, group A underwent additional TACE 3.3 times, and group B 2.8 times. The therapeutic effect of TACE was evaluated with computed tomography and by measuring alpha-fetoprotein levels. Complications were evaluated by means of gastrofibroscopy, laboratory data, and evaluation of the patients' clinical symptoms. The results obtained after six months and one year were compared within and between each group. At six months follow-up, CT findings had improved or were unchanged in 11 patients(69 %) in group A, and four patients(27 %) in group B(p = 0.032). In ten patients in each group, the level of alpha-fetoprotein was above 200 ng/ml. Its level was decreased in five patients(50 %) and three patients(30 %), respectively. The six-month survival rate was 81 % (13/16) in group A and 67% (10/15) in group B (p 0.43), while the one-year survival figures for these two groups were 50 % (8/16) and 20 % (3/15), respectively(p = 0.135). In group A, the CT findings were steady in five out of eight patients(63 %), while in groupB, CT findings showed that tumors with increased alpha-fetoprotein levels had increased in size and/or number. In group A, it was found that in two (33 %) of six

  11. Hepatocellular carcinoma with extensive hepatic artery injury: transcatheter arterial chemoembolization through collaterals after coil embolizatoin of gastric arteries

    Kim, Gab Choul; Yoon, Hyun Ki; Hwang, Jae Cheol; Lee, Duck Hee; Song, Ho Young; Suh, Dong Jin; Lee, Yung Sang; Chung, Young Hwa; Sung, Gyu Bo [Ulsan Univ. College of Medicine, Seoul (Korea, Republic of); Ko, Ki Young [Catholic Univ. College of Medicine, Seoul (Korea, Republic of)

    1999-09-01

    To evaluate the efficacy and safety of transcatheter arterial chemoembolization(TACE) after coil embolization of the gastroduodenal artery in hepatocellular carcinoma cases with multiple collateral arteries caused by proper hepatic artery injury. Between March 1997 and November 1998, a prospective trial of transcatheter arterial chemoembolization (TACE) was performed through collaterals from the gastroduodenal artery of 31 hepatocellular carcinoma patients with extensive proper hepatic artery injury due to repeated TACE. Among this number, 16 (group A) underwent TACE after coil embolization of the right gastric and gastroduodenal artery. The other 15 patients (group B) underwent TACE without coil embolization. The two groups had the same TNM stage and Clild-Pugh status. During the follow-up period, group A underwent additional TACE 3.3 times, and group B 2.8 times. The therapeutic effect of TACE was evaluated with computed tomography and by measuring alpha-fetoprotein levels. Complications were evaluated by means of gastrofibroscopy, laboratory data, and evaluation of the patients' clinical symptoms. The results obtained after six months and one year were compared within and between each group. At six months follow-up, CT findings had improved or were unchanged in 11 patients(69 %) in group A, and four patients(27 %) in group B(p = 0.032). In ten patients in each group, the level of alpha-fetoprotein was above 200 ng/ml. Its level was decreased in five patients(50 %) and three patients(30 %), respectively. The six-month survival rate was 81 % (13/16) in group A and 67% (10/15) in group B (p 0.43), while the one-year survival figures for these two groups were 50 % (8/16) and 20 % (3/15), respectively(p = 0.135). In group A, the CT findings were steady in five out of eight patients(63 %), while in groupB, CT findings showed that tumors with increased alpha-fetoprotein levels had increased in size and/or number. In group A, it was found that in two (33 %) of six

  12. Features of Hepatitis in Hepatitis-associated Aplastic Anemia: Clinical and Histopathologic Study.

    Patel, Kalyani R; Bertuch, Alison; Sasa, Ghadir S; Himes, Ryan W; Wu, Hao

    2017-01-01

    Hepatitis-associated aplastic anemia (HAA) is a rare variant of aplastic anemia in which patients present with severe pancytopenia after an episode of acute hepatitis. The marrow failure is often rapid, severe, and usually fatal if untreated. The preceding hepatitis is largely under-studied. Retrospective study of the clinical and histopathologic features of hepatitis in pediatric patients who subsequently developed aplastic anemia and comparison with consecutive cases of acute liver failure and random cases of autoimmune hepatitis during the same time frame. All 7 patients of HAA had significant elevations in aminotransferases and conjugated hyperbilirubinemia at initial presentation. Echoing liver function indices, cholestatic hepatitis with sinusoidal obstruction-type endothelial injury was seen histomorphologically. Autoimmune hepatitis serology such as anti-F-actin, anti-liver/kidney microsome, and hypergammaglobulinemia was negative in all patients. Five of 7 patients (71.4%) had, however, elevated antinuclear antibody, all with a speckled pattern. Hepatitis virus serology was negative in all patients. By immunohistochemical staining, the lobular CD8/CD4 lymphocyte ratio was markedly elevated in all of the initial samples with significant reduction in this ratio (P = 0.03) in 3 patients post treatment (ursodiol, antibiotics, and/or immunosuppressive therapy). Hepatitis preceding HAA is characterized by marked elevation of aminotransferases, conjugated hyperbilirubinemia, elevated antinuclear antibody with a speckled pattern, cholestatic hepatitis with sinusoidal obstruction morphology, and CD8 dominant lobular infiltrates. The present study suggests HAA may result from cytotoxic T-cell-mediated sinusoidal endothelial and hepatocytic injury.

  13. Stem cells in sepsis and acute lung injury.

    Cribbs, Sushma K; Matthay, Michael A; Martin, Greg S

    2010-12-01

    Sepsis and acute lung injury continue to be major causes of morbidity and mortality worldwide despite advances in our understanding of pathophysiology and the discovery of new management strategies. Recent investigations show that stem cells may be beneficial as prognostic biomarkers and novel therapeutic strategies in these syndromes. This article reviews the potential use of endogenous adult tissue-derived stem cells in sepsis and acute lung injury as prognostic markers and also as exogenous cell-based therapy. A directed systematic search of the medical literature using PubMed and OVID, with particular emphasis on the time period after 2002, was done to evaluate topics related to 1) the epidemiology and pathophysiology of sepsis and acute lung injury; and 2) the definition, characterization, and potential use of stem cells in these diseases. DATA SYNTHESIS AND FINDINGS: When available, preferential consideration was given to prospective nonrandomized clinical and preclinical studies. Stem cells have shown significant promise in the field of critical care both for 1) prognostic value and 2) treatment strategies. Although several recent studies have identified the potential benefit of stem cells in sepsis and acute lung injury, further investigations are needed to more completely understand stem cells and their potential prognostic and therapeutic value.

  14. Melatonin mitigates neomycin-induced hair cell injury in zebrafish.

    Oh, Kyoung Ho; Rah, Yoon Chan; Hwang, Kyu Ho; Lee, Seung Hoon; Kwon, Soon Young; Cha, Jae Hyung; Choi, June

    2017-10-01

    Ototoxicity due to medications, such as aminoglycosides, is irreversible, and free radicals in the inner ear are assumed to play a major role. Because melatonin has an antioxidant property, we hypothesize that it might mitigate hair cell injury by aminoglycosides. The objective of this study was to evaluate whether melatonin has an alleviative effect on neomycin-induced hair cell injury in zebrafish (Danio rerio). Various concentrations of melatonin were administered to 5-day post-fertilization zebrafish treated with 125 μM neomycin for 1 h. Surviving hair cells within four neuromasts were compared with that of a control group. Apoptosis was assessed via terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. The changes of ultrastructure were confirmed using a scanning electron microscope. Melatonin alleviated neomycin-induced hair cell injury in neuromasts (neomycin + melatonin 100 μM: 13.88 ± 0.91 cells, neomycin only: 7.85 ± 0.90 cells; n = 10, p melatonin for 1 h in SEM findings. Melatonin is effective in alleviating aminoglycoside-induced hair cell injury in zebrafish. The results of this study demonstrated that melatonin has the potential to reduce apoptosis induced by aminoglycosides in zebrafish.

  15. Defibrotide for the treatment of hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation.

    Corbacioglu, Selim; Kernan, Nancy; Lehmann, Leslie; Brochstein, Joel; Revta, Carolyn; Grupp, Stephan; Martin, Paul; Richardson, Paul G

    2012-06-01

    Hepatic veno-occlusive disease (VOD) is a serious complication of stem cell transplantation in children. VOD is characterized by rapid weight gain, hepatomegaly, hyperbilirubinemia and ascites. The pathogenesis of VOD is thought to involve chemotherapy and radiation-induced damage to the sinusoidal endothelium, resulting in endothelial injury, microthrombosis, subendothelial damage and cytokine activation. These processes lead to concomitant progressive hepatocellular dysfunction and subsequent fluid retention and renal impairment. Severe VOD is typically associated with multiorgan failure and high mortality. A number of possible strategies for the prevention and/or treatment of VOD in children have been investigated. The most promising agent to date is defibrotide, a novel polydeoxyribonucleotide with fibrinolytic properties but no major bleeding risk. Numerous studies, including Phase II/III trials, have shown clinical benefit in pediatric patients with the use of defibrotide treatment and prophylaxis. This review discusses VOD in children and focuses on therapeutic options, including defibrotide, in this patient population.

  16. Burn injury suppresses human dermal dendritic cell and Langerhans cell function

    van den Berg, Linda M.; de Jong, Marein A. W. P.; Witte, Lot de; Ulrich, Magda M. W.; Geijtenbeek, Teunis B. H.

    2011-01-01

    Human skin contains epidermal Langerhans cells (LCs) and dermal dendritic cells (DCs) that are key players in induction of adaptive immunity upon infection. After major burn injury, suppressed adaptive immunity has been observed in patients. Here we demonstrate that burn injury affects adaptive

  17. A rare case of hepatic T-cell rich B-cell lymphoma (TCRBCL) in a juvenile dog.

    Chung, Tae-Ho; Lamm, Catherine; Choi, Young-Chul; Lee, Jung-Woo; Yu, Dohyeon; Choi, Ul-Soo

    2014-10-01

    A 7-month-old castrated male French Bull dog was presented with vomiting, lethargy, anorexia and weight loss of 2 weeks duration. The patient's history and clinical manifestations of suspected hepatopathy were subjected to ultrasonography, radiography, biochemical investigations and cytology of hepatic lesion. The cytologic impression was hepatic lymphoma, which was later confirmed by histopathology. The neoplastic cells were strongly diffusely immunoreactive for PAX5, but not immunoreactive for CD3, and B lymphocyte specific clonal proliferation was detected using by assay of antigen receptor rearrangement. Large numbers of immunoreactive mature non-neoplastic lymphocytes were admixed with the neoplastic cell population. Therefore, the immunohistochemical results were definitively consistent with a T-cell rich B-cell lymphoma (TCRBCL). This is the first description of a hepatic TCRBCL in a juvenile dog showing a poor response to aggressive chemotherapy.

  18. Addressing liver fibrosis with Liposomes targeted to hepatic stellate cells

    Adrian, Joanna E.; Poelstra, Klaas; Kamps, Jan A. A. M.

    2007-01-01

    Liver fibrosis is a chronic disease that results from hepatitis B and C infections, alcohol abuse or metabolic and genetic disorders. Ultimately, progression of fibrosis leads to cirrhosis, a stage of the disease characterized by failure of the normal liver functions. Currently, the treatment of

  19. Effects of treatment with Maraviroc a CCR5 inhibitor on a human hepatic stellate cell line.

    Coppola, Nicola; Perna, Angelica; Lucariello, Angela; Martini, Salvatore; Macera, Margherita; Carleo, Maria A; Guerra, Germano; Esposito, Vincenzo; De Luca, Antonio

    2018-08-01

    After an acute liver damage, tissue regeneration repairs lesions with degradation of deposed fibrotic material, while mechanisms of tissue restoration are persistently activated following several repeated injuries, inducing deposition of extracellular matrix. (ECM). Factors responsible for ECM remodeling have been identified in a pathway involving a family of zinc-dependent enzyme matrix metalloproteinases (MMPs), together with tissue inhibitor of metalloproteinases (TIMPs). Recent experimental models suggested a role of CCR5 receptor in the genesis of liver fibrosis. Drawing from these background we decided to evaluate the effects of the treatment with the CCR5 inhibitor Maraviroc on LX-2, a human hepatic stellate cell line (HSC). Treatment with Maraviroc resulted in a block in S phase of LX-2 cells with increased expression levels of cyclin D1 and p21 while the expression of p53 was reduced. Treatment with Maraviroc was also able to block the accumulation of fibrillar collagens and extracellular matrix proteins (ECM), as demonstrated by the decrease of specific markers as Collagen type I, α-SMA, and TGF-β1. In addition we observed a down regulation of both metalloproteins (MMP-2, MMP-9), used for the degradation of the extracellular matrix and their inhibitors (TIMP-1, TIMP-2). The identification of a compound that may modulate the dynamic of liver fibrosis could be crucial in all chronic liver diseases. Maraviroc could play an important role because, in addition to its own anti-HIV activity, it could reduce the release of pro-inflammatory citokynes implicated in liver fibrogenesis. © 2018 Wiley Periodicals, Inc.

  20. Hepatitis E virus infection and acute non-traumatic neurological injury: A prospective multicentre study

    Dalton, H.R.; Eijk, J.J.J. van; Cintas, P.; Madden, R.G.; Jones, C.; Webb, G.W.; Norton, B.; Pique, J.; Lutgens, S.; Devooght-Johnson, N.; Woolson, K.; Baker, J.; Saunders, M.; Househam, L.; Griffiths, J.; Abravanel, F.; Izopet, J.; Kamar, N.; Alfen, N. van; Engelen, B.G.M. van; Hunter, J.G.; Eijk, A.A. van der; Bendall, R.P.; McLean, B.N.; Jacobs, B.C.

    2017-01-01

    BACKGROUND & AIMS: Hepatitis E virus (HEV) has been associated with a number of neurological syndromes, but causality has not yet been established. The aim of this study was to explore the relationship between HEV and neurological illness by prospective HEV testing of patients presenting with acute

  1. Synergistic protective effect of picrorhiza with honey in acetaminophen induced hepatic injury.

    Gupta, Prashant; Tripathi, Alok; Agrawal, Tripti; Narayan, Chandradeo; Singh, B M; Kumar, Mohan; Kumar, Arvind

    2016-08-01

    Rhizome of picrorhiza along with honey prevents hepatic damage and cure the acetaminophen (paracetamol) induced hepatotoxicity by modulating the activity of hepatic enzymes. Here, we studied the in vivo effects of Picrorhiza kurroa and honey on acetaminophen induced hepatotoxicity Balb/c mice model. Hepatic histopathological observations of acetaminophen fed (day-6) group showed more congestion, hemorrhage, necrosis, distorted hepatic architecture and nuclear inclusion. Such damages were recompensed to normal by picrorhiza or honey alone or both in combinations. We observed increased activity of SGPT and SGOT in injured liver tissues, and that too was compensated to normal with picrorhiza or honey alone or both in combinations. We observed 1.27 and 1.23-fold enhanced activity of SGPT in serum and liver lysate, respectively while SGOT showed 1.66 and 1.11 fold enhanced activity. These two enzymes are signature enzymes of liver damage. Thus, our results support that honey may be used with drug picrorhiza due to its synergistic role to enhance hepatoprotective and hepatoregenerative ability along with allopathic drugs to mitigate the hepatotoxic effects.

  2. Leptin is essential for the hepatic fibrogenic response to chronic liver injury

    Leclercq, IA; Farrell, GC; Schriemer, R; Robertson, GR

    Background/Aims: Obesity is associated with hyperleptinemia and is also a risk factor for fibrosis and severity of fibrosis in several chronic liver diseases. The correlation between increased leptin, obesity and hepatic fibrosis prompted us to hypothesise that leptin has profibrogenic effects on

  3. Association of serum retinoic acid with hepatic steatosis and liver injury in nonalcoholic fatty liver disease.

    Liu, Yan; Chen, Hongen; Wang, Jingjing; Zhou, Wenjing; Sun, Ruifang; Xia, Min

    2015-07-01

    Retinoic acid (RA), an active metabolite of vitamin A (retinol), has been implicated in the regulation of lipid metabolism and hepatic steatosis in animal models. However, the relation between RA and liver histology in patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is unknown. This study aimed at examining the association of RA with NAFLD and NASH in Chinese subjects. Serum RA concentration was determined by ELISA in 41 control subjects, 45 patients with NAFLD, and 38 patients with NASH. The associations of RA with adiposity, serum glucose, lipid profiles, and markers of liver damage were studied. Moreover, both mRNA and protein levels of retinoic X receptor α (RXRα) in the liver were analyzed in subjects with different degrees of hepatic steatosis. Serum RA concentrations in patients with NAFLD (1.42 ± 0.47 ng/mL) and NASH (1.14 ± 0.26 ng/mL) were significantly lower than those in control subjects (2.70 ± 0.52 ng/mL) (P hepatic steatosis. Both serum RA concentrations and RXRα mRNA levels were inversely correlated with intrahepatic triglyceride content (r = -0.700, P hepatic lipid metabolism and insulin resistance. This trial was registered at clinicaltrials.gov as NCT01940263. © 2015 American Society for Nutrition.

  4. 3D hepatic cultures simultaneously maintain primary hepatocyte and liver sinusoidal endothelial cell phenotypes.

    Yeonhee Kim

    Full Text Available Developing in vitro engineered hepatic tissues that exhibit stable phenotype is a major challenge in the field of hepatic tissue engineering. However, the rapid dedifferentiation of hepatic parenchymal (hepatocytes and non-parenchymal (liver sinusoidal endothelial, LSEC cell types when removed from their natural environment in vivo remains a major obstacle. The primary goal of this study was to demonstrate that hepatic cells cultured in layered architectures could preserve or potentially enhance liver-specific behavior of both cell types. Primary rat hepatocytes and rat LSECs (rLSECs were cultured in a layered three-dimensional (3D configuration. The cell layers were separated by a chitosan-hyaluronic acid polyelectrolyte multilayer (PEM, which served to mimic the Space of Disse. Hepatocytes and rLSECs exhibited several key phenotypic characteristics over a twelve day culture period. Immunostaining for the sinusoidal endothelial 1 antibody (SE-1 demonstrated that rLSECs cultured in the 3D hepatic model maintained this unique feature over twelve days. In contrast, rLSECs cultured in monolayers lost their phenotype within three days. The unique stratified structure of the 3D culture resulted in enhanced heterotypic cell-cell interactions, which led to improvements in hepatocyte functions. Albumin production increased three to six fold in the rLSEC-PEM-Hepatocyte cultures. Only rLSEC-PEM-Hepatocyte cultures exhibited increasing CYP1A1/2 and CYP3A activity. Well-defined bile canaliculi were observed only in the rLSEC-PEM-Hepatocyte cultures. Together, these data suggest that rLSEC-PEM-Hepatocyte cultures are highly suitable models to monitor the transformation of toxins in the liver and their transport out of this organ. In summary, these results indicate that the layered rLSEC-PEM-hepatocyte model, which recapitulates key features of hepatic sinusoids, is a potentially powerful medium for obtaining comprehensive knowledge on liver metabolism

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

    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 (ptraining slightly improved hepatic damage. PMID:26000905

  6. Cell injury, retrodifferentiation and the cancer treatment paradox.

    Uriel, José

    2015-09-01

    This "opinion article" is an attempt to take an overview of some significant changes that have happened in our understanding of cancer status during the last half century and its evolution under the progressive influence of molecular biology. As an active worker in cancer research and developmental biology during most of this period, I would like to comment briefly on these changes and to give my critical appreciation of their outcome as it affects our knowledge of cancer development as well as the current treatment of the disease. A recall of my own contribution to the subject is also included. Two subjects are particularly developed: cell injury and cell-killing therapies. Cell injury, whatever its origin, has acquired the status of a pivotal event for the initiation of cancer emergence. It is postulated that cell injury, a potential case of cellular death, may also be the origin of a process of stepwise cell reversion (retrodifferentiation or retroprogrammation) leading, by division, mature or stem cells to progressive immaturity. The genetic instability and mutational changes that accompanies this process of cell injury and rejuvenation put normal cells in a status favourable to neoplastic transformation or may evolve cancer cells toward clones with higher malignant potentiality. Thus, cell injury suggests lifestyle as the major upstream initiator of cancer development although this not exclude randomness as an unavoidable contributor to the disease. Cell-killing agents (mainly cytotoxic drugs and radiotherapy) are currently used to treat cancer. At the same time, it is agreed that agents with high cell injury potential (ultraviolet light, ionising radiations, tobacco, environmental pollutants, etc.) contribute to the emergence of malignant tumours. This represents a real paradox. In spite of the progress accomplished in cancer survival, one is tempted to suggest that we have very few chances of really cure cancer as long as we continue to treat malignancies

  7. RNAi screen reveals a role of SPHK2 in dengue virus-mediated apoptosis in hepatic cell lines.

    Atthapan Morchang

    Full Text Available Hepatic dysfunction is a feature of dengue virus (DENV infection. Hepatic biopsy specimens obtained from fatal cases of DENV infection show apoptosis, which relates to the pathogenesis of DENV infection. However, how DENV induced liver injury is not fully understood. In this study, we aim to identify the factors that influence cell death by employing an apoptosis-related siRNA library screening. Our results show the effect of 558 gene silencing on caspase 3-mediated apoptosis in DENV-infected Huh7 cells. The majority of genes that contributed to apoptosis were the apoptosis-related kinase enzymes. Tumor necrosis factor superfamily member 12 (TNFSF12, and sphingosine kinase 2 (SPHK2, were selected as the candidate genes to further validate their influences on DENV-induced apoptosis. Transfection of siRNA targeting SPHK2 but not TNFSF12 genes reduced apoptosis determined by Annexin V/PI staining. Knockdown of SPHK2 did not reduce caspase 8 activity; however, did significantly reduce caspase 9 activity, suggesting its involvement of SPHK2 in the intrinsic pathway of apoptosis. Treatment of ABC294649, an inhibitor of SPHK2, reduced the caspase 3 activity, suggesting the involvement of its kinase activity in apoptosis. Knockdown of SPHK2 significantly reduced caspase 3 activity not only in DENV-infected Huh7 cells but also in DENV-infected HepG2 cells. Our results were consistent across all of the four serotypes of DENV infection, which supports the pro-apoptotic role of SPHK2 in DENV-infected liver cells.

  8. The Effect of Emodin-Assisted Early Enteral Nutrition on Severe Acute Pancreatitis and Secondary Hepatic Injury

    Gang Wang

    2007-01-01

    Full Text Available Severe acute pancreatitis (SAP characterized by atrocious progression and numerous complications often leads to a high mortality rate due to hypermetabolism, systemic inflammatory response syndrome (SIRS, and multiple organs dysfunction syndrome (MODS. Studies have revealed that both early enteral nutrition (EEN and emodin are potent agents in the management of SAP. However, whether the combined strategy is rational and more effective than either one alone remains unknown. In this regard, Wistar rats were treated with emodin-assisted EEN (EAEEN through enteral nutrient tubes after induction of SAP by retrograde infusion of 5.0% sodium taurocholate into the common pancreatic duct. Serum levels of amylase, tumor necrosis factor-alpha (TNF-α, angiotensin II (AngII, maleic dialdehyde (MDA, glutamic pyruvic transaminase (ALT, glutamic oxaloacetic transaminase (AST and C-reactive protein (CRP, intestinal secretory IgA (SIgA, pancreatic and hepatic myeloperoxidase (MPO activity as well as plasma levels of D-lactate and endotoxin were measured. In addition, pathologic alterations of pancreas and liver were observed microscopically. We found that EAEEN could significantly ameliorate these parameters and prevent pancreas and liver from serious damage. In conclusion, Our results indicated that EAEEN could exert beneficial effects on experimental SAP and obviously abate the severity of secondary hepatic injury. The combined strategy was safe and more effective than either one alone in the acute stage of SAP. This study also provided an experimental base for the clinical treatment of SAP patients with EAEEN.

  9. A Prominent Role of Interleukin-18 in Acetaminophen-Induced Liver Injury Advocates Its Blockage for Therapy of Hepatic Necroinflammation

    Malte Bachmann

    2018-02-01

    Full Text Available Acetaminophen [paracetamol, N-acetyl-p-aminophenol (APAP]-induced acute liver injury (ALI not only remains a persistent clinical challenge but likewise stands out as well-characterized paradigmatic model of drug-induced liver damage. APAP intoxication associates with robust hepatic necroinflammation the role of which remains elusive with pathogenic but also pro-regenerative/-resolving functions being ascribed to leukocyte activation. Here, we shine a light on and put forward a unique role of the interleukin (IL-1 family member IL-18 in experimental APAP-induced ALI. Indeed, amelioration of disease as previously observed in IL-18-deficient mice was further substantiated herein by application of the IL-18 opponent IL-18-binding protein (IL-18BPd:Fc to wild-type mice. Data altogether emphasize crucial pathological action of this cytokine in APAP toxicity. Adding recombinant IL-22 to IL-18BPd:Fc further enhanced protection from liver injury. In contrast to IL-18, the role of prototypic pro-inflammatory IL-1 and tumor necrosis factor-α is controversially discussed with lack of effects or even protective action being repeatedly reported. A prominent detrimental function for IL-18 in APAP-induced ALI as proposed herein should relate to its pivotal role for hepatic expression of interferon-γ and Fas ligand, both of which aggravate APAP toxicity. As IL-18 serum levels increase in patients after APAP overdosing, targeting IL-18 may evolve as novel therapeutic option in those hard-to-treat patients where standard therapy with N-acetylcysteine is unsuccessful. Being a paradigmatic experimental model of ALI, current knowledge on ill-fated properties of IL-18 in APAP intoxication likewise emphasizes the potential of this cytokine to serve as therapeutic target in other entities of inflammatory liver diseases.

  10. Statin-induced liver injury in an area endemic for hepatitis B virus infection: risk factors and outcome analysis.

    Wang, Li Yueh; Huang, Yi-Shin; Perng, Chin-Lin; Huang, Bryan; Lin, Han-Chieh

    2016-09-01

    Statin-induced liver injury (SILI) is quite rare, but may be severe. Little is known about the impact of chronic hepatitis B infection (CHBI) on SILI. We aimed to investigate the risk factors and outcome of SILI, with special reference to its interaction with CHBI. Patients with SILI were recruited from our hospital, and three-to-one drug-matched controls were randomly selected. The clinical data of the patients were then compared. A total of 108 patients with SILI and 324 controls were enrolled. The patients with SILI were both older and had a higher statin dose than the controls. There was no predilection of liver injury associated with the seven available statins. Among the SILI patients, there was no statistical difference between the baseline and peak liver enzyme tests, and latency and severity between hepatitis B carriers (n = 16) and non-carriers (n = 92). High dose of statin and age were the two independent risk factors of SILI (OR and 95% CI: 1.93, 1.08-3.35, P = 0.025, and 1.73, 1.07-2.80, P = 0.027, respectively). Permanent discontinuation of statin was noted in 50 (46.3%) patients with SILI due to severe SILI or recurrent hepatotoxicity after rechallenge of other statins. High dose of statin and old age may increase patient susceptibility to SILI; however, CHBI and abnormal baseline liver tests are not risk factors of SILI. Nonetheless, SILI is still worthy of notice, because nearly half of the overt cases discontinued statin treatment due to severe hepatotoxicity in this study. © 2016 The British Pharmacological Society.

  11. Cytomegalovirus-Driven Adaptive-Like Natural Killer Cell Expansions Are Unaffected by Concurrent Chronic Hepatitis Virus Infections

    David F. G. Malone

    2017-05-01

    Full Text Available Adaptive-like expansions of natural killer (NK cell subsets are known to occur in response to human cytomegalovirus (CMV infection. These expansions are typically made up of NKG2C+ NK cells with particular killer-cell immunoglobulin-like receptor (KIR expression patterns. Such NK cell expansion patterns are also seen in patients with viral hepatitis infection. Yet, it is not known if the viral hepatitis infection promotes the appearance of such expansions or if effects are solely attributed to underlying CMV infection. In sizeable cohorts of CMV seropositive hepatitis B virus (HBV, hepatitis C virus (HCV, and hepatitis delta virus (HDV infected patients, we analyzed NK cells for expression of NKG2A, NKG2C, CD57, and inhibitory KIRs to assess the appearance of NK cell expansions characteristic of what has been seen in CMV seropositive healthy individuals. Adaptive-like NK cell expansions observed in viral hepatitis patients were strongly associated with CMV seropositivity. The number of subjects with these expansions did not differ between CMV seropositive viral hepatitis patients and corresponding healthy controls. Hence, we conclude that adaptive-like NK cell expansions observed in HBV, HCV, and/or HDV infected individuals are not caused by the chronic hepatitis infections per se, but rather are a consequence of underlying CMV infection.

  12. Dexmedetomidine (DEX) protects against hepatic ischemia/reperfusion (I/R) injury by suppressing inflammation and oxidative stress in NLRC5 deficient mice.

    Chen, Zong; Ding, Tao; Ma, Chuan-Gen

    2017-11-18

    Hepatic ischemia/reperfusion (I/R) injury could arise as a complication of liver surgery and transplantation. No specific therapeutic strategies are available to attenuate I/R injury. NOD-, LRR-and CARD-containing 5 (NLRC5), a member of the NOD-like protein family, has been suggested to negatively regulate nuclear factor kappa B (NF-κB) through interacting with IKKα and blocking their phosphorylation. Dexmedetomidine (DEX) has been shown to attenuate liver injury. In the current study, we investigated the pre-treatment of DEX on hepatic I/R injury in wild type (WT) and NLRC5 knockout (NLRC5 -/- ) mice. Our results indicated that NLRC5 -/- showed significantly stronger histologic damage, inflammatory response, oxidative stress and apoptosis after I/R compared to the WT group of mice, indicating the protective role of NLRC5 against liver I/R injury. Importantly, I/R-induced increase of NLRC5 was reduced by DEX pre-treatment. After hepatic I/R injury, WT and NLRC5 -/- mice pre-treated with DEX exhibited attenuated histological disruption, and reduced pro-inflammatory mediators, including tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-1β and inducible nitric oxide synthase (iNOS), which was associated with the inactivated NF-κB pathway. Moreover, suppression of oxidative stress and apoptosis was observed in DEX-treated mice with I/R injury, probably through enhancing nuclear factor erythroid 2-related factor 2 (Nrf2), reducing mitogen-activated protein kinases (MAPKs) and Caspase-3/poly (ADP-ribose) polymerase (PARP) pathways. In vitro, the results were further confirmed in WT and NLRC5 -/- hepatocytes pre-treated with or without DEX. Together, the findings illustrated that lack of NLRC5 resulted in severer liver I/R injury, which could be alleviated by DEX pre-treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. 5-lipoxygenase activation is involved in the mechanisms of chronic hepatic injury in a rat model of chronic aluminum overload exposure

    Mai, Shaoshan [Department of Pharmacology, Chongqing Medical University, Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing 400016 (China); He, Qin [Department of Heptobiliary Surgery, 1st Affiliated Hospital, Chongqing Medical University, Chongqing 400016 (China); Wang, Hong; Hu, Xinyue; Luo, Ying; Yang, Yang; Kuang, Shengnan; Tian, Xiaoyan; Ma, Jie [Department of Pharmacology, Chongqing Medical University, Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing 400016 (China); Yang, Junqing, E-mail: 1139627371@qq.com [Department of Pharmacology, Chongqing Medical University, Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing 400016 (China)

    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{sup 3+} 200 mg/kg per day, 5 days a week for 20 weeks). The 5-LO inhibitor, caffeic acid (10 and 30 mg/kg), was intragastrically administered 1 h 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. - Highlights: • 5-LO signaling contributes to mechanisms of hepatotoxicity of aluminum overload. • Oxidative and inflammatory reaction involve in chonic aluminum hepatotoxicity. • 5-LO inhibitor has a protective effect on aluminum-overload liver injury. • 5-LO signaling is a potential therapeutic target for non-infection liver diseases.

  14. Stem cell extracellular vesicles and kidney injury

    Grange, Cristina; Iampietro, Corinne; Bussolati, Benedetta

    2017-01-01

    Extracellular vesicles (EVs) appear as a new promising cell-free therapy for acute and chronic renal diseases. EVs retain characteristics of the cell of origin and those derived from stem cells may mimic their regenerative properties per se. In fact, EVs contain many active molecules such as proteins and RNA species that act on target cells through different mechanisms, stimulating proliferation and angiogenesis and reducing apoptosis and inflammation. There are several reports that demonstra...

  15. Molecular Imaging in Stem Cell Therapy for Spinal Cord Injury

    Fahuan Song

    2014-01-01

    Full Text Available Spinal cord injury (SCI is a serious disease of the center nervous system (CNS. It is a devastating injury with sudden loss of motor, sensory, and autonomic function distal to the level of trauma and produces great personal and societal costs. Currently, there are no remarkable effective therapies for the treatment of SCI. Compared to traditional treatment methods, stem cell transplantation therapy holds potential for repair and functional plasticity after SCI. However, the mechanism of stem cell therapy for SCI remains largely unknown and obscure partly due to the lack of efficient stem cell trafficking methods. Molecular imaging technology including positron emission tomography (PET, magnetic resonance imaging (MRI, optical imaging (i.e., bioluminescence imaging (BLI gives the hope to complete the knowledge concerning basic stem cell biology survival, migration, differentiation, and integration in real time when transplanted into damaged spinal cord. In this paper, we mainly review the molecular imaging technology in stem cell therapy for SCI.

  16. Dihydroartemisinin alleviates bile duct ligation-induced liver fibrosis and hepatic stellate cell activation by interfering with the PDGF-βR/ERK signaling pathway.

    Chen, Qin; Chen, Lianyun; Kong, Desong; Shao, Jiangjuan; Wu, Li; Zheng, Shizhong

    2016-05-01

    Liver fibrosis represents a frequent event following chronic insult to trigger wound healing responses in the liver. Activation of hepatic stellate cells (HSCs), which is a pivotal event during liver fibrogenesis, is accompanied by enhanced expressions of a series of marker proteins and pro-fibrogenic signaling molecules. Artemisinin, a powerful antimalarial medicine, is extracted from the Chinese herb Artemisia annua L., and can inhibit the proliferation of cancer cells. Dihydroartemisinin (DHA), the major active metabolite of artemisinin, is able to attenuate lung injury and fibrosis. However, the effect of DHA on liver fibrosis remains unclear. The aim of this study was to investigate the effect of DHA on bile duct ligation-induced injury and fibrosis in rats. DHA improved the liver histological architecture and attenuated collagen deposition in the fibrotic rat liver. Experiments in vitro showed that DHA inhibited the proliferation of HSCs and arrested the cell cycle at the S checkpoint by altering several cell-cycle regulatory proteins. Moreover, DHA reduced the protein expressions of a-SMA, α1 (I) collagen and fibronectin, being associated with interference of the platelet-derived growth factor β receptor (PDGF-βR)-mediated ERK pathway. These data collectively revealed that DHA relieved liver fibrosis possibly by targeting HSCs via the PDGF-βR/ERK pathway. DHA may be a therapeutic antifibrotic agent for the treatment of hepatic fibrosis. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Computed tomographic study of 50 patients with hypodense hepatic injuries in childhood

    Pereira, Ines Minniti Rodrigues; Alvares, Beatriz Regina; Baracat, Jamal; Martins, Daniel Lahan; Pereira, Ricardo Minniti Rodrigues

    2006-01-01

    Objective: To describe the different tomographic findings in hypodense hepatic lesions in children and its differential diagnosis. Materials and methods: computed tomographic studies were obtained from 50 patients (age range: 0-16 years) with low-density liver lesions previously diagnosed by ultrasound. Images were made before and after administration of intravenous contrast medium. Image findings were analyzed and afterwards correlated with anatomopathological diagnosis. Results: forty-seven of 50 cases were confirmed, 30 by anatomopathological diagnosis. Most of then were benign lesions, hemangioma in 20%. Such lesions presented a homogeneous contrast absorption, mainly at the delayed phase, differing from malignant lesions. Metastasis was the most frequently found malignant lesion (18%). Conclusion: computed tomographic study is of great value in complementing the diagnosis of hypodense hepatic lesions in children, and must follow ultrasound diagnosis as a routine procedure. (author)

  18. Mechanism of salutary effects of astringinin on rodent hepatic injury following trauma-hemorrhage: Akt-dependent hemeoxygenase-1 signaling pathways.

    Liu, Fu-Chao; Hwang, Tsong-Long; Lau, Ying-Tung; Yu, Huang-Ping

    2011-01-01

    Astringinin can attenuate organ injury following trauma-hemorrhage, the mechanism remains unknown. Protein kinase B/hemeoxygenase-1 (Akt/HO-1) pathway exerts potent anti-inflammatory effects in various tissues. The aim of this study is to elucidate whether Akt/HO-1 plays any role in astringinin-mediated attenuation of hepatic injury following trauma-hemorrhage. For study this, male Sprague-Dawley rats underwent trauma-hemorrhage (mean blood pressure 35-40 mmHg for 90 min) followed by fluid resuscitation. A single dose of astringinin (0.3 mg/kg body weight) with or without a PI3K inhibitor (wortmannin) or a HO antagonist (chromium-mesoporphyrin) was administered during resuscitation. Various parameters were measured at 24 h post-resuscitation. Results showed that trauma-hemorrhage increased plasma aspartate and alanine aminotransferases (AST and ALT) concentrations and hepatic myeloperoxidase activity, cytokine induced neutrophil chemoattractant (CINC)-1, CINC-3, intercellular adhesion molecule-1, and interleukin-6 levels. These parameters were significantly improved in the astringinin-treated rats subjected to trauma-hemorrhage. Astringinin treatment also increased hepatic Akt activation and HO-1 expression as compared with vehicle-treated trauma-hemorrhaged rats. Co-administration of wortmannin or chromium-mesoporphyrin abolished the astringinin-induced beneficial effects on post-resuscitation pro-inflammatory responses and hepatic injury. These findings collectively suggest that the salutary effects of astringinin administration on attenuation of hepatic injury after trauma-hemorrhage are likely mediated via Akt dependent HO-1 up-regulation.

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

    Deepak Sharma

    2016-01-01

    Full Text Available 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

  20. A retinoic acid receptor β2 agonist reduces hepatic stellate cell activation in nonalcoholic fatty liver disease.

    Trasino, Steven E; Tang, Xiao-Han; Jessurun, Jose; Gudas, Lorraine J

    2016-10-01

    Hepatic stellate cells (HSCs) are an important cellular target for the development of novel pharmacological therapies to prevent and treat nonalcoholic fatty liver diseases (NAFLD). Using a high fat diet (HFD) model of NAFLD, we sought to determine if synthetic selective agonists for retinoic acid receptor β2 (RARβ2) and RARγ can mitigate HSC activation and HSC relevant signaling pathways during early stages of NAFLD, before the onset of liver injury. We demonstrate that the highly selective RARβ2 agonist, AC261066, can reduce the activation of HSCs, marked by decreased HSC expression of α-smooth muscle actin (α-SMA), in mice with HFD-induced NAFLD. Livers of HFD-fed mice treated with AC261066 exhibited reduced steatosis, oxidative stress, and expression of pro-inflammatory mediators, such as tumor necrosis factor-alpha (TNFα), interleukin 1β (IL-1β), and monocyte chemotactic protein-1 (MCP-1). Kupffer cell (macrophage) expression of transforming growth factor-β1 (TGF-β1), which plays a critical role in early HSC activation, was markedly reduced in AC261066-treated, HFD-fed mice. In contrast, HFD-fed mice treated with an RARγ agonist (CD1530) showed no decreases in steatosis, HSC activation, or Kupffer cell TGF-β1 levels. In conclusion, our data demonstrate that RARβ2 is an attractive target for development of NAFLD therapies. • Hepatic stellate cells (HSCs) are an important pharmacological target for the prevention of nonalcoholic fatty liver diseases (NAFLD). • Retinoids and retinoic acid receptors (RARs) possess favorable metabolic modulating properties. • We show that an agonist for retinoic acid receptor-β2 (RARβ2), but not RARγ, mitigates HSC activation and NAFLD.

  1. Cell Therapy in Spinal Cord Injury: a Mini- Reivew

    Soraya Mehrabi

    2013-04-01

    Full Text Available Spinal cord injury (SCI is a debilitating disease which leads to progressive functional damages. Because of limited axonal regeneration in the central nervous system, there is no or little recovery expected in the patients. Different cellular and molecular approaches were investigated in SCI animal models. Cellular transplantation of stem cells can potentially replace damaged tissue and provide a suitable microenvironment for axons to regenerate. Here, we reviewed the last approaches applied by our colleagues and others in order to improve axonal regeneration following SCI. We used different types of stem cells via different methods. First, fetal olfactory mucosa, schwann, and bone marrow stromal cells were transplanted into the injury sites in SCI models. In later studies, was applied simultaneous transplantation of stem cells with chondroitinase ABC in SCI models with the aid of nanoparticles. Using these approaches, considerable functional recovery was observed. However, considering some challenges in stem cell therapy such as rejection, infection, and development of a new cancer, our more recent strategy was application of cytokines. We observed a significant improvement in motor function of rats when stromal derived factor-1 was used to attract innate stem cells to the injury site. In conclusion, it seems that co-transplantation of different cells accompanies with other factors like enzymes and growth factors via new delivery systems may yield better results in SCI.

  2. Dynamic changes of cytotoxic T lymphocytes (CTLs, natural killer (NK cells, and natural killer T (NKT cells in patients with acute hepatitis B infection

    Liu Bo

    2011-05-01

    Full Text Available Abstract Background The goal of this study is to observe changes in HBcAg-specific cytotoxic T lymphocytes (CTLs, natural killer (NK and natural killer T (NKT cells from peripheral blood and to relate such changes on viral clearance and liver injury in patients with acute hepatitis B (AHB. Methods Dynamic profiles on the frequency of HLA-A0201-restricted HBcAg18-27 pentamer complex (MHC-Pentamer-specific CTLs and lymphocyte subsets in AHB patients were analyzed in addition to liver function tests, HBV serological markers, and HBV DNA levels. ELISPOT was used to detect interferon-gamma (INF-γ secretion in specific CTLs stimulated with known T cell epitope peptides associated with HBV surface protein, polymerase, and core protein. Results HBV-specific CTL frequencies in AHB patients were much higher than in patients with chronic hepatitis B (CHB (p +CD8+ T cell numbers in AHB patients was more than observed in the healthy control group from the first to the fourth week after admission (p = 0.008 and 0.01, respectively; the number of CD3+CD8+ T cells and frequency of HBcAg18-27-specific CTLs in AHB patients reached peak levels at the second week after admission. NK and NKT cell numbers were negatively correlated with the frequency of HBcAg-specific CTLs (r = -0.266, p = 0.05. Conclusions Patients with AHB possess a higher frequency of HBcAg-specific CTLs than CHB patients. The frequency of specific CTLs in AHB patients is correlated with HBeAg clearance indicating that HBV-specific CTLs play an important role in viral clearance and the self-limited process of the disease. Furthermore, NK and NKT cells are likely involved in the early, non-specific immune response to clear the virus.

  3. Mincle Signaling Promotes Con-A Hepatitis

    Greco, Stephanie H.; Torres-Hernandez, Alejandro; Kalabin, Aleksandr; Whiteman, Clint; Rokosh, Rae; Ravirala, Sushma; Ochi, Atsuo; Gutierrez, Johana; Salyana, Muhammad Atif; Mani, Vishnu R.; Nagaraj, Savitha V.; Deutsch, Michael; Seifert, Lena; Daley, Donnele; Barilla, Rocky; Hundeyin, Mautin; Nikifrov, Yuriy; Tejada, Karla; Gelb, Bruce E.; Katz, Steven C.; Miller, George

    2016-01-01

    Concanavalin-A (Con-A) hepatitis is regarded as a T cell-mediated model of acute liver injury. Mincle is a C-type lectin receptor (CLR) that is critical in the immune response to mycobacteria and fungi, but does not have a well-defined role in pre-clinical models of non-pathogen mediated inflammation. Since Mincle can ligate the cell death ligand SAP130, we postulated that Mincle signaling drives intrahepatic inflammation and liver injury in Con-A hepatitis. Acute liver injury was assessed in the murine Con-A hepatitis model using C57BL/6, Mincle−/−, and Dectin-1−/− mice. The role of C/EBPβ and HIF-1α signaling was assessed using selective inhibitors. We found that Mincle was highly expressed in hepatic innate inflammatory cells and endothelial cells in both mice and humans. Furthermore, sterile Mincle ligands and Mincle signaling intermediates were increased in the murine liver in Con-A hepatitis. Most significantly, Mincle deletion or blockade protected against Con-A hepatitis whereas Mincle ligation exacerbated disease. Bone marrow chimeric and adoptive transfer experiments suggested that Mincle signaling in infiltrating myeloid cells dictates disease phenotype. Conversely, signaling via other CLRs did not alter disease course. Mechanistically, we found that Mincle blockade decreased the NF-κβ related signaling intermediates, C/EBPβ and HIF-1α, both of which are necessary in macrophage-mediated inflammatory responses. Accordingly, Mincle deletion lowered production of nitrites in Con-A hepatitis and inhibition of both C/EBPβ and HIF1-α reduced the severity of liver disease. Our work implicates a novel innate immune driver of Con-A hepatitis and, more broadly, suggests a potential role for Mincle in diseases governed by sterile inflammation. PMID:27559045

  4. Mincle Signaling Promotes Con A Hepatitis.

    Greco, Stephanie H; Torres-Hernandez, Alejandro; Kalabin, Aleksandr; Whiteman, Clint; Rokosh, Rae; Ravirala, Sushma; Ochi, Atsuo; Gutierrez, Johana; Salyana, Muhammad Atif; Mani, Vishnu R; Nagaraj, Savitha V; Deutsch, Michael; Seifert, Lena; Daley, Donnele; Barilla, Rocky; Hundeyin, Mautin; Nikifrov, Yuriy; Tejada, Karla; Gelb, Bruce E; Katz, Steven C; Miller, George

    2016-10-01

    Con A hepatitis is regarded as a T cell-mediated model of acute liver injury. Mincle is a C-type lectin receptor that is critical in the immune response to mycobacteria and fungi but does not have a well-defined role in preclinical models of non-pathogen-mediated inflammation. Because Mincle can ligate the cell death ligand SAP130, we postulated that Mincle signaling drives intrahepatic inflammation and liver injury in Con A hepatitis. Acute liver injury was assessed in the murine Con A hepatitis model using C57BL/6, Mincle(-/-), and Dectin-1(-/-) mice. The role of C/EBPβ and hypoxia-inducible factor-1α (HIF-1α) signaling was assessed using selective inhibitors. We found that Mincle was highly expressed in hepatic innate inflammatory cells and endothelial cells in both mice and humans. Furthermore, sterile Mincle ligands and Mincle signaling intermediates were increased in the murine liver in Con A hepatitis. Most significantly, Mincle deletion or blockade protected against Con A hepatitis, whereas Mincle ligation exacerbated disease. Bone marrow chimeric and adoptive transfer experiments suggested that Mincle signaling in infiltrating myeloid cells dictates disease phenotype. Conversely, signaling via other C-type lectin receptors did not alter disease course. Mechanistically, we found that Mincle blockade decreased the NF-κβ-related signaling intermediates C/EBPβ and HIF-1α, both of which are necessary in macrophage-mediated inflammatory responses. Accordingly, Mincle deletion lowered production of nitrites in Con A hepatitis and inhibition of both C/EBPβ and HIF-1α reduced the severity of liver disease. Our work implicates a novel innate immune driver of Con A hepatitis and, more broadly, suggests a potential role for Mincle in diseases governed by sterile inflammation. Copyright © 2016 by The American Association of Immunologists, Inc.

  5. Artemesia annua extract prevents glyoxal-induced cell injury in ...

    Purpose: To investigate the effect of Artemesia annua extract on glyoxal-induced injury in retinal microvascular endothelial cells (HRECs). Methods: HRECs were cultured in a medium containing 500 μM glyoxal or glyoxal plus 50μM Artemesia annua extract, or in the medium alone for 24 h. Apoptosis was analysed by flow ...

  6. Antiproliferative effect of isolated isoquinoline alkaloid from Mucuna pruriens seeds in hepatic carcinoma cells.

    Kumar, Pranesh; Rawat, Atul; Keshari, Amit K; Singh, Ashok K; Maity, Siddhartha; De, Arnab; Samanta, Amalesh; Saha, Sudipta

    2016-01-01

    The present study was undertaken to investigate the antiproliferative action of isolated M1 (6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) from Mucuna pruriens seeds using human hepatic carcinoma cell line (Huh-7 cells). Initially, docking studies was performed to find out the binding affinities of M1 to caspase-3 and 8 enzymes. Later, cytotoxic action of M1 was measured by cell growth inhibition (MTT), followed by caspase-3 and 8 enzymes assay colorimetrically. Our results collectively suggested that M1 had strong binding affinity to caspase-8 in molecular modelling. M1 possessed antiproliferative activity on Huh-7 cells (EC50 = 13.97 μM) and also inhibited the action of caspase-8 enzyme, signified process of apoptosis. M1 was active against Huh-7 cells that may be useful for future hepatic cancer treatment.

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

    Xufeng Tao

    2016-07-01

    Full Text Available 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.

  8. Generation and characterization of p53 null transformed hepatic progenitor cells: oval cells give rise to hepatocellular carcinoma.

    Dumble, Melissa L; Croager, Emma J; Yeoh, George C T; Quail, Elizabeth A

    2002-03-01

    Oval cells are bipotential liver stem cells able to differentiate into hepatocytes and bile duct epithelia. In normal adult liver oval cells are quiescent, existing in low numbers around the periportal region, and proliferate following severe, prolonged liver trauma. There is evidence implicating oval cells in the development of hepatocellular carcinoma, and hence the availability of an immortalized oval cell line would be invaluable for the study of liver cell lineage differentiation and carcinogenesis. A novel approach in the generation of cell lines is the use of the p53 knockout mouse. Absence of p53 allows a cell to cycle past the normal Hayflick limit, rendering it immortalized, although subsequent genetic alterations are thought necessary for transformation. p53 knockout mice were fed a choline-deficient, ethionine-supplemented diet, previously shown to increase oval cell numbers in wild-type mice. The oval cells were isolated by centrifugal elutriation and maintained in culture. Colonies of hepatic cells were isolated and characterized with respect to phenotype, growth characteristics and tumorigenicity. Analysis of gene expression by Northern blotting and immunocytochemistry suggests they are oval-like cells by virtue of albumin and transferrin expression, as well as the oval cell markers alpha fetoprotein, M(2)-pyruvate kinase and A6. Injection into athymic nude mice shows the cell lines are capable of forming tumors which phenotypically resemble hepatocellular carcinoma. Thus, the use of p53 null hepatic cells successfully generated immortalized and tumorigenic hepatic stem cell lines. The results presented support the idea that deleting p53 allows immortalization and contributes to the transformation of the oval-like cell lines. Further, the tumorigenic status of the cell lines is direct evidence for the participation of oval cells in the formation of hepatocellular carcinoma.

  9. Duodenorenal Fistula as a Complication of Radiofrequency Ablation of Hepatic Metastasis of Renal Cell Carcinoma

    Arman Erkan

    2017-06-01

    Full Text Available Duodenorenal fistula is a rare condition. The right kidney and the second part of the duodenum are in close anatomic proximity. Although unusual, fistulae can occur between these two anatomic structures. We report a patient who presented with duodenorenal fistula after radiofrequency ablation for renal cell carcinoma and its hepatic metastasis.

  10. Bile acids induce hepatic stellate cell proliferation via activation of the epidermal growth factor receptor

    Svegliati-Baroni, G; Ridolfi, F; Hannivoort, R; Saccomanno, S; Homan, M; De Minicis, S; Jansen, PLM; Candelaresi, C; Benedetti, A; Moshage, H

    Background B Aims: Hepatic stellate cell (HSC) proliferation is a key event in the development of liver fibrosis. In many liver diseases, HSCs are exposed to inflammatory cytokines, reactive oxygen species, and bile acids. Although inflammatory cytokines and reactive oxygen species are known to

  11. Bile acids induce hepatic stellate cell proliferation via activation of the epidermal growth factor receptor

    Svegliati-Baroni, Gianluca; Ridolfi, Francesco; Hannivoort, Rebekka; Saccomanno, Stefania; Homan, Manon; de Minicis, Samuele; Jansen, Peter L. M.; Candelaresi, Cinzia; Benedetti, Antonio; Moshage, Han

    2005-01-01

    BACKGROUND & AIMS: Hepatic stellate cell (HSC) proliferation is a key event in the development of liver fibrosis. In many liver diseases, HSCs are exposed to inflammatory cytokines, reactive oxygen species, and bile acids. Although inflammatory cytokines and reactive oxygen species are known to

  12. Relationships among hepatitis C virus, hepatocellular carcinoma, and diffuse large B cell lymphoma: A case report

    Byun, Hyuk Jun; Kim, Seong Hoon [Dept. of Radiology, Daegu Fatima Hospital, Daegu (Korea, Republic of)

    2015-07-15

    Hepatitis C virus (HCV) is one of the main causes of hepatocellular carcinoma (HCC). Recent studies have reported various associations between HCV and the incidence of non-Hodgkin's lymphoma. We report the radiologic findings in a rare case of simultaneous occurrence of HCC and diffuse large B cell lymphoma in a HCV carrier.

  13. Mitochondrial and bioenergetic dysfunction in human hepatic cells infected with dengue 2 virus

    El-Bacha , Tatiana; Midlej , Victor; Silva , Ana Paula Pereira Da; Costa , Leandro Silva Da; Benchimol , Marlene; Galina , Antonio; Poian , Andrea T. Da

    2007-01-01

    Mitochondrial and bioenergetic dysfunction in human hepatic cells infected with dengue 2 virus correspondence: Corresponding author. Fax: +55 21 22708647. (El-Bacha, Tatiana) (El-Bacha, Tatiana) Laboratorio de Bioquimica de Virus, Instituto de Bioquimica Medica, Universidade Federal do Rio de Janeiro - RJ-Brasil--> , Av. Bauhinia n? 400 ? CCS Bloco H 2? andar--> , sala 22. Ilha do Governador--> ...

  14. Mesenchymal stem cells induce dermal fibroblast responses to injury

    Smith, Andria N.; Willis, Elise; Chan, Vincent T.; Muffley, Lara A.; Isik, F. Frank; Gibran, Nicole S.; Hocking, Anne M.

    2010-01-01

    Although bone marrow-derived mesenchymal stem cells have been shown to promote repair when applied to cutaneous wounds, the mechanism for this response remains to be determined. The aim of this study was to determine the effects of paracrine signaling from mesenchymal stem cells on dermal fibroblast responses to injury including proliferation, migration and expression of genes important in wound repair. Dermal fibroblasts were co-cultured with bone marrow-derived mesenchymal stem cells grown in inserts, which allowed for paracrine interactions without direct cell contact. In this co-culture model, bone marrow-derived mesenchymal stem cells regulate dermal fibroblast proliferation, migration and gene expression. When co-cultured with mesenchymal stem cells, dermal fibroblasts show increased proliferation and accelerated migration in a scratch assay. A chemotaxis assay also demonstrated that dermal fibroblasts migrate towards bone marrow-derived mesenchymal stem cells. A PCR array was used to analyze the effect of mesenchymal stem cells on dermal fibroblast gene expression. In response to mesenchymal stem cells, dermal fibroblasts up-regulate integrin alpha 7 expression and down-regulate expression of ICAM1, VCAM1 and MMP11. These observations suggest that mesenchymal stem cells may provide an important early signal for dermal fibroblast responses to cutaneous injury.

  15. Glial cell line-derived neurotrophic factor protects against high-fat diet-induced hepatic steatosis by suppressing hepatic PPAR-γ expression.

    Mwangi, Simon Musyoka; Peng, Sophia; Nezami, Behtash Ghazi; Thorn, Natalie; Farris, Alton B; Jain, Sanjay; Laroui, Hamed; Merlin, Didier; Anania, Frank; Srinivasan, Shanthi

    2016-01-15

    Glial cell line-derived neurotrophic factor (GDNF) protects against high-fat diet (HFD)-induced hepatic steatosis in mice, however, the mechanisms involved are not known. In this study we investigated the effects of GDNF overexpression and nanoparticle delivery of GDNF in mice on hepatic steatosis and fibrosis and the expression of genes involved in the regulation of hepatic lipid uptake and de novo lipogenesis. Transgenic overexpression of GDNF in liver and other metabolically active tissues was protective against HFD-induced hepatic steatosis. Mice overexpressing GDNF had significantly reduced P62/sequestosome 1 protein levels suggestive of accelerated autophagic clearance. They also had significantly reduced peroxisome proliferator-activated receptor-γ (PPAR-γ) and CD36 gene expression and protein levels, and lower expression of mRNA coding for enzymes involved in de novo lipogenesis. GDNF-loaded nanoparticles were protective against short-term HFD-induced hepatic steatosis and attenuated liver fibrosis in mice with long-standing HFD-induced hepatic steatosis. They also suppressed the liver expression of steatosis-associated genes. In vitro, GDNF suppressed triglyceride accumulation in Hep G2 cells through enhanced p38 mitogen-activated protein kinase-dependent signaling and inhibition of PPAR-γ gene promoter activity. These results show that GDNF acts directly in the liver to protect against HFD-induced cellular stress and that GDNF may have a role in the treatment of nonalcoholic fatty liver disease.

  16. Distinct populations of hepatic stellate cells in the mouse liver have different capacities for retinoid and lipid storage.

    Diana N D'Ambrosio

    Full Text Available Hepatic stellate cell (HSC lipid droplets are specialized organelles for the storage of retinoid, accounting for 50-60% of all retinoid present in the body. When HSCs activate, retinyl ester levels progressively decrease and the lipid droplets are lost. The objective of this study was to determine if the HSC population in a healthy, uninjured liver demonstrates heterogeneity in its capacity for retinoid and lipid storage in lipid droplets. To this end, we utilized two methods of HSC isolation, which leverage distinct properties of these cells, including their vitamin A content and collagen expression. HSCs were isolated either from wild type (WT mice in the C57BL/6 genetic background by flotation in a Nycodenz density gradient, followed by fluorescence activated cell sorting (FACS based on vitamin A autofluorescence, or from collagen-green fluorescent protein (GFP mice by FACS based on GFP expression from a GFP transgene driven by the collagen I promoter. We show that GFP-HSCs have: (i increased expression of typical markers of HSC activation; (ii decreased retinyl ester levels, accompanied by reduced expression of the enzyme needed for hepatic retinyl ester synthesis (LRAT; (iii decreased triglyceride levels; (iv increased expression of genes associated with lipid catabolism; and (v an increase in expression of the retinoid-catabolizing cytochrome, CYP2S1.Our observations suggest that the HSC population in a healthy, uninjured liver is heterogeneous. One subset of the total HSC population, which expresses early markers of HSC activation, may be "primed" and ready for rapid response to acute liver injury.

  17. Antiproliferative and cytotoxic effects of purple pitanga (Eugenia uniflora L.) extract on activated hepatic stellate cells.

    Denardin, Cristiane C; Parisi, Mariana M; Martins, Leo A M; Terra, Silvia R; Borojevic, Radovan; Vizzotto, Márcia; Perry, Marcos L S; Emanuelli, Tatiana; Guma, Fátima T C R

    2014-01-01

    The presence of phenolic compounds in fruit- and vegetable-rich diets has attracted researchers' attention due to their health-promoting effects. The objective of this study was to evaluate the effects of purple pitanga (Eugenia uniflora L.) extract on cell proliferation, viability, mitochondrial membrane potential, cell death and cell cycle in murine activated hepatic stellate cells (GRX). Cell viability by 3-(4,5-dimethylthiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was significantly decreased on cells treated with 50 and 100 µg ml(-1) of purple pitanga extract for 48 and 72 h, and the percentage of dead cell stained with 7-amino-actinomycin D was significantly higher in treated cells. The reduction of cell proliferation was dose dependent, and we also observed alterations on cell cycle progression. At all times studied, GRX cells treated with 50 and 100 µg ml(-1) of purple pitanga showed a significant reduction in cellular mitochondrial content as well as a decrease in mitochondrial membrane potential. Furthermore, our results indicated that purple pitanga extract induces early and late apoptosis/necrosis and necrotic death in GRX cells. This is the first report describing the antiproliferative, cytotoxic and apoptotic activity for E. uniflora fruits in hepatic stellate cells. The present study provides a foundation for the prevention and treatment of liver fibrosis, and more studies will be carried to elucidate this effect. Copyright © 2013 John Wiley & Sons, Ltd.

  18. Induced Pluripotent Stem Cell Therapies for Cervical Spinal Cord Injury

    Doulames, Vanessa M.; Plant, Giles W.

    2016-01-01

    Cervical-level injuries account for the majority of presented spinal cord injuries (SCIs) to date. Despite the increase in survival rates due to emergency medicine improvements, overall quality of life remains poor, with patients facing variable deficits in respiratory and motor function. Therapies aiming to ameliorate symptoms and restore function, even partially, are urgently needed. Current therapeutic avenues in SCI seek to increase regenerative capacities through trophic and immunomodulatory factors, provide scaffolding to bridge the lesion site and promote regeneration of native axons, and to replace SCI-lost neurons and glia via intraspinal transplantation. Induced pluripotent stem cells (iPSCs) are a clinically viable means to accomplish this; they have no major ethical barriers, sources can be patient-matched and collected using non-invasive methods. In addition, the patient’s own cells can be used to establish a starter population capable of producing multiple cell types. To date, there is only a limited pool of research examining iPSC-derived transplants in SCI—even less research that is specific to cervical injury. The purpose of the review herein is to explore both preclinical and clinical recent advances in iPSC therapies with a detailed focus on cervical spinal cord injury. PMID:27070598

  19. Stem Cells: New Hope For Spinal Cord Injury

    Gazdic Marina

    2015-03-01

    Full Text Available Stem cell therapy offers several attractive strategies for spinal cord repair. The regenerative potential of pluripotent stem cells was confirmed in an animal model of Spinal Cord Injury (SCI; nevertheless, optimized growth and differentiation protocols along with reliable safety assays should be established prior to the clinical application of hESCs and iPSCs. Th e therapeutic effects of mesenchymal stem cells (MSCs in SCI result from neurotrophin secretion, angiogenesis, and antiinflammatory actions. Several preclinical SCI studies have reported that the occurrence of axonal extension, remyelination and neuroprotection occur after the transplantation of olfactory ensheathing cells (OECs. The transplantation of neural stem cells NSCs (NSCs promotes partial functional improvement after SCI because of their potential to differentiate into neurons, oligodendrocytes, and astrocytes. The ideal source of stem cells for safe and efficient cell-based therapy for SCI remains a challenging issue that requires further investigation.

  20. Obstructive renal injury: from fluid mechanics to molecular cell biology.

    Ucero, Alvaro C; Gonçalves, Sara; Benito-Martin, Alberto; Santamaría, Beatriz; Ramos, Adrian M; Berzal, Sergio; Ruiz-Ortega, Marta; Egido, Jesus; Ortiz, Alberto

    2010-04-22

    Urinary tract obstruction is a frequent cause of renal impairment. The physiopathology of obstructive nephropathy has long been viewed as a mere mechanical problem. However, recent advances in cell and systems biology have disclosed a complex physiopathology involving a high number of molecular mediators of injury that lead to cellular processes of apoptotic cell death, cell injury leading to inflammation and resultant fibrosis. Functional studies in animal models of ureteral obstruction using a variety of techniques that include genetically modified animals have disclosed an important role for the renin-angiotensin system, transforming growth factor-β1 (TGF-β1) and other mediators of inflammation in this process. In addition, high throughput techniques such as proteomics and transcriptomics have identified potential biomarkers that may guide clinical decision-making.

  1. Primary hepatic peripheral T-cell lymphoma mimicking hepatocellular carcinoma: a case report.

    Lee, Jisun; Park, Kil Sun; Kang, Min Ho; Kim, Yook; Son, Seung-Myoung; Choi, Hanlim; Choi, Jae-Woon; Ryu, Dong Hee

    2017-08-01

    Peripheral T-cell lymphomas (PTCLs) are aggressive neoplasms which may involve the liver. The imaging manifestations of hepatic lymphoma are highly variable and show overlapping appearances of numerous other hepatic diseases. As the management and prognosis of lymphoma differ markedly from those of other malignant diseases, prompt diagnosis and early effective treatment are very important. Here, we report an atypical case of primary PTCL not otherwise specified involving the liver that exhibited a solitary hepatic mass mimicking hepatocellular carcinoma (HCC) on CT. Liver biopsy is not commonly recommended in highly suspicious cases of HCC. However, in a patient without risk factors for HCC, consideration of other diagnostic possibilities is required and needle biopsy may be a more rational choice. An imaging approach, based on a careful review of clinical and laboratory findings is essential to prevent false-positive diagnosis of HCC and subsequent invasive treatment.

  2. Syngeneic peripheral blood stem cell transplantation with immunosuppression for hepatitis-associated severe aplastic anemia

    Aleksandar Savic

    2010-12-01

    Full Text Available Hepatitis-associated aplastic anemia occurs in up to 10% of all aplastic anemia cases. Syngeneic bone marrow transplantation is rare in patients with severe aplastic anemia and usually requires pre-transplant conditioning to provide engraftment. We report on a 29-year-old male patient with hepatitis-associated severe aplastic anemia who had a series of severe infectious conditions before transplantation, including tracheal inflammation. Life-threatening bleeding, which developed after bronchoscopy, was successfully treated with activated recombinant factor VII and platelet transfusions. Syngeneic peripheral blood stem cell transplantation using immunosuppressive treatment with antithymocyte globulin and cyclosporin A without high-dose pre-transplant conditioning was performed, followed by complete hematologic and hepatic recovery.

  3. Study on the peripheral dendritic cell function in patients with chronic hepatitis B

    Chen Ruihai; Chen Miaotian; Li Rui; Zheng Jiashui

    2007-01-01

    Objective: To study the effect of peripheral dendritic cell function on the clinical course and anti-viral treatment in patients with chronic hepatitis B. Methods: Dendritic cells (DCs) were cultured from peripheral blood mononuclear cells (PBMC) and surface markers (phenotype) examined with flow-cytometry in 71 patients with chronic hepatitis B, 17 chronic HBV carriers and 42 controls. Those patients with positive HBV-DNA (57/71) were treated with lamivudine or interferon-α and DCs reexamined after completion of treatment. Results: The expression of DCs phenotypes CD1a and CD86 in chronic hepatitis B patients and chronic carriers were significantly lower than those in controls (P<0.05 or P<0.01). Among the 71 patients, CD1a, CD40, CD80 and CD86 expressions in the 57 HBV - DNA positive patients were all lower than those in the 14 HBV-DNA negative patients, but the difference was significant only in the case of CD86 (P<0.05). After a course of lamivudine treatment (six months, 38 patients), only CD40 expression was significantly increased, but both CD40 and CD86 expressions were significantly higher than those before treatment in the 19 patients treated with interferon-α. Conclusion: DCs function impairment could be demonstrated in patients with chronic hepatitis B, especially in those with positive HBV-DNA. Lamivudine or interferon-α treatment could improve the DCs function. (authors)

  4. Cell culture system of a hepatitis C genotype 3a and 2a chimera

    2015-01-01

    A robust and genetically stable cell culture system for Hepatitis C Virus (HCV) genotype 3a is provided. A genotype 3a/2a (S52/JFH1) recombinant containing the structural genes (Core, E1, E2), p7 and NS2 of strain S52 was constructed and characterized in Huh7.5 cells. S52/JFH1 and J6/JFH viruses ...

  5. Sortilin 1 Loss-of-Function Protects Against Cholestatic Liver Injury by Attenuating Hepatic Bile Acid Accumulation in Bile Duct Ligated Mice.

    Li, Jibiao; Woolbright, Benjamin L; Zhao, Wen; Wang, Yifeng; Matye, David; Hagenbuch, Bruno; Jaeschke, Hartmut; Li, Tiangang

    2018-01-01

    Sortilin 1 (Sort1) is an intracellular trafficking receptor that mediates protein sorting in the endocytic or secretory pathways. Recent studies revealed a role of Sort1 in the regulation of cholesterol and bile acid (BA) metabolism. This study further investigated the role of Sort1 in modulating BA detoxification and cholestatic liver injury in bile duct ligated mice. We found that Sort1 knockout (KO) mice had attenuated liver injury 24 h after bile duct ligation (BDL), which was mainly attributed to less bile infarct formation. Sham-operated Sort1 KO mice had about 20% larger BA pool size than sham-operated wildtype (WT) mice, but 24 h after BDL Sort1 KO mice had significantly attenuated hepatic BA accumulation and smaller BA pool size. After 14 days BDL, Sort1 KO mice showed significantly lower hepatic BA concentration and reduced expression of inflammatory and fibrotic marker genes, but similar degree of liver fibrosis compared with WT mice. Unbiased quantitative proteomics revealed that Sort1 KO mice had increased hepatic BA sulfotransferase 2A1, but unaltered phase-I BA metabolizing cytochrome P450s or phase-III BA efflux transporters. Consistently, Sort1 KO mice showed elevated plasma sulfated taurocholate after BDL. Finally, we found that liver Sort1 was repressed after BDL, which may be due to BA activation of farnesoid x receptor. In conclusion, we report a role of Sort1 in the regulation of hepatic BA detoxification and cholestatic liver injury in mice. The mechanisms underlying increased hepatic BA elimination in Sort1 KO mice after BDL require further investigation. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  6. Branched-chain amino acids alleviate hepatic steatosis and liver injury in choline-deficient high-fat diet induced NASH mice.

    Honda, Takashi; Ishigami, Masatoshi; Luo, Fangqiong; Lingyun, Ma; Ishizu, Yoji; Kuzuya, Teiji; Hayashi, Kazuhiko; Nakano, Isao; Ishikawa, Tetsuya; Feng, Guo-Gang; Katano, Yoshiaki; Kohama, Tomoya; Kitaura, Yasuyuki; Shimomura, Yoshiharu; Goto, Hidemi; Hirooka, Yoshiki

    2017-04-01

    For successful treatment for nonalcoholic steatohepatitis (NASH), it may be important to treat the individual causative factors. At present, however, there is no established treatment for this disease. Branched-chain amino acids (BCAAs) have been used to treat patients with decompensated cirrhosis. In order to elucidate the mechanisms responsible for the effects of BCAAs on hepatic steatosis and disease progression, we investigated the effects of BCAA supplementation in mice fed a choline-deficient high-fat diet (CDHF), which induces NASH. Male mice were divided into four groups that received (1) choline-sufficient high fat (HF) diet (HF-control), (2) HF plus 2% BCAA in drinking water (HF-BCAA), (3) CDHF diet (CDHF-control), or (4) CDHF-BCAA for 8weeks. We monitored liver injury, hepatic steatosis and cholesterol, gene expression related to lipid metabolism, and hepatic fat accumulation. Serum alanine aminotransferase (ALT) levels and hepatic triglyceride (TG) were significantly elevated in CDHF-control relative to HF-control. Liver histopathology revealed severe steatosis, inflammation, and pericellular fibrosis in CDHF-control, confirming the NASH findings. Serum ALT levels and hepatic TG and lipid droplet areas were significantly lower in CDHF-BCAA than in CDHF-control. Gene expression and protein level of fatty acid synthase (FAS), which catalyzes the final step in fatty acid biosynthesis, was significantly decreased in CDHF-BCAA than in CDHF-control (PBCAA was significantly lower than those of CDHF-control. BCAA can alleviate hepatic steatosis and liver injury associated with NASH by suppressing FAS gene expression and protein levels. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Ionone Derivatives from the Mycelium of Phellinus linteus and the Inhibitory Effect on Activated Rat Hepatic Stellate Cells

    Shiow-Chyn Huang

    2016-05-01

    Full Text Available Three new γ-ionylideneacetic acid derivatives, phellinulins A–C (1–3, were characterized from the mycelium extract of Phellinus linteus. The chemical structures were established based on the spectroscopic analysis. In addition, phellinulin A (1 was subjected to the examination of effects on activated rat hepatic stellate cells and exhibited significant inhibition of hepatic fibrosis.

  8. Identification of valid reference genes for microRNA expression studies in a hepatitis B virus replicating liver cell line

    Jacobsen, Kari Stougaard; Nielsen, Kirstine Overgaard; Nordmann Winther, Thilde

    2016-01-01

    expressed microRNAs with liver-specific target genes in plasma from children with chronic hepatitis B. To further understand the biological role of these microRNAs in the pathogenesis of chronic hepatitis B, we have used the human liver cell line HepG2, with and without HBV replication, after transfection...

  9. Hepatic leukemia factor promotes resistance to cell death: Implications for therapeutics and chronotherapy

    Waters, Katrina M.; Sontag, Ryan L.; Weber, Thomas J.

    2013-01-01

    Physiological variation related to circadian rhythms and aberrant gene expression patterns are believed to modulate therapeutic efficacy, but the precise molecular determinants remain unclear. Here we examine the regulation of cell death by hepatic leukemia factor (HLF), which is an output regulator of circadian rhythms and is aberrantly expressed in human cancers, using an ectopic expression strategy in JB6 mouse epidermal cells and human keratinocytes. Ectopic HLF expression inhibited cell death in both JB6 cells and human keratinocytes, as induced by serum-starvation, tumor necrosis factor alpha and ionizing radiation. Microarray analysis indicates that HLF regulates a complex multi-gene transcriptional program encompassing upregulation of anti-apoptotic genes, downregulation of pro-apoptotic genes, and many additional changes that are consistent with an anti-death program. Collectively, our results demonstrate that ectopic expression of HLF, an established transcription factor that cycles with circadian rhythms, can recapitulate many features associated with circadian-dependent physiological variation. - Highlights: ► Circadian-dependent physiological variation impacts therapeutic efficacy. ► Hepatic leukemia factor inhibits cell death and is a candidate circadian factor. ► Hepatic leukemia factor anti-death program is conserved in murine and human cells. ► Transcriptomics indicates the anti-death program results from a systems response

  10. Modeling Inborn Errors of Hepatic Metabolism Using Induced Pluripotent Stem Cells.

    Pournasr, Behshad; Duncan, Stephen A

    2017-11-01

    Inborn errors of hepatic metabolism are because of deficiencies commonly within a single enzyme as a consequence of heritable mutations in the genome. Individually such diseases are rare, but collectively they are common. Advances in genome-wide association studies and DNA sequencing have helped researchers identify the underlying genetic basis of such diseases. Unfortunately, cellular and animal models that accurately recapitulate these inborn errors of hepatic metabolism in the laboratory have been lacking. Recently, investigators have exploited molecular techniques to generate induced pluripotent stem cells from patients' somatic cells. Induced pluripotent stem cells can differentiate into a wide variety of cell types, including hepatocytes, thereby offering an innovative approach to unravel the mechanisms underlying inborn errors of hepatic metabolism. Moreover, such cell models could potentially provide a platform for the discovery of therapeutics. In this mini-review, we present a brief overview of the state-of-the-art in using pluripotent stem cells for such studies. © 2017 American Heart Association, Inc.

  11. Novel Radiolytic Rotenone Derivative, Rotenoisin B with Potent Anti-Carcinogenic Activity in Hepatic Cancer Cells

    Srilatha Badaboina

    2015-07-01

    Full Text Available Rotenone, isolated from roots of derris plant, has been shown to possess various biological activities, which lead to attempting to develop a potent drug against several diseases. However, recent studies have demonstrated that rotenone has the potential to induce several adverse effects such as a neurodegenerative disease. Radiolytic transformation of the rotenone with gamma-irradiation created a new product, named rotenoisin B. The present work was designed to investigate the anticancer activity of rotenoisin B with low toxicity and its molecular mechanism in hepatic cancer cells compared to a parent compound, rotenone. Our results showed rotenoisin B inhibited hepatic cancer cells’ proliferation in a dose dependent manner and increased in apoptotic cells. Interestingly, rotenoisin B showed low toxic effects on normal cells compared to rotenone. Mitochondrial transmembrane potential has been decreased, which leads to cytochrome c release. Down regulation of anti-apoptotic Bcl-2 levels as well as the up regulation of proapoptotic Bax levels were observed. The cleaved PARP (poly ADP-ribose polymerase level increased as well. Moreover, phosphorylation of extracellular signal regulated kinase (ERK and p38 slightly up regulated and intracellular reactive oxygen species (ROS increased as well as cell cycle arrest predominantly at the G2/M phase observed. These results suggest that rotenoisin B might be a potent anticancer candidate similar to rotenone in hepatic cancer cells with low toxicity to normal cells even at high concentrations compared to rotenone.

  12. Hepatic leukemia factor promotes resistance to cell death: Implications for therapeutics and chronotherapy

    Waters, Katrina M. [Computational Biology and Bioinformatics, Pacific Northwest National Laboratory, Richland, WA 99354 (United States); Sontag, Ryan L. [Systems Toxicology Groups, Pacific Northwest National Laboratory, Richland, WA 99354 (United States); Weber, Thomas J., E-mail: Thomas.Weber@pnl.gov [Systems Toxicology Groups, Pacific Northwest National Laboratory, Richland, WA 99354 (United States)

    2013-04-15

    Physiological variation related to circadian rhythms and aberrant gene expression patterns are believed to modulate therapeutic efficacy, but the precise molecular determinants remain unclear. Here we examine the regulation of cell death by hepatic leukemia factor (HLF), which is an output regulator of circadian rhythms and is aberrantly expressed in human cancers, using an ectopic expression strategy in JB6 mouse epidermal cells and human keratinocytes. Ectopic HLF expression inhibited cell death in both JB6 cells and human keratinocytes, as induced by serum-starvation, tumor necrosis factor alpha and ionizing radiation. Microarray analysis indicates that HLF regulates a complex multi-gene transcriptional program encompassing upregulation of anti-apoptotic genes, downregulation of pro-apoptotic genes, and many additional changes that are consistent with an anti-death program. Collectively, our results demonstrate that ectopic expression of HLF, an established transcription factor that cycles with circadian rhythms, can recapitulate many features associated with circadian-dependent physiological variation. - Highlights: ► Circadian-dependent physiological variation impacts therapeutic efficacy. ► Hepatic leukemia factor inhibits cell death and is a candidate circadian factor. ► Hepatic leukemia factor anti-death program is conserved in murine and human cells. ► Transcriptomics indicates the anti-death program results from a systems response.

  13. Differential effects of arsenic trioxide on chemosensitization in human hepatic tumor and stellate cell lines

    Rangwala Fatima

    2012-09-01

    Full Text Available Abstract Background Crosstalk between malignant hepatocytes and the surrounding peritumoral stroma is a key modulator of hepatocarcinogenesis and therapeutic resistance. To examine the chemotherapy resistance of these two cellular compartments in vitro, we evaluated a well-established hepatic tumor cell line, HepG2, and an adult hepatic stellate cell line, LX2. The aim was to compare the chemosensitization potential of arsenic trioxide (ATO in combination with sorafenib or fluorouracil (5-FU, in both hepatic tumor cells and stromal cells. Methods Cytotoxicity of ATO, 5-FU, and sorafenib, alone and in combination against HepG2 cells and LX2 cells was measured by an automated high throughput cell-based proliferation assay. Changes in survival and apoptotic signaling pathways were analyzed by flow cytometry and western blot. Gene expression of the 5-FU metabolic enzyme, thymidylate synthase, was analyzed by real time PCR. Results Both HepG2 and LX2 cell lines were susceptible to single agent sorafenib and ATO at 24 hr (ATO IC50: 5.3 μM in LX2; 32.7 μM in HepG2; Sorafenib IC50: 11.8 μM in LX2; 9.9 μM in HepG2. In contrast, 5-FU cytotoxicity required higher concentrations and prolonged (48–72 hr drug exposure. Concurrent ATO and 5-FU treatment of HepG2 cells was synergistic, leading to increased cytotoxicity due in part to modulation of thymidylate synthase levels by ATO. Concurrent ATO and sorafenib treatment showed a trend towards increased HepG2 cytotoxicity, possibly due to a significant decrease in MAPK activation in comparison to treatment with ATO alone. Conclusions ATO differentially sensitizes hepatic tumor cells and adult hepatic stellate cells to 5-FU and sorafenib. Given the importance of both of these cell types in hepatocarcinogenesis, these data have implications for the rational development of anti-cancer therapy combinations for the treatment of hepatocellular carcinoma (HCC.

  14. Differential effects of arsenic trioxide on chemosensitization in human hepatic tumor and stellate cell lines

    Rangwala, Fatima; Williams, Kevin P; Smith, Ginger R; Thomas, Zainab; Allensworth, Jennifer L; Lyerly, H Kim; Diehl, Anna Mae; Morse, Michael A; Devi, Gayathri R

    2012-01-01

    Crosstalk between malignant hepatocytes and the surrounding peritumoral stroma is a key modulator of hepatocarcinogenesis and therapeutic resistance. To examine the chemotherapy resistance of these two cellular compartments in vitro, we evaluated a well-established hepatic tumor cell line, HepG2, and an adult hepatic stellate cell line, LX2. The aim was to compare the chemosensitization potential of arsenic trioxide (ATO) in combination with sorafenib or fluorouracil (5-FU), in both hepatic tumor cells and stromal cells. Cytotoxicity of ATO, 5-FU, and sorafenib, alone and in combination against HepG2 cells and LX2 cells was measured by an automated high throughput cell-based proliferation assay. Changes in survival and apoptotic signaling pathways were analyzed by flow cytometry and western blot. Gene expression of the 5-FU metabolic enzyme, thymidylate synthase, was analyzed by real time PCR. Both HepG2 and LX2 cell lines were susceptible to single agent sorafenib and ATO at 24 hr (ATO IC 50 : 5.3 μM in LX2; 32.7 μM in HepG2; Sorafenib IC 50 : 11.8 μM in LX2; 9.9 μM in HepG2). In contrast, 5-FU cytotoxicity required higher concentrations and prolonged (48–72 hr) drug exposure. Concurrent ATO and 5-FU treatment of HepG2 cells was synergistic, leading to increased cytotoxicity due in part to modulation of thymidylate synthase levels by ATO. Concurrent ATO and sorafenib treatment showed a trend towards increased HepG2 cytotoxicity, possibly due to a significant decrease in MAPK activation in comparison to treatment with ATO alone. ATO differentially sensitizes hepatic tumor cells and adult hepatic stellate cells to 5-FU and sorafenib. Given the importance of both of these cell types in hepatocarcinogenesis, these data have implications for the rational development of anti-cancer therapy combinations for the treatment of hepatocellular carcinoma (HCC)

  15. Hepatic ischemia-reperfusion injury: roles of Ca2+ and other intracellular mediators of impaired bile flow and hepatocyte damage.

    Nieuwenhuijs, Vincent B; De Bruijn, Menno T; Padbury, Robert T A; Barritt, Gregory J

    2006-06-01

    Liver resection and liver transplantation have been successful in the treatment of liver tumors and end-stage liver disease. This success has led to an expansion in the pool of patients potentially treatable by liver surgery and, in the case of transplantation, to a shortage of liver donors. At present, there are significant numbers of potential candidates for liver resection and liver donation who have fatty livers, are aged, or have livers damaged by chemotherapy. All of these are at high risk for ischemic reperfusion (IR) injury. The aims of this review are to assess current knowledge of the clinical effectiveness of ischemic preconditioning and intermittent ischemia in reducing IR damage in liver surgery; to evaluate the use of bile flow as a sensitive indicator of IR liver damage; and to analyze the molecular mechanisms, especially intracellular Ca2+, involved in IR injury and ischemic preconditioning. It is concluded that bile flow is a sensitive indicator of IR injury. Together with reactive oxygen species (ROS) and other extracellular and intracellular signaling molecules, intracellular Ca2+ in hepatocytes plays a key role in the normal regulation of bile flow and in IR-induced injury and cell death. Ischemic preconditioning is an effective strategy to reduce IR injury but there is considerable scope for improvement, especially in patients with fatty and aged livers. The development of effective new strategies to reduce IR injury will depend on improved understanding of the molecular mechanisms involved, especially by gaining a better perspective of the relative importance of the various intrahepatocyte signaling pathways involved.

  16. Cryo-chemical decellularization of the whole liver for mesenchymal stem cells-based functional hepatic tissue engineering.

    Jiang, Wei-Cheng; Cheng, Yu-Hao; Yen, Meng-Hua; Chang, Yin; Yang, Vincent W; Lee, Oscar K

    2014-04-01

    Liver transplantation is the ultimate treatment for severe hepatic failure to date. However, the limited supply of donor organs has severely hampered this treatment. So far, great potentials of using mesenchymal stem cells (MSCs) to replenish the hepatic cell population have been shown; nevertheless, there still is a lack of an optimal three-dimensional scaffold for generation of well-transplantable hepatic tissues. In this study, we utilized a cryo-chemical decellularization method which combines physical and chemical approach to generate acellular liver scaffolds (ALS) from the whole liver. The produced ALS provides a biomimetic three-dimensional environment to support hepatic differentiation of MSCs, evidenced by expression of hepatic-associated genes and marker protein, glycogen storage, albumin secretion, and urea production. It is also found that hepatic differentiation of MSCs within the ALS is much more efficient than two-dimensional culture in vitro. Importantly, the hepatic-like tissues (HLT) generated by repopulating ALS with MSCs are able to act as functional grafts and rescue lethal hepatic failure after transplantation in vivo. In summary, the cryo-chemical method used in this study is suitable for decellularization of liver and create acellular scaffolds that can support hepatic differentiation of MSCs and be used to fabricate functional tissue-engineered liver constructs. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. Distinct subpopulations of hepatitis C virus infectious cells with different levels of intracellular hepatitis C virus core protein

    Shu-Chi Wang

    2016-10-01

    Full Text Available Chronic infection by hepatitis C virus (HCV is a major risk factor for the development of hepatocellular carcinoma (HCC. Despite the clear clinical importance of virus-associated HCC, the underlying molecular mechanisms remain largely unclarified. Oxidative stress, in particular, DNA lesions associated with oxidative damage, plays a major role in carcinogenesis, and is strongly linked to the development of many cancers, including HCC. However, in identifying hepatocytes with HCV viral RNA, estimates of the median proportion of HCV-infected hepatocytes have been found as high as 40% in patients with chronic HCV infection. In order to explore the gene alternation and association between different viral loads of HCV-infected cells, we established a method to dissect high and low viral load cells and examined the expression of DNA damage-related genes using a quantitative polymerase chain reaction array. We found distinct expression patterns of DNA damage-related genes between high and low viral load cells. This study provides a new method for future study on virus-associated gene expression research.

  18. Hepatic Encephalopathy

    Full Text Available ... Disease Type 1 (von Gierke) Hemochromatosis Hepatic Encephalopathy Hepatitis A Hepatitis B Hepatitis C Intrahepatic Cholestasis of Pregnancy ( ... Disease Type 1 (von Gierke) Hemochromatosis Hepatic Encephalopathy Hepatitis A Hepatitis B Hepatitis C Intrahepatic Cholestasis of Pregnancy ( ...

  19. Hepatic stellate cells secreted hepatocyte growth factor contributes to the chemoresistance of hepatocellular carcinoma.

    Guofeng Yu

    Full Text Available As the main source of extracellular matrix proteins in tumor stroma, hepatic stellate cells (HSCs have a great impact on biological behaviors of hepatocellular carcinoma (HCC. In the present study, we have investigated a mechanism whereby HSCs modulate the chemoresistance of hepatoma cells. We used human HSC line lx-2 and chemotherapeutic agent cisplatin to investigate their effects on human HCC cell line Hep3B. The results showed that cisplatin resistance in Hep3B cells was enhanced with LX-2 CM (cultured medium exposure in vitro as well as co-injection with LX-2 cells in null mice. Meanwhile, in presence of LX-2 CM, Hep3B cells underwent epithelial to mesenchymal transition (EMT and upregulation of cancer stem cell (CSC -like properties. Besides, LX-2 cells synthesized and secreted hepatic growth factor (HGF into the CM. HGF receptor tyrosine kinase mesenchymal-epithelial transition factor (Met was activated in Hep3B cells after LX-2 CM exposure. The HGF level of LX-2 CM could be effectively reduced by using HGF neutralizing antibody. Furthermore, depletion of HGF in LX-2 CM abolished its effects on activation of Met as well as promotion of the EMT, CSC-like features and cisplatin resistance in Hep3B cells. Collectively, secreting HGF into tumor milieu, HSCs may decrease hepatoma cells sensitization to chemotherapeutic agents by promoting EMT and CSC-like features via HGF/Met signaling.

  20. Activated NKT cells facilitated functional switch of myeloid-derived suppressor cells at inflammation sites in fulminant hepatitis mice.

    Wu, Danxiao; Shi, Yu; Wang, Cheng; Chen, Hanwen; Liu, Qiaoyun; Liu, Jianhua; Zhang, Lihuang; Wu, Yihua; Xia, Dajing

    2017-02-01

    Myeloid-derived suppressor cells (MDSCs) confer immunosuppressive properties, but their roles in fulminant hepatitis have not been well defined. In this study, we systematically examined the distribution of MDSCs in bone marrow (BM), liver and spleen, and their functional and differentiation status in an acute fulminant hepatitis mouse model induced by lipopolysaccharide and D-galactosamine (LPS-GalN). Moreover, the interaction between NKT cells and MDSCs was determined. Our study revealed that BM contained the largest pool of MDSCs during pathogenesis of fulminant hepatitis compared with liver and spleen. MDSCs in liver/spleen expressed higher levels of chemokine receptors such as CCR2, CX3CR1 and CXCR2. At inflamed tissues such as liver or spleen, activated NKT cells induced differentiation of MDSCs through cell-cell interaction, which markedly dampened the immunosuppressive effects and promoted MDSCs to produce pro-inflammatory cytokines and activate inflammatory cells. Our findings thus demonstrated an unexpected pro-inflammatory state for MDSCs, which was mediated by the activated NKT cells that precipitated the differentiation and functional evolution of these MDSCs at sites of inflammation. Copyright © 2016. Published by Elsevier GmbH.

  1. Stem cell, cytokine and plastic surgical management for radiation injuries

    Akita, Sadanori; Hirano, Akiyoshi; Akino, Kozo

    2008-01-01

    Increasing concern on systemic and local radiation injuries caused by nuclear power plant accident, therapeutic irradiation or nuclear terrorism should be treated and prevented properly for life-saving and improved wound management. We therefore reviewed our therapeutic regimens and for local radiation injuries and propose surgical methods reflecting the importance of the systemic and general conditions. For local radiation injuries, after careful and complete debridement, sequential surgeries with local flap, arterialized or perforator flap and to free flap are used when the patients' general conditions allow. Occasionally, undetermined wound margins in acute emergency radiation injuries and the regenerative surgical modalities should be attempted with temporal artificial dermis impregnated and sprayed with angiogenic factor such as basic fibroblast growth factor (bFGF) and secondary reconstruction can be a candidate for demarcation and saving the donor morbidity. Human mesenchymal stem cells (hMSCs) and adipose-derived stem cells (ADSCs), together with angiogenic and mitogenic factor of basic fibroblast growth factor (bFGF) and an artificial dermis were applied over the excised irradiated skin defect are tested for differentiation and local stimulation effects in the radiation-exposed wounds. The perforator flap and artificial dermal template with growth factor were successful for reconstruction in patients who are suffering from complex underlying disease. Patients were uneventfully treated with minimal morbidities. The hMSCs are strongly proliferative even after 20 Gy irradiation in vitro. Immediate artificial dermis application impregnated with hMSCs and bFGF over the 20 Gy irradiated skin and soft tissues demonstrated the significantly improved fat angio genesis, architected dermal reconstitution and less inflammatory epidermal recovery. Even though emergent cases are more often experienced, detailed understanding of underlying diseases and rational

  2. Stem cell, cytokine and plastic surgical management for radiation injuries

    Akita, Sadanori; Hirano, Akiyoshi [Dept. of Plastic and Reconstructive Surgery, Nagasaki (Japan); Akino, Kozo [Nagasaki Univ. (Japan). Graduate School of Biomedical Sciences, Dept. of Neuroanatomy; Ohtsuru, Akira [Nagasaki Univ. Hospital (Japan). Takashi Nagai Memorial, International Hibakusha Medical Center; Yamashita, Shunichi [Nagasaki Univ. School of Medicine (Japan). Atomic Bomb Disease Institute; World Health Organization (WHO), Nagasaki (Japan)

    2008-07-01

    Increasing concern on systemic and local radiation injuries caused by nuclear power plant accident, therapeutic irradiation or nuclear terrorism should be treated and prevented properly for life-saving and improved wound management. We therefore reviewed our therapeutic regimens and for local radiation injuries and propose surgical methods reflecting the importance of the systemic and general conditions. For local radiation injuries, after careful and complete debridement, sequential surgeries with local flap, arterialized or perforator flap and to free flap are used when the patients' general conditions allow. Occasionally, undetermined wound margins in acute emergency radiation injuries and the regenerative surgical modalities should be attempted with temporal artificial dermis impregnated and sprayed with angiogenic factor such as basic fibroblast growth factor (bFGF) and secondary reconstruction can be a candidate for demarcation and saving the donor morbidity. Human mesenchymal stem cells (hMSCs) and adipose-derived stem cells (ADSCs), together with angiogenic and mitogenic factor of basic fibroblast growth factor (bFGF) and an artificial dermis were applied over the excised irradiated skin defect are tested for differentiation and local stimulation effects in the radiation-exposed wounds. The perforator flap and artificial dermal template with growth factor were successful for reconstruction in patients who are suffering from complex underlying disease. Patients were uneventfully treated with minimal morbidities. The hMSCs are strongly proliferative even after 20 Gy irradiation in vitro. Immediate artificial dermis application impregnated with hMSCs and bFGF over the 20 Gy irradiated skin and soft tissues demonstrated the significantly improved fat angio genesis, architected dermal reconstitution and less inflammatory epidermal recovery. Even though emergent cases are more often experienced, detailed understanding of underlying diseases and rational

  3. A hot water extract of turmeric (Curcuma longa) suppresses acute ethanol-induced liver injury in mice by inhibiting hepatic oxidative stress and inflammatory cytokine production.

    Uchio, Ryusei; Higashi, Yohei; Kohama, Yusuke; Kawasaki, Kengo; Hirao, Takashi; Muroyama, Koutarou; Murosaki, Shinji

    2017-01-01

    Turmeric ( Curcuma longa ) is a widely used spice that has various biological effects, and aqueous extracts of turmeric exhibit potent antioxidant activity and anti-inflammatory activity. Bisacurone, a component of turmeric extract, is known to have similar effects. Oxidative stress and inflammatory cytokines play an important role in ethanol-induced liver injury. This study was performed to evaluate the influence of a hot water extract of C. longa (WEC) or bisacurone on acute ethanol-induced liver injury. C57BL/6 mice were orally administered WEC (20 mg/kg body weight; BW) or bisacurone (60 µg/kg BW) at 30 min before a single dose of ethanol was given by oral administration (3·0 g/kg BW). Plasma levels of aspartate aminotransferase and alanine aminotransferase were markedly increased in ethanol-treated mice, while the increase of these enzymes was significantly suppressed by prior administration of WEC. The increase of alanine aminotransferase was also significantly suppressed by pretreatment with bisacurone. Compared with control mice, animals given WEC had higher hepatic tissue levels of superoxide dismutase and glutathione, as well as lower hepatic tissue levels of thiobarbituric acid-reactive substances, TNF-α protein and IL-6 mRNA. These results suggest that oral administration of WEC may have a protective effect against ethanol-induced liver injury by suppressing hepatic oxidation and inflammation, at least partly through the effects of bisacurone.

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

    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.

  5. Expression of hepatitis C virus envelope protein 2 induces apoptosis in cultured mammalian cells

    Li-Xin Zhu; Jing Liu; You-Hua Xie; Yu-Ying Kong; Ye Ye; Chun-Lin Wang; Guang-Di Li; Yuan Wang

    2004-01-01

    AIM: To explore the role of hepatitis C virus (HCV) envelope protein 2 (E2) in the induction of apoptosis.METHODS: A carboxyterminal truncated E2 (E2-661) was transiently expressed in several cultured mammalian cell lines or stably expressed in Chinese hamster ovary (CHO)cell line. Cell proliferation was assessed by 3H thymidine uptake. Apoptosis was examined by Hoechst 33258staining, flow cytometry and DNA fragmentation analysis.RESULTS: Reduced proliferation was readily observed in the E2-661 expressing cells. These cells manifested the typical features of apoptosis, including cell shrinkage,chromatin condensation and hypodiploid genomic DNA content. Similar apoptotic cell death was observed in an E2-661 stably expressing cell line.CONCLUSION: HCV E2 can induce apoptosis in cultured mammalian cells.

  6. Treatment of chronic hepatic cirrhosis with autologous bone marrow stem cells transplantation in rabbits

    Zhu Yinghe; Xu Ke; Zhang Xitong; Han Jinling; Ding Guomin; Gao Jue

    2008-01-01

    Objective: To evaluate the feasibility of treatment for rabbit model with hepatic cirrhosis by transplantation of autologous bone marrow-derived stem cells via the hepatic artery and evaluate the effect of hepatocyte growth-promoting factors (pHGF) in the treatment of stem cells transplantation to liver cirrhosis. To provide empirical study foundation for future clinical application. Methods: Chronic hepatic cirrhosis models of rabbits were developed by subcutaneous injection with 50% CCl 4 0.2 ml/kg. Twenty-five model rabbits were randomly divided into three experimental groups, stem cells transplant group (10), stem cells transplant + pHGF group (10) and control group (5). Autologous bone marrow was harvested from fibia of each rabbit, and stem cells were disassociated using density gradient centrifugation and transplanted into liver via the hepatic artery under fluoroscopic guidance. In the stem cells transplant + pHGF group, the hepatocyte growth-promoting factor was given via intravenous injection with 2 mg/kg every other day for 20 days. Liver function tests were monitored at 4, 8,12 weeks intervals and histopathologic examinations were performed at 12 weeks following transplantation. The data were analyzed using analysis of variance Results: Following transplantation of stern cells, the liver function of rabbits improved gradually. Twelve weeks after transplantation, the activity of ALT and AST decreased from (73.0±10.6) U/L and (152.4± 22.8) U/L to (48.0±1.0) U/L and (86.7±2.1) U/L respectively; and the level of ALB and PTA increased from (27.5±1.8) g/L and 28.3% to (33.2±0.5) g/L and 44.1% respectively. The changes did not have statistically significant difference when compared to the control group (P>0.05). However, in the stem cellstransplant + pHGF group, the activity of ALT and AST decreased to (43.3±0.6) U/L and (78.7±4.0) U/L respectively and the level of ALB and PTA increased to (35.7±0.4) g/L and 50.5% respectively. The difference was

  7. The spleen as an extramedullary source of inflammatory cells responding to acetaminophen-induced liver injury

    Mandal, Mili; Gardner, Carol R.; Sun, Richard; Choi, Hyejeong; Lad, Sonali; Mishin, Vladimir; Laskin, Jeffrey D.; Laskin, Debra L.

    2016-01-01

    Macrophages have been shown to play a role in acetaminophen (APAP)-induced hepatotoxicity, contributing to both pro- and anti-inflammatory processes. In these studies, we analyzed the role of the spleen as an extramedullary source of hepatic macrophages. APAP administration (300 mg/kg, i.p.) to control mice resulted in an increase in CD11b + infiltrating Ly6G + granulocytic and Ly6G − monocytic cells in the spleen and the liver. The majority of the Ly6G + cells were also positive for the monocyte/macrophage activation marker, Ly6C, suggesting a myeloid derived suppressor cell (MDSC) phenotype. By comparison, Ly6G − cells consisted of 3 subpopulations expressing high, intermediate, and low levels of Ly6C. Splenectomy was associated with increases in mature (F4/80 + ) and immature (F4/80 − ) pro-inflammatory Ly6C hi macrophages and mature anti-inflammatory (Ly6C lo ) macrophages in the liver after APAP; increases in MDSCs were also noted in the livers of splenectomized (SPX) mice after APAP. This was associated with increases in APAP-induced expression of chemokine receptors regulating pro-inflammatory (CCR2) and anti-inflammatory (CX3CR1) macrophage trafficking. In contrast, APAP-induced increases in pro-inflammatory galectin-3 + macrophages were blunted in livers of SPX mice relative to control mice, along with hepatic expression of TNF-α, as well as the anti-inflammatory macrophage markers, FIZZ-1 and YM-1. These data demonstrate that multiple subpopulations of pro- and anti-inflammatory cells respond to APAP-induced injury, and that these cells originate from distinct hematopoietic reservoirs. - Highlights: • Multiple inflammatory cell subpopulations accumulate in the spleen and liver following acetaminophen (APAP) intoxication. • Splenectomy alters liver inflammatory cell populations responding to APAP. • Inflammatory cells accumulating in the liver in response to APAP originate from the spleen and the bone marrow. • Hepatotoxicity is reduced in

  8. The spleen as an extramedullary source of inflammatory cells responding to acetaminophen-induced liver injury

    Mandal, Mili, E-mail: milimandal@gmail.com [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Gardner, Carol R., E-mail: cgardner@pharmacy.rutgers.edu [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Sun, Richard, E-mail: fishpower52@gmail.com [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Choi, Hyejeong, E-mail: choi@eohsi.rutgers.edu [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Lad, Sonali, E-mail: sonurose92@gmail.com [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Mishin, Vladimir, E-mail: mishinv@eohsi.rutgers.edu [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Laskin, Jeffrey D., E-mail: jlaskin@eohsi.rutgers.edu [Department of Environmental and Occupational Health, School of Public Health, Rutgers University, Piscataway, NJ 08854 (United States); Laskin, Debra L., E-mail: laskin@eohsi.rutgers.edu [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States)

    2016-08-01

    Macrophages have been shown to play a role in acetaminophen (APAP)-induced hepatotoxicity, contributing to both pro- and anti-inflammatory processes. In these studies, we analyzed the role of the spleen as an extramedullary source of hepatic macrophages. APAP administration (300 mg/kg, i.p.) to control mice resulted in an increase in CD11b{sup +} infiltrating Ly6G{sup +} granulocytic and Ly6G{sup −} monocytic cells in the spleen and the liver. The majority of the Ly6G{sup +} cells were also positive for the monocyte/macrophage activation marker, Ly6C, suggesting a myeloid derived suppressor cell (MDSC) phenotype. By comparison, Ly6G{sup −} cells consisted of 3 subpopulations expressing high, intermediate, and low levels of Ly6C. Splenectomy was associated with increases in mature (F4/80{sup +}) and immature (F4/80{sup −}) pro-inflammatory Ly6C{sup hi} macrophages and mature anti-inflammatory (Ly6C{sup lo}) macrophages in the liver after APAP; increases in MDSCs were also noted in the livers of splenectomized (SPX) mice after APAP. This was associated with increases in APAP-induced expression of chemokine receptors regulating pro-inflammatory (CCR2) and anti-inflammatory (CX3CR1) macrophage trafficking. In contrast, APAP-induced increases in pro-inflammatory galectin-3{sup +} macrophages were blunted in livers of SPX mice relative to control mice, along with hepatic expression of TNF-α, as well as the anti-inflammatory macrophage markers, FIZZ-1 and YM-1. These data demonstrate that multiple subpopulations of pro- and anti-inflammatory cells respond to APAP-induced injury, and that these cells originate from distinct hematopoietic reservoirs. - Highlights: • Multiple inflammatory cell subpopulations accumulate in the spleen and liver following acetaminophen (APAP) intoxication. • Splenectomy alters liver inflammatory cell populations responding to APAP. • Inflammatory cells accumulating in the liver in response to APAP originate from the spleen and the

  9. Defibrotide for children and adults with hepatic veno-occlusive disease post hematopoietic cell transplantation.

    Corbacioglu, Selim; Richardson, Paul G

    2017-10-01

    Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a complication that is typically associated with conditioning for hematopoietic stem cell transplantation (HSCT). In patients with concomitant multi-organ dysfunction, mortality may be >80%. Recently, the European Society for Blood and Marrow Transplantation established separate criteria for diagnosis and severity of VOD/SOS for adults and children, to better reflect current understanding of the disease. Areas covered: This review provides an overview of post-HSCT hepatic VOD/SOS and defibrotide, including its pharmacological, clinical, and regulatory profile. In children and adults following HSCT, defibrotide is approved for the treatment of hepatic VOD/SOS with concomitant renal or pulmonary dysfunction in the United States and for the treatment of severe hepatic VOD/SOS in the European Union. Day +100 survival rates with defibrotide are superior to those of historical controls receiving best supportive care only, and safety profiles are similar. Expert commentary: Defibrotide appears to act through multiple mechanisms to restore thrombo-fibrinolytic balance and protect endothelial cells, and there are promising data on the use of defibrotide for VOD/SOS prophylaxis in high-risk children undergoing HSCT. An ongoing randomized controlled trial in children and adults will better assess the clinical value of defibrotide as a preventive medication.

  10. Connexin 32 and connexin 43 are involved in lineage restriction of hepatic progenitor cells to hepatocytes

    Haiyun Pei

    2017-11-01

    Full Text Available Abstract Background Bi-potential hepatic progenitor cells can give rise to both hepatocytes and cholangiocytes, which is the last phase and critical juncture in terms of sequentially hepatic lineage restriction from any kind of stem cells. If their differentiation can be controlled, it might access to functional hepatocytes to develop pharmaceutical and biotechnology industries as well as cell therapies for end-stage liver diseases. Methods In this study, we investigated the influence of Cx32 and Cx43 on hepatocyte differentiation of WB-F344 cells by in vitro gain and loss of function analyses. An inhibitor of Cx32 was also used to make further clarification. To reveal p38 MAPK pathway is closely related to Cxs, rats with 70% partial hepatectomy were injected intraperitoneally with a p38 inhibitor, SB203580. Besides, the effects of p38 MAPK pathway on differentiation of hepatoblasts isolated from fetal rat livers were evaluated by addition of SB203580 in culture medium. Results In vitro gain and loss of function analyses showed overexpression of Connexin 32 and knockdown of Connexin 43 promoted hepatocytes differentiation from hepatic progenitor cells. In addition, in vitro and ex vivo research revealed inhibition of p38 mitogen-activated protein kinase pathway can improve hepatocytes differentiation correlating with upregulation of Connexin 32 expression and downregulation of Connexin 43 expression. Conclusions Here we demonstrate that Connexins play crucial roles in facilitating differentiation of hepatic progenitors. Our work further implicates that regulators of Connexins and their related pathways might provide new insights to improve lineage restriction of stem cells to mature hepatocytes.

  11. Portal inflammation during NAFLD is frequent and associated with the early phases of putative hepatic progenitor cell activation.

    Carotti, Simone; Vespasiani-Gentilucci, Umberto; Perrone, Giuseppe; Picardi, Antonio; Morini, Sergio

    2015-11-01

    We investigated whether portal tract inflammation observed in non-alcoholic fatty liver disease (NAFLD) is associated with hepatic progenitor cell compartment activation, as thoroughly evaluated with different markers of the staminal lineage. Fifty-two patients with NAFLD were studied. NAFLD activity score, fibrosis and portal inflammation were histologically evaluated. Putative hepatic progenitor cells, intermediate hepatobiliary cells and bile ductules/interlobular bile ducts were evaluated by immunohistochemistry for cytokeratin (CK)-7, CK-19 and epithelial cell adhesion molecule (EpCAM), and a hepatic progenitor cell compartment score was derived. Hepatic stellate cell and myofibroblast activity was determined by immunohistochemistry for α-smooth muscle actin. Portal inflammation was absent in a minority of patients, mild in 40% of cases and more than mild in about half of patients, showing a strong correlation with fibrosis (r=0.76, pcells (r=0.48, pcells (r=0.6, pcell compartment activation were associated with portal inflammation by univariate analysis. In the multivariate model, the only variable independently associated with portal inflammation was hepatic progenitor cell compartment activation (OR 3.7, 95% CI 1.1 to 12.6). Portal inflammation is frequent during NAFLD and strongly associated with activation of putative hepatic progenitor cells since the first steps of their differentiation, portal myofibroblast activity and fibrosis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  12. Adenoviral overexpression of Lhx2 attenuates cell viability but does not preserve the stem cell like phenotype of hepatic stellate cells

    Genz, Berit [Institute for Experimental Surgery, Rostock University Medical Center, Rostock (Germany); Thomas, Maria [Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart (Germany); Pützer, Brigitte M. [Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock (Germany); Siatkowski, Marcin; Fuellen, Georg [Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, Rostock (Germany); Vollmar, Brigitte [Institute for Experimental Surgery, Rostock University Medical Center, Rostock (Germany); Abshagen, Kerstin, E-mail: kerstin.abshagen@uni-rostock.de [Institute for Experimental Surgery, Rostock University Medical Center, Rostock (Germany)

    2014-11-01

    Hepatic stellate cells (HSC) are well known initiators of hepatic fibrosis. After liver cell damage, HSC transdifferentiate into proliferative myofibroblasts, representing the major source of extracellular matrix in the fibrotic organ. Recent studies also demonstrate a role of HSC as progenitor or stem cell like cells in liver regeneration. Lhx2 is described as stem cell maintaining factor in different organs and as an inhibitory transcription factor in HSC activation. Here we examined whether a continuous expression of Lhx2 in HSC could attenuate their activation and whether Lhx2 could serve as a potential target for antifibrotic gene therapy. Therefore, we evaluated an adenoviral mediated overexpression of Lhx2 in primary HSC and investigated mRNA expression patterns by qRT-PCR as well as the activation status by different in vitro assays. HSC revealed a marked increase in activation markers like smooth muscle actin alpha (αSMA) and collagen 1α independent from adenoviral transduction. Lhx2 overexpression resulted in attenuated cell viability as shown by a slightly hampered migratory and contractile phenotype of HSC. Expression of stem cell factors or signaling components was also unaffected by Lhx2. Summarizing these results, we found no antifibrotic or stem cell maintaining effect of Lhx2 overexpression in primary HSC. - Highlights: • We performed adenoviral overexpression of Lhx2 in primary hepatic stellate cells. • Hepatic stellate cells expressed stem cell markers during cultivation. • Cell migration and contractility was slightly hampered upon Lhx2 overexpression. • Lhx2 overexpression did not affect stem cell character of hepatic stellate cells.

  13. Adenoviral overexpression of Lhx2 attenuates cell viability but does not preserve the stem cell like phenotype of hepatic stellate cells

    Genz, Berit; Thomas, Maria; Pützer, Brigitte M.; Siatkowski, Marcin; Fuellen, Georg; Vollmar, Brigitte; Abshagen, Kerstin

    2014-01-01

    Hepatic stellate cells (HSC) are well known initiators of hepatic fibrosis. After liver cell damage, HSC transdifferentiate into proliferative myofibroblasts, representing the major source of extracellular matrix in the fibrotic organ. Recent studies also demonstrate a role of HSC as progenitor or stem cell like cells in liver regeneration. Lhx2 is described as stem cell maintaining factor in different organs and as an inhibitory transcription factor in HSC activation. Here we examined whether a continuous expression of Lhx2 in HSC could attenuate their activation and whether Lhx2 could serve as a potential target for antifibrotic gene therapy. Therefore, we evaluated an adenoviral mediated overexpression of Lhx2 in primary HSC and investigated mRNA expression patterns by qRT-PCR as well as the activation status by different in vitro assays. HSC revealed a marked increase in activation markers like smooth muscle actin alpha (αSMA) and collagen 1α independent from adenoviral transduction. Lhx2 overexpression resulted in attenuated cell viability as shown by a slightly hampered migratory and contractile phenotype of HSC. Expression of stem cell factors or signaling components was also unaffected by Lhx2. Summarizing these results, we found no antifibrotic or stem cell maintaining effect of Lhx2 overexpression in primary HSC. - Highlights: • We performed adenoviral overexpression of Lhx2 in primary hepatic stellate cells. • Hepatic stellate cells expressed stem cell markers during cultivation. • Cell migration and contractility was slightly hampered upon Lhx2 overexpression. • Lhx2 overexpression did not affect stem cell character of hepatic stellate cells

  14. MDCT of retractor-related hepatic injury following laparoscopic surgery: Appearances, incidence, and follow-up

    Orr, K.E.; Williams, M.P.

    2014-01-01

    Aims: To investigate the postoperative computed tomography (CT) features resulting from the use of Nathanson retractors during laparoscopic upper gastro-intestinal surgery. Materials and methods: A 3-year retrospective study of 176 patients who had undergone laparoscopic upper gastro-intestinal surgery for bariatric or malignant disease was performed. Postoperative CT images [divided into early (≤30 days) and late (>30 days)] were assessed by a consultant radiologist and liver abnormalities recorded. Results: The features of a retractor injury were a hypodense lesion, abutting the liver edge, usually triangular or linear in shape. Late postoperative features included focal subcapsular retraction and associated liver atrophy. Sixty-eight percent (52/77) of patients undergoing surgery for malignancy underwent postoperative CT, compared with 11% (11/99) of those undergoing bariatric surgery. Patients with malignancy were more likely to have retraction-related liver abnormalities (14/52, 27%) at postoperative CT than those in the bariatric group (2/11, 18%). Conclusion: Retractor-related liver injuries at MDCT are common following laparoscopic upper gastro-intestinal surgery. Recognition of the characteristic triad of features, a hypodense lesion abutting the liver edge with a triangular or linear shape, should allow confident diagnosis. CT follow-up reveals that over time these lesions may disappear, remain unchanged, or result in a focal subcapsular scar with associated atrophy. - Highlights: • Large numbers of patients undergo post-op CT after upper GI laparoscopic surgery. • Retractor injuries are common in the 30 days after laparoscopic upper GI surgery. • Characteristic features are hypodense, triangular/linear lesions at the liver edge

  15. Human endometrial regenerative cells alleviate carbon tetrachloride-induced acute liver injury in mice

    Shanzheng Lu

    2016-10-01

    Full Text Available Abstract Background The endometrial regenerative cell (ERC is a novel type of adult mesenchymal stem cell isolated from menstrual blood. Previous studies demonstrated that ERCs possess unique immunoregulatory properties in vitro and in vivo, as well as the ability to differentiate into functional hepatocyte-like cells. For these reasons, the present study was undertaken to explore the effects of ERCs on carbon tetrachloride (CCl4–induced acute liver injury (ALI. Methods An ALI model in C57BL/6 mice was induced by administration of intraperitoneal injection of CCl4. Transplanted ERCs were intravenously injected (1 million/mouse into mice 30 min after ALI induction. Liver function, pathological and immunohistological changes, cell tracking, immune cell populations and cytokine profiles were assessed 24 h after the CCl4 induction. Results ERC treatment effectively decreased the CCl4-induced elevation of serum alanine aminotransferase (ALT and aspartate aminotransferase (AST activities and improved hepatic histopathological abnormalities compared to the untreated ALI group. Immunohistochemical staining showed that over-expression of lymphocyte antigen 6 complex, locus G (Ly6G was markedly inhibited, whereas expression of proliferating cell nuclear antigen (PCNA was increased after ERC treatment. Furthermore, the frequency of CD4+ and CD8+ T cell populations in the spleen was significantly down-regulated, while the percentage of splenic CD4+CD25+FOXP3+ regulatory T cells (Tregs was obviously up-regulated after ERC treatment. Moreover, splenic dendritic cells in ERC-treated mice exhibited dramatically decreased MHC-II expression. Cell tracking studies showed that transplanted PKH26-labeled ERCs engrafted to lung, spleen and injured liver. Compared to untreated controls, mice treated with ERCs had lower levels of IL-1β, IL-6, and TNF-α but higher level of IL-10 in both serum and liver. Conclusions Human ERCs protect the liver from acute injury

  16. Parvovirus B19 Associated Hepatitis

    Bihari, Chhagan; Rastogi, Archana; Saxena, Priyanka; Rangegowda, Devraj; Chowdhury, Ashok; Gupta, Nalini; Sarin, Shiv Kumar

    2013-01-01

    Parvovirus B19 infection can present with myriads of clinical diseases and syndromes; liver manifestations and hepatitis are examples of them. Parvovirus B19 hepatitis associated aplastic anemia and its coinfection with other hepatotropic viruses are relatively underrecognized, and there is sufficient evidence in the literature suggesting that B19 infections can cause a spectrum of liver diseases from elevation of transaminases to acute hepatitis to fulminant liver failure and even chronic hepatitis. It can also cause fatal macrophage activation syndrome and fibrosing cholestatic hepatitis. Parvovirus B19 is an erythrovirus that can only be replicate in pronormoblasts and hepatocytes, and other cells which have globosides and glycosphingolipids in their membrane can also be affected by direct virus injury due to nonstructural protein 1 persistence and indirectly by immune mediated injury. The virus infection is suspected in bone marrow aspiration in cases with sudden drop of hemoglobin and onset of transient aplastic anemia in immunosuppressed or immunocompetent patients and is confirmed either by IgM and IgG positive serology, PCR analysis, and in situ hybridization in biopsy specimens or by application of both. There is no specific treatment for parvovirus B19 related liver diseases, but triple therapy regimen may be effective consisting of immunoglobulin, dehydrohydrocortisone, and cyclosporine. PMID:24232179

  17. Exosomes mediate hepatitis B virus (HBV) transmission and NK-cell dysfunction

    Yang, Yinli; Han, Qiuju; Hou, Zhaohua; Zhang, Cai; Tian, Zhigang; Zhang, Jian

    2017-01-01

    Evidence suggests that exosomes can transfer genetic material between cells. However, their roles in hepatitis B virus (HBV) infection remain unclear. Here, we report that exosomes present in the sera of chronic hepatitis B (CHB) patients contained both HBV nucleic acids and HBV proteins, and transferred HBV to hepatocytes in an active manner. Notably, HBV nucleic acids were detected in natural killer (NK) cells from both CHB patients and healthy donors after exposure to HBV-positive exosomes. Through real-time fluorescence microscopy and flow cytometry, 1,1'-dioctadecyl-3,3,3',3',-tetramethylindodicarbocyanine, 4-chlorobenzenesulfnate salt (DiD)-labeled exosomes were observed to interact with NK cells and to be taken up by NK cells, which was enhanced by transforming growth factor-β treatment. Furthermore, HBV-positive exosomes impaired NK-cell functions, including interferon (IFN)-γ production, cytolytic activity, NK-cell proliferation and survival, as well as the responsiveness of the cells to poly (I:C) stimulation. HBV infection suppressed the expression of pattern-recognition receptors, especially retinoic acid inducible gene I (RIG-I), on NK cells, resulting in the dampening of the nuclear factor κB(NF-κB) and p38 mitogen-activated protein kinase pathways. Our results highlight a previously unappreciated role of exosomes in HBV transmission and NK-cell dysfunction during CHB infection. PMID:27238466

  18. Dendritic cells limit fibroinflammatory injury in nonalcoholic steatohepatitis in mice.

    Henning, Justin R; Graffeo, Christopher S; Rehman, Adeel; Fallon, Nina C; Zambirinis, Constantinos P; Ochi, Atsuo; Barilla, Rocky; Jamal, Mohsin; Deutsch, Michael; Greco, Stephanie; Ego-Osuala, Melvin; Bin-Saeed, Usama; Rao, Raghavendra S; Badar, Sana; Quesada, Juan P; Acehan, Devrim; Miller, George

    2013-08-01

    Nonalcoholic steatohepatitis (NASH) is the most common etiology of chronic liver dysfunction in the United States and can progress to cirrhosis and liver failure. Inflammatory insult resulting from fatty infiltration of the liver is central to disease pathogenesis. Dendritic cells (DCs) are antigen-presenting cells with an emerging role in hepatic inflammation. We postulated that DCs are important in the progression of NASH. We found that intrahepatic DCs expand and mature in NASH liver and assume an activated immune phenotype. However, rather than mitigating the severity of NASH, DC depletion markedly exacerbated intrahepatic fibroinflammation. Our mechanistic studies support a regulatory role for DCs in NASH by limiting sterile inflammation through their role in the clearance of apoptotic cells and necrotic debris. We found that DCs limit CD8(+) T-cell expansion and restrict Toll-like receptor expression and cytokine production in innate immune effector cells in NASH, including Kupffer cells, neutrophils, and inflammatory monocytes. Consistent with their regulatory role in NASH, during the recovery phase of disease, ablation of DC populations results in delayed resolution of intrahepatic inflammation and fibroplasia. Our findings support a role for DCs in modulating NASH. Targeting DC functional properties may hold promise for therapeutic intervention in NASH. Copyright © 2013 American Association for the Study of Liver Diseases.

  19. Dendritic Cells Limit Fibro-Inflammatory Injury in NASH

    Henning, Justin R.; Graffeo, Christopher S.; Rehman, Adeel; Fallon, Nina C.; Zambirinis, Constantinos P.; Ochi, Atsuo; Barilla, Rocky; Jamal, Mohsin; Deutsch, Michael; Greco, Stephanie; Ego-Osuala, Melvin; Saeed, Usama Bin; Rao, Raghavendra S.; Badar, Sana; Quesada, Juan P.; Acehan, Devrim; Miller, George

    2013-01-01

    Non-alcoholic steatohepatitis (NASH) is the most common etiology of chronic liver dysfunction in the United States and can progress to cirrhosis and liver failure. Inflammatory insult resulting from fatty infiltration of the liver is central to disease pathogenesis. Dendritic cells (DC) are antigen presenting cells with an emerging role in hepatic inflammation. We postulated that DC are important in the progression of NASH. We found that intrahepatic DC expand and mature in NASH liver and assume an activated immune-phenotype. However, rather than mitigating the severity of NASH, DC depletion markedly exacerbated intrahepatic fibro-inflammation. Our mechanistic studies support a regulatory role for DC in NASH by limiting sterile inflammation via their role in clearance of apoptotic cells and necrotic debris. We found that DC limit CD8+ T cell expansion and restrict Toll-like receptor expression and cytokine production in innate immune effector cells in NASH, including Kupffer cells, neutrophils, and inflammatory monocytes. Consistent with their regulatory role in NASH, during the recovery phase of disease, ablation of DC populations results in delayed resolution of intrahepatic inflammation and fibroplasia. Conclusion Our findings support a role for DC in modulating NASH. Targeting DC functional properties may hold promise for therapeutic intervention in NASH. PMID:23322710

  20. Protective effect of bioactivity guided fractions of Ziziphus jujuba Mill. root bark against hepatic injury and chronic inflammation via inhibiting inflammatory markers and oxidative stress

    Raghuram Kandimalla

    2016-09-01

    Full Text Available The tribal communities of North Eastern India rely on herbal medicine to cure various disease conditions. Ziziphus jujuba Mill. (Rhamnaceae is one of such medicinal plants used for curing liver ailments, insomnia, anemia, diarrhea, diabetic complications, cancer and loss of appetite. The present study was aimed to describe the protective ability of Z. jujuba root bark against hepatic injury and chronic inflammation. Bioactivity guided fractionation of Z. jujuba methanol extract (ZJME was performed using different solvents of increasing polarity viz. hexane (ZJHF, chloroform (ZJCF, ethyl acetate (ZJEAF, water (ZJWF and residue (ZJMR. In vitro antioxidant results revealed that both ZJME and ZJWF possess strong antioxidant activity among all the fractions and mother extract tested. Further, ZJME and ZJWF showed significant protection against CCl4 intoxicated HepG2 cell lines by means of increased cell viability and decreased LDH levels compared to control group. ZJME at 200, 400 mg/kg and ZJWF at 50, 100 mg/kg inhibited the lipid peroxidation and significantly restored the liver function markers (AST, ALT, ALP, LDH, SOD and CAT and cytokine levels (TNF-α, Il-1β and Il-10 in CCl4 induced acute liver damage in rats. All the results were comparable with standard drug silymarin which was further confirmed by histopathology analysis of liver. Similarly, inflammation and increase inflammatory cytokines levels of carrageenan induced paw edema in rats have been refurbished to normal levels on par with the standard drug indomethacin. ZJWF demonstrated potent response than ZJME in all the biological tests conducted. The results of the study signify the ability of Z. jujuba root bark as good therapeutic agent for liver toxicity and chronic inflammation.

  1. Ameliorative Effect of Gallic Acid on Cyclophosphamide-Induced Oxidative Injury and Hepatic Dysfunction in Rats

    Olayinka, Ebenezer Tunde; Ore, Ayokanmi; Ola, Olaniyi Solomon; Adeyemo, Oluwatobi Adewumi

    2015-01-01

    Cyclophosphamide (CP), a bifunctional alkylating agent used in chemotherapy has been reported to induce organ toxicity mediated by generation of reactive oxygen species and oxidative stress. Gallic acid (GA), a phenolic substance, is a natural antioxidant with proven free radical scavenging activity and offers protection against oxidative damage. This research study was designed to investigate the ameliorative effect of GA against CP-induced toxicity in rats. Twenty-five male Wistar rats (180–200 g) were randomized into five treatment groups: (A) control, (B) CP, 2 mg/kg body weight (b.w.), (C) pre-treatment with GA (20 mg/kg b.w.) for seven days followed by CP (2 mg/kg b.w.) for seven days, (D) co-treatment with GA (20 mg/kg b.w) and CP (2 mg/kg b.w.) for seven days, and (E) GA (20 mg/kg b.w.) for seven days. CP induced marked renal and hepatic damages as plasma levels of urea, creatinine, bilirubin and activities of AST, ALT, ALP and GGT were significantly elevated (p acid. PMID:29083393

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

    Celalettin Semih Kunak

    2015-01-01

    Full Text Available 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.

  3. Long-term intake of a high protein diet increases liver triacylglycerol deposition pathways and hepatic signs of injury in rats

    Diaz Rua, Ruben

    2017-04-19

    Intake of high-protein (HP) diets has increased over the last years, mainly due to their popularity for body weight control. Liver is the main organ handling ingested macronutrients and it is associated with the beginning of different pathologies. We aimed to deepen our knowledge on molecular pathways affected by long-term intake of an HP diet. We performed a transcriptome analysis on liver of rats chronically fed with a casein-rich HP diet and analyzed molecular parameters related to liver injury. Chronic increase in the dietary protein/carbohydrate ratio up-regulated processes related with amino acid uptake/metabolism and lipid synthesis, promoting a molecular environment indicative of hepatic triacylglycerol (TG) deposition. Moreover, changes in expression of genes involved in acid–base maintenance and oxidative stress indicate alterations in the pH balance due to the high acid load of the diet, which has been linked to liver/health damage. Up-regulation of immune-related genes was also observed. In concordance with changes at gene expression level, we observed increased liver TG content and increased serum markers of hepatic injury/inflammation (aspartate transaminase, C-reactive protein and TNF-alpha). Moreover, the HP diet strongly increased hepatic mRNA and protein levels of HSP90, a marker of liver injury. Thus, we show for the first time that long-term consumption of an HP diet, resulting in a high acid load, results in a hepatic transcriptome signature reflecting increased TG deposition and increased signs of health risk (increased inflammation, alterations in the acid–base equilibrium and oxidative stress). Persistence of this altered metabolic status could have unhealthy consequences.

  4. Long-term intake of a high protein diet increases liver triacylglycerol deposition pathways and hepatic signs of injury in rats

    Diaz Rua, Ruben; Keijer, Jaap; Palou, Andreu; van Schothorst, Evert M.; Oliver, Paula

    2017-01-01

    Intake of high-protein (HP) diets has increased over the last years, mainly due to their popularity for body weight control. Liver is the main organ handling ingested macronutrients and it is associated with the beginning of different pathologies. We aimed to deepen our knowledge on molecular pathways affected by long-term intake of an HP diet. We performed a transcriptome analysis on liver of rats chronically fed with a casein-rich HP diet and analyzed molecular parameters related to liver injury. Chronic increase in the dietary protein/carbohydrate ratio up-regulated processes related with amino acid uptake/metabolism and lipid synthesis, promoting a molecular environment indicative of hepatic triacylglycerol (TG) deposition. Moreover, changes in expression of genes involved in acid–base maintenance and oxidative stress indicate alterations in the pH balance due to the high acid load of the diet, which has been linked to liver/health damage. Up-regulation of immune-related genes was also observed. In concordance with changes at gene expression level, we observed increased liver TG content and increased serum markers of hepatic injury/inflammation (aspartate transaminase, C-reactive protein and TNF-alpha). Moreover, the HP diet strongly increased hepatic mRNA and protein levels of HSP90, a marker of liver injury. Thus, we show for the first time that long-term consumption of an HP diet, resulting in a high acid load, results in a hepatic transcriptome signature reflecting increased TG deposition and increased signs of health risk (increased inflammation, alterations in the acid–base equilibrium and oxidative stress). Persistence of this altered metabolic status could have unhealthy consequences.

  5. Effects of hepatic ischemia-reperfusion injury on the blood-brain barrier permeability to [14C] and [13C]sucrose.

    Miah, Mohammad K; Bickel, Ulrich; Mehvar, Reza

    2017-12-01

    Hepatic encephalopathy that is associated with severe liver failure may compromise the blood-brain barrier (BBB) integrity. However, the effects of less severe liver diseases, in the absence of overt encephalopathy, on the BBB are not well understood. The goal of the current study was to investigate the effects of hepatic ischemia-reperfusion (IR) injury on the BBB tight junction permeability to small, hydrophilic molecules using the widely used [ 14 C]sucrose and recently-proposed alternative [ 13 C]sucrose as markers. Rats were subjected to 20 min of hepatic ischemia or sham surgery, followed by 8 h of reperfusion before administration of a single bolus dose of [ 14 C] or [ 13 C]sucrose and collection of serial (0-30 min) blood and plasma and terminal brain samples. The concentrations of [ 14 C] and [ 13 C]sucrose in the samples were determined by measurement of total radioactivity (nonspecific) and LC-MS/MS (specific), respectively. IR injury significantly increased the blood, plasma, and brain concentrations of both [ 14 C] and [ 13 C]sucrose. However, when the brain concentrations were corrected for their respective area under the blood concentration-time curve, only [ 14 C]sucrose showed significantly higher (30%) BBB permeability values in the IR animals. Because [ 13 C]sucrose is a more specific BBB permeability marker, these data indicate that our animal model of hepatic IR injury does not affect the BBB tight junction permeability to small, hydrophilic molecules. Methodological differences among studies of the effects of liver diseases on the BBB permeability may confound the conclusions of such studies.

  6. Long-term intake of a high-protein diet increases liver triacylglycerol deposition pathways and hepatic signs of injury in rats.

    Díaz-Rúa, Rubén; Keijer, Jaap; Palou, Andreu; van Schothorst, Evert M; Oliver, Paula

    2017-08-01

    Intake of high-protein (HP) diets has increased over the last years, mainly due to their popularity for body weight control. Liver is the main organ handling ingested macronutrients and it is associated with the beginning of different pathologies. We aimed to deepen our knowledge on molecular pathways affected by long-term intake of an HP diet. We performed a transcriptome analysis on liver of rats chronically fed with a casein-rich HP diet and analyzed molecular parameters related to liver injury. Chronic increase in the dietary protein/carbohydrate ratio up-regulated processes related with amino acid uptake/metabolism and lipid synthesis, promoting a molecular environment indicative of hepatic triacylglycerol (TG) deposition. Moreover, changes in expression of genes involved in acid-base maintenance and oxidative stress indicate alterations in the pH balance due to the high acid load of the diet, which has been linked to liver/health damage. Up-regulation of immune-related genes was also observed. In concordance with changes at gene expression level, we observed increased liver TG content and increased serum markers of hepatic injury/inflammation (aspartate transaminase, C-reactive protein and TNF-alpha). Moreover, the HP diet strongly increased hepatic mRNA and protein levels of HSP90, a marker of liver injury. Thus, we show for the first time that long-term consumption of an HP diet, resulting in a high acid load, results in a hepatic transcriptome signature reflecting increased TG deposition and increased signs of health risk (increased inflammation, alterations in the acid-base equilibrium and oxidative stress). Persistence of this altered metabolic status could have unhealthy consequences. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Retinol metabolism in hepatic stellate cells : a new vision

    Bin Md Ajat, M.M.

    2015-01-01

    Vitamin A (all-trans-retinol) or its derivatives are involved in many physiological processes ranging from vision to cells differentiation. In mammals retinol is stored as retinyl ester (RE) and the liver is the major site for RE storage in the body. The liver is made of various cell types and REs

  8. Endogenous hepatitis C virus homolog fragments in European rabbit and hare genomes replicate in cell culture.

    Eliane Silva

    Full Text Available Endogenous retroviruses, non-retroviral RNA viruses and DNA viruses have been found in the mammalian genomes. The origin of Hepatitis C virus (HCV, the major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma in humans, remains unclear since its discovery. Here we show that fragments homologous to HCV structural and non-structural (NS proteins present in the European rabbit (Oryctolagus cuniculus and hare (Lepus europaeus genomes replicate in bovine cell cultures. The HCV genomic homolog fragments were demonstrated by RT-PCR, PCR, mass spectrometry, and replication in bovine cell cultures by immunofluorescence assay (IFA and immunogold electron microscopy (IEM using specific MAbs for HCV NS3, NS4A, and NS5 proteins. These findings may lead to novel research approaches on the HCV origin, genesis, evolution and diversity.

  9. New Approaches to Attenuated Hepatitis a Vaccine Development: Cloning and Sequencing of Cell-Culture Adapted Viral cDNA.

    1987-10-13

    after multiple passages in vivo and in vitro. J. Gen. Virol. 67, 1741- 1744. Sabin , A.B. (1985). Oral poliovirus vaccine : history of its development...IN (N NEW APPROACHES TO ATTENUATED HEPATITIS A VACCINE DEVELOPMENT: Q) CLONING AND SEQUENCING OF CELL-CULTURE ADAPTED VIRAL cDNA I ANNUAL REPORT...6ll02Bsl0 A 055 11. TITLE (Include Security Classification) New Approaches to Attenuated Hepatitis A Vaccine Development: Cloning and Sequencing of Cell

  10. A novel porcine cell culture based protocol for the propagation of hepatitis E virus

    Walter Chingwaru

    2016-08-01

    Full Text Available Objective: To present a comprehensive protocol for the processing of hepatitis E virus (HEV infected samples and propagation of the virus in primary cell cultures. Methods: Hepatitis E was extracted from porcine liver and faecal samples following standard protocols. The virus was then allowed to attach in the presence of trypsin to primary cells that included porcine and bovine intestinal epithelial cells and macrophages over a period of up to 3 h. The virus was propagated by rotational passaging through the cell cultures. Propagation was confirmed by immunoblotting. Results: We developed a comprehensive protocol to propagate HEV in porcine cell model that includes (i rotational culturing of the virus between porcine cell types, (ii pre-incubation of infected cells for 210 min, (iii use of a semi-complete cell culture medium supplemented with trypsin (0.33 µg/mL and (iv the use of simple immunoblot technique to detect the amplified virus based on the open reading frame 2/3. Conclusions: This protocol opens doors towards systematic analysis of the mechanisms that underlie the pathogenesis of HEV in vitro. Using our protocol, one can complete the propagation process within 6 to 9 d.

  11. Natural killer T (NKT) cells in autoimmune hepatitis.

    Mattner, Jochen

    2013-12-01

    Natural killer T (NKT) cells represent an innate-like lymphocyte population endowed with unique antigen recognition and tissue distribution features. Their abundance in the microvascular compartments of the liver allows NKT cells to immediately respond to lipid antigens and soluble factors circulating through the portal vein system by releasing tremendous amounts of different cytokines and chemokines. Subsequently, dependent on the nature of the lipid antigen encountered as well as the accessory signal(s) provided, NKT cells not only contribute to the maintenance of immune tolerance, but also direct adverse immune reactions locally and systemically. Focusing on their potent immunomodulatory features and their interactions with various innate and adaptive immune cells, the role of NKT cells in perpetuating the loss of liver-specific immune tolerance will be discussed. Copyright © 2013 Elsevier Ltd. All rights reserved.

  12. Donor-Dependent and Other Nondefined Factors Have Greater Influence on the Hepatic Phenotype Than the Starting Cell Type in Induced Pluripotent Stem Cell Derived Hepatocyte-Like Cells.

    Heslop, James A; Kia, Richard; Pridgeon, Christopher S; Sison-Young, Rowena L; Liloglou, Triantafillos; Elmasry, Mohamed; Fenwick, Stephen W; Mills, John S; Kitteringham, Neil R; Goldring, Chris E; Park, Bong K

    2017-05-01

    Drug-induced liver injury is the greatest cause of post-marketing drug withdrawal; therefore, substantial resources are directed toward triaging potentially dangerous new compounds at all stages of drug development. One of the major factors preventing effective screening of new compounds is the lack of a predictive in vitro model of hepatotoxicity. Primary human hepatocytes offer a metabolically relevant model for which the molecular initiating events of hepatotoxicity can be examined; however, these cells vary greatly between donors and dedifferentiate rapidly in culture. Induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells (HLCs) offer a reproducible, physiologically relevant and genotypically normal model cell; however, current differentiation protocols produce HLCs with a relatively immature phenotype. During the reprogramming of somatic cells, the epigenome undergoes dramatic changes; however, this "resetting" is a gradual process, resulting in an altered differentiation propensity, skewed toward the lineage of origin, particularly in early passage cultures. We, therefore, performed a comparison of human hepatocyte- and dermal fibroblast-derived iPSCs, assessing the impact of epigenetic memory at all stages of HLC differentiation. These results provide the first isogenic assessment of the starting cell type in human iPSC-derived HLCs. Despite a trend toward improvement in hepatic phenotype in albumin secretion and gene expression, few significant differences in hepatic differentiation capacity were found between hepatocyte and fibroblast-derived iPSCs. We conclude that the donor and inter-clonal differences have a greater influence on the hepatocyte phenotypic maturity than the starting cell type. Therefore, it is not necessary to use human hepatocytes for generating iPSC-derived HLCs. Stem Cells Translational Medicine 2017;6:1321-1331. © 2017 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of Alpha

  13. Hepatitis B virus surface antigen impairs myeloid dendritic cell function: a possible immune escape mechanism of hepatitis B virus

    Op den Brouw, Marjoleine L; Binda, Rekha S; van Roosmalen, Mark H; Protzer, Ulrike; Janssen, Harry L A; van der Molen, Renate G; Woltman, Andrea M

    2009-01-01

    Chronic hepatitis B virus (HBV) infection is the result of an inadequate immune response towards the virus. Myeloid dendritic cells (mDC) of patients with chronic HBV are impaired in their maturation and function, resulting in more tolerogenic rather than immunogenic responses, which may contribute to viral persistence. The mechanism responsible for altered mDC function remains unclear. The HBV-infected patients display large amounts of HBV particles and viral proteins in their circulation, especially the surface antigen HBsAg, which allows multiple interactions between the virus, its viral proteins and DC. To assess whether HBV directly influences mDC function, the effects of HBV and HBsAg on human mDC maturation and function were investigated in vitro. As already described for internalization of HBV by DC, the present study shows that peripheral blood-derived mDC of healthy controls also actively take up HBsAg in a time-dependent manner. Cytokine-induced maturation in the presence of HBV or HBsAg resulted in a significantly more tolerogenic mDC phenotype as demonstrated by a diminished up-regulation of costimulatory molecules and a decreased T-cell stimulatory capacity, as assessed by T-cell proliferation and interferon-γ production. In addition, the presence of HBV significantly reduced interleukin-12 production by mDC. These results show that both HBV particles and purified HBsAg have an immune modulatory capacity and may directly contribute to the dysfunction of mDC in patients with chronic HBV. The direct immune regulatory effect of HBV and circulating HBsAg particles on the function of DC can be considered as part of the mechanism by which HBV escapes immunity. PMID:18624732

  14. Radiation injuries of plasmatic membrane and lethal action of radiation on cells

    Fomenko, B S; Akoev, I G [AN SSSR, Pushchino-na-Oke. Inst. Biologicheskoj Fiziki

    1984-01-01

    Data on modification of procaryotes and eukaryotes cell injuries using preparations not penetrating into cells and also membrane-specific drugs localized in cells in a lipid phase are generalized. A conclusion is drawn that radiation injuries of plasmatic membrane of prokaryotes and eukaryotes contribute considerably to lethal action of radiation on cells.

  15. Radiation injuries of plasmatic membrane and lethal action of radiation on cells

    Fomenko, B.S.; Akoev, I.G.

    1984-01-01

    Data on modification of procaryotes and eukaryotes cell injuries using preparations not penetrating into cells and also membrane-specific drugs localized in cells in a lipid phase are generalized. A conclusion is drawn that radiation injuries of plasmatic membrane of prokaryotes and eukaryotes contribute considerably to lethal action of radiation on cells

  16. Nuclear receptor CAR (NR1I3) is essential for DDC-induced liver injury and oval cell proliferation in mouse liver.

    Yamazaki, Yuichi; Moore, Rick; Negishi, Masahiko

    2011-11-01

    The liver is endowed with the ability to regenerate hepatocytes in response to injury. When this regeneration ability is impaired during liver injury, oval cells, which are considered to be postnatal hepatic progenitors, proliferate and differentiate into hepatocytes. Here we have demonstrated that 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) activates the nuclear receptor constitutive active/androstane receptor (CAR), resulting in proliferation of oval cells in mouse liver. Activation of CAR by DDC was shown by hepatic nuclear CAR accumulation and cytochrome P450 (CYP)2B10 mRNA induction after feeding a 0.1% DDC-containing diet to Car(+/+) mice. After being fed the DDC diet, Car(+/+), but not Car(-/-) mice, developed severe liver injury and an A6 antibody-stained ductular reaction in an area around the portal tract. Oval cell proliferation was confirmed by laser capture microdissection and real-time PCR; mRNAs for the two oval cell markers epithelial cell adhesion molecule and TROP2 were specifically induced in the periportal region of DDC diet-fed Car(+/+), but not Car(-/-) mice. Although rates of both hepatocyte growth and death were initially enhanced only in DDC diet-fed Car(+/+) mice, growth was attenuated when oval cells proliferated, whereas death continued unabated. DDC-induced liver injury, which differs from other CAR activators such as phenobarbital, occurred in the periportal region where cells developed hypertrophy, accumulated porphyrin crystals and inflammation developed, all in association with the proliferation of oval cells. Thus, CAR provides an excellent experimental model for further investigations into its roles in liver regeneration, as well as the development of diseases such as hepatocellular carcinoma.

  17. Saponins, especially platycodin D, from Platycodon grandiflorum modulate hepatic lipogenesis in high-fat diet-fed rats and high glucose-exposed HepG2 cells

    Hwang, Yong Pil [Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon 305-764 (Korea, Republic of); Department of Pharmaceutical Engineering, International University of Korea, Jinju (Korea, Republic of); Choi, Jae Ho; Kim, Hyung Gyun; Khanal, Tilak; Song, Gye Young [Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon 305-764 (Korea, Republic of); Nam, Myoung Soo [College of Agriculture and Life Sciences, Chungnam National University, Daejeon (Korea, Republic of); Lee, Hyun-Sun [Molecular Cancer Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon (Korea, Republic of); Chung, Young Chul; Lee, Young Chun [Division of Food Science, International University of Korea, Jinju (Korea, Republic of); Jeong, Hye Gwang, E-mail: hgjeong@cnu.ac.kr [Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon 305-764 (Korea, Republic of)

    2013-03-01

    AMP-activated protein kinase (AMPK) plays a central role in controlling hepatic lipid metabolism through modulating the downstream acetyl CoA carboxylase (ACC) and sterol regulatory element-binding protein-1c (SREBP-1c) pathway. Saponins, particularly platycodin D, from the roots of Platycodon grandiflorum (Changkil saponins, CKS) have a variety of pharmacological properties, including antioxidant and hepatoprotective properties. The aim of this study was to investigate the effects of CKS on hepatic lipogenesis and on the expression of genes involved in lipogenesis, and the mechanisms involved. CKS attenuated fat accumulation and the induction of the lipogenic genes encoding SREBP-1c and fatty acid synthase in the livers of HFD-fed rats and in steatotic HepG2 cells. Blood biochemical analyses and histopathological examinations showed that CKS prevented liver injury. CKS and platycodin D each increased the phosphorylation of AMPK and acetyl-CoA carboxylase in HFD-fed rats and HepG2 cells. The use of specific inhibitors showed that platycodin D activated AMPK via SIRT1/CaMKKβ in HepG2 cells. This study demonstrates that CKS or platycodin D alone can regulate hepatic lipogenesis via an AMPK-dependent signalling pathway. - Highlights: ► CKS attenuated fat accumulation in HFD-fed rats and in steatotic HepG2 cells. ► CKS and its major component, platycodin D, inhibited the levels of SREBP-1 and FAS. ► CKS and platycodin D increased the phosphorylation of AMPK and ACC. ► Platycodin D activated AMPK via SIRT1/CaMKKβ in HepG2 cells.

  18. Milrinone-induced postconditioning reduces hepatic ischemia-reperfusion injury in rats: the roles of phosphatidylinositol 3-kinase and nitric oxide.

    Toyoda, Tomomi; Tosaka, Shinya; Tosaka, Reiko; Maekawa, Takuji; Cho, Sungsam; Eguchi, Susumu; Nakashima, Masahiro; Sumikawa, Koji

    2014-01-01

    Ischemic postconditioning (PostC) protects the liver against ischemia-reperfusion (IR) injury. Milrinone, a phosphodiesterase 3 inhibitor, has been reported to exhibit preconditioning properties against hepatic IR injury; however, its PostC properties remain unknown. This study investigated whether milrinone has PostC properties against hepatic IR injury and the roles of phosphatidylinositol 3-kinase (PI3K) and nitric oxide synthase (NOS). Male Wistar rats were separated into six groups: (1) group S: animals that underwent sham operation without ischemia, (2) group C: ischemia followed by reperfusion with no other intervention, (3) group M: milrinone administered immediately after reperfusion, (4) group MW: wortmannin, a PI3K inhibitor, injected before milrinone administration, (5) group MN: l-NAME, a NOS inhibitor, injected before milrinone administration, and (6) group MD, milrinone administered 30 min after reperfusion. Except for group S, all groups underwent 1 h of warm ischemia of median and left lateral lobes, followed by 5 h of reperfusion. Biochemical liver function analysis and histologic examination were performed. Serum aspartate aminotransferase, alanine aminotransferase, and lactic dehydrogenase levels, histologic damage scores, and apoptotic rate in group M were significantly lower than those in group C. The inhibition of PI3K or NOS prevented this protective effect. Milrinone administered 30 min after reperfusion did not show obvious protective effects. Milrinone-induced PostC protects against hepatic IR injury when it is administered immediately after reperfusion, and PI3K and NOS may play an important role in this protective effect. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. [Phenotypic and functional features of NK and NKT cells in chronic hepatitis B].

    Wu, Shaofei; Li, Man; Sun, Xuehua; Zhou, Zhenhua; Zhu, Xiaojun; Zhang, Xin; Gao, Yueqiu

    2015-06-01

    To detect the ratio of natural killer (NK)/natural killer T (NKT) cells in peripheral blood, the levels of NKG2D/NKG2A, interferon γ (IFN-γ) and tumor necrosis factor α (TNF-α) in patients with chronic hepatitis B (CHB). Peripheral blood mononuclear cells (PBMCs) were harvested from CHB patients. The ratio of NK/NKT cells in PBMCs and the levels of NKG2D and NKG2A were detected by flow cytometry. The expressions of intracellular IFN-γ and TNF-α were analyzed by flow cytometry after the treatment with phorbol 12-myristate 13-acetate (PMA), brefeldin A (BFA) or ionomycin in vitro. The comparison between two groups was performed by independent sample t-test. The relationship of each index to hepatitis B virus load and serum alanine aminotransferase was analyzed by Pearson correlation analysis. Compared with healthy controls, CHB patients presented with significantly decreased peripheral blood NK/NKT cell ratio and significantly elevated proportions of NKG2A+ NK and NKG2A+NKT cells, and after the treatment with PMA/BFA/ionomycin, IFN-γ+ NK and IFN-γ+ NKT cells were significantly reduced in CHB patients. NK and NKT cells showed a reduced ratio, disordered receptor expressions and decreased cytokine secretion capacity in CHB patients.

  20. Liver X receptors balance lipid stores in hepatic stellate cells through Rab18, a retinoid responsive lipid droplet protein.

    O'Mahony, Fiona; Wroblewski, Kevin; O'Byrne, Sheila M; Jiang, Hongfeng; Clerkin, Kara; Benhammou, Jihane; Blaner, William S; Beaven, Simon W

    2015-08-01

    Liver X receptors (LXRs) are determinants of hepatic stellate cell (HSC) activation and liver fibrosis. Freshly isolated HSCs from Lxrαβ(-/-) mice have increased lipid droplet (LD) size, but the functional consequences of this are unknown. Our aim was to determine whether LXRs link cholesterol to retinoid storage in HSCs and how this impacts activation. Primary HSCs from Lxrαβ(-/-) and wild-type mice were profiled by gene array during in vitro activation. Lipid content was quantified by high-performance liquid chromatography and mass spectroscopy. Primary HSCs were treated with nuclear receptor ligands, transfected with small interfering RNA and plasmid constructs, and analyzed by immunocytochemistry. Lxrαβ(-/-) HSCs have increased cholesterol and retinyl esters. The retinoid increase drives intrinsic retinoic acid receptor signaling, and activation occurs more rapidly in Lxrαβ(-/-) HSCs. We identify Rab18 as a novel retinoic acid-responsive, LD-associated protein that helps mediate stellate cell activation. Rab18 mRNA, protein, and membrane insertion increase during activation. Both Rab18 guanosine triphosphatase activity and isoprenylation are required for stellate cell LD loss and induction of activation markers. These phenomena are accelerated in Lxrαβ(-/-) HSCs, where there is greater retinoic acid flux. Conversely, Rab18 knockdown retards LD loss in culture and blocks activation, just like the functional mutants. Rab18 is also induced with acute liver injury in vivo. Retinoid and cholesterol metabolism are linked in stellate cells by the LD-associated protein Rab18. Retinoid overload helps explain the profibrotic phenotype of Lxrαβ(-/-) mice, and we establish a pivotal role for Rab18 GTPase activity and membrane insertion in wild-type stellate cell activation. Interference with Rab18 may have significant therapeutic benefit in ameliorating liver fibrosis. © 2015 by the American Association for the Study of Liver Diseases.

  1. Liver X Receptors Balance Lipid Stores in Hepatic Stellate Cells via Rab18, a Retinoid Responsive Lipid Droplet Protein

    O’Mahony, Fiona; Wroblewski, Kevin; O’Byrne, Sheila M.; Jiang, Hongfeng; Clerkin, Kara; Benhammou, Jihane; Blaner, William S.; Beaven, Simon W.

    2014-01-01

    Liver X receptors (LXRs) are determinants of hepatic stellate cell (HSC) activation and liver fibrosis. Freshly isolated HSCs from Lxrαβ−/− mice have increased lipid droplet (LD) size but the functional consequences of this are unknown. Our aim was to determine whether LXRs link cholesterol to retinoid storage in HSCs and how this impacts activation. Primary HSCs from Lxrαβ−/− and wild-type (WT) mice were profiled by gene array during in vitro activation. Lipid content was quantified by HPLC and mass spectroscopy. Primary HSCs were treated with nuclear receptor ligands, transfected with siRNA and plasmid constructs, and analyzed by immunocytochemistry. Lxrαβ−/− HSCs have increased cholesterol and retinyl esters (CEs & REs). The retinoid increase drives intrinsic retinoic acid receptor (RAR) signaling and activation occurs more rapidly in Lxrαβ−/− HSCs. We identify Rab18 as a novel retinoic acid responsive, lipid droplet associated protein that helps mediate stellate cell activation. Rab18 mRNA, protein, and membrane insertion increase during activation. Both Rab18 GTPase activity and isoprenylation are required for stellate cell lipid droplet loss and induction of activation markers. These phenomena are accelerated in the Lxrαβ−/− HSCs, where there is greater retinoic acid flux. Conversely, Rab18 knockdown retards lipid droplet loss in culture and blocks activation, just like the functional mutants. Rab18 is also induced with acute liver injury in vivo. Conclusion Retinoid and cholesterol metabolism are linked in stellate cells by the LD associated protein, Rab18. Retinoid overload helps explain the pro-fibrotic phenotype of Lxrαβ−/− mice and we establish a pivotal role for Rab18 GTPase activity and membrane insertion in wild-type stellate cell activation. Interference with Rab18 may have significant therapeutic benefit in ameliorating liver fibrosis. PMID:25482505

  2. Stem cells and their role in renal ischaemia reperfusion injury.

    Bagul, Atul; Frost, Jodie H; Drage, Martin

    2013-01-01

    Ischaemia-reperfusion injury (IRI) remains one of the leading causes of acute kidney injury (AKI). IRI is an underlying multifactorial pathophysiological process which affects the outcome in both native and transplanted patients. The high morbidity and mortality associated with IRI/AKI and disappointing results from current available clinical therapeutic approaches prompt further research. Stem cells (SC) are undifferentiated cells that can undergo both renewal and differentiation into one or more cell types which can possibly ameliorate IRI. To carry out a detailed literature analysis and construct a comprehensive literature review addressing the role of SC in AKI secondary to IRI. Evidence favouring the role of SC in renal IRI and evidence showing no benefits of SC in renal IRI are the two main aspects to be studied. The search strategy was based on an extensive search addressing MESH terms and free text terms. The majority of studies in the field of renal IRI and stem cell therapy show substantial benefits. Studies were mostly conducted in small animal models, thus underscoring the need for further pre-clinical studies in larger animal models, and results should be taken with caution. SC therapy may be promising though controversy exists in the exact mechanism. Thorough scientific exploration is required to assess mechanism, safety profile, reproducibility and methods to monitor administered SC. Copyright © 2012 S. Karger AG, Basel.

  3. Hepatic overproduction of 13-HODE due to ALOX15 upregulation contributes to alcohol-induced liver injury in mice.

    Zhang, Wenliang; Zhong, Wei; Sun, Qian; Sun, Xinguo; Zhou, Zhanxiang

    2017-08-21

    Chronic alcohol feeding causes lipid accumulation and apoptosis in the liver. This study investigated the role of bioactive lipid metabolites in alcohol-induced liver damage and tested the potential of targeting arachidonate 15-lipoxygenase (ALOX15) in treating alcoholic liver disease (ALD). Results showed that chronic alcohol exposure induced hepatocyte apoptosis in association with increased hepatic 13-HODE. Exposure of 13-HODE to Hepa-1c1c7 cells induced oxidative stress, ER stress and apoptosis. 13-HODE also perturbed proteins related to lipid metabolism. HODE-generating ALOX15 was up-regulated by chronic alcohol exposure. Linoleic acid, but not ethanol or acetaldehyde, induced ALOX15 expression in Hepa-1c1c7 cells. ALOX15 knockout prevented alcohol-induced liver damage via attenuation of oxidative stress, ER stress, lipid metabolic disorder, and cell death signaling. ALOX15 inhibitor (PD146176) treatment also significantly alleviated alcohol-induced oxidative stress, lipid accumulation and liver damage. These results demonstrated that activation of ALOX15/13-HODE circuit critically mediates the pathogenesis of ALD. This study suggests that ALOX15 is a potential molecular target for treatment of ALD.

  4. Donor‐Dependent and Other Nondefined Factors Have Greater Influence on the Hepatic Phenotype Than the Starting Cell Type in Induced Pluripotent Stem Cell Derived Hepatocyte‐Like Cells

    Heslop, James A.; Kia, Richard; Pridgeon, Christopher S.; Sison‐Young, Rowena L.; Liloglou, Triantafillos; Elmasry, Mohamed; Fenwick, Stephen W.; Mills, John S.; Kitteringham, Neil R.; Park, Bong K.

    2017-01-01

    Abstract Drug‐induced liver injury is the greatest cause of post‐marketing drug withdrawal; therefore, substantial resources are directed toward triaging potentially dangerous new compounds at all stages of drug development. One of the major factors preventing effective screening of new compounds is the lack of a predictive in vitro model of hepatotoxicity. Primary human hepatocytes offer a metabolically relevant model for which the molecular initiating events of hepatotoxicity can be examined; however, these cells vary greatly between donors and dedifferentiate rapidly in culture. Induced pluripotent stem cell (iPSC)‐derived hepatocyte‐like cells (HLCs) offer a reproducible, physiologically relevant and genotypically normal model cell; however, current differentiation protocols produce HLCs with a relatively immature phenotype. During the reprogramming of somatic cells, the epigenome undergoes dramatic changes; however, this “resetting” is a gradual process, resulting in an altered differentiation propensity, skewed toward the lineage of origin, particularly in early passage cultures. We, therefore, performed a comparison of human hepatocyte‐ and dermal fibroblast‐derived iPSCs, assessing the impact of epigenetic memory at all stages of HLC differentiation. These results provide the first isogenic assessment of the starting cell type in human iPSC‐derived HLCs. Despite a trend toward improvement in hepatic phenotype in albumin secretion and gene expression, few significant differences in hepatic differentiation capacity were found between hepatocyte and fibroblast‐derived iPSCs. We conclude that the donor and inter‐clonal differences have a greater influence on the hepatocyte phenotypic maturity than the starting cell type. Therefore, it is not necessary to use human hepatocytes for generating iPSC‐derived HLCs. Stem Cells Translational Medicine 2017;6:1321–1331 PMID:28456008

  5. Hepatic stellate cell and myofibroblast-like cell gene expression in the explanted cirrhotic livers of patients undergoing liver transplantation.

    Estep, J Michael; O'Reilly, Linda; Grant, Geraldine; Piper, James; Jonsson, Johann; Afendy, Arian; Chandhoke, Vikas; Younossi, Zobair M

    2010-02-01

    Hepatic stellate cells (HSC) are involved in hepatic fibrogenesis. Cell signaling associated with an insult to the liver affects an HSC transdifferentiation to fibrogenic myofibroblast-like cells. To investigate the transcriptional expression distinguishing HSC and myofibroblast-like cells between livers with and without cirrhosis. Tissue from ten cirrhotic livers (undergoing transplant) and four non-cirrhotic livers from the National Disease Research Interchange underwent cell separation to extract HSC and myofibroblast-like cell populations. Separated cell types as well as LI-90 cells were subjected to microarray analysis. Selected microarray results were verified by quantitative real-time PCR. Differential expression of some genes, such as IL-1beta, IL-1alpha, and IL-6, was associated with both transdifferentiation and disease. Other genes, such as fatty acid 2-hydroxylase only show differential expression in association with disease. Functional analysis supported these findings, indicating some signal transduction pathways (IL-6) are involved in disease and activation, whereas retinoid X receptor signaling in HSC from cirrhotic and non-cirrhotic livers varies in scope and quality. These findings indicate distinct phenotypes for HSC from cirrhotic and non-cirrhotic livers. Furthermore, coordinated differential expression between genes involved in the same signal transduction pathways provides some insight into the mechanisms that may control the balance between fibrogenesis and fibrolysis.

  6. Prevalence of Hepatitis B surface antigen in children with sickle cell anemia

    Baba Jibrin

    2014-01-01

    Full Text Available Background: Hepatitis B virus is known to be endemic in Africa. The seroepidemiological studies of HBV have shown that infection commonly occurs in childhood in Africa resulting in an increased tendency to chronicity. This cross-sectional study was undertaken to determine the seroprevalence of hepatitis B surface antigen among pediatric patients with homozygous hemoglobin S. Materials and Methods: Three hundred sickle cell anemia children aged 6 months-15 years (both in steady state and in crises attending the SCA clinic and on admission in emergency pediatrics unit and pediatrics medical ward, Usmanu Danfodiyo University Teaching Hospital, Sokoto, Nigeria, were screened for hepatitis B infection using HBsAg as marker of infection. The sensitive enzyme linked immunosorbent assay method was used for detection of the marker. Three hundred children with minor illness attending pediatrics outpatient department and on admission in EPU/PMW for various treatment in the same hospital served as gender- and age-marched controls cohorts. Results: The sero-prevalence of HBsAg seropositivity for hepatitis B virus infection among SCA children was 17.3% (52/300 compared to 10.7% (32/300 of the control (P = 0.0875. The peak prevalence age group for HBV infection among SCA children was in the age group 1.1-5.0 years (6% compared to 10.1-15.0 years (4.7% in the control. Risk factors for HBV infection such as blood transfusion, traditional scarification/circumcision/uvulectomy, and tattooing did not significantly affect the prevalence of HBV infection in both SCA children and controls. Conclusion: Hepatitis B infection is common in Sokoto. The need for strict adherence to HBV immunization and further community-based studies on the risk factors are recommended.

  7. Magnetic resonance imaging and cell-based neurorestorative therapy after brain injury

    Quan Jiang

    2016-01-01

    Full Text Available Restorative cell-based therapies for experimental brain injury, such as stroke and traumatic brain injury, substantially improve functional outcome. We discuss and review state of the art magnetic resonance imaging methodologies and their applications related to cell-based treatment after brain injury. We focus on the potential of magnetic resonance imaging technique and its associated challenges to obtain useful new information related to cell migration, distribution, and quantitation, as well as vascular and neuronal remodeling in response to cell-based therapy after brain injury. The noninvasive nature of imaging might more readily help with translation of cell-based therapy from the laboratory to the clinic.

  8. Management of adult blunt hepatic trauma.

    Kozar, Rosemary A; McNutt, Michelle K

    2010-12-01

    To review the nonoperative and operative management of blunt hepatic injury in the adult trauma population. Although liver injury scale does not predict need for surgical intervention, a high-grade complex liver injury should alert the physician to a patient at increased risk of hepatic complications following nonoperative management. Blunt hepatic injury remains a frequent intraabdominal injury in the adult trauma population. The management of blunt hepatic injury has undergone a major paradigm shift from mandatory operative exploration to nonoperative management. Hemodynamic instability with a positive focused abdominal sonography for trauma and peritonitis are indications for emergent operative intervention. Although surgical intervention for blunt hepatic trauma is not as common as in years past, it is imperative that the current trauma surgeon be familiar with the surgical skill set to manage complex hepatic injuries. This study represents a review of both nonoperative and operative management of blunt hepatic injury.

  9. Copper-associated hepatitis in a patient with chronic myeloid leukemia following hematopoietic stem cell transplantation: A case report.

    Lee, Ching-Fen; Chen, Chi-Hua; Wen, Yu-Chuan; Chang, Tsung-Yen; Lai, Ming-Wei; Jaing, Tang-Her

    2017-12-01

    We report a complicated case of cholestatic hepatitis with suspected autoimmune hemolytic anemia (AIHA) and copper toxicity syndrome after HSCT and donor lymphocyte infusion (DLI). A 19-year-1-month-old girl presented with a history of CML. She underwent matched unrelated donor HSCT and donor lymphocyte infusion subsequently. Three months later, yellowish discoloration of the skin was found, which was accompanied by progressive itchy skin, easy fatigability, insomnia, and dark urine output. After admission, liver function disorders were observed. Methylprednisolone was administered for suspected hepatic GVHD. Although abdominal sonography revealed no evidence of biliary tract obstruction and the viral hepatitis survey disclosed unremarkable findings; silymarin and ursodeoxycholic acid were administered to preserve the liver function. In addition, rituximab was prescribed for suspected AIHA. Because hyperbilirubinemia was progressive, mycophenolate and high-dose intravenous immunoglobulin were accordingly administered. As drug-induced liver injury cannot be excluded, all potential unconfirmed causes of drug-related hepatoxicity were discontinued. In this case, the patient's history of shrimps and chocolate consumption led us to strongly suspect cholestatic hepatitis associated with copper toxicity syndrome. High 24-hour urine copper excretion and low serum zinc levels were also confirmed. Accordingly, D-penicillamine and zinc gluconate were administered. She succumbed to progressive hepatic failure and eventual multisystem organ failure 14 months after HSCT. No autopsy was performed. This report described the combined effects of hepatic GVHD, AIHA, drugs, and copper toxicity on liver damage, and demonstrated the potential diagnostic challenges and treatment dilemmas associated with this disease.

  10. CAR-T cell therapy in gastrointestinal tumors and hepatic carcinoma: From bench to bedside.

    Zhang, Qi; Zhang, Zimu; Peng, Meiyu; Fu, Shuyu; Xue, Zhenyi; Zhang, Rongxin

    2016-01-01

    The chimeric antigen receptor (CAR) is a genetically engineered receptor that combines a scFv domain, which specifically recognizes the tumor-specific antigen, with T cell activation domains. CAR-T cell therapies have demonstrated tremendous efficacy against hematologic malignancies in many clinical trials. Recent studies have extended these efforts to the treatment of solid tumors. However, the outcomes of CAR-T cell therapy for solid tumors are not as remarkable as the outcomes have been for hematologic malignancies. A series of hurdles has arisen with respect to CAR-T cell-based immunotherapy, which needs to be overcome to target solid tumors. The major challenge for CAR-T cell therapy in solid tumors is the selection of the appropriate specific antigen to demarcate the tumor from normal tissue. In this review, we discuss the application of CAR-T cells to gastrointestinal and hepatic carcinomas in preclinical and clinical research. Furthermore, we analyze the usefulness of several specific markers in the study of gastrointestinal tumors and hepatic carcinoma.

  11. Potential cellular receptors involved in hepatitis C virus entry into cells

    Muellhaupt Beat

    2005-04-01

    Full Text Available Abstract Hepatitis C virus (HCV infects hepatocytes and leads to permanent, severe liver damage. Since the genomic sequence of HCV was determined, progress has been made towards understanding the functions of the HCV-encoded proteins and identifying the cellular receptor(s responsible for adsorption and penetration of the virus particle into the target cells. Several cellular receptors for HCV have been proposed, all of which are associated with lipid and lipoprotein metabolism. This article reviews the cellular receptors for HCV and suggests a general model for HCV entry into cells, in which lipoproteins play a crucial role.

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

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

    2016-12-01

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

  13. In delicate balance: stem cells and spinal cord injury advocacy.

    Parke, Sara; Illes, Judy

    2011-09-01

    Spinal cord injury (SCI) is a major focus for stem cell therapy (SCT). However, the science of SCT has not been well matched with an understanding of perspectives of persons with SCI. The online advocacy community is a key source of health information for primary stakeholders and their caregivers. In this study, we sought to characterize the content of SCI advocacy websites with respect to their discussion of SCT and stem cell tourism. We performed a comprehensive analysis of SCI advocacy websites identified through a web search and verified by expert opinion. Two independent researchers coded the information for major themes (e.g., scientific & clinical facts, research & funding, policy, ethics) and valence (positive, negative, balanced, neutral). Of the 40 SCI advocacy websites that met inclusion criteria, 50% (N=20) contained information about SCT. Less than 18% (N=7) contained information on stem cell tourism. There were more than ten times as many statements about SCT with a positive valence (N=67) as with a negative valence (N=6). Ethics-related SCT information comprised 20% (N=37) of the total content; the largest proportion of ethics-related content was devoted to stem cell tourism (80%, N=30 statements). Of those, the majority focused on the risks of stem cell tourism (N=16). Given the still-developing science behind SCT, the presence of cautionary information about stem cell tourism at advocacy sites is ethically appropriate. The absence of stem cell tourism information at the majority of advocacy sites represents a lost educational opportunity.

  14. PHP14 regulates hepatic stellate cells migration in liver fibrosis via mediating TGF-β1 signaling to PI3Kγ/AKT/Rac1 pathway.

    Xu, Anjian; Li, Yanmeng; Zhao, Wenshan; Hou, Fei; Li, Xiaojin; Sun, Lan; Chen, Wei; Yang, Aiting; Wu, Shanna; Zhang, Bei; Yao, Jingyi; Wang, Huan; Huang, Jian

    2018-02-01

    Hepatic fibrosis is characterized by the activation of hepatic stellate cells (HSCs). Migration of the activated HSCs to the site of injury is one of the key characteristics during the wound healing process. We have previously demonstrated that 14 kDa phosphohistidine phosphatase (PHP14) is involved in migration and lamellipodia formation of HSCs. However, the role of PHP14 in liver fibrosis remains unknown. In this study, we first assessed PHP14 expression and distribution in liver fibrotic tissues using western blot, immunohistochemistry, and double immunofluorescence staining. Next, we investigated the role of PHP14 in liver fibrosis and, more specifically, the migration of HSCs by Transwell assay and 3D collagen matrices assay. Finally, we explored the possible molecular mechanisms of the effects of PHP14 on these processes. Our results show that the PHP14 expression is up-regulated in fibrotic liver and mainly in HSCs. Importantly, TGF-β1 can induce PHP14 expression in HSCs accompanied with the activation of HSCs. Consistent with the previous study, PHP14 promotes HSCs migration, especially, promotes 3D floating collagen matrices contraction but inhibits stressed-released matrices contraction. Mechanistically, the PI3Kγ/AKT/Rac1 pathway is involved in migration regulated by PHP14. Moreover, PHP14 specifically mediates the TGF-β1 signaling to PI3Kγ/AKT pathway and regulates HSC migration, and thus participates in liver fibrosis. Our study identified the role of PHP14 in liver fibrosis, particularly HSC migration, and suggested a novel mediator of transducting TGF-β1 signaling to PI3Kγ/AKT/Rac1 pathway. PHP14 is up-regulated in fibrotic liver and activated hepatic stellate cells. The expression of PHP14 is induced by TGF-β1. The migration of hepatic stellate cells is regulated by PHP14. PHP14 is a mediator of TGF-β1 signaling to PI3Kγ/AKT/Rac1 pathway in hepatic stellate cells.

  15. Methylation of Septin9 mediated by DNMT3a enhances hepatic stellate cells activation and liver fibrogenesis

    Wu, Yuting, E-mail: wuyuting1302@sina.com; Bu, Fangtian; Yu, Haixia; Li, Wanxia; Huang, Cheng; Meng, Xiaoming; Zhang, Lei; Ma, Taotao; Li, Jun, E-mail: lj@ahmu.edu.cn

    2017-01-15

    Liver fibrosis, resulting from chronic and persistent injury to the liver, is a worldwide health problem. Advanced liver fibrosis results in cirrhosis, liver failure and even hepatocellular cancer (HCC), often eventually requiring liver transplantation, poses a huge health burden on the global community. However, the specific pathogenesis of liver fibrosis remains not fully understood. Numerous basic and clinical studies have provided evidence that epigenetic modifications, especially DNA methylation, might contribute to the activation of hepatic stellate cells (HSCs), the pivotal cell type responsible for the fibrous scar in liver. Here, reduced representation bisulfite sequencing (RRBS) and bisulfite pyrosequencing PCR (BSP) analysis identified hypermethylation status of Septin9 (Sept9) gene in liver fibrogenesis. Sept9 protein was dramatically decreased in livers of CCl4-treated mice and immortalized HSC-T6 cells exposed to TGF-β1. Nevertheless, the suppression of Sept9 could be blocked by DNMT3a-siRNA and DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine (5-azadC). Overexpressed Sept9 attenuated TGF-β1-induced expression of myofibroblast markers α-SMA and Col1a1, accompanied by up-regulation of cell apoptosis-related proteins. Conversely, RNAi-mediated silencing of Sept9 enhanced accumulation of extracellular matrix. These observations suggested that Sept9 contributed to alleviate liver fibrosis might partially through promoting activated HSCs apoptosis and this anti-fibrogenesis effect might be blocked by DNMT-3a mediated methylation of Sept9. Therefore, pharmacological agents that inhibit Sept9 methylation and increase its expression could be considered as valuable treatments for liver fibrosis. - Highlights: • This is the first report of Sept9 methylation and function in liver fibrosis. • Ectopic expression of Sept9 could block the liver fibrogenesis. • DNMT3a might be responsible for the suppression of Sept9 in liver fibrosis.

  16. Methylation of Septin9 mediated by DNMT3a enhances hepatic stellate cells activation and liver fibrogenesis

    Wu, Yuting; Bu, Fangtian; Yu, Haixia; Li, Wanxia; Huang, Cheng; Meng, Xiaoming; Zhang, Lei; Ma, Taotao; Li, Jun

    2017-01-01

    Liver fibrosis, resulting from chronic and persistent injury to the liver, is a worldwide health problem. Advanced liver fibrosis results in cirrhosis, liver failure and even hepatocellular cancer (HCC), often eventually requiring liver transplantation, poses a huge health burden on the global community. However, the specific pathogenesis of liver fibrosis remains not fully understood. Numerous basic and clinical studies have provided evidence that epigenetic modifications, especially DNA methylation, might contribute to the activation of hepatic stellate cells (HSCs), the pivotal cell type responsible for the fibrous scar in liver. Here, reduced representation bisulfite sequencing (RRBS) and bisulfite pyrosequencing PCR (BSP) analysis identified hypermethylation status of Septin9 (Sept9) gene in liver fibrogenesis. Sept9 protein was dramatically decreased in livers of CCl4-treated mice and immortalized HSC-T6 cells exposed to TGF-β1. Nevertheless, the suppression of Sept9 could be blocked by DNMT3a-siRNA and DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine (5-azadC). Overexpressed Sept9 attenuated TGF-β1-induced expression of myofibroblast markers α-SMA and Col1a1, accompanied by up-regulation of cell apoptosis-related proteins. Conversely, RNAi-mediated silencing of Sept9 enhanced accumulation of extracellular matrix. These observations suggested that Sept9 contributed to alleviate liver fibrosis might partially through promoting activated HSCs apoptosis and this anti-fibrogenesis effect might be blocked by DNMT-3a mediated methylation of Sept9. Therefore, pharmacological agents that inhibit Sept9 methylation and increase its expression could be considered as valuable treatments for liver fibrosis. - Highlights: • This is the first report of Sept9 methylation and function in liver fibrosis. • Ectopic expression of Sept9 could block the liver fibrogenesis. • DNMT3a might be responsible for the suppression of Sept9 in liver fibrosis.

  17. Regulation of Hepatic Stellate Cells and Fibrogenesis by Fibroblast Growth Factors

    Justin D. Schumacher

    2016-01-01

    Full Text Available Fibroblast growth factors (FGFs are a family of growth factors critically involved in developmental, physiological, and pathological processes, including embryogenesis, angiogenesis, wound healing, and endocrine functions. In the liver, several FGFs are produced basally by hepatocytes and hepatic stellate cells (HSCs. Upon insult to the liver, expression of FGFs in HSCs is greatly upregulated, stimulating hepatocyte regeneration and growth. Various FGF isoforms have also been shown to directly induce HSC proliferation and activation thereby enabling autocrine and paracrine regulation of HSC function. Regulation of HSCs by the endocrine FGFs, namely, FGF15/19 and FGF21, has also recently been identified. With the ability to modulate HSC proliferation and transdifferentiation, targeting FGF signaling pathways constitutes a promising new therapeutic strategy to treat hepatic fibrosis.

  18. Malignant hepatic perivascular epithelioid cell tumor (PEComa)- Case report and a brief review

    Abhirup, B.; Kaushal, K.; Ganesh, N.; Sanket, M.

    2015-01-01

    Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal neoplasms which can arise from almost any location in the body. Diagnosing them pre-operatively is difficult as they mimic features of other hepatic neoplasms including hepatocellular carcinoma (HCC), fibrolamellar HCC, and focal nodular hyperplasia (FNH) among others. The unique feature of these tumors is the coexpression of muscle and melanocytic markers. These are identified immunohistochemically by the expression of Human Melanin Black-45 (HMB-45), Melan-A and Smooth Muscle Antigen (SMA) which are seen in the majority of tumors. The liver is uncommonly associated with a PEComa and the approach to a patient with hepatic PEComa is not well described. There is no consensus regarding the neo-adjuvant/adjuvant therapy in these patients. The natural history of this condition is not well documented making it an unpredictable disease. Here we have discussed a case and reviewed the literature concerning these rare tumors.

  19. Effect of cell phone distraction on pediatric pedestrian injury risk.

    Stavrinos, Despina; Byington, Katherine W; Schwebel, David C

    2009-02-01

    Early adolescents are using cell phones with increasing frequency. Cell phones are known to distract motor vehicle drivers to the point that their safety is jeopardized, but it is unclear if cell phones might also distract child pedestrians. This study was designed to examine the influence of talking on a cell phone for pediatric pedestrian injury risk. Seventy-seven children aged 10 to 11 years old completed simulated road crossings in an immersive, interactive virtual pedestrian environment. In a within-subjects design, children crossed the virtual street 6 times while undistracted and 6 times while distracted by a cell phone conversation with an unfamiliar research assistant. Participants also completed several other experimental tasks hypothesized to predict the impact of distraction while crossing the street and talking on a cell phone. Children's pedestrian safety was compromised when distracted by a cell phone conversation. While distracted, children were less attentive to traffic; left less safe time between their crossing and the next arriving vehicle; experienced more collisions and close calls with oncoming traffic; and waited longer before beginning to cross the street. Analyses testing experience using a cell phone and experience as a pedestrian yielded few significant results, suggesting that distraction on the cell phone might affect children's pedestrian safety no matter what their experience level. There was some indication that younger children and children who are less attentive and more oppositional may be slightly more susceptible to distraction while talking on the cell phone than older, more attentive, and less oppositional children. Our results suggest that cell phones distract preadolescent children while crossing streets.

  20. The protective role of nitric oxide and nitric oxide synthases in whole-body hyperthermia-induced hepatic injury in rats.

    Chen, Chao-Fuh; Wang, David; Leu, Fur-Jiang; Chen, Hsing I

    2012-01-01

    The present study was designed to elucidate the role of endothelial nitric oxide (NO) synthase (eNOS), inducible NOS (iNOS)-derived NO and heat-shock protein (Hsp70) in a rat model of whole-body hyperthermia (WBH)-induced liver injury. Real-time polymerase chain reaction, immunohistochemistry and western blot were used to observe the mRNA and protein expression of eNOS, iNOS and Hsp70. Rats were exposed to hyperthermia by immersion for 60 min at a conscious state in a water bath maintained at 41°C. Plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were used to assess liver injury 15 h after the hyperthermia challenge. Nitrosative and oxidative mediators, particularly NO and hydroxyl radical were measured. Plasma AST, ALT, hydroxyl radical, and NO were significantly increased after WBH. There were 4.14 ± 0.42, 2.82 ± 0.34 and 2.91 ± 0.16-fold increases in the mRNA expression of eNOS, iNOS and Hsp70. Immunohistochemistry and western blot showed up-regulation of eNOS, iNOS and Hsp70 protein. An eNOS inhibitor (N(ω)-nitro-L-arginine methyl ester (L-NAME)), or an iNOS inhibitor (aminoguanidine (AG)), significantly aggravated the liver injury. On the contrary, administration of NO precursor, L-arginine (L-ARG), attenuated the liver injury. Hsp70 inhibitor quercetin reduced Hsp70, while aggravating the WBH-induced hepatic changes. WBH induces increases in eNOS, iNOS and Hsp70 expression with increase in NO release. The deleterious effects of L-NAME and AG and the protective effects of L-ARG and Hsp70 inhibitor on the liver function and pathology suggest that NO and heat shock protein play a beneficial role in the WBH-induced hepatic injury.

  1. Interferon gamma peptidomimetic targeted to hepatic stellate cells ameliorates acute and chronic liver fibrosis in vivo.

    Bansal, Ruchi; Prakash, Jai; De Ruiter, Marieke; Poelstra, Klaas

    2014-04-10

    Hepatic stellate cells play a crucial role in the pathogenesis of hepatic fibrosis. Thus, pharmacological inhibition of pro-fibrotic activities of these cells might lead to an effective therapy for this disease. Among the potent anti-fibrotics, interferon gamma (IFNγ), a proinflammatory cytokine, is highly efficacious but it failed in clinical trials due to the poor efficacy and multiple adverse effects attributed to the ubiquitous IFNγ receptor (IFNγR) expression. To resolve these drawbacks, we chemically synthesized a chimeric molecule containing (a) IFNγ signaling peptide (IFNγ peptidomimetic, mimγ) that retains the agonistic activities of IFNγ but lacks an extracellular receptor recognition sequence for IFNγR; coupled via heterobifunctional PEG linker to (b) bicyclic platelet derived growth factor beta receptor (PDGFβR)-binding peptide (BiPPB) to induce internalization into the stellate cells that express PDGFβR. The synthesized targeted IFNγ peptidomimetic (mimγ-BiPPB) was extensively investigated for its anti-fibrotic and adverse effects in acute and chronic CCl4-induced liver fibrosis models in mice. Treatment with mimγ-BiPPB, after the onset of disease, markedly inhibited both early and established hepatic fibrosis as reflected by a reduced intrahepatic α-SMA, desmin and collagen-I mRNA expression and protein levels. While untargeted mimγ and BiPPB had no effect, and native IFNγ only induced a moderate reduction. Additionally, no off-target effects, e.g. systemic inflammation, were found with mimγ-BiPPB, which were substantially observed in mice treated with native IFNγ. The present study highlights the beneficial effects of a novel BiPPB mediated cell-specific targeting of IFNγ peptidomimetic to the disease-inducing cells and therefore represents a highly potential therapeutic approach to treat fibrotic diseases. Copyright © 2014 Elsevier B.V. All rights reserved.

  2. Hepatic stellate cells lack AP-1 responsiveness to electrophiles and phorbol 12-myristate-13-acetate

    Reichard, John F.; Petersen, Dennis R.

    2004-01-01

    Stellate cell profibrotic gene induction and transdifferentiation are central events in liver fibrosis. Oxidative stress has been implicated as an activator of the transcription factors Nrf2 and AP-1 through shared kinase signaling pathways that also purportedly contribute to stellate cell activation. The present study examined the role of oxidative stress in ARE- and TRE-regulated gene induction in isolated hepatic stellate cells. Using a portion of the human Nqo1 promoter consisting of an ARE imbedded TRE, it was demonstrated that while the ARE was responsible for mediating inducible gene expression in response to the electrophiles 4-HNE and tBHQ, the TRE was refractory to induction by either electrophiles or PMA. It was demonstrated that stellate cells possess nuclear TRE-binding proteins that were identified as JunB, JunD, Fra1, and Fra2, which were unaffected by either electrophiles or PMA treatment. This report demonstrates that, in contrast to the ARE, the TRE and its binding cognate AP-1 did not mediate independent gene induction in hepatic stellate cells. This observation is significant given the presumed importance attributed to AP-1 in mediating profibrogenic gene expression

  3. Hepatic differentiation of human pluripotent stem cells in miniaturized format suitable for high-throughput screen

    Arnaud Carpentier

    2016-05-01

    Full Text Available The establishment of protocols to differentiate human pluripotent stem cells (hPSCs including embryonic (ESC and induced pluripotent (iPSC stem cells into functional hepatocyte-like cells (HLCs creates new opportunities to study liver metabolism, genetic diseases and infection of hepatotropic viruses (hepatitis B and C viruses in the context of specific genetic background. While supporting efficient differentiation to HLCs, the published protocols are limited in terms of differentiation into fully mature hepatocytes and in a smaller-well format. This limitation handicaps the application of these cells to high-throughput assays. Here we describe a protocol allowing efficient and consistent hepatic differentiation of hPSCs in 384-well plates into functional hepatocyte-like cells, which remain differentiated for more than 3 weeks. This protocol affords the unique opportunity to miniaturize the hPSC-based differentiation technology and facilitates screening for molecules in modulating liver differentiation, metabolism, genetic network, and response to infection or other external stimuli.

  4. Chemical and biological insights into uranium-induced apoptosis of rat hepatic cell line

    Liu, Fang; You, Yong [University of South China, College of Hunan Province, Key Laboratory of Tumor Cellular and Molecular Pathology, Hengyang (China); Du, Ke-Jie [University of South China, School of Chemistry and Chemical Engineering, Hengyang (China); Fang, Zhen [Anhui Normal University, College of Chemistry and Materials Science, Wuhu (China); Wen, Ge-Bo [University of South China, College of Hunan Province, Key Laboratory of Tumor Cellular and Molecular Pathology, Hengyang (China); University of South China, Laboratory of Protein Structure and Function, Hengyang (China); Lin, Ying-Wu [University of South China, School of Chemistry and Chemical Engineering, Hengyang (China); University of South China, Laboratory of Protein Structure and Function, Hengyang (China)

    2015-05-15

    Uranium release into the environment is a threat to human health, and the mechanisms of cytotoxicity caused by uranium are not well-understood. To improve our understanding in this respect, we herein evaluated the effects of uranium exposure on normal rat hepatic BRL cells. As revealed by scanning electron microscopy and transmission electron microscope analysis, uranyl nitrate was found to be transformed into uranyl phosphate particles in the medium and taken up by BRL cells in an endocytotic uptake manner, which presumably initiates apoptosis of the cell, although soluble uranyl ion may also be toxic. The apoptosis of BRL cells upon uranium exposure was also confirmed by both the acridine orange and ethidium bromide double staining assay and the Annexin V/propidium iodide double staining assay. Further studies revealed that uranium induced the loss of mitochondrial membrane potential in a dose-dependent manner. Moreover, the uranium-induced apoptosis was found to be associated with the activation of caspase-3, caspase-8 and caspase-9, indicating both a mitochondria-dependent signaling pathway and a death receptor pathway by a crosstalk. This study provides new chemical and biological insights into the mechanism of uranium toxicity toward hepatic cells, which will help seek approaches for biological remediation of uranium. (orig.)

  5. Sulfatide-Reactive Natural Killer T Cells Abrogate Ischemia-Reperfusion Injury

    Yang, Seung Hee; Lee, Jung Pyo; Jang, Hye Ryoun; Cha, Ran-hui; Han, Seung Seok; Jeon, Un Sil; Kim, Dong Ki; Song, Junghan; Lee, Dong-Sup; Kim, Yon Su

    2011-01-01

    There is a significant immune response to ischemia-reperfusion injury (IRI), but the role of immunomodulatory natural killer T (NKT) cell subtypes is not well understood. Here, we compared the severity of IRI in mice deficient in type I/II NKT cells (CD1d−/−) or type I NKT cells (Jα18−/−). The absence of NKT cells, especially type II NKT cells, accentuated the severity of renal injury, whereas repletion of NKT cells attenuated injury. Adoptively transferred NKT cells trafficked into the tubul...

  6. Hepatic progenitors for liver disease: current position

    Alice Conigliaro

    2010-02-01

    Full Text Available Alice Conigliaro1, David A Brenner2, Tatiana Kisseleva21University “La Sapienza”, Dipartimento di Biotecnologie Cellulari ed Ematologia Policlinico Umberto I, V Clinica Medica, Rome, Italy; 2Department of Medicine, University of California, San Diego, La Jolla, CA, USAAbstract: Liver regeneration restores the original functionality of hepatocytes and cholangiocytes in response to injury. It is regulated on several levels, with different cellular populations contributing to this process, eg, hepatocytes, liver precursor cells, intrahepatic stem cells. In response to injury, mature hepatocytes have the capability to proliferate and give rise to new hepatocytes and cholangiocytes. Meanwhile, liver precursor cells (oval cells have become the most recognized bipotential precursor cells in the damaged liver. They rapidly proliferate, change their cellular composition, and differentiate into hepatocytes and cholangiocytes to compensate for the cellular loss and maintain liver homeostasis. There is a growing body of evidence that oval cells originate from the intrahepatic stem cell(s, which in turn give(s rise to epithelial, including oval cells, and/or other hepatic cells of nonepithelial origin. Since there is a close relationship between the liver and hematopoiesis, bone marrow derived cells can also contribute to liver regeneration by the fusion of myeloid cells with damaged hepatocytes, or differentiation of mesenchymal stem cells into hepatocyte-like cells. The current review discusses the contribution of different cells to liver regeneration and their characteristics.Keywords: hepatic progenitor, liver disease, liver precursor cells, oval cells, hepatocytes, intrahepatic stem cells, cholangiocytes

  7. THE STATE OF CELL MEDIATED IMMUNITY AMONG HEPATITIS B SURFACE ,ANTGENI CARRIERS IN IRAN,

    A. MASSOUD

    1987-06-01

    Full Text Available Cell-mediated immune (CMI s t a t us and sub- popul at i ons o f pe r ipheral b l ood lymphocytes were investigated in one hundre d volunt a ry blood donors who were car r ier s of Ag • HE S A signi f i c ant decr e ase of t otal T-cells observed in HB Ag carri e rs as compared t o normal controls. The percenS t age o f active T-cells a nd B-lymphocytes did not d i f f e r signi f icant ly between the t wo groups ."nAddi t ion of aut ologous serum from HE Ag c a r r iers t o s t heir l ymphocyt e s reduced the numbe r of detectabl e cells in HE Ag carriers . This reduction coul d be due to the s presence of a r osette i nhi bitory f actor in their serum. Our studies demonstrated a failur e o f CMI among HB Ags car r i ers detected by the l e ukocyte migr ation i nhibition (LMI test. This failure cannot be attributed to the presence of HE Ag-AB complexes in their serum. It is s possible that specific failure of CMI allows the hepatitis B virus to remain harmless in carriers a Hepatitis B surface-antigen (HE Ag; Hepatitis Bs coreantigen (HE Ag and Hepatitis Be-antigen (HE Ag, c e have been established as indicating ineffectivity in viral hepatitis B ({I, 6 , 20, 28."nA number of infected individuals also developed clini cal evidence of disease and HE Ag may s the serum of some subjects for a long rema•ln present I•n time (18. It has been suggested that to a defect in CMI, the persistence of HB Ag s whether liver disease is is related present or not, and impairment of the lymphocyte response to phytohaemagglutinin (PHA in this group is presented in evide•"nnee (8, •9 , 13, 24, 25 .In contrast, other workers report a normal respons e t o PHA in healthy carriers of HE Ag and s they concludE that the defective T-cell response is relat ed to the live!' disease rather than the immune system (31. Dudley et al (8 have suggested that liver damage occurring after hepatitis B infection, may be an effect of thymus-dependent lymphocytes (12."n

  8. Prediction of linear B-cell epitopes of hepatitis C virus for vaccine development

    2015-01-01

    Background High genetic heterogeneity in the hepatitis C virus (HCV) is the major challenge of the development of an effective vaccine. Existing studies for developing HCV vaccines have mainly focused on T-cell immune response. However, identification of linear B-cell epitopes that can stimulate B-cell response is one of the major tasks of peptide-based vaccine development. Owing to the variability in B-cell epitope length, the prediction of B-cell epitopes is much more complex than that of T-cell epitopes. Furthermore, the motifs of linear B-cell epitopes in different pathogens are quite different (e. g. HCV and hepatitis B virus). To cope with this challenge, this work aims to propose an HCV-customized sequence-based prediction method to identify B-cell epitopes of HCV. Results This work establishes an experimentally verified dataset comprising the B-cell response of HCV dataset consisting of 774 linear B-cell epitopes and 774 non B-cell epitopes from the Immune Epitope Database. An interpretable rule mining system of B-cell epitopes (IRMS-BE) is proposed to select informative physicochemical properties (PCPs) and then extracts several if-then rule-based knowledge for identifying B-cell epitopes. A web server Bcell-HCV was implemented using an SVM with the 34 informative PCPs, which achieved a training accuracy of 79.7% and test accuracy of 70.7% better than the SVM-based methods for identifying B-cell epitopes of HCV and the two general-purpose methods. This work performs advanced analysis of the 34 informative properties, and the results indicate that the most effective property is the alpha-helix structure of epitopes, which influences the connection between host cells and the E2 proteins of HCV. Furthermore, 12 interpretable rules are acquired from top-five PCPs and achieve a sensitivity of 75.6% and specificity of 71.3%. Finally, a conserved promising vaccine candidate, PDREMVLYQE, is identified for inclusion in a vaccine against HCV. Conclusions This work

  9. Calcium channel blockers ameliorate iron overload-associated hepatic fibrosis by altering iron transport and stellate cell apoptosis

    Zhang, Ying [Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China); Department of Pathology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China); Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Shijiazhuang 050200, Hebei (China); Zhao, Xin [Department of Hepatobiliary Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang 050051, Hebei (China); Chang, Yanzhong [Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang 050024, Hebei (China); Zhang, Yuanyuan [Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China); Chu, Xi [Department of Pharmacy, The Forth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei (China); Zhang, Xuan [Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China); Liu, Zhenyi; Guo, Hui [Department of Medicinal Chemistry, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China); Wang, Na [Department of Physiology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China); Gao, Yonggang [Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China); Zhang, Jianping, E-mail: zhangjianping14@126.com [Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China); Chu, Li, E-mail: chuli0614@126.com [Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China); Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Shijiazhuang 050200, Hebei (China)

    2016-06-15

    Liver fibrosis is the principal cause of morbidity and mortality in patients with iron overload. Calcium channel blockers (CCBs) can antagonize divalent cation entry into renal and myocardial cells and inhibit fibrogenic gene expression. We investigated the potential of CCBs to resolve iron overload-associated hepatic fibrosis. Kunming mice were assigned to nine groups (n = 8 per group): control, iron overload, deferoxamine, high and low dose verapamil, high and low dose nimodipine, and high and low dose diltiazem. Iron deposition and hepatic fibrosis were measured in mouse livers. Expression levels of molecules associated with transmembrane iron transport were determined by molecular biology approaches. In vitro HSC-T6 cells were randomized into nine groups (the same groups as the mice). Changes in proliferation, apoptosis, and metalloproteinase expression in cells were detected to assess the anti-fibrotic effects of CCBs during iron overload conditions. We found that CCBs reduced hepatic iron content, intracellular iron deposition, the number of hepatic fibrotic areas, collagen expression levels, and hydroxyproline content. CCBs rescued abnormal expression of α1C protein in L-type voltage-dependent calcium channel (LVDCC) and down-regulated divalent metal transporter-1 (DMT-1) expression in mouse livers. In iron-overloaded HSC-T6 cells, CCBs reduced iron deposition, inhibited proliferation, induced apoptosis, and elevated expression of matrix metalloproteinase-13 (MMP-13) and tissue inhibitor of metalloproteinase-1 (TIMP-1). CCBs are potential therapeutic agents that can be used to address hepatic fibrosis during iron overload. They resolve hepatic fibrosis probably correlated with regulating transmembrane iron transport and inhibiting HSC growth. - Highlights: • Calcium channel blockers (CCBs) reduced hepatic iron content. • CCBs decreased hepatic fibrotic areas and collagen expression levels. • CCBs resolve fibrosis by regulating iron transport and

  10. Copper ions stimulate the proliferation of hepatic stellate cells via oxygen stress in vitro.

    Xu, San-qing; Zhu, Hui-yun; Lin, Jian-guo; Su, Tang-feng; Liu, Yan; Luo, Xiao-ping

    2013-02-01

    This study examined the effect of copper ions on the proliferation of hepatic stellate cells (HSCs) and the role of oxidative stress in this process in order to gain insight into the mechanism of hepatic fibrosis in Wilson's disease. LX-2 cells, a cell line of human HSCs, were cultured in vitro and treated with different agents including copper sulfate, N-acetyl cysteine (NAC) and buthionine sulfoximine (BSO) for different time. The proliferation of LX-2 cells was measured by non-radioactive cell proliferation assay. Real-time PCR and Western blotting were used to detect the mRNA and protein expression of platelet-derived growth factor receptor β subunit (PDGFβR), ELISA to determine the level of glutathione (GSH) and oxidized glutathione (GSSG), dichlorofluorescein assay to measure the level of reactive oxygen species (ROS), and lipid hydroperoxide assay to quantify the level of lipid peroxide (LPO). The results showed that copper sulfate over a certain concentration range could promote the proliferation of LX-2 cells in a time- and dose-dependent manner. The effect was most manifest when LX-2 cells were treated with copper sulfate at a concentration of 100 μmol/L for 24 h. Additionally, copper sulfate could dose-dependently increase the levels of ROS and LPO, and decrease the ratio of GSH/GSSG in LX-2 cells. The copper-induced increase in mRNA and protein expression of PDGFβR was significantly inhibited in LX-2 cells pre-treated with NAC, a precursor of GSH, and this phenomenon could be reversed by the intervention of BSO, an inhibitor of NAC. It was concluded that copper ions may directly stimulate the proliferation of HSCs via oxidative stress. Anti-oxidative stress therapies may help suppress the copper-induced activation and proliferation of HSCs.

  11. Ontogenic differences in human liver 4-hydroxynonenal detoxification are associated with in vitro injury to fetal hematopoietic stem cells

    Gardner, James L.; Doi, Adriana M.; Pham, Robert T.; Huisden, Christiaan M.; Gallagher, Evan P.

    2003-01-01

    4-hydroxynonenal (4HNE) is a highly mutagenic and cytotoxic α,β-unsaturated aldehyde that can be produced in utero during transplacental exposure to prooxidant compounds. Cellular protection against 4HNE injury is provided by alcohol dehydrogenases (ADH), aldehyde reductases (ALRD), aldehyde dehydrogenases (ALDH), and glutathione S-transferases (GST). In the present study, we examined the comparative detoxification of 4HNE by aldehyde-metabolizing enzymes in a panel of adult and second-trimester prenatal liver tissues and report the toxicological ramifications of ontogenic 4HNE detoxification in vitro. The initial rates of 4HNE oxidation and reduction were two- to fivefold lower in prenatal liver subcellular fractions as compared to adult liver, and the rates of GST conjugation of 4HNE were not detectable in either prenatal or adult cytosolic fractions. GSH-affinity purification of hepatic cytosol yielded detectable and roughly equivalent rates of GST-4HNE conjugation for the two age groups. Consistent with the inefficient oxidative and reductive metabolism of 4HNE in prenatal liver, cytosolic fractions prepared from prenatal liver exhibited a decreased ability to protect against 4HNE-protein adduct formation relative to adults. Prenatal liver hematopoietic stem cells (HSC), which constitute a significant percentage of prenatal liver cell populations, exhibited ALDH activities toward 4HNE, but little reductive or conjugative capacity toward 4HNE through ALRD, ADH, and GST. Cultured HSC exposed to 5 μM 4HNE exhibited a loss in viability and readily formed one or more high molecular weight 4HNE-protein adduct(s). Collectively, our results indicate that second trimester prenatal liver has a lower ability to detoxify 4HNE relative to adults, and that the inefficient detoxification of 4HNE underlies an increased susceptibility to 4HNE injury in sensitive prenatal hepatic cell targets

  12. Cytotoxic effects and apoptosis induction of enrofloxacin in hepatic cell line of grass carp (Ctenopharyngodon idellus).

    Liu, Bo; Cui, Yanting; Brown, Paul B; Ge, Xianping; Xie, Jun; Xu, Pao

    2015-12-01

    We determined the effect of enrofloxacin on the lactate dehydrogenase (LDH) release, reactive oxygen species (ROS), superoxide dismutase (SOD), total antioxidant capacity (T-AOC), malondialdehyde (MDA), mitochondria membrane potential (ΔΨm) and apoptosis in the hepatic cell line of grass carp (Ctenopharyngodon idellus). Cultured cells were treated with different concentrations of enrofloxacin (12.5-200 ug/mL) for 24 h. We found that the cytotoxic effect of enrofloxacin was mediated by apoptosis, and that this apoptosis occurred in a dose-dependent manner. The doses of 50,100 and 200 μg/mL enrofloxacin increased the LDH release and MDA concentration, induced cell apoptosis and reduced the ΔΨm compared to the control. The highest dose of 200 ug/mL enrofloxacin also significantly induced apoptosis accompanied by ΔΨm disruption and ROS generation and significantly reduced T-AOC and increased MDA concentration compared to the control. Our results suggest that the dose of 200 ug/mL enrofloxacin exerts its cytotoxic effect and produced ROS via apoptosis by affecting the mitochondria of the hepatic cells of grass carp. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. Hepatitis C virus core protein potentiates proangiogenic activity of hepatocellular carcinoma cells.

    Shao, Yu-Yun; Hsieh, Min-Shu; Wang, Han-Yu; Li, Yong-Shi; Lin, Hang; Hsu, Hung-Wei; Huang, Chung-Yi; Hsu, Chih-Hung; Cheng, Ann-Lii

    2017-10-17

    Increased angiogenic activity has been demonstrated in hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC), but the mechanism was unclear. To study the role of HCV core protein, we used tube formation and Matrigel plug assays to assess the proangiogenic activity of an HCC cell line, HuH7, and 2 of its stable clones-HuH7-core-high and HuH7-core-low, with high and low HCV core protein expression, respectively. In both assays, HuH7-core-high and HuH7-core-low cells dose-dependently induced stronger angiogenesis than control cells. HuH7 cells with HCV core protein expression showed increased mRNA and protein expression of vascular endothelial growth factor (VEGF). VEGF inhibition by bevacizumab reduced the proangiogenic activity of HuH7-core-high cells. The promotor region of VEGF contains the binding site of activator protein-1 (AP-1). Compared with controls, HuH7-core-high cells had an increased AP-1 activity and nuclear localization of phospho-c-jun. AP-1 inhibition using either RNA knockdown or AP-1 inhibitors reduced the VEGF mRNA expression and the proangiogenic activity of HuH7-core-high cells. Among 131 tissue samples from HCC patients, HCV-related HCC revealed stronger VEGF expression than did hepatitis B virus-related HCC. In conclusion, increased VEGF expression through AP-1 activation is a crucial mechanism underlying the proangiogenic activity of the HCV core protein in HCC cells.

  14. Hepatic esterase activity is increased in hepatocyte-like cells derived from human embryonic stem cells using a 3D culture system.

    Choi, Young-Jun; Kim, Hyemin; Kim, Ji-Woo; Yoon, Seokjoo; Park, Han-Jin

    2018-05-01

    The aim of the study is to generate a spherical three-dimensional (3D) aggregate of hepatocyte-like cells (HLCs) differentiated from human embryonic stem cells and to investigate the effect of the 3D environment on hepatic maturation and drug metabolism. Quantitative real-time PCR analysis indicated that gene expression of mature hepatocyte markers, drug-metabolizing enzymes, and hepatic transporters was significantly higher in HLCs cultured in the 3D system than in those cultured in a two-dimensional system (p formation, were increased in HLCs cultured in the 3D system. In particular, 3D spheroidal culture increased expression of CES1 and BCHE, which encode hepatic esterases (p 3D spheroidal culture enhances the maturation and drug metabolism of stem cell-derived HLCs, and this may help to optimize hepatic differentiation protocols for hepatotoxicity testing.

  15. Two sides of one coin: massive hepatic necrosis and progenitor cell-mediated regeneration in acute liver failure

    Honglei eWeng

    2015-06-01

    Full Text Available Massive hepatic necrosis is a key event underlying acute liver failure, a serious clinical syndrome with high mortality. Massive hepatic necrosis in acute liver failure has unique pathophysiological characteristics including extremely rapid parenchymal cell death and removal. On the other hand, massive necrosis rapidly induces the activation of liver progenitor cells, the so-called second pathway of liver regeneration. The final clinical outcome of acute liver failure depends on whether liver progenitor cell-mediated regeneration can efficiently restore parenchymal mass and function within a short time. This review summarizes the current knowledge regarding massive hepatic necrosis and liver progenitor cell-mediated regeneration in patients with acute liver failure, the two sides of one coin.

  16. Two sides of one coin: massive hepatic necrosis and progenitor cell-mediated regeneration in acute liver failure.

    Weng, Hong-Lei; Cai, Xiaobo; Yuan, Xiaodong; Liebe, Roman; Dooley, Steven; Li, Hai; Wang, Tai-Ling

    2015-01-01

    Massive hepatic necrosis is a key event underlying acute liver failure, a serious clinical syndrome with high mortality. Massive hepatic necrosis in acute liver failure has unique pathophysiological characteristics including extremely rapid parenchymal cell death and removal. On the other hand, massive necrosis rapidly induces the activation of liver progenitor cells, the so-called "second pathway of liver regeneration." The final clinical outcome of acute liver failure depends on whether liver progenitor cell-mediated regeneration can efficiently restore parenchymal mass and function within a short time. This review summarizes the current knowledge regarding massive hepatic necrosis and liver progenitor cell-mediated regeneration in patients with acute liver failure, the two sides of one coin.

  17. Hepatitis C

    ... Workshops Follow Us Home Health Information Liver Disease Hepatitis (Viral) Hepatitis C Related Topics English English Español Section Navigation Hepatitis (Viral) What Is Viral Hepatitis? Hepatitis A Hepatitis B ...

  18. Trapping of oxidized LDL in lysosomes of Kupffer cells is a trigger for hepatic inflammation.

    Bieghs, Veerle; Walenbergh, Sofie M A; Hendrikx, Tim; van Gorp, Patrick J; Verheyen, Fons; Olde Damink, Steven W; Masclee, Ad A; Koek, Ger H; Hofker, Marten H; Binder, Christoph J; Shiri-Sverdlov, Ronit

    2013-08-01

    Non-alcoholic steatohepatitis (NASH) is characterized by steatosis and inflammation. The transition from steatosis towards NASH represents a key step in pathogenesis, as it will set the stage for further severe liver damage. Under normal conditions, lipoproteins that are endocytosed by Kupffer cells (KCs) are easily transferred from the lysosomes into the cytoplasm. Oxidized LDL (oxLDL) that is taken up by the macrophages in vitro is trapped within the lysosomes, while acetylated LDL (acLDL) is leading to normal lysosomal hydrolysis, resulting in cytoplasmic storage. We have recently demonstrated that hepatic inflammation is correlated with lysosomal trapping of lipids. So far, a link between lysosomal trapping of oxLDL and inflammation was not established. We hypothesized that lysosomal trapping of oxLDL in KCs will lead to hepatic inflammation. Ldlr(-/-) mice were injected with LDL, acLDL and oxLDL and sacrificed after 2, 6 and 24 h. Electron microscopy of KCs demonstrated that after oxLDL injection, small lipid inclusions were present inside the lysosomes after all time points and were mostly pronounced after 6 and 24 h. In contrast, no lipid inclusions were present inside KCs after LDL or acLDL injection. Hepatic expression of several inflammatory genes and scavenger receptors was higher after oxLDL injections compared with LDL or acLDL. These data suggest that trapping of oxLDL inside lysosomes of KCs in vivo is causally linked to increased hepatic inflammatory gene expression. Our novel observations provide new bases for prevention and treatment of NASH. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury.

    Keirstead, Hans S; Nistor, Gabriel; Bernal, Giovanna; Totoiu, Minodora; Cloutier, Frank; Sharp, Kelly; Steward, Oswald

    2005-05-11

    Demyelination contributes to loss of function after spinal cord injury, and thus a potential therapeutic strategy involves replacing myelin-forming cells. Here, we show that transplantation of human embryonic stem cell (hESC)-derived oligodendrocyte progenitor cells (OPCs) into adult rat spinal cord injuries enhances remyelination and promotes improvement of motor function. OPCs were injected 7 d or 10 months after injury. In both cases, transplanted cells survived, redistributed over short distances, and differentiated into oligodendrocytes. Animals that received OPCs 7 d after injury exhibited enhanced remyelination and substantially improved locomotor ability. In contrast, when OPCs were transplanted 10 months after injury, there was no enhanced remyelination or locomotor recovery. These studies document the feasibility of predifferentiating hESCs into functional OPCs and demonstrate their therapeutic potential at early time points after spinal cord injury.

  20. An in vitro expansion system for generation of human iPS cell-derived hepatic progenitor-like cells exhibiting a bipotent differentiation potential.

    Ayaka Yanagida

    Full Text Available Hepatoblasts, hepatic stem/progenitor cells in liver development, have a high proliferative potential and the ability to differentiate into both hepatocytes and cholangiocytes. In regenerative medicine and drug screening for the treatment of severe liver diseases, human induced pluripotent stem (iPS cell-derived mature functional hepatocytes are considered to be a potentially good cell source. However, induction of proliferation of these cells is difficult ex vivo. To circumvent this problem, we generated hepatic progenitor-like cells from human iPS cells using serial cytokine treatments in vitro. Highly proliferative hepatic progenitor-like cells were purified by fluorescence-activated cell sorting using antibodies against CD13 and CD133 that are known cell surface markers of hepatic stem/progenitor cells in fetal and adult mouse livers. When the purified CD13(highCD133(+ cells were cultured at a low density with feeder cells in the presence of suitable growth factors and signaling inhibitors (ALK inhibitor A-83-01 and ROCK inhibitor Y-27632, individual cells gave rise to relatively large colonies. These colonies consisted of two types of cells expressing hepatocytic marker genes (hepatocyte nuclear factor 4α and α-fetoprotein and a cholangiocytic marker gene (cytokeratin 7, and continued to proliferate over long periods of time. In a spheroid formation assay, these cells were found to express genes required for mature liver function, such as cytochrome P450 enzymes, and secrete albumin. When these cells were cultured in a suitable extracellular matrix gel, they eventually formed a cholangiocytic cyst-like structure with epithelial polarity, suggesting that human iPS cell-derived hepatic progenitor-like cells have a bipotent differentiation ability. Collectively these data indicate that this novel procedure using an in vitro expansion system is useful for not only liver regeneration but also for the determination of molecular mechanisms that

  1. Garlic and Resveratrol attenuate diabetic complications, loss of β-cells, pancreatic and hepatic oxidative stress in streptozotocin-induced diabetic rats

    Gagandeep Kaur

    2016-10-01

    Full Text Available Abstract:The study was aimed at finding the effect of garlic and resveratrol on loss of β-cells and diabetic complication in streptozotocin (STZ-induced Type-I diabetic rats. Rats were injected with single dose STZ (50mg/kg, i.p. for induction of type 1 diabetes (Dia and compared with control group. Rats from third (Dia+Gar, fourth (Dia+Resv and fifth (Dia+Met groups were fed raw garlic homogenate (250 mg/kg/day, resveratrol (25 mg/kg/day and metformin (500 mg/kg/day orally, respectively for a period of 4 weeks. Diabetic group had decreased serum insulin and hydrogen sulfide levels along with increased blood glucose and glycated hemoglobin, triglyceride, uric acid and nitric oxide levels. Significant (p<0.05 increase in pancreatic and hepatic TBARS, conjugated dienes, nitric oxide, and AGE level and significant (p<0.05 decrease in SOD, catalase, H2S, GSH level were observed in diabetic group. Administration of garlic, resveratrol and metformin significantly (p<0.05 normalized most of the altered metabolic and oxidative stress parameters as well as histopathological changes. Administration of garlic, resveratrol and 9metformin in diabetic rat decreases pancreatic β-cell damage and hepatic injury. Our data concluded that administration of garlic showed more promising effect in terms of reducing oxidative stress and pathological changes when compared to resveratrol and metformin groups.

  2. Tim-3/galectin-9 regulate the homeostasis of hepatic NKT cells in a murine model of nonalcoholic fatty liver disease.

    Tang, Zhao-Hui; Liang, Shuwen; Potter, James; Jiang, Xuan; Mao, Hai-Quan; Li, Zhiping

    2013-02-15

    T cell Ig and mucin domain (Tim)-3 is well known to interact with its natural ligand, Galectin-9 (Gal-9), to regulate T cell function. However, little is known about the function of Tim-3/Gal-9 signaling in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) mediated by hepatic NKT cells that also express Tim-3. In the current study, we define the role and the mechanism of Tim-3/Gal-9 signaling in hepatic NKT cell regulation in a mouse model of diet-induced NAFLD. Adult male wild-type or CD1d knockout C57BL/6 mice were fed a high-fat diet to induce steatosis. Some of the mice also received one or a combination of Gal-9, anti-IL-15R/IL-15 mAb, rIL-15, α-galactosylceramide, and multilamellar liposomes containing Cl(2)MDP. The expression of Tim-3 and various markers reflecting cell proliferation, activation, cytokine production, and apoptosis was analyzed. Liver histology, steatosis grade, and hepatic triglyceride content were also evaluated. In the liver, Tim-3(+) NKT cells are in an activated state, and Gal-9 directly induces Tim-3(+) NKT cell apoptosis and contributes to the depletion of NKT cells in diet-induced steatosis. However, Gal-9 also interacts with Tim-3-expressing Kupffer cells to induce secretion of IL-15, thus promoting NKT cell proliferation. Exogenous administration of Gal-9 significantly ameliorates diet-induced steatosis by modulating hepatic NKT cell function. In summary, the Tim-3/Gal-9-signaling pathway plays a critical role in the homeostasis of hepatic NKT cells through activation-induced apoptosis and secondary proliferation and, thus, contributes to the pathogenesis of NAFLD.

  3. Tim-3/Galectin-9 Regulate the Homeostasis of Hepatic NKT Cells in a Murine Model of Nonalcoholic Fatty Liver Disease

    Liang, Shuwen; Potter, James; Jiang, Xuan; Mao, Hai-Quan

    2013-01-01

    T cell Ig and mucin domain (Tim)-3 is well known to interact with its natural ligand, Galectin-9 (Gal-9), to regulate T cell function. However, little is known about the function of Tim-3/Gal-9 signaling in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) mediated by hepatic NKT cells that also express Tim-3. In the current study, we define the role and the mechanism of Tim-3/Gal-9 signaling in hepatic NKT cell regulation in a mouse model of diet-induced NAFLD. Adult male wild-type or CD1d knockout C57BL/6 mice were fed a high-fat diet to induce steatosis. Some of the mice also received one or a combination of Gal-9, anti–IL-15R/IL-15 mAb, rIL-15, α-galactosylceramide, and multilamellar liposomes containing Cl2MDP. The expression of Tim-3 and various markers reflecting cell proliferation, activation, cytokine production, and apoptosis was analyzed. Liver histology, steatosis grade, and hepatic triglyceride content were also evaluated. In the liver, Tim-3+ NKT cells are in an activated state, and Gal-9 directly induces Tim-3+ NKT cell apoptosis and contributes to the depletion of NKT cells in diet-induced steatosis. However, Gal-9 also interacts with Tim-3–expressing Kupffer cells to induce secretion of IL-15, thus promoting NKT cell proliferation. Exogenous administration of Gal-9 significantly ameliorates diet-induced steatosis by modulating hepatic NKT cell function. In summary, the Tim-3/Gal-9–signaling pathway plays a critical role in the homeostasis of hepatic NKT cells through activation-induced apoptosis and secondary proliferation and, thus, contributes to the pathogenesis of NAFLD. PMID:23296703

  4. Tranilast reduces serum IL-6 and IL-13 and protects against thioacetamide-induced acute liver injury and hepatic encephalopathy.

    Abdelaziz, Rania R; Elkashef, Wagdi F; Said, Eman

    2015-07-01

    Hepatic encephalopathy is a serious neuropsychiatric disorder usually affecting either acute or chronic hepatic failure patients. Hepatic encephalopathy was replicated in a validated rat model to assess the potential protective efficacy of tranilast against experimentally induced hepatic encephalopathy. Thioacetamide injection significantly impaired hepatic synthetic, metabolic and excretory functions with significant increase in serum NO, IL-6 and IL-13 levels and negative shift in the oxidant/antioxidant balance. Most importantly, there was a significant increase in serum ammonia levels with significant astrocytes' swelling and vacuolization; hallmarks of hepatic encephalopathy. Tranilast administration (300 mg/kg, orally) for 15 days significantly improved hepatic functions, restored oxidant/antioxidant balance, reduced serum NO, IL-6 and IL-13 levels. Meanwhile, serum ammonia significantly declined with significant reduction in astrocytes' swelling and vacuolization. Several mechanisms can be implicated in the observed hepato- and neuroprotective potentials of tranilast, such as its anti-inflammatory potential, its antioxidant potential as well as its immunomodulatory properties. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. Oligoclonal CD8+ T-cell expansion in patients with chronic hepatitis C is associated with liver pathology and poor response to interferon-alpha therapy.

    Manfras, Burkhard J; Weidenbach, Hans; Beckh, Karl-Heinz; Kern, Peter; Möller, Peter; Adler, Guido; Mertens, Thomas; Boehm, Bernhard O

    2004-05-01

    The role of CD8(+) T lymphocytes in chronic hepatitis C virus (HCV) infection and in liver injury with subsequent development of fibrosis and cirrhosis is poorly understood. To address this question, we performed a follow-up study including 27 chronically HCV-infected individuals. We determined clonality and phenotypes of circulating CD8(+) T cells employing TCRBV spectratyping. Antigen specificity was tested by rMHC-peptide tetramer staining and stimulation with recombinant HCV antigens. In addition, T-cell clonality and phenotypes were followed during the variable clinical response of interferon- (IFN) alpha treatment. We could demonstrate that CD8(+) T-cell expansions were significantly associated with liver fibrosis and cirrhosis. Likewise, increased oligoclonality of circulating CD8(+) T cells in chronic HCV infection was identified as an indicator for poor clinical response to IFN-alpha therapy. Moreover, we also found that IFN-alpha therapy enhanced the differentiation of CD8(+) T cells towards a late differentiation phenotype (CD28(-) CD57(+)). In cases of virus elimination the disappearance of expanded terminally differentiated CD8(+) cells was observed. Thus, this study identifies an association of clonal expansions of circulating CD8(+) T cells with liver pathology and provides a possible explanation for the fact that response to IFN-alpha therapy diminishes with the duration of infection.

  6. Removal of hepatitis C virus-infected cells by a zymogenized bacterial toxin.

    Assaf Shapira

    Full Text Available Hepatitis C virus (HCV infection is a major cause of chronic liver disease and has become a global health threat. No HCV vaccine is currently available and treatment with antiviral therapy is associated with adverse side effects. Moreover, there is no preventive therapy for recurrent hepatitis C post liver transplantation. The NS3 serine protease is necessary for HCV replication and represents a prime target for developing anti HCV therapies. Recently we described a therapeutic approach for eradication of HCV infected cells that is based on protein delivery of two NS3 protease-activatable recombinant toxins we named "zymoxins". These toxins were inactivated by fusion to rationally designed inhibitory peptides via NS3-cleavable linkers. Once delivered to cells where NS3 protease is present, the inhibitory peptide is removed resulting in re-activation of cytotoxic activity. The zymoxins we described suffered from two limitations: they required high levels of protease for activation and had basal activities in the un-activated form that resulted in a narrow potential therapeutic window. Here, we present a solution that overcame the major limitations of the "first generation zymoxins" by converting MazF ribonuclease, the toxic component of the E. coli chromosomal MazEF toxin-antitoxin system, into an NS3-activated zymoxin that is introduced to cells by means of gene delivery. We constructed an expression cassette that encodes for a single polypeptide that incorporates both the toxin and a fragment of its potent natural antidote, MazE, linked via an NS3-cleavable linker. While covalently paired to its inhibitor, the ribonuclease is well tolerated when expressed in naïve, healthy cells. In contrast, activating proteolysis that is induced by even low levels of NS3, results in an eradication of NS3 expressing model cells and HCV infected cells. Zymoxins may thus become a valuable tool in eradicating cells infected by intracellular pathogens that

  7. Removal of Hepatitis C Virus-Infected Cells by a Zymogenized Bacterial Toxin

    Shapira, Assaf; Shapira, Shiran; Gal-Tanamy, Meital; Zemel, Romy; Tur-Kaspa, Ran; Benhar, Itai

    2012-01-01

    Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and has become a global health threat. No HCV vaccine is currently available and treatment with antiviral therapy is associated with adverse side effects. Moreover, there is no preventive therapy for recurrent hepatitis C post liver transplantation. The NS3 serine protease is necessary for HCV replication and represents a prime target for developing anti HCV therapies. Recently we described a therapeutic approach for eradication of HCV infected cells that is based on protein delivery of two NS3 protease-activatable recombinant toxins we named “zymoxins”. These toxins were inactivated by fusion to rationally designed inhibitory peptides via NS3-cleavable linkers. Once delivered to cells where NS3 protease is present, the inhibitory peptide is removed resulting in re-activation of cytotoxic activity. The zymoxins we described suffered from two limitations: they required high levels of protease for activation and had basal activities in the un-activated form that resulted in a narrow potential therapeutic window. Here, we present a solution that overcame the major limitations of the “first generation zymoxins” by converting MazF ribonuclease, the toxic component of the E. coli chromosomal MazEF toxin-antitoxin system, into an NS3-activated zymoxin that is introduced to cells by means of gene delivery. We constructed an expression cassette that encodes for a single polypeptide that incorporates both the toxin and a fragment of its potent natural antidote, MazE, linked via an NS3-cleavable linker. While covalently paired to its inhibitor, the ribonuclease is well tolerated when expressed in naïve, healthy cells. In contrast, activating proteolysis that is induced by even low levels of NS3, results in an eradication of NS3 expressing model cells and HCV infected cells. Zymoxins may thus become a valuable tool in eradicating cells infected by intracellular pathogens that express

  8. Prevalence and chemotherapy-induced reactivation of occult hepatitis B virus among hepatitis B surface antigen negative patients with diffuse large B-cell lymphoma: Significance of hepatitis B core antibodies screening

    Elbedewy, T.A.; Elashtokhy, H.A.; Rabee, E.S.; Kheder, G.E.

    2015-01-01

    Background: Occult hepatitis B infection (OBI) is characterized by negative hepatitis B surface antigen (HBsAg) and detectable hepatitis B virus (HBV)-DNA in the liver and/or serum, with or without hepatitis B core antibody (anti-HBc). Anti-HBc is the most sensitive marker of previous HBV. HBV reactivation in patients under immunosuppressive treatment is life-threatening, occurring in both overt and occult HBV especially in hematological malignancies. Aim of the work: To evaluate the prevalence and chemotherapy-induced reactivation of OBI among hepatitis B surface antigen negative patients with diffuse large B-cell lymphoma (DLBCL) patients and to determine the significance of anti-HBc screening among this group of patients before receiving chemotherapy. Patients and methods: This cross-sectional study included 72 DLBCL patients negative for HBsAg, HBsAb and hepatitis C virus antibodies (anti-HCV). Patients were subjected to investigations including anti-HBc. All patients underwent alanine transaminase (ALT) monitoring before each cycle of chemotherapy and monthly for 12 months after the end of chemotherapy. Patients with suspected OBI were tested for HBV-DNA using real-time polymerase chain reaction (PCR). Results: Anti-HBc was detected in 10 of 72 HBsAg negative sera (13.89%) (95% confidence interval 6.9-22.2%). Five of the 10 anti-HBc positive patients in this study had OBI reactivation. Conclusion: The study concluded that anti-HBc screening is mandatory before chemotherapy. HBsAg-negative/anti-HBc-positive patients should be closely observed for signs of HBV reactivation through the regular monitoring of ALT. Prophylaxis lamivudine is recommended for anti-HBc positive patients before chemotherapy.

  9. Kupffer cells promote hepatic steatosis via interleukin-1beta-dependent suppression of peroxisome proliferator-activated receptor alpha activity

    Stienstra, Rinke; Saudale, Fredy; Duval, Caroline; Keshtkar, Shohreh; Groener, Johanna E. M.; van Rooijen, Nico; Staels, Bart; Kersten, Sander; Müller, Michael

    2010-01-01

    Kupffer cells have been implicated in the pathogenesis of various liver diseases. However, their involvement in metabolic disorders of the liver, including fatty liver disease, remains unclear. The present study sought to determine the impact of Kupffer cells on hepatic triglyceride storage and to

  10. Kupffer cells promote hepatic steatosis via interleukin-1-dependent suppression of peroxisome proliferator-activated receptor activity

    Stienstra, R.; Saudale, F.; Duval, C.N.C.; Keshtkar, S.; Groener, C.; Rooijen, van N.; Staels, B.; Kersten, A.H.; Müller, M.R.

    2010-01-01

    Kupffer cells have been implicated in the pathogenesis of various liver diseases. However, their involvement in metabolic disorders of the liver, including fatty liver disease, remains unclear. The present study sought to determine the impact of Kupffer cells on hepatic triglyceride storage and to

  11. A hepatocellular carcinoma cell line producing mature hepatitis B viral particles

    Fellig, Yakov; Almogy, Gidon; Galun, Eithan; Ketzinel-Gilad, Mali

    2004-01-01

    Current in vitro models for hepatitis B virus (HBV) are based on human hepatoblastoma cell lines transfected with HBV genome. The objective of this work was to develop an in vitro, hepatocellular carcinoma (HCC)-based system supporting HBV full replication and producing mature viral particles. The FLC4 human HCC cell line was stably transfected with a plasmid carrying a head-to-tail dimer of the adwHBV genome. One of the clones, FLC4A10 II , exhibited prolonged expression of HBV, as was demonstrated by secreted levels of HBsAg, HBeAg, and HBV DNA in the culture medium of the growing cells. Furthermore, the cells produced HBV particles that were detected by a cesium chloride density gradient performed on the culture medium. Analysis by Southern blot revealed that HBV DNA has integrated into the FLC4A10 II cell genome. The presence of HBV in the FLC4A10 II cells did not cause alterations in cell morphology and the cells continued to resemble mature hepatocytes. They do exhibit a high mitotic activity. The new HBV stably transfected cell line, FLC4A10 II , can serve as an important tool for further exploration of HBV host-pathogen interaction, viral life cycle, and for assessing new antiviral agents

  12. The effect of HIV infection and HCV viremia on inflammatory mediators and hepatic injury-The Women's Interagency HIV Study.

    Sheila M Keating

    Full Text Available Hepatitis C virus infection induces inflammation and while it is believed that HIV co-infection enhances this response, HIV control may reduce inflammation and liver fibrosis in resolved or viremic HCV infection. Measurement of systemic biomarkers in co-infection could help define the mechanism of inflammation on fibrosis and determine if HIV control reduces liver pathology. A nested case-control study was performed to explore the relationship of systemic biomarkers of inflammation with liver fibrosis in HCV viremic and/or seropositive women with and without HIV infection. Serum cytokines, chemokines, growth factors and cell adhesion molecules were measured in HIV uninfected (HIV-, n = 18, ART-treated HIV-controlled (ARTc, n = 20, uncontrolled on anti-retroviral therapy (ARTuc, n = 21 and elite HIV controllers (Elite, n = 20. All were HCV seroreactive and had either resolved (HCV RNA-; <50IU/mL or had chronic HCV infection (HCV RNA+. In HCV and HIV groups, aspartate aminotransferase to platelet ratio (APRI was measured and compared to serum cytokines, chemokines, growth factors and cell adhesion molecules. APRI correlated with sVCAM, sICAM, IL-10, and IP-10 levels and inversely correlated with EGF, IL-17, TGF-α and MMP-9 levels. Collectively, all HCV RNA+ subjects had higher sVCAM, sICAM and IP-10 compared to HCV RNA-. In the ART-treated HCV RNA+ groups, TNF-α, GRO, IP-10, MCP-1 and MDC were higher than HIV-, Elite or both. In ARTuc, FGF-2, MPO, soluble E-selectin, MMP-9, IL-17, GM-CSF and TGF-α are lower than HIV-, Elite or both. Differential expression of soluble markers may reveal mechanisms of pathogenesis or possibly reduction of fibrosis in HCV/HIV co-infection.

  13. Hepatic tissue environment in NEMO-deficient mice critically regulates positive selection of donor cells after hepatocyte transplantation.

    Michaela Kaldenbach

    Full Text Available BACKGROUND: Hepatocyte transplantation (HT is a promising alternative treatment strategy for end-stage liver diseases compared with orthotopic liver transplantation. A limitation for this approach is the low engraftment of donor cells. The deletion of the I-kappa B kinase-regulatory subunit IKKγ/NEMO in hepatocytes prevents nuclear factor (NF-kB activation and triggers spontaneous liver apoptosis, chronic hepatitis and the development of liver fibrosis and hepatocellular carcinoma. We hypothesized that NEMOΔhepa mice may therefore serve as an experimental model to study HT. METHODS: Pre-conditioned NEMOΔhepa mice were transplanted with donor-hepatocytes from wildtype (WT and mice deficient for the pro-apoptotic mediator Caspase-8 (Casp8Δhepa. RESULTS: Transplantation of isolated WT-hepatocytes into pre-conditioned NEMOΔhepa mice resulted in a 6-7 fold increase of donor cells 12 weeks after HT, while WT-recipients showed no liver repopulation. The use of apoptosis-resistant Casp8Δhepa-derived donor cells further enhanced the selection 3-fold after 12-weeks and up to 10-fold increase after 52 weeks compared with WT donors. While analysis of NEMOΔhepa mice revealed strong liver injury, HT-recipient NEMOΔhepa mice showed improved liver morphology and decrease in serum transaminases. Concomitant with these findings, the histological examination elicited an improved liver tissue architecture associated with significantly lower levels of apoptosis, decreased proliferation and a lesser amount of liver fibrogenesis. Altogether, our data clearly support the therapeutic benefit of the HT procedure into NEMOΔhepa mice. CONCLUSION: This study demonstrates the feasibility of the NEMOΔhepa mouse as an in vivo tool to study liver repopulation after HT. The improvement of the characteristic phenotype of chronic liver injury in NEMOΔhepa mice after HT suggests the therapeutic potential of HT in liver diseases with a chronic inflammatory phenotype and

  14. Role of Non-neuronal Cells in Tauopathies After Brain Injury

    2017-09-01

    AWARD NUMBER: W81XWH-15-1-0422 TITLE: Role of Nonneuronal Cells in Tauopathies After Brain Injury PRINCIPAL INVESTIGATOR: Sally A. Frautschy...AND SUBTITLE 5a. CONTRACT NUMBER Role of Non-neuronal Cells in Tauopathies After Brain Injury 5b. GRANT NUMBER W81XWH-15-1-0422 5c. PROGRAM...traumatic brain injury (TBI), specific inflammatory factors (complement proteins) elevated during long asymptomatic prodromal period are responsible

  15. Propofol promotes spinal cord injury repair by bone marrow mesenchymal stem cell transplantation

    Zhou, Ya-jing; Liu, Jian-min; Wei, Shu-ming; Zhang, Yun-hao; Qu, Zhen-hua; Chen, Shu-bo

    2015-01-01

    Propofol is a neuroprotective anesthetic. Whether propofol can promote spinal cord injury repair by bone marrow mesenchymal stem cells remains poorly understood. We used rats to investigate spinal cord injury repair using bone marrow mesenchymal stem cell transplantation combined with propofol administration via the tail vein. Rat spinal cord injury was clearly alleviated; a large number of newborn non-myelinated and myelinated nerve fibers appeared in the spinal cord, the numbers of CM-Dil-l...

  16. Exosome-associated hepatitis C virus in cell cultures and patient plasma

    Liu, Ziqing; Zhang, Xiugen; Yu, Qigui; He, Johnny J.

    2014-01-01

    Highlights: • HCV occurs in both exosome-free and exosome-associated forms. • Exosome-associated HCV is infectious and resistant to neutralizing antibodies. • More exosome-associated HCV than exosome-free HCV is present in patient plasma. - Abstract: Hepatitis C virus (HCV) infects its target cells in the form of cell-free viruses and through cell–cell contact. Here we report that HCV is associated with exosomes. Using highly purified exosomes and transmission electron microscopic imaging, we demonstrated that HCV occurred in both exosome-free and exosome-associated forms. Exosome-associated HCV was infectious and resistant to neutralization by an anti-HCV neutralizing antibody. There were more exosome-associated HCV than exosome-free HCV detected in the plasma of HCV-infected patients. These results suggest exosome-associated HCV as an alternative form for HCV infection and transmission

  17. Exosome-associated hepatitis C virus in cell cultures and patient plasma

    Liu, Ziqing [Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202 (United States); Zhang, Xiugen [Department of Cell Biology and Immunology, University of North Texas Health Science Center, Fort Worth, TX 76107 (United States); Yu, Qigui [Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202 (United States); He, Johnny J., E-mail: johnny.he@unthsc.edu [Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202 (United States); Department of Cell Biology and Immunology, University of North Texas Health Science Center, Fort Worth, TX 76107 (United States)

    2014-12-12

    Highlights: • HCV occurs in both exosome-free and exosome-associated forms. • Exosome-associated HCV is infectious and resistant to neutralizing antibodies. • More exosome-associated HCV than exosome-free HCV is present in patient plasma. - Abstract: Hepatitis C virus (HCV) infects its target cells in the form of cell-free viruses and through cell–cell contact. Here we report that HCV is associated with exosomes. Using highly purified exosomes and transmission electron microscopic imaging, we demonstrated that HCV occurred in both exosome-free and exosome-associated forms. Exosome-associated HCV was infectious and resistant to neutralization by an anti-HCV neutralizing antibody. There were more exosome-associated HCV than exosome-free HCV detected in the plasma of HCV-infected patients. These results suggest exosome-associated HCV as an alternative form for HCV infection and transmission.

  18. Integration-deficient lentivectors: an effective strategy to purify and differentiate human embryonic stem cell-derived hepatic progenitors.

    Yang, Guanghua; Si-Tayeb, Karim; Corbineau, Sébastien; Vernet, Rémi; Gayon, Régis; Dianat, Noushin; Martinet, Clémence; Clay, Denis; Goulinet-Mainot, Sylvie; Tachdjian, Gérard; Tachdjian, Gérard; Burks, Deborah; Vallier, Ludovic; Bouillé, Pascale; Dubart-Kupperschmitt, Anne; Weber, Anne

    2013-07-19

    Human pluripotent stem cells (hPSCs) hold great promise for applications in regenerative medicine. However, the safety of cell therapy using differentiated hPSC derivatives must be improved through methods that will permit the transplantation of homogenous populations of a specific cell type. To date, purification of progenitors and mature cells generated from either embryonic or induced pluripotent stem cells remains challenging with use of conventional methods. We used lentivectors encoding green fluorescent protein (GFP) driven by the liver-specific apoliprotein A-II (APOA-II) promoter to purify human hepatic progenitors. We evaluated both integrating and integration-defective lentivectors in combination with an HIV integrase inhibitor. A human embryonic stem cell line was differentiated into hepatic progenitors using a chemically defined protocol. Subsequently, cells were transduced and sorted at day 16 of differentiation to obtain a cell population enriched in hepatic progenitor cells. After sorting, more than 99% of these APOA-II-GFP-positive