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Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The clinical syndrome of acute liver failure produced by fulminant viral hepatitis can be reproduced in mice by infection with murine hepatitis virus strain 3 (MHV-3). Although it is clear that MHV-3-induced hepatitis depends upon macrophage activation and the expression of a specific prothrombinase, fgl-2, the signaling pathways involved in virally stimulated cell activation are unclear. Since we had previously found that MHV-3 induces the tyrosine phosphorylation of cellular proteins, we investigated the roles of the mitogen-activated protein kinase (MAPK) proteins. In a series of Western blots, immunoprecipitation and in vitro kinase assay studies, we found that both the extracellular signal-related kinase (ERK) and p38 MAPK proteins are tyrosine-phosphorylated and activated following exposure of murine peritoneal exudative macrophages (PEM) to MHV-3. Although p38 phosphorylation and activity are induced soon after MHV-3 exposure, peaking by 1-5 min, ERK phosphorylation and activity increase more gradually, peaking at 20-30 min and gradually fading thereafter. Interestingly, whereas selective p38 inhibition with SB203580 (1-20 microM) abolished the virally stimulated induction of fgl-2 mRNA, protein, and functional activity, selective ERK inhibition with PD98059 (1-50 microM) limited fgl-2 functional activity but had little to no effect on fgl-2 mRNA or protein levels. Moreover, whereas inhibition of ERK had no effect on p38 activity, p38 inhibition consistently increased MHV-3-induced ERK activity. To ensure that these pathways were relevant in vivo, MHV-3 was injected intraperitoneally, and peritoneal exudative macrophages were collected. Again, MHV-3 exposure led to increased p38 and ERK tyrosine phosphorylation. These data argue that MHV-3 induces tightly interconnected ERK and p38 MAPK cascades in the macrophage both in vitro and in vivo. Although the ERK and p38 MAPK proteins have discordant effects at the level of fgl-2 expression, both converge at the level of its activity, suggesting that targeted MAPK inhibition may ultimately be useful in the modulation of viral hepatitis.
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PMID:Murine hepatitis virus strain 3 induces the macrophage prothrombinase fgl-2 through p38 mitogen-activated protein kinase activation. 982

Analyses of mitogen-activated protein kinases (MAPKs) in a mouse hepatitis virus (MHV)-infected macrophage-derived J774.1 cell line showed activation of two MAPKs, p38 MAPK and c-Jun N-terminal kinase (JNK), but not of extracellular signal-regulated kinase (ERK). Activation of MAPKs was evident by 6 h postinfection. However, UV-irradiated MHV failed to activate MAPKs, which demonstrated that MHV replication was necessary for their activation. Several other MHV-permissive cell lines also showed activation of both p38 MAPK and JNK, which indicated that the MHV-induced stress-kinase activation was not restricted to any particular cell type. The upstream kinase responsible for activating MHV-induced p38 MAPK was the MAPK kinase 3. Experiments with a specific inhibitor of p38 MAPK, SB 203580, demonstrated that MHV-induced p38 MAPK activation resulted in the accumulation of interleukin-6 (IL-6) mRNAs and an increase in the production of IL-6, regardless of MHV-induced general host protein synthesis inhibition. Furthermore, MHV production was suppressed in SB 203580-treated cells, demonstrating that activated p38 MAPK played a role in MHV replication. The reduced MHV production in SB 203580-treated cells was, at least in part, due to a decrease in virus-specific protein synthesis and virus-specific mRNA accumulation. Interestingly, there was a transient increase in the amount of phosphorylation of the translation initiation factor 4E (eIF4E) in infected cells, and this eIF4E phosphorylation was p38 MAPK dependent; it is known that phosphorylated eIF4E enhances translation rates of cap-containing mRNAs. Furthermore, the upstream kinase responsible for eIF4E phosphorylation, MAPK-interacting kinase 1, was also phosphorylated and activated in response to MHV infection. Our data suggested that host cells, in response to MHV replication, activated p38 MAPK, which subsequently phosphorylated eIF4E to efficiently translate certain host proteins, including IL-6, during virus-induced severe host protein synthesis inhibition. MHV utilized this p38 MAPK-dependent increase in eIF4E phosphorylation to promote virus-specific protein synthesis and subsequent progeny virus production. Enhancement of virus-specific protein synthesis through virus-induced eIF4E activation has not been reported in any other viruses.
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PMID:Murine coronavirus replication-induced p38 mitogen-activated protein kinase activation promotes interleukin-6 production and virus replication in cultured cells. 1202 26

The viruses that cause hepatitis comprise of at least five different agents, which share the ability to cause inflammation and necrosis of the liver. The disease spectrum is quite diverse and the outcome of infection by the different hepatitis viruses can be rationalized based on virus-host cell interactions. New insights into the molecular basis of viral hepatitis reveal that three of these agents - the hepatitis B, C and E viruses (HBV, HCV and HEV) modulate the mitogen-activated protein kinase (MAPK) signaling pathway. In this review we briefly describe the structural organization of the MAPK cascade and emphasize its importance as a central pathway in the signaling network. Selected mechanisms through which HBV, HCV and HEV proteins target various steps in the MAPK pathway are discussed and used to propose a pro-survival outcome for the host cell. In addition, we offer an insight into how the common theme of MAPK activation and its downstream effects may be used to rationalize the different outcomes of hepatitis B, C and E.
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PMID:Hepatitis viruses and the MAPK pathway: is this a survival strategy? 1268 21

The endogenous cannabinoid anandamide, a lipid mediator, induces various physiologic events such as vascular relaxation, inhibition of gap-junctions formation, tumor proliferation, neurologic analgesia, and apoptosis. Although increased concentration of anandamide in plasma has been implicated in pathophysiologic states including endotoxin-induced hypotension, the effects of anandamide on hepatocytes still remain unclear. In this study, we present evidence that plasma anandamide concentration is highly increased in severe hepatitis and cirrhosis patients. In addition, concentrations of anandamide within the pathophysiologic range potently induced apoptosis of hepatoma cell line (Hep G2) and primary hepatocytes, suggesting a possible link between increased anandamide level and hepatocyte damage. Anandamide-induced cell death was preceded by G0/G1 cell-cycle arrest, activation of proapoptotic signaling (i.e., p38 MAPK and JNK), and inhibition of antiapoptotic signaling (i.e., PKB/Akt) pathways. Moreover, anandamide increased susceptibility to oxidative stress-induced hepatocyte damage. In this context, methyl-beta-cyclodextrin (MCD), a membrane cholesterol depletor, or mevastatin, an HMG-CoA reductase inhibitor, or N-acetyl cysteine, an antioxidant, potently inhibited the anandamide-induced proapoptotic events and cell death, whereas putative cannabinoid receptor antagonists did not exhibit an inhibitory effect on anandamide-induced cell death. Furthermore, binding assay using polymyxin beads revealed that anandamide could interact with cholesterol. In conclusion, our data suggest that cholesterol present in the cell membrane determines the fate of hepatocytes exposed to anandamide, possibly functioning as an anandamide receptor.
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PMID:Membrane cholesterol but not putative receptors mediates anandamide-induced hepatocyte apoptosis. 1457 55

We here review therapeutic application of a synthetic analog of retinoids (vitamin A and its derivatives), named acyclic retinoid (AR), towards chemoprevention of hepatocellular carcinoma (HCC), and its underlying molecular mechanisms. A high incidence of post-therapeutic recurrence has become a major determinant of the prognosis of HCC, especially in the patients of hepatitis virus-infected cirrhosis. Oral supplementation of AR successfully prevented the recurrence of HCC, associated with a disappearance in serum levels of lectin-reactive alpha-fetoprotein (AFP-L3), a marker of occult cancer clones in the liver, suggesting eradication of latent malignant clones from patients' liver. This led us a novel concept of 'clonal deletion' with AR as an agent that is conceptually similar to cancer chemotherapy. HCC in cirrhotic patients contains lower levels of endogenous retinoids and simultaneously is insensitive to retinoic acid (RA) because of malfunction of its nuclear receptor, retinoid X receptor alpha (RXRalpha). In HCC tissues, RXRalpha is constitutively phosphorylated by the action of extracellular signal-regulated kinase (Erk), thereby losing its transactivation activity and becoming resistant to degradation via ubiquitin/proteasome pathway. This leads to accumulation of phospho-inactivated RXRalpha, that functions as a dominant negative receptor and interferes with transactivation by remaining normal RXRalpha. AR but not natural RA prevents phosphorylation of RXRalpha and restores the function of RXRalpha via down-regulating Ras/Erk system, making HCC cells sensitive to the endogenous ligand, 9-cis-RA. This may link to both caspase-dependent and -independent apoptosis of the cancer cells via induction of growth suppressor(s) such as p21CIP1 and/or apoptosis inducer(s) including tissue transglutaminase. AR also enhances the sensitivity of HCC cells to interferons-alpha and -beta, and thereby indirectly promotes apoptosis induced by these interferons. In summary, our clinical experience and basic research together provide a strong rationale to use AR in the chemoprevention of HCC.
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PMID:Acyclic retinoid in the chemoprevention of hepatocellular carcinoma (review). 1501 Aug 15

Increasing evidence demonstrates that IL-6 has a protective role during liver injury. IL-6 activates intracellular pathways via the gp130 receptor. In order to identify IL-6-gp130 pathways involved in mediating liver protection, we analyzed hepatocyte-specific gp130 knockout mice in a concanavalin A-induced (Con A-induced) model of immune-mediated hepatitis. We demonstrated that IL-6-gp130-dependent pathways in hepatocytes alone are sufficient for triggering protection in Con A-induced hepatitis. gp130-STAT3 signaling in hepatocytes mediates the IL-6-triggered protective effect. This was demonstrated by analysis of IL-6-induced protection in mice selectively deficient for gp130-dependent STAT1/3 or gp130-SHP2-RAS signaling in hepatocytes. To identify IL-6-gp130-STAT1/3 dependently expressed liver-protective factors, we performed gene array analysis of hepatic gene expression in hepatocyte-specific gp130(-/-) mice as well as in gp130-STAT1/3- and gp130-SHP2-RAS-MAPK-deficient mice. The mouse IL-8 ortholog KC (also known as Gro-alpha) and serum amyloid A2 (SAA2) was identified as differentially IL-6-gp130-STAT3-regulated genes. Hepatic expression of KC and SAA2 mediate the liver-protective potential of IL-6, since treatment with recombinant KC or serum SAA2 effectively reduced liver injury during Con A-induced hepatitis. In summary, this study defines IL-6-gp130-STAT3-dependent gene expression in hepatocytes that mediates IL-6-triggered protection in immune-mediated Con A-induced hepatitis. Additionally, we identified the IL-6-gp130-STAT3-dependent proteins KC and SAA2 as new candidates for therapeutic targets in liver diseases.
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PMID:The IL-6-gp130-STAT3 pathway in hepatocytes triggers liver protection in T cell-mediated liver injury. 1576 98

The preventive effect of bicyclol, a novel anti-hepatitis drug, on hepatocarcinogenesis and its mechanism of action was studied in vitro. The results clearly indicated that bicyclol at non-toxic doses prevented the malignant transformation of WB-F344 cells (WB cells) induced by 3-methylcholanthrene (3MC) and 12-O-tetradecanoyl phorbol 13-acetate (TPA). Furthermore, bicyclol inhibited proliferation of quiescent WB cells stimulated by TPA and blocked TPA-induced down-regulation of the gap junctional intercellular communication (GJIC). Immunoblot analysis demonstrated that bicyclol exhibited a remarkable reversing effect on TPA-induced cPKC-alpha and phosphor-ERK1/2 expressions. In addition, bicyclol attenuated TPA-induced IkappaB-alpha degradation. In conclusion, our results support that bicyclol has chemopreventive action against hepatocarcinogenesis through inhibition of related signal transduction.
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PMID:Chemopreventive effect of bicyclol on malignant transformation of WB-F344 rat liver epithelial cells and its effect on related signal transduction in vitro. 1599 5

Hepatitis B virus X protein (HBx) has many cellular functions and is a major factor in hepatitis and hepatocellular carcinoma caused by HBV infection. A proteomic approach was used to search for HBx-interacting proteins in order to elucidate the molecular mechanism of hepatocarcinogenesis. HBx was attached to myc and flag tags (MEF tags) and expressed in 293T cells; the protein complex formed within the cells was purified and characterized by mass spectrometry. COP9 signalosome (CSN) subunits 3 and 4 were subsequently identified as HBx-interacting proteins. In addition, CSN subunit 5, Jun activation domain-binding protein 1 (Jab1), was shown to be a novel cellular target of HBx. In vivo and in vitro interactions between HBx and Jab1 were confirmed by standard immunoprecipitation and GST pull-down assays. An analysis of HBx deletion constructs showed that amino acids 30-125 of HBx were responsible for binding to Jab1. Confocal laser microscopy demonstrated that HBx was mainly localized in the cytoplasm, while Jab1 was found mainly in the nucleus and partially in the cytoplasm, and that the two proteins colocalized in the cytoplasm. The cotransfection of HBx and Jab1 resulted in substantial activator protein 1 (AP-1) activation and knockdown of endogenous Jab1 attenuated AP-1 activation caused by HBx. In addition, the coexpression of HBx and Jab1 potentiated phosphorylation of JNK, leading to the subsequent phosphorylation of c-Jun, whereas the level of c-Jun and JNK phosphorylation induced by HBx was decreased in Jab1 knockdown cells. These results suggest that the interaction between HBx and Jab1 enhances HBx-mediated AP-1 activation.
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PMID:The hepatitis B virus X protein enhances AP-1 activation through interaction with Jab1. 1624 77

TNF-alpha activates several intracellular pathways to regulate inflammation, cell death, and proliferation. In the liver, TNF-alpha is not only a mediator of hepatotoxicity but also contributes to the restoration of functional liver mass by driving hepatocyte proliferation and liver regeneration. This review summarizes recent advances in TNF-alpha signaling mechanisms that demonstrate how the IKK, ROS, and JNK pathways interact with each other to regulate hepatocyte apoptosis and proliferation. Activation of these pathways is causatively linked to liver injury induced by concanavalin A, TNF-alpha, and ischemia-reperfusion and to liver regeneration and hepatocarcinogenesis. In light of recent findings, pharmacological inhibitors of JNK and IKK and antioxidants may be promising new tools for the treatment of hepatitis, ischemia-reperfusion injury, and hepatocellular carcinoma.
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PMID:Mechanisms of Liver Injury. I. TNF-alpha-induced liver injury: role of IKK, JNK, and ROS pathways. 1653 70

We previously demonstrated that infection of cultured cells with murine coronavirus mouse hepatitis virus (MHV) resulted in activation of the mitogen-activated protein kinase (Raf/MEK/ERK) signal transduction pathway (Y. Cai et al., Virology 355:152-163, 2006). Here we show that inhibition of the Raf/MEK/ERK signaling pathway by the MEK inhibitor UO126 significantly impaired MHV progeny production (a reduction of 95 to 99% in virus titer), which correlated with the phosphorylation status of ERK1/2. Moreover, knockdown of MEK1/2 and ERK1/2 by small interfering RNAs suppressed MHV replication. The inhibitory effect of UO126 on MHV production appeared to be a general phenomenon since the effect was consistently observed in all six different MHV strains and in three different cell types tested; it was likely exerted at the postentry steps of the virus life cycle because the virus titers were similarly inhibited from infected cells treated at 1 h prior to, during, or after infection. Furthermore, the treatment did not affect the virus entry, as revealed by the virus internalization assay. Metabolic labeling and reporter gene assays demonstrated that translation of cellular and viral mRNAs appeared unaffected by UO126 treatment. However, synthesis of viral genomic and subgenomic RNAs was severely suppressed by UO126 treatment, as demonstrated by a reduced incorporation of [3H]uridine and a decrease in chloramphenicol acetyltransferase (CAT) activity in a defective-interfering RNA-CAT reporter assay. These findings indicate that the Raf/MEK/ERK signaling pathway is involved in MHV RNA synthesis.
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PMID:Suppression of coronavirus replication by inhibition of the MEK signaling pathway. 1707 28


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