Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

One function of N-linked glycans is to assist in the folding of glycoproteins by mediating interactions of the lectin-like chaperone proteins calnexin and calreticulin with nascent glycoproteins. These interactions can be prevented by inhibitors of the alpha-glucosidases, such as N-butyl-deoxynojirimycin (NB-DNJ) and N-nonyl-DNJ (NN-DNJ), and this causes some proteins to be misfolded and retained within the endoplasmic reticulum (ER). We have shown previously that the NN-DNJ-induced misfolding of one of the hepatitis B virus (HBV) envelope glycoproteins prevents the formation and secretion of virus in vitro and that this inhibitor alters glycosylation and reduces the viral levels in an animal model of chronic HBV infection. This led us to investigate the effect of glucosidase inhibitors on another ER-budding virus, bovine viral diarrhea virus, a tissue culture surrogate of human hepatitis C virus (HCV). Here we show that in MDBK cells alpha-glucosidase inhibitors prevented the formation and secretion of infectious bovine viral diarrhea virus. Data also are presented showing that NN-DNJ, compared with NB-DNJ, exhibits a prolonged retention in liver in vivo. Because viral secretion is selectively hypersensitive to glucosidase inhibition relative to the secretion of cellular proteins, the possibility that glucosidase inhibitors could be used as broad-based antiviral hepatitis agents is discussed. A single drug against HBV, HCV, and, possibly, HDV, which together chronically infect more than 400 million people worldwide, would be of great therapeutic value.
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PMID:Imino sugars inhibit the formation and secretion of bovine viral diarrhea virus, a pestivirus model of hepatitis C virus: implications for the development of broad spectrum anti-hepatitis virus agents. 1051 44

Galectin-1, an endogenous lectin with immunomodulatory activities, induces selective, Fas-independent apoptosis of activated T cells. The aim of the present study was to evaluate the effect galectin-1 exerts on concanavalin A (Con A)-induced hepatitis, a T-cell-dependent model of liver injury. Con A administration resulted in liver injury, as shown by the increased transaminase plasma levels and liver DNA fragmentation, and caused spleen T-cell activation, which was associated with a strong increment in liver infiltrating T helper cells. Moreover, Con A injection leads to a marked increase in plasma tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) levels. Galectin-1 pretreatment dose-dependently prevented both liver injury and T-helper cell liver infiltration induced by Con A. In vivo and in vitro experiments indicated that the protective effects of galectin-1 depend on the selective elimination of Con A-activated T cells. In addition, galectin-1 almost completely prevented the Con A-induced increase in plasma TNF-alpha and IFN-gamma, an effect that was, at least in part, independent on the elimination of activated T helper cells, because galectin-1 prevented lipopolysaccharide (LPS)-induced release of TNF-alpha and IFN-gamma also from macrophages in vitro, without affecting their viability. The present study suggests that galectin-1 is potentially useful in the treatment of T-cell-mediated human liver disorders.
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PMID:Galectin-1 exerts immunomodulatory and protective effects on concanavalin A-induced hepatitis in mice. 1065 63

Hepatocellular carcinoma (HCC) is increasing in many countries as a result of an increase in hepatitis C virus (HCV) infection since World War II. The epidemiology of HCC varies with the global region. There have been conflicting observations from different parts of the world concerning the frequency of HCC in patients who in the distant past had post-transfusion non-A, non-B hepatitis. The genetic basis of hepatocarcinogenesis is still poorly understood. In hepatitis B virus (HVB) associated HCC, codon 249 mutation in the p 53 gene seems more related to exposure to aflatoxin B1 than to hepatocarcinogenesis itself. HCC that occurs in children in high HBV endemic regions could be associated with germ-line mutations, but little information is available; not much is known about chemical hepatocarcinogens in the environment other than aflatoxins. The X gene of HBV seems to play an important role in HBV-associated hepatocarcinogenesis. There are preliminary observations on the molecular mechanism of HCV-associated HCC, such as HCV core protein inducing HCC in transgenic mice and the NS3 genome transforming NIH 3T3 cells. Pathological distinction between preneoplastic and very early transformed lesions still depends on classical morphology, and a more genetically oriented differential diagnosis is required. Clinical diagnosis based on modern imaging has improved greatly, but is still unsatisfactory in the differential diagnosis of preneoplastic and early transformed nodules, because the vasculature changes that occur within the nodule are not accurately discerned with the current imaging. Use of sensitive des-gamma-carboxy prothrombin (PIVKA II) assay, and lectin affinity chromatography separating HCC specific subspecies of AFP molecules with a more practical biochemical technique will further improve diagnosis. Early diagnosis and transplantation are the best treatment at the moment, but transplantation is not widely available because of the donor shortage. Despite successful resection, the remnant cirrhotic liver frequently develops new HCC lesions, seriously curtailing long-term survival. All-out efforts should be directed to the prevention of HCC, through prevention of viral hepatitis, prevention of acute hepatitis from becoming chronic, prevention of chronic hepatitis from progressing to cirrhosis, and prevention of the cirrhotic liver from developing HCC (chemoprevention). At the moment, very few such studies exist.
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PMID:Hepatocellular carcinoma. 1072 7

Most of the alpha-fetoprotein-producing gastric cancer is advanced at the time of presentation, and alpha-fetoprotein-producing early gastric cancer is extremely rare. Alpha-fetoprotein-producing early gastric cancer was confirmed by immunohistochemistry and serum analysis of alpha-fetoprotein concentration. Alpha-fetoprotein carbohydrate chain microheterogeneity was further evaluated by lectin binding specificity. A 71-year-old-male patient underwent total gastrectomy due to a depressed type of gastric cancer in the upper third of the stomach. There was no evidence of synchronous liver metastasis and hepatitis. Histological examination revealed that the tumor invasion was limited to the submucosal layer, and that the tumor consisted of both well-differentiated, papillo-tubular growth areas and trabecular and medullary growth areas resembling hepatoid carcinoma. Immunohistochemically, alpha-fetoprotein and cytokeratin localization were confirmed in the cancer cells, whereas simultaneous localization of carcinoembryonic antigen, carbohydrate antigen 19-9, and human chorionic gonadotropin could not be observed. The elevated preoperative serum alpha-fetoprotein concentration (113 ng/mL) promptly decreased to and remained within normal levels postoperatively (3.6 ng/mL). The predominance of a strong-bound fraction with lectin, which was demonstrated by lens culinalis agglutinin affinity chromatography, suggests that the alpha-fetoprotein carbohydrate chain species in the present case was a hepatic type. The patient received adjuvant intravenous chemotherapy consisting of 5-fluorouracil and cisplatin, and has been further supported by oral 5-fluorouracil administration. The patient has been disease free for 15 months following surgery. We report here a rare case of alpha-fetoprotein producing early gastric cancer. The alpha-fetoprotein carbohydrate phenotype analysis helps to consider the primary differentiation of alpha-fetoprotein-producing gastric cancer.
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PMID:A rare case of alpha-fetoprotein-producing early gastric cancer. 1146 4

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

Although neurovirulent mouse hepatitis virus (MHV) strain JHMV multiplies in a variety of brain cells, expression of its receptor carcinoembryonic antigen cell adhesion molecule 1 (CEACAM 1) (MHVR) is restricted only in microglia. The present study was undertaken to clarify the mechanism of an extensive JHMV infection in the brain by using neural cells isolated from mouse brain. In contrast to wild-type (wt) JHMV, a soluble-receptor-resistant mutant (srr7) infects and spreads solely in an MHVR-dependent fashion (F. Taguchi and S. Matsuyama, J. Virol. 76:950-958, 2002). In mixed neural cell cultures, srr7 infected a limited number of cells and infection did not spread, although wt JHMV induced syncytia in most of the cells. srr7-infected cells were positive for GS-lectin, a microglia marker. Fluorescence-activated cell sorter analysis showed that about 80% of the brain cells stained with anti-MHVR antibody (CC1) were also positive for GS-lectin. Pretreatment of those cells with CC1 prevented virus attachment to the cell surface and also blocked virus infection. These results show that microglia express functional MHVR that mediates JHMV infection. As expected, in microglial cell-enriched cultures, both srr7and wt JHMV produced syncytia in a majority of cells. Treatment with CC1 of mixed neural cell cultures and microglia cultures previously infected with wt virus failed to block the spread of infection, indicating that wt infection spreads in an MHVR-independent fashion. Thus, the present study indicates that microglial cells are the major population of the initial target for MHV infection and that the wt spreads from initially infected microglia to a variety of cells in an MHVR-independent fashion.
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PMID:Receptor-independent spread of a highly neurotropic murine coronavirus JHMV strain from initially infected microglial cells in mixed neural cultures. 1585 95

The Long-Evans Cinnamon (LEC) rat, an animal model of Wilson's disease, spontaneously develops hepatitis as the result of abnormal copper accumulation in liver. The findings of this study show that copper, hydrogen peroxide, and lipid peroxides accumulate to drastically high levels in LEC rat serum in acute hepatitis but not chronic hepatitis. The effect of these reactive oxygen species (ROS) on oligosaccharides of glycoproteins in the LEC rat serum was examined. Lectin blot and lectin ELISA analyses showed that sialic acid and galactose residues of serum glycoproteins including transferrin were decreased in acute hepatitis. Further analyses of oligosaccharide structures of transferrin demonstrated that di-sialylated and asialo-agalacto biantennary sugar chains, but not tri-sialylated sugar chain, exist on transferrin in the acute hepatitis rats. In addition, treatment of non-hepatitis rat serum with copper ions and hydrogen peroxide decreased tri-sialylated sugar chain of the normal transferrin and increased di-sialylated and asialo-agalacto biantennary sugar chains. This is the first evidence to show that ROS result in the cleavage of oligosaccharides of glycoproteins in vivo, and indicate this cleavage of oligosaccharides may contribute the development of acute hepatitis.
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PMID:Reactive oxygen species modify oligosaccharides of glycoproteins in vivo: a study of a spontaneous acute hepatitis model rat (LEC rat). 1648 Jun 86

Mannan binding lectin (MBL) is a pattern recognition molecule of the innate immune system that binds to sugars on the surface of invading micro-organisms. Target binding, complement activation and other functions of MBL are dependent on the presence of multiple carbohydrate recognition domains. Several polymorphisms in the promoter and structural regions of MBL2 adversely affect the plasma concentration and oligomeric state of MBL. The possession of mutant alleles has been linked to disease outcome for a variety of bacterial and viral infections. Viral hepatitis is caused by unrelated viruses referred to as hepatitis virus A-E. The disease usually has both acute and chronic phases, the latter leading to cirrhosis and hepatocellular carcinoma. Hepatitis viruses B and C (HBV and HCV, respectively) are a significant cause of morbidity worldwide. HBV encodes envelope glycoproteins termed large, middle, and small that may exist in glycosylated or unglycosylated forms on the virion. An interaction between HBV glycoproteins and MBL has been demonstrated in vitro. Significant associations between MBL levels, determined by MBL2 haplotypes, and HBV persistence and disease progression have been described. HCV encodes two highly glycosylated envelope proteins, E1 and E2, which are potential targets for interaction with MBL. Mutant MBL2 haplotypes have been linked to disease progression and response to therapy in HCV infection. Here we summarise the effect of MBL2 polymorphisms on MBL function and how this may relate to disease outcome in HBV and HCV infection.
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PMID:Mannan binding lectin and viral hepatitis. 1715 24

The immune response to foreign or self antigens mediates liver damage during viral or autoimmune hepatitis. However, it now appears that also specific antigen-independent liver diseases, where liver damage has been attributed to occur from oxygen radical formation, seem to be mediated by cells of the innate and adaptive immune response. These liver disorders include alcoholic liver disease, non-alcoholic fatty liver disease or non-alcoholic steatohepatitis, and ischemia/reperfusion injury that impairs the function of liver grafts. Here it seems that breakdown of the gastrointestinal barrier might increase the concentration of bacterial toxins in the portal blood, which then activate cells of the innate immune system, e. g., Kupffer cells, but, depending on the nature of the toxin, probably also conventional T cells. Invariant NKT cells which specifically recognize glycolipid antigens were supposed to become activated during metabolic disorders related to obesity. However, both steatohepatitis as well as ischemia/reperfusion injury are associated with a Th1 cytokine response characterized by IFNgamma and TNFalpha elevation, that might reflect an NKT cell response on the one hand, but also conventional T lymphocytes, in particular CD4 (+) T cells, are critical for the pathophysiology of these disorders. In 1992 we described a model of T cell-dependent liver injury inducible by the T cell-mitogenic lectin concanavalin A. This model of immune-mediated liver injury was intensively used to study pathophysiological immune effector mechanisms as well as cytokine signaling important for hepatocellular apoptosis, inhibition of apoptosis and regeneration. Recently it became evident that the inflammatory response in this model is regulated by specific cytokine signals as well as by immune regulator cells. The immune-regulatory functions of the liver are of particular interest with respect to the scavenger function of this organ, being continuously exposed to foreign antigenic material from the gut which should be eliminated without causing chronic disease.
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PMID:Cellular and cytokine-mediated mechanisms of inflammation and its modulation in immune-mediated liver injury. 1723 22

Concanavalin A (Con A), a lectin from Jack bean seeds that, once bound to the mannose moiety on the cell membrane glycoprotein, is internalized preferentially to the mitochondria. A BNIP3-mediated mitochondria autophagy is then induced, and causes the tumor cells to undergo autophagic cell death. Con A is also a T cell mitogen that can induce autoimmune hepatitis in mice. Because of the dual properties (autophagic cytotoxicity and immunomodulation) via the specific mannose binding, Con A can exert a potent anti-hepatoma therapeutic effect by inhibiting tumor nodule formation in the liver and prolonging the survival of the tumor-bearing mice. The anti-tumor effect is primarily mediated by activated CD8(+) T cells, and will also establish a tumor antigen-specific immune memory during the hepatic inflammation. This finding provides a novel mechanism in which Con A can be used as an anti-hepatoma agent, and also gives support for the search for natural lectins as anti-cancer compounds.
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PMID:Induction of autophagy by concanavalin A and its application in anti-tumor therapy. 1725 64


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