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)

Transgenic mice carrying the c-myc oncogene under control of woodchuck hepatitis virus (WHV) DNA sequences invariably develop hepatocellular carcinoma (HCC), despite a temporally limited expression of the transgene in the neonatal liver. To better characterize the different steps of the tumorigenic process, we analyzed the liver expression of the c-myc transgene and several growth-related genes by in situ hybridization and Northern blotting. In parallel studies, proliferated changes were investigated by detection of bromodeoxy-uridine-positive S-phase nuclei and apoptosis was evaluated by in situ nick end-labeling of DNA. During the neonatal period, high levels of c-myc messenger RNAs (mRNAs) were detected in all hepatocytes, and the expression of insulin-like growth factor II (IGF II) was frequently enhanced, correlating with increased cell proliferation. Despite elevated expression of the p53 gene, no change in liver cell apoptosis was observed. After weaning, c-myc transgene expression decreased to undetectable levels in all hepatocytes, whereas proliferation decreased but remained notably higher than in age-matched controls. The expression of c-fos, c-jun, and c-H-ras was highly variable during the preneoplastic period and in the tumors, with no consistent increase compared with controls. Resurgence of c-myc transgene expression was evidenced in all cells from hyperplastic lesions and carcinomas, accompanied with frequent focal reactivation of IGF II. Thus the strong proliferative stimulus induced by the combined effects of c-myc and IGF II in the neonatal liver might initiate a process characterized by persistent, dysregulated hepatocyte proliferation, in turn greatly increasing the risk of hepatocellular transformation.
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PMID:Hepatocarcinogenesis in woodchuck hepatitis virus/c-myc mice: sustained cell proliferation and biphasic activation of insulin-like growth factor II. 909 91

The interferon-gamma (IFN-gamma) transgenic mouse expresses the IFN-gamma gene strongly in the liver and develops chronic hepatitis from 6-10 weeks of age. Previously we reported the detection of hepatocyte apoptosis and the expression of the Fas system in the transgenic mouse liver. The objective of the present study was to examine the possible development of favorable conditions for predisposing cells to malignancy. The connection between the cell cycle and cancer has become evident, and the relation of cyclin D1 (CD1) with hepatocellular carcinomas has been strengthened. In the liver of transgenic mice of 48 weeks of age, c-myc and CD1 gene expression was induced, indicating progression of the cell cycles. p21 gene expression in the transgenic mouse liver might counteract cell-cycle progression promoted by c-myc and CD1. In the liver of 8-week-old transgenic mice, expression of c-myc mRNA was correlated with the levels of plasma transaminase activities. In these 8-week-old transgenic mice, however, CD1 mRNA was not induced, regardless of the progression of hepatitis. Based on these results, we conclude that long lasting hepatitis may lead to favorable conditions for predisposing cells to malignancy.
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PMID:Long lasting chronic hepatitis is accompanied by cyclin D1 gene expression in the mouse. 1042 76

Programmed cell death (apoptosis), a form of cell death, described by Kerr and Wyllie some 20 years ago, has generated considerable interest in recent years. The mechanisms by which this mode of cell death (seen both in animal and plant cells), takes place have been examined in detail. Extracellular signals and intracellular events have been elaborated. Of interest to the clinician, is the concentrated effort to study pharmacological modulation of programmed cell death. The attempt to influence the natural phenomenon of programmed cell death stems from the fact that it is reduced (like in cancer) or increased (like in neurodegenerative diseases) in several clinical situations. Thus, chemicals that can modify programmed cell death are likely to be potentially useful drugs. From foxglove, which gave digitalis to the Pacific Yew from which came taxol, plants have been a source of research material for useful drugs. Recently, a variety of plant extracts have been investigated for their ability to influence the apoptotic process. This article discusses some of the interesting data. The ability of plants to influence programmed cell death in cancerous cells in an attempt to arrest their proliferation has been the topic of much research. Various cell-lines like HL60, human hepatocellular carcinoma cell line (KIM-1), a cholangiocarcinoma cell-line (KMC-1), B-cell hybridomas, U937 a monocytic cell-line, HeLa cells, human lymphoid leukemia (MOLT-4B) cells and K562 cells have been studied. The agents found to induce programmed cell death (measured either morphologically or flow cytometrically) included extracts of plants like mistletoe and Semicarpus anacardium. Isolated compounds like bryonolic acid (from Trichosanthes kirilowii var. Japonica, crocin (from saffron) and allicin (from Allium sativum) have also been found to induce programmed cell death and therefore arrest proliferation. Even Chinese herbal medicine "Sho-saiko-to" induces programmed cell death in selected cancerous cell lines. Of considerable interest is the finding that Panax ginseng prevents irradiation-induced programmed cell death in hair follicles, suggesting important therapeutic implications. Nutraceuticals (dietary plants) like soya bean, garlic, ginger, green tea, etc. which have been suggested, in epidemiological studies, to reduce the incidence of cancer may do so by inducing programmed cell death. Soy bean extracts have been shown to prevent development of diseases like polycystic kidneys, while Artemisia asiatica attenuates cerulein-induced pancreatitis in rats. Interestingly enough, a number of food items as well as herbal medicines have been reported to produce toxic effects by inducing programmed cell death. For example, programmed cell death in isolated rat hepatocytes has been implicated in the hepatitis induced by a herbal medicine containing diterpinoids from germander. Other studies suggest that rapid progression of the betel- and tobacco-related oral squamous cell carcinomas may be associated with a simultaneous involvement of p53 and c-myc leading to inhibition of programmed cell death. Several mechanisms have been identified to underlie the modulation of programmed cell death by plants including endonuclease activation, induction of p53, activation of caspase 3 protease via a Bcl-2-insensitive pathway, potentiate free-radical formation and accumulation of sphinganine. Programmed cell death is a highly conserved mechanism of self-defense, also found to occur in plants. Hence, it is natural to assume that chemicals must exist in them to regulate programmed cell death in them. Thus, plants are likely to prove to be important sources of agents that will modulate programmed cell death.
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PMID:Modulation of programmed cell death by medicinal plants. 1072 85

Hepatitis virus, especially hepatitis C virus(HCV), is suggested to be associated with lymphomagenesis. A high prevalence(33%) of HCV among non-Hodgkin's lymphoma(NHL) patients has been reported mainly in Italy, but the prevalence is low in other countries. HCV-related NHL is varied histopathologically, including diffuse large B cell lymphoma, immunocytoma or follicular lymphoma(REAL). The HCV genotypes involved are 1b, 2a or 2c(Simmonds). Although HCV RNA + strand has been detected in lymphoma tissue in various studies, there are not many studies in which HCV RNA-strand has been detected. Recent studies have shown that BCL-2 plays an important role in lymphoproliferation by suppressing apoptosis, that HCV core protein regulates c-myc transcription and that BCL-2 and c-myc work together in lymphomagenesis. It seems difficult to provide reasonable explanations regarding these puzzling epidemiological findings and lymphomagenesis.
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PMID:[Hepatitis virus and malignant lymphoma]. 1074 Nov 25

The central role of T cell activation in hepatocellular injury has been well documented. In this article, we provide evidence suggesting that T cells may also play a protective role in liver disease by releasing interleukin-22 (IL-22), a recently identified T cell-derived cytokine whose biological significance is unclear. IL-22 messenger RNA and protein expression are significantly elevated in T cell-mediated hepatitis induced by concanavalin A (ConA) but are less extensively elevated in the carbon tetrachloride-induced liver injury model. Activated CD3(+) T cells are likely responsible for the production of IL-22 in the liver after injection of ConA. The IL-22 receptor is normally expressed at high levels by hepatocytes and further induced after ConA injection. IL-22 blockade with a neutralizing antibody reduces signal transducer and activator of transcription factor 3 (STAT3) activation and worsens liver injury in T cell-mediated hepatitis, whereas injection of recombinant IL-22 attenuates such injury. In vitro treatment with recombinant IL-22 or overexpression of IL-22 promotes cell growth and survival in human hepatocellular carcinoma HepG2 cells. Stable overexpression of IL-22 in HepG2 cells constitutively activates STAT3 and induces expression of a variety of antiapoptotic (e.g., Bcl-2, Bcl-xL, Mcl-1) and mitogenic (e.g., c-myc, cyclin D1, Rb2, CDK4) proteins. Blocking STAT3 activation abolishes the antiapoptotic and mitogenic actions of IL-22 in hepatic cells. In conclusion, the T cell-derived cytokine IL-22 is a survival factor for hepatocytes; this suggests that T cell activation may also prevent and repair liver injury by releasing hepatoprotective cytokine IL-22 in addition to its previously documented central role in hepatocellular injury.
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PMID:Interleukin 22 (IL-22) plays a protective role in T cell-mediated murine hepatitis: IL-22 is a survival factor for hepatocytes via STAT3 activation. 1512 62

Oral administration of 100 and 200 mg/kg body weight/day of 4,4-dimethoxy-5,6,5', 6'-dimethylene-dioxy-2-hydroxymethyl-2'-carbonyl biphenyl, Bicyclol, inhibited rat hepatic preneoplastic lesions induced by diethylnitrosamine (DEN). Bicyclol reduced densities of number and area of gamma-glutamyltransferase positive foci, indexes for neoplastic hyperplasia; and also suppressed protein expressions for glutathione S transferase P isoform (GST-P) and alpha-fetal protein and mRNA for N-ras, c-myc and PKCalpha genes. With increases of total microsomal P450 and specific CYP2B1 activities in normal rat liver, Bicyclol enhanced particularly the denitrosation of DEN, a low toxic pathway of metabolism. There is a minor effect of Bicyclol on the deethylation of DEN to produce highly mutagenic metabolites. These results suggest that Bicyclol exists the ability of protecting hepatocytes from the mutagenicity of DEN. Such hypothesis was validated by the observation that Bicyclol inhibited DEN-induced unscheduled DNA synthesis, a DNA damage index, in primary cultured rat hepatocytes. More, in virto Bicyclol inhibited two-stages transformation of mice fibroblastic Balb/c 3T3 cells induced by 3-methylcholanthrene and tetradecanoyl-phorbol 13-acetate (TPA), and blocked the anchorage-independent growth of transformed cells in soft agar. Bicyclol also suppressed TPA-stimulated Balb/c 3T3 cell proliferation in both cell number and 3H-thymidine incorporation. Dot blot indicated that Bicyclol inhibited mRNA expressions of H-ras, c-myc and PKCalpha genes by TPA-stimulation. These data demonstrate that Bicyclol prevents carcinogens-induced animal neoplasm and cell malignant transformation via mechanisms at stages of initiation and promotion. It substantiates those evidences that Bicyclol would be used as potential a chemopreventive agent for hepatocarcinogenesis along with its major therapy against chronic anti-hepatitis.
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PMID:Chemoprevention of bicyclol against hepatic preneoplastic lesions. 1742 Oct 70

Interferon-gamma (IFNgamma) is a central component of the complex cytokine and inflammatory response that contributes to liver cell injury in hepatitis. We report that in the primary hepatocyte IFNgamma synergizes with the mechanistically distinct apoptotic stimuli CD95, tumour necrosis factor-alpha (TNFalpha) and UV-irradiation. For the first time in primary hepatocytes, we show that IFNgamma-mediated apoptotic signalling requires the cell surface interaction of CD95 and its ligand, and we demonstrate that IFNgamma induces soluble CD95 ligand release from hepatocyte monolayers. Utilizing c-myc phosphorothioate antisense fragments, we suppresses hepatocyte apoptosis induced by IFNgamma. In summary, we identify apoptotic pathways that contribute to IFNgamma-mediated cell death. The hepatocellular response to IFNgamma signalling can be modulated by cytokines and by the interruption of CD95 interaction with its ligand. We present evidence to suggest that c-myc contributes to IFNgamma signalling.
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PMID:c-Myc partially mediates IFNgamma-induced apoptosis in the primary hepatocyte. 1750 42

The delta antigen (HDAg) is the only protein encoded by the hepatitis delta virus (HDV) RNA genome. The HDAg contains an RNA binding domain, a dimerization domain, and a nuclear localization signal (NLS). The nuclear import of HDV RNPs is thought to be one of the first tasks of the HDAg during the HDV replication cycle. Using c-myc-PK fusions with several regions of the HDAg in transfection assays in Huh7 cells, we found that the HDAg NLS consists of a single stretch of 10 amino acids, EGAPPAKRAR, located in positions 66-75. Deletion and mutation analysis of this region showed that both the acidic glutamic acid residue at position 66 and the basic arginine residue at position 75 are essential for promoting nuclear import.
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PMID:Characterization of the nuclear localization signal of the hepatitis delta virus antigen. 1789 93

The formation and development of cancer is associated with various genetic abnormalities. Recent progress in the study of genetic changes in hepatocellular carcinoma (HCC) have clarified the aberrations of oncogenes and tumor suppressor genes, as well as the role of the hepatitis virus in hepatocarcinogenesis. Overexpression of the c-myc gene, inactivation of the p53 and RB genes, and the loss of heterozygosity (LOH) of some chromosomes where tumor suppressor genes may be located have been reported in association with the progression of HCC. However, genetic abnormalities of HCC at the early stages have yet to be elucidated. On the other hand, the association between HCC and chronic infection with the hepatitis virus also shows the relevance of the oncogenic potential of the hepatitis virus to HCC formation. Some regions of HBV genome, especially the HBV X gene, stimulate the various cellular activities related to tumor promotion and contribute to hepatocarcinogenesis. The knowledge of genetic abnormalities is helpful in the elucidation of pathogenesis and probably in the diagnosis, prognosis and therapy of HCC. Further studies of these genetic changes will apparently promote molecular diagnosis and gene therapy in HCC.
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PMID:Molecular aspects of hepatocarcinogenesis and their clinical implications - review. 2156 67

CIP2A is a human oncoprotein that inhibits PP2A and stabilizes c-myc in human malignancies. Autoantibodies to CIP2A protein have been reported to be present in higher levels in sera from patients with hepatocellular carcinoma (HCC) than in sera of healthy individuals. The CIP2A gene has been demonstrated as a potential cancer susceptibility gene. To elucidate whether common CIP2A variants are associated with HCC susceptibility, we conducted a case-control study comprising 233 cases of HCC and 280 controls matched on age, gender and ethnicity in the Chinese Han population. Two haplotype-tagging single nucleotide polymorphisms (htSNPs) (rs2278911 and rs4855656) from the HapMap database were analyzed, which provide an almost complete coverage of the genetic variations in the CIP2A gene. We found that neither of these htSNPs and haplotypes were associated with the risk of HCC. However, an interaction was observed between hepatitis virus B and C infection (HBV and HCV) and the C carriers (TC or CC) of rs2278911 on HCC risk (OR=12.35; 95% CI, 4.93-19.87). No such association was found for rs4855656. Our study also demonstrated that two htSNPs (rs2278911 and rs4855656) in the CIP2A gene are not associated with the risk of HCC. HBV and HCV infection was found to exert a synergistic effect on the risk of HCC in individuals with the C carriers (TC or CC) of rs2278911 in the Chinese Han population.
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PMID:HapMap-based study of CIP2A gene polymorphisms and HCC susceptibility. 2284 83


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