Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019163 (hepatitis B)
 38,309 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Plasma of cAMP and cGMP in 30 cases of chronic active hepatitis (group of cholestatic patients) as well as in 20 cases of chronic hepatitis with submassive or massive necrosis (group of chronic severe hepatitis patients) were studied with 125I-marked radioimmunoassay. 50 cases with their serum bilirubin levels higher than 171 mumol/L were selected as subjects for this study. Among them, 42 were diagnosed as hepatitis B, 6 as coinfection of hepatitis A and B. According to differentiation of symptoms and signs of TCM, 24 were diagnosed as simple hepatitis due to blood stasis and blood heat, 17 as hepatitis due to blood stasis and blood heat accompanying symptoms of Yang deficiency of the Spleen and Kidney. 20 healthy persons were selected as controls. The results were as follows: cAMP was 56.82 +/- 25.54 ng/L and 80.32 +/- 20.73 ng/L, and cGMP was 9.07 +/- 6.56 ng/L and 19.49 +/- 9.34 ng/L in the group of cholestatic patients and in the group of chronic severe hepatitis patients respectively. Both were higher than those in the control group whose cAMP was 14.12 +/- 3.25 ng/L and cGMP was 5.87 +/- 1.44 ng/L (P less than 0.01). Increase in cGMP and decrease in the ratio of cAMP and cGMP in the cases accompanying symptoms of Yang deficiency of the Spleen and Kidney were much higher than those in the other two types of hepatitis patients (P less than 0.01 and 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Relation of changes in plasma cAMP, cGMP and the clinical conditions, pathology and the type of traditional Chinese medicine in 50 cases of chronic severe icteric hepatitis]. 216 73

A patient with long lasting non-parathyroid hormone mediated hypercalcaemia occurring within the context of hepatitis B virus chronic hepatitis is reported. Hepatocellular carcinoma and bone malignancy were carefully excluded. The biological pattern associated hypercalcaemia with normal phosphataemia, low nephrogenic cAMP level and high level of tubular reabsorption of phosphate. The usual causes of hypercalcaemia were ruled out. Hypercalcaemia may represent a rare biological feature of some advanced liver disease. The underlying mechanisms remain to be elucidated.
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PMID:Hypercalcaemia associated with chronic viral hepatitis. 260 2

The X gene product encoded by the hepatitis B virus, termed pX, is a promiscuous transactivator of a variety of viral and cellular genes under the control of diverse cis-acting elements. Although pX does not appear to directly bind DNA, pX-responsive elements include the NF-kappa B, AP-1, and CRE (cAMP response element) sites. Direct protein-protein interactions occur between viral pX and the CRE-binding transcription factors CREB and ATF. Here we examine the mechanism of the protein-protein interactions occurring between CREB and pX by using recombinant proteins and in vitro DNA-binding assays. We demonstrate that pX interacts with the basic region-leucine zipper domain of CREB but not with the DNA-binding domain of the yeast transactivator protein Gal4. The interaction between CREB and pX increases the affinity of CREB for the CRE site by an order of magnitude, although pX does not alter the rate of CREB dimerization. Methylation interference footprinting reveals differences between the CREB DNA and CREB-pX DNA complexes. These experiments demonstrate that pX titers the way CREB interacts with the CRE DNA and suggest that the basic, DNA-binding region of CREB is the target of pX. Transfection assays in PC12 cells with the CREB-dependent somatostatin promoter demonstrate a nearly 15-fold transcriptional induction after forskolin stimulation in the presence of pX. These results support the significance of the CREB-pX protein-protein interactions in vivo.
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PMID:The hepatitis B virus X protein targets the basic region-leucine zipper domain of CREB. 773 90

The hepatitis B virus X protein interacts with the basic-region, leucine zipper protein (bZip) domain of cAMP response element-binding protein increasing its affinity for the cAMP response element site in vitro and its transcriptional efficacy in vivo (Williams, J. S., and Andrisani, O. M. (1995) Proc. Natl. Acad. Sci. U. S. A. 92, 3819-3823). Here we examine pX interactions with bZip transcription factors ATF3, gadd153/Chop10, ICER IIgamma, and NF-IL6. We demonstrate direct interactions in vitro between pX and the bZip proteins tested. In contrast MyoD and Gal4(1-147) fail to interact with pX. We also demonstrate by the mammalian two-hybrid assay the direct interaction of pX with cAMP response element- binding protein, ICER IIgamma, ATF3, and NF-IL6 in hepatocytes. In addition, pX increases the DNA binding potential of bZip proteins for their cognate DNA-binding site in vitro. In transient transfections in hepatocytes (AML12 cell line), pX increases the transcriptional efficacy of the bZip transcription factors. NF-IL6-mediated transcriptional activation is enhanced 3-fold by pX. Most interestingly, pX augments the repression mediated by bZip repressors ATF3 and ICER IIgamma, by 6- and 7-fold, respectively, demonstrating for the first time the involvement of pX in gene repression. We conclude that pX is an enhancer of the DNA binding potential of bZip transcription factors, thereby increasing the transactivation or repression efficacy of bZip-responsive genes.
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PMID:The hepatitis B virus X protein enhances the DNA binding potential and transcription efficacy of bZip transcription factors. 925 88

The X gene product of the human hepatitis B virus (HBx), a major factor responsible for hepatitis and hepatocellular carcinoma, modulates transactivation by a variety of transcription factors. Herein, expression of the phosphoenolpyruvate carboxykinase (PEPCK) gene was found to be regulated transcriptionally by HBx through two distinct promoter regions. The cAMP response element (CRE)-1 site within the proximal promoter region mediated the HBx-induced transactivation of the PEPCK gene through C/EBP alpha and ATF-2. A retinoid X receptor (RXR) response element within the distal promoter region also contributed to the HBx-induced transactivation. Consistent with these results, HBx directly interacted with RXR, and the interaction interfaces were localized to the transactivation domain of HBx and the ligand binding domain of RXR.
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PMID:Direct binding of hepatitis B virus X protein and retinoid X receptor contributes to phosphoenolpyruvate carboxykinase gene transactivation. 1104 64

Although previous work has shown that the hepatitis B virus X protein (pX) stabilizes complexes between basic region leucine zipper (bZIP) proteins and target DNA, the relationship between enhanced binding and transcriptional activation has not been established. Here we show that interactions between CREB and pX, which coincidentally enhance DNA affinity, are necessary but not sufficient for increased transcriptional potency. Further, we show that transcriptional activation by pX requires a form of CREB in which Ser-133 is not phosphorylated. By stimulating the transcriptional potency of unphosphorylated CREB, pX can up-regulate the expression of cAMP-responsive genes implicated in hepatocyte proliferation, leading ultimately to the development of liver cancer after viral infection.
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PMID:Hepatitis B virus X protein activates transcription by bypassing CREB phosphorylation, not by stabilizing bZIP-DNA complexes. 1117 Mar 86

Cholera toxin (CT) and the Escherichia coli heat-labile enterotoxin (LT) are potent mucosal adjuvants in animals associated, at least in part, with their ability to induce cAMP. While toxicity generally precludes their use in humans, a number of different subunit or genetically detoxified mutants of CT and LT have been developed. Another type of adjuvant that has been shown to be effective at mucosal surfaces comprises synthetic oligodeoxynucleotides (ODN) containing immunostimulatory CpG motifs (CpG ODN). We have previously demonstrated a synergy between CpG ODN and native toxins after intranasal (IN) administration to mice, and herein have examined whether this synergy is linked to the cAMP activity. The adjuvanticity of CpG ODN was evaluated with IN and oral delivery of tetanus toxoid or the hepatitis B surface antigen, relative to and in combination with native LT holotoxin (LTh), three active site mutants (LTS61F, LTA69G, LTE112K), a protease site mutant (LTR192G), and the B subunit of LT (LTB). At an equivalent dose, the adjuvants could generally be divided into two groups: one that included CpG ODN, LTh, LTR192G, and LTA69G which acted as strong adjuvants; and the second which comprised LTB, LTS61F, and LTE112K, which produced significantly weaker immune responses. When CpG ODN was co-administered with bacterial toxin-derivatives, in most cases, no synergy between CpG and the LT derivatives was found for strength of the humoral response. Nevertheless, for both routes and antigens, CpG ODN combined with any LT derivative induced a more Type 1-like response than LT derivative alone. These results suggest that while the synergy seen previously with native toxins may have been due in part to inherent cAMP activity, it may have also depended on the particular antigen used and the route of immunization.
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PMID:Mucosal immunization of mice using CpG DNA and/or mutants of the heat-labile enterotoxin of Escherichia coli as adjuvants. 1139 11

MRP8 (ABCC11) is a recently identified cDNA that has been assigned to the multidrug resistance-associated protein (MRP) family of ATP-binding cassette transporters, but its functional characteristics have not been determined. Here we examine the functional properties of the protein using transfected LLC-PK1 cells. It is shown that ectopic expression of MRP8 reduces basal intracellular levels of cAMP and cGMP and enhances cellular extrusion of cyclic nucleotides in the presence or absence of stimulation with forskolin or SIN-1A. Analysis of the sensitivity of MRP8-overexpressing cells revealed that they are resistant to a range of clinically relevant nucleotide analogs, including the anticancer fluoropyrimidines 5'-fluorouracil (approximately 3-fold), 5'-fluoro-2'-deoxyuridine (approximately 5-fold), and 5'-fluoro-5'-deoxyuridine (approximately 3-fold), the anti-human immunodeficiency virus agent 2',3'-dideoxycytidine (approximately 6-fold) and the anti-hepatitis B agent 9'-(2'-phosphonylmethoxynyl)adenine (PMEA) (approximately 5-fold). By contrast, increased resistance was not observed for several natural product chemotherapeutic agents. In accord with the notion that MRP8 functions as a drug efflux pump for nucleotide analogs, MRP8-transfected cells exhibited reduced accumulation and increased efflux of radiolabeled PMEA. In addition, it is shown by the use of in vitro transport assays that MRP8 is able to confer resistance to fluoropyrimidines by mediating the MgATP-dependent transport of 5'-fluoro-2'-deoxyuridine monophosphate, the cytotoxic intracellular metabolite of this class of agents, but not of 5'-fluorouracil or 5'-fluoro-2'-deoxyuridine. We conclude that MRP8 is an amphipathic anion transporter that is able to efflux cAMP and cGMP and to function as a resistance factor for commonly employed purine and pyrimidine nucleotide analogs.
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PMID:MRP8, ATP-binding cassette C11 (ABCC11), is a cyclic nucleotide efflux pump and a resistance factor for fluoropyrimidines 2',3'-dideoxycytidine and 9'-(2'-phosphonylmethoxyethyl)adenine. 1276 37

Edema factor (EF), a key virulence factor in anthrax pathogenesis, has calmodulin (CaM)-activated adenylyl cyclase activity. We have found that adefovir dipivoxil, a drug approved to treat chronic infection of hepatitis B virus, effectively inhibits EF-induced cAMP accumulation and changes in cytokine production in mouse primary macrophages. Adefovir diphosphate (PMEApp), the active cellular metabolite of adefovir dipivoxil, inhibits the adenylyl cyclase activity of EF in vitro with high affinity (K(i) = 27 nM). A crystal structure of EF-CaM-PMEApp reveals that the catalytic site of EF forms better van der Waals contacts and more hydrogen bonds with PMEApp than with its endogenous substrate, ATP, providing an explanation for the approximately 10,000-fold higher affinity EF-CaM has for PMEApp versus ATP. Adefovir dipivoxil is a clinically approved drug that can block the action of an anthrax toxin. It can be used to address the role of EF in anthrax pathogenesis.
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PMID:Selective inhibition of anthrax edema factor by adefovir, a drug for chronic hepatitis B virus infection. 1497 83

Little is known about the regulation of the innate host defense peptide cathelicidin at the mucosal surfaces. Expression is believed to be transcriptionally regulated, and several cis-acting elements have been identified in the cathelicidin putative promoter. However, the trans-acting factors have not been clearly defined. We have recently reported that bacterial exotoxins suppress cathelicidin expression in sodium butyrate-differentiated intestinal epithelial cells (ECs), and this may be mediated through inducible cAMP early repressor. Here we have shown that cAMP-signaling pathways transcriptionally regulate cathelicidin expression in various ECs. cAMP-response element-binding protein (CREB) and AP-1 (activator protein-1) bind to the cathelicidin putative promoter in vitro. Additionally, transcriptional complexes containing CREB, AP-1, and cathelicidin upstream regulatory sequences are formed within ECs. We have also shown that these complexes may activate cathelicidin promoter and are required for its inducible expression in ECs. This is underscored by the fact that silencing of CREB and AP-1 results in failure of ECs to up-regulate cathelicidin, and hepatitis B virus X protein may use CREB to induce cathelicidin. On the other hand, inducible cAMP early repressor competes with CREB and AP-1 for binding to the cathelicidin promoter and represses transcription, thus functioning as a counter-regulatory mechanism. Finally, both CREB and AP-1 were shown to play major roles in the regulation of cathelicidin in sodium butyrate-differentiated HT-29 cells. This is the first report of a detailed mechanistic study of inducible cathelicidin expression in the mucosal ECs. At the same time, it describes a novel immunomodulatory function of cAMP.
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PMID:cAMP stringently regulates human cathelicidin antimicrobial peptide expression in the mucosal epithelial cells by activating cAMP-response element-binding protein, AP-1, and inducible cAMP early repressor. 1953 82


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