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)

It has been well demonstrated that interleukin-12 (IL-12) could be useful to defend against a variety of pathogens, to suppress tumor growth and metastasis, and even to be employed as an adjuvant of vaccines to enhance beneficial type 1 T helper (Th1) cell response over detrimental type 2 T helper (Th2) cell responses. To apply IL-12 genes in gene therapy such as a DNA vaccine, a pIL-12 vector was constructed that contained two cytomegalovirus (CMV) promoters to drive the expression of p35 and p40 subunits, respectively. In addition, a pscIL-12 vector was designed with a linker to fuse p35 cDNA with p40 cDNA to produce a single-chain IL-12 protein, ensuring not only that the expression of p35 and p40 subunits was equally expressed, but also that no free p40 subunits interfered with IL-12 activity. The data suggested pIL-12 could produce a rather high level of biologically active IL-12 after transfection of COS cell lines as well as C2C12 muscle cell lines, as measured by both concanavalin A blast proliferation assay and enzyme-linked immunosorbent assay. Interestingly, the pscIL-12 vector could also express a bioactive murine IL-12 fusion protein in vitro. Furthermore, in vivo functional studies also demonstrated that mice co-immunized with a pS vector expressing the major envelope protein of hepatitis B virus (HBV) and IL-12 vectors encoding native IL-12 or single-chain IL-12 fusion protein elicited higher levels of IgG2a anti-HBs antibody and of Th1-related cytokine. Because p35 and p40 genes can be expressed in a vector by using a single promoter, pscIL-12 should be useful in future applications for nucleic acid vaccination or for gene therapy against diseases.
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PMID:Construction of vectors expressing bioactive heterodimeric and single-chain murine interleukin-12 for gene therapy. 952 7

Epidemiology shows a clear correlation between chronic infection with the hepatitis B virus (HBV) and development of hepatocellular carcinoma (HCC). The potential role of the transactivating hepatitis B virus X protein (HBx) in transformation by HBV is controversial. Here we report that HBx suppresses transformation of primary rat embryo fibroblasts (REFs). Cooperating oncogenes like c-Ha-ras and c-myc transform REF very efficiently but cotransfection with HBx suppressed transformation of REFs down to 5%. Similarly, transfection of HBx together with the cooperating oncogenes Ha-ras and SV40 LTAg or c-Ha-ras and mutant p53 reduced the number of foci to 13%. Comparable results were obtained with HBx in the context of the whole HBV. Suppression of focus formation in REF could be partly relieved by cotransfection of apoptosis inhibitors Bcl-2 or E1B. However, cotransfection of apoptosis inhibitors crmA and p35 did not influence the proapoptotic functions of HBx. Thus, HBx may specifically activate the Bcl-2 sensitive pathway leading to apoptosis. Experiments with 13 HBx linker scanning mutants revealed that the domains necessary for HBx dependent transactivation overlap with the domains needed for the apoptotic/growth arrest functions of HBx.
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PMID:Induction of apoptosis by the transactivating domains of the hepatitis B virus X gene leads to suppression of oncogenic transformation of primary rat embryo fibroblasts. 1071 5

Polymerase of human hepatitis B virus is required for viral replication and pregenomic RNA encapsidation. Using recombinant GST fusion proteins, we show that the terminal protein domain of polymerase can interact specifically with a protein complex containing kinase activity and a tightly associated 35-kD protein (p35). This kinase is termed terminal-protein-associated kinase (TPAK). The phosphoamino acid analysis of phosphorylated p35 demonstrates that TPAK is a serine kinase. Analysis of deletion mutants shows that amino acids 1-95 of the terminal protein domain are required for the interaction with TPAK/p35 and phosphorylation of p35. TPAK/p35 are found predominantly in the cytoplasm. Furthermore, TPAK can be inhibited by heparin and manganese ions, but is resistant to spermidine, DRB, H89 or H7. These results indicate that TPAK is not protein kinase A or protein kinase C. Copyright 1997 S. Karger AG, Basel
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PMID:A Serine-Kinase-Containing Protein Complex Interacts with the Terminal Protein Domain of Polymerase of Hepatitis B Virus. 1172 48

Preclinical studies in several animal models as well as clinical trials have shown a reduction in tumor growth following immunotherapy with interleukin-12 (IL-12). This cytokine is appropriate to test in therapeutic clinical trials to treat hepatocarcinoma (HC), a pathology often associated with hepatitis B or C-induced cirrhosis. The local delivery into the liver would be achieved through ex vivo gene transfer using retroviral (rv) vectors in autologous fibroblast carriers. In support of this clinical trial, a rv vector has been constructed to express coordinately both chains p35 and p40 of human IL-12. Here, we have tested good manufacturing practices (GMP) clinical lots of viral vectors derived from the transfected packaging cell line, PG13rvIL-12. We have also devised methods to facilitate the isolation of fibroblasts from freshly harvested skin specimens, enhance their outgrowth in large-scale cultures and assay IL-12 production following transduction, without any selection and irradiation. Twenty-four human skin specimens were processed to obtain fibroblast suspensions that were typically maintained for up to 8 or 12 passages. The mean +/-s.d. overall time for obtaining the required number of transduced cells for the highest IL-12 need was 40 days. The procedure, in accordance with the French medical agency for gene therapy clinical trials, is now ready to begin a clinical trial.
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PMID:Preclinical study of an ex vivo gene therapy protocol for hepatocarcinoma. 1898 51

Epstein-Barr virus-induced gene 3 (Ebi3) and the p35 subunit of IL-12 have been reported to form a heterodimeric cytokine, named IL-35, in human and mouse. In mice, IL-35 has been shown to be constitutively expressed by CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) and suggested to contribute to their suppressive activity. However, human CD4(+)CD25(+)Foxp3(+) Tregs do not constitutively express detectable amounts of IL-35 in both mRNA and protein levels. Circulating CD4(+)CD25(+) Treg frequency of chronic Hepatitis B patients significantly correlates with serum viral load. In this study, we investigated whether IL-35 expression could be detected in CD4(+) T cells from peripheral blood of chronic Hepatitis B patients. Using both RT-PCR and immunoprecipitation plus Western blot analysis, we demonstrated that IL-35 expression could be detected in the CD4(+) T cells from peripheral blood of Chronic Hepatitis B patients.
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PMID:Detectable expression of IL-35 in CD4+ T cells from peripheral blood of chronic hepatitis B patients. 2128 6

Hepatitis B virus (HBV) replicates noncytopathically in hepatocytes, but HBV or proteins encoded by HBV genome could induce cytokines, chemokines expression by hepatocytes.IL-12 is a typical proinflammatory cytokine that plays a critical role in host defense against pathogens, including the HBV. However, the role of IL-12 in chronic hepatitis B (CHB) remains unclear. The aims of this study were to detect the expression of IL-12 in CHB patients and explore the molecular mechanism of HBV-induced IL-12 expression. The results showed that serum levels and hepatic expression of IL-12 were significantly upregulated in CHB patients. HBx protein increased IL-12 expression in a dose-dependent manner. Furthermore, inhibition of PI3K/Akt significantly decreased the HBx-induced IL-12 expression and Akt activation. Taken together, these results indicate that the molecular mechanism of HBV-induced IL-12 expression involves activation of the PI3K/Akt pathway by HBx, leading to transactivation of the IL-12 p35 and p40 promoters.
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PMID:Up-regulation of IL-12 expression in patients with chronic hepatitis B is mediated by the PI3K/Akt pathway. 2606 43