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Antiviral Effects (antiviral + effects)
Selected AbstractsNonstructural 3/4A protease of hepatitis C virus activates epithelial growth factor,induced signal transduction by cleavage of the T-cell protein tyrosine phosphatase,HEPATOLOGY, Issue 6 2009Erwin Daniel Brenndörfer The hepatitis C virus (HCV) is a worldwide major cause of chronic liver disease with a high tendency to establish a persistent infection. To permit persistent replication of viral genomes through the cellular translation machinery without affecting host cell viability, viruses must have developed mechanisms to control cellular cascades required for sufficient viral replication, on the one hand, and to adapt viral replication to the cellular requirements on the other hand. The present study aimed to further elucidate mechanisms by which HCV targets growth factor signaling of the host cell and their implications for viral replication. The study describes a novel mechanism by which HCV influences the activation of the epithelial growth factor receptor/Akt pathway through a nonstructural (NS)3/4A-dependent down-regulation of the ubiquitously expressed tyrosine phosphatase T cell protein tyrosine phosphatase (TC-PTP). NS3/4A is demonstrated to cleave TC-PTP protease-dependently in vitro at two cleavage sites. The in vivo relevance of this finding is supported by the fact that down-regulation of TC-PTP protein expression could also be demonstrated in HCV-infected individuals and in transgenic mice with intrahepatic expression of NS3/4A. Conclusion: This down-regulation of TC-PTP results in an enhancement of epithelial growth factor (EGF)-induced signal transduction and increases basal activity of Akt, which is demonstrated to be essential for the maintenance of sufficient viral replication. Hence, therapeutic targeting of NS3/4A may not only disturb viral replication by blocking the processing of the viral polyprotein but also exerts unforeseen indirect antiviral effects, further diminishing viral replication. (HEPATOLOGY 2009;49:1810,1820.) [source] Genotype-dependent sensitivity of hepatitis C virus to inhibitors of the p7 ion channel,HEPATOLOGY, Issue 6 2008Stephen Griffin The hepatitis C virus (HCV) p7 protein plays a critical role during particle formation in cell culture and is required for virus replication in chimpanzees. The discovery that it displayed cation channel activity in vitro led to its classification within the "viroporin" family of virus-coded ion channel proteins, which includes the influenza A virus (IAV) M2 protein. Like M2, p7 was proposed as a potential target for much needed new HCV therapies, and this was supported by our finding that the M2 inhibitor, amantadine, blocked its activity in vitro. Since then, further compounds have been shown to inhibit p7 function but the relationship between inhibitory effects in vitro and efficacy against infectious virus is controversial. Here, we have sought to validate multiple p7 inhibitor compounds using a parallel approach combining the HCV infectious culture system and a rapid throughput in vitro assay for p7 function. We identify a genotype-dependent and subtype-dependent sensitivity of HCV to p7 inhibitors, in which results in cell culture largely mirror the sensitivity of recombinant protein in vitro; thus building separate sensitivity profiles for different p7 sequences. Inhibition of virus entry also occurred, suggesting that p7 may be a virion component. Second site effects on both cellular and viral processes were identified for several compounds in addition to their efficacy against p7 in vitro. Nevertheless, for some compounds antiviral effects were specific to a block of ion channel function. Conclusion: These data validate p7 inhibitors as prototype therapies for chronic HCV disease. (HEPATOLOGY 2008;48:1779-1790.) [source] Hepatitis C virus replication is inhibited by 22,-methoxyolean-12-ene-3,, 24(4,)-diol (ME3738) through enhancing interferon-,,HEPATOLOGY, Issue 1 2008Yoichi Hiasa A derivative of soyasapogenol, 22,-methoxyolean-12-ene-3,, 24(4,)-diol (ME3738), ameliorates liver injury induced by Concanavalin A in mice. We examined whether ME3738 has independent antiviral effects against hepatitis C virus (HCV) using an established HCV replication model that expresses the full-length genotype 1a HCV complementary DNA plasmid (pT7-flHCV-Rz) under the control of a replication-defective adenoviral vector expressing T7 polymerase. Hepatocellular carcinoma (HepG2) cells, human hepatoma (Huh7) cells, or monkey kidney (CV-1) cells were transfected with pT7-flHCV-Rz, and infected with adenoviral vector expressing T7 polymerase. ME3738 or interferon-, (IFN-,) was added thereafter and then protein and RNA were harvested from the cells at 9 days after infection. HCV-positive and HCV-negative strands were measured by real-time reverse-transcription polymerase chain reaction and HCV core protein expression was measured using an enzyme-linked immunosorbent assay. The messenger RNA levels of innate antiviral response-related genes were assessed using real-time reverse-transcription polymerase chain reaction. ME3738 dose-dependently reduced HCV-RNA and core protein in hepatocyte-derived cell lines. The antiviral effect was more pronounced in HepG2 than in Huh7 cells. ME3738 increased messenger RNA levels of interferon-, (IFN-,) and of IFN-stimulated genes (2,-5, oligoadenylate synthetase, myxovirus resistance protein A [MxA]). Interferon-, knockdown by small interfering RNA abrogated the anti-HCV effect of ME3738. Moreover, the anti-HCV effects were synergistic when ME3738 was combined with IFN-,. Conclusion: ME3738 has antiviral effects against HCV. The enhancement of autocrine IFN-, suggests that ME3738 exerts antiviral action along the type I IFN pathway. This anti-HCV action by ME3738 was synergistically enhanced when combined with IFN-,. ME3738 might be a useful anti-HCV drug either with or without IFN-,. (HEPATOLOGY 2008.) [source] The role of type I interferons in non-viral infectionsIMMUNOLOGICAL REVIEWS, Issue 1 2004Christian Bogdan Summary:, For a long time, the family of type I interferons (IFN-,/,) has received little attention outside the fields of virology and tumor immunology. In recent years, IFN-,/, regained the interest of immunologists, due to the phenotypic and functional characterization of IFN-,/,-producing cells, the definition of novel immunomodulatory functions and signaling pathways of IFN-,/,, and the observation that IFN-,/, not only exerts antiviral effects but is also relevant for the pathogenesis or control of certain bacterial and protozoan infections. This review summarizes the current knowledge on the production and function of IFN-,/, during non-viral infections in vitro and in vivo. [source] TLRs antiviral effect on hepatitis B virus in HepG2 cellsJOURNAL OF APPLIED MICROBIOLOGY, Issue 5 2008C. Xia Abstract Aims:, A hepatoma cell line, HepG2, was used as a model system to detect Toll-like receptor (TLR) expression in hepatocytes and examine the antiviral effect on hepatitis B virus (HBV). Methods and Results:, Toll-like receptor expression was detected in HepG2 cells by RT-PCR. The TLRs, which were strongly expressed in HepG2 cells, were stimulated with specific ligands. Interferon (IFN) response was evaluated poststimulation with Western blotting for signal transduction and activators of transcription-1. Furthermore, HepG2 cells were transiently transfected with wild-type HBV 1·3-fold over-length plasmid and treated with specific ligands at indicated times. Replication of HBV DNA, transcription of HBV RNA intermediate and expression of HBV antigens were respectively detected by Southern blotting, real time PCR, ELISA and Western blotting. Activation of different TLRs induced antiviral effects on HBV to varying degrees. Conclusions:, The TLRs, which were strongly expressed in HepG2 cells, could be stimulated with specific ligands. Activation of TLRs induced apparent production of antiviral cytokines such as IFN-,/, and inhibited HBV lifecycle in the hepatocyte cell model. Significance and Impact of the Study:, Expression of TLRs in hepatocytes may be related to local immunity of liver and participate in the outcome of viral hepatitis. [source] Contents of hypericin and pseudohypericin in five commercial products of St John's wort (Hypericum perforatum)JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE, Issue 5 2004Zhao-Jun Wang Abstract Hypericin and pseudohypericin are the two major dianthrones of St John's wort (SJW, Hypericum perforatum) that are reported to have antidepressant and antiviral effects. In this study we used methanol extracts of five commercial SJW products to determine the two congeners using a modified reverse phase HPLC method with gradient elution. One SJW product is specified by the manufacturer to contain 340 µg hypericin per tablet (170 mg extract), while the other four products are specified to contain 900 µg hypericin per tablet (300 mg); none of the products is claimed to contain pseudohypericin. Our results showed that the actual contents of hypericin in these products ranged from 1.7 to 38.5% of the claimed amounts. However, the amounts of pseudohypericin were in general much higher than those of hypericin. When hypericin and pseudohypericin were combined as total hypericin, the four products that supposedly contain 900 µg per tablet were found to contain 26, 484, 587 and 615 µg total hypericin per tablet, or 2.9, 53.8, 65.2 and 68.3% of the claimed hypericin contents respectively. The product which supposedly contains 340 µg hypericin per tablet was found to contain 388 µg total hypericin per tablet, or 114% of the claimed hypericin content. The relatively low hypericin contents measured in these products are not a result of losses during extraction, because the two congeners had high recoveries (93.7 and 94.3% for hypericin and pseudohypericin respectively) when added before methanolic extraction to an SJW product with known amounts of the two congeners. Thus our results show that the commercial SJW products vary greatly in their amounts of total hypericin and that pseudohypericin, rather than hypericin, is the major hypericin in these products. Copyright © 2004 Society of Chemical Industry [source] Enhanced antiviral effect in cell culture of type 1 interferon and ribozymes targeting HCV RNAJOURNAL OF VIRAL HEPATITIS, Issue 6 2001D. G. Macejak We have recently shown that the replication of an HCV-poliovirus (PV) chimera that is dependent upon the hepatitis C virus (HCV) 5, untranslated region (UTR) can be inhibited by treatment with ribozymes targeting HCV RNA. To determine the antiviral effects of anti-HCV ribozyme treatment in combination with type 1 interferon (IFN), we analysed the replication of this HCV-PV chimera in HeLa cells treated with anti-HCV ribozyme and/or IFN-,2a, IFN-,2b, or consensus IFN. The anti-HCV ribozyme, or any of the IFNs alone have significant inhibitory effects on HCV-PV replication compared to control treatment (, 85%, P < 0.01). The maximal inhibition due to IFN treatment (94%, P < 0.01) was achieved with , 50 U/ml for either IFN-,2a or IFN-,2b compared to control treatment. A similar level of inhibition in viral replication could be achieved with a 5-fold lower dose of IFN if ribozyme targeting the HCV 5, UTR was given in combination. For consensus IFN, the dose could be reduced by > 12.5-fold if ribozyme targeting the HCV 5, UTR was given in combination. Conversely, the dose of ribozyme could be reduced 3-fold if given in combination with any of the IFN preparations. Moreover, treatment with low doses (1,25 U/mL) of IFN-,2a, IFN-,2b, or consensus IFN in combination with anti-HCV ribozyme resulted in > 98% inhibition of HCV-PV replication compared to control treatment (P < 0.01). These results demonstrate that IFN and ribozyme each have a beneficial antiviral effect that is augmented when given in combination. [source] Efficacy of lamivudine on hepatitis B viral status and liver function in patients with hepatitis B virus-related hepatocellular carcinomaLIVER INTERNATIONAL, Issue 2 2009Ji Hoon Kim Abstract Background/Aims: Treatment of patients with hepatocellular carcinoma (HCC) depends on the tumour extent and underlying liver function. Antiviral therapy with nucleoside/nucleotide analogues has been shown to be effective in improving the liver function of chronic hepatitis B (CHB) patients. We assessed whether lamivudine could induce biochemical and virological improvements in patients with hepatitis B virus-related HCC. Patients/Methods: Of 148 CHB patients treated with 100 mg/day lamivudine for at least 6 months, 80 had HCC (CHB/HCC group) and 68 did not (CHB group). Biochemical and virological parameters were serially monitored. Results: Compared with the CHB group, the CHB/HCC group was older, had higher male predominance, bilirubin levels and liver cirrhosis rate, and lower albumin and hepatitis B virus (HBV) DNA levels and hepatitis B e antigen (HBeAg) positivity (P<0.05 each). The two groups showed similar cumulative rates of alanine aminotransferase normalization, HBV DNA seroconversion, HBeAg loss and viral breakthrough during 12 months of lamivudine treatment. After 12 months, the CHB/HCC group showed, relative to baseline, increased albumin levels (3.51±0.5 vs. 3.72±0.5 mg/ml) and decreased ascites scores (1.63±0.7 vs. 1.45±0.6) and Child,Pugh scores (6.92±1.9 vs. 6.02±1.38) (P<0.05 each). Conclusion: Lamivudine had comparable antiviral effects both in patients with CHB and CHB/HCC, and improved underlying liver function in the latter group. Treatment of HBV may increase the chance of curative treatments in patients with HBV-related HCC. [source] Tannins: Current knowledge of food sources, intake, bioavailability and biological effectsMOLECULAR NUTRITION & FOOD RESEARCH (FORMERLY NAHRUNG/FOOD), Issue S2 2009José Serrano Abstract Tannins are a unique group of phenolic metabolites with molecular weights between 500 and 30 000 Da, which are widely distributed in almost all plant foods and beverages. Proanthocyanidins and hydrolysable tannins are the two major groups of these bioactive compounds, but complex tannins containing structural elements of both groups and specific tannins in marine brown algae have also been described. Most literature data on food tannins refer only to oligomeric compounds that are extracted with aqueous-organic solvents, but a significant number of non-extractable tannins are usually not mentioned in the literature. The biological effects of tannins usually depend on their grade of polymerisation and solubility. Highly polymerised tannins exhibit low bioaccessibility in the small intestine and low fermentability by colonic microflora. This review summarises a new approach to analysis of extractable and non-extractable tannins, major food sources, and effects of storage and processing on tannin content and bioavailability. Biological properties such as antioxidant, antimicrobial and antiviral effects are also described. In addition, the role of tannins in diabetes mellitus has been discussed. [source] Expression of Interferon-tau mRNA in Bovine Embryos Derived from Different ProceduresREPRODUCTION IN DOMESTIC ANIMALS, Issue 1 2009N Yao Contents Interferon-tau (IFN-,) is a secreted conceptus protein which plays a critical role in the establishment of ruminant pregnancy by its antiluteolytic and antiviral effects. In the present study, we hypothesized that IFN-, expression was temporally and spatially regulated in different pre-implantation embryos and the levels of IFN-, expression were different among bovine embryos derived from parthenogenetic activation (PA), in vitro fertilization (IVF) and somatic cell nuclear transfer (SCNT). By using in situ hybridization with Digoxingenin (DIG)-labelled IFN-, cDNA as a probe, we detected IFN-, mRNA in bovine embryos from days 3 to 9 in culture. However, the timing of the initiation of IFN-, mRNA expression was different among PA, IVF and SCNT embryos. Interferon-, mRNA was first expressed in 16-cell stage IVF embryos on day 4, in SCNT morula on day 5 and early PA blastocyst on day 6. Semi-quantitative RT-PCR analysis showed that the expression levels of IFN-, mRNA did not differ significantly among IVF, SCNT and PA embryos on day 7. In addition, freezing and thawing did not have a major impact either on IFN-, mRNA expression in IVF or in vivo -produced bovine blastocysts. [source] Development and characterization of a triple combination gene therapy vector inhibiting HIV-1 multiplicationTHE JOURNAL OF GENE MEDICINE, Issue 10 2008Maria B. Asparuhova Abstract Background RNA-based approaches are promising for long-term gene therapy against HIV-1. They can target virtually any step of the viral replication cycle. It is also possible to combine anti-HIV-1 transgenes targeting different facets of HIV replication to compensate for limitations of any individual construct, maximizing efficacy and decreasing chances of escape mutations. We have previously developed two strategies to inhibit HIV-1 multiplication. One was a short hairpin RNA targeting the host factor cyclophilin A implicated in HIV-1 replication. Additionally, an antisense derivative of U7 small nuclear RNA was designed to induce the skipping of the HIV-1 Tat and Rev internal exons. Results In the present study, we have established an additional tRNAval promoter-driven shRNA against the coding sequence of viral infectivity factor. When human T-cell lines or primary CD4+ T cells are transduced with a triple lentiviral vector encoding these three therapeutic RNAs, HIV-1 multiplication is very efficiently suppressed. Moreover, all three therapeutic RNAs exhibit antiviral effects at early stages of the viral replication cycle (i.e. prior to viral cDNA integration or gene expression). Conclusions These findings make this triple lentiviral vector an attractive candidate for a gene therapy against HIV/AIDS. Copyright © 2008 John Wiley & Sons, Ltd. [source] | |||||||||||||