Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.48 (transcriptase)
9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

As macrophages are often called to function at times of elevated ambient temperature (e.g., during local inflammation or systemic fever), it is possible that their production of critical effector molecules, such as nitric oxide (NO) or inducible NO synthase (iNOS), is sensitive to physiological changes in temperature. To test this possibility, the threshold requirements for production of NO and iNOS in murine peritoneal macrophages maintained under normothermic conditions (37 degrees C) or following mild (fever-range) hyperthermia (39.5 degrees C) were compared. We found that hyperthermia alone had no observable effect on basal NO production or iNOS protein or message. However, although interferon (IFN)-gamma and lipopolysaccharide (LPS) were needed to induce NO at 37 degrees C, we observed that addition of only LPS was sufficient for production of NO if there were a pretreatment at 39.5 degrees C. Further, if IFN-gamma and LPS were given after thermal exposure, a substantial increase in NO and iNOS was observed over that seen using cells kept at normothermic conditions. Macrophages isolated from mice lacking heat shock factor-1 did not attenuate the ability of mild thermal stress to modulate NO production. Reverse transcriptase-polymerase chain reaction data revealed that thermal regulation of iNOS expression is not entirely at the transcriptional level, suggesting possible points of post-transcriptional thermal sensitivity. These data support the concept that altering the thermal microenvironment is an important means by which the host can manipulate macrophage responses. Increases in temperature (e.g., during fever) may function to lower the activation threshold needed for production of effector molecules in times of infection.
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PMID:Nitric oxide production is regulated by fever-range thermal stimulation of murine macrophages. 1600 Mar 92

We previously found that hepatitis C virus (HCV) core protein (Core) activated the interferon (IFN)-inducible 40/46 kDa 2'-5'-oligoadenylate synthetase (2'-5'-OAS) gene through an IFN-stimulated response element (ISRE) in non-neoplastic human hepatocyte PH5CH8 cells. Here, we found that Core and NS5B synergistically enhanced the 2'-5'-OAS gene promoter activity through ISRE. Further analysis revealed that amino acid positions 12 and/or 13 of Core and RNA-dependent RNA polymerase activity of NS5B were essential for the activation of the 2'-5'-OAS gene promoter. Interestingly, we observed that the activation by Core or NS5B was still partially enhanced by even the NS5B or Core mutant lacking the activating ability, respectively, suggesting an indirect interaction between Core and NS5B. Furthermore, we showed that the activation by NS5B could be explained by NS5B's induction of IFN-beta, however, IFN-beta was not induced by Core. Moreover, we showed that the synergistic effect of Core and NS5B was not invalidated by NS3-4A, although NS3-4A significantly inhibited the activation by combination of Core and NS5B. Taken together, our findings reveal that NS5B/Core and NS3-4A exhibit conflicting effects (activation and inhibition) on the IFN system in PH5CH8 cells, and suggest that such effects may promote the distraction of the host defense system to lead to persistent infection.
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PMID:Hepatitis C virus proteins exhibit conflicting effects on the interferon system in human hepatocyte cells. 1613 43

Compounds A-782759 (an N-1-aza-4-hydroxyquinolone benzothiadiazine) and BILN-2061 are specific anti-hepatitis C virus (HCV) agents that inhibit the RNA-dependent RNA polymerase and the NS3 serine protease, respectively. Both compounds display potent activity against HCV replicons in tissue culture. In order to characterize the development of resistance to these anti-HCV agents, HCV subgenomic 1b-N replicon cells were cultured with A-782759 alone or in combination with BILN-2061 at concentrations 10 times above their corresponding 50% inhibitory concentrations in the presence of neomycin. Single substitutions in the NS5B polymerase gene (H95Q, N411S, M414L, M414T, or Y448H) resulted in substantial decreases in susceptibility to A-782759. Similarly, replicons containing mutations in the NS5B polymerase gene (M414L or M414T), together with single mutations in the NS3 protease gene (A156V or D168V), conferred high levels of resistance to both A-782759 and BILN-2061. However, the A-782759-resistant mutants remained susceptible to nucleoside and two other classes of nonnucleoside NS5B polymerase inhibitors, as well as interferon. In addition, we found that the frequency of replicons resistant to both compounds was significantly lower than the frequency of resistance to the single compound. Furthermore, the dually resistant mutants displayed significantly reduced replication capacities compared to the wild-type replicon. These findings provide strategic guidance for the future treatment of HCV infection.
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PMID:Mutations conferring resistance to a hepatitis C virus (HCV) RNA-dependent RNA polymerase inhibitor alone or in combination with an HCV serine protease inhibitor in vitro. 1618 12

RANTES, a CC chemokine, plays an important role in the inflammatory response associated with Helicobacter pylori infection. However, the mechanism by which H. pylori induces RANTES expression in the gastric mucosa is unknown. We cocultured gastric epithelial cells with wild-type H. pylori, isogenic oipA mutants, cag pathogenicity island (PAI) mutants, or double knockout mutants. Reverse transcriptase PCR showed that RANTES mRNA was induced by H. pylori and that the expression was both OipA and cag PAI dependent. Luciferase reporter gene assays and electrophoretic mobility shift assays showed that maximal H. pylori-induced RANTES gene transcription required the presence of the interferon-stimulated responsive element (ISRE), the cyclic AMP-responsive element (CRE), nuclear factor-interleukin 6 (NF-IL-6), and two NF-kappaB sites. OipA- and cag PAI-dependent pathways included NF-kappaB-->NF-kappaB/NF-IL-6/ISRE pathways, and cag PAI-dependent pathways additionally included Jun N-terminal kinase-->CRE/NF-kappaB pathways. The OipA-dependent pathways additionally included p38-->CRE/ISRE pathways. We confirmed the in vitro effects in vivo by examining RANTES mRNA levels in biopsy specimens from human gastric antral mucosa. RANTES mRNA levels in the antral mucosa were significantly higher for patients infected with cag PAI/OipA-positive H. pylori than for those infected with cag PAI/OipA-negative H. pylori or uninfected patients. The mucosal inflammatory response to H. pylori infection involves different signaling pathways for activation of the RANTES promoter, with both OipA and the cag PAI being required for full activation of the RANTES promoter.
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PMID:Regulation of RANTES promoter activation in gastric epithelial cells infected with Helicobacter pylori. 1623 64

To clarify the pathogenesis of hepatitis C virus (HCV), we have studied the effects of HCV proteins using human hepatocytes. Here, we found that HCV NS5B, an RNA-dependent RNA polymerase, delayed cell cycle progression through the S phase in PH5CH8 immortalized human hepatocyte cells. Since treatment with anti-interferon (IFN)-beta neutralizing antibody restored the cell cycle delay, IFN-beta was deemed responsible for the cell cycle delay in NS5B-expressing PH5CH8 cells. The induction of IFN-beta and the cell cycle delay were overridden by the down-regulation of Toll-like receptor 3 (TLR3) through RNA interference in NS5B-expressing PH5CH8 cells. Moreover, the NS5B full form was required for the cell cycle delay, the induction of IFN-beta, and the activation of the IFN-beta signaling pathway. Our findings revealed that NS5B induced IFN-beta through the TLR3 signaling pathway in immortalized human hepatocytes even without replicating viral genomes.
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PMID:Hepatitis C virus NS5B delays cell cycle progression by inducing interferon-beta via Toll-like receptor 3 signaling pathway without replicating viral genomes. 1632 82

Interaction of CD40L and its cognate receptor is an essential component of B-lymphocyte signaling, affecting various aspects of B-cell differentiation pathways and immunoglobulin gene expression. However, much less is known about the biological consequences of B-cell signaling through tumor necrosis factor (TNF)-alpha and its cognate receptors TNF-R1 and 2. We used Ramos Burkitt's lymphoma cell line as a model system to study the direct effects of these cytokines on B cells. Treatment of Ramos cells with either TNF-alpha or CD40L, but not with interleukin (IL)- 4, interferon (IFN)-gamma and transforming growth factor (TGF)-beta, resulted in enhanced cell aggregation and enhancement of adherence to glass cover-slips. Scanning electron microscopy showed that Ramos cells have a polarized cell surface morphology and exhibit at least 3 cell surface morphological domains: microvilli, filopodia and ruffled membranes. The cells adhered to the glass matrix through multiple filopodia/podopodia-like cell processes and demonstrated distinct ruffled-like membrane projections on their opposite pole. Induction by TNF-alpha or CD40L, but not with IL-4, IFN-gamma and TGF-beta, resulted in increased number and complexity of both types of membrane projections. TNF-alpha and CD40L upregulated the expression of the adhesion molecule intercellular adhesion molecule-1 and the Fas receptor on Ramos cells, without affecting the expression levels of membrane immunoglobulin M or its secretion rate. Reverse transcriptase-polymerase chain reaction, and flow cytometry demonstrated that Ramos cells expressed TNF-R1 but very little if any TNF-R2, indicating that TNF-alpha exerted its effects on Ramos cells through the former receptor.
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PMID:Tumor necrosis factor-alpha and CD40L modulate cell surface morphology and induce aggregation in Ramos Burkitt's lymphoma cells. 1652 91

Subacute sclerosing panencephalitis (SSPE) is a rare, but fatal outcome of measles virus (MeV) infection. SSPE develops after prolonged persistence of mutated MeV called SSPE virus. Although a combination therapy using interferon and inosiplex or ribavirin appears to prolong survival time to some extent, there is currently no effective treatment to completely cure SSPE and a new treatment strategy is greatly needed. In this study, we adopted RNA interference (RNAi) strategy and examined whether small interfering RNAs (siRNAs) can be used to inhibit replication of MeV and SSPE virus. We report here that siRNAs targeted against L mRNA of MeV, either synthetic siRNAs or those generated by pcPUR+U6i-based expression plasmids, effectively and specifically inhibited replication of both MeV and SSPE virus without exhibiting any cytotoxic effect. The L protein of MeV is a major component of RNA-dependent RNA polymerase that is essential for viral RNA replication, and yet it is least abundant among all the MeV proteins expressed. Therefore, mRNA encoding the L protein would be a good target for RNAi strategy. The present results imply the possibility that our siRNAs against MeV L mRNA are among the potential candidates to be used to treat patients with SSPE.
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PMID:Inhibition of measles virus and subacute sclerosing panencephalitis virus by RNA interference. 1653 Feb 74

There are a number of antivirals as well as antiviral strategies that could be envisaged to prevent or treat severe acute respiratory syndrome (SARS) (or similar) coronavirus (CoV) infections. Targets for the prophylactic or therapeutic interventions include interaction of the spike (S) glycoprotein (S1 domain) with the host cell receptor, fusion of the S2 domain with the host cell membrane, processing of the replicase polyproteins by the virus-encoded proteases (3C-like cysteine protease [3CLpro] and papain-like cysteine protease) and other virus-encoded enzymes such as the NTPase/helicase and RNA-dependent RNA polymerase. Human monoclonal antibody blocking S1 may play an important role in the immunoprophylaxis of SARS. Fusion inhibitors reminiscent of enfuvirtide in the case of HIV may also be developed for SARS-CoV. Various peptidomimetic and nonpeptidic inhibitors of 3CLpro have been described, the best ones inhibiting SARS-CoV replication with a selectivity index greater than 1000. Human interferons, in particular alpha- and beta-interferon, as well as short interfering RNAs could further be pursued for the control of SARS. Various other compounds, often with an ill-defined mode of action but selectivity indexes up to 100, have been reported to exhibit in vitro activity against SARS-CoV: valinomycin, glycopeptide antibiotics, plant lectins, hesperetin, glycyrrhizin, aurintricarboxylic acid, chloroquine, niclosamide, nelfinavir and calpain inhibitors.
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PMID:Potential antivirals and antiviral strategies against SARS coronavirus infections. 1659 9

Hepatitis B virus (HBV) is a human DNA virus, which replicates through an RNA intermediate because of the reverse-transcriptase (RT) activity of its DNA polymerase. As a result, the mutation rate for HBV is higher than the rate observed for most DNA viruses. HBVs are classified into genotypes based on genomic sequencing, and antigenic subtypes based on the antigenic properties of its major surface glycoprotein, the HBV surface antigen (HBsAg). Subgenotypes have been identified within most of the HBV genotypes. The HBV groups defined by the different genotype-HBsAg subtype associations found over the world display characteristic geographical distributions, reflecting the movements of human populations and other epidemiologically significant events. Such HBV groups constitute genetically stable viral populations sharing a common evolutionary history, but additional stable changes, originating from mutation and mutant selection, are observed within all of them. These viral sub-populations are known as the HBV variants, and some of which have medical and public health relevance. Pre-core (pre-C) defective variants have been shown to make HBV infection much less susceptible to interferon treatment, and treatment failures with other antiviral drugs have been associated with selection of resistant variants that display specific mutations in the genome region encoding the viral RT activity. Since the RT region of the genome overlaps the sequence encoding the HBsAg molecule, selection of drug resistant variants involves, in some cases, the indirect selection of HBsAg variants. Viral variants displaying changes in HBsAg seem to be very common among chronic HBV carriers; and some of these variants may emerge under the pressure of the neutralizing antibody response, leading to vaccine resistance and resistance to immunotherapy. Mutations conferring resistance to immunotherapy are noted often among liver transplant recipients and among babies born to HBV-carrier mothers. In addition, some of these HBsAg variants have been associated with lack of detection by HBsAg tests used for the diagnosis of HBV infection, for the identification of chronic carriers, for screening of blood donations for transfusion, and in the manufacture of therapeutic blood products.
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PMID:Hepatitis B virus genetic diversity. 1662 76

The review gives recent data on the structure of hepatitis C virus genome. Linear RNA comprises one translated and two nontranslated regions: 5'UTR and 3'UTR. Translation of viral RNA gives rise to a single polyprotein precursor that contains structural and nonstructural regions. The structural region comprises one nucleocapsid core-protein and two envelope proteins known as E1 and E2. E2 protein includes two hypervariable regions: HVR1 and HVR2. The nonstructural region consists of 7 proteins: p7 (NS1), NS (metalloproteinase), NS (serine protease/ helicase), NS4A (co-factor protease, co-factor RNA-dependent RNA polymerase), and NS4B, NS5A, NS5B (RNA-dependent RNA polymerase). NS5A includes ISDR (interferon-sensitivity-determining region).
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PMID:[Structural and functional organization of hepatitis C virus genome]. 1675 71


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