5 results on '"Schmidt, Warren N"'
Search Results
2. Hepatitis C virus infection inhibits a Src-kinase regulatory phosphatase and reduces T cell activation in vivo.
- Author
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Bhattarai, Nirjal, McLinden, James H., Xiang, Jinhua, Mathahs, M. Meleah, Schmidt, Warren N., Kaufman, Thomas M., and Stapleton, Jack T.
- Subjects
HEPATITIS C virus ,VIRUS diseases ,T cells ,T cell receptors ,SRC gene ,PHOSPHATASES - Abstract
Among human RNA viruses, hepatitis C virus (HCV) is unusual in that it causes persistent infection in the majority of infected people. To establish persistence, HCV evades host innate and adaptive immune responses by multiple mechanisms. Recent studies identified virus genome-derived small RNAs (vsRNAs) in HCV-infected cells; however, their biological significance during human HCV infection is unknown. One such vsRNA arising from the hepatitis C virus (HCV) E2 coding region impairs T cell receptor (TCR) signaling by reducing expression of a Src-kinase regulatory phosphatase (PTPRE) in vitro. Since TCR signaling is a critical first step in T cell activation, differentiation, and effector function, its inhibition may contribute towards HCV persistence in vivo. The effect of HCV infection on PTPRE expression in vivo has not been examined. Here, we found that PTPRE levels were significantly reduced in liver tissue and peripheral blood mononuclear cells (PBMCs) obtained from HCV-infected humans compared to uninfected controls. Loss of PTPRE expression impaired antigen-specific TCR signaling, and curative HCV therapy restored PTPRE expression in PBMCs; restoring antigen-specific TCR signaling defects. The extent of PTPRE expression correlated with the amount of sequence complementarity between the HCV E2 vsRNA and the PTPRE 3’ UTR target sites. Transfection of a hepatocyte cell line with full-length HCV RNA or with synthetic HCV vsRNA duplexes inhibited PTPRE expression, recapitulating the in vivo observation. Together, these data demonstrate that HCV infection reduces PTPRE expression in the liver and PBMCs of infected humans, and suggest that the HCV E2 vsRNA is a novel viral factor that may contribute towards viral persistence. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
3. HCV Induces Telomerase Reverse Transcriptase, Increases Its Catalytic Activity, and Promotes Caspase Degradation in Infected Human Hepatocytes.
- Author
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Zhu, Zhaowen, Tran, Huy, Mathahs, M. Meleah, Moninger, Thomas O., and Schmidt, Warren N.
- Subjects
HEPATITIS C virus ,TELOMERASE reverse transcriptase ,PROMOTERS (Genetics) ,CASPASES ,LIVER cells ,CATALYTIC activity ,BIODEGRADATION ,GENETICS - Abstract
Introduction: Telomerase repairs the telomeric ends of chromosomes and is active in nearly all malignant cells. Hepatitis C virus (HCV) is known to be oncogenic and potential interactions with the telomerase system require further study. We determined the effects of HCV infection on human telomerase reverse transcriptase (TERT) expression and enzyme activity in primary human hepatocytes and continuous cell lines. Results: Primary human hepatocytes and Huh-7.5 hepatoma cells showed early de novo TERT protein expression 2–4 days after infection and these events coincided with increased TERT promoter activation, TERT mRNA, and telomerase activity. Immunoprecipitation studies demonstrated that NS3-4A protease-helicase, in contrast to core or NS5A, specifically bound to the C-terminal region of TERT through interactions between helicase domain 2 and protease sequences. Increased telomerase activity was noted when NS3-4A was transfected into cells, when added to reconstituted mixtures of TERT and telomerase RNA, and when incubated with high molecular weight telomerase ‘holoenzyme’ complexes. The NS3-4A catalytic effect on telomerase was inhibited with primuline or danoprevir, agents that are known to inhibit NS3 helicase and protease activities respectively. In HCV infected cells, NS3-4A could be specifically recovered with telomerase holoenzyme complexes in contrast to NS5A or core protein. HCV infection also activated the effector caspase 7 which is known to target TERT. Activation coincided with the appearance of lower molecular weight carboxy-terminal fragment(s) of TERT, chiefly sized at 45 kD, which could be inhibited with pancaspase or caspase 7 inhibitors. Conclusions: HCV infection induces TERT expression and stimulates telomerase activity in addition to triggering Caspase activity that leads to increased TERT degradation. These activities suggest multiple points whereby the virus can influence neoplasia. The NS3-4A protease-helicase can directly bind to TERT, increase telomerase activity, and thus potentially influence telomere repair and host cell neoplastic behavior. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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- View/download PDF
4. Hepatitis C virus infection and hepatic stellate cell activation downregulate miR-29: miR-29 overexpression reduces hepatitis C viral abundance in culture.
- Author
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Bandyopadhyay S, Friedman RC, Marquez RT, Keck K, Kong B, Icardi MS, Brown KE, Burge CB, Schmidt WN, Wang Y, McCaffrey AP, Bandyopadhyay, Sarmistha, Friedman, Robin C, Marquez, Rebecca T, Keck, Kathy, Kong, Benjamin, Icardi, Michael S, Brown, Kyle E, Burge, Christopher B, and Schmidt, Warren N
- Subjects
CELL metabolism ,RNA metabolism ,RNA analysis ,ALGORITHMS ,BIOCHEMISTRY ,COLLAGEN ,EPITHELIAL cells ,HEPATITIS viruses ,LIVER ,PHENOMENOLOGY ,POLYMERASE chain reaction ,RESEARCH funding ,REVERSE transcriptase polymerase chain reaction ,CHRONIC hepatitis C - Abstract
Background: Chronic hepatitis C virus (HCV)-induced liver fibrosis involves upregulation of transforming growth factor (TGF)-β and subsequent hepatic stellate cell (HSC) activation. MicroRNAs (miRNAs) regulate HCV infection and HSC activation.Methods: TaqMan miRNA profiling identified 12 miRNA families differentially expressed between chronically HCV-infected human livers and uninfected controls. To identify pathways affected by miRNAs, we developed a new algorithm (pathway analysis of conserved targets), based on the probability of conserved targeting.Results: This analysis suggested a role for miR-29 during HCV infection. Of interest, miR-29 was downregulated in most HCV-infected patients. miR-29 regulates expression of extracellular matrix proteins. In culture, HCV infection downregulated miR-29, and miR-29 overexpression reduced HCV RNA abundance. miR-29 also appears to play a role in HSCs. Hepatocytes and HSCs contribute similar amounts of miR-29 to whole liver. Both activation of primary HSCs and TGF-β treatment of immortalized HSCs downregulated miR-29. miR-29 overexpression in LX-2 cells decreased collagen expression and modestly decreased proliferation. miR-29 downregulation by HCV may derepress extracellular matrix synthesis during HSC activation.Conclusions: HCV infection downregulates miR-29 in hepatocytes and may potentiate collagen synthesis by reducing miR-29 levels in activated HSCs. Treatment with miR-29 mimics in vivo might inhibit HCV while reducing fibrosis. [ABSTRACT FROM AUTHOR]- Published
- 2011
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5. Down-regulation of heme oxygenase-1 by hepatitis C virus infection in vivo and by the in vitro expression of hepatitis C core protein.
- Author
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Abdalla, Maher Y., Britigan, Bradley E., Feng Wen, Icardi, Michael, McCormick, Michael L., LaBrecque, Douglas R., Voigt, Michael, Brown, Kyle E., Schmidt, Warren N., and Wen, Feng
- Subjects
HEME oxygenase ,HEPATITIS C virus ,COMMUNICABLE diseases ,ANTIOXIDANTS ,INTERNAL medicine ,MEDICAL research ,PATHOLOGY ,PROTEIN metabolism ,RNA analysis ,BIOCHEMISTRY ,BIOPSY ,CELL lines ,COMPARATIVE studies ,HEPATITIS viruses ,IMMUNOHISTOCHEMISTRY ,LIVER ,PHENOMENOLOGY ,RESEARCH methodology ,MEDICAL cooperation ,MEMBRANE proteins ,OXIDOREDUCTASES ,POLYMERASE chain reaction ,RESEARCH ,RNA ,SUPEROXIDE dismutase ,WESTERN immunoblotting ,EVALUATION research ,REVERSE transcriptase polymerase chain reaction ,PHYSIOLOGY - Abstract
Antioxidant enzymes, including heme oxygenase (HO)-1, are an important line of defense against oxidant-mediated liver injury. Because hepatitis C virus (HCV) infection appears to increase the production of oxidants, we evaluated levels of antioxidant enzymes and HO-1 in liver-biopsy samples from HCV-infected patients by immunoblot and semiquantitative reverse-transcriptase polymerase chain reaction. In HCV-infected liver samples, levels of immunoreactive HO-1 and HO-1 mRNA were >4-fold lower than levels in control samples, but levels of superoxide dismutase and catalase were unaffected. Immunohistochemical results confirmed the decreased expression of HO-1 in hepatocytes from liver samples from HCV-infected patients but not in those from patients with other chronic liver diseases. The expression of HO-1 was also reduced in cell lines that stably express HCV core protein, which suggests that core gene products are capable of regulating the expression of HO-1. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
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