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mitochondrial hcv

Sander Kersten, Rinke Stienstra
The peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor that is abundantly expressed in liver. PPARα is activated by fatty acids and various other lipid species, as well as by a class of chemicals referred to as peroxisome proliferators. Studies in mice have shown that PPARα serves as the master regulator of hepatic lipid metabolism during fasting. In addition, PPARα suppresses inflammation and the acute phase response. Comparatively little is known about PPARα in human liver...
January 7, 2017: Biochimie
M T Sánchez-Aparicio, J Ayllón, A Leo-Macias, T Wolff, A García-Sastre
: The retinoic acid-inducible gene 1 (RIG-I) signaling pathway is essential for the recognition of viruses and the initiation of host interferon (IFN)-mediated antiviral responses. Once activated, RIG-I interacts with polyubiquitin chains generated by TRIM25 and binds mitochondrial antiviral signaling protein (MAVS), leading to the production of type I IFN. We now show specific interactions among these key partners in the RLR pathway through the use of bimolecular fluorescence complementation (BiFC) and super-resolution microscopy...
January 15, 2017: Journal of Virology
Sevİn Kirdar, Asli Gamze Sener, Merve Cengİz, Nerİman Aydin
The prevalence of autoantibody in the patients with chronic hepatitis C infection, and the relationship between the autoantibodies and HCV genotypes were investigated in this study. One hundred and eight anti-HCV positive and 86 anti-HCV negative patients were included in the study. Anti-HCV were studied by enzyme immunassay (EIA). HCV RNA was determined by real time polymerase chain reaction (PCR) and HCV genotypes were determined by a reverse-line blot hybridization. Anti-nuclear antibodies (ANA), anti-smooth muscle antibodies (ASMA), Anti-mitochondrial antibodies (AMA), liver kidney microsomal antibodies (LKM) were detected by indirect immunofluorescence assay...
November 2016: APMIS: Acta Pathologica, Microbiologica, et Immunologica Scandinavica
Mara Simopoulou, Laertis Gkoles, Panagiotis Bakas, Polina Giannelou, Theodoros Kalampokas, Konstantinos Pantos, Michael Koutsilieris
: Intracytoplasmic sperm injection (ICSI) is the most frequently applied method for fertilization making the process of identifying the perfect spermatozoon fundamental. Herein we offer a critical and thorough presentation on the techniques reported regarding (i) handling and preparing semen samples, (ii) identifying and 'fishing' spermatozoa, and (iii) improving key factors, such as motility for a successful ICSI practice. These approaches are suggested to make the process easier and more effective especially in atypical and challenging circumstances...
December 2016: Systems Biology in Reproductive Medicine
Martijn Fenaux, Xiaodong Lin, Fumiaki Yokokawa, Zachary Sweeney, Oliver Saunders, Lili Xie, Siew Pheng Lim, Marianne Uteng, Kyoko Uehara, Robert Warne, Wang Gang, Christopher Jones, Satya Yendluri, Helen Gu, Keith Mansfield, Julie Boisclair, Tycho Heimbach, Alexandre Catoire, Kathryn Bracken, Margaret Weaver, Heinz Moser, Weidong Zhong
Nucleoside or nucleotide inhibitors are a highly successful class of antivirals due to selectivity, potency, broad coverage, and high barrier to resistance. Nucleosides are the backbone of combination treatments for HIV, hepatitis B virus, and, since the FDA approval of sofosbuvir in 2013, also for hepatitis C virus (HCV). However, many promising nucleotide inhibitors have advanced to clinical trials only to be terminated due to unexpected toxicity. Here we describe the in vitro pharmacology of compound 1, a monophosphate prodrug of a 2'-ethynyluridine developed for the treatment of HCV...
December 2016: Antimicrobial Agents and Chemotherapy
Shanshan Wang, Yongzhi Chen, Chunfeng Li, Yaoxing Wu, Lei Guo, Changwei Peng, Yueping Huang, Genhong Cheng, F Xiao-Feng Qin
Tripartite motif 14 (TRIM14) was reported to function as a mitochondrial signaling adaptor in mediating innate immune responses. However, the involvement of TRIM14 in host defense against viral infection and molecular mechanisms remain unclear. Here, we demonstrated that enforced expression of TRIM14 could potently inhibit the infection and replication of HCV in hepatocytes, whereas TRIM14 knockout cells became more susceptible to HCV infection. Interestingly, further experiments revealed that such anti-HCV activity was independent of activating the NF-κB or interferon pathways but required the C-terminal SPRY domain of no signaling capacity...
2016: Scientific Reports
Gwon-Soo Jung, Jae-Han Jeon, Yeon-Kyung Choi, Se Young Jang, Soo Young Park, Sung-Woo Kim, Jun-Kyu Byun, Mi-Kyung Kim, Sungwoo Lee, Eui-Cheol Shin, In-Kyu Lee, Yu Na Kang, Keun-Gyu Park
During replication, hepatitis C virus (HCV) utilizes macromolecules produced by its host cell. This process requires host cellular metabolic reprogramming to favor elevated levels of aerobic glycolysis. Therefore, we evaluated whether pyruvate dehydrogenase kinase (PDK), a mitochondrial enzyme that promotes aerobic glycolysis, can regulate HCV replication. Levels of c-Myc, hypoxia-inducible factor-1α (HIF-1α), PDK1, PDK3, glucokinase, and serine biosynthetic enzymes were compared between HCV-infected and uninfected human liver and Huh-7...
2016: Scientific Reports
Ana Joaquina Pérez-Berná, Maria José Rodríguez, Francisco Javier Chichón, Martina Friederike Friesland, Andrea Sorrentino, Jose L Carrascosa, Eva Pereiro, Pablo Gastaminza
Chronic hepatitis C virus (HCV) infection causes severe liver disease in millions of humans worldwide. Pathogenesis of HCV infection is strongly driven by a deficient immune response of the host, although intersection of different aspects of the virus life cycle with cellular homeostasis is emerging as an important player in the pathogenesis and progression of the disease. Cryo soft X-ray tomography (cryo-SXT) was performed to investigate the ultrastructural alterations induced by the interference of HCV replication with cellular homeostasis...
July 26, 2016: ACS Nano
Andres Tabernilla, Ignacio Rego-Pérez, Marta Grandal, Berta Pernas, Sonia Pértega, Manuel Delgado, Ana Mariño, Hortensia Álvarez, Alvaro Mena, Iria Rodríguez-Osorio, Jose Domingo Pedreira, Francisco Javier Blanco, Eva Poveda
The impact of mitochondrial DNA haplogroups on the outcome of liver fibrosis was evaluated in 362 hepatitis C virus infection (HCV)-monoinfected and HIV/HCV-coinfected patients (147 and 215, respectively) in clinical follow-up at 2 reference hospitals in the Northwest of Spain. The mitochondrial DNA haplogroup H was the most prevalent (50.3%) in this population. The cluster Others and V were recognized as risk factors for the development of liver fibrosis while haplogroup H and HCV genotype 4 confer a lower risk...
October 1, 2016: Journal of Acquired Immune Deficiency Syndromes: JAIDS
Maryam Ehteshami, Sijia Tao, Tugba Ozturk, Longhu Zhou, Jong Hyun Cho, Hongwang Zhang, Sheida Amiralaei, Jadd R Shelton, Xiao Lu, Ahmed Khalil, Robert A Domaoal, Richard A Stanton, Justin E Suesserman, Biing Lin, Sam S Lee, Franck Amblard, Tony Whitaker, Steven J Coats, Raymond F Schinazi
Ribonucleoside analog inhibitors (rNAI) target the hepatitis C virus (HCV) RNA-dependent RNA polymerase nonstructural protein 5B (NS5B) and cause RNA chain termination. Here, we expand our studies on β-d-2'-C-methyl-2,6-diaminopurine-ribonucleotide (DAPN) phosphoramidate prodrug 1 (PD1) as a novel investigational inhibitor of HCV. DAPN-PD1 is metabolized intracellularly into two distinct bioactive nucleoside triphosphate (TP) analogs. The first metabolite, 2'-C-methyl-GTP, is a well-characterized inhibitor of NS5B polymerase, whereas the second metabolite, 2'-C-methyl-DAPN-TP, behaves as an adenosine base analog...
August 2016: Antimicrobial Agents and Chemotherapy
Gavin Ka Yu Siu, Fan Zhou, Mei Kuen Yu, Leiliang Zhang, Tuanlao Wang, Yongheng Liang, Yangchao Chen, Hsiao Chang Chan, Sidney Yu
Hepatitis C virus (HCV) has long been observed to take advantage of the host mitochondria to support viral replication and assembly. The HCV core protein has been implicated to fragment host mitochondria. In this report, we have discovered that the non-structural protein 5A (NS5A) plays an instructive role in attaching ER with mitochondria, causing mitochondrial fragmentation. Dynamin-related protein 1(Drp1), a host protein essential to mitochondrial membrane fission, does not play a role in NS5A-induced mitochondrial fragmentation...
2016: Scientific Reports
Ana R Ferreira, Ana C Magalhães, Fátima Camões, Ana Gouveia, Marta Vieira, Jonathan C Kagan, Daniela Ribeiro
Hepatitis C virus (HCV) is the cause of one of the most prevalent viral infections worldwide. Upon infection, the HCV genome activates the RIG-I-MAVS signalling pathway leading to the production of direct antiviral effectors which prevent important steps in viral propagation. MAVS localizes at peroxisomes and mitochondria and coordinate the activation of an effective antiviral response: peroxisomal MAVS is responsible for a rapid but short-termed antiviral response, while the mitochondrial MAVS is associated with the activation of a stable response with delayed kinetics...
April 2016: Journal of Cellular and Molecular Medicine
Zbigniew Wyżewski, Karolina P Gregorczyk, Justyna Struzik, Marek Niemiałtowski, Lidia Szulc-Dąbrowska
Mitochondrial antiviral signaling protein (MAVS) transmits activation signal of type I interferon (IFN) gene transcription in the molecular intracellular pathway, which depends on the protein encoded by retinoic acid inducible gene I (RIG-I) or melanoma differentiation-associated protein-5 (MDA-5). MAVS, as a signal molecule, performs an essential function in the development of an antiviral immune response. The molecule of MAVS consists of two domains: the N-terminal domain and the C-terminal domain. The N-terminal end of MAVS contains the caspase activation and recruitment domain (CARD)...
January 26, 2016: Postȩpy Higieny i Medycyny Doświadczalnej
Chia-Lin Chen, Dinesh Babu Uthaya Kumar, Vasu Punj, Jun Xu, Linda Sher, Stanley M Tahara, Sonja Hess, Keigo Machida
Stem cell markers, including NANOG, have been implicated in various cancers; however, the functional contribution of NANOG to cancer pathogenesis has remained unclear. Here, we show that NANOG is induced by Toll-like receptor 4 (TLR4) signaling via phosphorylation of E2F1 and that downregulation of Nanog slows down hepatocellular carcinoma (HCC) progression induced by alcohol western diet and hepatitis C virus protein in mice. NANOG ChIP-seq analyses reveal that NANOG regulates the expression of genes involved in mitochondrial metabolic pathways required to maintain tumor-initiating stem-like cells (TICs)...
January 12, 2016: Cell Metabolism
I K Kim, C Gaultier, J Steggerda, S-H Pan, A S Klein, A Annamalai, T Tran, N N Nissen
Liver transplantation in patients infected with the human immunodeficiency virus (HIV) has been increasingly performed with reasonable outcomes; however, medical management of both immunosuppression and antiretroviral therapy can be challenging owing to drug toxicities and interactions. Nucleoside reverse transcriptase inhibitors (NRTIs), a common backbone of highly active antiretroviral therapy (HAART), were the first class of effective antiretroviral drugs developed. NRTIs are commonly used for posttransplant HAART therapy and have a rare but fatal complication of mitochondrial toxicity, manifesting as severe lactic acidosis, hepatic steatosis, and lipoatrophy...
November 2015: Transplantation Proceedings
Donna N Douglas, Christopher Hao Pu, Jamie T Lewis, Rakesh Bhat, Anwar Anwar-Mohamed, Michael Logan, Garry Lund, William R Addison, Richard Lehner, Norman M Kneteman
Cytopathic effects are currently believed to contribute to hepatitis C virus (HCV)-induced liver injury and are readily observed in Huh7.5 cells infected with the JFH-1 HCV strain, manifesting as apoptosis highly correlated with growth arrest. Reactive oxygen species, which are induced by HCV infection, have recently emerged as activators of AMP-activated protein kinase. The net effect is ATP conservation via on/off switching of metabolic pathways that produce/consume ATP. Depending on the scenario, this can have either pro-survival or pro-apoptotic effects...
January 22, 2016: Journal of Biological Chemistry
Joy Y Feng, Yili Xu, Ona Barauskas, Jason K Perry, Shekeba Ahmadyar, George Stepan, Helen Yu, Darius Babusis, Yeojin Park, Krista McCutcheon, Michel Perron, Brian E Schultz, Roman Sakowicz, Adrian S Ray
Toxicity has emerged during the clinical development of many but not all nucleotide inhibitors (NI) of hepatitis C virus (HCV). To better understand the mechanism for adverse events, clinically relevant HCV NI were characterized in biochemical and cellular assays, including assays of decreased viability in multiple cell lines and primary cells, interaction with human DNA and RNA polymerases, and inhibition of mitochondrial protein synthesis and respiration. NI that were incorporated by the mitochondrial RNA polymerase (PolRMT) inhibited mitochondrial protein synthesis and showed a corresponding decrease in mitochondrial oxygen consumption in cells...
February 2016: Antimicrobial Agents and Chemotherapy
Silke Bender, Antje Reuter, Florian Eberle, Evelyne Einhorn, Marco Binder, Ralf Bartenschlager
Sensing viruses by pattern recognition receptors (PRR) triggers the innate immune system of the host cell and activates immune signaling cascades such as the RIG-I/IRF3 pathway. Mitochondrial antiviral-signaling protein (MAVS, also known as IPS-1, Cardif, and VISA) is the crucial adaptor protein of this pathway localized on mitochondria, peroxisomes and mitochondria-associated membranes of the endoplasmic reticulum. Activation of MAVS leads to the production of type I and type III interferons (IFN) as well as IFN stimulated genes (ISGs)...
November 2015: PLoS Pathogens
Doaa I Hashad, Amany S Elyamany, Perihan E Salem
AIM: To assess the use of mitochondrial DNA (mtDNA) content as a noninvasive molecular biomarker in hepatitis C virus-related hepatocellular carcinoma (HCV-HCC). MATERIALS AND METHODS: A total of 135 participants were enrolled in the study. Equal numbers of subjects were enrolled in each of three clinically defined groups: those with HCV-related cirrhosis (HCV-cirrhosis), those with HCV-HCC, and a control group of age- and sex-matched healthy volunteers with no evidence of liver disease...
November 2015: Genetic Testing and Molecular Biomarkers
Marika Piciocchi, Romilda Cardin, Umberto Cillo, Alessandro Vitale, Andrea Cappon, Claudia Mescoli, Maria Guido, Massimo Rugge, Patrizia Burra, Annarosa Floreani, Fabio Farinati
In viral hepatitis, inflammation is correlated with chronic oxidative stress, one of the biological events leading to DNA damage and hepatocellular carcinoma (HCC) development. Aim of this study was to investigate the complex molecular network linking oxidative damage to telomere length and telomerase activity and regulation in hepatitis C and B virus-related liver carcinogenesis. We investigated 142 patients: 21 with HCC (in both tumor and peritumor tissues) and 121 with chronic viral hepatitis in different stages...
February 2016: Translational Research: the Journal of Laboratory and Clinical Medicine
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