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https://www.readbyqxmd.com/read/29625557/case-report-lactic-acidosis-and-rhabdomyolysis-during-telbivudine-and-tenofovir-treatment-for-chronic-hepatitis-b
#1
Yue Ying, Yue-Kai Hu, Jia-Lin Jin, Ji-Ming Zhang, Wen-Hong Zhang, Yu-Xian Huang
BACKGROUND: Current treatment options for chronic hepatitis B (CHB) are pegylated interferon alpha and nucleoside analogues (NAs). NAs have relatively fewer side effects than interferon alpha, and generally well tolerated. Previously 12.9% of patients on telbivudine treatment were reported to develop severe elevation of serum creatine phosphokinase (CPK) levels, but related clinical disease, like lactic acidosis (LA) and rhabdomyolysis (RM) were rare. The pathophysiology may be mitochondrial toxicity, for the NAs inhibit not only hepatitis B virus (HBV) polymerase, but also the host mitochondrial DNA polymerase γ...
April 6, 2018: BMC Gastroenterology
https://www.readbyqxmd.com/read/29619244/antiviral-effects-of-ferric-ammonium-citrate
#2
Hongbin Wang, Zheng Li, Junling Niu, Yongfen Xu, Li Ma, Ailing Lu, Xun Wang, Zhikang Qian, Zhong Huang, Xia Jin, Qibin Leng, Jianhua Wang, Jin Zhong, Bing Sun, Guangxun Meng
Iron is an essential nutrient for cell survival and is crucial for DNA replication, mitochondrial function and erythropoiesis. However, the immunological role of iron in viral infections has not been well defined. Here we found the iron salt ferric ammonium citrate (FAC) inhibited Influenza A virus, HIV virus, Zika virus, and Enterovirus 71 (EV71) infections. Of note, both iron ion and citrate ion were required for the antiviral capability of FAC, as other iron salts and citrates did not exhibit viral inhibition...
2018: Cell Discovery
https://www.readbyqxmd.com/read/29440426/sting-dependent-translation-inhibition-restricts-rna-virus-replication
#3
Kate M Franz, William J Neidermyer, Yee-Joo Tan, Sean P J Whelan, Jonathan C Kagan
In mammalian cells, IFN responses that occur during RNA and DNA virus infections are activated by distinct signaling pathways. The RIG-I-like-receptors (RLRs) bind viral RNA and engage the adaptor MAVS (mitochondrial antiviral signaling) to promote IFN expression, whereas cGAS (cGMP-AMP synthase) binds viral DNA and activates an analogous pathway via the protein STING (stimulator of IFN genes). In this study, we confirm that STING is not necessary to induce IFN expression during RNA virus infection but also find that STING is required to restrict the replication of diverse RNA viruses...
February 27, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29295921/lymphocytes-eject-interferogenic-mitochondrial-dna-webs-in-response-to-cpg-and-non-cpg-oligodeoxynucleotides-of-class-c
#4
Björn Ingelsson, Daniel Söderberg, Tobias Strid, Anita Söderberg, Ann-Charlotte Bergh, Vesa Loitto, Kourosh Lotfi, Mårten Segelmark, Giannis Spyrou, Anders Rosén
Circulating mitochondrial DNA (mtDNA) is receiving increasing attention as a danger-associated molecular pattern in conditions such as autoimmunity, cancer, and trauma. We report here that human lymphocytes [B cells, T cells, natural killer (NK) cells], monocytes, and neutrophils derived from healthy blood donors, as well as B cells from chronic lymphocytic leukemia patients, rapidly eject mtDNA as web filament structures upon recognition of CpG and non-CpG oligodeoxynucleotides of class C. The release was quenched by ZnCl2 , independent of cell death (apoptosis, necrosis, necroptosis, autophagy), and continued in the presence of TLR9 signaling inhibitors...
January 16, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29214156/off-target-effects-of-drugs-that-disrupt-human-mitochondrial-dna-maintenance
#5
REVIEW
Matthew J Young
Nucleoside reverse transcriptase inhibitors (NRTIs) were the first drugs used to treat human immunodeficiency virus (HIV) the cause of acquired immunodeficiency syndrome. Development of severe mitochondrial toxicity has been well documented in patients infected with HIV and administered NRTIs. In vitro biochemical experiments have demonstrated that the replicative mitochondrial DNA (mtDNA) polymerase gamma, Polg, is a sensitive target for inhibition by metabolically active forms of NRTIs, nucleotide reverse transcriptase inhibitors (NtRTIs)...
2017: Frontiers in Molecular Biosciences
https://www.readbyqxmd.com/read/29180528/simple-in-vitro-assay-to-evaluate-the-incorporation-efficiency-of-ribonucleotide-analog-5-triphosphates-into-rna-by-human-mitochondrial-dna-dependent-rna-polymerase
#6
Gaofei Lu, Gregory R Bluemling, Shuli Mao, Michael Hager, Bharat P Gurale, Paul Collop, Damien Kuiper, Kasinath Sana, George R Painter, Abel De La Rosa, Alexander A Kolykhalov
There is a growing body of evidence suggesting that some ribonucleoside/ribonucleotide analogs may be incorporated into mitochondrial RNA by human mitochondrial DNA-dependent RNA polymerase (POLRMT) and disrupt mitochondrial RNA synthesis. An assessment of the incorporation efficiency of a ribonucleotide analog 5'-triphosphate by POLRMT may be used to evaluate the potential mitochondrial toxicity of the analog early in the development process. In this report, we provide a simple method to prepare active recombinant POLRMT...
February 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28710430/rlr-mediated-antiviral-innate-immunity-requires-oxidative-phosphorylation-activity
#7
Takuma Yoshizumi, Hiromi Imamura, Tomohiro Taku, Takahiro Kuroki, Atsushi Kawaguchi, Kaori Ishikawa, Kazuto Nakada, Takumi Koshiba
Mitochondria act as a platform for antiviral innate immunity, and the immune system depends on activation of the retinoic acid-inducible gene I (RIG-I)-like receptors (RLR) signaling pathway via an adaptor molecule, mitochondrial antiviral signaling. We report that RLR-mediated antiviral innate immunity requires oxidative phosphorylation (OXPHOS) activity, a prominent physiologic function of mitochondria. Cells lacking mitochondrial DNA or mutant cells with respiratory defects exhibited severely impaired virus-induced induction of interferons and proinflammatory cytokines...
July 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28620207/dengue-virus-activates-cgas-through-the-release-of-mitochondrial-dna
#8
Bo Sun, Karin B Sundström, Jun Jie Chew, Pradeep Bist, Esther S Gan, Hwee Cheng Tan, Kenneth C Goh, Tanu Chawla, Choon Kit Tang, Eng Eong Ooi
Cyclic GMP-AMP synthetase (cGAS) is a DNA-specific cytosolic sensor, which detects and initiates host defense responses against microbial DNA. It is thus curious that a recent study identified cGAS as playing important roles in inhibiting positive-sense single-stranded RNA (+ssRNA) viral infection, especially since RNA is not known to activate cGAS. Using a dengue virus serotype 2 (DENV-2) vaccine strain (PDK53), we show that infection creates an endogenous source of cytosolic DNA in infected cells through the release of mitochondrial DNA (mtDNA) to drive the production of cGAMP by cGAS...
June 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28073693/crosstalk-between-cytoplasmic-rig-i-and-sting-sensing-pathways
#9
REVIEW
Alessandra Zevini, David Olagnier, John Hiscott
Detection of evolutionarily conserved molecules on microbial pathogens by host immune sensors represents the initial trigger of the immune response against infection. Cytosolic receptors sense viral and intracellular bacterial genomes, as well as nucleic acids produced during replication. Once activated, these sensors trigger multiple signaling cascades, converging on the production of type I interferons and proinflammatory cytokines. Although distinct classes of receptors are responsible for the RNA and DNA sensing, the downstream signaling components are physically and functionally interconnected...
March 2017: Trends in Immunology
https://www.readbyqxmd.com/read/27989484/significant-impact-of-divalent-metal-ions-on-the-fidelity-sugar-selectivity-and-drug-incorporation-efficiency-of-human-primpol
#10
E John Tokarsky, Petra C Wallenmeyer, Kenneth K Phi, Zucai Suo
Human PrimPol is a recently discovered bifunctional enzyme that displays DNA template-directed primase and polymerase activities. PrimPol has been implicated in nuclear and mitochondrial DNA replication fork progression and restart as well as DNA lesion bypass. Published evidence suggests that PrimPol is a Mn2+ -dependent enzyme as it shows significantly improved primase and polymerase activities when binding Mn2+ , rather than Mg2+ , as a divalent metal ion cofactor. Consistently, our fluorescence anisotropy assays determined that PrimPol binds to a primer/template DNA substrate with affinities of 29 and 979nM in the presence of Mn2+ and Mg2+ , respectively...
January 2017: DNA Repair
https://www.readbyqxmd.com/read/27645237/antiviral-nucleotide-incorporation-by-recombinant-human-mitochondrial-rna-polymerase-is-predictive-of-increased-in-vivo-mitochondrial-toxicity-risk
#11
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
https://www.readbyqxmd.com/read/27474091/protection-from-interferon-%C3%AE-induced-neuronal-apoptosis-through-stimulation-of-muscarinic-acetylcholine-receptors-coupled-to-erk1-2-activation
#12
Maria C Olianas, Simona Dedoni, Pierluigi Onali
BACKGROUND AND PURPOSE: Although clinically useful for their immunomodulatory, antiproliferative and antiviral properties, type I interferons (IFNs) are involved in the pathogenesis of several neurodegenerative/neuroinflammatory diseases. In the present study, we investigated the ability of cholinergic stimulation to protect from IFN-β-induced neuronal apoptosis. EXPERIMENTAL APPROACH: The effects of the ACh receptor agonist carbachol (CCh) on IFN-β-induced apoptosis of human SH-SY5Y neuroblastoma cells were examined by using western blots, immunofluorescence and cytofluorimetry...
October 2016: British Journal of Pharmacology
https://www.readbyqxmd.com/read/27440888/hepatitis-b-virus-polymerase-localizes-to-the-mitochondria-and-its-terminal-protein-domain-contains-the-mitochondrial-targeting-signal
#13
Nuruddin Unchwaniwala, Nathan M Sherer, Daniel D Loeb
UNLABELLED: To understand subcellular sites of hepatitis B virus (HBV) replication, we visualized core (Cp), polymerase (Pol), and pregenomic RNA (pgRNA) in infected cells. Interestingly, we found that the majority of Pol localized to the mitochondria in cells undergoing viral replication. The mitochondrial localization of Pol was independent of both the cell type and other viral components, indicating that Pol contains an intrinsic mitochondrial targeting signal (MTS). Neither Cp nor pgRNA localized to the mitochondria during active replication, suggesting a role other than DNA synthesis for Pol at the mitochondria...
October 1, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27348524/hepatitis-b-virus-induced-parkin-dependent-recruitment-of-linear-ubiquitin-assembly-complex-lubac-to-mitochondria-and-attenuation-of-innate-immunity
#14
Mohsin Khan, Gulam Hussain Syed, Seong-Jun Kim, Aleem Siddiqui
Hepatitis B virus (HBV) suppresses innate immune signaling to establish persistent infection. Although HBV is a DNA virus, its pre-genomic RNA (pgRNA) can be sensed by RIG-I and activates MAVS to mediate interferon (IFN) λ synthesis. Despite of the activation of RIG-I-MAVS axis by pgRNA, the underlying mechanism explaining how HBV infection fails to induce interferon-αβ (IFN) synthesis remained uncharacterized. We demonstrate that HBV induced parkin is able to recruit the linear ubiquitin assembly complex (LUBAC) to mitochondria and abrogates IFN β synthesis...
June 2016: PLoS Pathogens
https://www.readbyqxmd.com/read/27302953/structural-basis-for-concerted-recruitment-and-activation-of-irf-3-by-innate-immune-adaptor-proteins
#15
Baoyu Zhao, Chang Shu, Xinsheng Gao, Banumathi Sankaran, Fenglei Du, Catherine L Shelton, Andrew B Herr, Jun-Yuan Ji, Pingwei Li
Type I IFNs are key cytokines mediating innate antiviral immunity. cGMP-AMP synthase, ritinoic acid-inducible protein 1 (RIG-I)-like receptors, and Toll-like receptors recognize microbial double-stranded (ds)DNA, dsRNA, and LPS to induce the expression of type I IFNs. These signaling pathways converge at the recruitment and activation of the transcription factor IRF-3 (IFN regulatory factor 3). The adaptor proteins STING (stimulator of IFN genes), MAVS (mitochondrial antiviral signaling), and TRIF (TIR domain-containing adaptor inducing IFN-β) mediate the recruitment of IRF-3 through a conserved pLxIS motif...
June 14, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27188236/moroxydine-hydrochloride-inhibits-grass-carp-reovirus-replication-and-suppresses-apoptosis-in-ctenopharyngodon-idella-kidney-cells
#16
Xiao-Bo Yu, Xiao-Hui Chen, Fei Ling, Kai Hao, Gao-Xue Wang, Bin Zhu
Moroxydine hydrochloride (Mor) is known to have multi-antiviral activities against DNA and RNA viruses but very little information exists on its pharmacology. The paper was undertaken to explore the antiviral response and antiapoptotic mechanism of Mor against grass carp reovirus (GCRV) in Ctenopharyngodon idella kidney (CIK) cells. The results showed that exposing GCRV-infected cell to 6.3 μg mL(-1) of Mor for 96 h avoid ca. 50% apoptosis. Meanwhile, Mor had lower cytotoxicity than ribavirin (Rib) as the value of safe concentration was threefold higher than effective concentration and the compound could ensure sufficient into and out of cells within 4 h when tested at the maximal safe concentration...
July 2016: Antiviral Research
https://www.readbyqxmd.com/read/26864061/-mavs-protein-and-its-interactions-with-hepatitis-a-b-and-c-viruses
#17
REVIEW
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
https://www.readbyqxmd.com/read/26552983/insights-into-the-molecular-mechanism-of-polymerization-and-nucleoside-reverse-transcriptase-inhibitor-incorporation-by-human-primpol
#18
Andrea C Mislak, Karen S Anderson
Human PrimPol is a newly identified DNA and RNA primase-polymerase of the archaeo-eukaryotic primase (AEP) superfamily and only the second known polymerase in the mitochondria. Mechanistic studies have shown that interactions of the primary mitochondrial DNA polymerase γ (mtDNA Pol γ) with nucleoside reverse transcriptase inhibitors (NRTIs), key components in treating HIV infection, are a major source of NRTI-associated toxicity. Understanding the interactions of host polymerases with antiviral and anticancer nucleoside analog therapies is critical for preventing life-threatening adverse events, particularly in AIDS patients who undergo lifelong treatment...
November 9, 2015: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/26386112/drug-induced-mitochondrial-dysfunction-and-cardiotoxicity
#19
REVIEW
Zoltán V Varga, Peter Ferdinandy, Lucas Liaudet, Pál Pacher
Mitochondria has an essential role in myocardial tissue homeostasis; thus deterioration in mitochondrial function eventually leads to cardiomyocyte and endothelial cell death and consequent cardiovascular dysfunction. Several chemical compounds and drugs have been known to directly or indirectly modulate cardiac mitochondrial function, which can account both for the toxicological and pharmacological properties of these substances. In many cases, toxicity problems appear only in the presence of additional cardiovascular disease conditions or develop months/years following the exposure, making the diagnosis difficult...
November 2015: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/26342080/the-deoxynucleoside-triphosphate-triphosphohydrolase-activity-of-samhd1-protein-contributes-to-the-mitochondrial-dna-depletion-associated-with-genetic-deficiency-of-deoxyguanosine-kinase
#20
Elisa Franzolin, Cristiano Salata, Vera Bianchi, Chiara Rampazzo
The dNTP triphosphohydrolase SAMHD1 is a nuclear antiviral host restriction factor limiting HIV-1 infection in macrophages and a major regulator of dNTP concentrations in human cells. In normal human fibroblasts its expression increases during quiescence, contributing to the small dNTP pool sizes of these cells. Down-regulation of SAMHD1 by siRNA expands all four dNTP pools, with dGTP undergoing the largest relative increase. The deoxyguanosine released by SAMHD1 from dGTP can be phosphorylated inside mitochondria by deoxyguanosine kinase (dGK) or degraded in the cytosol by purine nucleoside phosphorylase...
October 23, 2015: Journal of Biological Chemistry
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