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https://www.readbyqxmd.com/read/28622913/targeting-urate-to-reduce-oxidative-stress-in-parkinson-disease
#1
REVIEW
Grace F Crotty, Alberto Ascherio, Michael A Schwarzschild
Oxidative stress has been implicated as a core contributor to the initiation and progression of multiple neurological diseases. Genetic and environmental factors can produce oxidative stress through mitochondrial dysfunction leading to the degeneration of dopaminergic and other neurons underlying Parkinson disease (PD). Although clinical trials of antioxidants have thus far failed to demonstrate slowed progression of PD, oxidative stress remains a compelling target. Rather than prompting abandonment of antioxidant strategies, these failures have raised the bar for justifying drug and dosing selections and for improving study designs to test for disease modification by antioxidants...
June 13, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28618265/making-the-mark-the-role-of-adenosine-modifications-in-the-life-cycle-of-rna-viruses
#2
REVIEW
Sarah R Gonzales-van Horn, Peter Sarnow
Viral epitranscriptomics is a newly emerging field that has identified unique roles for RNA modifications in modulating life cycles of RNA viruses. Despite the observation of a handful of modified viral RNAs five decades ago, very little was known about how these modifications regulate viral life cycles, until recently. Here we review the pro- and anti-viral effects of methyl-6-adenosine in distinct viral life cycles, the role of 2' O-methyl modifications in RNA stability and innate immune sensing, and functions of adenosine to inosine modifications in retroviral life cycles...
June 14, 2017: Cell Host & Microbe
https://www.readbyqxmd.com/read/28604724/visualizing-adenosine-to-inosine-rna-editing-in-single-mammalian-cells
#3
Ian A Mellis, Rohit Gupte, Arjun Raj, Sara H Rouhanifard
Conversion of adenosine to inosine is a frequent type of RNA editing, but important details about the biology of this conversion remain unknown because of a lack of imaging tools. We developed inoFISH to directly visualize and quantify adenosine-to-inosine-edited transcripts in situ. We found that editing of the GRIA2, EIF2AK2, and NUP43 transcripts is uncorrelated with nuclear localization and paraspeckle association. Further, NUP43 exhibits constant editing levels between single cells, while GRIA2 editing levels vary...
June 12, 2017: Nature Methods
https://www.readbyqxmd.com/read/28601223/adenosine-deaminases-that-act-on-rna-adars
#4
Yuru Wang, Yuxuan Zheng, Peter A Beal
Inosine is one of the most common modifications found in human RNAs and the Adenosine Deaminases that act on RNA (ADARs) are the main enzymes responsible for its production. ADARs were first discovered in the 1980s and since then our understanding of ADARs has advanced tremendously. For instance, it is now known that defective ADAR function can cause human diseases. Furthermore, recently solved crystal structures of the human ADAR2 deaminase bound to RNA have provided insights regarding the catalytic and substrate recognition mechanisms...
2017: Enzymes
https://www.readbyqxmd.com/read/28599189/preclinical-activity-of-ff-10501-01-a-novel-inosine-5-monophosphate-dehydrogenase-inhibitor-in-acute-myeloid-leukemia
#5
Hui Yang, Zhihong Fang, Yue Wei, Zachary S Bohannan, Irene Gañán-Gómez, Ana Alfonso Pierola, Linda J Paradiso, Hiroyuki Iwamura, Guillermo Garcia-Manero
BACKGROUND: FF-10501-01 is a selective inosine monophosphate dehydrogenase (IMPDH) inhibitor that has shown activity in cancer cell lines. We studied whether FF-10501-01 is effective in targeting a variety of hypomethylating agent (HMA)-sensitive and -resistant acute myelogenous leukemia (AML) cell lines. METHODS: We treated multiple cell lines (including HMA-resistant cells) with FF-10501-01 and analyzed proliferation, apoptosis, and cell cycle status. We also assessed HMA-FF-10501-01 combinations and the ability of extracellular guanosine to rescue cell proliferation in FF-10501-01-treated cells...
May 26, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28597777/improved-metabolism-and-redox-state-with-a-novel-preservation-solution-implications-for-donor-lungs-after-cardiac-death-dcd
#6
David A Schipper, Anthony V Louis, Destiny S Dicken, Kitsie Johnson, Ryszard T Smolenski, Stephen M Black, Ray Runyan, John Konhilas, Joe G N Garcia, Zain Khalpey
Lungs donated after cardiac death (DCD) are an underutilized resource for a dwindling donor lung transplant pool. Our study investigates the potential of a novel preservation solution, Somah, to better preserve statically stored DCD lungs, for an extended time period, when compared to low-potassium dextran solution (LPD). We hypothesize that Somah is a metabolically superior organ preservation solution for hypothermic statically stored porcine DCD lungs, possibly improving lung transplant outcomes. Porcine DCD lungs (n = 3 per group) were flushed with and submerged in cold preservation solution...
April 2017: Pulmonary Circulation
https://www.readbyqxmd.com/read/28592827/a-comprehensive-characterisation-of-the-metabolic-profile-of-varicose-veins-implications-in-elaborating-plausible-cellular-pathways-for-disease-pathogenesis
#7
Muzaffar A Anwar, Kyrillos N Adesina-Georgiadis, K Spagou, P A Vorkas, J V Li, Joseph Shalhoub, Elaine Holmes, Alun H Davies
Metabolic phenotypes reflect both the genetic and environmental factors which contribute to the development of varicose veins (VV). This study utilises analytical techniques to provide a comprehensive metabolic picture of VV disease, with the aim of identifying putative cellular pathways of disease pathogenesis. VV (n = 80) and non-VV (n = 35) aqueous and lipid metabolite extracts were analysed using 600 MHz (1)H Nuclear Magnetic Resonance spectroscopy and Ultra-Performance Liquid Chromatography Mass Spectrometry...
June 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28572600/a-nucleotide-controlled-conformational-switch-modulates-the-activity-of-eukaryotic-imp-dehydrogenases
#8
Rubén M Buey, David Fernández-Justel, Íñigo Marcos-Alcalde, Graeme Winter, Paulino Gómez-Puertas, José María de Pereda, José Luis Revuelta
Inosine-5'-monophosphate dehydrogenase (IMPDH) is an essential enzyme for nucleotide metabolism and cell proliferation. Despite IMPDH is the target of drugs with antiviral, immunosuppressive and antitumor activities, its physiological mechanisms of regulation remain largely unknown. Using the enzyme from the industrial fungus Ashbya gossypii, we demonstrate that the binding of adenine and guanine nucleotides to the canonical nucleotide binding sites of the regulatory Bateman domain induces different enzyme conformations with significantly distinct catalytic activities...
June 1, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28560878/serial-metabolome-changes-in-a-prospective-cohort-of-subjects-with-influenza-viral-infection-and-comparison-with-dengue-fever
#9
Liang Cui, Jinling Fang, Eng Eong Ooi, Yie Hou Lee
Influenza virus infection (IVI) and dengue virus infection (DVI) are major public health threats. Between IVI and DVI, clinical symptoms can be overlapping yet infection-specific, but host metabolome changes are not well-described. Untargeted metabolomics and targeted oxylipinomic analyses were performed on sera serially collected at three phases of infection from a prospective cohort study of adult subjects with either H3N2 influenza infection or dengue fever. Untargeted metabolomics identified 26 differential metabolites and major perturbed pathways included purine metabolism, fatty acid biosynthesis and β-oxidation, tryptophan metabolism, phospholipid catabolism and steroid hormone pathway...
May 31, 2017: Journal of Proteome Research
https://www.readbyqxmd.com/read/28559490/adar-rna-editing-below-the-backbone
#10
Liam P Keegan, Anzer Khan, Dragana Vukic, Mary A O'Connell
ADAR RNA editing enzymes (Adenosine Deaminases acting on RNA), that convert adenosine bases to inosines were first identified biochemically thirty years ago. Since then studies on ADARs in genetic model organisms, and evolutionary comparisons between them, continue to reveal a surprising range of pleiotropic biological effects of ADARs. This review focuses on Drosophila melanogaster, which has a single Adar gene encoding a homolog of vertebrate ADAR2 that site-specifically edits hundreds of transcripts to change individual codons in ion channel subunits and membrane and cytoskeletal proteins...
May 30, 2017: RNA
https://www.readbyqxmd.com/read/28559277/cryptococcus-neoformans-ads-lyase-in-an-enzyme-essential-for-virulence-whose-crystal-structure-reveals-features-exploitable-in-antifungal-drug-design
#11
Jessica L Chitty, Kirsten L Blake, Ross D Blundell, Y Q Andre E Koh, Merinda Thompson, Avril A B Robertson, Mark S Butler, Matthew A Cooper, Ulrike Kappler, Simon J Williams, Bostjan Kobe, James A Fraser
There is significant clinical need for new antifungal agents to manage infections with pathogenic species such as Cryptococcus neoformans Because the purine biosynthesis pathway is essential for many metabolic processes, such as synthesis of DNA and RNA and energy generation, it may represent a potential target for developing new antifungals. Within this pathway, the bifunctional enzyme adenylosuccinate (ADS) lyase plays a role in the formation of the key intermediates inosine monophosphate and AMP involved in the synthesis of ATP and GTP, prompting us to investigate ADS lyase in C...
May 30, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28554472/a-case-of-neofunctionalization-of-a-putranjiva-roxburghii-pnp-protein-to-trypsin-inhibitor-by-disruption-of-pnp-udp-domain-through-an-insert-containing-inhibitory-site
#12
Preeti Verma, Girijesh K Patel, Bibekananda Kar, Ashwani K Sharma
The attainment of new function by a protein is achieved through convergent/divergent evolution. In present work, the sequence analysis of a 34kDa protein from Putranjiva roxburghii, earlier reported as a potent trypsin inhibitor, showed resemblance to some of the wound inducible and vegetative storage proteins. A detailed sequence analysis revealed that these proteins belong to PNP-UDP family. In case of P. roxburghii protein, an approximately 46 residue insert disrupts the PNP domain. Similar disruption of PNP domain is observed in related plant proteins...
July 2017: Plant Science: An International Journal of Experimental Plant Biology
https://www.readbyqxmd.com/read/28550310/a-to-i-editing-in-human-mirnas-is-enriched-in-seed-sequence-influenced-by-sequence-contexts-and-significantly-hypoedited-in-glioblastoma-multiforme
#13
Deepanjan Paul, Ashis Narayan Sinha, Arjun Ray, Megha Lal, Subhashree Nayak, Anchal Sharma, Bharati Mehani, Debasish Mukherjee, Saurabh V Laddha, Ashish Suri, Chitra Sarkar, Arijit Mukhopadhyay
Editing in microRNAs, particularly in seed can significantly alter the choice of their target genes. We show that out of 13 different human tissues, different regions of brain showed higher adenosine to inosine (A-to-I) editing in mature miRNAs. These events were enriched in seed sequence (73.33%), which was not observed for cytosine to uracil (17.86%) editing. More than half of the edited miRNAs showed increased stability, 72.7% of which had ΔΔG values less than -6.0 Kcal/mole and for all of them the edited adenosines mis-paired with cytosines on the pre-miRNA structure...
May 26, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28547528/manganese-ii-chloride-alters-nucleotide-and-nucleoside-catabolism-in-zebrafish-danio-rerio-adult-brain
#14
Stefani Altenhofen, Débora Dreher Nabinger, Talita Carneiro Brandão Pereira, Carlos Eduardo Leite, Maurício Reis Bogo, Carla Denise Bonan
ATP and adenosine, the main signaling molecules of purinergic system, are involved in toxicological effects induced by metals. The manganese (Mn) exposure induces several cellular changes, which could interfere with signaling pathways, such as the purinergic system. In this study, we evaluated the effects of exposure to manganese(II) chloride (MnCl2) during 96 h on nucleoside triphosphate diphosphohydrolase (NTPDase), ecto-5'-nucleotidase, and adenosine deaminase (ADA) activities, followed by analyzing the gene expression patterns of NTPDases (entpd1, entpd2a...
May 25, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28543779/inosine-can-increase-dna-s-susceptibility-to-photo-oxidation-by-a-ru-ii-complex-due-to-structural-change-in-the-minor-groove
#15
John M Kelly, Paraic Keane, James Hall, Fergus Poynton, Bjorn Poulsen, Sarah Gurung, Ian Clark, Igor Sazanovich, Michael Towrie, Thorfinnur Gunnlaugsson, Susan Quinn, Christine Cardin
Key to the development of DNA-targeting phototherapeutic drugs is determining the interplay between the photoactivity of the drug and its binding preference for a target sequence. For the photo-oxidising lambda-[Ru(TAP)2(dppz)]2+ (Ʌ-1) complex bound to either d{T1C2G3G4C5G6C7C8G9A10}2 (G9) or d{TCGGCGCCIA}2 (I9), the X-ray crystal structures shows the dppz intercalated at the terminal T1C2;G9A10 step or T1C2;I9A10 step. Thus substitution of the G9 nucleobase by inosine does not affect intercalation in the solid state although with I9 the dppz is more deeply inserted...
May 25, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28543275/the-role-of-itpa-and-ribavirin-transporter-genes-polymorphisms-in-prediction-of-ribavirin-induced-anemia-in-chronic-hepatitis-c-egyptian-patients
#16
Ehab S El Desoky, Alaa T Abdelhafez, Jessica Cusato, Sherif I Kamel, Abeer M R Hussein, Amedeo De Nicolo, Giovanni Di Perri, Antonio D'Avolio
Few data are available concerning the roles of polymorphisms of inosine triphosphatase (ITPA) gene and ribavirin (RBV) transporter genes in the prediction of RBV-induced anemia among Egyptians with chronic hepatitis C (CHC). Genotyping of 3 ITPA gene variants and 2 variants of RBV transporter genes has been performed in 123 patients under pegylated interferon-α/ribavirin treatment. The baseline hemoglobin and ITPA rs1127354 CA/AA have been found as predictors of anemia at 4, 8 and 12 weeks of RBV therapy. In addition, ITPA rs7270101 AC/CC and age predicted anemia after 12 weeks of therapy...
May 24, 2017: Clinical and Experimental Pharmacology & Physiology
https://www.readbyqxmd.com/read/28542129/adar1-mediated-3-utr-editing-and-expression-control-of-antiapoptosis-genes-fine-tunes-cellular-apoptosis-response
#17
Chang-Ching Yang, Yi-Tung Chen, Yi-Feng Chang, Hsuan Liu, Yu-Ping Kuo, Chieh-Tien Shih, Wei-Chao Liao, Hui-Wen Chen, Wen-Sy Tsai, Bertrand Chin-Ming Tan
Adenosine-to-inosine RNA editing constitutes a crucial component of the cellular transcriptome and critically underpins organism survival and development. While recent high-throughput approaches have provided comprehensive documentation of the RNA editome, its functional output remains mostly unresolved, particularly for events in the non-coding regions. Gene ontology analysis of the known RNA editing targets unveiled a preponderance of genes related to apoptosis regulation, among which proto-oncogenes XIAP and MDM2 encode two the most abundantly edited transcripts...
May 25, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28517175/comparison-of-the-human-a2a-adenosine-receptor-recognition-by-adenosine-and-inosine-new-insights-from-supervised-molecular-dynamics-simulations
#18
Giuseppe Deganutti, Ajith Welihinda, Stefano Moro
Adenosine deaminase converts adenosine to inosine. Differently by adenosine, modest attention has been dedicated to the physiological roles of inosine. Nevertheless, recent studies demonstrate that inosine has neuroprotective, cardioprotective immunomodulatory, and antidepressive effects. It has been recently reported by Welihinda and collaborators that inosine is a less potent agonist than adenosine at the A2A AR. To better depict the differences in receptor recognition mechanism of both adenosine and inosine, in this work supervised molecular dynamics (SuMD) simulations have been performed and analyzed...
May 18, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28513806/increased-activity-of-vascular-adenosine-deaminase-in-atherosclerosis-and-therapeutic-potential-of-its-inhibition
#19
Barbara Kutryb-Zajac, Lukasz Mateuszuk, Paulina Zukowska, Agnieszka Jasztal, Magdalena A Zabielska, Marta Toczek, Patrycja Jablonska, Agnieszka Zakrzewska, Barbara Sitek, Jan Rogowski, Romuald Lango, Ewa M Slominska, Stefan Chlopicki, Ryszard T Smolenski
Aims: Extracellular nucleotides and adenosine that are formed or degraded by membrane-bound ecto-enzymes could affect atherosclerosis by regulating the inflammation and thrombosis. This study aimed to evaluate a relation between ecto-enzymes that convert extracellular adenosine triphosphate to adenine dinucleotide phosphate, adenosine monophosphate, adenosine, and inosine on the surface of the vessel wall with the severity or progression of experimental and clinical atherosclerosis. Furthermore, we tested whether the inhibition of adenosine deaminase will block the development of experimental atherosclerosis...
November 1, 2016: Cardiovascular Research
https://www.readbyqxmd.com/read/28509906/therapeutic-efficacy-of-atypical-antipsychotic-drugs-by-targeting-multiple-stress-related-metabolic-pathways
#20
H L Cai, P Jiang, Q Y Tan, R L Dang, M M Tang, Y Xue, Y Deng, B K Zhang, P F Fang, P Xu, D X Xiang, H D Li, J K Yao
Schizophrenia (SZ) is considered to be a multifactorial brain disorder with defects involving many biochemical pathways. Patients with SZ show variable responses to current pharmacological treatments of SZ because of the heterogeneity of this disorder. Stress has a significant role in the pathophysiological pathways and therapeutic responses of SZ. Atypical antipsychotic drugs (AAPDs) can modulate the stress response of the hypothalamic-pituitary-adrenal (HPA) axis and exert therapeutic effects on stress by targeting the prefrontal cortex (PFC) and hippocampus...
May 16, 2017: Translational Psychiatry
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