DOCSLIB.ORG

Interindividual Variability in the Cardiac Expression of Anthracycline Reductases in Donors with and Without Down Syndrome

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

Pharm Res DOI 10.1007/s11095-013-1267-1 RESEARCH PAPER Interindividual Variability in the Cardiac Expression of Anthracycline Reductases in Donors With and Without Down Syndrome Adolfo Quiñones-Lombraña & Daniel Ferguson & Rachael Hageman Blair & James L. Kalabus & Almedina Redzematovic & Javier G. Blanco Received: 16 September 2013 /Accepted: 9 December 2013 # Springer Science+Business Media New York 2014 ABSTRACT CBR1 rs9024 genotype status impacts on cardiac CBR1 expres- Purpose The intracardiac synthesis of anthracycline alcohol sion in non-DS hearts. metabolites (e.g., daunorubicinol) contributes to the patho- Conclusions CBR1, AKR1A1, and AKR7A2 protein levels point genesis of anthracycline-related cardiotoxicity. Cancer pa- to be important determinants for predicting the synthesis of tients with Down syndrome (DS) are at increased risk for cardiotoxic daunorubicinol in heart. anthracycline-related cardiotoxicity. We profiled the expression of anthracycline metabolizing enzymes in hearts from donors with- KEY WORDS Aldo-keto reductases . Anthracycline-related and without- DS. cardiotoxicity . Anthracyclines . Carbonyl reductases . Down Methods Cardiac expression of CBR1, CBR3, AKR1A1, syndrome AKR1C3 and AKR7A2 was examined by quantitative real time PCR, quantitative immunoblotting, and enzyme activity assays ABBREVIATIONS using daunorubicin. The CBR1 polymorphism rs9024 was inves- aCGH Array comparative genomic hybridization tigated by allelic discrimination with fluorescent probes. The ACTB Actin B contribution of CBRs/AKRs proteins to daunorubicin reductase AKR1A1 Aldo-keto reductase family 1, member A1 activity was examined by multiple linear regression. AKR1C3 Aldo-keto reductase family 1, member C3 Results CBR1 was the most abundant transcript (average relative AKR7A2 Aldo-keto reductase family 7, member A2 expression; DS: 81%, non-DS: 58%), and AKR7A2 was the most AKRs Aldo-keto reductases abundant protein (average relative expression; DS: 38%, non- CBR1 Carbonyl reductase 1 DS: 35%). Positive associations between cardiac CBR1 protein CBR3 Carbonyl reductase 3 levels and daunorubicin reductase activity were found for samples CBRs Carbonyl reductases from donors with- and without- DS. Regression analysis suggests DS Down syndrome that sex, CBR1, AKR1A1, and AKR7A2 protein levels were LOD Limit of detection significant contributors to cardiac daunorubicin reductase activity. LOQ Limit of quantification Electronic supplementary material The online version of this article (doi:10.1007/s11095-013-1267-1) contains supplementary material, which is available to authorized users. : : : * A. Quiñones-Lombraña: D. Ferguson J. L. Kalabus J. G. Blanco ( ) A. Redzematovic J. G. Blanco Department of Pharmaceutical Sciences Department of Pharmaceutical Sciences University at Buffalo, The State University of New York, 470 Kapoor Hall School of Pharmacy and Pharmaceutical Sciences Buffalo, New York 14214-8033, USA The State University of New York at Buffalo e-mail: [email protected] Buffalo, New York, USA R. Hageman Blair Department of Biostatistics School of Public Health and Health Professions The State University of New York at Buffalo Buffalo, New York, USA Quiñones-Lombraña et al. INTRODUCTION goal of this study was to document the extent of interindivid- ual variability in the expression of CBR1, CBR3, AKR1A1, In humans, carbonyl reductases (CBRs) and aldo-keto reduc- AKR1C3 and AKR7A2 in a collection of heart samples from tases (AKRs) play predominant roles during the metabolism of donors with- and without- DS. The expression of CBRs and more than 30 clinically relevant drugs including the antipsy- AKRs was examined by quantitative real time PCR (qRT- chotic agent haloperidol, the opioid receptor antagonist naltrex- PCR) with specific primers, quantitative immunoblotting with one, the antiemetic dolasetron, the anti-inflammatory specific antibodies, and enzyme activity assays using the ketoprofen, and the anticancer anthracyclines doxorubicin anthracycline substrate daunorubicin. We also examined the and daunorubicin (1–3). The use of anthracyclines for the impact of a functional polymorphism in CBR1 (rs9024), chemotherapy of a variety of solid and hematological cancers known to impact CBR1 expression and daunorubicinol syn- is limited by the development of cardiotoxicity in some patients thesis in liver, on cardiac CBR1 gene expression and enzy- (4). For example, a study of children (n =115) who survived matic activity for the substrate daunorubicin (21,24,25). leukemia revealed that 60% of those treated with anthracyclines developed preclinical abnormalities in cardiac structure and function (5). Of note, pediatric cancer patients with Down MATERIALS AND METHODS syndrome (DS, trisomy 21) constitute a population at particu- larly greater risk for anthracycline-related cardiotoxicity, and a Human Heart Samples safe dose of anthracyclines for cancer patients with- DS remains to be defined (6,7). For example, children with- DS represent The Institutional Review Board of the State University of New 15% of pediatric acute myeloid leukemia (AML) cases, and a York at Buffalo approved this research. Heart samples from report from the Children’s Oncology group has documented donors with- (n =9) and without- DS (n =30) were procured clinically symptomatic cardiomyopathy in 17.5% of DS-AML from The National Disease Research Interchange (NDRI, patients treated with an anthracycline-containing regimen (7,8). funded by the National Center for Research Resources), The The complex pathogenesis of anthracycline-related Cooperative Human Tissue Network (CHTN, funded by the cardiotoxicity is mediated by a combination of oxidative stress National Cancer Institute), and the National Institute of Child and metabolic perturbations in myocardial tissue that are in- Health and Human Development (NICHD) Brain and Tissue duced by the C-13 anthracycline alcohol metabolites, whose Bank. The postmortem to tissue recovery interval was ≤10 h. formation is catalyzed by specific CBRs and AKRs (4,9–12). A Samples (2–20 g, myocardium, left ventricle only) were frozen growing cumulus of evidence indicates that two monomeric immediatelyafterrecoveryandstoredinliquidnitrogenuntil CBRs, namely CBR1 and CBR3, together with the members further processing. The main demographics from donors with- of the AKRs superfamily AKR1A1, AKR1C3 and AKR7A2 and without- DS are summarized in Supplementary Material catalyze the synthesis of cardiotoxic C-13 anthracycline alcohol Table I. Down syndrome status (yes/no) and relevant diagnoses metabolites (e.g., daunorubicinol and doxorubicinol) (13–16). In (Supplementary Material Table II) were obtained from anony- addition specific CBRs/AKRs genetic variants may contribute to mous medical histories. Heart samples were processed following the unpredictable pharmacological profile of anthracyclines in standardized procedures to isolate DNA and RNA as described cancer patients (17–19). For example, a recent study from the (24,26). Children’s Oncology group described the impact of functional single nucleotide polymorphisms in CBR1 and CBR3 on the risk Array CGH Analysis of anthracycline-related cardiomyopathy in childhood cancer survivors (20). Thus, interindividual variability in the expression Down syndrome status was confirmed by array comparative of CBRs and AKRs would impact the intracardiac formation of genomic hybridization (aCGH). Briefly, genomic DNA (3.0 μg) cardiotoxic C-13 anthracycline alcohol metabolites, and conse- from test samples and a euploid reference DNA sample were quently the pharmacodynamics of anthracycline drugs. fluorescentlylabeledandhybridizedtohighresolutionAgilent Furthermore, the CBR1 and CBR3 genesarelocatedinthe 244 K aCGH arrays containing +236,000 coding and non- DS critical region of chromosome 21 (21q21-21q22.3). The coding human probes. Changes in DNA copy number were alteredexpressionofCBRs as a result of the gene dosage effect determined by evaluating log2 ratios across whole chromo- may contribute to the increased risk of anthracycline-related somes. aCGH assays were performed at the Genomics core cardiotoxicity in cancer patients with- DS (21). facility, Roswell Park Cancer Institute (Buffalo, NY). In spite of the prominent contributions of CBRs and AKRs towards the pharmacodynamics of anthracycline drugs, re- Quantitative Real-Time PCR ports documenting gene expression levels and protein abun- dance in cardiac tissue are limited to the analysis of individual Cardiac CBR1, CBR3, AKR1A1, AKR1C3,andAKR7A2 samples or pooled tissue samples (13,22,23). Thus, the main mRNA expression was analyzed by qRT-PCR with gene Anthracycline Reductase Expression in Human Hearts specific primers (Table I) following the MIQE guidelines (27). AkR1C3 and AKR7A2, and 40 μg for CBR3) and corre- Briefly, 5 ng of total RNA was reverse transcribed and ampli- sponding recombinant protein standards (Abcam, fied using the one-step QuantiTect SYBR Green RT-PCR kit Cambridge, England) were separated by gel electrophoresis (Qiagen, Venlo, The Netherlands). Target genes and ACTB using NuPAGE Novex 4 - 12% Bis-Tris precast gels, and (reference gene) were amplified in parallel with the following transferred onto nitrocellulose membranes using the iBlot cycling parameters: 50°C for 30 min (reverse transcription), Gel Transfer Device (Invitrogen). Membranes were blocked 95°C for 10 min (Taq DNA polymerase activation), 40 cycles with 5% non-fat milk in 0.2% Tween 20-PBS for 1 h at room of 95°C for 15 s (denaturation), 56°C
Recommended publications
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus

    A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus

    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
  • Investigation of Copy Number Variations on Chromosome 21 Detected by Comparative Genomic Hybridization

    Investigation of Copy Number Variations on Chromosome 21 Detected by Comparative Genomic Hybridization

    Li et al. Molecular Cytogenetics (2018) 11:42 https://doi.org/10.1186/s13039-018-0391-3 RESEARCH Open Access Investigation of copy number variations on chromosome 21 detected by comparative genomic hybridization (CGH) microarray in patients with congenital anomalies Wenfu Li, Xianfu Wang and Shibo Li* Abstract Background: The clinical features of Down syndrome vary among individuals, with those most common being congenital heart disease, intellectual disability, developmental abnormity and dysmorphic features. Complex combination of Down syndrome phenotype could be produced by partially copy number variations (CNVs) on chromosome 21 as well. By comparing individual with partial CNVs of chromosome 21 with other patients of known CNVs and clinical phenotypes, we hope to provide a better understanding of the genotype-phenotype correlation of chromosome 21. Methods: A total of 2768 pediatric patients sample collected at the Genetics Laboratory at Oklahoma University Health Science Center were screened using CGH Microarray for CNVs on chromosome 21. Results: We report comprehensive clinical and molecular descriptions of six patients with microduplication and seven patients with microdeletion on the long arm of chromosome 21. Patients with microduplication have varied clinical features including developmental delay, microcephaly, facial dysmorphic features, pulmonary stenosis, autism, preauricular skin tag, eye pterygium, speech delay and pain insensitivity. We found that patients with microdeletion presented with developmental delay, microcephaly, intrauterine fetal demise, epilepsia partialis continua, congenital coronary anomaly and seizures. Conclusion: Three patients from our study combine with four patients in public database suggests an association between 21q21.1 microduplication of CXADR gene and patients with developmental delay. One patient with 21q22.13 microdeletion of DYRK1A shows association with microcephaly and scoliosis.
  • Enzyme DHRS7

    Enzyme DHRS7

    Toward the identification of a function of the “orphan” enzyme DHRS7 Inauguraldissertation zur Erlangung der Würde eines Doktors der Philosophie vorgelegt der Philosophisch-Naturwissenschaftlichen Fakultät der Universität Basel von Selene Araya, aus Lugano, Tessin Basel, 2018 Originaldokument gespeichert auf dem Dokumentenserver der Universität Basel edoc.unibas.ch Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät auf Antrag von Prof. Dr. Alex Odermatt (Fakultätsverantwortlicher) und Prof. Dr. Michael Arand (Korreferent) Basel, den 26.6.2018 ________________________ Dekan Prof. Dr. Martin Spiess I. List of Abbreviations 3α/βAdiol 3α/β-Androstanediol (5α-Androstane-3α/β,17β-diol) 3α/βHSD 3α/β-hydroxysteroid dehydrogenase 17β-HSD 17β-Hydroxysteroid Dehydrogenase 17αOHProg 17α-Hydroxyprogesterone 20α/βOHProg 20α/β-Hydroxyprogesterone 17α,20α/βdiOHProg 20α/βdihydroxyprogesterone ADT Androgen deprivation therapy ANOVA Analysis of variance AR Androgen Receptor AKR Aldo-Keto Reductase ATCC American Type Culture Collection CAM Cell Adhesion Molecule CYP Cytochrome P450 CBR1 Carbonyl reductase 1 CRPC Castration resistant prostate cancer Ct-value Cycle threshold-value DHRS7 (B/C) Dehydrogenase/Reductase Short Chain Dehydrogenase Family Member 7 (B/C) DHEA Dehydroepiandrosterone DHP Dehydroprogesterone DHT 5α-Dihydrotestosterone DMEM Dulbecco's Modified Eagle's Medium DMSO Dimethyl Sulfoxide DTT Dithiothreitol E1 Estrone E2 Estradiol ECM Extracellular Membrane EDTA Ethylenediaminetetraacetic acid EMT Epithelial-mesenchymal transition ER Endoplasmic Reticulum ERα/β Estrogen Receptor α/β FBS Fetal Bovine Serum 3 FDR False discovery rate FGF Fibroblast growth factor HEPES 4-(2-Hydroxyethyl)-1-Piperazineethanesulfonic Acid HMDB Human Metabolome Database HPLC High Performance Liquid Chromatography HSD Hydroxysteroid Dehydrogenase IC50 Half-Maximal Inhibitory Concentration LNCaP Lymph node carcinoma of the prostate mRNA Messenger Ribonucleic Acid n.d.
  • Taylor Et Al REVISED MS28926-1.Pdf

    Taylor Et Al REVISED MS28926-1.Pdf

    1 The effect of micronutrient supplementation on growth and hepatic 2 metabolism in diploid and triploid Atlantic salmon (Salmo salar) parr 3 fed a low marine ingredient diet 4 5 John F. Taylor a*, Luisa M. Vera a, Christian De Santis a, Erik-Jan Lock b, Marit Espe b, 6 Kaja H. Skjærven b, Daniel Leeming c, Jorge del Pozo d, Jose Mota-Velasco e, Herve 7 Migaud a, Kristin Hamre b, Douglas R. Tocher a 8 9 a Institute of Aquaculture, University of Stirling, Stirling, FK9 4LA, UK 10 b Institute of Marine Research, PO box 1870 Nordnes, 5817 Bergen, Norway 11 c BioMar Ltd., Grangemouth, FK3 8UL, UK 12 d The Royal (Dick) School of Veterinary Studies, Edinburgh, EH25 9RG, UK 13 e Hendrix Genetics, Landcatch Natural Selection Ltd., Lochgilphead, PA31 8PE, UK 14 15 Running Title: Dietary micronutrient supplementation in Atlantic salmon 16 17 ms. has 31 pg.s, 4 figures, 9 tables, 4 suppl. files 18 19 Corresponding Author: 20 Dr John F. Taylor 21 Institute of Aquaculture, University of Stirling, Stirling, FK9 4LA, UK 22 Tel: +44-01786 467929 ; Fax: +44-01768 472133 23 [email protected] 24 Accepted refereed manuscript of: Taylor JF, Vera LM, De Santis C, Lock E, Espe M, Skjaerven KH, Leeming D, Del Pozo J, Mota-Velasco J, Migaud H, Hamre K & Tocher DR (2019) The effect of micronutrient supplementation on growth and hepatic metabolism in diploid and triploid Atlantic salmon (Salmo salar) parr fed a low marine ingredient diet. Comparative Biochemistry and Physiology. Part B, Biochemistry and Molecular Biology, 227, pp.
  • Supplementary Materials

    Supplementary Materials

    Supplementary Materials COMPARATIVE ANALYSIS OF THE TRANSCRIPTOME, PROTEOME AND miRNA PROFILE OF KUPFFER CELLS AND MONOCYTES Andrey Elchaninov1,3*, Anastasiya Lokhonina1,3, Maria Nikitina2, Polina Vishnyakova1,3, Andrey Makarov1, Irina Arutyunyan1, Anastasiya Poltavets1, Evgeniya Kananykhina2, Sergey Kovalchuk4, Evgeny Karpulevich5,6, Galina Bolshakova2, Gennady Sukhikh1, Timur Fatkhudinov2,3 1 Laboratory of Regenerative Medicine, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, Moscow, Russia 2 Laboratory of Growth and Development, Scientific Research Institute of Human Morphology, Moscow, Russia 3 Histology Department, Medical Institute, Peoples' Friendship University of Russia, Moscow, Russia 4 Laboratory of Bioinformatic methods for Combinatorial Chemistry and Biology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia 5 Information Systems Department, Ivannikov Institute for System Programming of the Russian Academy of Sciences, Moscow, Russia 6 Genome Engineering Laboratory, Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region, Russia Figure S1. Flow cytometry analysis of unsorted blood sample. Representative forward, side scattering and histogram are shown. The proportions of negative cells were determined in relation to the isotype controls. The percentages of positive cells are indicated. The blue curve corresponds to the isotype control. Figure S2. Flow cytometry analysis of unsorted liver stromal cells. Representative forward, side scattering and histogram are shown. The proportions of negative cells were determined in relation to the isotype controls. The percentages of positive cells are indicated. The blue curve corresponds to the isotype control. Figure S3. MiRNAs expression analysis in monocytes and Kupffer cells. Full-length of heatmaps are presented.
  • The Identification of Human Aldo-Keto Reductase AKR7A2 As a Novel

    The Identification of Human Aldo-Keto Reductase AKR7A2 As a Novel

    Li et al. Cellular & Molecular Biology Letters (2016) 21:25 Cellular & Molecular DOI 10.1186/s11658-016-0026-9 Biology Letters SHORTCOMMUNICATION Open Access The identification of human aldo-keto reductase AKR7A2 as a novel cytoglobin- binding partner Xin Li, Shanshan Zou, Zhen Li, Gaotai Cai, Bohong Chen, Ping Wang and Wenqi Dong* * Correspondence: [email protected] Abstract Department of Biopharmaceutics, School of Laboratory Medicine and Cytoglobin (CYGB), a member of the globin family, is thought to protect cells from Biotechnology, Southern Medical reactive oxygen and nitrogen species and deal with hypoxic conditions and University, 1838 North Guangzhou oxidative stress. However, its molecular mechanisms of action are not clearly Avenue, Guangzhou 510515, China understood. Through immunoprecipitation combined with a two-dimensional electrophoresis–mass spectrometry assay, we identified a CYGB interactor: aldo-keto reductase family 7 member A2 (AKR7A2). The interaction was further confirmed using yeast two-hybrid and co-immunoprecipitation assays. Our results show that AKR7A2 physically interacts with CYGB. Keywords: CYGB, AKR7A2, Protein-protein interactions, Yeast two-hybrid assay, Co-immunoprecipitation, 2-DE, Oxidative stress Introduction Cytoglobin (CYGB), which is a member of the globin family, was discovered more than a decade ago in a proteomic screen of fibrotic liver [1]. It was originally named STAP (stellate activating protein). Human CYGB is a 190-amino acid, 21-kDa protein [2], encoded by a single copy gene mapped at the 17q25.3 chromosomal segment [3]. It has a compact helical conformation, giving it the ability to bind to heme, which allows reversible binding of gaseous, diatomic molecules, including oxygen (O2), nitric oxide (NO) and carbon monoxide (CO), just like hemoglobin (Hb), myoglobin (Mb) and neuroglobin (Ngb) [4].
  • AKR7A2 (NM 003689) Human Tagged ORF Clone Lentiviral Particle Product Data

    AKR7A2 (NM 003689) Human Tagged ORF Clone Lentiviral Particle Product Data

    OriGene Technologies, Inc. 9620 Medical Center Drive, Ste 200 Rockville, MD 20850, US Phone: +1-888-267-4436 [email protected] EU: [email protected] CN: [email protected] Product datasheet for RC214673L4V AKR7A2 (NM_003689) Human Tagged ORF Clone Lentiviral Particle Product data: Product Type: Lentiviral Particles Product Name: AKR7A2 (NM_003689) Human Tagged ORF Clone Lentiviral Particle Symbol: AKR7A2 Synonyms: AFAR; AFAR1; AFB1-AR1; AKR7 Vector: pLenti-C-mGFP-P2A-Puro (PS100093) ACCN: NM_003689 ORF Size: 1077 bp ORF Nucleotide The ORF insert of this clone is exactly the same as(RC214673). Sequence: OTI Disclaimer: The molecular sequence of this clone aligns with the gene accession number as a point of reference only. However, individual transcript sequences of the same gene can differ through naturally occurring variations (e.g. polymorphisms), each with its own valid existence. This clone is substantially in agreement with the reference, but a complete review of all prevailing variants is recommended prior to use. More info OTI Annotation: This clone was engineered to express the complete ORF with an expression tag. Expression varies depending on the nature of the gene. RefSeq: NM_003689.2 RefSeq Size: 1377 bp RefSeq ORF: 1080 bp Locus ID: 8574 UniProt ID: O43488, V9HWA2 Domains: aldo_ket_red Protein Families: Druggable Genome MW: 39.4 kDa This product is to be used for laboratory only. Not for diagnostic or therapeutic use. View online » ©2021 OriGene Technologies, Inc., 9620 Medical Center Drive, Ste 200, Rockville, MD 20850, US 1 / 2 AKR7A2 (NM_003689) Human Tagged ORF Clone Lentiviral Particle – RC214673L4V Gene Summary: The protein encoded by this gene belongs to the aldo/keto reductase (AKR) superfamily and AKR7 family, which are involved in the detoxification of aldehydes and ketones.
  • In Vivo Effect of Oracin on Doxorubicin Reduction, Biodistribution and Efficacy in Ehrlich Tumor Bearing Mice

    In Vivo Effect of Oracin on Doxorubicin Reduction, Biodistribution and Efficacy in Ehrlich Tumor Bearing Mice

    Pharmacological Reports Copyright © 2013 2013, 65, 445452 by Institute of Pharmacology ISSN 1734-1140 Polish Academy of Sciences Invivo effectoforacinondoxorubicinreduction, biodistributionandefficacyinEhrlichtumor bearingmice VeronikaHanušová1,PavelTomšík2,LenkaKriesfalusyová3, AlenaPakostová1,IvaBoušová1,LenkaSkálová1 1 DepartmentofBiochemicalSciences,CharlesUniversityinPrague,FacultyofPharmacy,Heyrovského1203, HradecKrálové,CZ-50005,CzechRepublic 2 DepartmentofMedicalBiochemistry,CharlesUniversityinPrague,FacultyofMedicine, Šimkova570, HradecKrálové,CZ-50038,CzechRepublic 3 Radio-IsotopeLaboratory,CharlesUniversityinPrague,FacultyofMedicine, Šimkova570,HradecKrálové, CZ-50038,CzechRepublic Correspondence: LenkaSkálová,e-mail:[email protected] Abstract: Background: The limitation of carbonyl reduction represents one possible way to increase the effectiveness of anthracycline doxo- rubicin (DOX) in cancer cells and decrease its toxicity in normal cells. In vitro, isoquinoline derivative oracin (ORC) inhibited DOX reduction and increased the antiproliferative effect of DOX in MCF-7 breast cancer cells. Moreover, ORC significantly decreases DOX toxicity in non-cancerous MCF-10A breast cells and in hepatocytes. The present study was designed to test in mice the in vivo effect of ORC on plasma and tissue concentrations of DOX and its main metabolite DOXOL. The effect of ORC on DOX efficacy in micebearingsolidEhrlichtumors(EST)wasalsostudied. Methods: DOX and DOX + ORC combinations were iv administered to healthy mice. Blood samples, livers
  • Reactive Carbonyls and Oxidative Stress: Potential for Therapeutic Intervention ⁎ Elizabeth M

    Reactive Carbonyls and Oxidative Stress: Potential for Therapeutic Intervention ⁎ Elizabeth M

    Pharmacology & Therapeutics 115 (2007) 13–24 www.elsevier.com/locate/pharmthera Associate editor: R.M. Wadsworth Reactive carbonyls and oxidative stress: Potential for therapeutic intervention ⁎ Elizabeth M. Ellis Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 204 George Street, Glasgow, G1 1XW, United Kingdom Abstract Reactive aldehydes and ketones are produced as a result of oxidative stress in several disease processes. Considerable evidence is now accumulating that these reactive carbonyl products are also involved in the progression of diseases, including neurodegenerative disorders, diabetes, atherosclerosis, diabetic complications, reperfusion after ischemic injury, hypertension, and inflammation. To counter carbonyl stress, cells possess enzymes that can decrease aldehyde load. These enzymes include aldehyde dehydrogenases (ALDH), aldo-keto reductases (AKR), carbonyl reductase (CBR), and glutathione S-transferases (GST). Some of these enzymes are inducible by chemoprotective compounds via Nrf2/ ARE- or AhR/XRE-dependent mechanisms. This review describes the metabolism of reactive carbonyls and discusses the potential for manipulating levels of carbonyl-metabolizing enzymes through chemical intervention. © 2007 Elsevier Inc. All rights reserved. Keywords: Aldehyde metabolism; Oxidative stress; Chemoprotection Contents 1. Introduction ............................................. 14 2. Production of reactive carbonyls in oxidant-exposed cells . .................... 14 2.1. Carbonyls produced
  • Biochemical and Pharmacological Characterization of Cytochrome B5 Reductase As a Potential Novel Therapeutic Target in Candida A

    Biochemical and Pharmacological Characterization of Cytochrome B5 Reductase As a Potential Novel Therapeutic Target in Candida A

    University of South Florida Scholar Commons Graduate Theses and Dissertations Graduate School January 2011 Biochemical and Pharmacological Characterization of Cytochrome b5 Reductase as a Potential Novel Therapeutic Target in Candida albicans Mary Jolene Patricia Holloway University of South Florida, [email protected] Follow this and additional works at: http://scholarcommons.usf.edu/etd Part of the American Studies Commons, Biochemistry Commons, Microbiology Commons, and the Molecular Biology Commons Scholar Commons Citation Holloway, Mary Jolene Patricia, "Biochemical and Pharmacological Characterization of Cytochrome b5 Reductase as a Potential Novel Therapeutic Target in Candida albicans" (2011). Graduate Theses and Dissertations. http://scholarcommons.usf.edu/etd/3730 This Dissertation is brought to you for free and open access by the Graduate School at Scholar Commons. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Scholar Commons. For more information, please contact [email protected]. Biochemical and Pharmacological Characterization of Cytochrome b5 Reductase as a Potential Novel Therapeutic Target in Candida albicans by Mary Jolene Holloway A dissertation written in partial fulfillment of the requirements for the degree of Doctor of Philosophy Department of Molecular Medicine College of Medicine University of South Florida Major Professor: Andreas Seyfang, Ph.D. Co-Major Professor: Robert Deschenes, Ph.D. Michael J. Barber, D.Phil Gloria Ferreira, Ph.D. Alberto van Olphen, Ph.D. Date of Approval: November 14, 2011 Keywords: Fungal drug resistance, protein biochemistry and structure, ergosterol biosynthesis, yeast knockouts, oxidoreductases Copyright © 2011, Mary Jolene Holloway i DEDICATION This work is dedicated to my mother, Theresa Holloway, for being my coach and friend.
  • Title CNV Analysis in Tourette Syndrome Implicates Large Genomic Rearrangements in COL8A1 and NRXN1 Author(S)

    Title CNV Analysis in Tourette Syndrome Implicates Large Genomic Rearrangements in COL8A1 and NRXN1 Author(S)

    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by HKU Scholars Hub CNV Analysis in Tourette Syndrome Implicates Large Genomic Title Rearrangements in COL8A1 and NRXN1 Nag, A; Bochukova, EG; Kremeyer, B; Campbell, DD; et al.,; Author(s) Ruiz-Linares, A Citation PLoS ONE, 2013, v. 8 n. 3 Issued Date 2013 URL http://hdl.handle.net/10722/189374 Rights Creative Commons: Attribution 3.0 Hong Kong License CNV Analysis in Tourette Syndrome Implicates Large Genomic Rearrangements in COL8A1 and NRXN1 Abhishek Nag1, Elena G. Bochukova2, Barbara Kremeyer1, Desmond D. Campbell1, Heike Muller1, Ana V. Valencia-Duarte3,4, Julio Cardona5, Isabel C. Rivas5, Sandra C. Mesa5, Mauricio Cuartas3, Jharley Garcia3, Gabriel Bedoya3, William Cornejo4,5, Luis D. Herrera6, Roxana Romero6, Eduardo Fournier6, Victor I. Reus7, Thomas L Lowe7, I. Sadaf Farooqi2, the Tourette Syndrome Association International Consortium for Genetics, Carol A. Mathews7, Lauren M. McGrath8,9, Dongmei Yu9, Ed Cook10, Kai Wang11, Jeremiah M. Scharf8,9,12, David L. Pauls8,9, Nelson B. Freimer13, Vincent Plagnol1, Andre´s Ruiz-Linares1* 1 UCL Genetics Institute, Department of Genetics, Evolution and Environment, University College London, London, United Kingdom, 2 University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, United Kingdom, 3 Laboratorio de Gene´tica Molecular, SIU, Universidad de Antioquia, Medellı´n, Colombia, 4 Escuela de Ciencias de la Salud, Universidad Pontificia
  • Genome-Wide Methylation Study on Depression: Differential Methylation and Variable Methylation in Monozygotic Twins

    Genome-Wide Methylation Study on Depression: Differential Methylation and Variable Methylation in Monozygotic Twins

    OPEN Citation: Transl Psychiatry (2015) 5, e557; doi:10.1038/tp.2015.49 www.nature.com/tp ORIGINAL ARTICLE Genome-wide methylation study on depression: differential methylation and variable methylation in monozygotic twins A Córdova-Palomera1,2, M Fatjó-Vilas1,2, C Gastó2,3,4, V Navarro2,3,4, M-O Krebs5,6,7 and L Fañanás1,2 Depressive disorders have been shown to be highly influenced by environmental pathogenic factors, some of which are believed to exert stress on human brain functioning via epigenetic modifications. Previous genome-wide methylomic studies on depression have suggested that, along with differential DNA methylation, affected co-twins of monozygotic (MZ) pairs have increased DNA methylation variability, probably in line with theories of epigenetic stochasticity. Nevertheless, the potential biological roots of this variability remain largely unexplored. The current study aimed to evaluate whether DNA methylation differences within MZ twin pairs were related to differences in their psychopathological status. Data from the Illumina Infinium HumanMethylation450 Beadchip was used to evaluate peripheral blood DNA methylation of 34 twins (17 MZ pairs). Two analytical strategies were used to identify (a) differentially methylated probes (DMPs) and (b) variably methylated probes (VMPs). Most DMPs were located in genes previously related to neuropsychiatric phenotypes. Remarkably, one of these DMPs (cg01122889) was located in the WDR26 gene, the DNA sequence of which has been implicated in major depressive disorder from genome-wide association studies. Expression of WDR26 has also been proposed as a biomarker of depression in human blood. Complementarily, VMPs were located in genes such as CACNA1C, IGF2 and the p38 MAP kinase MAPK11, showing enrichment for biological processes such as glucocorticoid signaling.