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Prabhakar Kedar, Anand Desai, Prashant Warang, Roshan Colah
OBJECTIVES: Congenital methemoglobinemia due to NADH-cytochrome b5 reductase 3 (CYB5R3) deficiencies is an autosomal recessive disorder that occurs sporadically worldwide, A sensitive, accurate, and rapid analysis of NADH-CYB5R enzyme concentrations is necessary for the diagnosis of RCM. Here we present an alternative microplate method that is based on a standard 96-well microplate format and microplate reader that simplify the quantification of NADH-CYB5R activity. METHODS: TECAN (Infinite 200 PRO series) microplate reader with Tecan's proven Magellan™ software measured the NADH-CYB5R enzyme activity in 250 normal controls and previously diagnosed 25 cases of RCM due to NADH-CYB5R deficiency in the Indian population using 96-well microplates using 200 μl of total reaction mixture and also compared with standard spectrophotometric assay...
November 18, 2016: Hematology (Amsterdam, Netherlands)
Birte Plitzko, Antje Havemeyer, Bettina Bork, Florian Bittner, Ralf Mendel, Bernd Clement
The importance of the mitochondrial amidoxime reducing component (mARC)-containing enzyme system in N-reductive metabolism has been studied extensively. It catalyzes the reduction of various N-hydroxylated compounds and therefore acts as the counterpart of cytochrome P450- and flavin-containing monooxygenase-catalyzed oxidations at nitrogen centers. This enzyme system was found to be responsible for the activation of amidoxime and N-hydroxyguanidine prodrugs in drug metabolism. The synergy of three components (mARC, cytochrome b5, and the appropriate reductase) is crucial to exert the N-reductive catalytic effect...
October 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Koji Yamanoi, Noriomi Matsumura, Susan K Murphy, Tsukasa Baba, Kaoru Abiko, Junzo Hamanishi, Ken Yamaguchi, Masafumi Koshiyama, Ikuo Konishi, Masaki Mandai
Anoikis resistance is a hallmark of cancer, and relates to malignant phenotypes, including chemoresistance, cancer stem like phenotypes and dissemination. The aim of this study was to identify key factors contributing to anoikis resistance in ovarian cancer using a functional genomics screen. A library of 81 000 shRNAs targeting 15 000 genes was transduced into OVCA420 cells, followed by incubation in soft agar and colony selection. We found shRNAs directed to ABHD2, ELAC2 and CYB5R3 caused reproducible anoikis resistance...
July 26, 2016: Oncotarget
Rikke R Lund, Rikke Leth-Larsen, Tina Di Caterino, Mikkel G Terp, Jeanette Nissen, Anne-Vibeke Lænkholm, Ole N Jensen, Henrik J Ditzel
Metastasis is the main cause of cancer-related deaths and remains the most significant challenge to management of the disease. Metastases are established through a complex multistep process involving intracellular signaling pathways. To gain insight to proteins central to specific steps in metastasis formation, we used a metastasis cell line model that allows investigation of extravasation and colonization of circulating cancer cells to lungs in mice. Using stable isotopic labeling by amino acids in cell culture and subcellular fractionation, the nuclear, cytosol, and mitochondria proteomes were analyzed by LC-MS/MS, identifying a number of proteins that exhibited altered expression in isogenic metastatic versus nonmetastatic cancer cell lines, including NADH-cytochrome b5 reductase 3 (CYB5R3), l-lactate dehydrogenase A (LDHA), Niemann-pick c1 protein (NPC1), and nucleolar RNA helicase 2 (NRH2)...
November 2015: Molecular & Cellular Proteomics: MCP
Alexandra Forestier, Serge Pissard, Justine Cretet, Adeline Mambie, Laurent Pascal, Manuel Cliquennois, Nathalie Cambier, Christian Rose
Methemoglobinemia can be acquired (oxidizing drugs or chemicals products) or inherited either by mutations affecting globin chains [M hemoglobins (M Hbs)] or by defects in the enzymatic system involved in the reduction of spontaneous Hb oxidation: nicotinamide adenine dinucleotide (NADH)-cytochrome b5 reductase. It is encoded by the CYB5R3 gene: there are two phenotypes of autosomal recessive congenital methemoglobinemia, in type II CYB5R deficiency is generalized and affects all cells, leading to an early onset, whereas in type I, the enzyme deficiency is restricted to erythrocytes, usually discovered in infancy but not exclusively...
2015: Hemoglobin
Alexandra Forestier, Serge Pissard, Justine Cretet, Adeline Mambie, Laurent Pascal, Manuel Cliquennois, Nathalie Cambier, Christian Rose
Methemoglobinemia can be acquired (oxidizing drugs or chemicals products) or inherited either by mutations affecting globin chains [M hemoglobins (M Hbs)] or by defects in the enzymatic system involved in the reduction of spontaneous Hb oxidation: nicotinamide adenine dinucleotide (NADH)-cytochrome b5 reductase. It is encoded by the CYB5R3 gene: there are two phenotypes of autosomal recessive congenital methemoglobinemia, in type II CYB5R deficiency is generalized and affects all cells, leading to an early onset, whereas in type I, the enzyme deficiency is restricted to erythrocytes, usually discovered in infancy but not exclusively...
July 31, 2015: Hemoglobin
Md Mizanur Rahaman, Fabio G Reinders, David Koes, Anh T Nguyen, Stephanie M Mutchler, Courtney Sparacino-Watkins, Roger A Alvarez, Megan P Miller, Dongmei Cheng, Bill B Chen, Edwin K Jackson, Carlos J Camacho, Adam C Straub
NADH cytochrome b5 reductase 3 (CYB5R3) is critical for reductive reactions such as fatty acid elongation, cholesterol biosynthesis, drug metabolism, and methemoglobin reduction. Although the physiological and metabolic importance of CYB5R3 has been established in hepatocytes and erythrocytes, emerging investigations suggest that CYB5R3 is critical for nitric oxide signaling and vascular function. However, advancement toward fully understanding CYB5R3 function has been limited due to a lack of potent small molecule inhibitors...
July 3, 2015: Journal of Biological Chemistry
Tyson D Fuller, Cassandra N Spracklen, Kelli K Ryckman, Lindsey A Knake, Tamara D Busch, Allison M Momany, Jeffrey C Murray, John M Dagle
BACKGROUND: In recent years, increasing numbers of preterm infants have been exposed to inhaled nitric oxide (iNO). This population has decreased methemoglobin (MetHb) reductase activity in their erythrocytes, which may increase the risk of MetHb toxicity. We sought to determine if genetic factors are associated with the observed variance in MetHb levels. METHODS: A population of 127 preterm infants was genotyped for five single-nucleotide polymorphisms (SNPs) in the CYB5A and CYB5R3 genes...
March 2015: Pediatric Research
Kristina L Blanke, James C Sacco, Robert C Millikan, Andrew F Olshan, Jingchun Luo, Lauren A Trepanier
PURPOSE: Cytochrome b 5 (encoded by CYB5A) and NADH cytochrome b 5 reductase (encoded by CYB5R3) detoxify aromatic and heterocyclic amine mammary carcinogens found in cigarette smoke. We hypothesized that CYB5A and CYB5R3 polymorphisms would be associated with breast cancer risk in women. METHODS: We characterized the prevalence of 18 CYB5A and CYB5R3 variants in genomic DNA from African American (AfrAm) and Caucasian (Cauc) women from the Carolina Breast Cancer Study population (1,946 cases and 1,747 controls) and determined their associations with breast cancer risk, with effect modification by smoking...
November 2014: Cancer Causes & Control: CCC
Jingli Wang, Chris P Guise, Gabi U Dachs, Yen Phung, Annie Huai-Ling Hsu, Neil K Lambie, Adam V Patterson, William R Wilson
SN30000 is a second-generation benzotriazine-N-oxide hypoxia-activated prodrug scheduled for clinical trial. Previously we showed that covalent binding of the hypoxia probe EF5 predicts metabolic activation of SN30000 in a panel of cancer cell lines under anoxia, suggesting that they are activated by the same reductases. However the identity of these reductases is unknown. Here, we test whether forced expression of nine oxidoreductases with known or suspected roles in bioreductive prodrug metabolism (AKR1C3, CYB5R3, FDXR, MTRR, NDOR1, NOS2A, NQO1, NQO2 and POR) enhances oxic or anoxic reduction of SN30000 and EF5 by HCT116 cells...
October 15, 2014: Biochemical Pharmacology
Anna B Nikiforova, Nils-Erik L Saris, Alexey G Kruglov
It was reported that VDAC1 possesses an NADH oxidoreductase activity and plays an important role in the activation of xenobiotics in the outer mitochondrial membrane. In the present work, we evaluated the participation of VDAC1 and Cyb5R3 in the NADH-dependent activation of various redox cyclers in mitochondria. We show that external NADH oxidoreductase caused the redox cycling of menadione ≫ lucigenin>nitrofurantoin. Paraquat was predominantly activated by internal mitochondria oxidoreductases. An increase in the ionic strength stimulated and suppressed the redox cycling of negatively and positively charged acceptors, as was expected for the Cyb5R3-mediated reduction...
September 2014: Free Radical Biology & Medicine
Emilio Siendones, Sara SantaCruz-Calvo, Alejandro Martín-Montalvo, María V Cascajo, Julia Ariza, Guillermo López-Lluch, José M Villalba, Cécile Acquaviva-Bourdain, Emmanuel Roze, Michel Bernier, Rafael de Cabo, Plácido Navas
AIMS: Membrane-bound CYB5R3 deficiency in humans causes recessive hereditary methaemoglobinaemia (RHM), an incurable disease that is characterized by severe neurological disorders. CYB5R3 encodes for NADH-dependent redox enzyme that contributes to metabolic homeostasis and stress protection; however, how it is involved in the neurological pathology of RHM remains unknown. Here, the role and transcriptional regulation of CYB5R3 was studied under nutritional and oxidative stress. RESULTS: CYB5R3-deficient cells exhibited a decrease of the NAD(+)/NADH ratio, mitochondrial respiration rate, ATP production, and mitochondrial electron transport chain activities, which were associated with higher sensitivity to oxidative stress, and an increase in senescence-associated β-galactosidase activity...
October 20, 2014: Antioxidants & Redox Signaling
N M Galeeva, M I Voevoda, M G Spiridonova, V A Stepanov, A V Poliakov
Type-1recessive congenital methemoglobinemia (RCM) is a rare autosomal disease characterized by a deficiency of the soluble form of nicotineamide adenine dinucleotide (NADH)-cytochrome b5 reductase (b5R) and clinically manifests as cyanosis of skin and mucous membranes. In the Russian Federation, type-I RCM is widely disturbed in Yakutia due to the local founder effect. The molecular genetics cause of type-I RCM in Yakutia is mutation c.806C > T in the CYB5R3 gene. In this work we used 13 polymorphic markers, which flanking the CYB5R3 gene to establish the founder haplotype...
April 2013: Genetika
I-J Wang, S-L Chen, T-P Lu, E Y Chuang, P-C Chen
BACKGROUND: The biological mechanisms of how prenatal smoke exposure leading to atopic disorders remain to be addressed. Whether prenatal smoke exposure affects DNA methylation leading to atopic disorders is not clear. OBJECTIVE: As most children suffering from atopic dermatitis (AD) continue to develop asthma later in life, we explored whether prenatal smoke exposure induces cord blood DNA methylation. METHODS: Methylation differences associated with smoke exposure were screened by Illumina Infinium 27K methylation arrays for 14 children from the Taiwan birth panel study cohort initially...
May 2013: Clinical and Experimental Allergy: Journal of the British Society for Allergy and Clinical Immunology
N M Galeeva, S A Nenasheva, I S Kleĭmenova, A V Poliakov
Hereditary types I and II methemoglobinemia is a rare autosomal recessive disease due to a deficiency of either soluble or soluble and membrane-bound forms of the enzyme NADH-cytochrome b5 reductase. The molecular genetic bases of both types of the disease consist in changes in the CYB5R3 gene. In this study, the novel and, to date, only large deletion in this gene is described, discovered in two unrelated families with types I and II methemoglobinemia. The common founder haplotype on the chromosomes carrying this mutation was identified...
November 2012: Genetika
Adam C Straub, Alexander W Lohman, Marie Billaud, Scott R Johnstone, Scott T Dwyer, Monica Y Lee, Pamela Schoppee Bortz, Angela K Best, Linda Columbus, Benjamin Gaston, Brant E Isakson
Models of unregulated nitric oxide (NO) diffusion do not consistently account for the biochemistry of NO synthase (NOS)-dependent signalling in many cell systems. For example, endothelial NOS controls blood pressure, blood flow and oxygen delivery through its effect on vascular smooth muscle tone, but the regulation of these processes is not adequately explained by simple NO diffusion from endothelium to smooth muscle. Here we report a new model for the regulation of NO signalling by demonstrating that haemoglobin (Hb) α (encoded by the HBA1 and HBA2 genes in humans) is expressed in human and mouse arterial endothelial cells and enriched at the myoendothelial junction, where it regulates the effects of NO on vascular reactivity...
November 15, 2012: Nature
James C Sacco, Mahmoud Abouraya, Alison Motsinger-Reif, Steven H Yale, Catherine A McCarty, Lauren A Trepanier
OBJECTIVE: To determine whether polymorphisms in the sulfonamide detoxification genes, CYB5A (encoding cytochrome b(5)), CYB5R3 (encoding cytochrome b(5) reductase), or NAT2 (encoding N-acetyltransferase 2) were over-represented in patients with delayed sulfonamide drug hypersensitivity, compared with control patients who tolerated a therapeutic course of trimethoprim-sulfamethoxazole without adverse event. METHODS: DNA from 99 nonimmunocompromised patients with sulfonamide hypersensitivity who were identified from the Personalized Medicine Research Project at the Marshfield Clinic, and from 99 age-matched, race-matched, and sex-matched drug-tolerant controls, were genotyped for four CYB5A and five CYB5R3 polymorphisms, and for all coding NAT2 SNPs...
October 2012: Pharmacogenetics and Genomics
J Funk-Keenan, J Sacco, Y Y Amos Wong, S Rasmussen, A Motsinger-Reif, L A Trepanier
BACKGROUND: Delayed hypersensitivity (HS) reactions to potentiated sulfonamide antimicrobials occur in both dogs and humans, and involve an intermediate hydroxylamine metabolite that is detoxified by cytochrome b(5) and NADH cytochrome b(5) reductase. HYPOTHESIS/OBJECTIVES: We hypothesized that polymorphisms in the genes (CYB5A and CYB5R3) encoding these 2 enzymes would be associated with risk of sulfonamide HS in dogs. ANIMALS: A total of 18 dogs with delayed HS to potentiated sulfonamide antimicrobials and 16 dogs that tolerated (TOL) a therapeutic course of these drugs without adverse effect...
September 2012: Journal of Veterinary Internal Medicine
Yu-Hsiu Huang, Chang-Long Tai, Yung-Hsiu Lu, Tina Jui-Ting Wu, Hong-Duo Chen, Dau-Ming Niu
Recessive congenital methemoglobinemia (RCM) is a very rare disorder caused by NADH-cytochrome b5 reductase (cb5r) deficiency. Two distinct clinical forms, types I and II, caused by cb5r deficiency have been recognized. In type I, the enzyme deficiency is restricted only to erythrocytes with cyanosis being the only major symptom. In contrast, in type II, the enzyme deficiency is generalized to all tissues and associated with neurological impairment, mental and growth retardation and reduced life expectancy, in addition to cyanosis...
August 15, 2012: Blood Cells, Molecules & Diseases
Bruno M Alexandre, Nuno Charro, Josip Blonder, Carlos Lopes, Pilar Azevedo, António Bugalho de Almeida, King C Chan, DaRue A Prieto, Haleem Issaq, Timothy D Veenstra, Deborah Penque
Structural and metabolic alterations in erythrocytes play an important role in the pathophysiology of Chronic Obstructive Pulmonary Disease (COPD). Whether these dysfunctions are related to the modulation of erythrocyte membrane proteins in patients diagnosed with COPD remains to be determined. Herein, a comparative proteomic profiling of the erythrocyte membrane fraction isolated from peripheral blood of smokers diagnosed with COPD and smokers with no COPD was performed using differential (16)O/(18)O stable isotope labeling...
December 5, 2012: Journal of Proteomics
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