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Veronika Binder, Brith Bergum, Stéphane Jaisson, Philippe Gillery, Carsten Scavenius, Endy Spriet, Anne Karin Nyhaug, Helen M Roberts, Iain L C Chapple, Annelie Hellvard, Nicolas Delaleu, Piotr Mydel
Carbamylation is a non-enzymatic post-translational modification induced upon exposure of free amino groups to urea-derived cyanate leading to irreversible changes of protein charge, structure and function. Levels of carbamylated proteins increase significantly in chronic kidney disease and carbamylated albumin is considered as an important biomarker indicating mortality risk. High plasma concentrations and long half-life make fibrinogen a prime target for carbamylation. As aggregation and cross-linking of fibrin monomers rely on lysine residues, it is likely that carbamylation impacts fibrinogen processing...
April 6, 2017: Thrombosis and Haemostasis
Jonathan D Jones, B JoNell Hamilton, William F C Rigby
OBJECTIVE: Anti-carbamylated protein antibodies (ACarPA) are associated with rheumatoid arthritis (RA) risk and severity and are primarily directed against fibrinogen. The lack of understanding of ACarPA reactivity has limited analysis of their immunopathogenic associations in RA. To address this shortcoming, we mapped ACarPA epitope reactivity in RA patient sera. METHODS: Immunoblotting identified a patient serum with specific reactivity to carbamylated human fibrinogen β-chain...
March 15, 2017: Arthritis & Rheumatology
Marije K Verheul, Alvin Yee, Andrea Seaman, George M Janssen, Peter A van Veelen, Jan W Drijfhout, Rene E M Toes, Michael Mahler, Leendert A Trouw
In 2011 a novel autoantibody system, anti-carbamylated protein (anti-CarP) antibodies, was described in rheumatoid arthritis (RA) patients. Anti-CarP antibody positivity associates with a more severe disease course, is observed years before disease onset, and may predict the development of RA in arthralgia patients. Although many clinical observations have been carried out, information on the antigenic targets of anti-CarP antibodies is limited. Most studies on anti-CarP antibodies utilize an ELISA-based assay with carbamylated fetal calf serum (Ca-FCS) as antigen, a complex mixture of proteins...
March 10, 2017: Journal of Autoimmunity
Caroline Ospelt, Holger Bang, Eugen Feist, Giovanni G Camici, Stephan Keller, Jacqueline Detert, Anette Krämer, Steffen Gay, Khetam Ghannam, Gerd R Burmester
OBJECTIVES: Smoking has been connected to citrullination of antigens and formation of anti-citrullinated peptide antibodies (ACPAs) in rheumatoid arthritis (RA). Since smoking can modify proteins by carbamylation (formation of homocitrulline), this study was conducted to investigate these effects on vimentin in animal models and RA. METHODS: The efficiency of enzymatic carbamylation of vimentin was characterised. B-cell response was investigated after immunisation of rabbits with different vimentin isoforms...
February 9, 2017: Annals of the Rheumatic Diseases
Richard D Semba, Indi Trehan, Ximin Li, Ruin Moaddel, M Isabel Ordiz, Kenneth M Maleta, Klaus Kraemer, Michelle Shardell, Luigi Ferrucci, Mark Manary
BACKGROUND: Environmental enteric dysfunction (EED), a condition characterized by small intestine inflammation and abnormal gut permeability, is widespread in children in developing countries and a major cause of growth failure. The pathophysiology of EED remains poorly understood. METHODS: We measured serum metabolites using liquid chromatography-tandem mass spectrometry in 400 children, aged 12-59months, from rural Malawi. Gut permeability was assessed by the dual-sugar absorption test...
March 2017: EBioMedicine
Jia Teng Sun, Ke Yang, Jing Yan Mao, Wei Feng Shen, Lin Lu, Qi Hong Wu, Yan Ping Wang, Li Ping Wu, Rui Yan Zhang
BACKGROUND: Cyanate has recently gained attention for its role in the pathogenesis of vascular injury. Nonetheless, the effect of cyanate on angiogenesis remains unclear. METHODS AND RESULTS: In this study, we demonstrated that oral administration of cyanate impaired blood perfusion recovery in a mouse hind-limb ischemia model. A reduction in blood perfusion recovery at day 21 was observed in the ischemic tissue of cyanate-treated mice. Likewise, there were fewer capillaries in the ischemic hind-limb tissue of cyanate-exposed mice...
December 16, 2016: Journal of the American Heart Association
Sanna Turunen, Johanna Huhtakangas, Tomi Nousiainen, Maarit Valkealahti, Jukka Melkko, Juha Risteli, Petri Lehenkari
BACKGROUND: Seropositive rheumatoid arthritis (RA) is characterized by autoantibodies binding to citrullinated and homocitrullinated proteins. We wanted to study the expression patterns of these disease-associated protein forms and if the rheumatoid nodule and synovial tissue itself contain biologically active levels of citrullinating peptidyl arginine deiminases 2, 3 and 4 and homocitrullination-facilitating neutrophil enzyme myeloperoxidase. METHOD: Total of 195 synovial samples from metatarsal joints from five ACPA/RF-positive RA patients (n = 77), synovial samples from knees of eight seropositive RA (n = 60), seven seronegative RA (n = 33) and five osteoarthritis (n = 25) patients were analyzed for citrulline and homocitrulline contents using HPLC...
October 20, 2016: Arthritis Research & Therapy
Zeneng Wang, Joseph A DiDonato, Jennifer Buffa, Suzy A Comhair, Mark A Aronica, Raed A Dweik, Nancy A Lee, James J Lee, Mary Jane Thomassen, Mani Kavuru, Serpil C Erzurum, Stanley L Hazen
The biochemical mechanisms through which eosinophils contribute to asthma pathogenesis are unclear. Here we show eosinophil peroxidase (EPO), an abundant granule protein released by activated eosinophils, contributes to characteristic asthma-related phenotypes through oxidative posttranslational modification (PTM) of proteins in asthmatic airways through a process called carbamylation. Using a combination of studies we now show EPO uses plasma levels of the pseudohalide thiocyanate (SCN(-)) as substrate to catalyze protein carbamylation, as monitored by PTM of protein lysine residues into N(ϵ)-carbamyllysine (homocitrulline), and contributes to the pathophysiological sequelae of eosinophil activation...
October 14, 2016: Journal of Biological Chemistry
Camille P Figueiredo, Holger Bang, Jayme Fogagnolo Cobra, Matthias Englbrecht, Axel J Hueber, Judith Haschka, Bernhard Manger, Arnd Kleyer, Michaela Reiser, Stephanie Finzel, Hans-Peter Tony, Stefan Kleinert, Joerg Wendler, Florian Schuch, Monika Ronneberger, Martin Feuchtenberger, Martin Fleck, Karin Manger, Wolfgang Ochs, Matthias Schmitt-Haendle, Hanns-Martin Lorenz, Hubert Nuesslein, Rieke Alten, Joerg Henes, Klaus Krueger, Jürgen Rech, Georg Schett
OBJECTIVE: To perform a detailed analysis of the autoantibody response against post-translationally modified proteins in patients with rheumatoid arthritis (RA) in sustained remission and to explore whether its composition influences the risk for disease relapse when tapering disease modifying antirheumatic drug (DMARD) therapy. METHODS: Immune responses against 10 citrullinated, homocitrullinated/carbamylated and acetylated peptides, as well as unmodified vimentin (control) and cyclic citrullinated peptide 2 (CCP2) were tested in baseline serum samples from 94 patients of the RETRO study...
February 2017: Annals of the Rheumatic Diseases
Stéphane Jaisson, Isabelle Kazes, Aurore Desmons, Fouad Fadel, Jean-Baptiste Oudart, Izabella C R Dos Santos-Weiss, Hervé Millart, Fatouma Touré, Philippe Rieu, Philippe Gillery
BACKGROUND: Homocitrulline (HCit) is a carbamylation-derived product (CDP) that has been identified as a valuable biomarker of morbidity and mortality in patients with chronic kidney disease (CKD). The aim of this study was to determine whether initiation of hemodialysis therapy (HD) could induce variations of HCit concentrations in CKD patients. METHODS: Serum HCit concentrations were determined by LC-MS/MS in CKD patients (n=108) just before (M0) and six months (M6) after the initiation of HD therapy...
September 1, 2016: Clinica Chimica Acta; International Journal of Clinical Chemistry
Ângela Zanatta, Marília Danyelle Nunes Rodrigues, Alexandre Umpierrez Amaral, Débora Guerini Souza, André Quincozes-Santos, Moacir Wajner
Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is caused by deficiency of ornithine translocase leading to predominant tissue accumulation and high urinary excretion of ornithine (Orn), homocitrulline (Hcit) and ammonia. Although affected patients commonly present neurological dysfunction manifested by cognitive deficit, spastic paraplegia, pyramidal and extrapyramidal signs, stroke-like episodes, hypotonia and ataxia, its pathogenesis is still poorly known. Although astrocytes are necessary for neuronal protection...
September 2016: Neurochemical Research
Evan Reed, Xia Jiang, Nastya Kharlamova, A Jimmy Ytterberg, Anca I Catrina, Lena Israelsson, Linda Mathsson-Alm, Monika Hansson, Lars Alfredsson, Johan Rönnelid, Karin Lundberg
BACKGROUND: In addition to anti-citrullinated protein antibodies (ACPAs), antibodies targeting carbamylated (i.e., homocitrullinated) proteins (anti-CarP antibodies) have been described in rheumatoid arthritis (RA). However, the extent to which anti-CarP antibodies are truly distinct from ACPA remains unclear, and few studies have focused on specific autoantigens. Here, we examine cross-reactivity between ACPA and anti-CarP antibodies, in the context of the candidate autoantigen α-enolase...
2016: Arthritis Research & Therapy
Sanna Turunen, Marja-Kaisa Koivula, Leila Risteli, Juha Risteli
The specificities and cross-reactions of antibodies induced by citrulline- and homocitrulline-containing proteins may give implications on the role of citrulline- and homocitrulline-binding antibodies in the pathogenesis and progression of rheumatoid arthritis (RA). Here we use rabbits as an experimental model of antibody development in RA. Thirty-two animals were immunized with peptide antigens containing either homocitrulline or citrulline. The sera were tested for binding to CCP and MCV antigens and to peptide sequences related to carboxyterminal telopeptides of type I and II collagens and containing arginine, citrulline, or homocitrulline...
April 21, 2016: Autoimmunity
Mona Ascha, Zeneng Wang, Mustafa S Ascha, Raed Dweik, Nizar N Zein, David Grove, J Mark Brown, Stephanie Marshall, Rocio Lopez, Ibrahim A Hanouneh
AIM: To identify plasma analytes using metabolomics that correlate with the diagnosis and severity of liver disease in patients with alcoholic hepatitis (AH). METHODS: We prospectively recruited patients with cirrhosis from AH (n = 23) and those with cirrhosis with acute decompensation (AD) from etiologies other than alcohol (n = 25). We used mass spectrometry to identify 29 metabolic compounds in plasma samples from fasted subjects. A receiver operating characteristics analysis was performed to assess the utility of biomarkers in distinguishing acute AH from alcoholic cirrhosis...
April 8, 2016: World Journal of Hepatology
Laëtitia Gorisse, Christine Pietrement, Vincent Vuiblet, Christian E H Schmelzer, Martin Köhler, Laurent Duca, Laurent Debelle, Paul Fornès, Stéphane Jaisson, Philippe Gillery
Aging is a progressive process determined by genetic and acquired factors. Among the latter are the chemical reactions referred to as nonenzymatic posttranslational modifications (NEPTMs), such as glycoxidation, which are responsible for protein molecular aging. Carbamylation is a more recently described NEPTM that is caused by the nonenzymatic binding of isocyanate derived from urea dissociation or myeloperoxidase-mediated catabolism of thiocyanate to free amino groups of proteins. This modification is considered an adverse reaction, because it induces alterations of protein and cell properties...
February 2, 2016: Proceedings of the National Academy of Sciences of the United States of America
Alain Cantagrel, Yannick Degboé
Citrullination, carbamylation and oxidation are posttranslational modifications of proteins that produce neoepitopes. Rheumatoid arthritis (RA) is an autoimmune disease of which one distinctive feature is the development of B-cell-mediated immunity against these neoepitopes. Antibodies to citrullinated proteins (ACPAs) were identified nearly two decades ago and are now widely used in clinical practice. The identification of additional citrullinated proteins as potential autoantibody targets has suggested new pathophysiological hypotheses and prompted studies of potential associations with disease severity or specific disease patterns...
January 2016: Joint, Bone, Spine: Revue du Rhumatisme
Håkon Reikvam, Ida-Sofie Grønningsæter, Aymen Bushra Ahmed, Kimberley Hatfield, Øystein Bruserud
Allogeneic stem cell transplantation is commonly used in the treatment of younger patients with severe hematological diseases, and endothelial cells seem to be important for the development of several posttransplant complications. Capillary leak syndrome is a common early posttransplant complication where endothelial cell dysfunction probably contributes to the pathogenesis. In the present study we investigated whether the pretreatment serum metabolic profile reflects a risk of posttransplant capillary leak syndrome...
2015: Disease Markers
Aditya D Joshi, Mehnaz G Mustafa, Cheryl F Lichti, Cornelis J Elferink
The aryl hydrocarbon receptor (AhR), a regulator of xenobiotic toxicity, is a member of the eukaryotic Per-Arnt-Sim domain protein family of transcription factors. Recent evidence identified a novel AhR DNA recognition sequence called the nonconsensus xenobiotic response element (NC-XRE). AhR binding to the NC-XRE in response to activation by the canonical ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin resulted in concomitant recruitment of carbamoyl phosphate synthase 1 (CPS1) to the NC-XRE. Studies presented here demonstrate that CPS1 is a bona fide nuclear protein involved in homocitrullination (hcit), including a key lysine residue on histone H1 (H1K34hcit)...
November 13, 2015: Journal of Biological Chemistry
Aurore Desmons, Stéphane Jaisson, Christine Pietrement, Philippe Rieu, Alain Wynckel, Philippe Gillery
BACKGROUND: Carbamylation is a non-enzymatic post-translational modification of proteins characterized by the addition of isocyanic acid to amino groups. As isocyanic acid mainly originates from the spontaneous dissociation of urea, carbamylation rate is increased during renal failure. The aim of the study was to evaluate serum homocitrulline (HCit), which results from the carbamylation of ε-amino groups of lysine (Lys) residues, in acute renal failure (ARF) and to determine if it could be useful for differentiating acute from chronic renal failure (CRF)...
January 2016: Clinical Chemistry and Laboratory Medicine: CCLM
Diego Martinelli, Daria Diodato, Emanuela Ponzi, Magnus Monné, Sara Boenzi, Enrico Bertini, Giuseppe Fiermonte, Carlo Dionisi-Vici
BACKGROUND: Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive disorder of the urea cycle. HHH has a panethnic distribution, with a major prevalence in Canada, Italy and Japan. Acute clinical signs include intermittent episodes of vomiting, confusion or coma and hepatitis-like attacks. Alternatively, patients show a chronic course with aversion for protein rich foods, developmental delay/intellectual disability, myoclonic seizures, ataxia and pyramidal dysfunction...
2015: Orphanet Journal of Rare Diseases
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