{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T22:09:11Z","timestamp":1791929351915,"version":"4.3.4"},"reference-count":48,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,1,6]],"date-time":"2021-01-06T00:00:00Z","timestamp":1609891200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005357","name":"Agent\u00fara na Podporu V\u00fdskumu a V\u00fdvoja","doi-asserted-by":"publisher","award":["APVV-17-0505"],"award-info":[{"award-number":["APVV-17-0505"]}],"id":[{"id":"10.13039\/501100005357","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008530","name":"European Regional Development Fund","doi-asserted-by":"publisher","award":["GenoScan LBquant NFP313010Q927"],"award-info":[{"award-number":["GenoScan LBquant NFP313010Q927"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ministerstvo zdravotn\u00edctva Slovenskej republiky","award":["2018\/10- UKMT-6"],"award-info":[{"award-number":["2018\/10- UKMT-6"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Circulating extracellular DNA (ecDNA) is known to worsen the outcome of many diseases. ecDNA released from neutrophils during infection or inflammation is present in the form of neutrophil extracellular traps (NETs). It has been shown that higher ecDNA concentration occurs in a number of inflammatory diseases including inflammatory bowel disease (IBD). Enzymes such as peptidyl arginine deiminases (PADs) are crucial for NET formation. We sought to describe the dynamics of ecDNA concentrations and fragmentation, along with NETosis during a mouse model of chemically induced colitis. Plasma ecDNA concentration was highest on day seven of dextran sulfate sodium (DSS) intake and the increase was time-dependent. This increase correlated with the percentage of cells undergoing NETosis and other markers of disease activity. Relative proportion of nuclear ecDNA increased towards more severe colitis; however, absolute amount decreased. In colon explant medium, the highest concentration of ecDNA was on day three of DSS consumption. Early administration of PAD4 inhibitors did not alleviate disease activity, but lowered the ecDNA concentration. These results uncover the biological characteristics of ecDNA in IBD and support the role of ecDNA in intestinal inflammation. The therapeutic intervention aimed at NETs and\/or nuclear ecDNA has yet to be fully investigated.<\/jats:p>","DOI":"10.3390\/cells10010081","type":"journal-article","created":{"date-parts":[[2021,1,6]],"date-time":"2021-01-06T09:15:16Z","timestamp":1609924516000},"page":"81","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Extracellular DNA Correlates with Intestinal Inflammation in Chemically Induced Colitis in Mice"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1201-5184","authenticated-orcid":false,"given":"Martin","family":"Maronek","sequence":"first","affiliation":[{"name":"Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University in Bratislava, 81108 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbora","family":"Gromova","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University in Bratislava, 81108 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Liptak","sequence":"additional","affiliation":[{"name":"Institute of Physiology, Faculty of Medicine, Comenius University in Bratislava, 81372 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbora","family":"Konecna","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University in Bratislava, 81108 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Pastorek","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University in Bratislava, 81108 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbora","family":"Cechova","sequence":"additional","affiliation":[{"name":"Department of Physiology, Third Faculty of Medicine, Charles University, 10000 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Harsanyova","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Faculty of Natural Sciences, Comenius University in Bratislava, 84215 Bratislava, Slovakia"},{"name":"Geneton Ltd., 84104 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaroslav","family":"Budis","sequence":"additional","affiliation":[{"name":"Geneton Ltd., 84104 Bratislava, Slovakia"},{"name":"Comenius University Science Park, Univerzita Komensk\u00e9ho, 84104 Bratislava, Slovakia"},{"name":"Slovak Centre of Scientific and Technical Information, 81104 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Smolak","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Faculty of Natural Sciences, Comenius University in Bratislava, 84215 Bratislava, Slovakia"},{"name":"Geneton Ltd., 84104 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9657-1198","authenticated-orcid":false,"given":"Jan","family":"Radvanszky","sequence":"additional","affiliation":[{"name":"Geneton Ltd., 84104 Bratislava, Slovakia"},{"name":"Comenius University Science Park, Univerzita Komensk\u00e9ho, 84104 Bratislava, Slovakia"},{"name":"Institute of Clinical and Translational Research, Biomedical Research Center, Slovak Academy of Sciences, 84505 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomas","family":"Szemes","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Faculty of Natural Sciences, Comenius University in Bratislava, 84215 Bratislava, Slovakia"},{"name":"Geneton Ltd., 84104 Bratislava, Slovakia"},{"name":"Comenius University Science Park, Univerzita Komensk\u00e9ho, 84104 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8195-3844","authenticated-orcid":false,"given":"Jana","family":"Harsanyiova","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alzbeta","family":"Kralova Trancikova","sequence":"additional","affiliation":[{"name":"Biomedical Center Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8211-907X","authenticated-orcid":false,"given":"Roman","family":"Gardlik","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University in Bratislava, 81108 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2769","DOI":"10.1016\/S0140-6736(17)32448-0","article-title":"Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: A systematic review of population-based studies","volume":"390","author":"Ng","year":"2018","journal-title":"Lancet"},{"key":"ref_2","first-page":"587","article-title":"Occurrence of dietary risk factors in inflammatory bowel disease: Influence on the nutritional status of patients in clinical remission","volume":"28","author":"Prescha","year":"2019","journal-title":"Adv. Clin. Exp. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1679","DOI":"10.3390\/ijerph15081679","article-title":"Rebuilding the gut microbiota ecosystem","volume":"15","author":"Gagliardi","year":"2018","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"De Meij, T.G.J., De Groot, E.F.J., Peeters, C.F.W., De Boer, N.K.H., Kneepkens, C.M.F., Eck, A., Benninga, M.A., Savelkoul, P.H.M., Van Bodegraven, A.A., and Budding, A.E. (2018). Variability of core microbiota in newly diagnosed treatment-na\u00efve paediatric inflammatory bowel disease patients. PLoS ONE, 13.","DOI":"10.1101\/317263"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1080\/17474124.2018.1511425","article-title":"Urban\u2013rural environmental exposure during childhood and subsequent risk of inflammatory bowel disease: A meta-analysis","volume":"13","author":"Song","year":"2019","journal-title":"Expert Rev. Gastroenterol. Hepatol."},{"key":"ref_6","first-page":"1257","article-title":"Extracellular nucleic acids and their potential as diagnostic, prognostic and predictive biomarkers","volume":"27","year":"2007","journal-title":"Anticancer Res."},{"key":"ref_7","first-page":"991","article-title":"Fluctuation of maternal and fetal free extracellular circulatory DNA in maternal plasma","volume":"96","author":"Zhong","year":"2000","journal-title":"Obstet. Gynecol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1373\/49.3.495","article-title":"Origin of plasma cell-free DNA after solid organ transplantation","volume":"49","author":"Lui","year":"2003","journal-title":"Clin. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s41232-020-00118-7","article-title":"Emerging roles of Toll-like receptor 9 in cardiometabolic disorders","volume":"40","author":"Nishimoto","year":"2020","journal-title":"Inflamm. Regen."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1146\/annurev.immunol.20.100301.064842","article-title":"CpG motifs in bacterial DNA and their immune effects","volume":"20","author":"Krieg","year":"2002","journal-title":"Annu. Rev. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Sharma, S., and Fitzgerald, K.A. (2011). Innate immune sensing of DNA. PLoS Pathog., 7.","DOI":"10.1371\/journal.ppat.1001310"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Avriel, A., Wiessman, M.P., Almog, Y., Perl, Y., Novack, V., Galante, O., Klein, M., Pencina, M.J., and Douvdevani, A. (2014). Admission cell free DNA levels predict 28-day mortality in patients with severe sepsis in intensive care. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0100514"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1159\/000440975","article-title":"The Role of Cell-Free Plasma DNA in Critically Ill Patients with Sepsis","volume":"41","author":"Clementi","year":"2016","journal-title":"Blood Purif."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.jss.2016.11.044","article-title":"Plasma DNA and RNA differentially impact coagulation during abdominal sepsis-an explorative study","volume":"210","author":"Schneck","year":"2017","journal-title":"J. Surg. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2395","DOI":"10.7754\/Clin.Lab.2016.160615","article-title":"Cell Free DNA and Procalcitonin as Early Markers of Complications in ICU Patients with Multiple Trauma and Major Surgery","volume":"62","author":"Ahmed","year":"2016","journal-title":"Clin. Lab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e1501332","DOI":"10.1126\/sciadv.1501332","article-title":"Obesity-induced DNA released from adipocytes stimulates chronic adipose tissue inflammation and insulin resistance","volume":"2","author":"Nishimoto","year":"2016","journal-title":"Sci. Adv."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1007\/s00383-014-3607-6","article-title":"Dynamic pathology for circulating free DNA in a dextran sodium sulfate colitis mouse model","volume":"30","author":"Koike","year":"2014","journal-title":"Pediatr. Surg. Int."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"167","DOI":"10.14712\/fb2018064050167","article-title":"Extracellular DNA is Increased in Dextran Sulphate Sodium-Induced Colitis in Mice","volume":"64","author":"Maronek","year":"2018","journal-title":"Folia Biol. (Praha)"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1007\/s12253-014-9766-x","article-title":"Intravenous administration of a single-dose free-circulating DNA of colitic origin improves severe murine DSS-colitis","volume":"20","author":"Sipos","year":"2014","journal-title":"Pathol. Oncol. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.cimid.2017.06.005","article-title":"Cell-free DNA-induced alteration of autophagy response and TLR9-signaling: Their relation to amelioration of DSS-colitis","volume":"52","author":"Kiss","year":"2017","journal-title":"Comp. Immunol. Microbiol. Infect. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1136\/jim-2020-001296","article-title":"Preconditioning with cell-free DNA prevents DSS-colitis by promoting cell protective autophagy","volume":"68","author":"Constantinovits","year":"2020","journal-title":"J. Investig. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1532","DOI":"10.1126\/science.1092385","article-title":"Neutrophil Extracellular Traps Kill Bacteria","volume":"303","author":"Brinkmann","year":"2004","journal-title":"Science"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"eaax8847","DOI":"10.1126\/sciadv.aax8847","article-title":"Neutrophil extracellular traps exacerbate neurological deficits after traumatic brain injury","volume":"6","author":"Vaibhav","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1055\/s-0040-1715474","article-title":"Netting Liver Disease: Neutrophil Extracellular Traps in the Initiation and Exacerbation of Liver Pathology","volume":"46","author":"Meijenfeldt","year":"2020","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e139388","DOI":"10.1172\/jci.insight.139388","article-title":"Neutrophil extracellular traps mediate articular cartilage damage and enhance cartilage component immunogenicity in rheumatoid arthritis","volume":"5","author":"Carlucci","year":"2020","journal-title":"JCI Insight"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Lin, E.Y.H., Lai, H.J., Cheng, Y.K., Leong, K.Q., Cheng, L.C., Chou, Y.C., Peng, Y.C., Hsu, Y.H., and Chiang, H. (2020). Sen Neutrophil extracellular traps impair intestinal barrier function during experimental colitis. Biomedicines, 8.","DOI":"10.20944\/preprints202007.0130.v1"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/978-3-030-44518-8_2","article-title":"Neutrophil Elastase and Neutrophil Extracellular Traps in the Tumor Microenvironment","volume":"Volume 1263","author":"Huang","year":"2020","journal-title":"Advances in Experimental Medicine and Biology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4384","DOI":"10.7150\/jca.44215","article-title":"IL-8 mediates a positive loop connecting increased neutrophil extracellular traps (NETs) and colorectal cancer liver metastasis","volume":"11","author":"Yang","year":"2020","journal-title":"J. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.biopha.2017.06.009","article-title":"Exogenous deoxyribonuclease has a protective effect in a mouse model of sepsis","volume":"93","author":"Laukova","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_30","first-page":"G457","article-title":"Deoxyribonuclease partially ameliorates thioacetamide-induced hepatorenal injury","volume":"312","author":"Hodosy","year":"2017","journal-title":"Am. J. Physiol. Liver Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1021\/acs.accounts.9b00024","article-title":"Protein Arginine Deiminases (PADs): Biochemistry and Chemical Biology of Protein Citrullination","volume":"52","author":"Mondal","year":"2019","journal-title":"Acc. Chem. Res."},{"key":"ref_32","first-page":"1","article-title":"A Review of Neutrophil Extracellular Traps (NETs) in Disease: Potential Anti-NETs Therapeutics","volume":"1","author":"Mutua","year":"2020","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.mito.2016.05.003","article-title":"Accurate quantification of mouse mitochondrial DNA without co-amplification of nuclear mitochondrial insertion sequences","volume":"29","author":"Malik","year":"2016","journal-title":"Mitochondrion"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"106583","DOI":"10.1016\/j.intimp.2020.106583","article-title":"Evaluation of protein arginine deiminase-4 inhibitor in TNBS- induced colitis in mice","volume":"84","author":"Zhang","year":"2020","journal-title":"Int. Immunopharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Kim, J.J., Shajib, M.S., Manocha, M.M., and Khan, W.I. (2012). Investigating intestinal inflammation in DSS-induced model of IBD. J. Vis. Exp., 1\u20136.","DOI":"10.3791\/3678-v"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1093\/ecco-jcc\/jjy215","article-title":"Neutrophil Extracellular Traps Sustain Inflammatory Signals in Ulcerative Colitis","volume":"13","author":"Dinallo","year":"2019","journal-title":"J. Crohns. Colitis"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.1093\/bioinformatics\/btu170","article-title":"Trimmomatic: A flexible trimmer for Illumina sequence data","volume":"30","author":"Bolger","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_38","first-page":"945861","article-title":"Impaired deoxyribonuclease I activity in patients with inflammatory bowel diseases","volume":"2011","author":"Zima","year":"2011","journal-title":"Autoimmune Dis."},{"key":"ref_39","unstructured":"Babraham, A. (2020, October 31). Bioinformatics. Available online: http:\/\/www.bioinformatics.babraham.ac.uk\/projects\/fastqc\/."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1158\/0008-5472.CAN-18-2797","article-title":"Citrullination in cancer","volume":"79","author":"Yuzhalin","year":"2019","journal-title":"Cancer Res."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Xu, H., Luo, X., Qian, J., Pang, X., Song, J., Qian, G., Chen, J., and Chen, S. (2012). FastUniq: A Fast De Novo Duplicates Removal Tool for Paired Short Reads. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0052249"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3153","DOI":"10.1038\/onc.2010.51","article-title":"Coordination of PAD4 and HDAC2 in the regulation of p53-target gene expression","volume":"29","author":"Li","year":"2010","journal-title":"Oncogene"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/nmeth.1923","article-title":"Fast gapped-read alignment with Bowtie 2","volume":"9","author":"Langmead","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"10","DOI":"10.14712\/fb2018064010010","article-title":"Extracellular DNA as a Prognostic and Therapeutic Target in Mouse Colitis under DNase I Treatment","volume":"64","author":"Babickova","year":"2018","journal-title":"Folia Biol. (Praha)"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1186\/s13059-019-1891-0","article-title":"Improved metagenomic analysis with Kraken 2","volume":"20","author":"Wood","year":"2019","journal-title":"Genome Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3662","DOI":"10.3390\/ijms20153662","article-title":"Cell-Free Nucleic Acids and their Emerging Role in the Pathogenesis and Clinical Management of Inflammatory Bowel Disease","volume":"20","author":"Kubiritova","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"G929","DOI":"10.1152\/ajpgi.00435.2010","article-title":"Suppression of colitis in mice by Cl-amidine: A novel peptidylarginine deiminase inhibitor","volume":"300","author":"Chumanevich","year":"2011","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_48","unstructured":"Dreyton, C., Jones, J., Knuckley, B., Subramanian, V., Anderson, E., Brown, S., Fernandez-Vega, V., Eberhart, C., Spicer, T., and Zuhl, A. (2013). Optimization and characterization of a pan protein arginine deiminase (PAD) inhibitor. Probe Reports from the NIH Molecular Libraries Program [Internet], National Center for Biotechnology Information."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/1\/81\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:07:33Z","timestamp":1760159253000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/1\/81"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,6]]},"references-count":48,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,1]]}},"alternative-id":["cells10010081"],"URL":"https:\/\/doi.org\/10.3390\/cells10010081","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,6]]}}}