{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T00:43:24Z","timestamp":1783039404278,"version":"3.54.6"},"reference-count":36,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2024,1,23]],"date-time":"2024-01-23T00:00:00Z","timestamp":1705968000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Matisse Pharmaceuticals"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Extracellular histones have been shown to act as DAMPs in a variety of inflammatory diseases. Moreover, they have the ability to induce cell death. In this study, we show that M6229, a low-anticoagulant fraction of unfractionated heparin (UFH), rescues rats that were challenged by continuous infusion of calf thymus histones at a rate of 25 mg histones\/kg\/h. Histone infusion by itself induced hepatic and homeostatic dysfunction characterized by elevated activity of hepatic enzymes (ASAT and ALAT) and serum lactate levels as well as by a renal dysfunction, which contributed to the significantly increased mortality rate. M6229 was able to restore normal levels of both hepatic and renal parameters at 3 and 9 mg M6229\/kg\/h and prevented mortality of the animals. We conclude that M6229 is a promising therapeutic agent to treat histone-mediated disease.<\/jats:p>","DOI":"10.3390\/ijms25031376","type":"journal-article","created":{"date-parts":[[2024,1,23]],"date-time":"2024-01-23T04:17:40Z","timestamp":1705983460000},"page":"1376","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["M6229 Protects against Extracellular-Histone-Induced Liver Injury, Kidney Dysfunction, and Mortality in a Rat Model of Acute Hyperinflammation"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2334-9403","authenticated-orcid":false,"given":"Chris P. M.","family":"Reutelingsperger","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6200 MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion J.","family":"Gijbels","sequence":"additional","affiliation":[{"name":"Department of Pathology, Maastricht University Medical Center, MUMC+, 6202 AZ Maastricht, The Netherlands"},{"name":"Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences\u2014Atherosclerosis & Ischemic Syndrome, Amsterdam Infection and Immunity\u2014Inflammatory Diseases, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3858-334X","authenticated-orcid":false,"given":"Henri","family":"Spronk","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6200 MD Maastricht, The Netherlands"},{"name":"Coagulation Profile B.V., 6229 EV Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rene","family":"Van Oerle","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6200 MD Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roy","family":"Schrijver","sequence":"additional","affiliation":[{"name":"Matisse Pharmaceuticals B.V., 6163 JT Geleen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0164-2633","authenticated-orcid":false,"given":"Peter","family":"Ekhart","sequence":"additional","affiliation":[{"name":"Matisse Pharmaceuticals B.V., 6163 JT Geleen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sjef","family":"de Kimpe","sequence":"additional","affiliation":[{"name":"Matisse Pharmaceuticals B.V., 6163 JT Geleen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2482-0412","authenticated-orcid":false,"given":"Gerry A. 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