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dc.contributor.authorSiddiqui, Shoib S
dc.contributor.authorDhar, Chirag
dc.contributor.authorSundaramurthy, Venkatasubramaniam
dc.contributor.authorSasmal, Aniruddha
dc.contributor.authorYu, Hai
dc.contributor.authorBandala-Sanchez, Esther
dc.contributor.authorLi, Miaomiao
dc.contributor.authorZhang, Xiaoxiao
dc.contributor.authorChen, Xi
dc.contributor.authorHarrison, Leonard C
dc.contributor.authorXu, Ding
dc.contributor.authorVarki, Ajit
dc.date.accessioned2021-03-11T11:00:01Z
dc.date.available2021-03-11T11:00:01Z
dc.date.issued2021-03-09
dc.identifier.citationSiddiqui , S S , Dhar , C , Sundaramurthy , V , Sasmal , A , Yu , H , Bandala-Sanchez , E , Li , M , Zhang , X , Chen , X , Harrison , L C , Xu , D & Varki , A 2021 , ' Sialoglycan recognition is a common connection linking acidosis, zinc, and HMGB1 in sepsis ' , Proceedings of the National Academy of Sciences of the United States of America , vol. 118 , no. 10 , e2018090118 . https://doi.org/10.1073/pnas.2018090118
dc.identifier.issn0027-8424
dc.identifier.urihttp://hdl.handle.net/2299/24063
dc.description© 2021 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/
dc.description.abstractBlood pH is tightly maintained between 7.35 and 7.45, and acidosis (pH <7.3) indicates poor prognosis in sepsis, wherein lactic acid from anoxic tissues overwhelms the buffering capacity of blood. Poor sepsis prognosis is also associated with low zinc levels and the release of High mobility group box 1 (HMGB1) from activated and/or necrotic cells. HMGB1 added to whole blood at physiological pH did not bind leukocyte receptors, but lowering pH with lactic acid to mimic sepsis conditions allowed binding, implying the presence of natural inhibitor(s) preventing binding at normal pH. Testing micromolar concentrations of divalent cations showed that zinc supported the robust binding of sialylated glycoproteins with HMGB1. Further characterizing HMGB1 as a sialic acid-binding lectin, we found that optimal binding takes place at normal blood pH and is markedly reduced when pH is adjusted with lactic acid to levels found in sepsis. Glycan array studies confirmed the binding of HMGB1 to sialylated glycan sequences typically found on plasma glycoproteins, with binding again being dependent on zinc and normal blood pH. Thus, HMGB1-mediated hyperactivation of innate immunity in sepsis requires acidosis, and micromolar zinc concentrations are protective. We suggest that the potent inflammatory effects of HMGB1 are kept in check via sequestration by plasma sialoglycoproteins at physiological pH and triggered when pH and zinc levels fall in late stages of sepsis. Current clinical trials independently studying zinc supplementation, HMGB1 inhibition, or pH normalization may be more successful if these approaches are combined and perhaps supplemented by infusions of heavily sialylated molecules.en
dc.format.extent8
dc.format.extent1274157
dc.language.isoeng
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of America
dc.subjectCOVID-19
dc.subjectCytokine storm
dc.subjectHMGB1
dc.subjectNeu5Ac
dc.subjectSialic acid
dc.subjectGeneral
dc.titleSialoglycan recognition is a common connection linking acidosis, zinc, and HMGB1 in sepsisen
dc.contributor.institutionDepartment of Clinical, Pharmaceutical and Biological Science
dc.contributor.institutionSchool of Life and Medical Sciences
dc.contributor.institutionBiosciences Research Group
dc.contributor.institutionCentre for Research in Mechanisms of Disease and Drug Discovery
dc.contributor.institutionCentre for Future Societies Research
dc.description.statusPeer reviewed
dc.identifier.urlhttp://www.scopus.com/inward/record.url?scp=85102420226&partnerID=8YFLogxK
rioxxterms.versionofrecord10.1073/pnas.2018090118
rioxxterms.typeJournal Article/Review
herts.preservation.rarelyaccessedtrue


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