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DOI	10.1073/pnas.2018090118
	Sialoglycan recognition is a common connection linking acidosis, zinc, and HMGB1 in sepsis
	Siddiqui 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.
发表日期	2021
ISSN	00278424
卷号	118 期号:10
英文摘要	Blood 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. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	COVID-19; Cytokine storm; HMGB1; Neu5Ac; Sialic acid
语种	英语
scopus关键词	glycan; high mobility group B1 protein; lactic acid; sialoglycoprotein; zinc; carrier protein; high mobility group B1 protein; lipopolysaccharide; polysaccharide; sialic acid derivative; sialoglycoprotein; zinc; acidosis; Article; blood pH; concentration (parameter); controlled study; enzyme linked immunosorbent assay; Escherichia coli; human; neutrophil; nonhuman; priority journal; prognosis; protein binding; sepsis; acidosis; blood; chemistry; immunology; innate immunity; metabolism; pathology; pH; sepsis; Acidosis; Carrier Proteins; HMGB1 Protein; Humans; Hydrogen-Ion Concentration; Immunity, Innate; Lipopolysaccharides; Polysaccharides; Sepsis; Sialic Acids; Sialoglycoproteins; Zinc
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180348
作者单位	Department of Medicine, University of California San Diego, San Diego, CA 92093, United States; Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, CA 92093, United States; Glycobiology Research and Training Center, University of California San Diego, San Diego, CA 92093, United States; Department of Chemistry, University of California, Davis, CA 95616, United States; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia; Department of Oral Biology, School of Dental Medicine, University at Buffalo, The State University of New York, Buffalo, NY 14214, United States
推荐引用方式 GB/T 7714	Siddiqui S.S.,Dhar C.,Sundaramurthy V.,et al. Sialoglycan recognition is a common connection linking acidosis, zinc, and HMGB1 in sepsis[J],2021,118(10).
APA	Siddiqui S.S..,Dhar C..,Sundaramurthy V..,Sasmal A..,Yu H..,...&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,118(10).
MLA	Siddiqui S.S.,et al."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 118.10(2021).