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dc.contributor.authorZhang, Xing
dc.contributor.authorHan, Xiaorui
dc.contributor.authorXia, Ke
dc.contributor.authorXu, Yongmei
dc.contributor.authorYang, Yimu
dc.contributor.authorOshima, Kaori
dc.contributor.authorHaeger, Sarah M.
dc.contributor.authorPerez, Mario J.
dc.contributor.authorMcMurtry, Sarah A.
dc.contributor.authorHippensteel, Joseph A.
dc.contributor.authorFord, Joshay A.
dc.contributor.authorHerson, Paco S.
dc.contributor.authorLiu, Jian
dc.contributor.authorSchmidt, Eric P.
dc.contributor.authorLinhardt, Robert J.
dc.date2019
dc.date.accessioned2022-06-27T15:47:40Z
dc.date.available2022-06-27T15:47:40Z
dc.date.issued2019-05-07
dc.identifier.citationCirculating heparin oligosaccharides rapidly target the hippocampus in sepsis potentially impacting cognitive functions, X. Zhang, X. Han, K. Xia, Y. Xu, Y. Yang, K. Oshima, S. M. Haeger, M. J. Perez, S. A. McMurtry, J. A. Hippensteel, J. A. Ford P. S. Herson, J. Liu, E. P. Schmidt, R. J. Linhardt, Proceedings of the National Academy of Sciences (USA), 116, 9208–9213, 2019.
dc.identifier.issn10916490
dc.identifier.issn278424
dc.identifier.urihttps://doi.org/10.1073/pnas.1902227116
dc.identifier.urihttps://hdl.handle.net/20.500.13015/5546
dc.descriptionProceedings of the National Academy of Sciences (USA), 116, 9208–9213
dc.descriptionNote : if this item contains full text it may be a preprint, author manuscript, or a Gold OA copy that permits redistribution with a license such as CC BY. The final version is available through the publisher’s platform.
dc.description.abstractSepsis induces heparanase-mediated degradation of the endothelial glycocalyx, a heparan sulfate-enriched endovascular layer critical to vascular homeostasis, releasing highly sulfated domains of heparan sulfate into the circulation. These domains are oligosaccharides rich in heparin-like trisulfated disaccharide repeating units. Using a chemoenzymatic approach, an undecasaccharide containing a uniformly 13C-labeled internal 2-sulfoiduronic acid residue was synthesized on a p-nitrophenylglucuronide acceptor. Selective periodate cleavage afforded a heparin nonasaccharide having a natural structure. This 13C-labeled nonasaccharide was intravenously administered to septic (induced by cecal ligation and puncture, a model of polymicrobial peritonitis-induced sepsis) and nonseptic (sham) mice. Selected tissues and biological fluids from the mice were harvested at various time points over 4 hours, and the 13C-labeled nonasaccharide was recovered and digested with heparin lyases. The resulting 13C-labeled trisulfated disaccharide was quantified, without interference from endogenous mouse heparan sulfate/heparin, using liquid chromatography–mass spectrometry with sensitive and selective multiple reaction monitoring. The 13C-labeled heparin nonasaccharide appeared immediately in the blood and was rapidly cleared through the urine. Plasma nonasaccharide clearance was only slightly prolonged in septic mice (t1/2 ∼ 90 minutes). In septic mice, the nonasaccharide penetrated into the hippocampus but not the cortex of the brain; no hippocampal or cortical brain penetration occurred in sham mice. The results of this study suggest that circulating heparan sulfates are rapidly cleared from the plasma during sepsis and selectively penetrate the hippocampus, where they may have functional consequences.
dc.description.sponsorshipNational Institutes of Health
dc.languageen_US
dc.language.isoENG
dc.relation.ispartofThe Linhardt Research Labs Online Collection
dc.relation.ispartofRensselaer Polytechnic Institute, Troy, NY
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of America
dc.relation.urihttps://harc.rpi.edu/
dc.subjectBiology
dc.subjectChemistry and chemical biology
dc.subjectChemical and biological engineering
dc.subjectBiomedical engineering
dc.titleCirculating heparin oligosaccharides rapidly target the hippocampus in sepsis potentially impacting cognitive functions
dc.typeArticle
dcterms.isPartOfJournal
dcterms.isVersionOfhttps://doi.org/10.1073/pnas.1902227116
dc.rights.holderIn Copyright : this Item is protected by copyright and/or related rights. You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s). https://rightsstatements.org/page/InC/1.0/
dc.creator.identifierhttps://orcid.org/0000-0003-2219-5833
dc.relation.departmentThe Linhardt Research Labs.
dc.relation.departmentThe Shirley Ann Jackson, Ph.D. Center for Biotechnology and Interdisciplinary Studies (CBIS)
rpi.description.pages9208-9213
rpi.description.volume116


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