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    Design of anti-inflammatory heparan sulfate to protect against acetaminophen-induced acute liver failure

    Author
    Arnold, Katelyn; Xu, Yongmei; Sparkenbaugh, Erica M.; Li, Miaomiao; Han, Xiaorui; Zhang, Xing; Xia, Ke; Piegore, Mark; Zhang, Fuming; Zhang, Xiaoxiao; Henderson, Mike; Pagadala, Vijayakanth; Su, Guowei; Tan, Lisi; Park, Pyong Woo; Stravitz, Richard T.; Key, Nigel S.; Linhardt, Robert J.; Pawlinski, Rafal; Xu, Ding; Liu, Jian
    ORCID
    https://orcid.org/0000-0003-2219-5833
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    DESIGN OF ANTI-INFLAMMATORY HEPARAN SULFATE TO PROTECT AGAINST.pdf (2.724Mb)
    Other Contributors
    Date Issued
    2020-03-18
    Subject
    Biology; Chemistry and chemical biology; Chemical and biological engineering; Biomedical engineering
    Degree
    Terms of Use
    In 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/;
    Full Citation
    Design of anti-inflammatory heparan sulfate to protect against acetaminophen-induced acute liver failure, K. Arnold, Y. Xu, E. M. Sparkenbaugh, M. Li, X. Han, X. Zhang, K. Xia, M. Piegore, F. Zhang, X. Zhang, M. Henderson, V. Pagadala, G. Su, L. Tan, P. W. Park, R. T. Stravitz, N. S. Key, R. J. Linhardt, R. Pawlinski, D. Xu, J. Liu, Science Translational Medicine, 12, eaav8075, 2020.
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    URI
    https://hdl.handle.net/20.500.13015/5395; https://doi.org/10.1126/scitranslmed.aav8075
    Abstract
    Acetaminophen/paracetamol (APAP) overdose is the leading cause of drug-induced acute liver failure (ALF) in the United States and Europe. The progression of the disease is attributed to sterile inflammation induced by the release of high mobility group box 1 (HMGB1) and the interaction with receptor for advanced glycation end products (RAGE). A specific, effective, and safe approach to neutralize the proinflammatory activity of HMGB1 is highly desirable. Here, we found that a heparan sulfate (HS) octadecasaccharide (18-mer-HP or hepatoprotective 18-mer) displays potent hepatoprotection by targeting the HMGB1/RAGE axis. Endogenous HS proteoglycan, syndecan-1, is shed in response to APAP overdose in mice and humans. Furthermore, purified syndecan-1, but not syndecan-1 core protein, binds to HMGB1, suggesting that HMGB1 binds to HS polysaccharide side chains of syndecan-1. Last, we compared the protection effect between 18-mer-HP and N-acetyl cysteine, which is the standard of care to treat APAP overdose. We demonstrated that 18-mer-HP administered 3 hours after a lethal dose of APAP is fully protective; however, the treatment of N-acetyl cysteine loses protection. Therefore, 18-mer-HP may offer a potential therapeutic advantage over N-acetyl cysteine for late-presenting patients. Synthetic HS provides a potential approach for the treatment of APAP-induced ALF.;
    Description
    Science Translational Medicine, 12, eaav8075; Note : 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.
    Department
    The Linhardt Research Labs.; The Shirley Ann Jackson, Ph.D. Center for Biotechnology and Interdisciplinary Studies (CBIS);
    Publisher
    American Association for the Advancement of Science (AAAS)
    Relationships
    The Linhardt Research Labs Online Collection; Rensselaer Polytechnic Institute, Troy, NY; Science Translational Medicine; https://harc.rpi.edu/;
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