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.
Heparan sulfate is a sulfated polysaccharide that displays essential physiological functions. Here, we report a LC-MS/MS-based method for quantitatively determining the individual disaccharide composition and total amount of heparan sulfate. Using eight 13 C-labeled disaccharide calibrants and one 13 C-labeled polysaccharide calibrant, we complete the analysis in one-pot process. The method is both sensitive and has the throughput to analyze heparan sulfate from mouse tissues and plasma.
Heparan sulfate (HS) is widely present on the animal cell surface and in the extracellular matrix. HS achieves its biological functions by interacting with proteins to change proteins' conformation, oligomerization state and cellular location. The challenging question to study HS is how to dissect the relationship between the structures of HS and the biological activities. In the past several years, crucial techniques have been developed to overcome this challenge. A novel chemoenzymatic method to synthesize structurally defined HS oligosaccharides has offered a key access to this class of sulfated carbohydrate molecules. Recent rapid progress of HS microarray technology allows screening of the interaction of a target protein with a large number of HS oligosaccharides. The improved availability of HS oligosaccharides and HS microarray analysis will undoubtedly accelerate the investigation of the contribution of the specific sulfated carbohydrate structures of HS in a wide range of biological contexts.
The 3-O-sulfated
glucosamine in heparan sulfate
(HS) is a low-abundance structural component, but it is a key saccharide
unit for the biological activities of HS. A method to determine the
level of 3-O-sulfated HS is lacking. Here, we describe
a LC–MS/MS based method to analyze the structural motifs. We
determined the levels of 3-O-sulfated structural
motifs from pharmaceutical heparin manufactured from bovine, porcine,
and ovine. We discovered that saccharide chains carrying 3-O-sulfation from enoxaparin, an FDA-approved low-molecular
weight heparin, displayed a slower clearance rate than non-3-O-sulfated sugar chains in a mouse model. Lastly, we detected
the 3-O-sulfated HS from human brain. Furthermore,
we found that a specific 3-O-sulfated structural
motif, tetra-1, is elevated in the brain HS from Alzheimer’s
disease patients (n = 5, p = 0.0020).
Our method offers a practical solution to measure 3-O-sulfated HS from biological sources with the sensitivity and quantitative
capability.
Heparan sulfate (HS) is a sulfated glycosaminoglycan abundant on the cell surface and in the extracellular matrix and has several biological activities including anticoagulation and anti-inflammation. Liver ischemia reperfusion injury is associated with coagulation and inflammatory responses. Here, we synthesized HS oligosaccharides with defined sulfation patterns and show that synthetic anticoagulant HS oligosaccharides limit liver ischemia reperfusion injury in a mouse model. Using a small targeted HS library, we demonstrate that an oligosaccharide that possesses both anticoagulant activity and binding affinity to HMGB1, the inflammatory target, decreases injury greater than oligosaccharides that only bind to HMGB1 or only have anticoagulant activity. HS oligosaccharides may represent a potential new therapeutic option for decreasing liver damage resulting from ischemia reperfusion injury.
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