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Chemical Synthesis and Anti-Inflammatory Activity of Bikunin Associated Chondroitin Sulfate 24-mer.

ABSTRACT: Bikunin, a chondroitin sulfate (CS) proteoglycan clinically used to treat acute inflammation and sepsis, contains a CS chain with more than 20 monosaccharide units. To understand the function of the CS chain of bikunin, synthesis of long CS chains is needed. After exploring multiple glycosylation approaches and protective group chemistry, we report herein the successful generation of the longest CS chain to date (24-mer) in an excellent overall yield on a multi-mg scale. The anti-inflammatory activities of both bikunin and the synthetic 24-mer were determined, and the results demonstrate that both the glycan and the core protein are important for anti-inflammatory activities of bikunin by reducing macrophage production of proinflammatory cytokines.

SUBMITTER: Ramadan S

PROVIDER: S-EPMC7318065 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Chemical Synthesis and Anti-Inflammatory Activity of Bikunin Associated Chondroitin Sulfate 24-mer.

Ramadan Sherif S Li Tianlu T Yang Weizhun W Zhang Jicheng J Rashidijahanabad Zahra Z Tan Zibin Z Parameswaran Narayanan N Huang Xuefei X

ACS central science 20200601 6

Bikunin, a chondroitin sulfate (CS) proteoglycan clinically used to treat acute inflammation and sepsis, contains a CS chain with more than 20 monosaccharide units. To understand the function of the CS chain of bikunin, synthesis of long CS chains is needed. After exploring multiple glycosylation approaches and protective group chemistry, we report herein the successful generation of the longest CS chain to date (24-mer) in an excellent overall yield on a multi-mg scale. The anti-inflammatory ac ...[more]

PMID: 32607438

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Sulfation of the bikunin chondroitin sulfate chain determines heavy chain·hyaluronan complex formation.

Project description:Inter-?-trypsin inhibitor (I?I) is a complex comprising two heavy chains (HCs) that are covalently bound by an ester bond to chondroitin sulfate (CS), which itself is attached to Ser-10 of bikunin. I?I is essential for the trans-esterification of HCs onto hyaluronan (HA). This process is important for the stabilization of HA-rich matrices during ovulation and some inflammatory processes. Bikunin has been isolated previously by anion exchange chromatography with a salt gradient up to 0.5 M NaCl and found to contain unsulfated and 4-sulfated CS disaccharides. In this study, bikunin-containing fractions in plasma and urine were separated by anion exchange chromatography with a salt gradient of 0.1-1.0 M NaCl, and fractions were analyzed for their reactivity with the 4-sulfated CS linkage region antibody (2B6). The fractions that reacted with the 2B6 antibody (0.5-0.8 M NaCl) were found to predominantly contain sulfated CS disaccharides, including disulfated disaccharides, whereas the fractions that did not react with this antibody (0.1-0.5 M NaCl) contained unsulfated and 4-sulfated CS disaccharides. I?I in the 0.5-0.8 M NaCl plasma fraction was able to promote the trans-esterification of HCs to HA in the presence of TSG-6, whereas the 0.1-0.5 M NaCl fraction had a much reduced ability to transfer HC proteins to HA, suggesting that the CS containing 4-sulfated linkage region structures and disulfated disaccharides are involved in the HC transfer. Furthermore, these data highlight that the structure of the CS attached to bikunin is important for the transfer of HC onto HA and emphasize a specific role of CS chain sulfation.

| S-EPMC3743471 | biostudies-literature

Structure and Anti-Inflammatory Activity of a New Unusual Fucosylated Chondroitin Sulfate from <i>Cucumaria djakonovi</i>.

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Enzymatic Synthesis of Homogeneous Chondroitin Sulfate Oligosaccharides.

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Chondroitin Sulfate and Fucosylated Chondroitin Sulfate as Stimulators of Hematopoiesis in Cyclophosphamide-Induced Mice.

Project description:The immunosuppression and inhibition of hematopoiesis are considered to be reasons for the development of complications after intensive chemotherapy and allogeneic hematopoietic stem cell transplantation. Chondroitin sulfate (CS), isolated from the fish Salmo salar, and fucosylated chondroitin sulfate (FCS), isolated from the sea cucumber Apostichopus japonicus, were studied for their roles as stimulators of hematopoiesis in a model of cyclophosphamide-induced immunosuppression in mice. The recombinant protein r G-CSF was applied as a reference. The studied polysaccharides were shown to stimulate the release of white and red blood cells, as well as platelets from bone marrow in immunosuppressed mice, while r G-CSF was only responsible for the significant increase in the level of leucocytes. The analysis of different populations of leucocytes in blood indicated that r G-CSF mainly stimulated the production of neutrophils, whereas in the cases of the studied saccharides, increases in the levels of monocytes, lymphocytes and neutrophils were observed. The normalization of the level of the pro-inflammatory cytokine IL-6 in the serum and the recovery of cell populations in the spleen were observed in immunosuppressed mice following treatment with the polysaccharides. An increase in the proliferative activity of hematopoietic cells CD34(+)CD45(+) was observed following ex vivo polysaccharide exposure. Further study on related oligosaccharides regarding their potential as promising drugs in the complex prophylaxis and therapy of hematopoiesis inhibition after intensive chemotherapy and allogeneic hematopoietic stem cell transplantation seems to be warranted.

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| S-EPMC4853428 | biostudies-literature

LC-MS(n) analysis of isomeric chondroitin sulfate oligosaccharides using a chemical derivatization strategy.

Project description:Improved methods for structural analyses of glycosaminoglycans (GAGs) are required to understand their functional roles in various biological processes. Major challenges in structural characterization of complex GAG oligosaccharides using liquid chromatography-mass spectrometry (LC-MS) include the accurate determination of the patterns of sulfation due to gas-phase losses of the sulfate groups upon collisional activation and inefficient on-line separation of positional sulfation isomers prior to MS/MS analyses. Here, a sequential chemical derivatization procedure including permethylation, desulfation, and acetylation was demonstrated to enable both on-line LC separation of isomeric mixtures of chondroitin sulfate (CS) oligosaccharides and accurate determination of sites of sulfation by MS(n). The derivatized oligosaccharides have sulfate groups replaced with acetyl groups, which are sufficiently stable to survive MS(n) fragmentation and reflect the original sulfation patterns. A standard reversed-phase LC-MS system with a capillary C18 column was used for separation, and MS(n) experiments using collision-induced dissociation (CID) were performed. Our results indicate that the combination of this derivatization strategy and MS(n) methodology enables accurate identification of the sulfation isomers of CS hexasaccharides with either saturated or unsaturated nonreducing ends. Moreover, derivatized CS hexasaccharide isomer mixtures become separable by LC-MS method due to different positions of acetyl modifications.

| S-EPMC3187560 | biostudies-literature

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