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1.
N-glycan-mediated shielding of ADAMTS13 prevents binding of pathogenic autoantibodies in immune-mediated TTP.
Ercig, B, Graça, NAG, Kangro, K, Arfman, T, Wichapong, K, Hrdinová, J, Kaijen, P, van Alphen, FPJ, van den Biggelaar, M, Vanhoorelbeke, K, et al
Blood. 2021;(19):2694-2698
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Abstract
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is an autoimmune disorder caused by the development of autoantibodies targeting different domains of ADAMTS13. Profiling studies have shown that residues R568, F592, R660, Y661, and Y665 within exosite-3 of the spacer domain provide an immunodominant region of ADAMTS13 for pathogenic autoantibodies that develop in patients with iTTP. Modification of these 5 core residues with the goal of reducing autoantibody binding revealed a significant tradeoff between autoantibody resistance and proteolytic activity. Here, we employed structural bioinformatics to identify a larger epitope landscape on the ADAMTS13 spacer domain. Models of spacer-antibody complexes predicted that residues R568, L591, F592, K608, M609, R636, L637, R639, R660, Y661, Y665, and L668 contribute to an expanded epitope within the spacer domain. Based on bioinformatics-guided predictions, we designed a panel of N-glycan insertions in this expanded epitope to reduce the binding of spacer domain autoantibodies. One N-glycan variant (NGLY3-ADAMTS13, containing a K608N substitution) showed strongly reduced reactivity with TTP patient sera (28%) as compared with WT-ADAMTS13 (100%). Insertion of an N-glycan at amino acid position 608 did not interfere with processing of von Willebrand factor, positioning the resulting NGLY3-ADAMTS13 variant as a potential novel therapeutic option for treatment of iTTP.
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2.
Extraction of polysaccharides from edible mushrooms: Emerging technologies and recent advances.
Leong, YK, Yang, FC, Chang, JS
Carbohydrate polymers. 2021;:117006
Abstract
Mushroom-derived polysaccharides (especially β-glucans) are gaining much interest from researchers and industries recently due to their antioxidant, antitumor, immune-modulating activities, and other health benefits. Besides conventional extraction methods, a wide range of advanced extraction technologies is available nowadays for the recovery of these bioactive ingredients from mushrooms, such as ultrasonic-assisted extraction (UAE), microwave-assisted extraction (MAE), enzyme-assisted extraction (EAE), ultrasonic-microwave synergistic extraction (UMSE), subcritical water extraction (SWE), pulsed electric field-assisted extraction (PEFAE), aqueous two-phase extraction (ATPE), integrated extraction techniques, and other novel extraction technologies. This review describes the background of edible mushrooms, followed by the structural characteristics and biological activities of mushroom-derived polysaccharides. Then, the recent developments in the technologies used for the extraction of mushroom polysaccharides are discussed and summarized, together with their strengths and limitations as well as the underlying mechanisms. Finally, these advanced extraction techniques are compared and critically analyzed. Future outlook has also been proposed.
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3.
Glycan-Induced Protein Dynamics in Human Norovirus P Dimers Depend on Virus Strain and Deamidation Status.
Dülfer, J, Yan, H, Brodmerkel, MN, Creutznacher, R, Mallagaray, A, Peters, T, Caleman, C, Marklund, EG, Uetrecht, C
Molecules (Basel, Switzerland). 2021;(8)
Abstract
Noroviruses are the major cause of viral gastroenteritis and re-emerge worldwide every year, with GII.4 currently being the most frequent human genotype. The norovirus capsid protein VP1 is essential for host immune response. The P domain mediates cell attachment via histo blood-group antigens (HBGAs) in a strain-dependent manner but how these glycan-interactions actually relate to cell entry remains unclear. Here, hydrogen/deuterium exchange mass spectrometry (HDX-MS) is used to investigate glycan-induced protein dynamics in P dimers of different strains, which exhibit high structural similarity but different prevalence in humans. While the almost identical strains GII.4 Saga and GII.4 MI001 share glycan-induced dynamics, the dynamics differ in the emerging GII.17 Kawasaki 308 and rare GII.10 Vietnam 026 strain. The structural aspects of glycan binding to fully deamidated GII.4 P dimers have been investigated before. However, considering the high specificity and half-life of N373D under physiological conditions, large fractions of partially deamidated virions with potentially altered dynamics in their P domains are likely to occur. Therefore, we also examined glycan binding to partially deamidated GII.4 Saga and GII.4 MI001 P dimers. Such mixed species exhibit increased exposure to solvent in the P dimer upon glycan binding as opposed to pure wildtype. Furthermore, deamidated P dimers display increased flexibility and a monomeric subpopulation. Our results indicate that glycan binding induces strain-dependent structural dynamics, which are further altered by N373 deamidation, and hence hint at a complex role of deamidation in modulating glycan-mediated cell attachment in GII.4 strains.
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Intestinal epithelial glycosylation in homeostasis and gut microbiota interactions in IBD.
Kudelka, MR, Stowell, SR, Cummings, RD, Neish, AS
Nature reviews. Gastroenterology & hepatology. 2020;(10):597-617
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Abstract
Inflammatory bowel disease (IBD) affects 6.8 million people globally. A variety of factors have been implicated in IBD pathogenesis, including host genetics, immune dysregulation and gut microbiota alterations. Emerging evidence implicates intestinal epithelial glycosylation as an underappreciated process that interfaces with these three factors. IBD is associated with increased expression of truncated O-glycans as well as altered expression of terminal glycan structures. IBD genes, glycosyltransferase mislocalization, altered glycosyltransferase and glycosidase expression and dysbiosis drive changes in the glycome. These glycan changes disrupt the mucus layer, glycan-lectin interactions, host-microorganism interactions and mucosal immunity, and ultimately contribute to IBD pathogenesis. Epithelial glycans are especially critical in regulating the gut microbiota through providing bacterial ligands and nutrients and ultimately determining the spatial organization of the gut microbiota. In this Review, we discuss the regulation of intestinal epithelial glycosylation, altered epithelial glycosylation in IBD and mechanisms for how these alterations contribute to disease pathobiology. We hope that this Review provides a foundation for future studies on IBD glycosylation and the emergence of glycan-inspired therapies for IBD.
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The Effect of a Polysaccharide-Based Multinutrient Dietary Supplementation Regimen on Infections and Immune Functioning in Multiple Sclerosis.
Reginald McDaniel, H, LaGanke, C, Bloom, L, Goldberg, S, Lages, LC, Lantigua, LA, Atlas, SE, Woolger, JM, Lewis, JE
Journal of dietary supplements. 2020;(2):184-199
Abstract
Multiple sclerosis (MS) is a progressive neurodegenerative disease associated with increased infection rates, chronic inflammation, and premature death. Optimization of nutritional status via dietary supplementation may improve immune function in people suffering from MS and lead to decreased rates of infection. Fifteen individuals with a diagnosis of relapsing-remitting MS for an average of 12.4 years (SD =7.4; R = 2, 25) were enrolled in a one-year open-label clinical trial. Participants consumed a broad-spectrum dietary supplement regimen containing polysaccharides, phytochemicals, antioxidants, vitamins, and minerals three times per day. The occurrence of infections and a panel of cytokines, growth factors, and T- and B-cell subsets were assessed at baseline and 12 months. Seven female and 8 male participants with an average age of 51.3 years (SD =7.2; R = 38, 65) completed the study. At the end of the intervention, participants had fewer total infections (M = 7.9, SD =8.1 at baseline and M = 2.5, SD =4.3 at 12-month follow-up). At 12 months, IL-2, TNF-α, EGF, and CD95 + CD34+ significantly increased, while IL-1β significantly decreased. No major adverse effects were reported; only mild gastrointestinal intolerance was reported in four cases. A decreased occurrence of infection was observed in MS patients treated with 12 months of a polysaccharide-based multinutrient dietary supplement. Significant changes were also noted in several key biomarkers that would be physiologically favorable to the MS population. Thus, the results of this study suggest an immunomodulatory effect of the dietary supplement regimen studied.
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Effect of vitamin D supplementation on N-glycan branching and cellular immunophenotypes in MS.
Bäcker-Koduah, P, Infante-Duarte, C, Ivaldi, F, Uccelli, A, Bellmann-Strobl, J, Wernecke, KD, Sy, M, Demetriou, M, Dörr, J, Paul, F, et al
Annals of clinical and translational neurology. 2020;(9):1628-1641
Abstract
OBJECTIVE To investigate the effect of cholecalciferol (vitamin D3) supplementation on peripheral immune cell frequency and N-glycan branching in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS Exploratory analysis of high-dose (20 400 IU) and low-dose (400 IU) vitamin D3 supplementation taken every other day of an 18-month randomized controlled clinical trial including 38 RRMS patients on stable immunomodulatory therapy (NCT01440062). We investigated cholecalciferol treatment effects on N-glycan branching using L-PHA stain (phaseolus vulgaris leukoagglutinin) at 6 months and frequencies of T-, B-, and NK-cell subpopulations at 12 months with flow cytometry. RESULTS High-dose supplementation did not change CD3+ T cell subsets, CD19+ B cells subsets, and NK cells frequencies, except for CD8+ T regulatory cells, which were reduced in the low-dose arm compared to the high-dose arm at 12 months. High-dose supplementation decreased N-glycan branching on T and NK cells, measured as L-PHA mean fluorescence intensity (MFI). A reduction of N-glycan branching in B cells was not significant. In contrast, low-dose supplementation did not affect N-glycan branching. Changes in N-glycan branching did not correlate with cell frequencies. INTERPRETATION Immunomodulatory effect of vitamin D may involve regulation of N-glycan branching in vivo. Vitamin D3 supplementation did at large not affect the frequencies of peripheral immune cells.
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Research progress on the biological activities of selenium polysaccharides.
Zhou, N, Long, H, Wang, C, Yu, L, Zhao, M, Liu, X
Food & function. 2020;(6):4834-4852
Abstract
Selenium polysaccharides are a new type of functional polysaccharide that combines inorganic selenium with polysaccharides to form an organic selenium product. Selenium polysaccharides are obtained using three different methods, have no toxicity or side effects, and are easily absorbed and utilized by the body. A number of studies have demonstrated that selenium polysaccharides possess better antioxidant, antitumour, immune regulation, hypoglycaemic, and heavy metal removal activities than that of either polysaccharides or inorganic selenium. Selenium polysaccharides have gradually become a research topic of interest for the development of functional foods and pharmaceutical products. However, further studies are required to investigate the structures and mechanisms of selenium polysaccharides. At present, reviews that focus on the bioactivities of selenium polysaccharides are lacking. The aim of this study was to summarize the selenium polysaccharide bioactivity reports from the past decades, describe the mechanisms and shortcomings of these studies, and evaluate the need for further development.
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Glycan utilisation system in Bacteroides and Bifidobacteria and their roles in gut stability and health.
Singh, RP
Applied microbiology and biotechnology. 2019;(18):7287-7315
Abstract
Gut residential hundred trillion microbial cells are indispensable for maintaining gut homeostasis and impact on host physiology, development and immune systems. Many of them have displayed excellence in utilising dietary- and host-derived complex glycans and are producing useful postbiotics including short-chain fatty acids to primarily fuel different organs of the host. Therefore, employing individual microbiota is nowadays becoming a propitious target in biomedical for improving gut dysbiosis conditions of the host. Among other gut microbial communities, Bacteroides and Bifidobacteria are coevolved to utilise diverse ranges of diet- and host-derived glycans through harmonising distinct glycan utilisation systems. These gut symbionts frequently share digested oligosaccharides, carbohydrate-active enzymes and fermentable intermediate molecules for sustaining gut microbial symbiosis and improving fitness of own or other communities. Genomics approaches have provided unprecedented insights into these functions, but their precise mechanisms of action have poorly known. Sympathetic glycan-utilising strategy of each gut commensal will provide overview of mechanistic dynamic nature of the gut environment and will then assist in applying aptly personalised nutritional therapy. Thus, the review critically summarises cutting edge understanding of major plant- and host-derived glycan-utilising systems of Bacteroides and Bifidobacteria. Their evolutionary adaptation to gut environment and roles of postbiotics in human health are also highlighted.
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Hemicellulose from Plant Biomass in Medical and Pharmaceutical Application: A Critical Review.
Liu, X, Lin, Q, Yan, Y, Peng, F, Sun, R, Ren, J
Current medicinal chemistry. 2019;(14):2430-2455
Abstract
BACKGROUND Due to the non-toxicity, abundance and biodegradability, recently more and more attention has been focused on the exploration of hemicellulose as the potential substrate for the production of liquid fuels and other value-added chemicals and materials in different fields. This review aims to summarize the current knowledge on the promising application of nature hemicellulose and its derivative products including its degradation products, its new derivatives and hemicellulosebased medical biodegradable materials in the medical and pharmaceutical field, especially for inmmune regulation, bacteria inhibition, drug release, anti-caries, scaffold materials and anti-tumor. METHODS We searched the related papers about the medical and pharmaceutical application of hemicellulose and its derivative products, and summarized their preparation methods, properties and use effects. RESULTS Two hundred and twenty-seven papers were included in this review. Forty-seven papers introduced the extraction and application in immune regulation of nature hemicellulose, such as xylan, mannan, xyloglucan (XG) and β-glucan. Seventy-seven papers mentioned the preparation and application of degradation products of hemicellulose for adjusting intestinal function, maintaining blood glucose levels, enhancing the immunity and alleviating human fatigue fields such as xylooligosaccharides, xylitol, xylose, arabinose, etc. The preparation of hemicellulose derivatives were described in thirty-two papers such as hemicellulose esters, hemicellulose ethers and their effects on anticoagulants, adsorption of creatinine, the addition of immune cells and the inhibition of harmful bacteria. Finally, the preparations of hemicellulose-based materials such as hydrogels and membrane for the field of drug release, cell immobilization, cancer therapy and wound dressings were presented using fifty-five papers. CONCLUSION The structure of hemicellulose-based products has the significant impact on properties and the use effect for the immunity, and treating various diseases of human. However, some efforts should be made to explore and improve the properties of hemicellulose-based products and design the new materials to broaden hemicellulose applications.
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Immunoglobulin A N-glycosylation Presents Important Body Fluid-specific Variations in Lactating Mothers.
Goonatilleke, E, Smilowitz, JT, Mariño, KV, German, BJ, Lebrilla, CB, Barboza, M
Molecular & cellular proteomics : MCP. 2019;(11):2165-2177
Abstract
Secretory Immunoglobulin A (SIgA) is central to mucosal immunity: represents one of the main immunological mechanisms of defense against the potential attack of pathogens. During lactation SIgA is produced by plasmablasts in the mammary gland and is present in breast milk, playing a vital role in the passive immunity of the newborn. Interestingly, the different components of SIgA are highly N-glycosylated, and these N-Glycans have an essential role in health maintenance. In this work, we performed a glycomic study to compare N-glycosylation of SIgA purified from mature breast milk and saliva, and plasma IgA from the same lactating participants. Our results revealed a greater diversity than previously reported, with 89 glycan compositions that may correspond to over 250 structures. Among these glycans, 54 glycan compositions were characterized as body-fluid specific. Most of these unique N-Glycan compositions identified in SIgA from mature milk and IgA from plasma were fucosylated and both fucosylated and sialylated species, whereas in salivary SIgA the unique structures were mainly undecorated complex N-Glycans. In addition, we evaluated the effect of delivery mode on (S)IgA glycosylation. Lactating participants who had given birth by vaginal delivery presented an increased proportion of high mannose and fucosylated glycans in salivary SIgA, and selected high mannose, fucosylated, sialylated, and both fucosylated and sialylated glycans in plasma IgA, indicating that the hormonal changes during vaginal delivery could affect plasma and saliva IgA. These results reveal the structural details that provide a new dimension to the roles of (S)IgA N-Glycans in different tissues, and especially in maternal and new-born protection and infant development. The design of optimal recombinant IgA molecules specifically targeted to protect mucosal surfaces will need to include this dimension of structural detail.