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Special Issue "Exploring the Multifaceted Roles of Glycosaminoglycans (GAGs) - New Advances and Further Challenges"

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (30 November 2020) | Viewed by 40866

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Prof. Dr. Dragana Nikitovic
E-Mail Website
Guest Editor
Laboratory of Histology-Embryology, School of Medicine, The University of Crete, 71003 Heraklion, Greece
Interests: matrix pathobiology; cancer; inflammation; oxidative stress; cytotoxicity
Special Issues, Collections and Topics in MDPI journals
Dr. Serge Perez
E-Mail Website
Guest Editor
National Centre for Scientific Research, University of Grenoble Alpes, CNRS, CERMAV, 38000 Grenoble, France
Interests: structural glycosciences; oligo & polysaccharide structure and function; carbohydrate-protein interactions; diffraction methods; computational methods; glycobioinformatics; chemical biology

Special Issue Information

Dear Colleagues,

Glycosaminoglycans are linear, anionic polysaccharides (GAGs) consisting of repeating disaccharides. Indeed, most GAG chains are formed from repeating disaccharide units of hexosamine and hexuronic acid. The exception is keratan sulfate, whose building blocks consist of hexosamine and galactose. Differences in the structure of the primary disaccharide unit regarding types of uronic acid and hexosamine, the number and position of the sulfate residues, the presence of N-acetyl and/or N-sulfate groups and the relative molecular mass are evident. All such differences bestow these biomolecules with impressive complexity and diversity. The fine structure of the disaccharide units defines the types of GAGs. These include chondroitin/dermatan sulfate (CS/DS), heparin/heparan sulfate (Hep/HS), and keratan sulfate (KS), as well as non-sulfated hyaluronan (HA). GAGs are ubiquitously localized throughout the extracellular matrix (ECM) and to the cell membranes of cells in all tissues. They are either conjugated to protein cores in the form of proteoglycans, e.g., CS/DS, HS, and KS or as free GAGs (HA and Hep). Through their interaction with proteins, GAGs can affect cell–ECM and cell–cell interactions, finely modulating ligand-receptor binding and, thus, chemokine and cytokine activities, as well as growth factor sequestration. Indeed, it is well established that GAGs participate in the regulation of all biological processes under homeostasis; they also participate in disease progression. Significant advances have lately been achieved in analytic, sequencing, and structural characterization of GAG oligosaccharides, as well as in GAG profiling in tissues and cells (GAGomics). Moreover, studies focused on the structure/sequence–function relationships of GAGs have resulted in critical novel insights. Furthermore, advances in the characterization of protein-GAG complexes provide invaluable tools to decipher GAG roles in the intricate tissue milieu and answer critical questions on GAG participation in the molecular basis of disease and embryonic development. The Special Issue of Biomolecules entitled "Exploring the multifaceted roles of glycosaminoglycans (GAGs)—new advances and further challenges” will feature recent findings in the analysis, sequencing, and structural characterization of GAG oligosaccharides. Such features shed light on biological processes and GAG structure/ function relationships. We invite investigators to submit reviews or regular research articles highlighting these significant advances.

Prof. Dr. Dragana Nikitovic
Dr. Serge Perez
Guest Editors

Manuscript Submission Information

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Keywords

  • GAGs: Hyaluronic Acid, Heparan (Sulfate) Heparin, Heparosan
  • Chondroitin
  • Dermatan
  • Keratan, GAGs like
  • Peri and Extracellular Matrix
  • Regulation & Biosynthesis of GAG
  • Extraction of GAGs
  • Synthesis of GAGs (chemical, metabolic engineering,...)
  • Characterization of GAGs sequence
  • molecular weight, degree of polymerization, 3D structures,....)
  • GAGs structure/properties relationships
  • GAG oligosaccharides
  • Glycobiology
  • GAG structure/function relationship
  • Protein-GAG complexes
  • GAGs in disease
  • GAG-based biomaterials
  • GAGs as nanocarriers

Published Papers (17 papers)

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Editorial

Jump to: Research, Review

Editorial
Preface for the Special Issue on the Exploration of the Multifaceted Roles of Glycosaminoglycans: GAGs
Biomolecules 2021, 11(11), 1630; https://doi.org/10.3390/biom11111630 - 04 Nov 2021
Cited by 2 | Viewed by 1181
Abstract
Glycosaminoglycans (GAGs) are linear, anionic polysaccharides that consist of repeating disaccharides of hexosamine and hexuronic acid [...] Full article
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Research

Jump to: Editorial, Review

Article
HA and HS Changes in Endothelial Inflammatory Activation
Biomolecules 2021, 11(6), 809; https://doi.org/10.3390/biom11060809 - 29 May 2021
Cited by 5 | Viewed by 1690
Abstract
Cardiovascular diseases are a group of disorders caused by the presence of a combination of risk factors, such as tobacco use, unhealthy diet and obesity, physical inactivity, etc., which cause the modification of the composition of the vessel’s matrix and lead to the [...] Read more.
Cardiovascular diseases are a group of disorders caused by the presence of a combination of risk factors, such as tobacco use, unhealthy diet and obesity, physical inactivity, etc., which cause the modification of the composition of the vessel’s matrix and lead to the alteration of blood flow, matched with an inflammation condition. Nevertheless, it is not clear if the inflammation is a permissive condition or a consequent one. In order to investigate the effect of inflammation on the onset of vascular disease, we treated endothelial cells with the cytokine TNF-α that is increased in obese patients and is reported to induce cardiometabolic diseases. The inflammation induced a large change in the extracellular matrix, increasing the pericellular hyaluronan and altering the heparan sulfate Syndecans sets, which seems to be related to layer permeability but does not influence cell proliferation or migration nor induce blood cell recruitment or activation. Full article
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Article
Supramolecular Structuring of Hyaluronan-Lactose-Modified Chitosan Matrix: Towards High-Performance Biopolymers with Excellent Biodegradation
Biomolecules 2021, 11(3), 389; https://doi.org/10.3390/biom11030389 - 05 Mar 2021
Cited by 15 | Viewed by 1745
Abstract
Non-covalent interactions in supramolecular chemistry provide useful systems to understand biological processes, and self-assembly systems are suitable assets to build-up innovative products for biomedical applications. In this field, polyelectrolyte complexes are interesting, especially when polysaccharides are involved, due to their non-toxicity and bio-absorbability. [...] Read more.
Non-covalent interactions in supramolecular chemistry provide useful systems to understand biological processes, and self-assembly systems are suitable assets to build-up innovative products for biomedical applications. In this field, polyelectrolyte complexes are interesting, especially when polysaccharides are involved, due to their non-toxicity and bio-absorbability. In this work, we investigated a polyelectrolyte formed by hyaluronic acid (HA), a negatively charged linear polysaccharide, with Chitlac (Ch), a positively charged lactose-modified chitosan. The aim of the study was the investigation of a novel Ch–HA polyelectrolyte complex, to understand the interaction between the two polysaccharides and the stability towards enzymatic activity. By means of gel permeation chromatography–triple detector array (GPC–TDA), nuclear magnetic resonance (NMR), dynamic viscosity, Zeta Potential and scanning electron microscopy (SEM), the polyelectrolyte complex properties were identified and compared to individual polysaccharides. The complex showed monodisperse molecular weight distribution, high viscosity, negative charge, and could be degraded by specific enzymes, such as hyaluronidase and lysozyme. The results suggest a close interaction between the two polysaccharides in the complex, which could be considered a self-assembly system. Full article
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Article
Hair Histology and Glycosaminoglycans Distribution Probed by Infrared Spectral Imaging: Focus on Heparan Sulfate Proteoglycan and Glypican-1 during Hair Growth Cycle
Biomolecules 2021, 11(2), 192; https://doi.org/10.3390/biom11020192 - 30 Jan 2021
Cited by 2 | Viewed by 1480
Abstract
The expression of glypicans in different hair follicle (HF) compartments and their potential roles during hair shaft growth are still poorly understood. Heparan sulfate proteoglycan (HSPG) distribution in HFs is classically investigated by conventional histology, biochemical analysis, and immunohistochemistry. In this report, a [...] Read more.
The expression of glypicans in different hair follicle (HF) compartments and their potential roles during hair shaft growth are still poorly understood. Heparan sulfate proteoglycan (HSPG) distribution in HFs is classically investigated by conventional histology, biochemical analysis, and immunohistochemistry. In this report, a novel approach is proposed to assess hair histology and HSPG distribution changes in HFs at different phases of the hair growth cycle using infrared spectral imaging (IRSI). The distribution of HSPGs in HFs was probed by IRSI using the absorption region relevant to sulfation as a spectral marker. The findings were supported by Western immunoblotting and immunohistochemistry assays focusing on the glypican-1 expression and distribution in HFs. This study demonstrates the capacity of IRSI to identify the different HF tissue structures and to highlight protein, proteoglycan (PG), glycosaminoglycan (GAG), and sulfated GAG distribution in these structures. The comparison between anagen, catagen, and telogen phases shows the qualitative and/or quantitative evolution of GAGs as supported by Western immunoblotting. Thus, IRSI can simultaneously reveal the location of proteins, PGs, GAGs, and sulfated GAGs in HFs in a reagent- and label-free manner. From a dermatological point of view, IRSI shows its potential as a promising technique to study alopecia. Full article
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Article
Perlecan in the Natural and Cell Therapy Repair of Human Adult Articular Cartilage: Can Modifications in This Proteoglycan Be a Novel Therapeutic Approach?
Biomolecules 2021, 11(1), 92; https://doi.org/10.3390/biom11010092 - 13 Jan 2021
Cited by 8 | Viewed by 1537
Abstract
Articular cartilage is considered to have limited regenerative capacity, which has led to the search for therapies to limit or halt the progression of its destruction. Perlecan, a multifunctional heparan sulphate (HS) proteoglycan, promotes embryonic cartilage development and stabilises the mature tissue. We [...] Read more.
Articular cartilage is considered to have limited regenerative capacity, which has led to the search for therapies to limit or halt the progression of its destruction. Perlecan, a multifunctional heparan sulphate (HS) proteoglycan, promotes embryonic cartilage development and stabilises the mature tissue. We investigated the immunolocalisation of perlecan and collagen between donor-matched biopsies of human articular cartilage defects (n = 10 × 2) that were repaired either naturally or using autologous cell therapy, and with age-matched normal cartilage. We explored how the removal of HS from perlecan affects human chondrocytes in vitro. Immunohistochemistry showed both a pericellular and diffuse matrix staining pattern for perlecan in both natural and cell therapy repaired cartilage, which related to whether the morphology of the newly formed tissue was hyaline cartilage or fibrocartilage. Immunostaining for perlecan was significantly greater in both these repair tissues compared to normal age-matched controls. The immunolocalisation of collagens type III and VI was also dependent on tissue morphology. Heparanase treatment of chondrocytes in vitro resulted in significantly increased proliferation, while the expression of key chondrogenic surface and genetic markers was unaffected. Perlecan was more prominent in chondrocyte clusters than in individual cells after heparanase treatment. Heparanase treatment could be a means of increasing chondrocyte responsiveness to cartilage injury and perhaps to improve repair of defects. Full article
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Article
Misincorporation of Galactose by Chondroitin Synthase of Escherichia coli K4: From Traces to Synthesis of Chondbiuronan, a Novel Chondroitin-Like Polysaccharide
Biomolecules 2020, 10(12), 1667; https://doi.org/10.3390/biom10121667 - 12 Dec 2020
Cited by 3 | Viewed by 1963
Abstract
Chondroitin synthase KfoC is a bifunctional enzyme which polymerizes the capsular chondroitin backbone of Escherichia coli K4, composed of repeated β3N-acetylgalactosamine (GalNAc)-β4-glucuronic acid (GlcA) units. Sugar donors UDP-GalNAc and UDP-GlcA are the natural precursors of bacterial chondroitin synthesis. We have expressed KfoC in [...] Read more.
Chondroitin synthase KfoC is a bifunctional enzyme which polymerizes the capsular chondroitin backbone of Escherichia coli K4, composed of repeated β3N-acetylgalactosamine (GalNAc)-β4-glucuronic acid (GlcA) units. Sugar donors UDP-GalNAc and UDP-GlcA are the natural precursors of bacterial chondroitin synthesis. We have expressed KfoC in a recombinant strain of Escherichia coli deprived of 4-epimerase activity, thus incapable of supplying UDP-GalNAc in the bacterial cytoplasm. The strain was also co-expressing mammal galactose β-glucuronyltransferase, providing glucuronyl-lactose from exogenously added lactose, serving as a primer of polymerization. We show by the mean of NMR analyses that in those conditions, KfoC incorporates galactose, forming a chondroitin-like polymer composed of the repeated β3-galactose (Gal)-β4-glucuronic acid units. We also show that when UDP-GlcNAc 4-epimerase KfoA, encoded by the K4-operon, was co-expressed and produced UDP-GalNAc, a small proportion of galactose was still incorporated into the growing chain of chondroitin. Full article
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Article
GAG-DB, the New Interface of the Three-Dimensional Landscape of Glycosaminoglycans
Biomolecules 2020, 10(12), 1660; https://doi.org/10.3390/biom10121660 - 11 Dec 2020
Cited by 10 | Viewed by 2170
Abstract
Glycosaminoglycans (GAGs) are complex linear polysaccharides. GAG-DB is a curated database that classifies the three-dimensional features of the six mammalian GAGs (chondroitin sulfate, dermatan sulfate, heparin, heparan sulfate, hyaluronan, and keratan sulfate) and their oligosaccharides complexed with proteins. The entries are structures of [...] Read more.
Glycosaminoglycans (GAGs) are complex linear polysaccharides. GAG-DB is a curated database that classifies the three-dimensional features of the six mammalian GAGs (chondroitin sulfate, dermatan sulfate, heparin, heparan sulfate, hyaluronan, and keratan sulfate) and their oligosaccharides complexed with proteins. The entries are structures of GAG and GAG-protein complexes determined by X-ray single-crystal diffraction methods, X-ray fiber diffractometry, solution NMR spectroscopy, and scattering data often associated with molecular modeling. We designed the database architecture and the navigation tools to query the database with the Protein Data Bank (PDB), UniProtKB, and GlyTouCan (universal glycan repository) identifiers. Special attention was devoted to the description of the bound glycan ligands using simple graphical representation and numerical format for cross-referencing to other databases in glycoscience and functional data. GAG-DB provides detailed information on GAGs, their bound protein ligands, and features their interactions using several open access applications. Binding covers interactions between monosaccharides and protein monosaccharide units and the evaluation of quaternary structure. GAG-DB is freely available. Full article
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Article
Glycosaminoglycans and Contrast Agents: The Role of Hyaluronic Acid as MRI Contrast Enhancer
Biomolecules 2020, 10(12), 1612; https://doi.org/10.3390/biom10121612 - 28 Nov 2020
Cited by 8 | Viewed by 1736
Abstract
A comprehensive understanding of the behaviour of Glycosaminoglycans (GAGs) combined with imaging or therapeutic agents can be a key factor for the rational design of drug delivery and diagnostic systems. In this work, physical and thermodynamic phenomena arising from the complex interplay between [...] Read more.
A comprehensive understanding of the behaviour of Glycosaminoglycans (GAGs) combined with imaging or therapeutic agents can be a key factor for the rational design of drug delivery and diagnostic systems. In this work, physical and thermodynamic phenomena arising from the complex interplay between GAGs and contrast agents for Magnetic Resonance Imaging (MRI) have been explored. Being an excellent candidate for drug delivery and diagnostic systems, Hyaluronic acid (HA) (0.1 to 0.7%w/v) has been chosen as a GAG model, and Gd-DTPA (0.01 to 0.2 mM) as a relevant MRI contrast agent. HA samples crosslinked with divinyl sulfone (DVS) have also been investigated. Water Diffusion and Isothermal Titration Calorimetry studies demonstrated that the interaction between HA and Gd-DTPA can form hydrogen bonds and coordinate water molecules, which plays a leading role in determining both the polymer conformation and the relaxometric properties of the contrast agent. This interaction can be modulated by changing the GAG/contrast agent molar ratio and by acting on the organization of the polymer network. The fine control over the combination of GAGs and imaging agents could represent an enormous advantage in formulating novel multifunctional diagnostic probes paving the way for precision nanomedicine tools. Full article
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Article
Stability Evaluation and Degradation Studies of DAC® Hyaluronic-Polylactide Based Hydrogel by DOSY NMR Spectroscopy
Biomolecules 2020, 10(11), 1478; https://doi.org/10.3390/biom10111478 - 24 Oct 2020
Cited by 2 | Viewed by 1597
Abstract
The stability and the degradation of polymers in physiological conditions are very important issues in biomedical applications. The copolymer of hyaluronic acid and poly-D,L-lactic acid (made available in a product called DAC®) produces a hydrogel which retains the hydrophobic character of [...] Read more.
The stability and the degradation of polymers in physiological conditions are very important issues in biomedical applications. The copolymer of hyaluronic acid and poly-D,L-lactic acid (made available in a product called DAC®) produces a hydrogel which retains the hydrophobic character of the poly-D,L-lactide sidechains and the hydrophilic character of a hyaluronic acid backbone. This hydrogel is a suitable device for the coating of orthopedic implants with structured surfaces. In fact, this gel creates a temporary barrier to bacterial adhesion by inhibiting colonization, thus preventing the formation of the biofilm and the onset of an infection. Reabsorbed in about 72 h after the implant, this hydrogel does not hinder bone growth processes. In the need to assess stability and degradation of both the hyaluronan backbone and of the polylactic chains along time and temperature, we identified NMR spectroscopy as a privileged technique for the characterization of the released species, and we applied diffusion-ordered NMR spectroscopy (DOSY-NMR) for the investigation of molecular weight dispersion. Our diffusion studies of DAC® in physiological conditions provided a full understanding of the product degradation by overcoming the limitations observed in applying classical chromatography approaches by gel permeation UV. Full article
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Communication
Discovery of Sulfated Small Molecule Inhibitors of Matrix Metalloproteinase-8
Biomolecules 2020, 10(8), 1166; https://doi.org/10.3390/biom10081166 - 09 Aug 2020
Cited by 4 | Viewed by 1898
Abstract
Elevated matrix metalloproteinase-8 (MMP-8) activity contributes to the etiology of many diseases, including atherosclerosis, pulmonary fibrosis, and sepsis. Yet, very few small molecule inhibitors of MMP-8 have been identified. We reasoned that the synthetic non-sugar mimetics of glycosaminoglycans may inhibit MMP-8 because natural [...] Read more.
Elevated matrix metalloproteinase-8 (MMP-8) activity contributes to the etiology of many diseases, including atherosclerosis, pulmonary fibrosis, and sepsis. Yet, very few small molecule inhibitors of MMP-8 have been identified. We reasoned that the synthetic non-sugar mimetics of glycosaminoglycans may inhibit MMP-8 because natural glycosaminoglycans are known to modulate the functions of various MMPs. The screening a library of 58 synthetic, sulfated mimetics consisting of a dozen scaffolds led to the identification of only two scaffolds, including sulfated benzofurans and sulfated quinazolinones, as promising inhibitors of MMP-8. Interestingly, the sulfated quinazolinones displayed full antagonism of MMP-8 and sulfated benzofuran appeared to show partial antagonism. Of the two, sulfated quinazolinones exhibited a >10-fold selectivity for MMP-8 over MMP-9, a closely related metalloproteinase. Molecular modeling suggested the plausible occupancy of the S1 pocket on MMP-8 as the distinguishing feature of the interaction. Overall, this work provides the first proof that the sulfated mimetics of glycosaminoglycans could lead to potent, selective, and catalytic activity-tunable, small molecular inhibitors of MMP-8. Full article
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Communication
Heparin Administered to Anopheles in Membrane Feeding Assays Blocks Plasmodium Development in the Mosquito
Biomolecules 2020, 10(8), 1136; https://doi.org/10.3390/biom10081136 - 01 Aug 2020
Cited by 3 | Viewed by 2575
Abstract
Innovative antimalarial strategies are urgently needed given the alarming evolution of resistance to every single drug developed against Plasmodium parasites. The sulfated glycosaminoglycan heparin has been delivered in membrane feeding assays together with Plasmodium berghei-infected blood to Anopheles stephensi mosquitoes. The transition [...] Read more.
Innovative antimalarial strategies are urgently needed given the alarming evolution of resistance to every single drug developed against Plasmodium parasites. The sulfated glycosaminoglycan heparin has been delivered in membrane feeding assays together with Plasmodium berghei-infected blood to Anopheles stephensi mosquitoes. The transition between ookinete and oocyst pathogen stages in the mosquito has been studied in vivo through oocyst counting in dissected insect midguts, whereas ookinete interactions with heparin have been followed ex vivo by flow cytometry. Heparin interferes with the parasite’s ookinete–oocyst transition by binding ookinetes, but it does not affect fertilization. Hypersulfated heparin is a more efficient blocker of ookinete development than native heparin, significantly reducing the number of oocysts per midgut when offered to mosquitoes at 5 µg/mL in membrane feeding assays. Direct delivery of heparin to mosquitoes might represent a new antimalarial strategy of rapid implementation, since it would not require clinical trials for its immediate deployment. Full article
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Article
Multiplex Soluble Biomarker Analysis from Pleural Effusion
Biomolecules 2020, 10(8), 1113; https://doi.org/10.3390/biom10081113 - 28 Jul 2020
Cited by 6 | Viewed by 1604
Abstract
Malignant pleural mesothelioma (MPM) is a highly aggressive and therapy resistant pleural malignancy that is caused by asbestos exposure. MPM is associated with poor prognosis and a short patient survival. The survival time is strongly influenced by the subtype of the tumor. Dyspnea [...] Read more.
Malignant pleural mesothelioma (MPM) is a highly aggressive and therapy resistant pleural malignancy that is caused by asbestos exposure. MPM is associated with poor prognosis and a short patient survival. The survival time is strongly influenced by the subtype of the tumor. Dyspnea and accumulation of pleural effusion in the pleural cavity are common symptoms of MPM. The diagnostic distinction from other malignancies and reactive conditions is done using histopathology or cytopathology, always supported by immunohistochemistry, and sometimes also by analyses of soluble biomarkers in effusion supernatant. We evaluated the soluble angiogenesis related molecules as possible prognostic and diagnostic biomarkers for MPM by Luminex multiplex assay. Pleural effusion from 42 patients with malignant pleural mesothelioma (MPM), 36 patients with adenocarcinoma (AD) and 40 benign (BE) effusions were analyzed for 10 different analytes that, in previous studies, were associated with angiogenesis, consisting of Angiopoietin-1, HGF, MMP-7, Osteopontin, TIMP-1, Galectin, Mesothelin, NRG1-b1, Syndecan-1 (SDC-1) and VEGF by a Human Premixed Multi-Analyte Luminex kit. We found that shed SDC-1 and MMP-7 levels were significantly lower, whereas Mesothelin and Galectin-1 levels were significantly higher in malignant mesothelioma effusions, compared to adenocarcinoma. Galectin-1, HGF, Mesothelin, MMP-7, Osteopontin, shed SDC-1, NRG1-β1, VEGF and TIMP-1 were significantly higher in malignant pleural mesothelioma effusions compared to benign samples. Moreover, there is a negative correlation between Mesothelin and shed SDC-1 and positive correlation between VEGF, Angiopoietin-1 and shed SDC-1 level in the pleural effusion from malignant cases. Shed SDC-1 and VEGF have a prognostic value in malignant mesothelioma patients. Collectively, our data suggest that MMP-7, shed SDC-1, Mesothelin and Galectin-1 can be diagnostic and VEGF and SDC-1 prognostic markers in MPM patients. Additionally, Galectin-1, HGF, Mesothelin, MMP-7, Osteopontin, shed SDC-1 and TIMP-1 can be diagnostic for malignant cases. Full article
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Article
Efficient Construction of Atomic-Resolution Models of Non-Sulfated Chondroitin Glycosaminoglycan Using Molecular Dynamics Data
Biomolecules 2020, 10(4), 537; https://doi.org/10.3390/biom10040537 - 02 Apr 2020
Cited by 13 | Viewed by 2780
Abstract
Glycosaminoglycans (GAGs) are linear, structurally diverse, conformationally complex carbohydrate polymers that may contain up to 200 monosaccharides. These characteristics present a challenge for studying GAG conformational thermodynamics at atomic resolution using existing experimental methods. Molecular dynamics (MD) simulations can overcome this challenge but [...] Read more.
Glycosaminoglycans (GAGs) are linear, structurally diverse, conformationally complex carbohydrate polymers that may contain up to 200 monosaccharides. These characteristics present a challenge for studying GAG conformational thermodynamics at atomic resolution using existing experimental methods. Molecular dynamics (MD) simulations can overcome this challenge but are only feasible for short GAG polymers. To address this problem, we developed an algorithm that applies all conformational parameters contributing to GAG backbone flexibility (i.e., bond lengths, bond angles, and dihedral angles) from unbiased all-atom explicit-solvent MD simulations of short GAG polymers to rapidly construct models of GAGs of arbitrary length. The algorithm was used to generate non-sulfated chondroitin 10- and 20-mer ensembles which were compared to MD-generated ensembles for internal validation. End-to-end distance distributions in constructed and MD-generated ensembles have minimal differences, suggesting that our algorithm produces conformational ensembles that mimic the backbone flexibility seen in simulation. Non-sulfated chondroitin 100- and 200-mer ensembles were constructed within a day, demonstrating the efficiency of the algorithm and reduction in time and computational cost compared to simulation. Full article
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Review

Jump to: Editorial, Research

Review
Glycosaminoglycans: Carriers and Targets for Tailored Anti-Cancer Therapy
Biomolecules 2021, 11(3), 395; https://doi.org/10.3390/biom11030395 - 08 Mar 2021
Cited by 11 | Viewed by 2476
Abstract
The tumor microenvironment (TME) is composed of cancerous, non-cancerous, stromal, and immune cells that are surrounded by the components of the extracellular matrix (ECM). Glycosaminoglycans (GAGs), natural biomacromolecules, essential ECM, and cell membrane components are extensively altered in cancer tissues. During disease progression, [...] Read more.
The tumor microenvironment (TME) is composed of cancerous, non-cancerous, stromal, and immune cells that are surrounded by the components of the extracellular matrix (ECM). Glycosaminoglycans (GAGs), natural biomacromolecules, essential ECM, and cell membrane components are extensively altered in cancer tissues. During disease progression, the GAG fine structure changes in a manner associated with disease evolution. Thus, changes in the GAG sulfation pattern are immediately correlated to malignant transformation. Their molecular weight, distribution, composition, and fine modifications, including sulfation, exhibit distinct alterations during cancer development. GAGs and GAG-based molecules, due to their unique properties, are suggested as promising effectors for anticancer therapy. Considering their participation in tumorigenesis, their utilization in drug development has been the focus of both industry and academic research efforts. These efforts have been developing in two main directions; (i) utilizing GAGs as targets of therapeutic strategies and (ii) employing GAGs specificity and excellent physicochemical properties for targeted delivery of cancer therapeutics. This review will comprehensively discuss recent developments and the broad potential of GAG utilization for cancer therapy. Full article
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Review
Heparan Sulfate Glycosaminoglycans: (Un)Expected Allies in Cancer Clinical Management
Biomolecules 2021, 11(2), 136; https://doi.org/10.3390/biom11020136 - 21 Jan 2021
Cited by 14 | Viewed by 2712
Abstract
In an era when cancer glycobiology research is exponentially growing, we are witnessing a progressive translation of the major scientific findings to the clinical practice with the overarching aim of improving cancer patients’ management. Many mechanistic cell biology studies have demonstrated that heparan [...] Read more.
In an era when cancer glycobiology research is exponentially growing, we are witnessing a progressive translation of the major scientific findings to the clinical practice with the overarching aim of improving cancer patients’ management. Many mechanistic cell biology studies have demonstrated that heparan sulfate (HS) glycosaminoglycans are key molecules responsible for several molecular and biochemical processes, impacting extracellular matrix properties and cellular functions. HS can interact with a myriad of different ligands, and therefore, hold a pleiotropic role in regulating the activity of important cellular receptors and downstream signalling pathways. The aberrant expression of HS glycan chains in tumours determines main malignant features, such as cancer cell proliferation, angiogenesis, invasion and metastasis. In this review, we devote particular attention to HS biological activities, its expression profile and modulation in cancer. Moreover, we highlight HS clinical potential to improve both diagnosis and prognosis of cancer, either as HS-based biomarkers or as therapeutic targets. Full article
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Review
Glycosaminoglycans in Tissue Engineering: A Review
Biomolecules 2021, 11(1), 29; https://doi.org/10.3390/biom11010029 - 29 Dec 2020
Cited by 41 | Viewed by 6020
Abstract
Glycosaminoglycans are native components of the extracellular matrix that drive cell behavior and control the microenvironment surrounding cells, making them promising therapeutic targets for a myriad of diseases. Recent studies have shown that recapitulation of cell interactions with the extracellular matrix are key [...] Read more.
Glycosaminoglycans are native components of the extracellular matrix that drive cell behavior and control the microenvironment surrounding cells, making them promising therapeutic targets for a myriad of diseases. Recent studies have shown that recapitulation of cell interactions with the extracellular matrix are key in tissue engineering, where the aim is to mimic and regenerate endogenous tissues. Because of this, incorporation of glycosaminoglycans to drive stem cell fate and promote cell proliferation in engineered tissues has gained increasing attention. This review summarizes the role glycosaminoglycans can play in tissue engineering and the recent advances in their use in these constructs. We also evaluate the general trend of research in this niche and provide insight into its future directions. Full article
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Review
Aggrecan, the Primary Weight-Bearing Cartilage Proteoglycan, Has Context-Dependent, Cell-Directive Properties in Embryonic Development and Neurogenesis: Aggrecan Glycan Side Chain Modifications Convey Interactive Biodiversity
Biomolecules 2020, 10(9), 1244; https://doi.org/10.3390/biom10091244 - 27 Aug 2020
Cited by 17 | Viewed by 3973
Abstract
This review examines aggrecan’s roles in developmental embryonic tissues, in tissues undergoing morphogenetic transition and in mature weight-bearing tissues. Aggrecan is a remarkably versatile and capable proteoglycan (PG) with diverse tissue context-dependent functional attributes beyond its established role as a weight-bearing PG. The [...] Read more.
This review examines aggrecan’s roles in developmental embryonic tissues, in tissues undergoing morphogenetic transition and in mature weight-bearing tissues. Aggrecan is a remarkably versatile and capable proteoglycan (PG) with diverse tissue context-dependent functional attributes beyond its established role as a weight-bearing PG. The aggrecan core protein provides a template which can be variably decorated with a number of glycosaminoglycan (GAG) side chains including keratan sulphate (KS), human natural killer trisaccharide (HNK-1) and chondroitin sulphate (CS). These convey unique tissue-specific functional properties in water imbibition, space-filling, matrix stabilisation or embryonic cellular regulation. Aggrecan also interacts with morphogens and growth factors directing tissue morphogenesis, remodelling and metaplasia. HNK-1 aggrecan glycoforms direct neural crest cell migration in embryonic development and is neuroprotective in perineuronal nets in the brain. The ability of the aggrecan core protein to assemble CS and KS chains at high density equips cartilage aggrecan with its well-known water-imbibing and weight-bearing properties. The importance of specific arrangements of GAG chains on aggrecan in all its forms is also a primary morphogenetic functional determinant providing aggrecan with unique tissue context dependent regulatory properties. The versatility displayed by aggrecan in biodiverse contexts is a function of its GAG side chains. Full article
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