Biochemistry, Genetics and Molecular Biology › Cell Biology

Proteoglycans and glycosaminoglycans research

Works Count: 48741

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Description

This cluster of papers explores the role of extracellular matrix components such as hyaluronan, proteoglycans, and heparan sulfate in regulating cell signaling, synaptic plasticity, inflammation, and angiogenesis. It delves into the molecular interactions and functions of these matrix molecules in various biological processes.

Keywords

Hyaluronan; Proteoglycans; Heparan Sulfate; CD44; Cell Signaling; Glycosaminoglycans; Toll-like Receptors; Synaptic Plasticity; Inflammation; Angiogenesis

CD44: Structure, Function and Association with the Malignant Process

1997-01-01

David Naor , Ronit Vogt Sionov , Dvorah Ish‐Shalom

CD44 and Its Interaction with Extracellular Matrix

1993-01-01

Jayne Lesley , Robert Hyman , P W Kincade

Enzymatic Methods for the Determination of Small Quantities of Isomeric Chondroitin Sulfates

1968-04-01

Hiroshi Saito , T Yamagata , S Suzuki

Micromethods have been developed for the measurement of as little as 3 µg of chondroitin sulfate A, B, or C in mixtures with other mucopolysaccharides by the use of chondroitinase-ABC, … Micromethods have been developed for the measurement of as little as 3 µg of chondroitin sulfate A, B, or C in mixtures with other mucopolysaccharides by the use of chondroitinase-ABC, chondroitinase-AC, chondro-4-sulfatase, and chondro-6-sulfatase. With these methods, 35S-labeled chondroitin sulfates A, B, and C in a given mixture have been precisely and rapidly determined by measuring radioactivity alone. The methods have also been utilized to determine chondroitin sulfates A, B, and C in as little as 4 ml of normal urine.

Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms.

1992-12-01

Keith A. Houck , David W. M. Leung , Ann M. Rowland +2 more

The vascular endothelial growth factor (VEGF) family encompasses four polypeptides that result from alternative splicing of mRNA. We have previously demonstrated differences in the secretion pattern of these polypeptides. Stable … The vascular endothelial growth factor (VEGF) family encompasses four polypeptides that result from alternative splicing of mRNA. We have previously demonstrated differences in the secretion pattern of these polypeptides. Stable cell lines expressing VEGFs were established in human embryonic kidney CEN4 cells. VEGF121, the shortest form, was secreted and freely soluble in tissue culture medium. VEGF189 was secreted, but was almost entirely bound to the cell surface or extracellular matrix. VEGF165 displayed an intermediary behavior. Suramin induced the release of VEGF189, permitting its characterization as a more basic protein with higher affinity for heparin than VEGF165 or VEGF121, but with similar endothelial cell mitogenic activity. Heparin, heparan sulfate, and heparinase all induced the release of VEGF165 and VEGF189, suggesting heparin-containing proteoglycans as candidate VEGF-binding sites. Finally, VEGF165 and VEGF189 were released from their bound states by treatment with plasmin. The released 34-kDa dimeric species are active as endothelial cell mitogens and as vascular permeability agents. We conclude that the bioavailability of VEGF may be regulated at the genetic level by alternative splicing that determines whether VEGF will be soluble or incorporated into a biological reservoir and also through proteolysis following plasminogen activation.

Purification and Properties of Bacterial Chondroitinases and Chondrosulfatases

1968-04-01

T Yamagata , Hidehiko Saito , Osami Habuchi +1 more

Abstract 1. An enzyme, has been purified to apparent homogeneity from extracts of Proteus vulgaris, NCTC 4636, which was adapted on a medium containing chondroitin sulfate C. It has the … Abstract 1. An enzyme, has been purified to apparent homogeneity from extracts of Proteus vulgaris, NCTC 4636, which was adapted on a medium containing chondroitin sulfate C. It has the following properties. (a) At pH 8, it degrades chondroitin sulfates A, B, and C at greater rates than chondroitin and hyaluronic acid. It does not attack keratosulfate, heparin, or heparitin sulfate. (b) It carries out an elimination reaction, yielding Δ4,5-unsaturated disaccharides. (c) In the crude extract it is accompanied by two different types of sulfatase, which are removed during purification. 2. The two sulfatases, chondro-4-sulfatase and chondro-6-sulfatase, have been separated from chondroitinase-ABC and from each other; both are required for the hydrolytic desulfation of chondroitinase products, Δ4,5-unsaturated disaccharide sulfates. They do not attack polymer chondroitin sulfates, hexa-, penta-, tetra-, or trisaccharides derived from chondroitin sulfates A and C by digestion with crude testicular hyaluronidase, or acetylgalactosamine 4-and 6-sulfates. One of these enzymes, chondro-4-sulfatase, catalyzes the conversion of Δ4,5-unsaturated disaccharide 4-sulfate (i.e. the product from the degradation of chondroitin sulfate A or B by chondroitinase-ABC) and its saturated analogue (i.e. acetylchondrosin 4-sulfate) to the corresponding nonsulfated disaccharides and inorganic sulfate, but does not attack Δ4,5-unsaturated disaccharide 6-sulfate (i.e. the product from the degradation of chondroitin sulfate C by chondroitinase-ABC) or its saturated analogue (i.e. acetylchondrosin 6-sulfate). In contrast, chondro-6-sulfatase carries out the desulfation of the disaccharide 6-sulfates and acetylgalactosamine 4,6-disulfate at position 6 while it does not attack the disaccharide 4-sulfate isomers. 3. Another type of chondroitinase, chondroitinase-AC, has been purified also to apparent homogeneity from extracts of Flavobacterium heparinum, ATCC 13125, which was adapted on a medium containing chondroitin sulfate C. Its properties have been compared with those of chondroitinase-ABC from P. vulgaris. (a) Unlike chondroitinase-ABC, it has no measurable activity with chondroitin sulfate B; like chondroitinase-ABC it carries out essentially the same reactions with chondroitin sulfates A and C, chondroitin, and hyaluronic acid. (b) In the crude extract it is accompanied by an enzyme similar to chondroitinase-ABC, an enzyme similar to chondro-4-sulfatase, and a glucuronidase which hydrolyzes the β-glucuronidic bond of unsaturated disaccharides but not the bond of saturated disaccharides. All these accompanying enzymes are removed during purification.

The Purification and Mechanism of Action of Human Antithrombin-Heparin Cofactor

1973-09-01

Robert Rosenberg , Paul S. Damus

A procedure is presented for purifying antithrombin-heparin cofactor from human plasma. The final product is homogeneous as judged by disc gel electrophoresis, sodium dodecyl sulfate gel electrophoresis, and immunoelectrophoresis. The … A procedure is presented for purifying antithrombin-heparin cofactor from human plasma. The final product is homogeneous as judged by disc gel electrophoresis, sodium dodecyl sulfate gel electrophoresis, and immunoelectrophoresis. The final yield averages 12%. A specific antibody directed against pure inhibitor preparations precipitates virtually all of both antithrombin and heparin cofactor activity from defibrinated plasma. The purification, the immunoprecipitation, and other data, indicate that both activities are properties of a single molecular species. The inhibitor and thrombin form a 1:1 stoichiometric complex which cannot be dissociated with denaturing and reducing agents. Addition of heparin, a widely used anticoagulant which specifically accelerates the action of our inhibitor, increases the rate of formation of this complex without altering its stoichiometry or its dissociability. Interaction of thrombin with antithrombin-heparin cofactor requires the presence of the active center serine of the enzyme and arginine residue(s) on the inhibitor, since chemical modification of either of these critical residues inhibits complex formation both in the presence and absence of heparin. We suggest that, in analogous fashion to trypsin-trypsin inhibitor systems, a specific interaction occurs between the active center serine of thrombin and a unique arginine-x reactive site on the antithrombin-heparin cofactor. Furthermore, lysyl residues of the inhibitor probably serve as a binding site for heparin, since chemical modification of these residues virtually eliminates heparin cofactor activity with only minimal reduction of antithrombin activity. We postulate that heparin binds to the inhibitor and causes a conformational change which results in a more favorable exposure of the arginine reactive site, allowing a rapid interaction with thrombin.

Glycosaminoglycans: molecular properties, protein interactions, and role in physiological processes

1991-04-01

Raven Jackson , S J Busch , A D Cardin

Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor

1991-02-01

Avner Yayon , Michael Klagsbrun , Jeffrey D. Esko +2 more

Autoimmunity to type II collagen an experimental model of arthritis.

1977-09-01

David E. Trentham , Alexander S. Townes , A H Kang

We have found that intradermal injection of native type II collagen extracted from human, chick or rat cartilage induces an inflammatory arthritis in approximately 40% of rats of several strains … We have found that intradermal injection of native type II collagen extracted from human, chick or rat cartilage induces an inflammatory arthritis in approximately 40% of rats of several strains whether complete Freund's adjuvant or incomplete Freund's adjuvant is used. Type I or III collagen extracted from skin, cartilage proteoglycans and alpha1(II) chains were incapable of eliciting arthritis, as was type II collagen injected without adjuvant. The disease is a chronic proliferative synovitis, resembling adjuvant arthritis in rats and rheumatoid arthritis in humans. Native type II co-lagen modified by limited pepsin digestion still produces arthritis, suggesting that type-specific determinants residing in the helical region of the molecule are responsible for the induction of disease. Since homologous type II collagen emulsified in oil without bacterial preparations regularly causes the disease, this new animal model of arthritis represents a unique example of experimentally-inducible autoimmunity to a tissue component.

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Heparin-Protein Interactions

2002-01-29

Ishan Capila , Robert J. Linhardt

Heparin, a sulfated polysaccharide belonging to the family of glycosaminoglycans, has numerous important biological activities, associated with its interaction with diverse proteins. Heparin is widely used as an anticoagulant drug … Heparin, a sulfated polysaccharide belonging to the family of glycosaminoglycans, has numerous important biological activities, associated with its interaction with diverse proteins. Heparin is widely used as an anticoagulant drug based on its ability to accelerate the rate at which antithrombin inhibits serine proteases in the blood coagulation cascade. Heparin and the structurally related heparan sulfate are complex linear polymers comprised of a mixture of chains of different length, having variable sequences. Heparan sulfate is ubiquitously distributed on the surfaces of animal cells and in the extracellular matrix. It also mediates various physiologic and pathophysiologic processes. Difficulties in evaluating the role of heparin and heparan sulfate in vivo may be partly ascribed to ignorance of the detailed structure and sequence of these polysaccharides. In addition, the understanding of carbohydrate–protein interactions has lagged behind that of the more thoroughly studied protein–protein and protein–nucleic acid interactions. The recent extensive studies on the structural, kinetic, and thermodynamic aspects of the protein binding of heparin and heparan sulfate have led to an improved understanding of heparin–protein interactions. A high degree of specificity could be identified in many of these interactions. An understanding of these interactions at the molecular level is of fundamental importance in the design of new highly specific therapeutic agents. This review focuses on aspects of heparin structure and conformation, which are important for its interactions with proteins. It also describes the interaction of heparin and heparan sulfate with selected families of heparin-binding proteins.

Heparan sulphate proteoglycans fine-tune mammalian physiology

2007-04-01

Joseph R. Bishop , Manuela Schuksz , Jeffrey D. Esko

Differential staining of acid glycosaminoglycans (mucopolysaccharides) by Alcian blue in salt solutions

1965-01-01

J. E. Scott , J. Dorling

Hyaluronan fragments: An information-rich system

2006-07-07

Robert Stern , Akira Asari , Kazuki N. Sugahara

Requirement of Heparan Sulfate for bFGF-Mediated Fibroblast Growth and Myoblast Differentiation

1991-06-21

Alan C. Rapraeger , Alison Krufka , Bradley B. Olwin

Basic fibroblast growth factor (bFGF) binds to heparan sulfate proteoglycans at the cell surface and to receptors with tyrosine kinase activity. Prevention of binding between cell surface heparan sulfate and … Basic fibroblast growth factor (bFGF) binds to heparan sulfate proteoglycans at the cell surface and to receptors with tyrosine kinase activity. Prevention of binding between cell surface heparan sulfate and bFGF (i) substantially reduces binding of fibroblast growth factor to its cell-surface receptors, (ii) blocks the ability of bFGF to support the growth of Swiss 3T3 fibroblasts, and (iii) induces terminal differentiation of MM14 skeletal muscle cells, which is normally repressed by fibroblast growth factor. These results indicate that cell surface heparan sulfate is directly involved in bFGF cell signaling.

Functions of hyaluronan in wound repair

1999-03-01

W. Y. John Chen , Giovanni Abatangelo

Hyaluronan is a major carbohydrate component of the extracellular matrix and can be found in skin, joints, eyes and most other organs and tissues. It has a simple, repeated disaccharide … Hyaluronan is a major carbohydrate component of the extracellular matrix and can be found in skin, joints, eyes and most other organs and tissues. It has a simple, repeated disaccharide linear copolymer structure that is completely conserved throughout a large span of the evolutionary tree, indicating a fundamental biological importance. Amongst extracellular matrix molecules, it has unique hygroscopic, rheological and viscoelastic properties. Hyaluronan binds to many other extracellular matrix molecules, binds specifically to cell bodies through cell surface receptors, and has a unique mode of synthesis in which the molecule is extruded immediately into the extracellular space upon formation. Through its complex interactions with matrix components and cells, hyaluronan has multifaceted roles in biology utilizing both its physicochemical and biological properties. These biological roles range from a purely structural function in the extracellular matrix to developmental regulation through effects of cellular behavior via control of the tissue macro- and microenvironments, as well as through direct receptor mediated effects on gene expression. Hyaluronan is also thought to have important biological roles in skin wound healing, by virtue of its presence in high amounts in skin. Hyaluronan content in skin is further elevated transiently in granulation tissue during the wound healing process. In this review, the general physicochemical and biological properties of hyaluronan, and how these properties may be utilized in the various processes of wound healing: inflammation, granulation and reepithelization, are presented.

Chondrogenic Differentiation of Mesenchymal Stem Cells from Bone Marrow: Differentiation-Dependent Gene Expression of Matrix Components

2001-08-01

Frank Barry , Raymond Boynton , Beishan Liu +1 more

Improved quantitation and discrimination of sulphated glycosaminoglycans by use of dimethylmethylene blue

1986-09-04

Richard W. Farndale , David J. Buttle , A. John Barrett

Signaling Properties of Hyaluronan Receptors

2002-02-01

Eva A. Turley , Paul W. Noble , Lilly Bourguignon

CD44: From adhesion molecules to signalling regulators

2003-01-01

Helmut Ponta , Larry S. Sherman , Peter Herrlich

An Overview of Epithelio-Mesenchymal Transformation

1995-01-01

Elizabeth D. Hay

Epithelium is the tissue phenotype of early embryos and primitive adults of the chordate phylum. A second tissue type, however, is produced by epithelial-mesenchymal transformation (EMT) in higher chordates, such … Epithelium is the tissue phenotype of early embryos and primitive adults of the chordate phylum. A second tissue type, however, is produced by epithelial-mesenchymal transformation (EMT) in higher chordates, such as vertebrata. Mesenchymal cells have the ability, which true epithelia do not, to invade and migrate through the extracellular matrix (ECM) to create dramatic cell transpositions. The first-formed or primary mesenchymal cells in amniote vertebrates migrate from the primitive streak to differentiate into the mesodermal and endodermal epithelia. Definitive mesenchyme with connective tissue and muscle potentials arises from the epithelial mesoderm at about the same time as the neural crest mesenchyme forms from the ectoderm. Later on in embryogenesis. EMT is used to remodel unwanted epithelia, such as that of the palate medial edges. We discuss the mechanisms by which epithelial cells transform into mesenchyme and vice versa. On the one hand, cells activate putative mesenchymal master genes, turn off epithelial genes, and acquire motility machinery that allows them to interact in 3 dimensions (3D) with ECM via actin cortex while sliding their endoplasm into their new front ends. On the other hand, primary mesenchymal cells can reactivate epithelial regulatory genes, such as E-cadherin, turn off the motility machinery for invading ECM, and reexpress apical-basal polarity. We review the genes, such as FSPI, src, ras, andfos, that are activated in cells transforming to mesenchyme and the genes their neighbors activate to induce EMT, such as those for TGFβ, NT-3, and sonic hedgehog. Suspension in 3D collagen gels can induce adult epithelium to undergo EMT; α5βl integrin is activated on surfaces in contact with collagen, including apical surfaces that do not normally express integrins. In vivo, it is possible that pathological manipulations of a cell’s environment likewise induce EMT. Of the examples we give, the creation of invasive metastatic carcinoma cells by EMT is the most fearful. Interestingly, transfection of either metastatic cells or normal embryonic fibroblasts with the E-cadherin gene converts them to the epithelial phenotype. It may be possible in the future to manipulate the tissue phenotype of diseased cells to the advantage of the animal.

Self-assembling peptide hydrogel fosters chondrocyte extracellular matrix production and cell division: Implications for cartilage tissue repair

2002-07-15

John D. Kisiday , Moonsoo M. Jin , Bodo Kurz +4 more

Emerging medical technologies for effective and lasting repair of articular cartilage include delivery of cells or cell-seeded scaffolds to a defect site to initiate de novo tissue regeneration. Biocompatible scaffolds … Emerging medical technologies for effective and lasting repair of articular cartilage include delivery of cells or cell-seeded scaffolds to a defect site to initiate de novo tissue regeneration. Biocompatible scaffolds assist in providing a template for cell distribution and extracellular matrix (ECM) accumulation in a three-dimensional geometry. A major challenge in choosing an appropriate scaffold for cartilage repair is the identification of a material that can simultaneously stimulate high rates of cell division and high rates of cell synthesis of phenotypically specific ECM macromolecules until repair evolves into steady-state tissue maintenance. We have devised a self-assembling peptide hydrogel scaffold for cartilage repair and developed a method to encapsulate chondrocytes within the peptide hydrogel. During 4 weeks of culture in vitro , chondrocytes seeded within the peptide hydrogel retained their morphology and developed a cartilage-like ECM rich in proteoglycans and type II collagen, indicative of a stable chondrocyte phenotype. Time-dependent accumulation of this ECM was paralleled by increases in material stiffness, indicative of deposition of mechanically functional neo-tissue. Taken together, these results demonstrate the potential of a self-assembling peptide hydrogel as a scaffold for the synthesis and accumulation of a true cartilage-like ECM within a three-dimensional cell culture for cartilage tissue repair.

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Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells

1989-06-01

Napoleone Ferrara , William J. Henzel

Negative regulation of transforming growth factor-β by the proteoglycan decorin

1990-07-01

Yu Yamaguchi , David Mann , Erkki Ruoslahti

Proteoglycans as modulators of growth factor activities

1991-03-01

Erkki Ruoslahti , Yu Yamaguchi

Enzymatic Targeting of the Stroma Ablates Physical Barriers to Treatment of Pancreatic Ductal Adenocarcinoma

2012-03-01

Paolo P. Provenzano , Carlos Cuevas , Amy Chang +3 more

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A Direct Spectrophotometric Microassay for Sulfated Glycosaminoglycans in Cartilage Cultures

1982-01-01

Richard W. Farndale , C A Sayers , A. John Barrett

A rapid spectrophotometric procedure is described for the estimation of sulfated glycosaminoglycans in cartilage cultures. Papain digestion of tissue or culture medium provides glycosaminoglycans in solution for assay; an aliquot … A rapid spectrophotometric procedure is described for the estimation of sulfated glycosaminoglycans in cartilage cultures. Papain digestion of tissue or culture medium provides glycosaminoglycans in solution for assay; an aliquot of the digest is mixed with the dye 1,9-dimethylmethylene blue. The assay is based on the metachromatic shift in absorption maximum which occurs when the dye is complexed with sulfated glycosaminoglycans. The reagent is stable, and the method is substantially free from interference, is sensitive to less than 1 μg (4 μg/ml) of chondroitin sulfate, and provides a simple alternative to the traditional methods for glycosaminoglycan determinations.

Proteoglycan form and function: A comprehensive nomenclature of proteoglycans

2015-02-18

Renato V. Iozzo , Liliana Schaefer

We provide a comprehensive classification of the proteoglycan gene families and respective protein cores. This updated nomenclature is based on three criteria: Cellular and subcellular location, overall gene/protein homology, and … We provide a comprehensive classification of the proteoglycan gene families and respective protein cores. This updated nomenclature is based on three criteria: Cellular and subcellular location, overall gene/protein homology, and the utilization of specific protein modules within their respective protein cores. These three signatures were utilized to design four major classes of proteoglycans with distinct forms and functions: the intracellular, cell-surface, pericellular and extracellular proteoglycans. The proposed nomenclature encompasses forty-three distinct proteoglycan-encoding genes and many alternatively-spliced variants. The biological functions of these four proteoglycan families are critically assessed in development, cancer and angiogenesis, and in various acquired and genetic diseases where their expression is aberrant.

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Angiogenesis Induced by Degradation Products of Hyaluronic Acid

1985-06-14

David C. West , Ian Hampson , Frank Arnold +1 more

Partial degradation products of sodium hyaluronate produced by the action of testicular hyaluronidase induced an angiogenic response (formation of new blood vessels) on the chick chlorioallantoic membrane. Neither macromolecular hyaluronate … Partial degradation products of sodium hyaluronate produced by the action of testicular hyaluronidase induced an angiogenic response (formation of new blood vessels) on the chick chlorioallantoic membrane. Neither macromolecular hyaluronate nor exhaustively digested material had any angiogenic potential. Fractionation of the digestion products established that the activity was restricted to hyaluronate fragments between 4 and 25 disaccharides in length.

CD44 is the principal cell surface receptor for hyaluronate

1990-06-01

Alejandro Aruffo , Ivan Stamenkovic , Michael Melnick +2 more

New method for quantitative determination of uronic acids

1973-08-01

Nelly Blumenkrantz , G. Asboe‐Hansen

Hyaluronan: from extracellular glue to pericellular cue

2004-07-01

Bryan P. Toole

Molecular modeling of protein-glycosaminoglycan interactions.

1989-01-01

A D Cardin , Herschel J. R. Weintraub

Forty-nine regions in 21 proteins were identified as potential heparin-binding sites based on the sequence organizations of their basic and nonbasic residues. Twelve known heparin-binding sequences in vitronectin, apolipoproteins E … Forty-nine regions in 21 proteins were identified as potential heparin-binding sites based on the sequence organizations of their basic and nonbasic residues. Twelve known heparin-binding sequences in vitronectin, apolipoproteins E and B-100, and platelet factor 4 were used to formulate two search strings for identifying potential heparin-binding regions in other proteins. Consensus sequences for glycosaminoglycan recognition were determined as [-X-B-B-X-B-X-] and [-X-B-B-B-X-X-B-X-] where B is the probability of a basic residue and X is a hydropathic residue. Predictions were then made as to the heparin-binding domains in endothelial cell growth factor, purpurin, and antithrombin-III. Many of the natural sequences conforming to these consensus motifs show prominent amphipathic periodicities having both alpha-helical and beta-strand conformations as determined by predictive algorithms and circular dichroism studies. The heparin-binding domain of vitronectin was modeled and formed a hydrophilic pocket that wrapped around and folded over a heparin octasaccharide, yielding a complementary structure. We suggest that these consensus sequence elements form potential nucleation sites for the recognition of polyanions in proteins and may provide a useful guide in identifying heparin-binding regions in other proteins. The possible relevance of protein-glycosaminoglycans interactions in atherosclerosis is discussed.

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Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation.

1991-03-01

P S Linsley , William Brady , Laura S. Grosmaire +3 more

A successful immune response requires intercellular contact between T and B lymphocytes. We recently showed that CD28, a T cell surface protein that regulates an activation pathway, could mediate intercellular … A successful immune response requires intercellular contact between T and B lymphocytes. We recently showed that CD28, a T cell surface protein that regulates an activation pathway, could mediate intercellular adhesion with activated B cells by interaction with the B7 antigen. Here we show that CD28 is the primary receptor for B7 on activated peripheral blood T cells, that CD28 binds to B7 in the absence of other accessory molecules, and that interaction between CD28 and B7 is costimulatory for T cell activation. To characterize the binding of CD28 to B7, we have produced genetic fusions of the extracellular portions of B7 and CD28, and immunoglobulin (Ig) C gamma 1 chains. 125I-labeled B7 Ig bound to CD28-transfected Chinese hamster ovary (CHO) cells, and to immobilized CD28 Ig with a Kd approximately 200 nM. B7 Ig also inhibited CD28-mediated cellular adhesion. The function of CD28-B7 interactions during T cell activation was investigated with soluble fusion proteins and with B7-transfected CHO cells. Immobilized B7 Ig and B7+ CHO cells costimulated T cell proliferation. Stimulation of T cells with B7+ CHO cells also specifically increased levels of interleukin 2 transcripts. These results demonstrate that the CD28 signaling pathway could be activated by B7, resulting in increased T cell cytokine production and T cell proliferation. Cellular interactions mediated by B7 and CD28 may represent an important component of the functional interactions between T and B lymphoid cells.

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Role of extracellular matrix assembly in interstitial transport in solid tumors.

2000-05-01

Paolo A. Netti , David A. Berk , Melody A. Swartz +2 more

The extracellular matrix (ECM) may contribute to the drug resistance of a solid tumor by preventing the penetration of therapeutic agents. We measured differences in interstitial resistance to macromolecule (IgG) … The extracellular matrix (ECM) may contribute to the drug resistance of a solid tumor by preventing the penetration of therapeutic agents. We measured differences in interstitial resistance to macromolecule (IgG) motion in four tumor types and found an unexpected correspondence between transport resistance and the mechanical stiffness. The interstitial diffusion coefficient of IgG was measured in situ by fluorescence redistribution after photobleaching. Tissue elastic modulus and hydraulic conductivity were measured by confined compression of excised tissue. In apparent contradiction to an existing paradigm, these functional properties are correlated with total tissue content of collagen, not glycosaminoglycan. An extended collagen network was observed in the more penetration-resistant tumors. Collagenase treatment of the more penetration-resistant tumors significantly increased the IgG interstitial diffusion rate. We conclude that collagen influences the tissue resistance to macromolecule transport, possibly by binding and stabilizing the glycosaminoglycan component of the ECM. These findings suggest a new method to screen tumors for potential resistance to macromolecule-based therapy. Moreover, collagen and collagen-proteoglycan bonds are identified as potential targets of treatment to improve macromolecule delivery.

Biology of the Syndecans: A Family of Transmembrane Heparan Sulfate Proteoglycans

1992-11-01

Merton Bernfield , Robert Kokenyesi , Masato Kato +4 more

Cells organize many of their biochemical reactions in non-membrane compartments. Recent evidence has shown that many of these compartments are liquids that form by phase separation from the cytoplasm. Here … Cells organize many of their biochemical reactions in non-membrane compartments. Recent evidence has shown that many of these compartments are liquids that form by phase separation from the cytoplasm. Here we discuss the basic physical concepts necessary ...Read More

Endothelial cell-derived basic fibroblast growth factor: synthesis and deposition into subendothelial extracellular matrix.

1987-04-01

Israël Vlodavsky , Judah Folkman , Robert Sullivan +4 more

Bovine aortic and corneal endothelial cells synthesize a growth factor that remains mostly cell-associated but can also be extracted from the subendothelial extracellular matrix (ECM) deposited by these cells. The … Bovine aortic and corneal endothelial cells synthesize a growth factor that remains mostly cell-associated but can also be extracted from the subendothelial extracellular matrix (ECM) deposited by these cells. The endothelial cell-derived growth factors extracted from cell lysates and from the extracellular matrix appear to be structurally related to basic fibroblast growth factor by the criteria that they bind to heparin-Sepharose and are eluted at 1.4-1.6 M NaCl, have a molecular weight of about 18,400, cross-react with anti-basic fibroblast growth factor antibodies when analyzed by electrophoretic blotting and immunoprecipitation, and are potent mitogens for bovine aortic and capillary endothelial cells. It is suggested that endothelium can store growth factors capable of autocrine growth promotion in two ways: by sequestering growth factor within the cell and by incorporating it into the underlying extracellular matrix.

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LYVE-1, a New Homologue of the CD44 Glycoprotein, Is a Lymph-specific Receptor for Hyaluronan

1999-02-22

Suneale Banerji , Jian Ni , Shuxia Wang +5 more

The extracellular matrix glycosaminoglycan hyaluronan (HA) is an abundant component of skin and mesenchymal tissues where it facilitates cell migration during wound healing, inflammation, and em- bryonic morphogenesis. Both during … The extracellular matrix glycosaminoglycan hyaluronan (HA) is an abundant component of skin and mesenchymal tissues where it facilitates cell migration during wound healing, inflammation, and em- bryonic morphogenesis. Both during normal tissue homeostasis and particularly after tissue injury, HA is mobilized from these sites through lymphatic vessels to the lymph nodes where it is degraded before entering the circulation for rapid uptake by the liver. Currently, however, the identities of HA binding molecules which control this pathway are unknown. Here we describe the first such molecule, LYVE-1, which we have identified as a major receptor for HA on the lymph vessel wall. The deduced amino acid sequence of LYVE-1 predicts a 322-residue type I integral membrane polypeptide 41% similar to the CD44 HA receptor with a 212-residue extracellular domain containing a single Link module the prototypic HA binding domain of the Link protein superfamily. Like CD44, the LYVE-1 molecule binds both soluble and immobilized HA. However, unlike CD44, the LYVE-1 molecule colocalizes with HA on the luminal face of the lymph vessel wall and is completely absent from blood vessels. Hence, LYVE-1 is the first lymph-specific HA receptor to be characterized and is a uniquely powerful marker for lymph vessels themselves.

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Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer

2012-03-30

Michael A. Jacobetz , Derek Chan , Albrecht Neeße +7 more

<h3>Objective</h3> Pancreatic ductal adenocarcinoma (PDA) is characterised by stromal desmoplasia and vascular dysfunction, which critically impair drug delivery. This study examines the role of an abundant extracellular matrix component, the … <h3>Objective</h3> Pancreatic ductal adenocarcinoma (PDA) is characterised by stromal desmoplasia and vascular dysfunction, which critically impair drug delivery. This study examines the role of an abundant extracellular matrix component, the megadalton glycosaminoglycan hyaluronan (HA), as a novel therapeutic target in PDA. <h3>Methods</h3> Using a genetically engineered mouse model of PDA, the authors enzymatically depleted HA by a clinically formulated PEGylated human recombinant PH20 hyaluronidase (PEGPH20) and examined tumour perfusion, vascular permeability and drug delivery. The preclinical utility of PEGPH20 in combination with gemcitabine was assessed by short-term and survival studies. <h3>Results</h3> PEGPH20 rapidly and sustainably depleted HA, inducing the re-expansion of PDA blood vessels and increasing the intratumoral delivery of two chemotherapeutic agents, doxorubicin and gemcitabine. Moreover, PEGPH20 triggered fenestrations and interendothelial junctional gaps in PDA tumour endothelia and promoted a tumour-specific increase in macromolecular permeability. Finally, combination therapy with PEGPH20 and gemcitabine led to inhibition of PDA tumour growth and prolonged survival over gemcitabine monotherapy, suggesting immediate clinical utility. <h3>Conclusions</h3> The authors demonstrate that HA impedes the intratumoral vasculature in PDA and propose that its enzymatic depletion be explored as a means to improve drug delivery and response in patients with pancreatic cancer.

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Proteoglycans: many forms and many functions

1992-02-01

Tim Hardingham , Amanda Fosang

Proteoglycans are produced by most eukaryotic cells and are versatile components of pericellular and extracellular matrices. They belong to many different protein families. Their functions vary from the physical effects … Proteoglycans are produced by most eukaryotic cells and are versatile components of pericellular and extracellular matrices. They belong to many different protein families. Their functions vary from the physical effects of the proteoglycan aggrecan, which binds with link protein to hyaluronan to form multi-molecular aggregates in cartilage; to the intercalated membrane protein CD44 that has a proteoglycan form and is a receptor and a cell-binding site for hyaluronan; to heparan sulfate proteoglycans of the syndecan and other families that provide matrix binding sites and cell-surface receptors for growth factors such as fibroblast growth factor (FGF). One feature that recurs in proteoglycan biology is that their structure is open to extensive modulation during cellular expression. Examples of protein changes are known, but a major source of structural variation is in the glycosaminoglycan chains. The number of chains and their length can vary, as well as their pattern of sulfation. This may result in the switching of different chain types with different properties, e.g., chondroitin sulfate and heparan sulfate, and it may also result in the selective expression of sulfated chain sequences that have specific functions. The control of glycosaminoglycan structure is not well understood, but it does appear to be used to change the properties of proteoglycans to suit different biological needs. Proteoglycan forms of proteins are thus important modifiers of the organization of the pericellular and extracellular matrices and modulators of the processes that occur there.—Hardingham, T. E., Fosang, A. J. Protoglycans: many forms and many functions. FASEB J. 6: 861-870; 1992.

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Fibroblast growth factors, their receptors and signaling.

2000-09-01

Ciaran Powers , Sandra W. McLeskey , Anton Wellstein

Fibroblast growth factors (FGFs) are small polypeptide growth factors, all of whom share in common certain structural characteristics, and most of whom bind heparin avidly. Many FGFs contain signal peptides … Fibroblast growth factors (FGFs) are small polypeptide growth factors, all of whom share in common certain structural characteristics, and most of whom bind heparin avidly. Many FGFs contain signal peptides for secretion and are secreted into the extracellular environment, where they can bind to the heparan-like glycosaminoglycans (HLGAGs) of the extracellular matrix (ECM). From this reservoir, FGFs may act directly on target cells, or they can be released through digestion of the ECM or the activity of a carrier protein, a secreted FGF binding protein. FGFs bind specific receptor tyrosine kinases in the context of HLGAGs and this binding induces receptor dimerization and activation, ultimately resulting in the activation of various signal transduction cascades. Some FGFs are potent angiogenic factors and most play important roles in embryonic development and wound healing. FGF signaling also appears to play a role in tumor growth and angiogenesis, and autocrine FGF signaling may be particularly important in the progression of steroid hormone-dependent cancers to a hormone-independent state.

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Hyaluronan: its nature, distribution, functions and turnover

1997-07-01

J. R. E. Fraser , T.C. Laurent , U. B. G. Laurent

Fraser JRE, Laurent TC, Laurent UBG (Monash University, Clayton, Victoria, Australia; and University of Uppsala, Uppsala, Sweden). Hyaluronan: its nature, distribution, functions and turnover (Minisymposium: Hyaluronan). J Intern Med 1997; … Fraser JRE, Laurent TC, Laurent UBG (Monash University, Clayton, Victoria, Australia; and University of Uppsala, Uppsala, Sweden). Hyaluronan: its nature, distribution, functions and turnover (Minisymposium: Hyaluronan). J Intern Med 1997; 242 : 27–33. Hyaluronan is a polysaccharide found in all tissues and body fluids of vertebrates as well as in some bacteria. It is a linear polymer of exceptional molecular weight, especially abundant in loose connective tissue. Hyaluronan is synthesized in the cellular plasma membrane. It exists as a pool associated with the cell surface, another bound to other matrix components, and a largely mobile pool. A number of proteins, the hyaladherins, specifically recognize the hyaluronan structure. Interactions of this kind bind hyaluronan with proteoglycans to stabilize the structure of the matrix, and with cell surfaces to modify cell behaviour. Because of the striking physicochemical properties of hyaluronan solutions, various physiological functions have been assigned to it, including lubrication, water homeostasis, filtering effects and regulation of plasma protein distribution. In animals and man, the half‐life of hyaluronan in tissues ranges from less than 1 to several days. It is catabolized by receptor‐mediated endocytosis and lysosomal degradation either locally or after transport by lymph to lymph nodes which degrade much of it. The remainder enters the general circulation and is removed from blood, with a half‐life of 2–5 min, mainly by the endothelial cells of the liver sinuoids.

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MATRIX PROTEOGLYCANS: From Molecular Design to Cellular Function

1998-06-01

Renato V. Iozzo

The proteoglycan superfamily now contains more than 30 full-time molecules that fulfill a variety of biological functions. Proteoglycans act as tissue organizers, influence cell growth and the maturation of specialized … The proteoglycan superfamily now contains more than 30 full-time molecules that fulfill a variety of biological functions. Proteoglycans act as tissue organizers, influence cell growth and the maturation of specialized tissues, play a role as biological filters and modulate growth-factor activities, regulate collagen fibrillogenesis and skin tensile strength, affect tumor cell growth and invasion, and influence corneal transparency and neurite outgrowth. Additional roles, derived from studies of mutant animals, indicate that certain proteoglycans are essential to life whereas others might be redundant. The review focuses on the most recent genetic and molecular biological studies of the matrix proteoglycans, broadly defined as proteoglycans secreted into the pericellular matrix. Special emphasis is placed on the molecular organization of the protein core, the utilization of protein modules, the gene structure and transcriptional control, and the functional roles of the various proteoglycans. When possible, proteoglycans have been grouped into distinct gene families and subfamilies offering a simplified nomenclature based on their protein core design. The structure-function relationship of some paradigmatic proteoglycans is discussed in depth and novel aspects of their biology are examined.

Heparan Sulfate Proteoglycans

2011-06-20

Sandrine Sarrazin , William C. Lamanna , Jeffrey D. Esko

Stephane Sarrazin1, William C. Lamanna1 and Jeffrey D. Esko Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California 92093 Correspondence: … Stephane Sarrazin1, William C. Lamanna1 and Jeffrey D. Esko Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California 92093 Correspondence: jesko{at}ucsd.edu

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Order Out of Chaos: Assembly of Ligand Binding Sites in Heparan Sulfate

2002-06-01

Jeffrey D. Esko , Scott B. Selleck

▪ Abstract Virtually every cell type in metazoan organisms produces heparan sulfate. These complex polysaccharides provide docking sites for numerous protein ligands and receptors involved in diverse biological processes, including … ▪ Abstract Virtually every cell type in metazoan organisms produces heparan sulfate. These complex polysaccharides provide docking sites for numerous protein ligands and receptors involved in diverse biological processes, including growth control, signal transduction, cell adhesion, hemostasis, and lipid metabolism. The binding sites consist of relatively small tracts of variably sulfated glucosamine and uronic acid residues in specific arrangements. Their formation occurs in a tissue-specific fashion, generated by the action of a large family of enzymes involved in nucleotide sugar metabolism, polymer formation (glycosyltransferases), and chain processing (sulfotransferases and an epimerase). New insights into the specificity and organization of the biosynthetic apparatus have emerged from genetic studies of cultured cells, nematodes, fruit flies, zebrafish, rodents, and humans. This review covers recent developments in the field and provides a resource for investigators interested in the incredible diversity and specificity of this process.

Extracellular matrix and cell signalling: the dynamic cooperation of integrin, proteoglycan and growth factor receptor

2011-02-09

Soo‐Hyun Kim , Jeremy E. Turnbull , Scott E. Guimond

Extracellular matrices (ECM) are secreted molecules that constitute the cell microenvironment, composed of a dynamic and complex array of glycoproteins, collagens, glycosaminoglycans and proteoglycans. ECM provides the bulk, shape and … Extracellular matrices (ECM) are secreted molecules that constitute the cell microenvironment, composed of a dynamic and complex array of glycoproteins, collagens, glycosaminoglycans and proteoglycans. ECM provides the bulk, shape and strength of many tissues in vivo , such as basement membrane, bone and cartilage. In vitro , most animal cells can only grow when they are attached to surfaces through ECM. ECM is also the substrate for cell migration. However, ECM provides much more than just mechanical and structural support, with implications in developmental patterning, stem cell niches and cancer. ECM imparts spatial context for signalling events by various cell surface growth factor receptors and adhesion molecules such as integrins. The external physical properties of ECM may also have a role in the signalling process. ECM molecules can be flexible and extendable, and mechanical tension can expose cryptic sites, which could further interact with growth factors or their receptors. ECM proteins and structures can determine the cell behaviour, polarity, migration, differentiation, proliferation and survival by communicating with the intracellular cytoskeleton and transmission of growth factor signals. Integrins and proteoglycans are the major ECM adhesion receptors which cooperate in signalling events, determining the signalling outcomes, and thus the cell fate. This review focuses on the emerging concept of spatial cell biology of ECM, especially the current understanding of integrins and heparan sulphate proteoglycans as the essential cellular machineries that sense, integrate and respond to the physical and chemical environmental information either by directly connecting with the local adhesion sites or by regulating global cellular processes through growth factor receptor signalling pathways, leading to the integration of both external and internal signals in space and time.

Functions of Cell Surface Heparan Sulfate Proteoglycans

1999-06-01

Merton Bernfield , Martin Götte , Pyong Woo Park +4 more

▪ Abstract The heparan sulfate on the surface of all adherent cells modulates the actions of a large number of extracellular ligands. Members of both cell surface heparan sulfate proteoglycan … ▪ Abstract The heparan sulfate on the surface of all adherent cells modulates the actions of a large number of extracellular ligands. Members of both cell surface heparan sulfate proteoglycan families, the transmembrane syndecans and the glycosylphosphoinositide-linked glypicans, bind these ligands and enhance formation of their receptor-signaling complexes. These heparan sulfate proteoglycans also immobilize and regulate the turnover of ligands that act at the cell surface. The extracellular domains of these proteoglycans can be shed from the cell surface, generating soluble heparan sulfate proteoglycans that can inhibit interactions at the cell surface. Recent analyses of genetic defects in Drosophila melanogaster, mice, and humans confirm most of these activities in vivo and identify additional processes that involve cell surface heparan sulfate proteoglycans. This chapter focuses on the mechanisms underlying these activities and on the cellular functions that they regulate.

The biology and role of CD44 in cancer progression: therapeutic implications

2018-05-10

Chen Chen , Shujie Zhao , Anand B. Karnad +1 more

CD44, a non-kinase transmembrane glycoprotein, is overexpressed in several cell types including cancer stem cells and frequently shows alternative spliced variants that are thought to play a role in cancer … CD44, a non-kinase transmembrane glycoprotein, is overexpressed in several cell types including cancer stem cells and frequently shows alternative spliced variants that are thought to play a role in cancer development and progression. Hyaluronan, the main ligand for CD44, binds to and activates CD44 resulting in activation of cell signaling pathways that induces cell proliferation, increases cell survival, modulates cytoskeletal changes, and enhances cellular motility. The different functional roles of CD44 standard (CD44s) and specific CD44 variant (CD44v) isoforms are not fully understood. CD44v contain additional peptide motifs that can interact with and sequester growth factors and cytokines at the cell surface thereby functioning as coreceptors to facilitate cell signaling. Moreover, CD44v were expressed in metastasized tumors, whereas switching between CD44v and CD44s may play a role in regulating epithelial to mesenchymal transition (EMT) and in the adaptive plasticity of cancer cells. Here, we review current data on the structural and functional properties of CD44, the known roles for CD44 in tumorigencity, the regulation of CD44 expression, and the potential for targeting CD44 for cancer therapy.

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Perineuronal nets stabilize the grid cell network

2021-01-11

Ane Charlotte Christensen , Kristian Kinden Lensjø , Mikkel Elle Lepperød +5 more

Abstract Grid cells are part of a widespread network which supports navigation and spatial memory. Stable grid patterns appear late in development, in concert with extracellular matrix aggregates termed perineuronal … Abstract Grid cells are part of a widespread network which supports navigation and spatial memory. Stable grid patterns appear late in development, in concert with extracellular matrix aggregates termed perineuronal nets (PNNs) that condense around inhibitory neurons. It has been suggested that PNNs stabilize synaptic connections and long-term memories, but their role in the grid cell network remains elusive. We show that removal of PNNs leads to lower inhibitory spiking activity, and reduces grid cells’ ability to create stable representations of a novel environment. Furthermore, in animals with disrupted PNNs, exposure to a novel arena corrupted the spatiotemporal relationships within grid cell modules, and the stored representations of a familiar arena. Finally, we show that PNN removal in entorhinal cortex distorted spatial representations in downstream hippocampal neurons. Together this work suggests that PNNs provide a key stabilizing element for the grid cell network.

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Hyaluronan <sup>1</sup>

1992-04-01

Torvard C. Laurent , J. R. E. Fraser

Hyaluronan (hyaluronic acid) is a high-molecular-mass polysaccharide found in the extracellular matrix, especially of soft connective tissues. It is synthesized in the plasma membrane of fibroblasts and other cells by … Hyaluronan (hyaluronic acid) is a high-molecular-mass polysaccharide found in the extracellular matrix, especially of soft connective tissues. It is synthesized in the plasma membrane of fibroblasts and other cells by addition of sugars to the reducing end of the polymer, whereas the nonreducing end protrudes into the pericellular space. The polysaccharide is eatabolized locally or carried by lymph to lymph nodes or the general circulation, from where it is cleared by the endothelial cells of the liver sinusoids. The overall turnover rate is surprisingly rapid for a connective tissue matrix component (t½ 0.5 to a few days). Hyaluronan has been assigned various physiological functions in the intercellular matrix, e.g., in water and plasma protein homeostasis. Hyaluronan production increases in proliferating cells and the polymer may play a role in mitosis. Extensive hyaluronidase-sensitive coats have been identified around mesenchymal cells. They are either anchored firmly in the plasma membrane or bound via hyaluronan-specific binding proteins (receptors). Such receptors have now been identified on many different cells, e.g., the lymphocyte homing receptor CD 44. Interaction between a hyaluronan receptor and extracellular polysaccharide has been connected with locomotion and cell migration. Hyaluronan seems to play an important role during development and differentiation and has other cell regulatory activities. Hyaluronan has also been recognized in clinical medicine. A concentrated solution of hyaluronan (10 mg/ml) has, through its tissue protective and rheological properties, become a device in ophthalmic surgery. Analysis of serum hyaluronan is promising in the diagnosis of liver disease and various inflammatory conditions, e.g., rheumatoid arthritis. Interstitial edema caused by accumulation of hyaluronan may cause dysfunction in various organs.—Laurent, T. C.; Fraser, J. R. E. Hyaluronan. FASEB J. 6: 2397-2404; 1992.

Proteoglycans: Structures And Interactions

1991-01-01

Lena Kjellén

The Hippo pathway was initially discovered in Drosophila melanogaster as a key regulator of tissue growth. It is an evolutionarily conserved signaling cascade regulating numerous biological processes, including cell growth … The Hippo pathway was initially discovered in Drosophila melanogaster as a key regulator of tissue growth. It is an evolutionarily conserved signaling cascade regulating numerous biological processes, including cell growth and fate decision, organ size ...Read More

The Safety and Efficacy of Glucosamine and/or Chondroitin in Humans: A Systematic Review

2025-06-24

Kyrie Eleyson R. Baden , Sarah L. Hoeksema , Nathan Gibson +5 more | Nutrients

Background/Objectives: Glucosamine and chondroitin are natural substances often used alone or in combination for conditions affecting the joints. Our objective was to evaluate the efficacy and safety of glucosamine and/or … Background/Objectives: Glucosamine and chondroitin are natural substances often used alone or in combination for conditions affecting the joints. Our objective was to evaluate the efficacy and safety of glucosamine and/or chondroitin supplementation in humans as well as to determine the common dosages used. Methods: A systematic review was conducted using PRISMA methodology. Searches were performed in PubMed and Web of Science and uploaded into Covidence where two independent researchers reviewed articles according to inclusion and exclusion criteria. Quality assessment was performed using the Mixed Methods Appraisal Tool (MMAT). Results: Of the 2013 articles screened, 146 studies were included in our review, with nearly 60% being randomized controlled trials and most conducted in Europe, Asia, or the U.S. Most studies focused on osteoarthritis and joint pain, with over 90% of efficacy studies reporting positive outcomes and most safety studies indicating minimal or no adverse effects. Glucosamine and chondroitin were most commonly administered together at daily doses of 1500 mg and 1200 mg, respectively, and often compared to a placebo or celecoxib. Conclusions: Overall, the evidence suggests that glucosamine and chondroitin are generally effective and well-tolerated, particularly for managing osteoarthritis and joint pain. Consistent dosing strategies and favorable safety profiles across a diverse range of studies support their continued use in clinical practice, but further research is needed related to other disease states.

Elucidating the multifaceted role and therapeutic potential of Sulf-2 in human tumor biology

2025-06-22

Huanyan Peng , Man Liu , S. Liu +2 more | Biomarkers in Medicine

Sulf-2, a key member of the sulfatase family, regulated tumor progression, invasion, and metastasis through various mechanisms including genetic alterations, epigenetic modifications, transcriptional regulation, and microenvironmental influences. The dysregulation of … Sulf-2, a key member of the sulfatase family, regulated tumor progression, invasion, and metastasis through various mechanisms including genetic alterations, epigenetic modifications, transcriptional regulation, and microenvironmental influences. The dysregulation of Sulf-2 has been implicated as a pivotal driver in the development of numerous tumors. The lack of a comprehensive understanding of Sulf-2 enzymatic activities has limited the advancement of research progress, largely due to the intricate modulation of heparan sulfate (HS) biology by this enzyme. In this review, we will comprehensively discuss the structure, function, and regulatory mechanisms of Sulf-2, elucidated the mechanisms of Sulf-2 in different human-type tumors. Furthermore, we would summarize the potential applications and limitations of Sulf-2 as a target in combining therapies for human tumors, providing insights that could be instrumental in advancing targeted cancer treatments. Our comprehensive review will shed light on the multifaceted role and therapeutic potential of Sulf-2 in human tumor biology.

Matrix: a complex amalgam of structures and functions in tumor microenvironment

2025-06-21

Spyros S. Skandalis , Evgenia Tsoukala , Theodora D. Sarantopoulou +1 more | FEBS Open Bio

Cancer cells surrounded by a rich diversity of nonmalignant cell types are collectively embedded in the matrix, which is a dynamic, intricate three‐dimensional mesh of biomolecules with both structural and … Cancer cells surrounded by a rich diversity of nonmalignant cell types are collectively embedded in the matrix, which is a dynamic, intricate three‐dimensional mesh of biomolecules with both structural and functional properties. The matrix contains proteins, carbohydrates, and other glycoproteins that facilitate essential cellular communication and impact in various ways a broad spectrum of cellular functions, such as anchoring cells, guiding migration, and shaping signal gradients driving cell growth, apoptosis, survival, and differentiation. This review deals with the complexity of this amalgam of structures and functions and highlights the importance of the tumor microenvironment in the maintenance and evolution of tumors by describing certain bioactive macromolecules of the matrix, such as proteoglycans, hyaluronan, collagens, elastin, matricellular proteins as well as their cellular receptors like integrins and CD44.

Prognostic impact of syndecan‑1 expression and serum concentration in colorectal cancer

2025-06-19

Kakeru Tawada , Hirokatsu Hayashi , Masahide Endo +7 more | Oncology Letters

Anticoagulant Potential of Modified Sulfated Exopolysaccharides from Deep-Sea Bacteria: Toward Non-Animal Heparin Alternatives

2025-06-19

Antoine Babuty , Agata Zykwinska , Sergey A. Samsonov +7 more | Polysaccharides

Heparin, a widely used polysaccharidic anticoagulant of animal origin, is associated with risks of contamination and adverse effects, notably bleeding and thrombocytopenia. These limitations have prompted interest in alternative sulfated … Heparin, a widely used polysaccharidic anticoagulant of animal origin, is associated with risks of contamination and adverse effects, notably bleeding and thrombocytopenia. These limitations have prompted interest in alternative sulfated polysaccharides with anticoagulant properties and improved safety profiles. This study explored the anticoagulant potential of two marine bacterial exopolysaccharides (EPS), infernan and diabolican. It assessed whether chemical modifications (depolymerization, oversulfation) could enhance their anticoagulant properties compared to unfractionated and low molecular weight heparins. Native EPS were depolymerized to generate different molecular weights and then chemically oversulfated to increase negative charge density. Anticoagulant activities were evaluated using clotting and thrombin generation assays (TGA). Molecular docking was performed to model interactions with antithrombin and heparin cofactor II. Only highly sulfated derivatives significantly prolonged activated partial thromboplastin time while showing negligible effect on thrombin time and anti-factor Xa activity. They present different structures, and their binding to antithrombin is not achieved via the classic pentasaccharide motif. In TGA, these derivatives inhibited thrombin formation at higher doses than heparin but induced a marked delay in clot generation. Docking analyses supported their ability to bind serpins, albeit with lower specificity than heparin. Their limited anti-Xa activity and non-animal origin position them as promising anticoagulant candidates.

Postoperative Loss of Perineuronal Nets in the Hippocampal CA1 Region Results in Memory Consolidation Deficits

2025-06-19

Zhouyan Feng , Jiang‐Nan Wu , Guicheng Wang +5 more | Brain Research Bulletin

Postoperative cognitive dysfunction (POCD) is a common postoperative neurological complication, with memory consolidation deficits being one of its prominent features. However, the mechanisms underlying postoperative memory consolidation deficits are still … Postoperative cognitive dysfunction (POCD) is a common postoperative neurological complication, with memory consolidation deficits being one of its prominent features. However, the mechanisms underlying postoperative memory consolidation deficits are still unclear. The perineuronal net (PNN) is a specialized extracellular matrix that predominantly surrounds parvalbumin (PV) interneurons and is closely associated with cognitive functions, including learning and memory. Theta oscillations in the hippocampal CA1 region are crucial for memory consolidation. However, the relationships among postoperative memory consolidation deficits, theta oscillation abnormalities, and PNNs remain unclear. The aim of this study was to investigate the role of PNNs in the CA1 region in postoperative memory consolidation deficits and theta oscillation abnormalities. The experiments revealed that, after anesthesia and surgery, the mice exhibited memory consolidation deficits, abnormal theta oscillations, and PNNs loss in the hippocampal CA1 region. Increasing the density of PNNs alleviated postoperative memory consolidation deficits and theta oscillation abnormalities. In contrast, normal mice treated with chondroitinase ABC (ChABC) to degrade PNNs presented a similar phenotype of postoperative memory consolidation deficits. Further investigations revealed that PNNs loss in surgical mice weakened the inhibitory function of PV interneurons. Increase the density of PNNs reversed these changes, while ChABC degradation of PNNs also weakened the inhibitory function of PV interneurons. Notably， PNNs loss after surgery was associated with increased microglial phagocytosis. In conclusion, the PNNs loss caused by increased microglial phagocytosis in the hippocampal CA1 region after surgery palys an important role in postoperative memory consolidation deficits and theta oscillation abnormalities, which is associated with the impaired function of PV interneurons. This study provides new theoretical insights and potential targets for preventing and treating postoperative memory consolidation deficits.

Hyaluronan accumulation is associated with reduced hyaluronidase expression in renal cell carcinoma, with <scp>CD44</scp>, <scp>HAS1</scp>, and <scp>HYAL2</scp> emerging as prognostic markers

2025-06-18

Otto Jokelainen , Teemu Rintala , Satu Remes +3 more | The Journal of Pathology Clinical Research

Abstract Hyaluronan (HA), a large extracellular matrix glycosaminoglycan, is associated with malignant features in several human cancers. The accumulation of HA in renal cell carcinomas (RCC) correlates with unfavorable outcomes, … Abstract Hyaluronan (HA), a large extracellular matrix glycosaminoglycan, is associated with malignant features in several human cancers. The accumulation of HA in renal cell carcinomas (RCC) correlates with unfavorable outcomes, higher tumor grade, and more advanced disease stages. However, the mechanisms responsible for HA buildup in these neoplasms remain unclear, and studies on the expression of hyaluronan‐metabolizing and ‐degrading enzymes are either lacking or conflicting. This study aims to address this knowledge gap. Formalin‐fixed paraffin‐embedded (FFPE) RCC samples of various histological subtypes from 315 patients were immunohistochemically stained for CD44 (the main receptor of HA), hyaluronan‐synthesizing enzymes HAS1–3, and degrading enzymes HYAL1–2. Protein expression levels were correlated with clinicopathological variables and their prognostic significance was evaluated. Additionally, the mRNA expression levels of these proteins were examined using RNA extracted from the same samples and publicly available data from the cancer genome atlas (TCGA). CD44 protein expression was associated with increased tumoral HA content, poor prognosis, higher tumor grade, advanced stage, and sarcomatoid/rhabdoid changes. HYAL1 and HYAL2 protein levels were reduced in HA‐positive tumors, and low HYAL2 expression predicted worse prognosis. Elevated HAS2 protein expression was associated with poor differentiation, while low HAS1 protein levels were associated with reduced survival. mRNA levels of CD44 and HYAL2 correlated with their respective protein expression levels, and CD44 mRNA expression was also associated with HA content. In RCC, HA accumulation appears to be primarily driven by decreased degradation. HAS1 and HYAL2 were identified as novel prognostic biomarkers. These findings provide new insights into HA metabolism in RCC and open potential avenues for better understanding and management of these tumors.

Blocking the functional domain of cancer cell surface TIP1 upregulates Midkine via the β-catenin/Wnt signaling pathway

2025-06-18

Minakshi Saikia , Harendra K. Shah , Dennis E. Hallahan +2 more | Cancer Gene Therapy

Dermatan sulfate regulates apoptosis and osteogenic differentiation of hBMSCs through estrogen-like effects

2025-06-18

Junyan Cai , Zili Sun , Qing Yang +2 more | International Journal of Biological Macromolecules

Simultaneous determination of sodium hyaluronate and gluconolactone in cosmetic products

2025-06-17

S. Ramachandra Shetty , Richa Mehta , R. Paul Choudhury | International Journal of Cosmetic Science

Abstract Objective The increasing prevalence of sodium hyaluronate and gluconolactone in a wide range of cosmetic formulations has created a crucial need for robust and reliable analytical methods to ensure … Abstract Objective The increasing prevalence of sodium hyaluronate and gluconolactone in a wide range of cosmetic formulations has created a crucial need for robust and reliable analytical methods to ensure product quality, optimize formulations and meet regulatory standards. Sodium hyaluronate and gluconolactone, two highly sought‐after humectants renowned for their remarkable water‐binding properties, present significant analytical challenges during quantification. Sodium hyaluronate, a complex polymeric structure, lacks a UV‐absorbing chromophore and gluconolactone needs an indirect technique (derivatization/conversion to gluconic acid) to be quantified, which makes these analyses quite challenging in cosmetic products. Method This study directly addresses this critical gap in cosmetic analysis by developing and validating a novel method for the simultaneous determination of sodium hyaluronate and gluconolactone in cosmetic compositions. This method employs size exclusion liquid chromatography (SEC), a powerful separation technique ideal for analysing polymers and macromolecules, coupled with sensitive UV detection. Using a BioSep SEC S2000 column and an isocratic mobile phase of 0.05 M potassium dihydrogen phosphate (pH 7.0), we achieved efficient separation and detection at 205 nm, enabling the quantification of both compounds despite the absence of strong chromophores. Results Rigorous method validation confirmed the reliability and robustness of this approach. The method demonstrated excellent linearity ( r 2 > 0.999) over a wide concentration range of 25–1000 μg/mL for both sodium hyaluronate and gluconolactone, ensuring accurate quantification across diverse formulation concentrations. Additionally, high precision (RSD ≤1.22%), specificity against common cosmetic excipients and satisfactory recovery rates (80%–120%) further validate the method's suitability for routine quality control analysis in the cosmetic industry. Conclusion This sensitive, accurate and robust SEC‐UV method provides a valuable new tool for cosmetic manufacturers to ensure the quality, efficacy and consumer safety of products containing these key ingredients.

Pharmacological aspects of hyaluronic acid metabolism: A review

2025-06-17

Е. Н. Карева , Sergey V. Donskov | GYNECOLOGY

Hyaluronic acid (HA) is a key component of the extracellular matrix involved in regulating inflammation, fibrosis, and tissue repair. Its biological properties depend on molecular weight: high-molecular-weight HA (HMW-HA) exhibits … Hyaluronic acid (HA) is a key component of the extracellular matrix involved in regulating inflammation, fibrosis, and tissue repair. Its biological properties depend on molecular weight: high-molecular-weight HA (HMW-HA) exhibits anti-inflammatory effects, whereas low-molecular-weight fragments (LMW-HA) induce inflammation and fibrosis by activating CD44, TLR, and RHAMM receptors. An imbalance between these forms may contribute to chronic inflammatory and fibrotic processes. HA metabolism is regulated by synthases (HAS) and hyaluronidases (HYAL). During chronic inflammation, HYAL-2 degrades HMW-HA into LMW-HA, which accumulates and sustains the inflammatory response. Native hyaluronidase preparations have limited efficacy due to rapid inactivation. Conjugation of the enzyme with azoximer enhances its resistance to inhibitors and proteases while prolonging its action. Bovhyaluronidase azoximer (Longidaza) breaks down pro-inflammatory LMW-HA into safe ultra-low-molecular-weight fragments, suppressing inflammation and fibrosis. The drug is active in the acidic environment of inflamed tissues without damaging healthy tissue. Its anti-fibrotic and anti-adhesive properties have been confirmed experimentally and clinically. Clinical studies demonstrate the drug’s efficacy in various fields: preventing postoperative adhesions, treating fibrotic changes in pulmonology, and correcting scars in dermatology. Thus, modulation of HA metabolism using conjugated hyaluronidase represents a promising approach for managing chronic inflammatory and fibrotic conditions.

High and Low Molecular Weight Hyaluronic Acid Affect the Expression of Surface Molecules by Monocytes Stimulated with Porphyromonas gingivalis In vitro

2025-06-16

Edson Costa e Silva , Hércules Henrique Onibene Castro , Luara Isabela dos Santos +7 more | Archives of Current Research International

Aims: Hyaluronic acid (HA) has been used as an adjunct in the treatment of periodontal disease. HA molecules of different molecular weights act on different cell types, inducing differentiation, activation, … Aims: Hyaluronic acid (HA) has been used as an adjunct in the treatment of periodontal disease. HA molecules of different molecular weights act on different cell types, inducing differentiation, activation, migration, and production of inflammatory mediators. The aim of this study was to evaluate the effect of low (LMWHA) and high (HMWHA) molecular weight HA on the expression of costimulatory molecules and toll-like receptors by monocyte subpopulations stimulated in vitro with Porphyromonas gingivalis (Pg). Study Design: In vitro experimental study. Place and Duration of Study: Laboratory of Biology and Immunology of Infectious and Parasitic Diseases, Instituto René Rachou, Fiocruz Minas, between 2018 and 2019. Methodology: Peripheral blood mononuclear cells (PBMCs) from 10 donors were stimulated with Pg during 1 hour and then incubated with 0.2% LMWHA or HMWHA for another sixteen hours. Immunostaining and flow cytometry were performed for detection of CD40, CD80, CD86, HLA-DR, TLR2 and TLR4 expression by CD14+ monocytes and subpopulations of classical (CD14+CD16-) and non-classical/intermediate monocytes (CD14+CD16+). Results: LMWHA or HMWHA increased TLR2 and reduced TLR4 expression, but did not affect CD40, CD80, CD86 or HLA-DR in total and classical monocytes. Considering Pg-stimulated cells, HMWHA increased the expression of CD40, HLA-DR and TLR2 in non-classical/intermediate monocytes. Conclusion: The effect of HA used topically in the periodontal tissues seems to directly involve modulation of surface molecules responsible for cell signaling and control of periodontal immunoinflammatory processes.

Targeting <scp>CA2</scp> Perineuronal Nets Restores Recognition Memory and Theta Oscillations in Aged Mice

2025-06-16

Sonam Fathima Mehak , Apoorva Bettagere Shivakumar , Feyba Jijimon +3 more | Aging Cell

ABSTRACT Remembering familiar versus novel stimuli is fundamental to survival, but it is compromised in several neurodegenerative disorders where aging is a key factor. Although the components of the extracellular … ABSTRACT Remembering familiar versus novel stimuli is fundamental to survival, but it is compromised in several neurodegenerative disorders where aging is a key factor. Although the components of the extracellular matrix (ECM) have been suggested to be implicated in memory maintenance, the mechanistic and behavioral roles of ECM during the aging process remain unclear. Here, we employed an accelerated mouse model of aging to elucidate the causal link between ECM dynamics and recognition memory during aging. Aged mice exhibited impaired social and non‐social recognition memory, accompanied by increased intensity of perineuronal nets (PNNs), specialized ECM structures in the hippocampal dorsal CA2 (dCA2). A reduction in the power of theta oscillations (3–7 Hz) in the dCA2 of aged mice was also observed. Notably, selective degradation of PNNs in the dCA2 using chondroitinase ABC (ChABC) rescued recognition memory deficits and restored theta oscillations. Together, our findings identify abnormal PNN in the CA2 as a critical factor for age‐related deficits in hippocampal‐dependent recognition memory and network rhythmicity. These insights raise the possibility that targeting CA2 PNNs could facilitate the development of diagnostic and therapeutic strategies to address age‐associated cognitive frailty.

Applications of Hyaluronic acid and its derivatives in advanced drug delivery system: A future direction

2025-06-15

Suryakanta Swain , Apala Chakraborty | Indian Journal of Pharmacy and Pharmacology

Applications of Surface Plasmon Resonance in Heparan Sulfate Interactome Research

2025-06-14

P.K. Datta , Jonathan S. Dordick , Fuming Zhang | Biomedicines

Surface plasmon resonance (SPR) is a powerful tool for analyzing biomolecular interactions and is widely used in basic biomedical research and drug discovery. Heparan sulfate (HS) is a linear complex … Surface plasmon resonance (SPR) is a powerful tool for analyzing biomolecular interactions and is widely used in basic biomedical research and drug discovery. Heparan sulfate (HS) is a linear complex polysaccharide and a key component of the extracellular matrix and cell surfaces. HS plays a pivotal role in maintaining cellular functions and tissue homeostasis by interacting with numerous proteins, making it essential for normal physiological processes and disease states. Deciphering the interactome of HS unlocks the mechanisms underlying its biological functions and the potential for novel HS-related therapeutics. This review presents an overview of the recent advances in the application of SPR technology to HS interactome research. We discuss methodological developments, emerging trends, and key findings that illustrate how SPR is expanding our knowledge of HS-mediated molecular interactions. Additionally, we highlight the potential of SPR-based approaches in identifying novel therapeutic targets and developing HS-mimetic drugs, thereby opening new avenues for intervention in HS-related diseases.

Defining the extracellular matrix for targeted immunotherapy in adult and pediatric brain cancer

2025-06-14

Zoe I. Day , Samuel Roberts-Thomson , Yasmin Nouri +7 more | npj Precision Oncology

Abstract High-grade gliomas (HGGs), including glioblastoma (GBM) and pediatric diffuse midline gliomas (DMGs), remain highly fatal despite therapeutic advances. The tumor microenvironment (TME), particularly the extracellular matrix (ECM), plays a … Abstract High-grade gliomas (HGGs), including glioblastoma (GBM) and pediatric diffuse midline gliomas (DMGs), remain highly fatal despite therapeutic advances. The tumor microenvironment (TME), particularly the extracellular matrix (ECM), plays a crucial role in tumor progression, immune exclusion, and drug resistance. We performed a comprehensive proteomic, transcriptomic, and pathological characterization of the ECM in primary adult and pediatric HGGs. Using cell surface proteomics, TCGA transcriptomics, and immunohistochemistry, we identified key ECM components influencing immune infiltration. We integrated these findings into ImmunoTar , a computational model prioritizing immunotherapeutic targets. Our study presents the first in-depth cell surface proteomic landscape of HGG ECM, identifying CSPG4/5, PTPRZ1, SDC1, TGFBR3, PLG, and GPC2 as key targets. We validate ECM-targeted CAR T cell therapy, including Glypican-2 (GPC2), which shows strong efficacy against pediatric DIPG. These findings highlight ECM-focused immunotherapy as a promising strategy to overcome HGGs’ immunosuppressive TME, particularly in pediatric patients.

Electrostatically enhanced host-guest complexation: a fluorescence platform for highly sensitive detection of heparin

2025-06-14

Yu Liu , Maolin Lu , Yutian Jiao +4 more | International Journal of Biological Macromolecules

Recombinant Small Leucine-Rich Proteoglycans Modulate Fiber Structure and Mechanical Properties of Collagen Gels

2025-06-13

Serafina G. Lopez , Henrique Reis Moura , Erik Chow +3 more | ACS Biomaterials Science & Engineering

Collagen is a key extracellular matrix protein found in connective tissues. The structure and organization of collagen fibers play a crucial role in determining tissue function and how tissues respond … Collagen is a key extracellular matrix protein found in connective tissues. The structure and organization of collagen fibers play a crucial role in determining tissue function and how tissues respond to mechanical loads. Small leucine-rich proteoglycans (SLRPs) are well-known facilitators of collagen fibrillogenesis in connective tissues. While the role of SLRPs has been extensively documented in tissues such as tendon and skin, their functions are primarily inferred from changes observed in knockout models. Additionally, their specific roles and influences of their addition to a system, particularly in collagen gel-based materials, remain underexplored. Previous in vitro studies of SLRPs have been partly limited by the challenges associated with obtaining pure SLRPs in sufficient quantities and with appropriate glycosylation. Therefore, novel methods to reliably produce SLRPs at the required quality and scale are needed. In this study, we first evaluated the feasibility of producing recombinant decorin, biglycan, and fibromodulin using HEK293-F cells. Subsequently, we investigated the effect of SLRP supplementation on high-density collagen gels using scanning electron microscopy and assessed the impact on tensile properties. Our findings demonstrated that each SLRP uniquely influenced collagen structure at both the fibril and fiber levels, consequently modifying the tissues' mechanical response to load. Decorin, in particular, exhibited significant differences in tensile properties compared to biglycan and fibromodulin, underscoring its distinct role in promoting a structurally and mechanically robust response under tensile load.

Abstract P5-08-25: Inhibiting Breast Cancer Metastasis by Targeting Chemokine-Glycosaminoglycan Interactions

2025-06-13

Mohammed Imad Malki , Ibrahim Elmakaty , Amr Ouda | Clinical Cancer Research

Abstract Breast cancer exhibits a specific metastatic pattern potentially influenced by the interaction between the chemokine receptor CCR7 on breast cancer cells and its ligand CCL21, which is expressed at … Abstract Breast cancer exhibits a specific metastatic pattern potentially influenced by the interaction between the chemokine receptor CCR7 on breast cancer cells and its ligand CCL21, which is expressed at metastatic sites. Glycosaminoglycans (GAGs) on endothelial cell surfaces bind chemokines and are thought to be critical in presenting chemokines to responsive cancer cells. This study aimed to test the hypothesis that soluble GAG molecules, such as heparinoids, can disrupt the normal presentation of CCL21, potentially reducing metastasis of CCR7-expressing breast cancer cells. Human breast cancer samples were analyzed for the expression of CCR7, CCL21, and GAG, correlating this expression with tumor grade. The cytokines IFN-γ and TNF-α were found to influence the endothelial cell GAG’s ability to present chemokines to passing cancer cells. Both GAG-expressing Chinese Hamster Ovary (CHO) cells and GAG-deficient mutant CHO cells were transfected with CCR7, and their intracellular calcium flux and chemotactic migration were assayed in response to CCL21 and heparinoid. It was discovered that GAG expression by the responding cells was not essential for chemokine receptor activation. However, heparinoids, including Low Molecular Weight Heparins, effectively blocked the binding of 125I-CCL21 to a monolayer of GAG-expressing CCR7 transfectants, inhibiting both CCR7 ligation and subsequent signaling. Further experiments with CCR7-expressing MDA-MB-231 breast cancer cells demonstrated that heparinoids significantly inhibited the chemotactic response within a CCL21 diffusion gradient. Additionally, heparin and both low and high doses of Tinzaparin treatment in SCID mice, at clinically relevant dosages, prevented both the number and area of metastases following intravenous injection of MDA-MB-231 cells. These findings suggest that heparinoids inhibit the interaction between CCL21 and CCR7 and may serve as effective agents to prevent breast cancer metastasis. Citation Format: Mohammed Imad Malki, Ibrahim Elmakaty, Amr Ouda. Inhibiting Breast Cancer Metastasis by Targeting Chemokine-Glycosaminoglycan Interactions [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-08-25.

Chitosan Hydrogels Enriched with Biocompounds Extracted from Marine Sponges: Potential to Modulate the Inflammatory Process in an <i>In Vitro</i> Study

2025-06-12

Mirian Bonifácio , Cintia Cristina Santi Martignago , Dalete Christine S. Souza +7 more | ACS Omega

Targeting inflammatory macrophages with hyaluronan tetrasaccharide: effects on fibroblast collagen degradation and synthesis

2025-06-05

Eiko Uno , Florence Kim , Mihoko Yoshino +5 more | Frontiers in Immunology

Hyaluronan (HA) provides moisturizing benefits and exhibits unique biological activities based on its molecular weight. While the anti-inflammatory effects of high-molecular-weight HA have been well studied, the impact of hyaluronan … Hyaluronan (HA) provides moisturizing benefits and exhibits unique biological activities based on its molecular weight. While the anti-inflammatory effects of high-molecular-weight HA have been well studied, the impact of hyaluronan tetrasaccharide (HA4), an ultralow-molecular-weight HA, on the skin immune system is not fully understood. Thus, we investigated how HA4 affects the differentiation of M1 macrophages, which increase during photoaging. As a result, we added HA4 during the M1 macrophage differentiation phase and conducted a gene expression analysis. HA4 partially decreased the transition from M0 to M1 macrophages and reduced the expression of proinflammatory cytokines like IL-6. However, the M2 marker IL-1ra increased, while IL-10 levels remained constant, suggesting that HA4 does not fully polarize macrophages toward the M2 phenotype. Normal human dermal fibroblasts (NHDF) were treated with an M1 macrophage-conditioned medium (M1-CM) and a modified version containing HA4 (M1+HA4-CM). The M1+HA4-CM notably decreased the expression of IL-6 and IL-8, along with the collagen-degrading enzyme MMP1. Collagen synthesis assays showed that HA4 helped restore collagen fiber formation. Moreover, RNA-seq analysis of NHDF treated with the conditioned medium confirmed that M1+HA4-CM amplified the expression of genes related to collagen production while decreasing collagen-degrading enzyme gene expression. Neutralization assays employing a TLR4 antibody suggested that decreasing IL-6 in NHDF by HA4 may be independent of the TLR4 signaling pathway. HA4 is vital in partially suppressing M1 macrophage differentiation and the release of inflammatory factors, as well as regulating collagen remodeling in NHDF. These findings indicate that HA4 holds promise as a molecule for mitigating inflammation-induced collagen degradation by modulating macrophage activity in photoaged skin.

Alician Blue Staining in Histological Assessment of Acid Mucopolysaccharides in Salivary Gland Tumors: A Diagnostic Perspective

2025-06-01

Amit K. Srivastava , Anand Srivastava , Surendra Jain +3 more | Journal of Pharmacy And Bioallied Sciences

A BSTRACT Background: Acid mucopolysaccharides (AMPs) are essential components of extracellular matrices and play a significant role in salivary gland tumors. Their differential expression can provide diagnostic insights into tumor … A BSTRACT Background: Acid mucopolysaccharides (AMPs) are essential components of extracellular matrices and play a significant role in salivary gland tumors. Their differential expression can provide diagnostic insights into tumor behavior. Alician Blue (AB) staining has emerged as a reliable histochemical technique for detecting AMPs, offering enhanced visualization. This study aims to evaluate the utility of AB staining in identifying AMPs across benign and malignant salivary gland tumors, providing a novel diagnostic perspective. Materials and Methods: A total of 60 salivary gland tumor samples were analyzed, including 30 benign (e.g., pleomorphic adenoma) and 30 malignant (e.g., mucoepidermoid carcinoma, adenoid cystic carcinoma) cases. Formalin-fixed, paraffin-embedded sections were stained using AB at pH 2.5 to specifically detect AMPs. The intensity of staining was graded on a 0–3 scale: 0 (no staining), 1 (mild), 2 (moderate), and 3 (intense). The distribution of AMPs was compared between benign and malignant groups using a Chi-square test, with a P value < 0.05 considered statistically significant. Results: Benign salivary gland tumors predominantly showed mild to moderate staining (Grade 1–2), with 80% (24/30) of the cases demonstrating moderate AMP accumulation. In contrast, malignant tumors exhibited intense staining (Grade 3) in 73% (22/30) of cases. The staining intensity in malignant tumors was significantly higher ( P < 0.01) than in benign counterparts. Additionally, adenoid cystic carcinoma demonstrated diffuse and intense AMP staining, while mucoepidermoid carcinoma exhibited focal, high-intensity AMP deposits. Conclusion: AB staining at pH 2.5 is a valuable tool for assessing AMPs in salivary gland tumors, offering diagnostic distinction between benign and malignant lesions. The higher AMP expression in malignant tumors suggests its potential role in tumor aggressiveness and progression. Incorporating AB staining in routine histological evaluation could enhance diagnostic accuracy, particularly in differentiating complex tumor subtypes.

Development of a multifunctional, injectable biomaterial using hyaluronan as a bioactive nanocarrier

2025-06-01

Louis S. Paone , Ying Jin , Julien Bouyer +2 more | Biomaterials