Terminal fucose mediates progression of human cholangiocarcinoma through EGF/EGFR activation and the Akt/Erk signaling pathway.

Aberrant glycosylation is recognized as a cancer hallmark that is associated with cancer development and progression. In this study, the clinical relevance and significance of terminal fucose (TFG), by fucosyltransferase-1 (FUT1) in carcinogenesis and progression of cholangiocarcinoma (CCA) were demonstrated. TFG expression in human and hamster CCA tissues were determined using Ulex europaeus agglutinin-I (UEA-I) histochemistry. Normal bile ducts rarely expressed TFG while 47% of CCA human tissues had high TFG expression and was correlated with shorter survival of patients. In the CCA-hamster model, TFG was elevated in hyperproliferative bile ducts and gradually increased until CCA was developed. This evidence indicates the involvement of TFG in carcinogenesis and progression of CCA. The mechanistic insight was performed in 2 CCA cell lines. Suppression of TFG expression using siFUT1 or neutralizing the surface TFG with UEA-I significantly reduced migration, invasion and adhesion of CCA cells in correlation with the reduction of Akt/Erk signaling and epithelial-mesenchymal transition. A short pulse of EGF could stimulate Akt/Erk signaling via activation of EGF-EGFR cascade, however, decreasing TFG using siFUT1 or UEA-I treatment reduced the EGF-EGFR activation and Akt/Erk signaling. This evidence provides important insight into the relevant role and molecular mechanism of TFG in progression of CCA.

Diversity in recognition of glycans by F-type lectins and galectins: molecular, structural, and biophysical aspects.

Although lectins are "hard-wired" in the germline, the presence of tandemly arrayed carbohydrate recognition domains (CRDs), of chimeric structures displaying distinct CRDs, of polymorphic genes resulting in multiple isoforms, and in some cases, of a considerable recognition plasticity of their carbohydrate binding sites, significantly expand the lectin ligand-recognition spectrum and lectin functional diversification. Analysis of structural/functional aspects of galectins and F-lectins-the most recently identified lectin family characterized by a unique CRD sequence motif (a distinctive structural fold) and nominal specificity for l-Fuc-has led to a greater understanding of self/nonself recognition by proteins with tandemly arrayed CRDs. For lectins with a single CRD, however, recognition of self and nonself glycans can only be rationalized in terms of protein oligomerization and ligand clustering and presentation. Spatial and temporal changes in lectin expression, secretion, and local concentrations in extracellular microenvironments, as well as structural diversity and spatial display of their carbohydrate ligands on the host or microbial cell surface, are suggestive of a dynamic interplay of their recognition and effector functions in development and immunity.

Fucans, but not fucomannoglucuronans, determine the biological activities of sulfated polysaccharides from Laminaria saccharina brown seaweed.

Sulfated polysaccharides from Laminaria saccharina (new name: Saccharina latissima) brown seaweed show promising activity for the treatment of inflammation, thrombosis, and cancer; yet the molecular mechanisms underlying these properties remain poorly understood. The aim of this work was to characterize, using in vitro and in vivo strategies, the anti-inflammatory, anti-coagulant, anti-angiogenic, and anti-tumor activities of two main sulfated polysaccharide fractions obtained from L. saccharina: a) L.s.-1.0 fraction mainly consisting of O-sulfated mannoglucuronofucans and b) L.s.-1.25 fraction mainly composed of sulfated fucans. Both fractions inhibited leukocyte recruitment in a model of inflammation in rats, although L.s.-1.25 appeared to be more active than L.s.-1.0. Also, these fractions inhibited neutrophil adhesion to platelets under flow. Only fraction L.s.-1.25, but not L.s.-1.0, displayed anticoagulant activity as measured by the activated partial thromboplastin time. Investigation of these fractions in angiogenesis settings revealed that only L.s.-1.25 strongly inhibited fetal bovine serum (FBS) induced in vitro tubulogenesis. This effect correlated with a reduction in plasminogen activator inhibitor-1 (PAI-1) levels in L.s.-1.25-treated endothelial cells. Furthermore, only parent sulfated polysaccharides from L. saccharina (L.s.-P) and its fraction L.s.-1.25 were powerful inhibitors of basic fibroblast growth factor (bFGF) induced pathways. Consistently, the L.s.-1.25 fraction as well as L.s.-P successfully interfered with fibroblast binding to human bFGF. The incorporation of L.s.-P or L.s.-1.25, but not L.s.-1.0 into Matrigel plugs containing melanoma cells induced a significant reduction in hemoglobin content as well in the frequency of tumor-associated blood vessels. Moreover, i.p. administrations of L.s.-1.25, as well as L.s.-P, but not L.s.-1.0, resulted in a significant reduction of tumor growth when inoculated into syngeneic mice. Finally, L.s.-1.25 markedly inhibited breast cancer cell adhesion to human platelet-coated surfaces. Thus, sulfated fucans are mainly responsible for the anti-inflammatory, anticoagulant, antiangiogenic, and antitumor activities of sulfated polysaccharides from L. saccharina brown seaweed.

Effect of N-acetyl-D-glucosamine on bovine sperm-oocyte interactions.

N-Acetyl-D-glucosamine (GlcNAc) is a major component of glycosaminoglycan, which is involved in sperm-oocyte interactions. We examined the effect of adding GlcNAc and other monosaccharides, D-mannose and D-fucose, to the in vitro fertilization (IVF) medium on bovine sperm-oocyte interactions. In medium in which sperm and a zona pellucida (ZP) were co-incubated with monosaccharides for 5 min, addition of GlcNAc (5 or 25 mM) significantly reduced the number of sperm that attached to the ZP. Pretreatment of gametes with GlcNAc (5 mM) prior to co-incubation also suppressed sperm-ZP attachment. Addition of GlcNAc (5 or 25 mM) to the medium in which sperm and a ZP were co-incubated for 5 h, however, significantly increased the number of sperm binding to and penetrating the ZP in a concentration-related manner. The other monosaccharides, D-fucose and D-mannose, did not have this effect. Supplementation of the sperm-oocyte co-incubation medium with 5 mM GlcNAc also enhanced the rate of polyspermic fertilization. When the ZPs were removed from the oocytes, GlcNAc did not affect the fertilization rate. Furthermore, incubation of sperm with 5 mM GlcNAc induced sperm membrane destabilization and an acrosome reaction, as evidenced by the hypo-osmotic swelling test and fluorescein isothiocyanate-labeled peanut agglutinin/propidium iodide (FITC-PNA/PI) staining. Finally, GlcNAc suppressed ZP hardening following fertilization, as determined by measuring the time required for pronase to dissolve the ZP. In conclusion, supplementation of IVF medium with GlcNAc has various effects on sperm-oocyte interactions including suppression of initial attachment, induction of sperm membrane destabilization and acrosome reaction, increase in the number of sperm secondarily bound to and penetrating the ZP, suppression of ZP hardening following sperm-oocyte co-incubation and increase in the rate of polyspermic fertilization.

Expression of senescence-associated beta-galactosidase (SA-beta-Gal) by human skin fibroblasts, effect of advanced glycation end-products and fucose or rhamnose-rich polysaccharides.

Expression by cells of the SA-beta-Gal was shown to be a reliable indicator of the switch mechanism used by cells to enter the senescent phenotype. We used this method in order to explore the variation of SA-beta-Gal-positive cells with passage number and time spent in culture. Both parameters produced an increase of SA-beta-Gal-positive cells. The addition of a Maillard-product (advanced glycation end-product=AGE) to the fibroblast cultures also increased SA-beta-Gal expression. Fucose- and rhamnose-rich oligo- and polysaccharides (FROPs and RROPs, respectively) provided a significant protection against this AGE-induced increase of SA-beta-Gal-positive cells. It is speculated that these processes might well play an important role in skin aging.

Alterations in human breast cancer adhesion-motility in response to changes in cell surface glycoproteins displaying alpha-L-fucose moieties.

Glycosylation of proteins plays multiple roles in cell-cell and cell-matrix interactions. Fucose is a monosaccharide associated with glycosylation events and is known to be over-expressed in many malignant tumors. By using alpha-L-fucosidase (alpha-L-fase), a glycosidase that specifically removes alpha-L-fucose (alpha-L-f), we have examined the potential effects of defucosylation on tumor functions, focusing on tumor progression in the context of the interaction of tumor cells with the extracellular microenvironment. In this submission, we report that alpha-L-fase treatment decreases, in static assays, tumor cell adhesion to a wide variety of ECM components including fibronectin, laminin, collagen I, hyaluronic acid and the complex human biomatrix, HuBiogel(R). By immunofluorescence, co-localization of beta1 integrin and alpha-L-f was found to decrease accordingly. Sialyl Lewis X, an alpha-L-f-containing tetrasaccharide, which modulates the rolling of leukocytes and tumor cells on endothelium, was found to be diminished on human breast cancer cells after alpha-L-fase treatment. Using a dynamic flow chamber system, we were able to determine that defucosylation impaired the rolling of mammary cancer cells on human umbilical vein endothelial cells while significantly increasing their flow speed. Further, the rolling capability of these defucosylated tumor cells was also impaired on purified E and P-selectin matrices. Based on these data, we hypothesize that decreased fucosylation impairs the interaction between tumor cells and their external milieu, which in turn, affects key cell functions modulating tumor progression. Building on our previous studies which demonstrated alpha-L-fase decreased tumor cell invasion while significantly reducing MMP-9 activity, when added to the fact that decreased adhesion on HUVEC occurs in the presence of alpha-L-fase also leads us to propose that defucosylation may modulate metastasis, and thus provides a promising additional glycobiotic target for novel therapies.

Roles of Pofut1 and O-fucose in mammalian Notch signaling.

Mammalian Notch receptors contain 29-36 epidermal growth factor (EGF)-like repeats that may be modified by protein O-fucosyltransferase 1 (Pofut1), an essential component of the canonical Notch signaling pathway. The Drosophila orthologue Ofut1 is proposed to function as both a chaperone required for stable cell surface expression of Notch and a protein O-fucosyltransferase. Here we investigate these dual roles of Pofut1 in relation to endogenous Notch receptors of Chinese hamster ovary and murine embryonic stem (ES) cells. We show that fucosylation-deficient Lec13 Chinese hamster ovary cells have wild type levels of Pofut1 and cell surface Notch receptors. Nevertheless, they have reduced binding of Notch ligands and low levels of Delta1- and Jagged1-induced Notch signaling. Exogenous fucose but not galactose rescues both ligand binding and Notch signaling. Murine ES cells lacking Pofut1 also have wild type levels of cell surface Notch receptors. However, Pofut1-/- ES cells do not bind Notch ligands or exhibit Notch signaling. Although overexpression of fucosyltransferase-defective Pofut1 R245A in Pofut1-/- cells partially rescues ligand binding and Notch signaling, this effect is not specific. The same rescue is achieved by an unrelated, inactive, endoplasmic reticulum glucosidase. Therefore, mammalian Notch receptors require Pofut1 for the generation of optimally functional Notch receptors, but, in contrast to Drosophila, Pofut1 is not required for stable cell surface expression of Notch. Importantly, we also show that, under certain circumstances, mammalian Notch receptors are capable of signaling in the absence of Pofut1 and O-fucose.

Characterization and role of fucose mutarotase in mammalian cells.

L-Fucose for mammalian glycosylation contains an anomeric carbon atom generating alpha- and beta-L-fucoses. Based on sequence comparison of mouse and human homologs with the prokaryotic fucose mutarotases (FucU) characterized previously, we investigated their function in mammalian cells. By nuclear magnetic resonance (NMR) measurement with saturation difference analysis, the purified mammalian mutarotases were demonstrated to be involved in an interconversion between the two anomeric forms with comparable efficiency as that of the Escherichia coli FucU. The mouse gene was widely expressed in various tissues and cell lines, including kidney, liver, and pancreas, although expression was marginal in muscle and testis. By generating stably expressed cell lines for mutarotase genes in HepG2, it was shown that fucose incorporations into cellular proteins were increased as demonstrated by an incorporation of radiolabeled fucose into the cells. Furthermore, intracellular levels of GDP-L-fucose, measured with high performance liquid chromatography (HPLC), were enhanced by an overproduction of cellular mutarotase, which was reversed by gene silencing of mutarotase based on RNA interference. The results suggest that the mammalian mutarotase is functional in facilitated incorporation of fucose through the salvage pathway.

Roles of O-fucosyltransferase 1 and O-linked fucose in notch receptor function.

O-fucosyltransferase 1 (Ofut1) is a soluble endoplasmic reticulum protein that directly transfers fucose onto serine or threonine residues of EGF domain-containing proteins such as Notch receptors. Genetic analysis indicates that Ofut1 is essential for Notch receptor activation. To explore the molecular basis for the absolute requirement of Ofut1 for Notch function, biochemical and cell biological approaches were used. Ligand-binding assay revealed that Ofut1 is essential for Notch receptors to physically interact with their ligands. In addition, secretion assay and cell surface staining showed that secretion of Notch receptors is impaired in OFUT1-depleted cells, indicating that the structure of Notch receptors is altered. Interestingly, promotion of Notch secretion by OFUT1 does not require its enzyme activity. Together with the fact that OFUT1 physically associates with Notch and that OFUT1 prevents misfolding of Notch mutants, it is proposed that OFUT1 acts as a chaperone that promotes the folding of the EGF repeat of Notch receptors. This chapter focuses on the methods used to analyze the roles of Ofut1 in Notch receptor structure and function.

Roles of O-fucose glycans in notch signaling revealed by mutant mice.

Notch receptor signaling is important for many developmental processes in the metazoa. Insights into how Notch receptor signaling is regulated have been obtained from the characterization of mutants of model organisms in which Notch signaling is perturbed. Here we describe the effects of mutations that alter the glycosylation of Notch receptors and Notch ligands in the mouse. The extracellular domain of Notch receptors and Notch ligands carries N-glycans and O-glycans, including O-fucose and O-glucose glycans. Mutations in several genes that inhibit the synthesis of O-fucose glycans, and one that also affects the maturation of N-glycans, cause Notch signaling defects and disrupt development.

Low molecular weight fucan prevents transplant coronaropathy in rat cardiac allograft model.

INTRODUCTION: Transplant arteriosclerosis is the main cause of long-term failure after cardiac transplantation. Vascular rejection is thought to be due to intimal proliferation occurring in response to arterial wall immune-mediated injury. A low molecular weight fucan (LMWF) compound, a sulfated polysaccharide, has been demonstrated to increase plasma levels of stromal cell-derived factor 1 (SDF-1) and consequently to mobilize bone marrow-derived vascular progenitor cells (BMVPC). The aim of this study was to evaluate the capacity of LMWF to prevent coronary intimal proliferation in a rat cardiac allograft model. METHODS: Heterotopic abdominal cardiac graftings were performed in Brown Norway (BN) and Lewis (LEW) rats. Animals were divided into 4 groups of 10 rats. Two groups were treated intramuscularly with LMWF (5 mg/kg/day) (one BN to BN isograft group, and one BN to LEW allograft group); and two control groups were LMWF-untreated (one BN to BN isograft group and one BN to LEW allograft group). All animals were treated by cyclosporin (15 mg/kg/day) sub-cutaneously and sacrificed at day 30. The cardiac grafts were assessed by morphometry of structural parameters and by histological and immunohistochemical analyses. RESULTS: All cardiac isografts were devoid of any coronary and parenchymal lesions. In contrast, the majority of untreated allografts developed coronary intimal proliferation in close association with intimal and adventitial inflammatory CD68(+) cell infiltration. Further, the parenchyma exhibited large areas of actin(+) cells (myofibroblasts) of recipient origin colocalized with the CD68(+) infiltrating cells. Interestingly, all LMWF-treated allografts were well protected against coronary and parenchymal lesions and the coronary arteries exhibited an intimal monolayer of flat cells, which however were CD34 negative. CONCLUSION: treatment with LMWF appeared very effective in this rat cardiac allograft model to prevent arterial and parenchymal lesions occurring in response to alloimmune injury. However this protective effect does not appear to depend on mobilization of bone marrow-derived cells.

Core fucosylation regulates epidermal growth factor receptor-mediated intracellular signaling.

alpha1,6-Fucosyltransferase (Fut8) catalyzes the transfer of a fucose residue to N-linked oligosaccharides on glycoproteins via an alpha1,6-linkage to form core fucosylation in mammals. We recently found that disruption of the Fut8 gene induces severe growth retardation and early postnatal death. To investigate the molecular mechanism involved, we have established embryonic fibroblasts of Fut8+/+ and Fut8-/-, derived from wild-type and Fut8-null mice, respectively. Interestingly, the epidermal growth factor (EGF)-induced phosphorylation levels of the EGF receptor (EGFR) were substantially blocked in Fut8-/- cells, compared with Fut8+/+ cells, while there are no significant changes in the total activities of tyrosine phosphatase for phosphorylated EGFR between two cells. The inhibition of EGFR phosphorylation was completely restored by re-introduction of the Fut8 gene to Fut8-/- cells. Consistent with this, EGFR-mediated JNK or ERK activation was significantly suppressed in Fut8-/- cells. Finally, we found that the core fucosylation of N-glycans is required for the binding of the EGF to its receptor, whereas no effect was observed for the expression levels of EGFR on the cell surface. Collectively, these results strongly suggest that core fucosylation is essential for EGF receptor-mediated biological functions.

A role for fucose alpha(1-2) galactose carbohydrates in neuronal growth.

We report a fucose alpha(1-2) galactose-mediated pathway for the modulation of neuronal growth and morphology. Our studies provide strong evidence for the presence of Fucalpha(1-2)Gal glycoproteins and lectin receptors in hippocampal neurons. Additionally, we show that manipulation of Fucalpha(1-2)Gal-associated proteins using small-molecule and lectin probes induces dramatic changes in neuronal morphology. These findings may provide a novel pathway to stimulate neuronal growth and regeneration.

Role of glycosylation in development.

Researchers have long predicted that complex carbohydrates on cell surfaces would play important roles in developmental processes because of the observation that specific carbohydrate structures appear in specific spatial and temporal patterns throughout development. The astounding number and complexity of carbohydrate structures on cell surfaces added support to the concept that glycoconjugates would function in cellular communication during development. Although the structural complexity inherent in glycoconjugates has slowed advances in our understanding of their functions, the complete sequencing of the genomes of organisms classically used in developmental studies (e.g., mice, Drosophila melanogaster, and Caenorhabditis elegans) has led to demonstration of essential functions for a number of glycoconjugates in developmental processes. Here we present a review of recent studies analyzing function of a variety of glycoconjugates (O-fucose, O-mannose, N-glycans, mucin-type O-glycans, proteoglycans, glycosphingolipids), focusing on lessons learned from human disease and genetic studies in mice, D. melanogaster, and C. elegans.

The roles of terminal sugar residues of surface glycans in the metastatic potential of human hepatocarcinoma.

PURPOSE: The roles of terminal sialyl and fucosyl residues in cell surface glycans in the metastatic potential of H7721 cells, a human hepatocarcinoma cell line, were studied. METHODS: Neuraminidase and alpha-L-fucosidase were used to remove the sialyl and fucosyl residues, respectively. Cell adhesion to fibronectin (Fn), laminin (Ln), and human umbilical vein epithelial cell (HUVEC), as well as chemotactic cell migration and invasion, were selected as the parameters of metastatic potential ex vivo. RESULTS: Sialyl residue is not essential for cell adhesion to Fn, but is important in cell adhesion to Ln and invasion, and is crucial in cell adhesion to HUVEC and migration. In contrast, fucosyl residue contributes more than sialyl residue to cell adhesion to Fn and Ln, but less to adhesion to HUVEC, and is not essential in chemotactic cell migration and invasion. Cell adhesion to HUVEC, migration, and invasion were inhibited by the monoclonal antibody of sialyl Lewis X, but not by the antibody of non-sialyl Lewis X. CONCLUSION: Terminal sialyl residues on cell surface glycans are more important than fucosyl residues in mediating cell adhesion to HUVEC and cell migration/invasion, but the reverse is true in cell adhesion to Fn and Ln.

CD11b/CD18-dependent interactions of neutrophils with intestinal epithelium are mediated by fucosylated proteoglycans.

CD11b/CD18-mediated adhesive interactions play a key role in regulating polymorphonuclear leukocytes (PMN)) migration across intestinal epithelium. However, the identity of epithelial ligands for migrating PMN remains obscure. In this study we investigated the role of carbohydrates in mediating adhesive interactions between T84 intestinal epithelial cells and CD11b/CD18 purified from PMN. Fucoidin, heparin/heparin sulfate, N-acetyl-D-glucosamine, mannose-6-phosphate, and laminarin were found to inhibit adhesion of T84 cells to CD11b/CD18. The most potent inhibitory effects were observed with fucoidin (50% inhibition at 1-5 x 10(-8) M). Binding assays demonstrated that fucoidin directly bound to CD11b/CD18 in a divalent cation- and sulfation-dependent fashion that was blocked by anti-CD11b mAbs. Experiments employing CD11b/CD18 as a probe to blot T84 cell fucosylated proteins purified via fucose-specific lectin column revealed several candidate CD11b/CD18 binding proteins with molecular masses of 95, 50, 30, 25, and 20 kDa. Fucosidase treatment of T84 cells resulted in significantly reduced cell adhesion to CD11b/CD18, while no inhibition was observed after neuraminidase treatment. Finally, significant inhibition of T84 cell adhesion to CD11b/CD18 was observed after blocking cell proteoglycan synthesis with p-nitrophenyl-beta-D-xylopyranoside. These findings implicate epithelial cell surface proteoglycans decorated with sulfated fucose moieties as ligands for CD11b/CD18 during PMN migration across mucosal surfaces.

Regulation of elastase-type endopeptidase activity, MMP-2 and MMP-9 expression and activation in human dermal fibroblasts by fucose and a fucose-rich polysaccharide.

Tissue loss during ageing and age-dependent pathologies are the result of a disturbed regulation of proteolytic activities. Elastase-type endopeptidases, especially MMP-2 and -9, play an important role in this respect. Dermal fibroblast cultures and skin explant cultures were used in order to measure the efficiency of fucose and fucose-rich polysaccharides to downregulate the elastase-type endopeptidase activity. Fucose and fucose-rich polysaccharides were shown to downregulate this elastase-type activity, the basic activity and also the hyaluronan or kappa-elastin-stimulated activity. In skin explant cultures, we could demonstrate that fucose and fucose-rich polysaccharides produced an inhibition of the activation of the pro-form to the active form of MMP-9. Here, we show that mono-, di-, oligo- and polysaccharides acting on the elastin-laminin receptor and/or on the fucose-mannose receptor are efficient inhibitors of such enzymes by downregulating elastase-type endopeptidase activity, both at the level of their biosynthesis and at the level of the activation of the pro-enzymes. Fucose and fucose-rich polysaccharide preparations were shown to be efficient modulators of MMP-2 and MMP-9, activity with potential therapeutic applications in age-related pathologies accompanied by tissue loss.

Fucose in alpha(1-6)-linkage regulates proliferation and histogenesis in reaggregated retinal spheroids of the chick embryo.

We have used the lectin from Aleuria aurantia (AAL) which is highly specific for alpha(1-6)-linked fucose, to examine its effect on chicken retinogenesis in a reaggregation culture system. When dispersed cells of the embryonic chick retina are reaggregated to form histotypic retinospheroids, AAL elicits strong inhibition of spheroid growth. The action of AAL is specific, since its effect is dose-dependent, saturable, and inhibited by an excess of fucose. Fucosidase treatment entirely abolishes reaggregation. In contrast, Anguilla anguilla agglutinin (AAA) binding to fucose in alpha(1-2)-linkage does not show any effects. Incubation with CAB4-a specific monoclonal antibody for fucose in alpha(1-6)-linkage-reduces spheroid size and shape. AAL does not much affect primary aggregation, but rather subsequent processes of cell proliferation and histogenesis. In particular, AAL inhibits uptake of bromo-desoxyuridine (BrdU), most efficiently so during days in vitro 2 (div2) and div3. As a consequence, the histological differentiation is entirely disturbed, as evidenced by vimentin immunostaining; particularly, rosettes are not forming and the radial glia scaffold is disorganized. We conclude that glycoproteins exhibiting fucose in alpha(1-6)-linkage may play major roles in early processes of retinal tissue formation.

Effect of biochemical components on rheologic properties of nasal mucus in chronic sinusitis.

The effect of biochemical components on the viscoelasticity of nasal mucus from 24 patients with chronic sinusitis (CS) was investigated by multiple stepwise regression analysis. The dynamic viscosity (eta') and the elastic modulus (G') of nasal mucus were determined with an oscillating sphere magnetic rheometer at oscillatory frequencies of 1 and 10 Hz. The eta' and G' values of mucus determined at 1 Hz were 1.6 +/- 1.5 Pa/s and 31.8 +/- 31.0 Pa, respectively, and these values were much higher than optimal viscoelasticity for mucociliary transport. The concentrations of fucose, N-acetyl neuraminic acid, albumin, IgG, secretory-IgA, and lysozyme were measured in the same mucus samples. The multiple regression analysis showed that the concentration of fucose, a marker of mucous glycoproteins, was the most important determinant of eta' and G'. The analysis also revealed that the level of IgG was the next important determinant. The coefficients of multiple determination for fucose and IgG were 0.732 and 0.733 when the response variables were eta' and G', respectively. The results indicate that locally produced mucous glycoproteins may largely contribute to the high viscoelasticity of nasal mucus in CS.

Alpha-L-fucose: a potentially critical molecule in pathologic processes including neoplasia.

Alpha-L-fucose is a 6-carbon deoxyhexose that is commonly incorporated into human glycoproteins and glycolipids. It is found at the terminal or preterminal positions of many cell-surface oligosaccharide ligands that mediate cell-recognition and adhesion-signaling pathways. These include such normal events as early embryologic development and blood group recognition and pathologic processes including inflammation, infectious disease recognition, and neoplastic progression. Fucosylated oligosaccharide ligands mediate cell-cell adhesion through binding to cell-surface selectins (calcium-dependent binding proteins) and calcium-dependent interactions with other cell-surface carbohydrate counterligands. A number of fucose-containing "natural ligands" are common to inflammatory and malignant cell processes. We review evidence that alpha-L-fucose is critically important for cell-cell and cell-matrix adhesion in a variety of normal and pathologic processes, particularly neoplasia. Current results suggest that alpha-L-fucose provides the essential structure that enables carbohydrate ligands to bind to selectins and to carbohydrate counterligands and thereby alter cellular homeostasis.