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PubMed2006

Amino- and glycoconjugates of pyrido[4,3,2-kl]acridine. Synthesis, antitumor activity, and DNA binding.

A series of amino- and glycoconjugates of pyrido[4,3,2-kl]acridine and pyrido[4,3,2-kl]acridin-4-one have been prepared. The most active molecules, the amino conjugates 7 and 11, display a cytostatic activity against HT-29 cancer cells at micromolar concentration. This activity correlates well with a strong DNA binding. The molecules, amino or glycoconjugates, bind DNA by intercalation, the amino or glyco substituent being located in one groove. None of the molecules inhibits topoisomerase activity.

Acridines↗
PubMed2004

0,2An cross-ring cleavage as a general diagnostic tool for glycan assignment in glycoconjugate mixtures.

In contrast to proteomics significantly less efficient analytical tools are presently available for high throughput glycomics using mass spectrometry. In this article, a strategy to use the (0,2)A(n) ring cleavage ion at the reducing end of free glycans as a diagnostic ion for assignment of free glycans, in presence of glycopeptides containing similar glycosylation patterns, is presented for rapid distinction in complex mixtures by mass spectrometry. The MS to MS/MS automatic switching, already previously introduced for the on-line LC-MS and CE-MS analysis, is shown in this contribution to be highly functional to obtain diagnostic fragmentation patterns of free glycan precursors in rapid screening of highly complex glycoconjugate mixtures obtained from clinical samples, namely from the urine of patients suffering from congenital disorders of glycosylation. Congenital disorders of glycosylation (CDG) are inherited metabolic diseases based on defects in the glycosylation pathways of glycoconjugates. The urine of CDG patients was reported to contain O-glycans and glycosylated amino acids at concentrations two to three orders of magnitude higher in comparison with the healthy control, characterized by a high degree of heterogeneity concerning the type, number, and values of molecular ions. Using the (0,2)A(n) ring cleavage ion approach by tandem MS, it was possible to sort out free glycans and get them assigned.

Glycopeptides↗
PubMed2005

Cellular uptake and photocytotoxicity of glycoconjugated chlorins in HeLa cells.

Eight 5,10,15,20-tetrakis[3- or 4-(beta-D-glycopyranosyloxy)phenyl]chlorins were synthesized by means of the Whitlock method with diimide reduction and purified by reversed-phase thin layer chromatography (RP-TLC). All compounds were characterized by (1)H NMR spectroscopy, electron-spray ionization time-of-flight mass spectrometry (ESI-TOF MS), and UV-Vis spectroscopy. ESI-TOF MS could detect the 2H difference in molecular weight between a glycoconjugated chlorin and its corresponding porphyrin (i.e., 5,10,15,20-tetrakis[3- or 4-(beta-D-glycopyranosyloxy)phenyl]porphyrin). The cellular uptake of the eight chlorins was evaluated in HeLa cells. All glycoconjugated chlorins showed higher cellular uptake than tetraphenylporphyrin tetrasulfonic acid (TPPS), and 5,10,15,20-tetrakis[3-(beta-D-xylopyranosyloxy)phenyl]chlorin showed 50-fold higher uptake than TPPS. The photocytotoxicity of 5,10,15,20-tetrakis[3-(beta-D-glucopyranosyloxy)phenyl]chlorin, 5,10,15,20-tetrakis[3-(beta-D-xylopyranosyloxy)phenyl]chlorin and TPPS towards HeLa cells was examined at the concentration of 2x10(-7) M (mol/dm(3)). These photosensitizers had no cytotoxicity in the dark, but their photocytotoxicity decreased in the order of 5,10,15,20-tetrakis[3-(beta-D-glucopyranosyloxy)phenyl]chlorin>5,10,15,20-tetrakis[3-(beta-D-xylopyranosyloxy)phenyl]chlorin>TPPS. The results indicate that the photocytotoxicity is not related simply to cellular uptake.

Biological Transport↗
PubMed1982

Purification and properties of antibodies having specificity for the carbohydrate moieties of synthetic glycoconjugates.

Three types of antibodies having specificity for carbohydrate moieties of glycoconjugate antigens have been isolated from the sera of rabbits immunized with vaccines of beta-D-glucosyl-bovine serum albumin, beta-D-galactosyl-bovine serum albumin, or beta-lactosyl-bovine serum albumin. The antibodies were isolated by affinity chromatography on adsorbents bearing appropriate carbohydrate ligands. The antibody types are specific for the beta-D-glucosyl, beta-D-galactosyl, or beta-lactosyl groups of the synthetic glycoconjugates. The specificities have been established by data on hapten-inhibition, agar-diffusion, periodate-oxidation, and affinity-chromatography experiments. Each antibody type is of the IgG class of immunoglobulins and is of uniform molecular size, with molecular weight of 1.5 X 10(5). Data from gel-isoelectrofocusing experiments showed that each preparation of antibodies, although specific for identical determinant groups of the same antigen, nevertheless consisted of a set of different proteins. The anti-D-glucose antibodies consisted of five proteins, the anti-D-galactose antibodies of eleven proteins, and the anti-lactose antibodies of seventeen proteins. The suggestion has been made earlier that the members of such a set of antibodies, in which each member is induced by the same determinant group of an antigen and each member combines with this group in the precipitin reaction, be called isoantibodies.

Animals↗
PubMed1987

Effect of vitamin A on glycoconjugate: synthesis in the trabecular meshwork. A preliminary report.

We studied the effect of vitamin A on glycoconjugate synthesis in trabecular meshwork (TM) cells in vivo. The aqueous flow system of two cats and one monkey was exposed in vivo to retinoic acid dissolved in dimethyl sulfoxide (DMSO). One hour prior to enucleation, [3H]glucosamine was injected into all eyes. The tissue was subsequently processed for autoradiography. The density of grains (grains micron-2) in the vitamin A-treated eyes of Cats I and II was 77% and 30% less, respectively, than the density of grains in the control eyes. In the monkey the grain density was 56% less in the experimental eye compared with the control eye. These data suggest that exogenous vitamin A suppresses glycoconjugate synthesis in TM cells in vivo.

Animals↗
PubMed2001

Immunogenicity in mice of pneumococcal glycoconjugate vaccines using pneumococcal protein carriers.

Antibody response and protective immunity were evaluated in mice immunized with pneumococcal glycoconjugate vaccines using two pneumococcal protein carriers. Mice injected with type 9V polysaccharide (PS) conjugated to inactivated pneumolysin (Ply) or autolysin (Aly) produced high levels of IgG and IgM antibodies to both the PS and the protein carrier. Higher PS antibody titers to the pneumococcal PS conjugates were measured by ELISA using PS-Ply or PS-tetanus toxoid (TT) conjugate as a coating antigen compared with PS mixed with methylated human serum albumin. Type 9V PS (10 microg) inhibited most of the 9V IgM and IgG antibody binding to the 9V-TT coated plate. In contrast, absorption with 19F PS did not inhibit 9V antibody binding. The avidity index of IgG antibodies in the 9V PS-Ply serum was 55.5 +/- 0.9, compared with 47.8 +/- 1.4 for 9V PS-Aly serum. Thus, high avidity of serum antibodies in conjugate-immunized mice can provide more effective functional activity for protection against pneumococcal infection. Mice immunized with these glycoconjugates exhibited rapid bacterial clearance from blood and provided cross-protection against challenge with heterologous serotypes of virulent pneumococci. These results reveal that conjugates using pneumococcal protein carriers can induce opsonophagocytic activity to destroy homologous and heterologous pneumococci, indicating that such conjugates can confer broader protective immunity than conjugates using non-pneumococcal proteins.

Animals↗
PubMed1999

Isolation and cytotoxic properties of a novel glycoconjugate from corms of saffron plant (Crocus sativus L.).

A novel glycoconjugate isolated from saffron corm extracts shows remarkable cytotoxic activity on cultured human cancer cells (HeLa). Its polysaccharide part represents 94.5% of the molecule, and is dominated by a 36.4% of rhamnose. The protein backbone is composed mainly of aspartic acid/asparagine, alanine, glutamic acid/glutamine, glycine and serine. HeLa cells exposed to this glycoconjugate showed swelling and local plasma membrane evaginations, suggesting that cytotoxicity is mediated by extracellular fluid uptake.

Amino Acids↗
PubMed1999

Developmental patterns and neuropsychological assessment in patients with carbohydrate-deficient glycoconjugate syndrome type IA (phosphomannomutase deficiency).

Carbohydrate-deficient glycoconjugate (CDG) syndrome type I due to phosphomannomutase deficiency (CDGIA) is the most common among a group of metabolic disorders characterized by a defective glycosylation of glycoconjugates. Clinically it is a multisystem disease with an important involvement of the central nervous system including pontocerebellar atrophy. Here the developmental patterns and results of neuropsychological assessment of four young adults with CDGIA syndrome are reported. The patients, aged 14-26 years, had classical clinical findings of CDGIA syndrome and olivopontocerebellar atrophy of severe degree. They had a marked delay in all areas of psychomotor development and gained to walk with aid, perform manipulative abilities and develop a communicative language after the 7th year. Later on, the acquired abilities remained stable, while self-help skills gradually improved, allowing the patients to join the family life. On neuropsychological assessment, there was mental retardation of variable degree with a special impairment of visuoperceptual skills, visuospatial organization, eye-hand coordination, verbal memory and language. Such findings, may be partially explained by the supratentorial atrophy in our patients and add more evidences to the role of the cerebellum and brainstem in the acquisition of non-motor cognitive functions. This study expands our understanding on the clinical spectrum of CDGIA syndrome and may be helpful for planning rehabilitation and education.

Adolescent↗
PubMed1999

Immunogenic glycoconjugates implicated in parasitic nematode diseases.

Parasitic nematodes infect billions of people world-wide, often causing chronic infections associated with high morbidity. The greatest interface between the parasite and its host is the cuticle surface, the outer layer of which in many species is covered by a carbohydrate-rich glycocalyx or cuticle surface coat. In addition many nematodes excrete or secrete antigenic glycoconjugates (ES antigens) which can either help to form the glycocalyx or dissipate more extensively into the nematode's environment. The glycocalyx and ES antigens represent the main immunogenic challenge to the host and could therefore be crucial in determining if successful parasitism is established. This review focuses on a few selected model systems where detailed structural data on glycoconjugates have been obtained over the last few years and where this structural information is starting to provide insight into possible molecular functions.

Animals↗
PubMed1999

Glycoconjugates in Leishmania infectivity.

Leishmaniasis is a major health problem to humans and is caused by one of the world's major pathogens, the Leishmania parasite. These protozoa have the remarkable ability to avoid destruction in hostile environments they encounter throughout their life cycle. That Leishmania parasites have adapted to not only survive, but to proliferate largely is due to the protection conferred by unique glycoconjugates that are either on the parasites' cell surface or secreted. Most of these specialized molecules are members of a family of phosphoglycans while others are a family of glycosylinositol phospholipids. Together they have been implicated in a surprisingly large number of functions for the parasites throughout their life cycle and, therefore, are key players in their pathogenesis. This review summarizes the biological roles of these glycoconjugates and how they are believed to contribute to Leishmania survival in destructive surroundings.

Animals↗
PubMed2000

Absence of lipophosphoglycan-like glycoconjugates in Entamoeba dispar.

Invasive amoebiasis is the result of infection of Entamoeba histolytica. The closely related Entamoeba dispar can colonize the human gut but does not cause invasive disease. In this study, E. dispar was analysed for the presence of the lipophosphoglycan-like (LPG) glycoconjugate known to be present on the cell surface of E. histolytica. E. dispar cells were radio-isotope labelled with [3H]galactose or [3H]inositol. The acidic glycoconjugates were extracted and analysed by hydrophobic chromatography over phenyl-Sepharose and by sodium dodecyl sulphate polyacrylamide gel electrophoresis. No LPG-like molecules could be identified in E. dispar in contrast to E. histolytica, suggesting that these molecules may be absent in the non-pathogenic species.

Animals↗
PubMed1976

A comparison of membrane glycoconjugates from mouse cells transformed by murine and primate RNA sarcoma viruses.

Kirsten murine sarcoma virus (Ki-MSV) transformed Balb/eT3 mouse cells (K-Balb) were found to have altered membrane glycoconjugates compared to normal Balb/3T3 cells. There were reduced amounts of mono- and disialogangliosides, GM1 and GD1a, and activity of the specific galactosyltransferase required for synthesis of these gangliosides was reduced to between 0 and 18.5% of normal in the several K-Balb clones examined. When fucose-labeled glycopeptides derived from the surfaces of Balb/3T3 and K-Balb cells were compared by gel filtration chromatography, the glycopeptides from the transformed cells were enriched in earlier eluting components. These differences were also observed when the glycopeptides were derived from the entire cell and were diminished when the surface or cellular glycopeptides from Balb/3T3 and K-Balb were digested with neuraminidase prior to chromatographic analysis. Changes in these membrane sialoglycolipids and sialoglycopeptides were not influenced by Rauscher leukemia virus infection. In marked contrast, these changes in membrane glycoconjugates were not observed in Wooley monkey sarcoma virus (WSV) transformed Balb/3T3 cells (W-Balb). Although W-Balb cells like K-Balb were transformed by tissue culture criteria, their ganglioside composition, galactosyltransferase activity, and glycopeptide patterns were similar to normal Balb/3T3. These findings have potential implications concerning the role of these complex carbohydrates in the phenotypic alterations of transformed cells.

Animals↗
PubMed2006

Photodynamic efficiency of diethylene glycol-linked glycoconjugated porphyrins in human retinoblastoma cells.

Photodynamic therapy (PDT) is emerging as a new strategy for the conservative treatment of hereditary retinoblastoma. The glycoconjugated porphyrins TPP(p-Deg-O-alpha-GalOH)(3), TPP(p-Deg-O-beta-GalOH)(3), TPP(p-Deg-O-alpha-ManOH)(3), and their S-analogues were synthesized to obtain efficient photosensitizers with some retinoblastoma cell affinity. In these systems, a sugar motif and porphyrin core were linked by a diethylene glycol spacer (Deg). Cellular uptake, localization, and photoactivity have been examined in human retinoblastoma cells (Y79). After preincubation with corresponding glycosylated albumin, the uptake of TPP(p-Deg-O-beta-GalOH)(3) and TPP(p-Deg-O-alpha-ManOH)(3) was 40-45% inhibited, indicating a possible cell-sugar-receptor saturation. High photoactivity was observed for the two alpha-galacto/manno porphyrins 8 and 10 (LD(50) = 0.05 and 0.35 muM, respectively) at 514 nm and low fluence (1 J/cm(2)). Analysis by MALDI-TOF mass spectrometry only indicated a small metabolic cleavage of the O-glycoconjugates and a good stability of the S-glycoside porphyrins. On the basis of these in vitro data, TPP(p-Deg-O-alpha-GalOH)(3) and TPP(p-Deg-O-alpha-ManOH)(3) were selected for in vivo studies.

Animals↗
PubMed2004

The novel lectin KM+ detects a specific subset of mannosyl-glycoconjugates in the rat cerebellum.

KM+ is a D(+)mannose-specific lectin with a carbohydrate structure-affinity relationship different from those of most mannose-binding lectins. KM+ elicits carbohydrate-dependent biological effects in several mammalian cell types, but it has not yet been employed as a probe for the detection of its specific ligands. We show here for the first time the screening and partial identification of cerebellar mannosyl-glycoconjugates recognized by KM+, by means of lectin-histochemistry and lectin-blotting. Biotinylated KM+ stained most cellular structures in the adult rat cerebellum, particularly Purkinje cells bodies and the surface of granule cells, but not cellular processes. Capillaries in the choroid plexus were also strongly decorated, while blood vessels in the cerebellar parenchyma remained unstained. D(+)mannose, but not D(+)galactose, abolished the staining of all cerebellar structures. Higher inhibitory potencies were found for mannosyl-glycans such as mannotriose (man-alpha1,3-[man-alpha1,6]-man) and the biantennary heptasaccharide carried by the enzyme horseradish peroxidase. After separation of cerebellar proteins by SDS-PAGE, KM+ recognized three major unidentified mannosyl-glycoproteins of 132, 83 and 49 kDa. KM+ also detected high-Mw bands corresponding to the light and heavy chains of Type-I laminin, but not a 160-kDa cleavage product of laminin. We conclude that KM+ binds preferentially to a specific subset of mannose-containing glycoproteins in cerebellar tissue, thus being much more restricted than other mannose-specific lectins. KM+ can be used as a novel probe to screen the central nervous system for this specific subset of complex mannosyl-glycoconjugates.

Animals↗
PubMed1985

Interactions of soya-bean agglutinin with purified glycoconjugates and soya-bean seed components.

A radioaffinity assay for lectin binding to receptors was developed and characterized by using the interactions between soya-bean agglutinin and four glycoconjugates, namely thyroglobulin, galactomannan, fetuin and asialofetuin. On application of the assay to soya-bean extracts a wide range of seed components were found to have the capacity to interact with soya-bean agglutinin. These included both trichloroacetic acid-soluble and trichloroacetic acid-insoluble glycoconjugates and two classes of particulate matter distinguished by their differential solubility in Triton X-100.

Asialoglycoproteins↗
PubMed1996

Regulation of the expression of nitric oxide synthase and leishmanicidal activity by glycoconjugates of Leishmania lipophosphoglycan in murine macrophages.

Lipophosphoglycan (LPG) glycoconjugates from promastigotes of Leishmania were not able to induce the expression of the cytokine-inducible nitric oxide synthase (iNOS) by the murine macrophage cell line, J774. However, they synergize with interferon gamma to stimulate the macrophages to express high levels of iNOS. This synergistic effect was critically time-dependent. Preincubation of J774 cells with the LPG glycans 4-18 h before stimulation with interferon gamma resulted in a significant reduction in the expression of iNOS mRNA and of NO synthesis, compared with cells preincubated with culture medium alone. The regulatory effect on the induction of iNOS by LPG is located in the LPG phosphoglycan disaccharide backbone. Synthetic fragments of this backbone had a similar regulatory effect on NO synthesis. Further, the production of NO by activated macrophages in the present system was correlated directly with the leishmanicidal capacity of the cells. These data therefore demonstrate that LPG glycoconjugates have a profound effect on the survival of Leishmania parasites through their ability to regulate the expression of iNOS by macrophages.

Animals↗
PubMed2005

Mucosal immunity induced by pneumococcal glycoconjugate.

Host defenses against Streptococcus pneumoniae involve opsonophagocytosis mediated by antibodies and complement. Because the pneumococcus is a respiratory pathogen, mucosal immunity may play an important role in the defense against infection. The mechanism for protection in mucosal immunity consists of induction of immunity by the activation of lymphocytes within the mucosal-associated lymphoid tissues, transport of antigen-specific B and T cells from inductive sites through bloodstream and distribute to distant mucosal effector sites. Secretory IgA is primarily involved in protection of mucosal surfaces. Mucosal immunization is an effective way of inducing immune responses at mucosal surfaces. Several mucosal vaccines are in various stages of development. A number of mucosal adjuvants have been proposed. CpG oligodeoxynucleotide (ODN) has been shown to be an effective mucosal adjuvant for various antigens. Mucosal immunity induced by intranasal immunization was studied with a pneumococcal glycoconjugate, using CpG ODN as adjuvant. Mice immunized with type 9V polysaccharide (PS) conjugated to inactivated pneumolysin (Ply) plus CpG produced high levels of 9V PS IgG and IgA antibodies compared to the group that received the conjugate alone. High levels of subclasses of IgGI, IgG2 and IgG3 antibodies were also observed in sera of mice immunized with 9V PS-Ply plus CpG. In addition, high IgG and IgA antibody responses were observed in sera of young mice immunized with 9V PS-Ply plus CpG or the conjugate plus non-CpG compared with the group received the conjugate alone. These results reveal that mucosal immunization with pneumococcal glycoconjugate using CpG as adjuvant can confer protective immunity against pneumococcal infection.

Administration, Intranasal↗
PubMed1986

Evidence for a novel enzymatic mechanism of neural crest cell migration on extracellular glycoconjugate matrices.

Migrating embryonic cells have high levels of cell surface galactosyltransferase (GalTase) activity. It has been proposed that GalTase participates during migration by recognizing and binding to terminal N-acetylglucosamine (GlcNAc) residues on glycoconjugates within the extracellular matrix (Shur, B. D., 1982, Dev. Biol. 91:149-162). We tested this hypothesis using migrating neural crest cells as an in vitro model system. Cell surface GalTase activity was perturbed using three independent sets of reagents, and the effects on cell migration were analyzed by time-lapse microphotography. The GalTase modifier protein, alpha-lactalbumin (alpha-LA), was used to inhibit surface GalTase binding to terminal GlcNAc residues in the underlying substrate. alpha-LA inhibited neural crest cell migration on basal lamina-like matrices in a dose-dependent manner, while under identical conditions, alpha-LA had no effect on cell migration on fibronectin. Control proteins, such as lysozyme (structurally homologous to alpha-LA) and bovine serum albumin, did not effect migration on either matrix. Second, the addition of competitive GalTase substrates significantly inhibited neural crest cell migration on basal lamina-like matrices, but as above, had no effect on migration on fibronectin. Comparable concentrations of inappropriate sugars also had no effect on cell migration. Third, addition of the GalTase catalytic substrate, UDPgalactose, produced a dose-dependent increase in the rate of cell migration. Under identical conditions, the inappropriate sugar nucleotide, UDPglucose, had no effect. Quantitative enzyme assays confirmed the presence of GalTase substrates in basal lamina matrices, their absence in fibronectin matrices, and the ability of alpha-LA to inhibit GalTase activity towards basal lamina substrates. Laminin was found to be a principle GalTase substrate in the basal lamina, and when tested in vitro, alpha-LA inhibited cell migration on laminin. Together, these experiments show that neural crest cells have at least two distinct mechanisms for interacting with the substrate during migration, one that is fibronectin-dependent and one that uses GalTase recognition of basal lamina glycoconjugates.

Animals↗