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Building multivalent iminosugar-based ligands on calixarene cores via nitrone cycloadditions.

A novel and challenging approach for the construction of multivalent iminosugar architectures directly on calixarene scaffolds is presented, which exploits multiple cycloaddition reactions of a carbohydrate-derived nitrone on diversely functionalized calix[4]arenes. Regardless of the 4-fold reiteration on a single calixarene, the reactions take place with high regio- and stereoselectivity, demonstrating this method as an appealing one for the synthesis of calixarene-based neoglycoconjugates.

Lipopolysaccharide: a tool and target in enterobacterial vaccine development.

Lipopolysaccharide (LPS) is an essential component of Gram-negative bacteria. While mutants exhibiting truncated LPS molecules are usually over-attenuated, alternative approaches that affect the extent or timing of LPS expression, as well as its modification may establish the optimal balance for a live vaccine strain of sufficient attenuation and retained immunogenicity. On the other hand, a specific immune response to LPS molecules in itself is capable of conferring protective immunity to certain enterobacterial pathogens. Therefore, purified LPS derivatives could be used as parenteral vaccin

Salmonella enterica serovar Typhi O:1,9,12 polysaccharide-protein conjugate as a diagnostic tool for typhoid fever.

Serologic tests play an important role in diagnosis of typhoid fever. In an effort to develop a more defined reagent for these tests, purified Salmonella enterica serovar Typhi (ST) O:1,9,12 polysaccharide was conjugated to human serum albumin (HSA), and the conjugate was purified chromatographically to yield a reagent with 2 moles ST O polysaccharide per mole HSA. In 40 patients with bacteriologically confirmed typhoid fever, significant dot immunobinding titers (> or =20,000) were present in 28 (70%) tested with 100 ng of ST O antigen-HSA (ST O-HSA) conjugate, in 38 (95%) tested with 100 ng

Histochemistry of complex carbohydrate in the major salivary glands of hoary bamboo rats (Rhizomys purinosus).

The major salivary glands (parotid glands, monostomatic sublingual glands and submandibular glands) were obtained from hoary bamboo rats (Rhizomys purinosus) and fixed in Bouin's solution. Paraffin sections were subjected to a battery of staining methods including lectin staining for demonstration of complex carbohydrates. Among the three major salivary glands, unique histochemical features were observed in the submandibular gland. Different from most myomorpha species, submandibular glands of the hoary bamboo rats have two types of secretory cells in the secretory endpieces. One type of cells

Visualization of carbohydrate chains in rabbit salivary glands by means of enzymatic degradation and plant lectins.

We investigated the structure of glycoconjugates contained within the secretory end-pieces and ductal segments in the rabbit submandibular and sublingual glands. Glycosidic sequences were examined by means of enzymatic degradation with specific glycosidases (sialidase, alpha-fucosidase, beta-galactosidase, alpha-mannosidase) followed by lectin binding with PNL-HRP, WPL-HRP, WGL-HRP, SBL-HRP, Con A-HRP. It was found that this procedure represents a valid tool for studying carbohydrates, in so far as their characterization and localization were based only on colour reactions. In particular, this…

The role of sialidases in the pathogenesis of bacterial vaginosis and their use as a promising pharmacological target in bacterial vaginosis.

Bacterial vaginosis (BV) is an infection of the genital tract characterized by disturbance of the normally Lactobacilli-dominated vaginal flora due to the overgrowth of Gardnerella and other anaerobic bacteria. Gardnerella vaginalis, an anaerobic pathogen and the major pathogen of BV, produces sialidases that cleave terminal sialic acid residues off of human glycans. By desialylation, sialidases not only alter the function of sialic acid-containing glycoconjugates but also play a vital role in the attachment, colonization and spread of many other vaginal pathogens. With known pathogenic effect…

Galectin-9 - ligand axis: an emerging therapeutic target for multiple myeloma.

Galectin-9 (Gal-9) is a tandem-repeat galectin with diverse roles in immune homeostasis, inflammation, malignancy, and autoimmune diseases. In cancer, Gal-9 displays variable expression patterns across different tumor types. Its interactions with multiple binding partners, both intracellularly and extracellularly, influence key cellular processes, including immune cell modulation and tumor microenvironment dynamics. Notably, Gal-9 binding to cell-specific glycoconjugate ligands has been implicated in both promoting and suppressing tumor progression. Here, we provide insights into Gal-9 and its

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… They specifically recognize and bind to β-galactoside on glycoconjugates (proteins, lipids, or other molecules) through these CRDs. … Gal-9 and its glycoconjugate ligands Gal-9 binds to β-galactoside-bearing glycoconjugates on the cell surface through its CRDs, influencing diverse cellular functions and signaling pathways ( 38 – 43 ). …

Correlation of group C meningococcal conjugate vaccine response with B- and T-lymphocyte activity.

Despite the success of conjugate vaccination against meningococcal group C (MenC) disease, post-vaccination, some individuals still exhibit rapid waning of initially protective bactericidal antibody levels. The mechanism of this relative loss of humoral protection remains undetermined. In this report we have investigated the relationship between T- and B-cell activation and co-stimulation and the loss of protective antibody titers. We have found that healthy volunteers who lose protective MenC antibody levels one year after receipt of glycoconjugate vaccine exhibit no detectable cellular defec

Quantification of residual EDU (N-ethyl-N'-(dimethylaminopropyl) carbodiimide (EDC) hydrolyzed urea derivative) and other residual by LC-MS/MS.

An LC-MS/MS method for determination of the break down product of N-ethyl-N'-(3-dimethylaminopropyl) carbodiimide (EDC) urea derivative, EDU, has been developed and validated for monitoring the residual coupling reagents. Results indicate that the method exhibits suitable specificity, sensitivity, precision, linearity and accuracy for quantification of residual EDU in the presence of meningococcal polysaccharide-diphtheria toxoid conjugate vaccine and other vaccine matrix compounds. The assay has been validated for a detection range of 10-100 ng/mL and then successfully transferred to quality

Hypothalamic-mediated model for Creutzfeldt-Jakob disease: relation to hemispheric chemical dominance.

The isoprenoid pathway including endogenous digoxin was assessed in Creutzfeldt-Jakob Disease (CJD). This was also studied for comparison in patients with right hemispheric and left hemispheric dominance. The isoprenoid pathway was upregulated with increased digoxin synthesis in patients with CJD and in those with right hemispheric chemical dominance. In this group of patients (i) the tryptophan catabolites were increased and the tyrosine catabolites reduced, (ii) the dolichol and glycoconjugate levels were elevated, (iii) lysosomal stability was reduced, (iv) ubiquinone levels were low and fr

Advances in chemoenzymatic synthesis of glycosaminoglycans and proteoglycans.

Proteoglycans (PGs) are intricate macromolecules decorated with linear polysulfated glycosaminoglycans (GAGs) that play critical roles in orchestrating a wide range of physiological and pathological events. Advances in the utilization of recombinant enzymes and biosynthetic pathways have expedited the production of defined and homogeneous GAGs, helping overcome traditional barriers of chemical synthesis. Furthermore, the synthesis of GAG chains has been increasingly integrated with other critical structural elements, most notably the core proteins. Robust synthetic methodologies toward well-de

Advances in Helicobacter pylori lipopolysaccharide structure and function.

Helicobacter pylori is a widespread pathogen responsible for chronic gastritis, peptic ulcers, and an elevated risk of gastric cancer. Lipopolysaccharide (LPS), localized exclusively in the outer leaflet of the outer membrane, is essential for maintaining bacterial integrity. Recent advances have deepened our understanding of H. pylori LPS structure, particularly lipid A modifications and the redefinition of the core oligosaccharide and O-antigen regions. The complete set of enzymes involved in LPS biosynthesis has been identified in the reference strain G27, and comparative genomics has revea

NMR Assays for Estimating the O-Acetyl Content of Meningococcal Polysaccharide Serogroup A in Quadrivalent Conjugate Vaccine Formulation.

The use of multivalent glycoconjugate vaccines has dramatically contributed to reduce the incidence of meningococcal infectious disease. The advanced structural characterization of polysaccharide conjugates leads to enhancements in the quality and control of the products. Here, we report a novel nuclear magnetic resonance (NMR) method to confirm the identity and structural conformity (e.g., O-acetyl content) of saccharide antigens that comprise a licensed tetravalent meningococcal serogroups A, C, W, and Y vaccine. For the first time, the NMR methodology is applied on a formulation (licensed v

Uridine Bisphosphonates Differentiate Phosphoglycosyl Transferase Superfamilies.

Complex bacterial glycoconjugates are essential for bacterial survival, and drive interactions between pathogens and symbionts, and their human hosts. Glycoconjugate biosynthesis is initiated at the membrane interface by phosphoglycosyl transferases (PGTs), which catalyze the transfer of a phosphosugar from a soluble uridine diphospho-sugar (UDP-sugar) substrate to a membrane-bound polyprenol-phosphate (Pren-P). Two distinct superfamilies of PGT enzymes, denoted as polytopic and monotopic, carry out this reaction but show striking differences in structure and mechanism. With the goal of creati…

Ovarian angiogenesis. Phenotypic characterization of endothelial cells in a physiological model of blood vessel growth and regression.

Angiogenesis occurs during embryogenesis and is a down-regulated process in the healthy adult that is almost exclusively linked to pathologi … essing blood vessels and provide additional evidence for the importance of endothelial cell surface glycoconjugates during angiogenesis.

The genome of Leishmania panamensis: insights into genomics of the L. (Viannia) subgenus.

Kinetoplastid parasites of the Leishmania genus cause several forms of leishmaniasis. Leishmania species pathogenic to human are separated i … of molecular processes involving nucleic acid manipulation and differential modification of surface glycoconjugates. These differences may in part explain some phenotypic characteristics of the Viannia parasites, including their increased adaptive capacity and enhanced metastatic ability.

Shotgun glycomics: a microarray strategy for functional glycomics.

Major challenges of glycomics are to characterize a glycome and identify functional glycans as ligands for glycan-binding proteins (GBPs). To address these issues we developed a general strategy termed shotgun glycomics. We focus on glycosphingolipids (GSLs), a class of glycoconjugates that is challenging to study, recognized by toxins, antibodies and GBPs. We derivatized GSLs extracted from cells with a heterobifunctional fluorescent tag suitable for covalent immobilization. We separated fluorescent GSLs by multidimensional chromatography, quantified them and coupled them to glass slides to c…

Regional differences in lectin binding to colonic epithelium by fluorescent and electron microscopy.

The distribution of glycosubstances in colonic epithelium using lectins that were rhodaminated for fluorescent microscopy or coupled to colloidal gold for electron microscopy has been studied. Findings, based on lectin binding patterns, indicate that the right, transverse, and left colon of the guinea pig differ in their content of glycoconjugates within goblet cells and along the brush border. Local variations of labeling were also observed within goblet cells between the upper and lower portions of crypts. Throughout the colon, corresponding to a region of supranuclear fluorescence, Ricin II…

Recent advances in anomeric C-S bond activation: Emerging opportunities for stereoselective glycosides.

Carbohydrates are essential biomolecules in nature for their numerous biological functions. To advance in-depth understanding of complex bio … anomeric C-S bond activation, showing significant potential for synthesizing biologically relevant glycoconjugates and carbohydrate-based scaffolds.

Proximity Labeling and Genetic Screening Reveal that DSG2 is a Counter Receptor of Siglec-9 and Suppresses Macrophage Phagocytosis.

Cancer cells present sialylated glycoconjugates that modulate the activity of various immune cells within the tumor microenvironment through trans interaction with immunosuppressive Siglec receptors. Identifying counter receptors for Siglecs can provide valuable targets for cancer immunotherapy, but it presents significant challenges. Here, the identification of DSG2 (Desmoglein 2) as a dominant counter receptor of Siglec-9 in melanoma cells is reported, using a workflow that combines the strength of proximity labeling and the advantage of CRISPR knockout screening. It is further demonstrated …