Glycoconjugate Journal最新文献

Mutations in the glucocerebrosidase GBA gene, encoding the lysosomal enzyme β-glucocerebrosidase, represent the most frequent genetic risk factor for Parkinson's disease, leading to lysosomal dysfunction, α-synuclein aggregation, and mitochondrial impairment. In this study, we investigated the therapeutic potential of GM1 ganglioside and its oligosaccharide portion (OligoGM1) in a cellular model of GBA-associated Parkinson's disease, using SH-SY5Y neuroblastoma cells carrying the L444P GBA mutation. We observed that both GM1 and OligoGM1 reduced α-synuclein accumulation and improved cell viability. Notably, only OligoGM1 attenuated lysosomal overload and restored mitophagy. Additionally, OligoGM1 significantly prevented 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity, including lysosomal dysfunction, reactive oxidative species-overproduction, and mitochondrial energy failure, whereas GM1 failed to provide protection. These findings highlight the selective and multifaceted neuroprotective actions of OligoGM1 under both genetic conditions and environmental stress. Due to its small, hydrophilic nature and capacity to cross the blood-brain barrier, OligoGM1 emerges as a promising therapeutic candidate for GBA-related and potentially idiopathic forms of Parkinson's Disease.

Recently, Breiman et al. (2021) reported that the level of anti-Tn in the blood of healthy donors and COVID-19 patients is significantly lower in individuals of blood group A than B. This prompted us to look for qualitative differences in the repertoire of anti-Tn like specificity in individuals of different blood groups (BG). To this end, we isolated antibodies from the pooled sera of BG A and BG B healthy donors using GalNAcα-sepharose, followed by Printed Glycan Array analysis. As expected, antibodies affinity isolated from BG A donors completely lack species directed to canonical (GalNAcα-transferase dependent) A-glycans, such as A (types 1, 2 and 4), GalNAcα1-3(Fucα1-2)Gal, GalNAcα1-3Galβ1-4GlcNAc (linear A), and ALe^Y. Unexpectedly, GalNAcα1-4Galβ1-4GlcNAc, glycan with an unnatural 1-4 bond fell into the same group, i.e., antibodies to it were found only in BG B donors. Other unexpected results include the following: (1) for GalNAcα1-OCH₂CH(COOH)NH₂ (GalNAcα-OSer, immobilized by NH₂ group) the opposite result was observed, i.e. affinity isolated anti-Tn antibodies of BG A donors demonstrated significantly higher titer than of BG B; (2) in BG A donors, the level of antibodies to GalNGcα1-3GalNAcα (i.e. disaccharide in N-glycolyl form) is close to background, while there is a significant level of these antibodies in the BG B donors. Since antiglycan antibodies are known to play both a protective role in antimicrobial immunity and to promote infectivity, the knowledge gained about the difference in the specificity profiles of anti-Tn antibodies signals the need to take blood group into account in developing therapeutic strategies.

Cystic Fibrosis (CF), a life-threatening hereditary disease, arises from mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, which encodes a chloride-conducting channel widely expressed in epithelial cells. The most common mutation, F508del, causes CFTR misfolding, premature degradation, and impaired mucociliary clearance, leading to recurrent respiratory infections and inflammation. The triple combination therapy with Elexacaftor, Tezacaftor, and Ivacaftor (ETI) has revolutionized CF management by partially restoring mutated CFTR function. However, enhancing CFTR rescue and stabilizing host immune responses remain critical challenges. In airway epithelial cells, CFTR interacts with proteins and lipids in macromolecular complexes that influence its stability. Among these, the ganglioside GM1 plays a key role in modulating plasma membrane protein dynamics, including CFTR. This study investigates the effects of exogenous GM1 supplementation as an adjuvant to ETI treatment. Our results demonstrate that GM1 enhances F508del-CFTR maturation and stability, even under Pseudomonas aeruginosa infection, which typically suppresses CFTR expression and function. Furthermore, GM1 restores xenophagic activity in bronchial epithelial cells, improving host defence mechanisms against the bacteria. These findings underscore the therapeutic potential of GM1 and its analogues in optimizing the plasma membrane environment for CFTR correction, suggesting that by enhancing the efficacy of CFTR modulators, GM1 could pave the way for innovative approaches to improve CF management.

Intestinal gel-forming mucins are high-molecular weight glycoproteins, and their glycan moieties vary depending on the intestinal site. Although the means of analyzing mucin glycans are limited, monoclonal antibodies are expected to be a powerful analysis tool. In this study, 12 monoclonal antibodies were generated using rat intestinal mucin as the immunogen, and the epitopes of the antibodies were studied. The analyses using resins with the glycans of blood group-associated antigens and neoglycolipids synthesized from mucin glycans revealed that most antibodies recognize glycans. Furthermore, some recognize blood group-related antigens on glycans, whereas others recognize immaturely synthesized mucin-type glycans. Immunostaining of the rat jejunum, ileum, proximal colon, and distal colon with antibodies produced a site-dependent staining intestinal image. Affinity chromatography using an antibody-conjugated column was utilized to fractionate rat small intestinal mucins. Mucins with various glycan compositions were produced, suggesting the possibility of obtaining site-specific mucins. The site-specific mucins with various glycan compositions result in site-specific glycan functions, and the antibodies developed in this study could be useful tools for their analysis.

DDOST is an important subunit of N-glycosylated oligosaccharyltransferase and is closely related to protein N-glycosylation. Some studies have reported that abnormal expression of DDOST is associated with congenital disorders of glycosylation, solid tumours and other diseases. To better understand the progress of research on DDOST in diseases, we herein provide a comprehensive review of the basic functions of DDOST, interactions molecules, DDOST-congenital disorders of glycosylation (DDOST-CDG) and solid tumours. Our review findings will lay a foundation for researchers to better understand the functions of DDOST and to investigate its specific mechanisms of action.

The role of Advanced Glycation End Products (AGEs) in the pathophysiology of salivary gland dysfunction in diabetes has not been fully addressed. In this work, we discuss the pathophysiological mechanisms of salivary gland dysfunctions in diabetes, focusing on the role of AGEs. Hyperglycemia induces the generation and accumulation of AGEs, induces oxidative stress, and activates the receptor for AGEs (RAGE), with detrimental effects on the salivary glands and the submandibular autonomic innervation. Structural and ultrastructural alterations have been described in the three major salivary glands, and hypo-salivation development has been linked to early autonomic neuropathy. Poor metabolic control aggravates the salivary flow rate via injury to the autonomic nerve fiber bundles or direct damage to the secretory acinar cells of the glands. Chronic hyperglycemia, the most crucial feature of diabetes, leads to the generation and accumulation of advanced glycation end products (AGEs). The interest in the role of AGEs in the pathogenesis of diabetic complications has grown exponentially, and AGEs have been implicated as a primary culprit in the pathophysiology of diabetes and its various complications, including neuropathy, nephropathy, retinopathy, vasculopathy, and cardiomyopathy.

The Carbohydrate Recognition Domain (CRD) of immune system's c-type lectin receptors (CLRs) preferentially interacts with the Capsular Polysaccharides (CPS) units. Implicit Ca²⁺ ions are crucial to CRD function. Increment of the ionic concentration explicitly affects the CPS recognition by CRD many-fold. DC-SIGN is one such CLR that acts for the differential recognition of the microbial CPS. The CPS mannotriose had the lowest binding energy (ΔG -4.7 kcal/mol) and the maximum affinity for DC-SIGN with implicit Ca²⁺ ion. In the present investigation the ligand affinity increases with the rise of Ca²⁺ concentration up to 1.5 M. Again, within the CRD the residues viz; Glutamate (347), Proline (348), and Asparagine (349) (EPN) were reported previously as essential for CPS unit coordination. Our analysis demonstrated that besides the EPN residues, CPS unit interacts with the neighboring Asparagine (350), Glutamate (354) and Asparagine (355) residues. Thus, these residues were replaced one at a time with Alanine (a charge neutral residue) to test their effect on the contact event. The CRD loses its affinity for recognition on the N350A, E354A, and D355A substitutions. Thus, this heterogeneity of CRD recognition towards Carbohydrate provides fresh information about the immune system's theragnostic function. This new understanding of Ca²⁺-induced recognition may help design new theragnostic applications that boost our immune defenses against pathogenic evasion.

Zwitterionic modifications of glycans such as phosphorylcholine or phosphoethanolamine occur in a wide range of prokaryotic and eukaryotic organisms and are known for interaction with the mammalian immune system. Unlike the biosynthesis of membrane phospholipids which is well elucidated, very little is known about the transfer of zwitterionic phosphodiester moieties onto glycoconjugates. The presence and function of relevant enzymes has been suggested by gene knockout or mutation and corresponding aberrant phosphorylcholine metabolism. In the current study, the Mycoplasma fermentans phosphorylcholine transferase mf1, with previously confirmed in-vitro activity synthesizing phosphorylcholine-α-glucosyl-1,2-dipalmitoyl glycerol, is demonstrated to not only transfer phosphorylcholine but also phosphoethanolamine from CDP-ethanolamine. Moreover, mf1 is capable of using the β-configuration of the presumed natural substrate but transfers neither to simpler substrates with glucose moieties such as β-D-octyl-glucopyranoside nor to an extended lipid substrate with an additional galactose residue. These findings suggest a certain, but limited, substrate flexibility for bacterial PC-transferases. Mf1 activity is inhibited by β-glycerophosphate, an isomer of part of CDP-glycerol which is known to compete with CDP-ribitol in enzymatic reactions catalyzed by fukutin, a human protein sharing structural homology with mf1. For the first time, a phosphorylcholine transferase, mf1, could be biochemically characterized in vitro and its lipid products with zwitterionic phosphodiesters attached could be detected specifically with the pentraxin serum amyloid P.

Plant glycosides have a broad spectrum of pharmaceutical activities primarily due to the glycosidic residues present in their structure. Especially, the therapeutic glycosides can be classified into many compounds based on the sugar moiety, chains/ saccharide units, glycosidic linkages, and aglycones. Among many classes, the widely used pharmacological classification is based on the aglycones linked to the glycoside molecule. Based on these non-sugar moiety (aglycones), plant glycosides are further classified into twelve different types of glycosides along with the recent discovery of novel (cannabinoid) glycosides. They are called alcoholic, anthraquinone, coumarin, chromone, cyanogenic, flavonoid, phenolic, cardiac, saponin, thio, steviol, iridoid, and cannabinoid glycosides. Each of the plant glycosides has been discussed in this paper with, origin, structure, and abundant presence in a specific family of plants. Besides, the therapeutic roles of these plant glycosides are further described in detail to validate their efficacies in the human health care system. On the other hand, glycosides are inactive until enzymatic hydrolysis releases their active aglycone, enabling targeted drug delivery. This process enhances aglycone solubility and stability, improving bioavailability and therapeutic efficacy. They target specific receptors or enzymes, minimizing off-target effects and enhancing pharmacological outcomes. Derived from plants, glycosides offer diverse chemical structures for drug development. They are integral to traditional medicine and modern pharmaceuticals, utilized in therapies ranging from cardiology to antimicrobial treatments.