Glycoconjugate Journal最新文献

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.

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.

Cystic Fibrosis (CF) is a life-threatening hereditary disease resulting from mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene that encodes a chloride channel essential for ion transport in epithelial cells. Mutations in CFTR, notably the prevalent F508del mutation, impair chloride transport, severely affecting the respiratory system and leading to recurrent infections. Recent therapeutic advancements include CFTR modulators such as ETI, a combination of two correctors (Elexacaftor and Tezacaftor) and a potentiator (Ivacaftor), that can improve CFTR function in patients with the F508del mutation. This study investigated ETI's impact on the maturation of the mutated CFTR, the expression levels of its scaffolding proteins, and lipid composition of cells using bronchial epithelial cell lines expressing both wild-type and F508del CFTR. Our findings revealed that ETI treatment enhances CFTR and its scaffolding proteins expression and aids in rescuing mature F508del CFTR, causing also significant alterations in the lipid profile including reduced levels of lactosylceramide and increased content of gangliosides GM1 and GD1a. These changes were linked to ETI's influence on enzymes involved in the sphingolipid metabolism, in particular GM3 synthase and sialidase. Through this work, we aim to deepen understanding CFTR interactions with lipids, and to elucidate the mechanisms of action of CFTR modulators. Our findings may support the development of potential therapeutic strategies contributing to the ongoing efforts to design effective correctors and potentiators for CF treatment.

Chondroitin sulphate (CS) is a sulphated glycosaminoglycan (GAG) polysaccharide found on proteoglycans (CSPGs) in extracellular and pericellular matrices. Chondroitinase ABC (CSase ABC) derived from Proteus vulgaris is an enzyme that has gained attention for the capacity to cleave chondroitin sulphate (CS) glycosaminoglycans (GAG) from various proteoglycans such as Aggrecan, Neurocan, Decorin etc. The substrate specificity of CSase ABC is well-known for targeting various structural motifs of CS chains and has gained popularity in the field of neuro-regeneration by selective degradation of CS GAG chains. Within this context, our investigation into the biochemistry of CSase ABC led us to a previously unreported inhibition of CSase ABC activity by Dextran Sulphate (DexS). To understand the inhibitory effects of DexS, we compared its inhibition of CSase ABC to that of other polysaccharides such as Heparan Sulphate, Heparin, Colominic Acid, Fucoidan, and Dextran. This analysis identified key structural factors such as monosaccharide composition and linkage, sulphation degree and overall charge as influencing CSase ABC inhibition. Remarkably, DexS emerged as a unique inhibitor of CSase ABC, with distinctive inhibitory effects that correlate with its chain length. DexS has been used to reliably induce ulcerative colitis in mice, effectively mimicking inflammatory bowel diseases in humans, and has been previously shown to inhibit both RNA polymerase and reverse transcriptase. Our investigation emphasizes the interplay between the properties of DexS and CSase ABC, providing significant insights into the utilization of polysaccharide-based inhibitors for modulating enzyme activity.

Reduction of glucose transporter 1 (GLUT1), even deletion, may results in cartilage fibrosis and osteoarthritis. This study aims to investigate the SUMOylation of GLUT1 in osteoarthritis through small ubiquitin-like modifier 1(SUMO1), and explore the role of SUMOylated GLUT1 in glycometabolism, proliferation and apoptosis in chondrocytes. Human chondrocytes were incubated with 10 ng/mL of IL-1β to mimic osteoarthritis in vitro. GLUT1, SUMO1 and Chondrocyte-related genes including COL2A1, MMP13 and ADAMTS4 were evaluated using western blot. Cell viability and cell apoptosis of chondrocytes were measured by cell counting kit-8 assay and flow cytometry, respectively. The changes in glycometabolism were evaluated using extracellular acidification rate (ECAR) and glucose uptake assay. Co-immunoprecipitation (Co-IP) was used to verify the interaction between GLUT1 and SUMO1. The stabilization role of SUMO1 in GLUT1 was determined by cycloheximide assay. IL-1β induced the decrease of GLUT1, cell viability, ECAR, glucose uptake and COL2A1 and the increase of cell apoptosis, MMP13 and ADAMTS4 in chondrocytes. However, overexpression of SUMO1 led to the reduction of cell apoptosis, MMP13 and ADAMTS4 and the elevation of GLUT1, cell viability, ECAR, glucose uptake and COL2A1 in IL-1β-stimulated chondrocytes. There was SUMOylation sites on GLUT1. Intriguingly, SUMO1 was significantly enriched in GLUT1 using Co-IP assay, and stabilized GLUT1 in chondrocytes. SUMO1-mediated SUMOylation is capable of stabilizing GLUT1 to inhibit glycometabilsm disorder and cell apoptosis in IL-1β-stimulated chondrocytes.

Glycosaminoglycans (GAGs) are essential bone extracellular matrix molecules that regulate osteoblast differentiation. Numerous studies have explored endogenous and exogenous GAG osteoanabolic activities using appropriate in vitro and in vivo models. However, GAGs' underlying the mechanism of action and structure-function relationships need to be elucidated in detail. Earlier, we showed that exogenous GAG can bring about osteogenesis in pre-osteoblast cells. In the present study, we have elucidated the mechanism of action of exogenous GAGs, especially of the chondroitin sulfate/dermatan sulfate (CS/DS) class on osteogenesis. GAGs were immobilized, and osteoblast differentiation was evaluated in MC3T3-E1 cells. Results indicated that GAGs supported osteoblast differentiation by promoting collagen production, extracellular matrix formation, and subsequent mineralization. We elucidated the mechanisms underlying these effects by assessing the key signaling molecules involved in osteogenesis in response to exogenous CS/DS with/without BMP2. CS/DS alone significantly increased pERK1/2 and ATF4 expression levels differentially in a time-dependent manner without significant effects on BMP2, RUNX2, and pSMAD5 protein expression. On the other hand, CS/DS, in the presence of BMP2, differentially increased BMP2, pSMAD5, pERK1/2, RUNX2, and ATF4 expression levels at various time points. Collectively, these results strongly suggest that CS/DS can promote osteogenesis, and in the presence of BMP2, it could promote SMAD-mediated ERK-dependent osteogenesis.

In this study, spatial and single-cell transcriptome techniques were used to investigate the role of beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1) in promoting peritoneal metastasis in ovarian cancer epithelial cells. We collected single-cell transcriptomic (GSE130000) and spatial transcriptomic datasets (GSE211956) from the Gene Expression Omnibus and RNA-sequencing data from The Cancer Genome Atlas. The Robust Cell Type Decomposition (RCTD) approach was implemented to integrate spatial and single-cell transcriptomic data. In addition, pseudo-time trajectory analysis, cell-cell communication networks, transcription factor activity profiling, spatial interaction mapping, and prognostic significance of gene expression were assessed. A significant enrichment of ST6GAL1 was observed in the epithelial cells of ovarian cancer, particularly in peritoneal metastases, which exhibited elevated metabolic activity compared to primary tumors. The levels of ST6GAL1 were significantly high in peritumoral and adjacent non-tumorous tissues, with increased metabolic activity, while the tumor core demonstrated ST6GAL1-negative epithelial cells. Extensive cell-cell communication and transcription factor networks were unraveled, potentially influencing vascular permeability and intracellular signaling. Clinically, high expression of ST6GAL1 in epithelial cells is associated with diminished progression-free survival, indicating its prognostic potential. In conclusion, ST6GAL1 is likely to significantly impact the progression and metastasis of ovarian cancer.

Dengue viruses (DENV) are transmitted to humans through mosquito bites and infect millions globally. DENV uses heparan sulfate (HS) for attachment and cell entry by binding the envelope protein to highly sulfated HS on target cells. Therefore, inhibiting the binding between DENV and HS could be a promising strategy for preventing DENV infection. In the current study, the interactions between DENV envelope protein (from Type 2 DENV) and heparin (a surrogate for HS) were analyzed using competition solution SPR. Results demonstrate that heparin binds to DENV envelope protein with high affinity (K_D = 8.83 nM). Competitive Solution SPR assays using surface-immobilized heparin and a series of naturally-sourced and semi-synthetic sulfated glycans demonstrated significant inhibitory activity against the binding of DENV envelope proteins to heparin. This study of molecular interactions could provide insights into the development of therapeutics for DENV infection.

Glycoconjugates, including glycans on proteins and lipids, have obtained significant attention due to their critical roles in both intracellular and intercellular biological functions and processes. Notably, recent discoveries have revealed the presence of glycosylated RNAs (glycoRNAs) on cell surfaces. Despite the well-characterized roles of RNA modifications, RNA glycosylation remains relatively unexplored. In this study, we investigate the relationship between N-glycosylation and RNA glycosylation. Using a recombinant Siglec11-Fc as a probe, we detected surface sialylated glycoRNAs in human cell lines and identified their dependency on the catalytic isoforms of the oligosaccharyltransferase (OST) complex, implicating STT3A-dependent protein glycosylation as a predominant contributor for affecting indirect generation of glycoRNAs. Additionally, perturbations in N-glycan biosynthesis pathways or changes in N-glycan structure impact surface sialylated glycoRNA levels, indicating a regulatory role of glycan metabolic pathways in RNA glycosylation. Together, our results underscore the intricate relationship between protein N-glycosylation and processing and RNA biology.

Lysosomal storage diseases (LSDs) are genetic disorders caused by mutations in lysosomal enzymes, lysosomal membrane proteins or genes related to intracellular transport that result in impaired lysosomal function. Currently, the primary treatment for several LSDs is enzyme replacement therapy (ERT), which involves intravenous administration of the deficient lysosomal enzymes to ameliorate symptoms. The efficacy of ERT largely depends on the mannose-6-phosphate (M6P) modification of the N-glycans associated with the enzyme, as M6P is a marker for the recognition and trafficking of lysosomal enzymes. In cells, N-glycan processing and M6P modification occur in the endoplasmic reticulum and Golgi apparatus. This is a complex process involving multiple enzymes. In the trans-Golgi network (TGN), M6P-modified enzymes are recognized by the cation-independent mannose-6-phosphate receptor (CIMPR) and transported to the lysosome to exert their activities. In this study, we used the 9th domain of CIMPR, which exhibits a high affinity for M6P binding, and fused it with the Fc domain of human immunoglobulin G₁ (IgG₁). The resulting fusion protein specifically binds to M6P-modified proteins. This provides a tool for the rapid detection and concentration of M6P-containing recombinant enzymes to assess the effectiveness of ERT. The advantages of this approach include its high specificity and sensitivity and may lead to the development of new treatments for LSDs.