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Enzymatic glycosylation is a versatile and sustainable biotechnological approach that plays a pivotal role in the production of bioactive compounds. This process involves the enzymatic transfer of sugar moieties onto various acceptor molecules, such as small molecules, peptides, or proteins, resulting in the synthesis of glycosides. These glycosides often exhibit enhanced bioactivity, improved solubility, and enhanced stability, making them valuable in pharmaceuticals, nutraceuticals, and the food industry. This review explores the diverse enzymatic glycosylation strategies employed in the synthesis of bioactive compounds. It highlights the enzymatic catalysts involved, including glycosyltransferases, glycosidases, glycophosphorylases, and glycosynthases. It considers the advantages and disadvantages of these biocatalysts in the stereoselective and regioselective synthesis of different types of glycosylated molecules, phenolic and aliphatic alcohols, oligosaccharides, polysaccharides, glycoderivatives, glycopeptides, and glycoproteins with a clear focus on food and pharmaceutical chemistry. Furthermore, the review outlines various sources of sugar donors, activated glycosides, and sugar nucleotides, as well as the utilization of engineered enzymes and microorganisms for glycosylation reactions. The advantages of enzymatic glycosylation, including its high regioselectivity, stereoselectivity, and sustainability, are emphasized. Therefore, these approaches combining the use of different catalytic systems, the improvement of tools such as immobilization technology or chemical or genetic modification to improve the glycosylation process, could be useful tools in continuous biotechnological advancements.

Bacteroides fragilis, a prominent commensal of the human gut microbiota, plays a vital role in immune system regulation through its capsular polysaccharide A (PSA), which requires a glycolipid anchor structurally reminiscent of lipid A. While canonical Escherichia coli lipid A acts as a potent TLR4 agonist contributing to septic shock and inflammatory disorders, certain B. fragilis-derived glycolipids demonstrate antagonistic effects, offering potential as anti-inflammatory agents. In this study, we report the synthesis and preliminary computational evaluation of a library of glycolipids inspired by B. fragilis lipid A. Three lipid As, including a tetra-acylated 1-phosphoryl lipid A analog (Tetra C-1), were synthesized and assessed using molecular docking simulations targeting the human TLR4/MD-2 complex. Docking results reveal that Tetra C-1 exhibits more favorable antagonist binding characteristics compared to the well-studied TLR4 antagonist Eritoran. This work highlights a microbiota-informed strategy for the development of novel TLR4 antagonists, potentially enabling targeted modulation of innate immunity for therapeutic applications in inflammatory diseases and as vaccine adjuvants.

Sodium–glucose co-transporter 1 (SGLT1) is primarily expressed on the membrane of enterocytes, a type of epithelial cell found in the intestines, where it mediates the unidirectional absorption of glucose and galactose. Beyond its well-established role in nutrient absorption, SGLT1 also plays a protective role in maintaining the integrity of the intestinal barrier. Specifically, the natural ligand of SGLT1 (d-glucose) and a synthetic C-glucoside developed by our group can induce a protective anti-inflammatory effect on the intestinal epithelium. In this paper, we report the creation of a small library of C-glycoside, putative ligands for SGLT1, to gain further insights into its unclear mechanism of action. Preliminary biological experiments performed on an in vitro model of doxorubicin-induced mucositis, a severe intestinal inflammatory condition, indicate that the aromatic moiety present in all the compounds of the library is crucial for biological activity, while the sugar component appears to have less influence. These findings will be exploited to develop new, more potent anti-inflammatory compounds and to better understand and rationalize the protective mechanism of action.

Background. Several research findings suggest that sodium–glucose co-transporter 1 (SGLT1) is implicated in the progression and control of infections and inflammation processes at the pulmonary level. Moreover, our previous works indicate an engagement of SGLT1 in inhibiting the inflammatory response induced in intestinal epithelial cells by TLR agonists. In this study, we report the anti-inflammatory effects observed in the lung upon engagement of the transporter, and upon the use of glucose and BLF501, a synthetic SGLT1 ligand, for the treatment of animal models of lung inflammation, including a model of allergic asthma. Methods. In vitro experiments were carried out on human pneumocytes stimulated with LPS from Pseudomonas aeruginosa and co-treated with glucose or BLF501, and the production of IL-8 was determined. The anti-inflammatory effect associated with SGLT1 engagement was then assessed in in vivo models of LPS-induced lung injury, as well as in a murine model of ovalbumin (OVA)-induced asthma, treating mice with aerosolized LPS and the synthetic ligand. After the treatments, lung samples were collected and analyzed for morphological alterations by histological examination and immunohistochemical analysis; serum and BALF samples were collected for the determination of several pro- and anti-inflammatory markers. Results. In vitro experiments on human pneumocytes treated with LPS showed significant inhibition of IL-8 production. The results of two in vivo experimental models, mice exposed to aerosolized LPS and OVA-induced asthma, revealed that the engagement of glucose transport protein 1 (SGLT1) induced a significant anti-inflammatory effect in the lungs. In the first model, the acute respiratory distress induced in mice was abrogated by co-treatment with the ligand, with almost complete recovery of the lung morphology and physiology. Similar results were observed in the OVA-induced model of allergic asthma, both with aerosolized and oral BLF501, suggesting an engagement of SGLT1 expressed both in intestinal and alveolar cells. Conclusions. Our results confirmed the engagement of SGLT1 in lung inflammation processes and suggested that BLF501, a non-metabolizable synthetic ligand of the co-transporter, might represent a drug candidate for therapeutic intervention against lung inflammation states.

Sodium–glucose co-transporter 1 (SGLT1) and sodium-dependent neutral amino acid transporter (B0AT1) are mainly expressed on the membrane of enterocytes, a type of epithelial cell found in the intestines. In addition to their physiological role in the absorption of nutrients, a protective role in the integrity of the intestinal barrier has been established. The natural ligands of SGLT1 (d-glucose) and of B0AT1 (l-glutamine) can trigger a protective anti-inflammatory effect on the intestinal epithelium. The literature suggests the activation of common intracellular pathways upon engagement of the two transporters, whose functional forms are composed of oligomers or clusters. Simultaneous activation of these two co-transporters could lead to a potential multitarget and synergistic anti-inflammatory effect. Therefore, nanoplatforms containing multiple copies of the ligands could represent chemical tools to study the potential simultaneous activation of the two co-transporters. For these reasons, in this study, a set of different gold nanoparticles decorated with derivatives of d-glucose and of l-glutamine were designed and prepared. In particular, the synthesis of suitable sulfur-ending functionalized ligand derivatives, including a C-glucoside derivative, their anchoring to gold nanoparticles and their physical–chemical characterization have been carried out. The obtained nanostructures could represent promising multifunctional platforms for further investigation of the existence of possible multitarget and synergistic effects toward the two co-transporters SGLT1 and B0AT1.

Gold nanoparticles (AuNPs) are a promising tool for drug delivery due to their unique chemical properties that make them biocompatible and easy to functionalize. However, when AuNPs are introduced into biological systems, they are coated by the so-called protein corona (PC), which affects their biodistribution and limits their therapeutic efficacy. The functionalization of AuNPs with endogenous carbohydrates can be a possible strategy to reduce immune recognition, thus enhancing their biocompatibility and circulation time. Suitable candidates for this approach are the ABO blood sugar antigens, di- and tri-saccharides that represent the terminal portion of some glycolipids and glycoproteins present on the surface of human red blood cells and other tissues. In this work, we illustrate the synthesis of trisaccharide antigen A derivative, whose last step is worthy of investigation. During the final hydrogenolysis reaction, intended to remove protecting groups, an unexpected side reaction occurred, the isolated product bearing an N,N-dimethyl moiety on the anomeric propyl linker. This side reaction might be ascribed to the in situ formation of formaldehyde and successive imine formation and reduction. The obtained compound can be used as a monomeric control compound in biochemical and structural biology studies involving ABO blood sugar antigens.