Progress in the Studies of Triterpene Glycosides From Sea Cucumbers (Holothuroidea, Echinodermata) Between 2017 and 2021

Structural diversity of triterpene glycosides produced by sea cucumbers or holothurians (Holothuroidea, Echinodermata) is extremely high, although all of them are either lanostane derivatives or, rarely, products of their molecular rearrangements. The majority of them are holostane derivatives possessing an 18(20)-lanostane lactone as aglycone. They contain carbohydrate chains consisting of one to six monosaccharide units including sulfated ones. The glycosides demonstrate interesting biological activities, mainly caused by membranolytic action, namely cytotoxic, ichthyotoxic, antifungal, and hemolytic properties, as well as a series of additional effects at sub-toxic doses, including immunomodulatory, and cancer preventive. This review summarizes the literature data concerning structures and biological activities of all the new triterpene glycosides isolated from sea cucumbers during 2017 to 2021.

Dectin-2 mediates phagocytosis of Lactobacillus paracasei KW3110 and IL-10 production by macrophages

Lactic acid bacteria (LAB) are most generally used as probiotics and some strains of LAB are known to have anti-inflammatory effects. A specific strain of lactic acid bacteria, Lactobacillus paracasei KW3110 (KW3110), activates macrophages to produce interleukin-10 (IL-10), an anti-inflammatory cytokine; however, the biological mechanism remains unclear. In this study, we showed that the amount of incorporated KW3110 into a macrophage cell line, RAW 264.7, was higher than other genetically related strains using fluorescence microscopy. RNA-seq analysis indicated that treatment of macrophages with KW3110 induced Dectin-2 gene expression, which is a pattern recognition receptor, recognizing α-mannose. In addition, antibody treatment and knock down of Dectin-2, or factors downstream in the signaling pathway, decreased the amount of incorporated KW3110 and IL-10 production. Substantial lectin array analysis also revealed that KW3110 had higher binding affinities to lectins, which recognize the carbohydrate chains comprised of α-mannose, than two other LAB. In conclusion, KW3110 is readily incorporated into macrophages, leading to IL-10 production. Dectin-2 mediated the phagocytosis of KW3110 into macrophages and this may be involved with the characteristic carbohydrate chains of KW3110.

Correlation of N-glycan dynamics and interaction network with allosteric antigen binding and Fc receptor recognition

Aim: Fragment crystallizable (Fc) glycans modulate Fc conformations and functions, and glycan may also regulate antigen recognition. In the antibody drug development, glycosylation patterns affect antibody drug characteristics and quality control. In order to provide a global feature of N-glycan interactions in response to antigen and Fc receptor bindings, the interactions among Fc N-glycans and N-glycans’ interaction with Fc CH2 and CH3 domains have been studied. Methods: Molecular dynamics simulations were used to generate conformation ensembles of free antibody, antibody-antigen complex, antibody-human Fc-gamma-receptor-I (hFcγRI) and antibody-antigen-hFcγRI, the hydrogen bonds and radial distance distribution involving N-glycans carbohydrate chains have been analyzed. Results: Two important interaction patterns have been observed. The first is the strong but non-specific interactions between two carbohydrate chains in free antibody. Secondly, it has been found that N-glycans carbohydrate chains can directly interact with CH3 domain in free antibody, and that the distance distribution between carbohydrate chains and CH3 domain clearly differentiate the free antibody, antibody-antigen complex, antibody-hFcγRI complex, and final antibody-antigen-hFcγRI complex. Conclusions: N-glycans partially acts as allosteric sensor and respond to antigen and hFcγRI binding.

Triterpene Glycosides from the Far Eastern Sea Cucumber Thyonidium (=Duasmodactyla) kurilensis (Levin): The Structures, Cytotoxicities, and Biogenesis of Kurilosides A3, D1, G, H, I, I1, J, K, and K1

Nine new mono-, di-, and trisulfated triterpene penta- and hexaosides, kurilosides A3 (1), D1 (2), G (3), H (4), I (5), I1 (6), J (7), K (8), and K1 (9) and two desulfated derivatives, DS-kuriloside L (10), having a trisaccharide branched chain, and DS-kuriloside M (11), having hexa-nor-lanostane aglycone with a 7(8)-double bond, have been isolated from the Far-Eastern deep-water sea cucumber Thyonidium (=Duasmodactyla) kurilensis (Levin) and their structures were elucidated based on 2D NMR spectroscopy and HR-ESI mass-spectrometry. Five earlier unknown carbohydrate chains and two aglycones (having a 16β,(20S)-dihydroxy-fragment and a 16β-acetoxy,(20S)-hydroxy fragment) were found in these glycosides. All the glycosides 1–9 have a sulfate group at C-6 Glc, attached to C-4 Xyl1, while the positions of the other sulfate groups vary in different groups of kurilosides. The analysis of the structural features of the aglycones and the carbohydrate chains of all the glycosides of T. kurilensis showed their biogenetic relationships. Cytotoxic activities of the compounds 1–9 against mouse neuroblastoma Neuro 2a, normal epithelial JB-6 cells, and erythrocytes were studied. The highest cytotoxicity in the series was demonstrated by trisulfated hexaoside kuriloside H (4), having acetoxy-groups at C(16) and C(20), the latter one obviously compensated the absence of a side chain, essential for the membranolytic action of the glycosides. Kuriloside I1 (6), differing from 4 in the lacking of a terminal glucose residue in the bottom semi-chain, was slightly less active. The compounds 1–3, 5, and 8 did not demonstrate cytotoxic activity due to the presence of hydroxyl groups in their aglycones.

Tandem Electrospray Mass Spectrometry of Cyclic N-Substituted Oligo-β-(1→6)-D-glucosamines

High-resolution electrospray mass spectra (MS and MS/MS CID) of positive ions of a series of protonated, ammoniated, and metallated molecules of cyclic N-substituted oligo-β-(1→6)-D-glucosamines differing in cycle size and N-acyl substituents were registered and interpreted. It was shown that the main type of fragmentation is a cleavage of glycosidic bonds of a cycle, and in some cases fragmentation of amide side chains is possible. If labile fragments in substituents (e.g., carbohydrate chains) are present, a decay of the cycle and an elimination of labile fragments are of comparable possibility. It was found that in some cases rearrangements with loss of an internal carbohydrate residue (IRL), or an internal part of a side chain, are feasible.

Tumor-associated carbohydrates and immunomodulatory lectins as targets for cancer immunotherapy

During oncogenesis, tumor cells present specific carbohydrate chains that are new targets for cancer immunotherapy. Whereas these tumor-associated carbohydrates (TACA) can be targeted with antibodies and vaccination approaches, TACA including sialic acid-containing glycans are able to inhibit anticancer immune responses by engagement of immune receptors on leukocytes. A family of immune-modulating receptors are sialic acid-binding Siglec receptors that have been recently described to inhibit antitumor activity mediated by myeloid cells, natural killer cells and T cells. Other TACA-binding receptors including selectins have been linked to cancer progression. Recent studies have shown that glycan-lectin interactions can be targeted to improve cancer immunotherapy. For example, interactions between the immune checkpoint T cell immunoglobulin and mucin-domain containing-3 and the lectin galectin-9 are targeted in clinical trials. In addition, an antibody against the lectin Siglec-15 is being tested in an early clinical trial. In this review, we summarize the previous and current efforts to target TACA and to inhibit inhibitory immune receptors binding to TACA including the Siglec-sialoglycan axis.

POLYSACCHARIDES OF THREE SAUSSUREA DC SPECIES (S. CONTROVERSA, S. SALICIFOLIA, S. FROLOVII): ISOLATION, CHARACTERIZATION AND INFLUENCE ON NO-PRODUCING PROPERTIES OF MACROPHAGES

Polysaccharides PS1 and PS2 with a yield 1–2% were obtained from the above-ground part of three species of Saussurea: S. controversa DC., S. salicifolia L. and S. frolovii Ledeb. sequential extraction with water at 25 and 70 °C. PS1 free from protein impurities. A protein that is not removed by the Sevag method is co-extracted with PS2. All polysaccharides contain residues of uronic acids, the highest content found in PS1 and PS2 from S. contrоversa. The molecular weights (Mw) of PS1 from S. controversa, S. salicifolia and S. frolovii were 448.13, 158.49, 64.03 kDa and PS2 – 101.82, 94.60, 225.42 kDa, respectively. Interspecific differences in the monosaccharide composition of polysaccharides were revealed. Galactose (Gal) and Arabinose (Ara) residues are major, and Rhamnose (Rha), Xylose (Xyl) and Mannose (Man) residues are minor components of the carbohydrate chains isolated by PS. PS1 S. salicifolia and S. frolovii and PS2 S. salicifolia do not contain endotoxins impurities and have a NO-activating effect on antigen-presenting cells (macrophages), significantly exceeding the effect of muramyl dipeptide.