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Special Issue "Complex Carbohydrates and Glycoconjugates: Structure, Functions and Applications 2021"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: 28 February 2022.

Special Issue Editor

Dr. Alexander O. Chizhov
E-Mail Website
Guest Editor
N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Russia
Interests: carbohydrate analysis; carbohydrate structure; glycoconjugates; mass spectrometry; electrospray ionization; MALDI; fragmentation of ions; activation of ions; sample preparation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The study of carbohydrates has a long history, spanning across two centuries, during which research paved the way from “sweet matter” to glycomics. The complexity of cabohydrates under such studies grew enormously: The term “complex carbohydrates” includes large oligosaccharides (dozens of carbohydrate units) and polysaccharides, both regular and irregular. Carbohydrate studies were inevitably expanded to adjacent areas, which is reflected by the general term “glycoconjugate” (a compound, in which molecule carbohydrate part(s) is/are covalently bonded with noncarbohydrate part(s)).

At present, carbohydrate science is an integral part of molecular biology along with genomics and proteomics. It includes structural studies of glycans, glycoproteins, proteoglycans, glycolipids, and low-molecular and complex glycosides of plant, animal, fungal, and bacterial origin. Supramolecular structural studies such as cell wall reconstruction are developed. The functional studies of carbohydrates concern molecular recognition such as carbohydrate–lectin or glycoside–enzyme interactions, cell recognition (normal and in pathologies), viral adhesion/penetration, oligo- and polysaccharide biosynthesis, and many other phenomena. In such studies, artificial carbohydrate-containing molecular probes (synthetic glycoconjugates) are widely used now.

Structural and functional studies are extremely stimulated by the progress of instrumental methods, especially in chromatography, electrophoresis, multidimensional NMR spectrometry, high-resolution mass spectrometry, and surface plasmon resonance (SPR). There is no modern carbohydrate analysis without hyphenated techniques, such as HPLC-MS.

This Special Issue welcomes the submission of original research papers or comprehensive reviews that demonstrate or summarize significant advances in the field of carbohydrate chemistry and biochemistry. The papers may be devoted to targeted synthesis of complex carbohydrates and glycoconjugates, isolation and structure determination of complex carbohydrates and glycoconjugates, and elucidation of their biological activities. Papers concerning development of applications of instrumental methods in carbohydrate chemistry and biology are also welcome in this Special Issue. Critical reviews and discussion papers revealing problems and drawing future perspectives of the carbohydrate science are especially invited (though we are not looking for papers with a far too general focus). Nontargeted syntheses and manuscripts without chemical structures will not be considered. All molecular structures must be firmly established. Clinical trials and animal and cell testings are not suitable for this Special Issue if they are not strongly needed to support hypotheses or theories concerning structure–function correlations.

Dr. Alexander O. Chizhov
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Complex carbohydrates
  • Glycoconjugates
  • Structure
  • Oligosaccharides
  • Polysaccharides
  • Glycomics
  • Carbohydrate analysis
  • Carbohydrate synthesis
  • Glycoside bond
  • Glycoproteins
  • Proteoglycans
  • Molecular recognition
  • Lectin
  • Cell wall
  • Cell surface
  • Molecular probe
  • Biosynthesis of complex carbohydrates
  • High-resolution mass spectrometry
  • Nuclear magnetic resonance
  • Chromatography
  • Capillary electrophoresis

Published Papers (11 papers)

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Research

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Article
New Insights into the Structure of Kappa/Beta-Carrageenan: A Novel Potential Inhibitor of HIV-1
Int. J. Mol. Sci. 2021, 22(23), 12905; https://doi.org/10.3390/ijms222312905 - 29 Nov 2021
Viewed by 211
Abstract
New insights into the structure of the hybrid κ/β-carrageenan (κ/β-CRG) of the red alga Tichocarpus crinitus have been obtained. Carrageenan oligosaccharides were prepared through the chemical and enzymatic depolymerization of κ/β-CRG with κ-carrageenase and its the enzyme-resistant fraction. The composition and distribution of [...] Read more.
New insights into the structure of the hybrid κ/β-carrageenan (κ/β-CRG) of the red alga Tichocarpus crinitus have been obtained. Carrageenan oligosaccharides were prepared through the chemical and enzymatic depolymerization of κ/β-CRG with κ-carrageenase and its the enzyme-resistant fraction. The composition and distribution of the repetition units of κ/β- CRG were investigated by using the negative ion tandem MALDI-TOFMS and ESIMS method, which made it possible to prove and characterize the hybrid structure of this polysaccharide. An analysis revealed the blockwise distribution of the long β-blocks along the polysaccharide chain, with the inclusion of κ/β, μ/ν-blocks and some ι-blocks. Furthermore, the desulfated κ/β-CRG was shown to contain of –G–D– repeating units up to 3.5 kDa. Previous studies have demonstrated that CRGs suppress the replication of several viruses. Here, we established that κ/β-CRG and its oligosaccharides significantly inhibit the transduction efficiency of replication-defective lentiviral particles pseudotyped with the envelope proteins of three different viruses. We found that the polysaccharide and its oligosaccharides strongly reduced the transduction efficiency of lentiviral particles pseudotyped with GP160—the envelope protein of the human immunodeficiency virus HIV-1—when added to T-lymphocyte Jurkat cells. The CRG oligosaccharides displayed significantly higher antiviral activity. Full article
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Article
Structural Determination and Genetic Identification of the O-Antigen from an Escherichia coli Strain, LL004, Representing a Novel Serogroup
Int. J. Mol. Sci. 2021, 22(23), 12746; https://doi.org/10.3390/ijms222312746 - 25 Nov 2021
Viewed by 211
Abstract
The O-antigen is the outermost component of the lipopolysaccharide layer in Gram-negative bacteria, and the variation of O-antigen structure provides the basis for bacterial serological diversity. Here, we determined the O-antigen structure of an Escherichia coli strain, LL004, which is totally different from [...] Read more.
The O-antigen is the outermost component of the lipopolysaccharide layer in Gram-negative bacteria, and the variation of O-antigen structure provides the basis for bacterial serological diversity. Here, we determined the O-antigen structure of an Escherichia coli strain, LL004, which is totally different from all of the E. coli serogroups. The tetrasaccharide repeating unit was determined as →4)-β-d-Galp-(1→3)-β-d-GlcpNAc6OAc(~70%)-(1→3)-β-d-GalpA-(1→3)-β-d-GalpNAc-(1→ with monosaccharide analysis and NMR spectra. We also characterized the O-antigen gene cluster of LL004, and sequence analysis showed that it correlated well with the O-antigen structure. Deletion and complementation testing further confirmed its role in O-antigen biosynthesis, and indicated that the O-antigen of LL004 is assembled via the Wzx/Wzy dependent pathway. Our findings, in combination, suggest that LL004 should represent a novel serogroup of E. coli. Full article
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Article
Midecamycin Is Inactivated by Several Different Sugar Moieties at Its Inactivation Site
Int. J. Mol. Sci. 2021, 22(23), 12636; https://doi.org/10.3390/ijms222312636 - 23 Nov 2021
Viewed by 185
Abstract
Glycosylation inactivation is one of the important macrolide resistance mechanisms. The accumulated evidences attributed glycosylation inactivation to a glucosylation modification at the inactivation sites of macrolides. Whether other glycosylation modifications lead to macrolides inactivation is unclear. Herein, we demonstrated that varied glycosylation modifications [...] Read more.
Glycosylation inactivation is one of the important macrolide resistance mechanisms. The accumulated evidences attributed glycosylation inactivation to a glucosylation modification at the inactivation sites of macrolides. Whether other glycosylation modifications lead to macrolides inactivation is unclear. Herein, we demonstrated that varied glycosylation modifications could cause inactivation of midecamycin, a 16-membered macrolide antibiotic used clinically and agriculturally. Specifically, an actinomycetic glycosyltransferase (GT) OleD was selected for its glycodiversification capacity towards midecamycin. OleD was demonstrated to recognize UDP-D-glucose, UDP-D-xylose, UDP-galactose, UDP-rhamnose and UDP-N-acetylglucosamine to yield corresponding midecamycin 2′-O-glycosides, most of which displayed low yields. Protein engineering of OleD was thus performed to improve its conversions towards sugar donors. Q327F was the most favorable variant with seven times the conversion enhancement towards UDP-N-acetylglucosamine. Likewise, Q327A exhibited 30% conversion enhancement towards UDP-D-xylose. Potent biocatalysts for midecamycin glycosylation were thus obtained through protein engineering. Wild OleD, Q327F and Q327A were used as biocatalysts for scale-up preparation of midecamycin 2′-O-glucopyranoside, midecamycin 2′-O-GlcNAc and midecamycin 2′-O-xylopyranoside. In contrast to midecamycin, these midecamycin 2′-O-glycosides displayed no antimicrobial activities. These evidences suggested that besides glucosylation, other glycosylation patterns also could inactivate midecamycin, providing a new inactivation mechanism for midecamycin resistance. Cumulatively, glycosylation inactivation of midecamycin was independent of the type of attached sugar moieties at its inactivation site. Full article
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Article
Chemoenzymatic Synthesis and Antibody Binding of HIV-1 V1/V2 Glycopeptide-Bacteriophage Qβ Conjugates as a Vaccine Candidate
Int. J. Mol. Sci. 2021, 22(22), 12538; https://doi.org/10.3390/ijms222212538 - 21 Nov 2021
Viewed by 244
Abstract
The broadly neutralizing antibody PG9 recognizes a unique glycopeptide epitope in the V1V2 domain of HIV-1 gp120 envelope glycoprotein. The present study describes the design, synthesis, and antibody-binding analysis of HIV-1 V1V2 glycopeptide-Qβ conjugates as a mimic of the proposed neutralizing epitope [...] Read more.
The broadly neutralizing antibody PG9 recognizes a unique glycopeptide epitope in the V1V2 domain of HIV-1 gp120 envelope glycoprotein. The present study describes the design, synthesis, and antibody-binding analysis of HIV-1 V1V2 glycopeptide-Qβ conjugates as a mimic of the proposed neutralizing epitope of PG9. The glycopeptides were synthesized using a highly efficient chemoenzymatic method. The alkyne-tagged glycopeptides were then conjugated to the recombinant bacteriophage (Qβ), a virus-like nanoparticle, through a click reaction. Antibody-binding analysis indicated that the synthetic glycoconjugates showed significantly enhanced affinity for antibody PG9 compared with the monomeric glycopeptides. It was also shown that the affinity of the Qβ-conjugates for antibody PG9 was dependent on the density of the glycopeptide antigen display. The glycopeptide-Qβ conjugates synthesized represent a promising candidate of HIV-1 vaccine. Full article
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Article
Comparison and Optimization of Quantification Methods for Shigella flexneri Serotype 6 O-antigen Containing Galacturonic Acid and Methyl-Pentose
Int. J. Mol. Sci. 2021, 22(22), 12160; https://doi.org/10.3390/ijms222212160 - 10 Nov 2021
Viewed by 435
Abstract
Shigella is a leading diarrheal cause of morbidity and mortality worldwide, especially in low- and middle-income countries and in children under five years of age. Increasing levels of antimicrobial resistance make vaccine development an even higher global health priority. S. flexneri serotype 6 [...] Read more.
Shigella is a leading diarrheal cause of morbidity and mortality worldwide, especially in low- and middle-income countries and in children under five years of age. Increasing levels of antimicrobial resistance make vaccine development an even higher global health priority. S. flexneri serotype 6 is one of the targets of many multicomponent vaccines in development to ensure broad protection against Shigella. The O-antigen (OAg) is a key active ingredient and its content is a critical quality attribute for vaccine release in order to monitor their stability and to ensure appropriate immune response. Here, the optimization of two methods to quantify S. flexneri 6 OAg is reported together with the characterization of their performances. The optimized Dische colorimetric method allows a tenfold increment of the sensitivity with respect to the original method and is useful for fast analysis detecting selectively methyl-pentoses, as rhamnose in S. flexneri 6 OAg. Also, a more specific HPAEC-PAD method was developed, detecting the dimer galacturonic acid-galactosamine (GalA-GalN) coming from S. flexneri 6 OAg acid hydrolysis. These methods will facilitate characterization of S. flexneri 6 OAg based vaccines. The colorimetric method can be used for quantification of other polysaccharide containing methyl-pentoses, and the HPAEC-PAD could be extended to other polysaccharides containing uronic acids. Full article
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Article
Characterization of Human Medullary Thyroid Carcinoma Glycosphingolipids Identifies Potential Cancer Markers
Int. J. Mol. Sci. 2021, 22(19), 10463; https://doi.org/10.3390/ijms221910463 - 28 Sep 2021
Viewed by 348
Abstract
Medullary thyroid carcinoma (MTC) accounts for only 1–2% of thyroid cancers; however, metastatic MTC is a mortal disease with no cure. In this study, glycosphingolipids were isolated from human MTCs and characterized by mass spectrometry and binding of carbohydrate recognizing ligands. The tissue [...] Read more.
Medullary thyroid carcinoma (MTC) accounts for only 1–2% of thyroid cancers; however, metastatic MTC is a mortal disease with no cure. In this study, glycosphingolipids were isolated from human MTCs and characterized by mass spectrometry and binding of carbohydrate recognizing ligands. The tissue distribution of selected compounds was investigated by immunohistochemistry. The amount of acid glycosphingolipids in the MTCs was higher than in the normal thyroid glands. The major acid glycosphingolipid was the GD3 ganglioside. Sulfatide and the gangliosides GM3 and GD1a were also present. The majority of the complex non-acid glycosphingolipids had type 2 (Galβ4GlcNAc) core chains, i.e., the neolactotetraosylceramide, the Lex, H type 2 and x2 pentaosylceramides, the Ley and A type 2 hexaosylceramides, and the A type 2 heptaosylceramide. There were also compounds with globo (GalαGalβ4Glc) core, i.e., globotriaosylceramide, globotetraosylceramide, the Forssman pentaosylceramide, and the Globo H hexaosylceramide. Immunohistochemistry demonstrated an extensive expression av Ley in the MTC cells and also a variable intensity and prevalence of Globo H and Lex. One individual with multiple endocrine neoplasia type 2B expressed the Forssman determinant, which is rarely found in humans. This study of human MTC glycosphingolipids identifies glycans that could serve as potential tumor-specific markers. Full article
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Article
Mass Spectrometric Evaluation of β-Cyclodextrins as Potential Hosts for Titanocene Dichloride
Int. J. Mol. Sci. 2021, 22(18), 9789; https://doi.org/10.3390/ijms22189789 - 10 Sep 2021
Viewed by 466
Abstract
Bent metallocene dichlorides (Cp2MCl2, M = Ti, Mo, Nb, …) have found interest as anti-cancer drugs in order to overcome the drawbacks associated with platinum-based therapeutics. However, they suffer from poor hydrolytic stability at physiological pH. A promising approach [...] Read more.
Bent metallocene dichlorides (Cp2MCl2, M = Ti, Mo, Nb, …) have found interest as anti-cancer drugs in order to overcome the drawbacks associated with platinum-based therapeutics. However, they suffer from poor hydrolytic stability at physiological pH. A promising approach to improve their hydrolytic stability is the formation of host-guest complexes with macrocyclic structures, such as cyclodextrins. In this work, we utilized nanoelectrospray ionization tandem mass spectrometry to probe the interaction of titanocene dichloride with β-cyclodextrin. Unlike the non-covalent binding of phenylalanine and oxaliplatin to β-cyclodextrin, the mixture of titanocene and β-cyclodextrin led to signals assigned as [βCD + Cp2Ti–H]+, indicating a covalent character of the interaction. This finding is supported by titanated cyclodextrin fragment ions occurring from collisional activation. Employing di- and trimethylated β-cyclodextrins as hosts enabled the elucidation of the influence of the cyclodextrin hydroxy groups on the interaction with guest structures. Masking of the hydroxy groups was found to impair the covalent interaction and enabling the encapsulation of the guest structure within the hydrophobic cavity of the cyclodextrin. Findings are further supported by breakdown curves obtained by gas-phase dissociation of the various complexes. Full article
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Article
Two Paralogous Gb3/CD77 Synthases in Birds Show Different Preferences for Their Glycoprotein and Glycosphingolipid Substrates
Int. J. Mol. Sci. 2021, 22(18), 9761; https://doi.org/10.3390/ijms22189761 - 09 Sep 2021
Viewed by 589
Abstract
Most glycosyltransferases show remarkable gross and fine substrate specificity, which is reflected in the old one enzyme-one linkage paradigm. While human Gb3/CD77 synthase is a glycosyltransferase that synthesizes the Galα1→4Gal moiety mainly on glycosphingolipids, its pigeon homolog prefers glycoproteins as acceptors. In this [...] Read more.
Most glycosyltransferases show remarkable gross and fine substrate specificity, which is reflected in the old one enzyme-one linkage paradigm. While human Gb3/CD77 synthase is a glycosyltransferase that synthesizes the Galα1→4Gal moiety mainly on glycosphingolipids, its pigeon homolog prefers glycoproteins as acceptors. In this study, we characterized two Gb3/CD77 synthase paralogs found in pigeons (Columba livia). We evaluated their specificities in transfected human teratocarcinoma 2102Ep cells by flow cytofluorometry, Western blotting, high-performance thin-layer chromatography, mass spectrometry and metabolic labelling with 14C-galactose. We found that the previously described pigeon Gb3/CD77 synthase (called P) can use predominately glycoproteins as acceptors, while its paralog (called M), which we serendipitously discovered while conducting this study, efficiently synthesizes Galα1→4Gal caps on both glycoproteins and glycosphingolipids. These two paralogs may underlie the difference in expression profiles of Galα1→4Gal-terminated glycoconjugates between neoavians and mammals. Full article
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Article
OGT Protein Interaction Network (OGT-PIN): A Curated Database of Experimentally Identified Interaction Proteins of OGT
Int. J. Mol. Sci. 2021, 22(17), 9620; https://doi.org/10.3390/ijms22179620 - 06 Sep 2021
Viewed by 953
Abstract
Interactions between proteins are essential to any cellular process and constitute the basis for molecular networks that determine the functional state of a cell. With the technical advances in recent years, an astonishingly high number of protein–protein interactions has been revealed. However, the [...] Read more.
Interactions between proteins are essential to any cellular process and constitute the basis for molecular networks that determine the functional state of a cell. With the technical advances in recent years, an astonishingly high number of protein–protein interactions has been revealed. However, the interactome of O-linked N-acetylglucosamine transferase (OGT), the sole enzyme adding the O-linked β-N-acetylglucosamine (O-GlcNAc) onto its target proteins, has been largely undefined. To that end, we collated OGT interaction proteins experimentally identified in the past several decades. Rigorous curation of datasets from public repositories and O-GlcNAc-focused publications led to the identification of up to 929 high-stringency OGT interactors from multiple species studied (including Homo sapiens, Mus musculus, Rattus norvegicus, Drosophila melanogaster, Arabidopsis thaliana, and others). Among them, 784 human proteins were found to be interactors of human OGT. Moreover, these proteins spanned a very diverse range of functional classes (e.g., DNA repair, RNA metabolism, translational regulation, and cell cycle), with significant enrichment in regulating transcription and (co)translation. Our dataset demonstrates that OGT is likely a hub protein in cells. A webserver OGT-Protein Interaction Network (OGT-PIN) has also been created, which is freely accessible. Full article
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Article
Acinetobacter baumannii K106 and K112: Two Structurally and Genetically Related 6-Deoxy-l-talose-Containing Capsular Polysaccharides
Int. J. Mol. Sci. 2021, 22(11), 5641; https://doi.org/10.3390/ijms22115641 - 26 May 2021
Cited by 4 | Viewed by 942
Abstract
Whole genome sequences of two Acinetobacter baumannii clinical isolates, 48-1789 and MAR24, revealed that they carry the KL106 and KL112 capsular polysaccharide (CPS) biosynthesis gene clusters, respectively, at the chromosomal K locus. The KL106 and KL112 gene clusters are related to the previously [...] Read more.
Whole genome sequences of two Acinetobacter baumannii clinical isolates, 48-1789 and MAR24, revealed that they carry the KL106 and KL112 capsular polysaccharide (CPS) biosynthesis gene clusters, respectively, at the chromosomal K locus. The KL106 and KL112 gene clusters are related to the previously described KL11 and KL83 gene clusters, sharing genes for the synthesis of l-rhamnose (l-Rhap) and 6-deoxy-l-talose (l-6dTalp). CPS material isolated from 48-1789 and MAR24 was studied by sugar analysis and Smith degradation along with one- and two-dimensional 1H and 13C NMR spectroscopy. The structures of K106 and K112 oligosaccharide repeats (K units) l-6dTalp-(1→3)-D-GlcpNAc tetrasaccharide fragment share the responsible genes in the respective gene clusters. The K106 and K83 CPSs also have the same linkage between K units. The KL112 cluster includes an additional glycosyltransferase gene, Gtr183, and the K112 unit includes α l-Rhap side chain that is not found in the K106 structure. K112 further differs in the linkage between K units formed by the Wzy polymerase, and a different wzy gene is found in KL112. However, though both KL106 and KL112 share the atr8 acetyltransferase gene with KL83, only K83 is acetylated. Full article
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Review

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Review
Prospects and Challenges of the Study of Anti-Glycan Antibodies and Microbiota for the Monitoring of Gastrointestinal Cancer
Int. J. Mol. Sci. 2021, 22(21), 11608; https://doi.org/10.3390/ijms222111608 - 27 Oct 2021
Viewed by 423
Abstract
Over the past decades, a large amount of data has been accumulated in various subfields of glycobiology. However, much clinically relevant data and many tools are still not widely used in medicine. Synthetic glycoconjugates with the known structure of glycans are an accurate [...] Read more.
Over the past decades, a large amount of data has been accumulated in various subfields of glycobiology. However, much clinically relevant data and many tools are still not widely used in medicine. Synthetic glycoconjugates with the known structure of glycans are an accurate tool for the study of glycan-binding proteins. We used polyacrylamide glycoconjugates (PGs) including PGs with tumour-associated glycans (TAGs) in immunoassays to assess the prognostic potential of the serum level of anti-glycan antibodies (AG Abs) in gastrointestinal cancer patients and found an association of AG Abs with survival. The specificity of affinity-isolated AG Abs was investigated using synthetic and natural glycoconjugates. AG Abs showed mainly a low specificity to tumour-associated and tumour-derived mucins; therefore, the protective role of the examined circulating AG Abs against cancer remains a challenge. In this review, our findings are analysed and discussed in the context of the contribution of bacteria to the AG Abs stimulus and cancer progression. Examples of the influence of pathogenic bacteria colonising tumours on cancer progression and patient survival through mechanisms of interaction with tumours and dysregulated immune response are considered. The possibilities and problems of the integrative study of AG Abs and the microbiome using high-performance technologies are discussed. Full article
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