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Nature Aging Mar 2022Impaired T cell immunity with aging increases mortality from infectious disease. The branching of Asparagine-linked glycans is a critical negative regulator of T cell...
Impaired T cell immunity with aging increases mortality from infectious disease. The branching of Asparagine-linked glycans is a critical negative regulator of T cell immunity. Here we show that branching increases with age in females more than males, in naïve more than memory T cells, and in CD4 more than CD8 T cells. Female sex hormones and thymic output of naïve T cells (T) decrease with age, however neither thymectomy nor ovariectomy altered branching. Interleukin-7 (IL-7) signaling was increased in old female more than male mouse T cells, and triggered increased branching. N-acetylglucosamine, a rate-limiting metabolite for branching, increased with age in humans and synergized with IL-7 to raise branching. Reversing elevated branching rejuvenated T cell function and reduced severity of infection in old female mice. These data suggest sex-dimorphic antagonistic pleiotropy, where IL-7 initially benefits immunity through T maintenance but inhibits T function by raising branching synergistically with age-dependent increases in N-acetylglucosamine.
Topics: Humans; Male; Female; Animals; Mice; CD8-Positive T-Lymphocytes; Acetylglucosamine; Interleukin-7; Aging; Polysaccharides
PubMed: 35528547
DOI: 10.1038/s43587-022-00187-y -
Frontiers in Immunology 2023Upregulation of surface expressed sialoglycans on tumor cells is one of the mechanisms which promote tumor growth and progression. Specifically, the interactions of...
Upregulation of surface expressed sialoglycans on tumor cells is one of the mechanisms which promote tumor growth and progression. Specifically, the interactions of sialic acids with sialic acid-binding immunoglobulin-like lectins (Siglecs) on lymphoid or myeloid cells transmit inhibitory signals and lead to suppression of anti-tumor responses. Here, we show that neutrophils express among others Siglec-9, and that EGFR and HER2 positive breast tumor cells express ligands for Siglec-9. Treatment of tumor cells with neuraminidases or a sialyl transferase inhibitor significantly reduced binding of a soluble recombinant Siglec-9-Fc fusion protein, while EGFR and HER2 expression remained unchanged. Importantly, the cytotoxic activity of neutrophils driven by therapeutic EGFR or HER2 antibodies was increased by blocking the sialic acid/Siglec interaction, either by reducing tumor cell sialylation or by a Siglec-9 blocking antibody containing an effector silenced Fc domain. a short-term xenograft mouse model confirmed the improved therapeutic efficacy of EGFR antibodies against sialic acid depleted, by a sialyltransferase inhibitor, tumor cells compared to untreated cells. Our studies demonstrate that sialic acid/Siglec interactions between tumor cells and myeloid cells can impair antibody dependent tumor cell killing, and that Siglec-9 on polymorphonuclear cells (PMN) is critically involved. Considering that PMN are often a highly abundant cell population in the tumor microenvironment, Siglec-9 constitutes a promising target for myeloid checkpoint blockade to improve antibody-based tumor immunotherapy.
Topics: Humans; Mice; Animals; N-Acetylneuraminic Acid; Neutrophils; Sialic Acid Binding Immunoglobulin-like Lectins; Neoplasms; Antibodies; Sialic Acids; ErbB Receptors; Tumor Microenvironment
PubMed: 37346044
DOI: 10.3389/fimmu.2023.1178817 -
Current Opinion in Structural Biology Jun 2021O-GlcNAcylation is an enzymatic post-translational modification occurring in hundreds of protein substrates. This modification occurs through the addition of the... (Review)
Review
O-GlcNAcylation is an enzymatic post-translational modification occurring in hundreds of protein substrates. This modification occurs through the addition of the monosaccharide N-acetylglucosamine to serine and threonine residues on intracellular proteins in the cytosol, nucleus, and mitochondria. As a highly dynamic form of modification, changes in O-GlcNAc levels coincide with alterations in metabolic state, the presence of stressors, and cellular health. At the protein level, the consequences of the sugar modification can vary, thus necessitating biochemical investigations on protein-specific and site-specific effects. To this end, enzymatic and chemical methods to 'encode' the modification have been developed and the utilization of these synthetic glycopeptides and glycoproteins has since been instrumental in the discovery of the mechanisms by which O-GlcNAcylation can affect a diverse array of biological processes.
Topics: Acetylglucosamine; Glycoproteins; Peptides; Protein Processing, Post-Translational
PubMed: 33434850
DOI: 10.1016/j.sbi.2020.12.005 -
Journal of Enzyme Inhibition and... Dec 2019Allosamidins come from the secondary metabolites of species, and they have the pseudotrisaccharide structures. Allosamidins are chitinase inhibitors that can be used to... (Review)
Review
Allosamidins come from the secondary metabolites of species, and they have the pseudotrisaccharide structures. Allosamidins are chitinase inhibitors that can be used to study the physiological effects of chitinases in a variety of organisms. They have the novel antiasthmatic activity and insecticidal/antifungal activities. Herein, the synthesis and activities of allosamidins were summarized and analyzed.
Topics: Acetylglucosamine; Animals; Anti-Asthmatic Agents; Antifungal Agents; Asthma; Fungi; Humans; Insecticides; Molecular Conformation; Moths; Streptomyces; Trisaccharides
PubMed: 31307248
DOI: 10.1080/14756366.2019.1623208 -
Frontiers in Endocrinology 2022Although traditionally considered a glucose metabolism-associated modification, the -linked β-N-Acetylglucosamine (GlcNAc) regulatory system interacts extensively with... (Review)
Review
Although traditionally considered a glucose metabolism-associated modification, the -linked β-N-Acetylglucosamine (GlcNAc) regulatory system interacts extensively with lipids and is required to maintain lipid homeostasis. The enzymes of GlcNAc cycling have molecular properties consistent with those expected of broad-spectrum environmental sensors. By direct protein-protein interactions and catalytic modification, -GlcNAc cycling enzymes may provide both acute and long-term adaptation to stress and other environmental stimuli such as nutrient availability. Depending on the cell type, hyperlipidemia potentiates or depresses GlcNAc levels, sometimes biphasically, through a diversity of unique mechanisms that target UDP-GlcNAc synthesis and the availability, activity and substrate selectivity of the glycosylation enzymes, -GlcNAc Transferase (OGT) and -GlcNAcase (OGA). At the same time, OGT activity in multiple tissues has been implicated in the homeostatic regulation of systemic lipid uptake, storage and release. Hyperlipidemic patterns of -GlcNAcylation in these cells are consistent with both transient physiological adaptation and feedback uninhibited obesogenic and metabolic dysregulation. In this review, we summarize the numerous interconnections between lipid and GlcNAc metabolism. These links provide insights into how the GlcNAc regulatory system may contribute to lipid-associated diseases including obesity and metabolic syndrome.
Topics: Acetylglucosamine; Glucose; Glycosylation; Lipids; Uridine Diphosphate
PubMed: 36111295
DOI: 10.3389/fendo.2022.943576 -
International Journal of Molecular... Sep 2022The interaction between selective nutrients and linked genes involving a specific organ reveals the genetic make-up of an individual in response to a particular... (Review)
Review
The interaction between selective nutrients and linked genes involving a specific organ reveals the genetic make-up of an individual in response to a particular nutrient. The interaction of genes with food opens opportunities for the addition of bioactive compounds for specific populations comprising identical genotypes. The slight difference in the genetic blueprints of humans is advantageous in determining the effect of nutrients and their metabolism in the body. The basic knowledge of emerging nutrigenomics and nutrigenetics can be applied to optimize health, prevention, and treatment of diseases. In addition, nutrient-mediated pathways detecting the cellular concentration of nutrients such as sugars, amino acids, lipids, and metabolites are integrated and coordinated at the organismal level via hormone signals. This review deals with the interaction of nutrients with various aspects of nutrigenetics and nutrigenomics along with pathways involved in nutrient sensing and regulation, which can provide a detailed understanding of this new leading edge in nutrition research and its potential application to dietetic practice.
Topics: Amino Sugars; Diet; Hormones; Humans; Lipids; Nutrients; Nutrigenomics; Perception
PubMed: 36232603
DOI: 10.3390/ijms231911305 -
Journal of Molecular Cell Biology Feb 2023O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) is a highly dynamic and widespread post-translational modification (PTM) that regulates the activity, subcellular... (Review)
Review
O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) is a highly dynamic and widespread post-translational modification (PTM) that regulates the activity, subcellular localization, and stability of target proteins. O-GlcNAcylation is a reversible PTM controlled by two cycling enzymes: O-linked N-acetylglucosamine transferase and O-GlcNAcase. Emerging evidence indicates that O-GlcNAcylation plays critical roles in innate immunity, inflammatory signaling, and cancer development. O-GlcNAcylation usually occurs on serine/threonine residues, where it interacts with other PTMs, such as phosphorylation. Thus, it likely has a broad regulatory scope. This review discusses the recent research advances regarding the regulatory roles of O-GlcNAcylation in innate immunity and inflammation. A more comprehensive understanding of O-GlcNAcylation could help to optimize therapeutic strategies regarding inflammatory diseases and cancer.
Topics: Humans; Protein Processing, Post-Translational; Phosphorylation; Neoplasms; Immunity, Innate; Inflammation; Acetylglucosamine
PubMed: 36473120
DOI: 10.1093/jmcb/mjac065 -
The Journal of Biological Chemistry 2021The elongated antennae decorating eukaryotic glycans are built from polylactosamine repeats. Polylactosamine forms a lectin recognition site and also acts as a platform...
The elongated antennae decorating eukaryotic glycans are built from polylactosamine repeats. Polylactosamine forms a lectin recognition site and also acts as a platform for presenting diverse additional modifications (e.g., terminal cell-surface antigens); it therefore plays important roles in cell adherence, development, and immunity. Two new papers present a detailed structural and mechanistic investigation of β1-3-N-acetylgucosaminyltransferase 2, a key enzyme in antennae synthesis. The resulting insights will also help decipher other members of GT31, the single largest human glycosyltransferase family.
Topics: Amino Sugars; Glycosylation; N-Acetylglucosaminyltransferases; Polysaccharides
PubMed: 33453284
DOI: 10.1016/j.jbc.2020.100212 -
Chemistry (Weinheim An Der Bergstrasse,... Sep 2020The O-linked β-N-acetylglucosamine (O-GlcNAc) modification, termed O-GlcNAcylation, is an essential and dynamic post-translational modification in cells. O-GlcNAc... (Review)
Review
The O-linked β-N-acetylglucosamine (O-GlcNAc) modification, termed O-GlcNAcylation, is an essential and dynamic post-translational modification in cells. O-GlcNAc transferase (OGT) installs this modification on serine and threonine residues, whereas O-GlcNAcase (OGA) hydrolyzes it. O-GlcNAc modifications are found on thousands of intracellular proteins involved in diverse biological processes. Dysregulation of O-GlcNAcylation and O-GlcNAc cycling enzymes has been detected in many diseases, including cancer, diabetes, cardiovascular and neurodegenerative diseases. Here, recent advances in the development of molecular tools to investigate OGT and OGA functions and substrate recognition are discussed. New chemical approaches to study O-GlcNAc dynamics and its potential roles in the immune system are also highlighted. It is hoped that this minireview will encourage more research in these areas to advance the understanding of O-GlcNAc in biology and diseases.
Topics: Acetylglucosamine; N-Acetylglucosaminyltransferases; Protein Processing, Post-Translational; Serine; Threonine; beta-N-Acetylhexosaminidases
PubMed: 32207184
DOI: 10.1002/chem.202000155 -
International Journal of Molecular... Sep 2022Jellyfishes are considered a new potential resource in food, pharmaceutical and biomedical industries. In these latter cases, they are studied as source of active...
Jellyfishes are considered a new potential resource in food, pharmaceutical and biomedical industries. In these latter cases, they are studied as source of active principles but are also exploited to produce marine collagen. In the present work, jellyfish skin polysaccharides (JSP) with glycosaminoglycan (GAG) features were extracted from , a main blooming species of Mediterranean Sea, massively augmented by climate leaded "jellyfishication" of the sea. Two main fractions of JSP (RP-JSPs) were isolated and characterized, namely a neutral fraction (RP-JSP1) and a sulphate rich, negatively charged fraction (RP-JSP2). The two fractions have average molecular weights of 121 kDa and 590 kDa, respectively. Their sugar composition was evaluated through LC-MS analysis and the result confirmed the presence of typical GAG saccharides, such as glucose, galactose, glucosamine and galactosamine. Their use as promoters of wound healing was evaluated through in vitro scratch assay on murine fibroblast cell line (BALB/3T3 clone A31) and human keratinocytes (HaCaT). Both RP-JSPs demonstrated an effective confluency rate activity leading to 80% of scratch repair in two days, promoting both cell migration and proliferation. Additionally, RP-JSPs exerted a substantial protection from oxidative stress, resulting in improved viability of treated fibroblasts exposed to HO. The isolated GAG-like polysaccharides appear promising as functional component for biomedical skin treatments, as well as for future exploitation as pharmaceutical excipients.
Topics: Animals; Carbohydrates; Cnidaria; Collagen; Excipients; Fibroblasts; Galactosamine; Galactose; Glucosamine; Glucose; Glycosaminoglycans; Humans; Hydrogen Peroxide; Mice; Polysaccharides; Scyphozoa; Sulfates; Wound Healing
PubMed: 36232791
DOI: 10.3390/ijms231911491