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Cells Feb 2022Unresolved hyperglycaemia, a hallmark of type 2 diabetes mellitus (T2DM), is a well characterised manifestation of altered fuel homeostasis and our understanding of its... (Review)
Review
Unresolved hyperglycaemia, a hallmark of type 2 diabetes mellitus (T2DM), is a well characterised manifestation of altered fuel homeostasis and our understanding of its role in the pathologic activation of the inflammatory system continues to grow. Metabolic disorders like T2DM trigger changes in the regulation of key cellular processes such as cell trafficking and proliferation, and manifest as chronic inflammatory disorders with severe long-term consequences. Activation of inflammatory pathways has recently emerged as a critical link between T2DM and inflammation. A substantial body of evidence has suggested that this is due in part to increased flux through the hexosamine biosynthetic pathway (HBP). The HBP, a unique nutrient-sensing metabolic pathway, produces the activated amino sugar UDP-GlcNAc which is a critical substrate for protein -GlcNAcylation, a dynamic, reversible post-translational glycosylation of serine and threonine residues in target proteins. Protein -GlcNAcylation impacts a range of cellular processes, including inflammation, metabolism, trafficking, and cytoskeletal organisation. As increased HBP flux culminates in increased protein -GlcNAcylation, we propose that targeting -GlcNAcylation may be a viable therapeutic strategy for the prevention and management of glucose-dependent pathologies with inflammatory components.
Topics: Diabetes Mellitus, Type 2; Glycosylation; Hexosamines; Humans; Inflammation; Protein Processing, Post-Translational; Proteins
PubMed: 35203353
DOI: 10.3390/cells11040705 -
Molecular Microbiology Feb 2022N-acetylglucosamine (GlcNAc), an important amino sugar at the infection sites of the fungal pathogen Candida albicans, triggers multiple cellular processes. GlcNAc...
N-acetylglucosamine (GlcNAc), an important amino sugar at the infection sites of the fungal pathogen Candida albicans, triggers multiple cellular processes. GlcNAc import at the cell surface is mediated by GlcNAc transporter, Ngt1 which seems to play a critical role during GlcNAc signaling. We have investigated the Ngt1 dynamics that provide a platform for further studies aimed at understanding the mechanistic insights of regulating process(es) in C. albicans. The expression of this transporter is prolific and highly sensitive to even very low levels (˂2 µM) of GlcNAc. Under these conditions, Ngt1 undergoes phosphorylation-associated ubiquitylation as a code for internalization. This ubiquitylation process involves the triggering proteins like protein kinase Snf1, arrestin-related trafficking adaptors (ART) protein Rod1, and yeast ubiquitin ligase Rsp5. Interestingly, analysis of ∆snf1 and ∆rsp5 mutants revealed that while Rsp5 is promoting the endosomal trafficking of Ngt1-GFPɤ, Snf1 hinders the process. Furthermore, colocalization experiments of Ngt1 with Vps17 (an endosomal marker), Sec7 (a trans-Golgi marker), and a vacuolar marker revealed the fate of Ngt1 during sugar-responsive endosomal trafficking. ∆ras1 and ∆ubi4 mutants showed decreased ubiquitylation and delayed endocytosis of Ngt1. According to our knowledge, this is the first report which illustrates the mechanistic insights that are responsible for endosomal trafficking of a GlcNAc transporter in an eukaryotic organism.
Topics: Acetylglucosamine; Candida albicans; Endocytosis; Endosomal Sorting Complexes Required for Transport; Fungal Proteins; Gene Expression Regulation, Fungal; Phosphoenolpyruvate Sugar Phosphotransferase System; Sugars
PubMed: 34877729
DOI: 10.1111/mmi.14857 -
Cell Death & Disease Apr 2024This study aimed to elucidate the role of O-GlcNAc cycling in 6-hydroxydopamine (6-OHDA)-induced Parkinson's disease (PD)-like neurodegeneration and the underlying...
This study aimed to elucidate the role of O-GlcNAc cycling in 6-hydroxydopamine (6-OHDA)-induced Parkinson's disease (PD)-like neurodegeneration and the underlying mechanisms. We observed dose-dependent downregulation of O-GlcNAcylation, accompanied by an increase in O-GlcNAcase following 6-OHDA treatment in both mouse brain and Neuro2a cells. Interestingly, elevating O-GlcNAcylation through glucosamine (GlcN) injection provided protection against PD pathogenesis induced by 6-OHDA. At the behavioral level, GlcN mitigated motor deficits induced by 6-OHDA, as determined using the pole, cylinder, and apomorphine rotation tests. Furthermore, GlcN attenuated 6-OHDA-induced neuroinflammation and mitochondrial dysfunction. Notably, augmented O-GlcNAcylation, achieved through O-GlcNAc transferase (OGT) overexpression in mouse brain, conferred protection against 6-OHDA-induced PD pathology, encompassing neuronal cell death, motor deficits, neuroinflammation, and mitochondrial dysfunction. These collective findings suggest that O-GlcNAcylation plays a crucial role in the normal functioning of dopamine neurons. Moreover, enhancing O-GlcNAcylation through genetic and pharmacological means could effectively ameliorate neurodegeneration and motor impairment in an animal model of PD. These results propose a potential strategy for safeguarding against the deterioration of dopamine neurons implicated in PD pathogenesis.
Topics: Animals; Oxidopamine; Mice; N-Acetylglucosaminyltransferases; Parkinson Disease; Mice, Inbred C57BL; Male; Glucosamine; Dopaminergic Neurons; Mitochondria; Acetylglucosamine; Brain; beta-N-Acetylhexosaminidases; Disease Models, Animal
PubMed: 38654003
DOI: 10.1038/s41419-024-06670-1 -
Anais Brasileiros de Dermatologia Jul 2019Galectin 3 is a unique ~31 kDa protein that recognizes the N-acetyl-lactosamine structure of several glycoconjugates. It mainly occurs in epithelial and myeloid cells,... (Review)
Review
Galectin 3 is a unique ~31 kDa protein that recognizes the N-acetyl-lactosamine structure of several glycoconjugates. It mainly occurs in epithelial and myeloid cells, but is also found in a variety of human cell types. In view of the crucial role played by galectin 3 in the regulation of cellular processes of essential importance and in the pathogenetic mechanisms of diverse disorders, it is not surprising that, particularly in the last three decades, the attention of the scientific community has been increasingly drawn to this extraordinary and multifunctional galectin. In this paper the authors summarize current knowledge on the expression of galectin 3 in normal and diseased human skin, its implications in the pathogenesis, diagnosis and prognosis of cutaneous disorders, and the perspectives of a novel approach to the treatment of the latter using galectin 3 or its inhibitors/antagonists.
Topics: Amino Sugars; Blood Proteins; Dermatitis; Galectin 3; Galectins; Humans
PubMed: 31365668
DOI: 10.1590/abd1806-4841.20198426 -
Cell Reports Feb 2024The tumor suppressor p53 controls cell fate decisions and prevents malignant transformation, but its functions in antiviral immunity remain unclear. Here, we demonstrate...
The tumor suppressor p53 controls cell fate decisions and prevents malignant transformation, but its functions in antiviral immunity remain unclear. Here, we demonstrate that p53 metabolically promotes antiviral innate immune responses to RNA viral infection. p53-deficient macrophages or mice display reduced expression of glutamine fructose-6-phosphate amidotransferase 2 (GFPT2), a key enzyme of the hexosamine biosynthetic pathway (HBP). Through transcriptional upregulation of GFPT2, p53 drives HBP activity and de novo synthesis of UDP-GlcNAc, which in turn leads to the O-GlcNAcylation of mitochondrial antiviral signaling protein (MAVS) and UBX-domain-containing protein 1 (UBXN1) during virus infection. Moreover, O-GlcNAcylation of UBXN1 blocks its interaction with MAVS, thereby further liberating MAVS for tumor necrosis factor receptor-associated factor 3 binding to activate TANK-binding kinase 1-interferon (IFN) regulatory factor 3 signaling cascades and IFN-β production. Genetic or pharmaceutical inhibition of GFPT efficiently reduces MAVS activation and abrogates the antiviral innate immunity promoted by p53 in vitro and in vivo. Our findings reveal that p53 drives HBP activity and O-GlcNAcylation of UBXN1 and MAVS to enhance IFN-β-mediated antiviral innate immunity.
Topics: Animals; Mice; Hexosamines; Immunity, Innate; Interferon Regulatory Factor-3; Interferons; Macrophages; Tumor Suppressor Protein p53
PubMed: 38294905
DOI: 10.1016/j.celrep.2024.113724 -
International Immunopharmacology Jul 2023Accumulating evidence suggests that sialic acids is closely related to atherosclerosis. However, the effects and underlying mechanisms of sialic acids in atherosclerosis...
Accumulating evidence suggests that sialic acids is closely related to atherosclerosis. However, the effects and underlying mechanisms of sialic acids in atherosclerosis have been not defined. Macrophages are one of the most important cells during plaque progression. In this study, we investigated the role of sialic acids in the M1 macrophage polarization and pathogenesis of atherosclerosis. Here we found that sialic acids can promote the polarization of RAW264.7 cells to the M1 phenotype, thereby promoting the expression of proinflammatory cytokines in vitro. The proinflammatory effect of sialic acids may result from the inhibition of LKB1-AMPK-Sirt3 signaling pathway to upregulate intracellular ROS and impairing autophagy-lysosome system to block autophagic flux. In the APOE mice, sialic acids in plasma increased during the development of atherosclerosis. Moreover, exogenous supplement of sialic acids can promote plaque progression in aortic arch and aortic sinus being accompanied by the differentiation of macrophages into M1 type in peripheral tissues. These studies demonstrated that sialic acids can promote macrophage polarization toward the M1 phenotype to accentuate atherosclerosis via inducing mitochondrial ROS and blocking autophagy, thus providing clue to a novel therapeutic strategy for atherosclerosis.
Topics: Mice; Animals; Reactive Oxygen Species; Sialic Acids; Atherosclerosis; Plaque, Atherosclerotic; Macrophages; Autophagy
PubMed: 37270929
DOI: 10.1016/j.intimp.2023.110410 -
Journal of the American Chemical Society Mar 2022Posttranslational modifications alter the biophysical properties of proteins and thereby influence cellular physiology. One emerging manner by which such modifications...
Posttranslational modifications alter the biophysical properties of proteins and thereby influence cellular physiology. One emerging manner by which such modifications regulate protein functions is through their ability to perturb protein stability. Despite the increasing interest in this phenomenon, there are few methods that enable global interrogation of the biophysical effects of posttranslational modifications on the proteome. Here, we describe an unbiased proteome-wide approach to explore the influence of protein modifications on the thermodynamic stability of thousands of proteins in parallel. We apply this profiling strategy to study the effects of O-linked -acetylglucosamine (O-GlcNAc), an abundant modification found on hundreds of proteins in mammals that has been shown in select cases to stabilize proteins. Using this thermal proteomic profiling strategy, we identify a set of 72 proteins displaying O-GlcNAc-dependent thermostability and validate this approach using orthogonal methods targeting specific proteins. These collective observations reveal that the majority of proteins influenced by O-GlcNAc are, surprisingly, destabilized by O-GlcNAc and cluster into distinct macromolecular complexes. These results establish O-GlcNAc as a bidirectional regulator of protein stability and provide a blueprint for exploring the impact of any protein modification on the meltome of, in principle, any organism.
Topics: Acetylglucosamine; Animals; Mammals; Protein Processing, Post-Translational; Proteome; Proteomics
PubMed: 35230102
DOI: 10.1021/jacs.1c10621 -
Frontiers in Cellular and Infection... 2022The theory of "entero-pulmonary axis" proves that pneumonia leads to gut microbiota disturbance and Treg/Th17 immune imbalance. This study is aimed to explore the...
BACKGROUNDS AND PURPOSE
The theory of "entero-pulmonary axis" proves that pneumonia leads to gut microbiota disturbance and Treg/Th17 immune imbalance. This study is aimed to explore the potential mechanism of fecal microbiota transplantation (FMT) in the treatment of pneumonia, in order to provide new insights into the treatment of pneumonia.
METHODS
and C57/BL6 mice were used to construct the acute pneumonia mouse model, and FMT was treated. Histopathological changes in lung and spleen were observed by HE staining. The expression of CD25, Foxp3 and IL-17 was observed by immunofluorescence. The proportion of Treg and Th17 cells was analyzed by flow cytometry. Serum IL-6, LPS, and IFN-γ levels were detected by ELISA. The expression of TNF-α, IFN-γ, IL-6, IL-2, Foxp3, IL-17, IL-10, and TGFβ1 in lung tissue homogenate was detected by qRT-PCR. 16S rRNA sequencing and non-targeted metabolomics were used to analyze gut microbiota and metabolism.
RESULTS
caused the decrease of body weight, food and water intake, lung tissue, and spleen injury in mice with pneumonia. Meanwhile, it caused lung tissue and serum inflammation, and Treg/Th17 cell imbalance in mice with pneumonia. reduced the diversity and number of gut microbiota in pneumonia mice, resulting in metabolic disorders, superpathway of quinolone and alkylquinolone biosynthesis. It also led to the decrease of 2-heptyl-3-hydroxy-4(1H)-quinolone biosynthesis, and the enrichment of Amino sugar and nucleotide sugar metabolism. FMT with or without antibiotic intervention restored gut microbiota abundance and diversity, suppressed inflammation and tissue damage, and promoted an immunological balance of Treg/Th17 cells in mice with pneumonia. In addition, FMT inhibited the aerobactin biosynthesis, 4-hydroxyphenylacetate degradation, superpathway of lipopolysaccharide biosynthesis and L-arabinose degradation IV function of microbiota, and improved amino sugar and nucleotide sugar metabolism.
CONCLUSIONS
FMT restored the Treg/Th17 cells' balance and improved inflammation and lung injury in mice with pneumonia by regulating gut microbiota disturbance and metabolic disorder.
Topics: Amino Sugars; Animals; Forkhead Transcription Factors; Gastrointestinal Microbiome; Inflammation; Interleukin-17; Interleukin-6; Mice; Nucleotides; Pneumonia; Pseudomonas aeruginosa; Quinolones; RNA, Ribosomal, 16S; T-Lymphocytes, Regulatory; Th17 Cells
PubMed: 35782123
DOI: 10.3389/fcimb.2022.856633 -
Frontiers in Cellular and Infection... 2021Carbohydrates or glycans are ubiquitous components of the cell surface which play crucial biological and structural roles. Sialic acids (Sias) are nine-carbon atoms... (Review)
Review
Carbohydrates or glycans are ubiquitous components of the cell surface which play crucial biological and structural roles. Sialic acids (Sias) are nine-carbon atoms sugars usually present as terminal residues of glycoproteins and glycolipids on the cell surface or secreted. They have important roles in cellular communication and also in infection and survival of pathogens. More than 20 pathogens can synthesize or capture Sias from their hosts and incorporate them into their own glycoconjugates and derivatives. Sialylation of pathogens' glycoconjugates may be crucial for survival inside the host for numerous reasons. The role of Sias in protozoa such as and was demonstrated in previous studies. This review highlights the importance of Sias in several pathogenic infections, focusing on . We describe in detail the contributions of Sias, Siglecs (sialic acid binding Ig-like lectins) and Neuraminidase 1 (NEU 1) in the course of infection. A detailed view on the structural and functional diversity of -related Sias and host-cell receptors will be provided, as well as the results of functional studies performed with different species.
Topics: Glycoconjugates; Humans; Leishmania; Leishmaniasis; Sialic Acid Binding Immunoglobulin-like Lectins; Sialic Acids
PubMed: 34055669
DOI: 10.3389/fcimb.2021.671913 -
The Journal of Organic Chemistry Jun 2023We report the syntheses of 1,3,4-tri--acetyl-2-amino-2,6-dideoxy-β-d-glucopyranose and allyl 2-amino-2,6-dideoxy-β-d-glucopyranoside from d-glucosamine hydrochloride....
We report the syntheses of 1,3,4-tri--acetyl-2-amino-2,6-dideoxy-β-d-glucopyranose and allyl 2-amino-2,6-dideoxy-β-d-glucopyranoside from d-glucosamine hydrochloride. The potential of these two versatile scaffolds as key intermediates to a diversity of orthogonally protected rare deoxyamino hexopyranosides is exemplified in the context of fucosamine, quinovosamine, and bacillosamine. The critical C-6 deoxygenation step to 2,6-dideoxy aminosugars is performed at an early stage on a precursor featuring an imine moiety or a trifluoroacetamide moiety in place of the 2-amino group, respectively. Robustness and scalability are demonstrated for a combination of protecting groups and incremental chemical modifications that sheds light on the promise of the yet unreported allyl 2,6-dideoxy-2--trifluoroacetyl-β-d-glucopyranoside when addressing the feasibility of synthetic zwitterionic oligosaccharides. In particular, allyl 3--acetyl-4-azido-2,4,6-trideoxy-2-trifluoroacetamido-β-d-galactopyranoside, an advanced 2-acetamido-4-amino-2,4,6-trideoxy-d-galactopyranose building block, was achieved on the 30 g scale from 1,3,4,6-tetra--acetyl-β-d-glucosamine hydrochloride in 50% yield and nine steps, albeit only two chromatography purifications.
Topics: Sugars; Glucosamine; Oligosaccharides; Galactose
PubMed: 37141399
DOI: 10.1021/acs.joc.2c03016