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EMBO Reports Nov 2023Fate determination of primordial germ cells (PGCs) is regulated in a multi-layered manner, involving signaling pathways, epigenetic mechanisms, and transcriptional...
Fate determination of primordial germ cells (PGCs) is regulated in a multi-layered manner, involving signaling pathways, epigenetic mechanisms, and transcriptional control. Chemical modification of macromolecules, including epigenetics, is expected to be closely related with metabolic mechanisms but the detailed molecular machinery linking these two layers remains poorly understood. Here, we show that the hexosamine biosynthetic pathway controls PGC fate determination via O-linked β-N-acetylglucosamine (O-GlcNAc) modification. Consistent with this model, reduction of carbohydrate metabolism via a maternal ketogenic diet that decreases O-GlcNAcylation levels causes repression of PGC formation in vivo. Moreover, maternal ketogenic diet intake until mid-gestation affects the number of ovarian germ cells in newborn pups. Taken together, we show that nutritional and metabolic mechanisms play a previously unappreciated role in PGC fate determination.
Topics: Infant, Newborn; Humans; Signal Transduction; Acetylglucosamine; Gene Expression Regulation; Epigenesis, Genetic; Germ Cells; Protein Processing, Post-Translational
PubMed: 37842859
DOI: 10.15252/embr.202356845 -
International Journal of Molecular... Jan 2022The frequency and severity of extreme climatic conditions such as drought, salinity, cold, and heat are increasing due to climate change. Moreover, in the field, plants...
The frequency and severity of extreme climatic conditions such as drought, salinity, cold, and heat are increasing due to climate change. Moreover, in the field, plants are affected by multiple abiotic stresses simultaneously or sequentially. Thus, it is imperative to compare the effects of stress combinations on crop plants relative to individual stresses. This study investigated the differential regulation of physio-biochemical and metabolomics parameters in peanut ( L.) under individual (salt, drought, cold, and heat) and combined stress treatments using multivariate correlation analysis. The results showed that combined heat, salt, and drought stress compounds the stress effect of individual stresses. Combined stresses that included heat had the highest electrolyte leakage and lowest relative water content. Lipid peroxidation and chlorophyll contents did not significantly change under combined stresses. Biochemical parameters, such as free amino acids, polyphenol, starch, and sugars, significantly changed under combined stresses compared to individual stresses. Free amino acids increased under combined stresses that included heat; starch, sugars, and polyphenols increased under combined stresses that included drought; proline concentration increased under combined stresses that included salt. Metabolomics data that were obtained under different individual and combined stresses can be used to identify molecular phenotypes that are involved in the acclimation response of plants under changing abiotic stress conditions. Peanut metabolomics identified 160 metabolites, including amino acids, sugars, sugar alcohols, organic acids, fatty acids, sugar acids, and other organic compounds. Pathway enrichment analysis revealed that abiotic stresses significantly affected amino acid, amino sugar, and sugar metabolism. The stress treatments affected the metabolites that were associated with the tricarboxylic acid (TCA) and urea cycles and associated amino acid biosynthesis pathway intermediates. Principal component analysis (PCA), partial least squares-discriminant analysis (PLS-DA), and heatmap analysis identified potential marker metabolites (pinitol, malic acid, and xylopyranose) that were associated with abiotic stress combinations, which could be used in breeding efforts to develop peanut cultivars that are resilient to climate change. The study will also facilitate researchers to explore different stress indicators to identify resistant cultivars for future crop improvement programs.
Topics: Antioxidants; Arachis; Discriminant Analysis; Gene Expression Regulation, Plant; Ions; Least-Squares Analysis; Metabolome; Metabolomics; Multivariate Analysis; Plant Leaves; Principal Component Analysis; RNA, Messenger; Reactive Oxygen Species; Stress, Physiological
PubMed: 35054846
DOI: 10.3390/ijms23020660 -
Trends in Microbiology Feb 2021Nonulosonic acids (NulOs) are a diverse family of 9-carbon α-keto acid sugars that are involved in a wide range of functions across all branches of life. The family of... (Review)
Review
Nonulosonic acids (NulOs) are a diverse family of 9-carbon α-keto acid sugars that are involved in a wide range of functions across all branches of life. The family of NulOs includes the sialic acids as well as the prokaryote-specific NulOs. Select bacteria biosynthesize the sialic acid N-acetylneuraminic acid (Neu5Ac), and the ability to produce this sugar and its subsequent incorporation into cell-surface structures is implicated in a variety of bacteria-host interactions. Furthermore, scavenging of sialic acid from the environment for energy has been characterized across a diverse group of bacteria, mainly human commensals and pathogens. In addition to sialic acid, bacteria have the ability to biosynthesize prokaryote-specific NulOs, of which there are several known isomers characterized. These prokaryotic NulOs are similar in structure to Neu5Ac but little is known regarding their role in bacterial physiology. Here, we discuss the diversity in structure, the biosynthesis pathways, and the functions of bacteria-specific NulOs. These carbohydrates are phylogenetically widespread among bacteria, with numerous structurally unique modifications recognized. Despite the diversity in structure, the NulOs are involved in similar functions such as motility, biofilm formation, host colonization, and immune evasion.
Topics: Bacteria; Biosynthetic Pathways; Humans; N-Acetylneuraminic Acid; Phylogeny; Sugar Acids
PubMed: 32950378
DOI: 10.1016/j.tim.2020.08.002 -
The British Journal of Radiology Dec 2022Contrast-enhanced MRI could be useful to guide high-intensity focused ultrasound treatment (HIFU), but the effects of HIFU on gadolinium-based agents is not known. Here,...
OBJECTIVE
Contrast-enhanced MRI could be useful to guide high-intensity focused ultrasound treatment (HIFU), but the effects of HIFU on gadolinium-based agents is not known. Here, we tested in vitro the stability of gadoteridol and gadobenate dimeglumine, two widely used MR contrast agents, after exposure to HIFU at power levels typically applied in the clinical practice.
METHODS
0.5 M (gadoteridol and gadobenate dimeglumine) and diluted formulations (1:10 gadoteridol in saline) were exposed to different HIFU sequences. Unexposed and exposed solutions were characterized by high-performance liquid chromatography in terms of concentration of gadolinium complex, free gadolinium and free ligand.
RESULTS
Gadoteridol formulation after treatment showed concentrations of the complex not significantly different from control. Free Gd and/or free ligand concentrations in the order of 0.002/0.004% w/w, were observed occasionally without significant correlation with intensity and duration of exposure to HIFU. Gadobenate dimeglumine formulation after treatment showed complex assay content values, by-products (0.24-0.26%) and free BOPTA levels (0.07%) comparable to control sample within the experimental error.
CONCLUSION
In the range of conditions explored, HIFU exposure did not induce significant dissociations of gadoteridol and gadobenate dimeglumine, nor a detectable increase in the concentration of free species.
ADVANCES IN KNOWLEDGE
Our study strengthens the hypothesis that gadolinium-based contrast agents are stable during HIFU treatment for body applications ( thermal ablation of uterine fibroids).
Topics: Humans; Gadolinium; Contrast Media; Gadolinium DTPA; Ligands; Meglumine; Organometallic Compounds; Magnetic Resonance Imaging
PubMed: 36169642
DOI: 10.1259/bjr.20220619 -
Frontiers in Immunology 2022The -linked β--acetylglucosamine (-GlcNAc) glycosylation of proteins is an essential and dynamic post-translational modification in mammalian cells that is regulated by... (Review)
Review
The -linked β--acetylglucosamine (-GlcNAc) glycosylation of proteins is an essential and dynamic post-translational modification in mammalian cells that is regulated by the action of two enzymes. -GlcNAc transferase (OGT) incorporates this monosaccharide on serine/threonine residues, whereas -GlcNAcase (OGA) removes it. This modification is found on thousands of intracellular proteins involved in vital cellular processes, both under physiological and pathological conditions. Aberrant expression of -GlcNAc has been implicated in diseases such as Alzheimer, diabetes, and cancer, and growing evidence over the last decade has also revealed key implications of -GlcNAcylation in immunity. While some key signaling pathways involving -GlcNAcylation in immune cells have been discovered, a complete mechanistic understanding of how -GlcNAcylated proteins function in the immune system remains elusive, partly because of the difficulties in mapping and quantifying -GlcNAc sites. In this minireview, we discuss recent progress on chemical biology tools and approaches to investigate the role of -GlcNAcylation in immune cells, with the intention of encouraging further research and developments in chemical glycoimmunology that can advance our understanding of -GlcNAc in immunity.
Topics: Animals; Acetylglucosaminidase; Glycosylation; Mammals; Protein Processing, Post-Translational; Proteins; Immunity; Acetylglucosamine
PubMed: 36776401
DOI: 10.3389/fimmu.2022.1089824 -
Scientific Reports Sep 2023The human polysialyltransferases ST8Sia II and ST8Sia IV catalyze the transfer of several Neu5Ac residues onto glycoproteins forming homopolymers with essential roles...
The human polysialyltransferases ST8Sia II and ST8Sia IV catalyze the transfer of several Neu5Ac residues onto glycoproteins forming homopolymers with essential roles during different physiological processes. In salmonids, heterogeneous set of sialic acids polymers have been described in ovary and on eggs cell surface and three genes st8sia4, st8sia2-r1 and st8sia2-r2 were identified that could be implicated in these heteropolymers. The three polysialyltransferases from the salmonid Coregonus maraena were cloned, recombinantly expressed in HEK293 cells and the ST8Sia IV was biochemically characterized. The MicroPlate Sialyltransferase Assay and the non-natural donor substrate CMP-SiaNAl were used to demonstrate enzyme activity and optimize polysialylation reactions. Polysialylation was also carried out with natural donor substrates CMP-Neu5Ac, CMP-Neu5Gc and CMP-Kdn in cell-free and cell-based assays and structural analyses of polysialylated products using the anti-polySia monoclonal antibody 735 and endoneuraminidase N and HPLC approaches. Our data highlighted distinct specificities of human and salmonid polysialyltransferases with notable differences in donor substrates use and the capacity of fish enzymes to generate heteropolymers. This study further suggested an evolution of the biological functions of polySia. C. maraena ST8Sia IV of particular interest to modify glycoproteins with a variety of polySia chains.
Topics: Animals; Female; Humans; N-Acetylneuraminic Acid; Salmonidae; HEK293 Cells; Biological Assay
PubMed: 37730806
DOI: 10.1038/s41598-023-42095-0 -
International Journal of Molecular... Aug 2022Sialic acids and heparan sulfates make up the outermost part of the cell membrane and the extracellular matrix. Both structures are characterized by being negatively... (Review)
Review
Sialic acids and heparan sulfates make up the outermost part of the cell membrane and the extracellular matrix. Both structures are characterized by being negatively charged, serving as receptors for various pathogens, and are highly expressed in the respiratory and digestive tracts. Numerous viruses use heparan sulfates as receptors to infect cells; in this group are HSV, HPV, and SARS-CoV-2. Other viruses require the cell to express sialic acids, as is the case in influenza A viruses and adenoviruses. This review aims to present, in a general way, the participation of glycoconjugates in viral entry, and therapeutic strategies focused on inhibiting the interaction between the virus and the glycoconjugates. Interestingly, there are few studies that suggest the participation of both glycoconjugates in the viruses addressed here. Considering the biological redundancy that exists between heparan sulfates and sialic acids, we propose that it is important to jointly evaluate and design strategies that contemplate inhibiting the interactions of both glycoconjugates. This approach will allow identifying new receptors and lead to a deeper understanding of interspecies transmission.
Topics: COVID-19; Glycoconjugates; Heparitin Sulfate; Humans; N-Acetylneuraminic Acid; Receptors, Virus; SARS-CoV-2; Sialic Acids; Sulfates; Virus Attachment; Viruses
PubMed: 36077240
DOI: 10.3390/ijms23179842 -
Cells Jan 2021Sialic acids are sugars with a nine-carbon backbone, present on the surface of all cells in humans, including immune cells and their target cells, with various... (Review)
Review
Sialic acids are sugars with a nine-carbon backbone, present on the surface of all cells in humans, including immune cells and their target cells, with various functions. Natural Killer (NK) cells are cells of the innate immune system, capable of killing virus-infected and tumor cells. Sialic acids can influence the interaction of NK cells with potential targets in several ways. Different NK cell receptors can bind sialic acids, leading to NK cell inhibition or activation. Moreover, NK cells have sialic acids on their surface, which can regulate receptor abundance and activity. This review is focused on how sialic acids on NK cells and their target cells are involved in NK cell function.
Topics: Humans; Killer Cells, Natural; Lymphocyte Activation; Receptors, Cell Surface; Sialic Acids; Viral Proteins
PubMed: 33572710
DOI: 10.3390/cells10020263 -
Journal of Virology Mar 2022Influenza A viruses (IAV) initiate infection by binding to glycans with terminal sialic acids on the cell surface. Hosts of IAV variably express two major forms of...
Influenza A viruses (IAV) initiate infection by binding to glycans with terminal sialic acids on the cell surface. Hosts of IAV variably express two major forms of sialic acid, -acetylneuraminic acid (NeuAc) and -glycolylneuraminic acid (NeuGc). NeuGc is produced in most mammals, including horses and pigs, but is absent in humans, ferrets, and birds. The only known naturally occurring IAV that exclusively bind NeuGc are extinct highly pathogenic equine H7N7 viruses. We determined the crystal structure of a representative equine H7 hemagglutinin (HA) in complex with NeuGc and observed high similarity in the receptor-binding domain with an avian H7 HA. To determine the molecular basis for NeuAc and NeuGc specificity, we performed systematic mutational analyses, based on the structural insights, on two distant avian H7 HAs and an H15 HA. We found that the A135E mutation is key for binding α2,3-linked NeuGc but does not abolish NeuAc binding. The additional mutations S128T, I130V, T189A, and K193R converted the specificity from NeuAc to NeuGc. We investigated the residues at positions 128, 130, 135, 189, and 193 in a phylogenetic analysis of avian and equine H7 HAs. This analysis revealed a clear distinction between equine and avian residues. The highest variability was observed at key position 135, of which only the equine glutamic acid led to NeuGc binding. These results demonstrate that genetically distinct H7 and H15 HAs can be switched from NeuAc to NeuGc binding and vice versa after the introduction of several mutations, providing insights into the adaptation of H7 viruses to NeuGc receptors. Influenza A viruses cause millions of cases of severe illness and deaths annually. To initiate infection and replicate, the virus first needs to bind to a structure on the cell surface, like a key fitting in a lock. For influenza A viruses, these "keys" (receptors) on the cell surface are chains of sugar molecules (glycans). The terminal sugar on these glycans is often either -acetylneuraminic acid (NeuAc) or -glycolylneuraminic acid (NeuGc). Most influenza A viruses bind NeuAc, but a small minority bind NeuGc. NeuGc is present in species like horses, pigs, and mice but not in humans, ferrets, and birds. Here, we investigated the molecular determinants of NeuGc specificity and the origin of viruses that bind NeuGc.
Topics: Animals; Hemagglutinin Glycoproteins, Influenza Virus; Horses; Humans; Influenza A Virus, H7N7 Subtype; N-Acetylneuraminic Acid; Neuraminic Acids; Phylogeny; Polysaccharides; Protein Binding
PubMed: 35044215
DOI: 10.1128/jvi.02120-21 -
Biomedicine & Pharmacotherapy =... Oct 2023Long-acting and specific targeting are two important properties of excellent drug delivery systems. Currently, the long-acting strategies based on polyethylene glycol... (Review)
Review
Long-acting and specific targeting are two important properties of excellent drug delivery systems. Currently, the long-acting strategies based on polyethylene glycol (PEG) are controversial, and PEGylation is incapable of simultaneously possessing targeting ability. Thus, it is crucial to identify and develop approaches to produce long-acting and targeted drug delivery systems. Sialic acid (SA) is an endogenous, negatively charged, nine-carbon monosaccharide. SA not only mediates immune escape in the body but also binds to numerous disease related targets. This suggests a potential strategy, namely "sialylation," for preparing long-acting and targeted drug delivery systems. This review focuses on the application status of SA-based long-acting and targeted agents as a reference for subsequent research.
Topics: Carbon; Drug Delivery Systems; Monosaccharides; N-Acetylneuraminic Acid; Polyethylene Glycols
PubMed: 37611437
DOI: 10.1016/j.biopha.2023.115353