-
Journal of Controlled Release :... Nov 2019
Review
Topics: Acetylgalactosamine; Cytokines; Drug Carriers; Gene Knockdown Techniques; Genetic Therapy; Humans; Inflammation; Lipids; Liver; RNA Interference; RNA, Small Interfering; Transfection
PubMed: 31682911
DOI: 10.1016/j.jconrel.2019.10.056 -
Hamostaseologie 2017
Review
Topics: Acetylgalactosamine; Adolescent; Adult; Antibodies, Bispecific; Antibodies, Monoclonal, Humanized; Blood Coagulation Factors; Congresses as Topic; Factor VIIa; Hemophilia A; Hemophilia B; Hemorrhage; Humans; RNA, Small Interfering; Recombinant Proteins; Thromboembolism
PubMed: 29582931
DOI: 10.5482/20170004 -
Advances in Neurobiology 2023Glycoproteins carrying O-linked N-acetylgalactosamine, N-acetylglucosamine, mannose, fucose, glucose, and xylose are found in the nervous system. Lipids are glycosylated...
Glycoproteins carrying O-linked N-acetylgalactosamine, N-acetylglucosamine, mannose, fucose, glucose, and xylose are found in the nervous system. Lipids are glycosylated by distinct glycosylation enzymes as well. Membrane lipid, ceramide, is modified by the addition of either glucose or galactose to form glycosphingolipid, galactosylceramide, or glucosylceramide. Recent careful analyses by MS have identified glucosylated lipids of cholesterol and phosphatidic acid. These O-linked carbohydrate residues are found primarily on the outer surface of the plasma membrane or in the extracellular space. Their expression is cell or tissue specific and developmentally regulated. Due to their structural diversity, they play important roles in a variety of biological processes such as membrane transport, metabolic stress responses, cell-cell interactions and so on. Discoveries of human diseases associated with glycosylation enzyme deficits have proved modification of lipids and proteins with carbohydrates play critical roles in human health and disease in the nervous systems.
Topics: Humans; Fucose; Acetylgalactosamine; Acetylglucosamine; Galactose; Mannose; Glucosylceramides; Xylose; Galactosylceramides; Glycoconjugates; Carbohydrates; Glycoproteins; Nervous System; Glucose; Phosphatidic Acids
PubMed: 36255673
DOI: 10.1007/978-3-031-12390-0_4 -
Journal of Medicinal Chemistry Feb 2023Conjugation of synthetic triantennary -acetyl-d-galactosamine (GalNAc) to small interfering RNA (siRNA) mediates binding to the asialoglycoprotein receptor (ASGPR) on...
Conjugation of synthetic triantennary -acetyl-d-galactosamine (GalNAc) to small interfering RNA (siRNA) mediates binding to the asialoglycoprotein receptor (ASGPR) on the surface of hepatocytes, facilitating liver-specific uptake and siRNA-mediated gene silencing. The natural β-glycosidic bond of the GalNAc ligand is rapidly cleaved by glycosidases in vivo. Novel GalNAc ligands with -, and -glycosides with both α- and β-anomeric linkages, -glycosides with β-anomeric linkage, and the glycoside with α-anomeric linkage were synthesized and conjugated to siRNA either on-column during siRNA synthesis or through a high-throughput, post-synthetic method. Unlike natural GalNAc, modified ligands were resistant to glycosidase activity. The siRNAs conjugated to newly designed ligands had similar affinities for ASGPR and similar silencing activity in mice as the parent GalNAc-siRNA conjugate. These data suggest that other factors, such as protein-nucleic acid interactions and loading of the antisense strand into the RNA-induced silencing complex (RISC), are more critical to the duration of action than the stereochemistry and stability of the anomeric linkage between the GalNAc moiety of the ligand conjugated to the sense strand of the siRNA.
Topics: Animals; Mice; Acetylgalactosamine; Asialoglycoprotein Receptor; Galactosamine; Glycoside Hydrolases; Glycosides; Hepatocytes; Ligands; RNA, Small Interfering; RNA-Induced Silencing Complex
PubMed: 36757090
DOI: 10.1021/acs.jmedchem.2c01337 -
Zoological Science Aug 2015In the present study we histochemically and lectinhistochemically characterized the growing oocytes of the pink cuskeel (Genypterus blacodes). We used histochemical...
In the present study we histochemically and lectinhistochemically characterized the growing oocytes of the pink cuskeel (Genypterus blacodes). We used histochemical methods for the localization and characterization of glycoconjugates (GCs) and lectin histochemical techniques for the identification of specific sugar residues. We analyzed presence and distribution of GCs in the different structures of the growing follicles (cortical alveoli, globules, yolk granules and zona radiata). During the initial stage of vitellogenesis, the oocytes presented small yolk granules composed of GCs that gradually increased during exogenous vitellogenesis. These GCs contained moderate quantities of α-D-mannose, D-glucose, N-acetylglucosamine and N-acetyl-neuraminic acid. The cortical alveoli contained both neutral and carboxylated GCs, and lectin techniques detected N-acetylgalactosamine, galactose and L-fucose. The zona radiata showed a strong positive reaction to PAS and it reacted weakly with more specific techniques, such as KOH/PA*S and PA/Bh/KOH/PAS. This structure showed GCs with oxidizable vicinal diols, O-acyl sugars and sialic acid residues with different substitution types and presented N-acetylgalactosamine and L-fucose specific residues. The oocytes follicular envelope evidenced neutral and acidic non-sulfated GCs and high concentrations of α-D-mannose, D-glucose, galactose and N-acetylgalactosamine. The intergranular cytoplasmic GCs were mainly rich in α-D-mannose, D-glucose, N-acetylgalactosamine, N-acetylglucosamine and N-acetyl-neuraminic acid. These results enhance the comprehension of the structure and functionality of the pink cuskeel ovarian follicles, and provide a useful tool for the study of this tissue in other teleost species.
Topics: Animals; Female; Fishes; Oocytes
PubMed: 26245226
DOI: 10.2108/zs140235 -
The New England Journal of Medicine Nov 2020
Topics: Acetylgalactosamine; Amides; Humans; Porphyria, Acute Intermittent; Pyrrolidines; RNA Interference; RNAi Therapeutics
PubMed: 33176091
DOI: 10.1056/NEJMc2026458 -
European Journal of Pharmaceutics and... Aug 2018Oligonucleotide-based therapeutics have been implemented as a new therapeutic modality in biotech industry, which offers the opportunity to develop formulation platforms...
Oligonucleotide-based therapeutics have been implemented as a new therapeutic modality in biotech industry, which offers the opportunity to develop formulation platforms for robust parenteral formulations. The aim of this study was to gain a better understanding of stabilizing/de-stabilizing effects of different formulation parameters on unconjugated and N-acetylgalactosamine (GalNAc) conjugated single stranded oligonucleotides with locked nucleic acid modifications (LNA SSO), as model oligonucleotides. Various buffer systems, pH levels and different excipients were evaluated to optimize conditions for LNA SSO in liquid formulations. LNA SSO were exposed to different temperature conditions, mechanical stress as well as oxidative conditions, and the maximum feasible LNA SSO concentrations regarding handling and processing were determined. Finally, options for terminal sterilization of LNA SSO were evaluated. Results show that the tested LNA SSO were most stable under slightly alkaline conditions. A decrease in viscosity was best accomplished in the presence of spermine and lysine. Heat treatment and gamma irradiation caused high levels of degradation of the LNA SSO. Crucial formulation parameters, as identified in this study, should contribute to a significant increase in future productivity in drug product development for single-stranded oligonucleotides.
Topics: Acetylgalactosamine; Drug Carriers; Drug Compounding; Drug Stability; Excipients; Gamma Rays; Hydrogen-Ion Concentration; Oligonucleotides; Solutions; Sterilization
PubMed: 29802983
DOI: 10.1016/j.ejpb.2018.05.029 -
Nature Protocols Aug 2020Protein glycosylation is one of the most common protein modifications. A major type of protein glycosylation is O-GalNAcylation, in which GalNAc-type glycans are...
Protein glycosylation is one of the most common protein modifications. A major type of protein glycosylation is O-GalNAcylation, in which GalNAc-type glycans are attached to protein Ser or Thr residues via an O-linked glycosidic bond. O-GalNAcylation is thought to play roles in protein folding, stability, trafficking and protein interactions, and identification of the site-specific O-GalNAc glycoproteome is a crucial step toward understanding the biological significance of the modification. However, lack of suitable methodology, absence of consensus sequon of O-GalNAcylation sites and complex O-GalNAc glycan structures pose analytical challenges. We recently developed a mass spectrometry-based method called extraction of O-linked glycopeptides (EXoO) that enables large-scale mapping of site-specific mucin-type O-GalNAcylation sites. Here we provide a detailed protocol for EXoO, which includes seven stages of: (1) extraction and proteolytic digestion of proteins to peptides, (2) sequential guanidination and de-salting of peptides, (3) enrichment of glycopeptides, (4) solid-phase peptide conjugation and release of O-GalNAc glycopeptides using the OpeRATOR protease, (5) liquid chromatography with tandem mass spectrometry analysis of O-GalNAc glycopeptides, (6) identification of O-GalNAc glycopeptides by database search and (7) quantification of O-GalNAc glycopeptides. Using this protocol, thousands of O-GalNAcylation sites from hundreds of glycoproteins with information regarding site-specific O-GalNAc glycan can be identified and quantified from complex samples. The protocol can be performed by a researcher with basic proteomics skills and takes about 4 d to complete.
Topics: Acetylgalactosamine; Glycoproteins; Humans; Proteomics
PubMed: 32681153
DOI: 10.1038/s41596-020-0345-1 -
BMJ Open Diabetes Research & Care Oct 2022Disentangling the specific factors that regulate glycemia from prediabetes to normoglycemia could improve type 2 diabetes prevention strategies. Metabolomics provides...
INTRODUCTION
Disentangling the specific factors that regulate glycemia from prediabetes to normoglycemia could improve type 2 diabetes prevention strategies. Metabolomics provides substantial insights into the biological understanding of environmental factors such as diet. This study aimed to identify metabolomic markers of regression to normoglycemia in the context of a lifestyle intervention (LSI) in individuals with prediabetes.
RESEARCH DESIGN AND METHODS
We conducted a single-arm intervention study with 24 weeks of follow-up. Eligible study participants had at least one prediabetes criteria according to the American Diabetes Association guidelines, and body mass index between 25 and 45 kg/m. LSI refers to a hypocaloric diet and >150 min of physical activity per week. Regression to normoglycemia (RNGR) was defined as achieving hemoglobin A1c (HbA1c) <5.5% in the final visit. Baseline and postintervention plasma metabolomic profiles were measured using liquid chromatography-tandem mass spectrometry. To select metabolites associated with RNGR, we conducted the least absolute shrinkage and selection operator-penalized regressions.
RESULTS
The final sample was composed of 82 study participants. Changes in three metabolites were significantly associated with regression to normoglycemia; N-acetyl-D-galactosamine (OR=0.54; 95% CI 0.32 to 0.82), putrescine (OR=0.90, 95% CI 0.81 to 0.98), and 7-methylguanine (OR=1.06; 95% CI 1.02 to 1.17), independent of HbA1c and weight loss. In addition, metabolomic perturbations due to LSI displayed enrichment of taurine and hypotaurine metabolism pathway (p=0.03) compatible with biomarkers of protein consumption, lower red meat and animal fats and higher seafood and vegetables.
CONCLUSIONS
Evidence from this study suggests that specific metabolomic markers have an influence on glucose regulation in individuals with prediabetes after 24 weeks of LSI independently of other treatment effects such as weight loss.
Topics: Acetylgalactosamine; Biomarkers; Diabetes Mellitus, Type 2; Diet, Reducing; Dietary Proteins; Glucose; Glycated Hemoglobin; Humans; Metabolomics; Obesity; Prediabetic State; Putrescine; Taurine; Weight Loss
PubMed: 36253014
DOI: 10.1136/bmjdrc-2022-003010 -
The New England Journal of Medicine Jun 2020
Topics: Acetylgalactosamine; Humans; Porphyria, Acute Intermittent; Porphyrias; Pyrrolidines; RNA Interference; RNAi Therapeutics; Running
PubMed: 32521139
DOI: 10.1056/NEJMe2010986