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RSC Advances May 2024GalNAc-conjugated siRNA has shown remarkable potential in liver-targeted delivery in recent years. In general, tetrahydroxymethylmethane or other branching clusters...
GalNAc-conjugated siRNA has shown remarkable potential in liver-targeted delivery in recent years. In general, tetrahydroxymethylmethane or other branching clusters constitute the basis of GalNAc's structure, which yields trivalent or tetravalent ligands. A novel diamine-scaffold GalNAc conjugate was synthesized and evaluated for its efficiency in siRNA administration. It exhibits comparable siRNA delivery effectiveness to a GalNAc NAG37 phase II clinical drug candidate targeting ANGPTL3. In addition, it exhibits more powerful silencing activity when connected to the 3'-end of the sense strand with an additional PS-linkage instead of a PO linkage between the ligand and the oligomer compared to a GalNAc L96 standard targeting TTR. Taken together, the incorporation of a diamine-scaffold into the GalNAc conjugate structure has potential in the field of gene therapy.
PubMed: 38818366
DOI: 10.1039/d4ra03023k -
Journal of Biomedical Research Jan 2024Core 1 synthase glycoprotein-N-acetylgalactosamine 3-β-galactosyltransferase 1 (C1GALT1) is known to play a critical role in the development of gastric cancer, but few...
Core 1 synthase glycoprotein-N-acetylgalactosamine 3-β-galactosyltransferase 1 (C1GALT1) is known to play a critical role in the development of gastric cancer, but few studies have elucidated associations between genetic variants in and gastric cancer susceptibility. By using the genome-wide association study data from the database of Genotype and Phenotype (dbGAP), we evaluated these associations with a logistic regression model and identified that the rs35999583 in was associated with gastric cancer risk (odd ratio, 0.83; 95% confidence interval [CI], 0.75-0.92; = 3.95 × 10 ]. mRNA expression was significantly higher in gastric tumor tissues, and gastric cancer patients with higher mRNA levels had the worse overall survival rates (hazards ratio, 1.33; 95% CI, 1.05-1.68; = 1.90 × 10 ). Furthermore, we found that copy number variations differed in various immune cells and mRNA expression was positively correlated with the infiltrating levels of CD4 T cells and macrophages. These results highlight that genetic variants of may play an important role in gastric cancer risk and provide a new insight for to be a promising predictor of gastric cancer susceptibility and immune status.
PubMed: 38807485
DOI: 10.7555/JBR.37.20230161 -
Biochimica Et Biophysica Acta.... Aug 2024
Corrigendum to "Exogenous recombinant N-acetylgalactosamine-4-sulfatase (Arylsulfatase B; ARSB) inhibits progression of B16F10 cutaneous melanomas and modulates cell signaling" [Biochim. Biophys. Acta Mol. Basis Dis. 1870(1) (2024)166913-25, PMID: 37813168].
PubMed: 38760288
DOI: 10.1016/j.bbadis.2024.167231 -
Immunology and Cell Biology May 2024Delta inulin, or Advax, is a polysaccharide vaccine adjuvant that significantly enhances vaccine-mediated immune responses against multiple pathogens and was recently...
Delta inulin, or Advax, is a polysaccharide vaccine adjuvant that significantly enhances vaccine-mediated immune responses against multiple pathogens and was recently licensed for use in the coronavirus disease 2019 (COVID-19) vaccine SpikoGen. Although Advax has proven effective as an immune adjuvant, its specific binding targets have not been characterized. In this report, we identify a cellular receptor for Advax recognition. In vitro uptake of Advax particles by macrophage cell lines was substantially greater than that of latex beads of comparable size, suggesting an active uptake mechanism by phagocytic cells. Using a lectin array, Advax particles were recognized by lectins specific for various carbohydrate structures including mannosyl, N-acetylgalactosamine and galactose moieties. Expression in nonphagocytic cells of dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), a C-type lectin receptor, resulted in enhanced uptake of fluorescent Advax particles compared with mock-transfected cells. Advax uptake was reduced with the addition of ethylenediaminetetraacetic acid and mannan to cells, which are known inhibitors of DC-SIGN function. Finally, a specific blockade of DC-SIGN using a neutralizing antibody abrogated Advax uptake in DC-SIGN-expressing cells. Together, these results identify DC-SIGN as a putative receptor for Advax. Given the known immunomodulatory role of DC-SIGN, the findings described here have implications for the use of Advax adjuvants in humans and inform future mechanistic studies.
PubMed: 38757764
DOI: 10.1111/imcb.12774 -
BioRxiv : the Preprint Server For... May 2024Proteins harboring intrinsically disordered regions (IDRs) that lack regular secondary or tertiary structure are abundant across three domains of life. Here, using a...
Proteins harboring intrinsically disordered regions (IDRs) that lack regular secondary or tertiary structure are abundant across three domains of life. Here, using a deep neural network (DNN)-based method we predict IDRs in the extracytoplasmic proteome of , and . We identify a subset of the serine/threonine-rich IDRs and demonstrate that they are -glycosylated with glucose by a GtrB-like glucosyltransferase in and , and N-acetylgalactosamine by a Pgf-dependent mechanism in . Loss of glycosylation leads to a defect in biofilm formation under ethanol-stressed conditions in . We link this phenotype to a C-terminal IDR of peptidyl-prolyl isomerase PrsA which is protected from proteolytic degradation by -glycosylation. The IDR length attenuates the efficiency of glycosylation and expression of PrsA. Taken together, our data support a model in which extracytoplasmic IDRs function as dynamic switches of protein homeostasis in streptococci.
PubMed: 38746434
DOI: 10.1101/2024.05.05.592596 -
Nucleic Acids Research Jun 2024Oral delivery is the most widely used and convenient route of administration of medicine. However, oral administration of hydrophilic macromolecules is commonly limited...
Oral delivery is the most widely used and convenient route of administration of medicine. However, oral administration of hydrophilic macromolecules is commonly limited by low intestinal permeability and pre-systemic degradation in the gastrointestinal (GI) tract. Overcoming some of these challenges allowed emergence of oral dosage forms of peptide-based drugs in clinical settings. Antisense oligonucleotides (ASOs) have also been investigated for oral administration but despite the recent progress, the bioavailability remains low. Given the advancement with highly potent and durable trivalent N-acetylgalactosamine (GalNAc)-conjugated small interfering RNAs (siRNAs) via subcutaneous (s.c.) injection, we explored their activities after oral administration. We report robust RNA interference (RNAi) activity of orally administrated GalNAc-siRNAs co-formulated with permeation enhancers (PEs) in rodents and non-human primates (NHPs). The relative bioavailability calculated from NHP liver exposure was <2.0% despite minimal enzymatic degradation in the GI. To investigate the impact of oligonucleotide size on oral delivery, highly specific GalNAc-conjugated single-stranded oligonucleotides known as REVERSIRs with different lengths were employed and their activities for reversal of RNAi effect were monitored. Our data suggests that intestinal permeability is highly influenced by the size of oligonucleotides. Further improvements in the potency of siRNA and PE could make oral delivery of GalNAc-siRNAs as a practical solution.
Topics: Animals; Acetylgalactosamine; RNA, Small Interfering; Administration, Oral; Mice; Rats; RNA Interference; Male; Biological Availability; Humans; Rats, Sprague-Dawley; Macaca fascicularis; Liver; Macaca mulatta
PubMed: 38742636
DOI: 10.1093/nar/gkae350 -
Nature Communications May 2024β-N-Acetylgalactosamine-containing glycans play essential roles in several biological processes, including cell adhesion, signal transduction, and immune responses....
β-N-Acetylgalactosamine-containing glycans play essential roles in several biological processes, including cell adhesion, signal transduction, and immune responses. β-N-Acetylgalactosaminidases hydrolyze β-N-acetylgalactosamine linkages of various glycoconjugates. However, their biological significance remains ambiguous, primarily because only one type of enzyme, exo-β-N-acetylgalactosaminidases that specifically act on β-N-acetylgalactosamine residues, has been documented to date. In this study, we identify four groups distributed among all three domains of life and characterize eight β-N-acetylgalactosaminidases and β-N-acetylhexosaminidase through sequence-based screening of deep-sea metagenomes and subsequent searching of public protein databases. Despite low sequence similarity, the crystal structures of these enzymes demonstrate that all enzymes share a prototype structure and have diversified their substrate specificities (oligosaccharide-releasing, oligosaccharide/monosaccharide-releasing, and monosaccharide-releasing) through the accumulation of mutations and insertional amino acid sequences. The diverse β-N-acetylgalactosaminidases reported in this study could facilitate the comprehension of their structures and functions and present evolutionary pathways for expanding their substrate specificity.
Topics: Metagenome; Substrate Specificity; Acetylgalactosamine; Glycoside Hydrolases; beta-N-Acetylhexosaminidases; Phylogeny; Crystallography, X-Ray; Amino Acid Sequence; Animals
PubMed: 38730244
DOI: 10.1038/s41467-024-47653-2 -
Scandinavian Journal of Immunology Jun 2024Antiphospholipid syndrome is a rare autoimmune disease characterized by persistent antiphospholipid antibodies. Immunoglobulin G plays a vital role in disease...
Antiphospholipid syndrome is a rare autoimmune disease characterized by persistent antiphospholipid antibodies. Immunoglobulin G plays a vital role in disease progression, with its structure and function affected by glycosylation. We aimed to investigate the changes in the serum immunoglobulin G glycosylation pattern in antiphospholipid syndrome patients. We applied lectin microarray on samples from 178 antiphospholipid syndrome patients, 135 disease controls (including Takayasu arteritis, rheumatoid arthritis and cardiovascular disease) and 100 healthy controls. Lectin blots were performed for validation of significant differences. Here, we show an increased immunoglobulin G-binding level of soybean agglutinin (p = 0.047, preferring N-acetylgalactosamine) in antiphospholipid syndrome patients compared with healthy and disease controls. Additionally, the immunoglobulin G from antiphospholipid syndrome patients diagnosed with pregnancy events had lower levels of fucosylation (p = 0.001, recognized by Lotus tetragonolobus) and sialylation (p = 0.030, recognized by Sambucus nigra I) than those with simple thrombotic events. These results suggest the unique serum immunoglobulin G glycosylation profile of antiphospholipid syndrome patients, which may inform future studies to design biomarkers for more accurate diagnosis of antiphospholipid syndrome and even for the prediction of clinical symptoms in patients.
Topics: Humans; Antiphospholipid Syndrome; Glycosylation; Female; Male; Immunoglobulin G; Adult; Middle Aged; Pregnancy; Lectins; Biomarkers; Protein Array Analysis; Antibodies, Antiphospholipid; Plant Lectins; Aged; Glycoproteins
PubMed: 38720518
DOI: 10.1111/sji.13366 -
Journal of Bacteriology May 2024Whole genome sequencing has revealed that the genome of possesses an uncharacterized 5-gene operon (SAOUHSC_00088-00092 in strain 8325 genome) that encodes factors with...
UNLABELLED
Whole genome sequencing has revealed that the genome of possesses an uncharacterized 5-gene operon (SAOUHSC_00088-00092 in strain 8325 genome) that encodes factors with functions related to polysaccharide biosynthesis and export, indicating the existence of a new extracellular polysaccharide species. We designate this locus as for staphylococcal surface carbohydrate. We found that the genes were weakly expressed and highly repressed by the global regulator MgrA. To characterize Ssc, Ssc was heterologously expressed in and extracted by heat treatment. Ssc was also conjugated to AcrA from in using protein glycan coupling technology (PGCT). Analysis of the heat-extracted Ssc and the purified Ssc-AcrA glycoconjugate by tandem mass spectrometry revealed that Ssc is likely a polymer consisting of -acetylgalactosamine. We further demonstrated that the expression of the genes in affected phage adsorption and susceptibility, suggesting that Ssc is surface-exposed.
IMPORTANCE
Surface polysaccharides play crucial roles in the biology and virulence of bacterial pathogens. produces four major types of polysaccharides that have been well-characterized. In this study, we identified a new surface polysaccharide containing N-acetylgalactosamine (GalNAc). This marks the first report of GalNAc-containing polysaccharide in . Our discovery lays the groundwork for further investigations into the chemical structure, surface location, and role in pathogenesis of this new polysaccharide.
Topics: Staphylococcus aureus; Acetylgalactosamine; Polysaccharides, Bacterial; Gene Expression Regulation, Bacterial; Bacterial Proteins; Escherichia coli; Campylobacter jejuni
PubMed: 38712944
DOI: 10.1128/jb.00048-24 -
European Review For Medical and... Apr 2024We describe the first case of a pediatric patient with acute intermittent porphyria and severe chronic porphyric neuropathy treated with givosiran, a small-interfering...
BACKGROUND
We describe the first case of a pediatric patient with acute intermittent porphyria and severe chronic porphyric neuropathy treated with givosiran, a small-interfering RNA that drastically decreases delta-aminolevulinic acid production and reduces porphyric attacks' recurrence.
CASE REPORT
A 12-year-old male patient with refractory acute intermittent porphyria and severe porphyric neuropathy was followed prospectively for 12 months after givosiran initiation (subcutaneous, 2.5 mg/kg monthly). Serial neurological, structural, and resting-state functional magnetic resonance imaging (MRI) evaluations were performed, including clinical scales and neurophysiological tests. Delta-aminolevulinic acid urinary levels dropped drastically during treatment. In parallel, all the administered neurological rating scales and neurophysiological assessments showed improvement in all domains. Moreover, an improvement in central motor conduction parameters and resting-state functional connectivity in the sensory-motor network was noticed. At the end of the follow-up, the patient could walk unaided after using a wheelchair for 5 years.
CONCLUSIONS
A clear beneficial effect of givosiran was demonstrated in our patient with both clinical and peripheral nerve neurophysiologic outcome measures. Moreover, we first reported a potential role of givosiran in recovering central motor network impairment in acute intermittent porphyria (AIP), which was previously unknown. This study provides Class IV evidence that givosiran improves chronic porphyric neuropathy.
Topics: Humans; Male; Porphyria, Acute Intermittent; Child; Acetylgalactosamine; Aminolevulinic Acid; Magnetic Resonance Imaging; Pyrrolidines; Uridine; Recovery of Function; Chronic Disease; Treatment Outcome
PubMed: 38708485
DOI: 10.26355/eurrev_202404_36055