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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 -
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 -
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 -
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 -
Hepatology Communications May 2024Human genetic studies have identified several mitochondrial amidoxime-reducing component 1 (MTARC1) variants as protective against metabolic dysfunction-associated...
BACKGROUND
Human genetic studies have identified several mitochondrial amidoxime-reducing component 1 (MTARC1) variants as protective against metabolic dysfunction-associated steatotic liver disease. The MTARC1 variants are associated with decreased plasma lipids and liver enzymes and reduced liver-related mortality. However, the role of mARC1 in fatty liver disease is still unclear.
METHODS
Given that mARC1 is mainly expressed in hepatocytes, we developed an N-acetylgalactosamine-conjugated mouse Mtarc1 siRNA, applying it in multiple in vivo models to investigate the role of mARC1 using multiomic techniques.
RESULTS
In ob/ob mice, knockdown of Mtarc1 in mouse hepatocytes resulted in decreased serum liver enzymes, LDL-cholesterol, and liver triglycerides. Reduction of mARC1 also reduced liver weight, improved lipid profiles, and attenuated liver pathological changes in 2 diet-induced metabolic dysfunction-associated steatohepatitis mouse models. A comprehensive analysis of mARC1-deficient liver from a metabolic dysfunction-associated steatohepatitis mouse model by metabolomics, proteomics, and lipidomics showed that Mtarc1 knockdown partially restored metabolites and lipids altered by diet.
CONCLUSIONS
Taken together, reducing mARC1 expression in hepatocytes protects against metabolic dysfunction-associated steatohepatitis in multiple murine models, suggesting a potential therapeutic approach for this chronic liver disease.
Topics: Animals; Mice; Disease Models, Animal; Hepatocytes; Gene Knockdown Techniques; Liver; Male; RNA, Small Interfering; Mitochondrial Proteins; Non-alcoholic Fatty Liver Disease; Mice, Inbred C57BL
PubMed: 38696369
DOI: 10.1097/HC9.0000000000000419 -
Microorganisms Apr 2024contributes to frequent, persistent, and, often, polymicrobial respiratory tract infections for individuals with cystic fibrosis (CF). Chronic CF infections lead to...
contributes to frequent, persistent, and, often, polymicrobial respiratory tract infections for individuals with cystic fibrosis (CF). Chronic CF infections lead to bronchiectasis and a shortened lifespan. expresses numerous adhesins, including lectins known to bind the epithelial cell and mucin glycoconjugates. Blocking carbohydrate-mediated host-pathogen and intra-biofilm interactions critical to the initiation and perpetuation of colonization offer promise as anti-infective treatment strategies. To inform anti-adhesion therapies, we profiled the monosaccharide binding of from CF and non-CF sources, and assessed whether specific bacterial phenotypic characteristics affected carbohydrate-binding patterns. Focusing at the cellular level, microscopic and spectrofluorometric tools permitted the solution-phase analysis of binding to a panel of fluorescent glycopolymers possessing distinct pendant monosaccharides. All demonstrated significant binding to glycopolymers specific for α-D-galactose, β-D--acetylgalactosamine, and β-D-galactose-3-sulfate. In each culture, a small subpopulation accounted for the binding. The carbohydrate anomeric configuration and sulfate ester presence markedly influenced binding. While this opportunistic pathogen from CF hosts presented with various colony morphologies and physiological activities, no phenotypic, physiological, or structural feature predicted enhanced or diminished monosaccharide binding. Important to anti-adhesive therapeutic strategies, these findings suggest that, regardless of phenotype or clinical source, maintain a small subpopulation that may readily associate with specific configurations of specific monosaccharides. This report provides insights into whole-cell carbohydrate-binding profiles and into the context within which successful anti-adhesive and/or anti-virulence anti-infective agents for CF must contend.
PubMed: 38674745
DOI: 10.3390/microorganisms12040801 -
Marine Drugs Apr 2024Fucosylated chondroitin sulfate is a unique glycosaminoglycan isolated from sea cucumbers, with excellent anticoagulant activity. The fucosyl branch in FCS is generally...
Fucosylated chondroitin sulfate is a unique glycosaminoglycan isolated from sea cucumbers, with excellent anticoagulant activity. The fucosyl branch in FCS is generally located at the 3-OH of -glucuronic acid but, recently, a novel structure with α--fucose linked to the 6-OH of -acetyl-galactosamine has been found. Here, using functionalized monosaccharide building blocks, we prepared novel FCS tetrasaccharides with fucosyl branches both at the 6-OH of GalNAc and 3-OH of GlcA. In the synthesis, the protective group strategy of selective -sulfation, as well as stereoselective glycosylation, was established, which enabled the efficient synthesis of the specific tetrasaccharide compounds. This research enriches knowledge on the structural types of FCS oligosaccharides and facilitates the exploration of the structure-activity relationship in the future.
Topics: Chondroitin Sulfates; Animals; Oligosaccharides; Sea Cucumbers; Glycosylation; Fucose; Anticoagulants; Structure-Activity Relationship; Acetylgalactosamine
PubMed: 38667801
DOI: 10.3390/md22040184 -
International Journal of Molecular... Mar 2024Mucopolysaccharidosis type IVA (MPS IVA; Morquio A syndrome) is a rare autosomal recessive lysosomal storage disease (LSD) caused by deficiency of a hydrolase enzyme,...
Mucopolysaccharidosis type IVA (MPS IVA; Morquio A syndrome) is a rare autosomal recessive lysosomal storage disease (LSD) caused by deficiency of a hydrolase enzyme, N-acetylgalactosamine-6-sulfate sulfatase, and characterized clinically by mainly musculoskeletal manifestations. The mechanisms underlying bone involvement in humans are typically explored using invasive techniques such as bone biopsy, which complicates analysis in humans. We compared bone proteomes using DDA and SWATH-MS in wild-type and MPS IVA knockout mice (UNT) to obtain mechanistic information about the disease. Our findings reveal over 1000 dysregulated proteins in knockout mice, including those implicated in oxidative phosphorylation, oxidative stress (reactive oxygen species), DNA damage, and iron transport, and suggest that lactate dehydrogenase may constitute a useful prognostic and follow-up biomarker. Identifying biomarkers that reflect MPS IVA clinical course, severity, and progression have important implications for disease management.
Topics: Humans; Animals; Mice; Mucopolysaccharidosis IV; Cartilage Diseases; Bone Diseases; Chondroitinsulfatases; Mice, Knockout
PubMed: 38542208
DOI: 10.3390/ijms25063232 -
Genes Mar 2024β-1,4-N-acetylgalactosamine transferase 2 () is a vital candidate gene that affects the growth traits in sheep. However, whether it has the same function in goats...
β-1,4-N-acetylgalactosamine transferase 2 () is a vital candidate gene that affects the growth traits in sheep. However, whether it has the same function in goats remains to be investigated further. This study selected 348 Nanjiang Yellow goats, screened all exons, and conserved non-coding regions of the gene for single-nucleotide polymorphisms (SNPs). Our results revealed the presence of a synonymous mutation, rs672215506, within the exon of the gene in the Nanjiang Yellow goat population. The mutation resulted in a decrease in the mRNA stability of the gene. The results of SNP detection of the conserved non-coding region of the gene showed five potential regulatory SNPs in the Nanjiang Yellow goat population. Except for rs66095343, the ~500 bp fragments of the other four SNPs (rs649127714, rs649573228, rs652899012, and rs639183528) significantly increased the luciferase activity both in goat skeletal muscle satellite cells (MuSCs) and 293T cells. The genetic diversity indexes indicated low or intermediate levels for all six SNPs analyzed, and the genotype frequencies were in Hardy-Weinberg equilibrium. Association analysis showed that rs660965343, rs649127714, and rs649573228 significantly correlate with growth traits in the later stage of growth and development of Nanjiang Yellow goats. The haplotype combinations of H2H3 and H2H2 had higher body weight and greater body size. Moreover, H2H2 haplotype combinations significantly correlated with the litter size of the Nanjiang Yellow goats. The results of our study demonstrate the potential role of the gene as a functional genetic marker in the breeding programs of Nanjiang Yellow goats.
Topics: Pregnancy; Female; Animals; Sheep; Goats; Polymorphism, Single Nucleotide; Genotype; Haplotypes; Litter Size
PubMed: 38540389
DOI: 10.3390/genes15030330 -
Marine Drugs Feb 2024Sulfation is gaining increased interest due to the role of sulfate in the bioactivity of many polysaccharides of marine origin. Hence, sulfatases, enzymes that control...
Sulfation is gaining increased interest due to the role of sulfate in the bioactivity of many polysaccharides of marine origin. Hence, sulfatases, enzymes that control the degree of sulfation, are being more extensively researched. In this work, a novel sulfatase (SulA1) encoded by the gene was characterized. The -gene is located upstream of a chondroitin lyase encoding gene in the genome of the marine Arthrobacter strain (MAT3885). The sulfatase was produced in . Based on the primary sequence, the enzyme is classified under sulfatase family 1 and the two catalytic residues typical of the sulfatase 1 family-Cys57 (post-translationally modified to formyl glycine for function) and His190-were conserved. The enzyme showed increased activity, but not improved stability, in the presence of Ca, and conserved residues for Ca binding were identified (Asp17, Asp18, Asp277, and Asn278) in a structural model of the enzyme. The temperature and pH activity profiles (screened using -nitrocatechol sulfate) were narrow, with an activity optimum at 40-50 °C and a pH optimum at pH 5.5. The was significantly higher (67 °C) than the activity optimum. Desulfation activity was not detected on polymeric substrates, but was found on GalNAc4S, which is a sulfated monomer in the repeated disaccharide unit (GlcA-GalNAc4S) of, e.g., chondroitin sulfate A. The position of the sulA1 gene upstream of a chondroitin lyase gene and combined with the activity on GalNAc4S suggests that there is an involvement of the enzyme in the chondroitin-degrading cascade reaction, which specifically removes sulfate from monomeric GalNAc4S from chondroitin sulfate degradation products.
Topics: Sulfates; Acetylgalactosamine; Arthrobacter; Sulfatases; Escherichia coli; Galactosamine; Chondroitin Lyases; Cloning, Molecular
PubMed: 38535445
DOI: 10.3390/md22030104