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Diagnosis and Pathobiology
Published in Franklyn De Silva, Jane Alcorn, The Elusive Road Towards Effective Cancer Prevention and Treatment, 2023
Franklyn De Silva, Jane Alcorn
The covalent linking of a carbohydrate to another molecule is known as glycation (nonenzymatic glycosylation, which is a process of joining glycans to proteins, lipids, or other organic molecules via catalysis) [368]. Over 50% of proteins undergo this type of PTM and influence multiple activities involving cellular adhesion, proliferation, inflammation, oncogenesis, immunological responses, and viral replication [368]. While histones can be O-GlcNAc-modified proteins, the joining of O-linked β-N-acetylglucosamine (O-GlcNAc) moieties to serine and threonine residues of nuclear, mitochondrial, and cytoplasmic proteins (histone and nonhistone) is termed ‘O-GlcNAcylation' [387, 419–423]. This is a noncanonical glycosylation and is linked to metabolic disorders because of its sensitivity to cellular stress (e.g., nutrient deprivation, heat shock, hypoxia) [421, 424–426]. O-GlcNAcylation is the hexosamine biosynthetic pathway (HBP) nutrient flux product [421]. HBP combines amino acid, glucose, nucleotide, and fatty acid metabolism to produce the O-GlcNAcylation donor substrate [421]. The transfer of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc: donor substrate), to the target protein is catalyzed by O-GlcNAc transferase (OGT) and the removal of the sugar is performed by β-N-acetylglucosaminidase (O-GlcNAcase or OGA) [387, 419, 421].
Metabolic Diseases
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Stephanie Grünewald, Alex Broomfield, Callum Wilson
Sanfilippo syndrome is a group of four autosomal recessive lysosomal storage diseases resulting from a failure to degrade heparan sulphate. The four biochemical subtypes of MPS III (types A–D) are caused by the deficiency of one of the four enzymes required for the removal of N-acetylglucosamine at the non-reducing end of the saccharide chain. Heparan-N-sulfamidase is deficient in MPS IIIA, a-N-acetylglucosaminidase is deficient in MPS IIIB, acetylCoA:alpha-glucosaminide N-acetyl transferase is deficient in MPS IIIC and N-acetylglucosamine 6-sulfatase is deficient in MPS IIID. Type C and D are uncommon.
Introduction
Published in Emmanuel Opara, NUTRITION and DIABETES, 2005
Hyperglycemia also stimulates release of xanthine oxidase from liver cells into plasma, where this enzyme further contributes to worsening oxidative stress through generation of superoxide ion [48]. There is evidence to suggest that increased superoxide-anion production also activates the hexosamine pathway, which inhibits eNOS activation by O-acetylglucsoaminylation at the Protein Kinase B, a serine threonine protein kinase (Akt) site of the eNOS protein [47]. Shunting of excess glucose into the hexosamine pathway is also believed to result in increased activity of the enzyme O-GlcNAc-β-N-acetylglucosaminidase [49]. This activation likely results in O-acetylglucoaminylation of the transcription factor Sp1 and other glucose-responsive genes, thereby modulating both gene expression and protein function in the vascular wall to contribute to the pathogenesis of diabetic complications.
Pulicaria crispa mitigates nephrotoxicity induced by carbon tetrachloride in rats via regulation oxidative, inflammatory, tubular and glomerular indices
Published in Biomarkers, 2022
Wessam M. Aziz, Manal A. Hamed, Howaida I. Abd-Alla, Samia A. Ahmed
The proximal tubule lysosomal enzyme N-acetylglucosaminidase (NAG) has been shown to be a sensitive, long-lasting, and reliable indication of tubular damage, where nephrotoxicants exposure is linked to an increase in its levels (Shebeko et al. 2019). Many researchers used urinary NAG as a biomarker of AKI in rats (Zhou et al., 2008; Shebeko et al. 2019). Fujita et al. (2002) stated that endogenous urea, as well as a variety of nephrotoxicants and heavy metals, has been demonstrated to limit urinary NAG activity. Increased urine NAG levels have also been seen in severe AKI and in many diseases, including rheumatoid arthritis, poor glucose tolerance, and hyperthyroidism. Shebeko et al (2020) also reported that the amino sugar glucosamine found in glomerular basement membrane is affected through the active metabolite of NAG that is expressed in the damaged kidney membranes. In this context, the present studied revealed a significant elevation in NAG in kidney tissue of CCl4 injured rats.
Prevention of crystalline silica-induced inflammation by the anti-malarial hydroxychloroquine
Published in Inhalation Toxicology, 2019
Rachel Burmeister, Joseph F. Rhoderick, Andrij Holian
Lysosome membrane permeabilization (LMP) was assessed using methods modified from Aits et al. (2015) and as described previously by our laboratory (Jessop et al. 2017). BMDM were plated in 24 well plates at a density of 2 × 105 cells per well. Cells were treated with or without HCQ (25 μM) and with or without cSiO2 (50 μg/mL−1). Cells were washed twice with PBS and placed on ice. BMDM were then incubated with 200 μL of cytosol extraction buffer, which consisted of 250 mM sucrose, 20 mM Hepes, 10 mM KCl, 1.5 mM MgCl2, 1 mM EDTA, 1 mM EGTA, 0.5 mM pefabloc (Sigma–Aldrich cat. 76307-100 mg), pH 7.5, and digitonin (15 μg/mL−1) (Sigma–Aldrich cat. D141-100MG), for 15 min on ice with rocking. The concentration of digitonin for optimal extraction of the cytosolic fraction was determined by titration. β-N-acetylglucosaminidase (NAG) activity was measured by adding 30 μL cytosolic extract to 100 μL of NAG reaction buffer (0.2 M sodium citrate, pH 4.5 with 300 μg/mL−1 4-methylumbelliferyl-2-acetamido-2-deoxy-β-d-glucopyranoside (Sigma-Aldrich cat. 37067-30-4) and assessed on a plate reader (20 min; 45 s intervals; 356 nm excitation; 444 nm emission). Extracted cytosolic LDH activity was measured as described above and used as a control to which the NAG activities were normalized.
Glucosamine for the Treatment of Osteoarthritis: The Time Has Come for Higher-Dose Trials
Published in Journal of Dietary Supplements, 2019
Mark F. McCarty, James H. O'Keefe, James J. DiNicolantonio
At the level of molecular biology, how does glucosamine achieve anti-inflammatory effects? After entering cells via glucose transporters, glucosamine is rapidly phosphorylated by hexokinase to glucosamine-6-phosphate, which enters the hexosamine biosynthesis pathway (Uldry et al., 2002). Glucosamine-6-phosphate is then converted, in three enzyme-catalyzed steps, to UDP-N-acetylglucosamine (Laczy et al., 2009). This serves as substrate in the synthesis of hyaluronic acid and mucopolysaccharides and in the glycosylation of proteins within the endoplasmic reticulum. This compound is also employed as a donor by the enzyme β-N-acetylglucosaminyltransferase, which covalently links N-acetylglucosamine to the serine and threonine groups of many proteins. This linkage, in turn, is cleaved by the enzyme β-N-acetylglucosaminidase (Laczy et al., 2009). The reversible O-GlcNAcylation of proteins is now known to play a key regulatory role in intracellular metabolism, much like reversible phosphorylation does (Hanover et al., 2010).