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At least 127 records · Page 7Linked to original sources
PubMed2003

High glucose stimulates angiotensinogen gene expression and cell hypertrophy via activation of the hexosamine biosynthesis pathway in rat kidney proximal tubular cells.

The present study investigated whether activation of the hexosamine biosynthesis pathway might mediate at least in part the high glucose effect on angiotensinogen (ANG) gene expression and immortalized renal proximal tubular cell (IRPTC) hypertrophy. IRPTC were cultured in monolayer. ANG, renin, and beta-actin mRNA expression were determined by specific RT-PCR assays. Phosphorylation of p38 MAPK, activating transcription factor-2 (ATF-2), and cAMP-responsive element-binding protein (CREB) was determined by Western blot analysis. Cell hypertrophy was assessed by flow cytometry, intracellular p27kip1 protein levels, and [3H]leucine incorporation into proteins. Glucosamine stimulated ANG and renin mRNA expression and enhanced p38 MAPK, ATF-2, and CREB phosphorylation in normal glucose (5 mm) medium. Azaserine and 6-diazo-5-oxo-l-norleucine (inhibitors of glutamine: fructose-6-phosphate amino transferase enzyme) blocked the stimulatory effect of high glucose, but not that of glucosamine, on ANG gene expression in IRPTCs. SB 203580 (a specific p38 MAPK inhibitor) attenuated glucosamine action on ANG gene expression as well as p38 MAPK and ATF-2 phosphorylation, but not that of CREB. GF 109203X and calphostin C (inhibitors of protein kinase C) blocked the effect of glucosamine on ANG gene expression and CREB phosphorylation, but had no impact on p38 MAPK and ATF-2 phosphorylation. Finally, both glucosamine and high glucose induced IRPTC hypertrophy. The hypertrophic effect of glucosamine was blocked in the presence of GF 109203X, but not azaserine and SB 203580. In contrast, the hypertrophic effect of high glucose was blocked in the presence of azaserine and GF 109203X, but not SB203580. Our studies demonstrate that the stimulatory effect of high glucose on ANG gene expression and IRPTC hypertrophy may be mediated at least in part via activation of hexosamine biosynthesis pathway signaling.

Activating Transcription Factor 2↗
PubMed1993

Glucose regulation of transforming growth factor-alpha expression is mediated by products of the hexosamine biosynthesis pathway.

We have recently shown that glucose and glucosamine regulate the transcription of transforming growth factor-alpha (TGF alpha) in rat aortic smooth muscle (RASM) cells. Based on the increased potency of glucosamine compared to glucose, we hypothesized that stimulation of TGF alpha transcription by glucose is mediated through the hexosamine biosynthesis pathway. The yeast cDNA for the rate-limiting enzyme of this pathway, glutamine:fructose-6-phosphate amidotransferase (GFA), was therefore expressed in RASM cells. GFA-transfected cells showed an increase in GFA activity, exhibiting a 2.2-fold increase in the synthesis of glucosamine-6-phosphate, the first product of the hexosamine biosynthetic pathway. To test the effect of GFA overexpression on TGF alpha transcriptional activity, cells were transiently cotransfected with GFA along with a reporter plasmid containing the firefly luciferase gene under control of the TGF alpha promoter. GFA-transfected cells exhibited a glucose-dependent 2-fold increase in TGF alpha activity compared to control cells. Maximal stimulation of TGF alpha-luciferase activity by glucosamine, however, was equivalent in GFA-and control-transfected cells, confirming that the stimulation observed by both agents operated through the same pathway. This increase in TGF alpha activity was inhibited (85% at 0.5 mM glucose and 69% at 30 mM glucose) by the glutamine analog and inhibitor of GFA, 6-diazo-5-oxonorleucine (10 microM). Control studies confirmed that the increased TGF alpha-luciferase activity in the GFA-expressing cells was not an artifact of altered growth, survival, or transfection efficiency.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1995

Effects of diabetes and hyperglycemia on the hexosamine synthesis pathway in rat muscle and liver.

In vitro studies suggested that increased flux of glucose through the hexosamine biosynthesis pathway (HexNSP) contributes to glucose-induced insulin resistance. Glutamine:fructose-6- phosphate amidotransferase (GFAT) catalyzes glucose flux via HexSNP; its major products are uridine diphosphate (UDP)-N-acetyl hexosamines (UDP-HexNAc). We examined whether streptozotocin (STZ)-induced diabetes (4-10 days) or sustained hyperglycemia (1-2 h) in normal rats alters absolute or relative concentrations of nucleotide-linked sugars in skeletal muscle and liver in vivo. UDP-HexNAc and UDP-hexoses (UDP-Hex) were increased and decreased, respectively, in muscles of diabetic rats, resulting in an approximately 50% increase in the UDP-HexNAc:UDPHex ratio (P < 0.01). No significant changes in nucleotide sugars were observed in livers of diabetic rats. In muscles of normal rats, UDP-HexNAc concentrations increased (P < 0.01) and UDP-Hex decreased (P < 0.01) during hyperglycemia. The UDP-HexNAc:UDP-Hex ratio increased approximately 40% (P < 0.01) and correlated strongly with plasma glucose concentrations. Changes in liver were similar to muscle but were less marked. GFAT activity in muscle and liver was unaffected by 1-2 h of hyperglycemia. GFAT activity decreased 30-50% in muscle, liver, and epididymal fat of diabetic rats, and this was reversible with insulin therapy. No significant change in GFAT mRNA expression was detected, suggesting post-transcriptional regulation. The data suggest that glucose flux via HexNSP increases in muscle during hyperglycemic hyperinsulinemia and that the relative flux of glucose via HexNSP is increased in muscle in STZ-induced diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1999

Activation of the hexosamine pathway by glucosamine in vivo induces insulin resistance of early postreceptor insulin signaling events in skeletal muscle.

To explore potential cellular mechanisms by which activation of the hexosamine pathway induces insulin resistance, we have evaluated insulin signaling in conscious fasted rats infused for 2-6 h with saline, insulin (18 mU x kg(-1) x min(-1)), or insulin and glucosamine (30 micromol x kg(-1) x min(-1)) under euglycemic conditions. Glucosamine infusion increased muscle UDP-N-acetylglucosamine concentrations 3.9- and 4.3-fold over saline- or insulin-infused animals, respectively (P < 0.001). Glucosamine induced significant insulin resistance to glucose uptake both at the level of the whole body and in rectus abdominis muscle, and it blunted the insulin-induced increase in muscle glycogen content. At a cellular level, these metabolic effects were paralleled by inhibition of postreceptor insulin signaling critical for glucose transport and glycogen storage, including a 45% reduction in insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation (P = 0.02), a 44% decrease in IRS-1 association with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase (P = 0.03), a 34% reduction in IRS-1-associated PI 3-kinase activity (P = 0.03), and a 51% reduction in insulin-stimulated glycogen synthase activity (P = 0.03). These alterations in postreceptor insulin signaling were time-dependent and paralleled closely the progressive inhibition of systemic glucose disposal from 2 to 6 h of glucosamine infusion. We also demonstrated that glucosamine infusion results in O-linked N-acetylglucosamine modification of IRS-1 and IRS-2. These data indicate that activation of the hexosamine pathway may directly modulate early postreceptor insulin signal transduction, perhaps via posttranslation modification of IRS proteins, and thus contribute to the insulin resistance induced by chronic hyperglycemia.

Animals↗
PubMed2003

Palmitate-induced activation of the hexosamine pathway in human myotubes: increased expression of glutamine:fructose-6-phosphate aminotransferase.

The nutrient sensing capacity of the hexosamine biosynthetic pathway (HBP) has been implicated in the development of insulin resistance of skeletal muscle. To study the molecular mechanism of the free fatty acid (FFA)-induced activation of the HBP myotubes obtained from muscle biopsies of metabolically characterized, subjects were stimulated with different fatty acids for 20 h. Incubation with the saturated fatty acids palmitate and stearate (0.5 mmol/l) resulted in a three- to fourfold increase in mRNA expression of glutamine:fructose-6-phosphate aminotransferase (GFAT), the key and rate-limiting enzyme of the hexosamine pathway. Unsaturated fatty acids or 30 mmol/l glucose had little or no effect. Palmitate increased the amount of GFAT protein nearly two-fold, and subsequently, the concentration of UDP-N-acetylglucosamine, the end product of the HBP, was 1.3-fold enhanced in the palmitate-stimulated myotubes. The nonmetabolized fatty acid bromopalmitate had no effect. The DNA binding activity of the transcription factor Sp1, a target downstream of the HBP, was increased by palmitate and completely lost after enzymatic removal of O-GlcNAc. No correlation was found between the palmitate-induced increase in GFAT protein and the insulin resistance in the respective subjects. The findings reveal a new mechanism for how FFAs induce the activation of the HBP.

Cells, Cultured↗
PubMed1976

Changes in the hexosamine content and swelling ratio of articular cartilage as functions of depth from the surface.

The hexasamine content and swelling ratio of adult bovine articular cartilage were determined as functions of depth. Progressing from the surface downward, the hexosamine content increased rapidly to a depth equivalent to approximately 30 to 35 per cent of the total thickness of the uncalcified portion of the tissue, and thereafter decreased at a less rapid rate. The swelling ratio was relatively constant throughtout the first quarter of the tissue but diminished thereafter. At depths below 35 per cent, the curve for the decrease in swelling ratio with depth was similar in form to that for the decrease in hexosamine content. Considering the factors that determine the swelling ratio of polyelectrolyte gels, it is proposed that progressing down from the surface, the interaction between the macromolecular components of the tissue is increased to a depth equivalent to about one-third of the total thickness of the cartilage.

Animals↗
PubMedDate not supplied

[Effect of fructose on the hexosamine turnover in the rat crystalline lens].

Rats were given isocaloric rations containing starch (control) and varying amounts of fructose as carbohydrates. Hexosamines were isolated from the lens, glycoproteins--from the blood serum, and their turnover was studied. A drastic deceleration of hexosamine turnover in the lens was observed at high-fructose diets (20 and 40% of fuel value), while glycoprotein turnover in the blood plasma was not changed as compared to the control, glucose-6-phosphate dehydrogenase in red blood cells was decreased, insulin level was lowered, and glucose level in the blood serum rose insignificantly. It has been suggested that fructose may be cataractogenic in animals.

Animals↗
PubMedDate not supplied

[Turnover of hexosamines in the lens and glycoproteins in the blood of rats given a xylose-containing diet].

To elucidate the action of xylose admixtures during the biotechnological production of monosaccharides, rats were given rations containing xylose that comprised 2.10 and 20% of the total amount of carbohydrates. Hexosamines of the lens and general blood globulin fraction were isolated and their turnover was investigated. The activity of glucoso-6-phosphate dehydrogenase, and the content of reduced and oxidized glutathione were assayed in the eyes and red blood cells. The content of xylose was determined in the plasma, eyes and red blood cells. Xylose inclusion into the ration of rats induced a pronounced increase in the half-life of hexosamines in the lens. The general blood globulin fraction turnover was unchanged. The activity of glucoso-6-phosphate dehydrogenase and the amount of total and reduced glutathione in red blood cells were decreased. Xylose content in the eyes and red blood cells was unchanged, while in the plasma it rose proportionally to the increase of its amount in the ration.

Animals↗
PubMed1977

[Human serum hexosamine. Determination in neoplastic disease (author's transl)].

The serum hexosamine levels of 93 patients with neoplastic disease and of 30 normal individuals chosen among medical students were determined. The mean values obtained in both groups show that in neoplastic disease the levels are higher than in normal persons. The application of Student (/t/) indicates a significant differences in the mean values (/t/) = 6.93 P less than 0.001). It is concluded that serum hexosamine contents are elevated in neoplastic disease.

Hexosamines↗
PubMed2000

Effect of 6-O-sulfonate hexosamine residue on anticoagulant activity of fully O-sulfonated glycosaminoglycans.

Intact and fully O-sulfonated glycosaminoglycans (GAGs) including chondroitin sulfate, dermatan sulfate, hyaluronan, heparan sulfate and heparin were chemically de-O-sulfonated on their hexosamine C-6 position (6-O-desulfonation) using N,O-bis(trimethylsilyl) acetamide. 1H NMR spectroscopy and chemical compositional analysis showed that the chemical de-O-sulfonation at C-6 position of hexosamine residues in both intact and fully O-sulfonated GAGs was completely achieved. Since GAGs and their derivatives are often used as anticoagulant agents, their anti-amidolytic activities were determined. While most of anticoagulant activity of fully O-sulfonated GAGs (FGAGs) and heparin disappeared following chemical 6-O-desulfonation, the activity of 6-O-desulfonated fully O-sulfonated dermatan sulfate (De6FDS) remained. This observation suggests the importance of the position of O-sulfonate groups for anti-coagulant activity.

Anticoagulants↗
PubMed1976

Distribution of Protein-bound Hexosamine in Chloroplasts.

Intact chloroplasts of spinach (Spinacia oleracea L.), sunflower (Helianthus annuus L.), and maize (Zea mays L.) mesophyll cells contained 0.33, 0.50, and 0.14% of bound hexosamine on a protein basis, respectively. Undifferentiated maize chloroplasts contained 0.19%. Values for chloroplast lamellae were, respectively, 0.16, 0.18, 0.12, and 0.06% and for envelope membranes they were 1.6, 2.5, 3.8, and 2.7%. Thus most of the hexosamine of chloroplasts is located in the envelope membrane.

Journal Article↗
PubMed1977

The hyphal wall of Mucor mucedo. 2. Hexosamine-containing polymers.

Nitrous acid, which specifically depolymerises polymers containing hexosamines with a primary amino group, was used to analyse the hexosamine-containing polymers in the hyphal wall of Mucor mucedo. N-Acetylglucosamine was found to occur in three polymeric fractions. One fraction which was solubilised by HNO2 treatment contained-N-acetylglucosamine interspersed with glucosamine; no homopolymer of glucosamine (chitosan) was detected. Another fraction became HNO2-soluble after treatment with pronase or alkali; this points to the occurrence of a heteropolymer containing N-acetylglucosamine and glucosamine in which some of the glucosamine residues are linked to peptides via their amino groups. The residue remaaining after pronase and HNO* treatment appeared to consist of a homopolymer of N-acetylglucosamine (chitin).

Acetylglucosamine↗
PubMed2001

Hexosamines and nutrient excess induce leptin production and leptin receptor activation in pancreatic islets and clonal beta-cells.

Activation of the hexosamine biosynthesis pathway leads to insulin resistance in muscle and adipose tissue. In these tissues leptin gene expression is increased by glucosamine. In the present study we found that glucosamine rapidly activates the production of leptin and OB-Rb, which encodes the functional leptin receptor, in both primary pancreatic islets and clonal beta-cells. Secretion of leptin from clonal beta-cells into the medium was detected readily. In addition, the level of the transcripts encoding signal transducer and activator of transcription-3 and -5, both implicated in leptin signal transduction in islet beta-cells, was increased by glucosamine, although to a lesser degree than mRNA levels of leptin and OB-Rb. High glucose (16.7 mM) induced leptin biosynthesis in primary pancreatic islet cells, and the addition of 1 mM palmitate caused an additional incremental effect. The hexosamine-mediated induction of the leptin system in clonal beta-cells was associated with increased responsiveness to leptin, as demonstrated by a 2.6 +/- 0.3-fold (P < 0.01) increase in tyrosine phosphorylation of signal transducer and activator of transcription-3. These findings are the first evidence of inducible leptin production in pancreatic islets and suggest that islet cells, like skeletal muscle, demonstrate a linkage between increased nutrient availability and both leptin expression and leptin responsiveness.

Animals↗
PubMedDate not supplied

[Hexosamine content of normal and pathological human sperm].

Glucosamine and galactosamin were determined in 96 human ejaculates. The principal hexosamine of spermatozoa was galactosamin on the other hand glucosamin was the principal aminosugar of seminal plasma. The results were compared with the fertility parameters. Our results show no definity relation between the hexosamine concentration and the andrological conditions.

Fertility↗
PubMed2006

Semiquantitative analysis of isomeric oligosaccharides by negative-ion mode UV-MALDI TOF postsource decay mass spectrometry and their fragmentation mechanism study at N-acetyl hexosamine moiety.

Postsource decay (PSD) spectra of isomeric neutral lactooligosaccharide mixtures were measured from the chlorinated molecules [M + Cl]- by negative-ion mode ultraviolet matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (UV-MALDI TOF MS) to estimate quantitatively the mixing ratios in their mixtures. The PSD ions specific to each isomeric structure were used to distinguish the linkage and branching isomers, and the molar ratios of the isomers were estimated from their ion abundances. The relative ion abundances changed linearly in the PSD spectra of the mixtures of the isomers as their molar ratio was varied in the analyte solutions. Therefore, the molar ratios of the isomers in the analyte mixtures could be estimated semiquantitatively. In addition, we studied their fragmentation mechanisms in N-acetyl hexosamines such as GlcNAc, which enabled us to quantitatively analyze the structures of the isomers of lactooligosaccharides. The conjugated systems elongate in the chemical species of the Z-type fragmentation on the 3-linked GlcNAc owing to the acetoamido groups at the C-2 positions, which made the chemical species of the Z-type ions stable. The glycosyl bonds of the front of GlcNAc cleaved easily as a C-type fragmentation because the negative charge at the anomeric position could be delocalized to the carbonyl oxygen atom at the acetoamido group of GlcNAc. These factors caused the stabilization of the chemical species of the C/Z fragment ions produced by the double cleavage around GlcNAc.

Computer Simulation↗
PubMed1994

A novel chemical procedure for the selective removal of nonreducing terminal N-acetyl hexosamine residues from glycolipids.

A two-step oxidative hydrolysis procedure is described for the selective removal of nonreducing terminal N-acetylhexosamine residues from glycolipids. The procedure gives a 50-60% yield of the n-1 hexosyl ceramide, the remainder being peeling products (n-2, n-3, etc.). The reaction is dependent on the selective deacetylation of nonreducing terminal N-acetyl hexosamine residues by aqueous base hydrolysis. Deglycosylation then occurs in the presence of hydrogen peroxide. Glycolipids containing internal or no N-acetylhexosamine residues are unaltered in these reactions. This method is suitable for the large-scale deglycosylation of appropriate glycolipids and may also be used as an adjunct in structural determination of unknown amino sugar-containing glycolipids.

Acetylation↗
PubMed1977

A lipid linked oligosaccharide which contains hexosamine, mannose and glucose.

Previous work showed that liver microsomes catalyze the transfer of glucose from dolichol monophosphate glucose to an endogenous acceptor believed to be a dolichol pyrophosphate derivative of an oligosaccharide. This oligosaccharide has now been prepared on a larger scale so as to permit the determination of its sugars. The purification procedure includes, as a last step, a thin layer chromatography on kieselguhr-silica gel to obviate glucose-containing contaminants. After complete hydrolysis mannose, glucose and a small amount of hexosamine were detected.

Animals↗