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PubMed2004

Differentiation of underivatized diastereomeric hexosamine monosaccharides and their quantification in a mixture using the kinetic method under electrospray ionization conditions.

A simple method to differentiate underivatized diastereomeric hexosamine monosaccharides, glucosamine, galactosamine, and mannosamine is reported by applying the kinetic method using N-acetylhexosamines or naturally occurring amino acids as reference bases under electrospray ionization conditions. The observed differences to distinguish the diastereomeric hexosamines are found mainly due to the proton affinity (PA) differences between the analyte and the reference base. The PA values of the hexosamines are not available in the literature, and hence, we estimated them by the kinetic method using N-acetylhexosamines as reference bases. The determined PA values are 223.97 kcal/mol for glucosamine, 224.99 kcal/mol for mannosamine, and 224.71 kcal/mol for galactosamine. The similar PA values were also obtained by using amino acids as reference bases. We have applied the same methodology to quantify these hexosamines in a mixture following the three-point calibration method suggested in the literature.

Calibration↗
PubMed2000

Role of the hexosamine biosynthetic pathway in diabetic nephropathy.

The hexosamine biosynthetic pathway has been hypothesized to be involved in the development of insulin resistance and diabetic vascular complications. In particular, it was demonstrated that hyperglycemia-induced production of transforming growth factor-beta (TGF-beta1), a prosclerotic cytokine causally involved in the development of diabetic nephropathy. Several lines of evidence indicate that TGF-beta1 induction is mediated by the hexosamine pathway. In cultured mesangial cells, high glucose levels induce TGF-beta1 production. This effect is eliminated by inhibition of glutamine: fructose-6-phosphate-amidotransferase (GFAT), the rate-limiting enzyme of this pathway. Furthermore, stable overexpression of GFAT increased levels of TGF-beta1 protein, mRNA, and promoter activity. Inasmuch as stimulation or inhibition of GFAT increased or decreased high glucose-stimulated activity of protein kinase C (PKC), respectively, the observed effects appear to be transduced by PKC. In similar experiments, involvement of the hexosamine pathway in hyperglycemia-induced production of cytokines (TGF-alpha and basic fibroblast growth factor [bFGF]) was demonstrated in vascular smooth muscle cells. These studies also revealed a rapid increase in GFAT activity by treatment with agents that elevated levels of cyclic adenosine 3',5' monophosphate (cAMP), thus indicating that GFAT activity is tightly regulated by cAMP-dependent phosphorylation. Using immunohistochemistry and in situ hybridization, high expression of GFAT was found in human adipocytes, skeletal muscle, vascular smooth muscle cells, and renal tubular epithelial cells. whereas glomerular cells remained essentially unstained. However, significant staining occurred in glomerular cells of patients with diabetic nephropathy. Current data indicate that the flux through the hexosamine pathway, regulated by GFAT, may be causally involved in the development of diabetic vascular disease, particularly diabetic nephropathy.

Animals↗
PubMed2007

Chronic hexosamine flux stimulates fatty acid oxidation by activating AMP-activated protein kinase in adipocytes.

The hexosamine biosynthesis pathway (HBP) serves as a nutrient sensor and has been implicated in the development of type 2 diabetes. We previously demonstrated that fatty acid oxidation was enhanced in transgenic mouse adipocytes, wherein the rate-limiting enzyme of the HBP, glutamine:fructose-6-phosphate amidotransferase (GFA), was overexpressed. To explore the molecular mechanism of the HBP-induced fatty acid oxidation in adipocytes, we studied AMP-activated protein kinase (AMPK), an energy sensor that stimulates fatty acid oxidation by regulating acetyl-CoA carboxylase (ACC) activity. Phosphorylation and activity of AMPK were increased in transgenic fat pads and in 3T3L1 adipocytes treated with glucosamine to stimulate hexosamine flux. Glucosamine also stimulated phosphorylation of ACC and fatty acid oxidation in 3T3L1 adipocytes, and these stimulatory effects were diminished by adenovirus-mediated expression of a dominant negative AMPK in 3T3L1 adipocytes. Conversely, blocking the HBP with a GFA inhibitor reduced AMPK activity, ACC phosphorylation, and fatty acid oxidation. These changes are not explained by alterations in the cellular AMP/ATP ratio. Further demonstrating that AMPK is regulated by the HBP, we found that AMPK was recognized by succinylated wheat germ agglutinin, which specifically binds O-GlcNAc. The levels of AMPK in succinylated wheat germ agglutinin precipitates correlated with hexosamine flux in mouse fat pads and 3T3L1 adipocytes. Moreover, removal of O-GlcNAc by hexosaminidase reduced AMPK activity. We conclude that chronically high hexosamine flux stimulates fatty acid oxidation by activating AMPK in adipocytes, in part through O-linked glycosylation.

3T3-L1 Cells↗
PubMed1998

Geranylgeranylacetone, an anti-ulcer drug, stimulates hexosamine production in a rat gastric mucosal cell line through binding to a specific cytosolic protein.

An anti-ulcer drug, geranylgeranylacetone (GGA), stimulates hexosamine production in a rat gastric mucosal cell line (RGM-1). The aim of this study was to elucidate the mechanism of this action. The role of protein kinase A, inositol phospholipid turnover and tyrosine kinase in the stimulatory action of GGA on hexosamine production in RGM-1 was determined by observing cAMP production, [3H]-inositol phosphate turnover and western blotting of tyrosine phosphorylation, respectively. Any trophic effect of GGA on RGM-1 was also checked by [3H]-thymidine incorporation. Our experiments showed that GGA has no effect on cAMP production, inositol phospholipid turnover, tyrosine phosphorylation or DNA synthesis in RGM-1. Finally, a [14C]-GGA competitive receptor binding assay was performed on RGM-1 and we found that [14C]-GGA specifically bound to RGM-1 cytosolic protein. Although retinoic acid (RA), another polyisoprenoid compound significantly stimulated hexosamine production in RGM-1, we confirmed that the [14C]-GGA binding site in RGM-1 is different from the RA binding site. In summary, GGA stimulates hexosamine production in RGM-1 and this action is probably mediated through its binding to a specific cytosolic protein in RGM-1.

Animals↗
PubMed2002

Transgenic mice overexpressing the rate-limiting enzyme for hexosamine synthesis in skeletal muscle or adipose tissue exhibit total body insulin resistance.

High concentrations of glucose induce insulin resistance and impair insulin secretion in a manner that mirrors type 2 diabetes, a phenomenon known as glucose toxicity. High concentrations of hexosamines mimic these effects, leading to the hypothesis that cells use hexosamine flux as a glucose- and satiety-sensing pathway. Overexpression of the rate-limiting enzyme for hexosamine synthesis (glutamine:fructose-6-phosphate amidotransferase, GFA) in muscle and fat results in insulin resistance and hyperleptinemia. GFA overexpression targeted to liver results in hyperlipidemia and to the beta cell in increased insulin secretion. Thus, excess hexosamine flux leads to a coordinated response whereby fuel is shunted toward long-term storage, mirroring the "thrifty phenotype". The results suggest a mechanism by which chronic overnutrition leads to the phenotype of type 2 diabetes.

Adipose Tissue↗
PubMed1977

Effect of strain variation and growth phase of culture on dry weight and hexosamine content of cell wall layers of a marine pseudomonad.

Two variants of marine pseudomonad B-16 (ATCC 19855) differing in that one, variant 3, formed opaque colonies and the other, variant 7, formed translucent colonies were examined to determine if the variants differed in the amount and hexosamine content of their three outer cell wall layers. In both variants, the three outer layers of the cell wall, the loosely bound outer layer, the outer double-track layer, and the underlying (periplasmic space) layer contributed less to the dry weight of the cells when the cells were harvested in the stationary than in the logarithmic phase of growth. The hexosamine content of the layers of variant 3 increased dramatically as the cells went from the logarithmic to the stationary phase. The hexosamine content of the layers of variant 7 changed little by comparison. Thus cells of the variant which forms opaque colonies enrich the outer layers of their cell wall with hexosamine when grown to stationary phase.

Cell Wall↗
PubMed2005

Hexosamines regulate sensitivity of glucose-stimulated insulin secretion in beta-cells.

Hexosamines serve a nutrient-sensing function through enzymatic O-glycosylation of proteins. We previously characterized transgenic (Tg) mice with overexpression of the rate-limiting enzyme in hexosamine production, glutamine:fructose-6-phosphate amidotransferase, in beta-cells. Animals were hyperinsulinemic, resulting in peripheral insulin resistance. Glucose tolerance deteriorated with age, and males developed diabetes. We therefore examined islet function in these mice by perifusion in vitro. Young (2-mo-old) Tg animals had enhanced sensitivity to glucose of insulin secretion. Insulin secretion was maximal at 20 mM and half maximal at 9.9 +/- 0.5 mM glucose in Tg islets compared with maximal at 30 mM and half maximal at 13.5 +/- 0.7 mM glucose in wild type (WT; P < 0.005). Young Tg animals secreted more insulin in response to 20 mM glucose (Tg, 1,254 +/- 311; WT, 425 +/- 231 pg x islet(-1) x 35 min(-1); P < 0.01). Islets from older (8-mo-old) Tg mice became desensitized to glucose, with half-maximal secretion at 16.1 +/- 0.8 mM glucose, compared with 11.8 +/- 0.7 mM in WT (P < 0.05). Older Tg mice secreted less insulin in response to 20 mM glucose (Tg, 2,256 +/- 342; WT, 3,493 +/- 367 pg x islet(-1) x 35 min(-1); P < 0.05). Secretion in response to carbachol was similar in WT and Tg at both ages. Glucose oxidation was blunted in older Tg islets. At 5 mM glucose, islet CO2 production was comparable between Tg and WT. However, WT mice increased islet CO2 production 2.7 +/- 0.4-fold in 20 mM glucose, compared with only 1.4 +/- 0.1-fold in Tg (P < 0.02). Results demonstrate that hexosamines are involved in nutrient sensing for insulin secretion, acting at least in part by modulating glucose oxidation pathways. Prolonged excess hexosamine flux results in glucose desensitization and mimics glucose toxicity.

Animals↗
PubMed2004

Adipocytes with increased hexosamine flux exhibit insulin resistance, increased glucose uptake, and increased synthesis and storage of lipid.

The hexosamine signaling pathway has been shown to serve a nutrient-sensing function. We have previously shown that overexpression of the rate-limiting enzyme for hexosamine synthesis (glutamine-fructose-6-phosphate amidotransferase) in adipose tissue of transgenic mice results in skeletal muscle insulin resistance and altered regulation of leptin and adiponectin. To dissect the pathways by which the hexosamine pathway affects fuel storage and energy homeostasis, we have examined the characteristics of adipocytes from these animals. After 3 mo of age, epididymal fat pads from adult transgenic animals are 42% heavier (P = 0.003) and individual adipocytes are 23% larger in diameter (P < 0.05) than those from littermate wild-type controls. Isolated adipocytes from transgenic mice are insulin resistant, with a 2.5-fold increase in the ED50 for stimulation of 2-deoxy-D-glucose uptake. However, maximal insulin-stimulated glucose uptake is increased in transgenic adipocytes by 39% (P < 0.05). This upregulation of glucose uptake was associated with a 41% increase in the expression of GLUT4 mRNA and a 28% increase in GLUT4 protein in transgenics compared with controls (P < 0.05). GLUT1 mRNA and protein did not significantly differ between fasted control and transgenics. Total lipid synthesis was also increased in epididymal adipocytes from transgenic animals by 206% compared with controls (P < 0.05). Fatty acid oxidation was increased 1.6-fold in the transgenic adipocytes (P < 0.05). We conclude that the hexosamine signaling pathway upregulates fat storage in adipocytes in states of carbohydrate excess, in part by increasing GLUT4 and glucose uptake and by augmenting fatty acid synthesis.

Adipocytes↗
PubMed2000

Hexosamines regulate leptin production in human subcutaneous adipocytes.

The hexosamine biosynthetic pathway has recently been proposed as a mechanism through which cells "sense" nutrient flux to regulate leptin release. This study was undertaken to examine the regulation of leptin production by hexosamines in human adipocytes. Adipose tissue UDP-N-acetylglucosamine, an end product of hexosamine biosynthesis, was elevated 3.2-fold, and ob messenger ribonucleic acid was elevated 2-fold in the sc adipose tissue of 17 obese [body mass index (BMI), 41.3+/-12.0 kg/m2; age, 31+/-5 yr] subjects compared to 14 lean (BMI, 23.4+/-1.6 kg/m2; age, 33+/-11 yr) subjects. Serum leptin was increased 2.7-fold in the obese subjects. A significant positive relationship was found between adipose tissue UDP-N-acetylglucosamine and BMI (Spearman correlation = 0.576; P = 0.0007) and between UDP-N-acetylglucosamine and serum leptin (Spearman correlation = 0.4650; P = 0.0145). Treatment of isolated sc adipocytes with 1 mmol/L glucosamine, an intermediate product in UDP-N-acetylglucosamine biosynthesis, increased leptin release 21.4+/-17.6% (mean +/- SD) over control (P = 0.0365) and 74.5+/-82.8% over control (P = 0.0271) in adipocytes from lean (BMI, 23.2+/-1.6 kg/m2; n = 6) and obese (BMI, 55.4+/-13.0 kg/m2,; n = 9) subjects, respectively, by 48 h of culture. Inhibition of UDP-N-acetylglucosamine biosynthesis with 6-diazo-5-oxo-norleucine reduced glucose-stimulated leptin release from cultured adipocytes 21.8+/-32.4% (P = 0.0395; n = 12) and ob gene expression 19.9+/-18.9% (P = 0.0208; n = 8) by 48 h of treatment. These findings suggest that hexosamine biosynthesis regulates leptin production in human adipose tissue.

Adipocytes↗
PubMed2003

Exploring levels of hexosamine biosynthesis pathway intermediates and protein kinase C isoforms in muscle and fat tissue of Zucker Diabetic Fatty rats.

Many studies suggest that insulin resistance develops and/or is maintained by an increased flux of glucose through the hexosamine biosynthesis pathway. This pathway may attenuate insulin-stimulated glucose uptake by activating protein kinase C (PKC). Therefore, we investigated whether the concentrations of the major hexosamine metabolites, uridine diphosphate- N-acetyl-glucosamine (UDP-GlcNAc) and uridine diphosphate- N-acetyl-galactosamine (UDP-GalNAc), and the expression levels of PKC isoforms were affected in Zucker Diabetic Fatty (ZDF) rats, an animal model widely used to study type 2 diabetes mellitus. At the age of 6 wk, control and ZDF rats were normoglycemic. Whereas control rats remained normoglycemic, the ZDF rats became hyperglycemic. The amount of UDP-GlcNAc and UDP-GalNAc in muscle tissue of ZDF rats was similar at 6, 12, 18, and 24 wk of age. Moreover, the concentration of both hexosamines did not differ among ZDF, phlorizin-treated ZDF, and control rats. Western blot analysis revealed that PKCalpha, delta, epsilon, andzeta, but not PKCbeta and gamma, were expressed in muscle and fat tissues from 6- and 24-wk-old control and ZDF rats. In addition, we did not observe changes in the expression levels of the PKC isoforms following prolonged hyperglycemia. Taken together, these findings indicate that the amounts of several metabolites from the hexosamine biosynthesis pathway and PKC isoforms, both hypothesized to be important in the development and/or maintenance of the insulin-resistant state of muscle and fat tissue, are not different in ZDF compared with nondiabetic rats.

Adipose Tissue↗
PubMed1996

Regulation of glycogen synthase and protein phosphatase-1 by hexosamines.

The hexosamine biosynthesis pathway has been hypothesized to be involved in mediating some of the adverse effects of high glucose. We have previously shown that glucose downregulates basal glycogen synthase (GS) activity in Rat-1 cells and that overexpressing the rate-limiting enzyme in the hexosamine biosynthesis pathway (glutamine:fructose-6-phosphate amidotransferase [GFA]) makes the cells more sensitive to these effects of glucose. GFA overexpression also leads to a reduction in insulin sensitivity of GS. Here we examine the effects of glucose and glucosamine on insulin-stimulated GS activity and on protein phosphatase-1 (PP1) activity. These activities were assayed in cytoplasmic extracts from Rat-1 fibroblasts overexpressing human GFA and cultured in varying glucose concentrations. Both maximal insulin-stimulated GS activity and insulin sensitivity decreased with increasing glucose. Overexpression of GFA leads to a further reduction in insulin sensitivity but not in maximal insulin-stimulated GS activity. Because there were no differences in total (glucose-6-phosphate-dependent) GS activity between cell lines or as a function of glucose concentration, these results most likely reflect a change in the phosphorylation state of the synthase. Activity of PP1, a potential mediator of these effects, was responsive to glucose and hexosamines. Control cells showed a 9.3 +/- 4.3% decrease in PP1 activity with increasing glucose. GFA cells showed a greater response to glucose, with PP1 activity decreasing 34.2 +/- 5.5% with increasing glucose. Glucosamine was more potent than glucose in decreasing PP1 activity in control cells. Cells overexpressing the normal human insulin receptor (HIRc-B) were used to facilitate analysis of insulin-stimulated PP1 activity. Stimulation with 1.7 mmol/l insulin led to a 37.6 +/- 9.9% increase in PP1 activity in HIRc-B cells cultured in 1 mmol/l glucose, while cells cultured in 5 mmol/l glucosamine or 20 mmol/l glucose demonstrated only 3.79 +/- 0.60 or 1.6 +/- 0.75% increases, respectively. We conclude that both basal and insulin- stimulable GS and PP1 activity are downregulated by high glucose in fibroblasts and this regulation is mediated by products of the hexosamine biosynthesis pathway.

Animals↗
PubMed2001

Hexosamine-induced fibronectin protein synthesis in mesangial cells is associated with increases in cAMP responsive element binding (CREB) phosphorylation and nuclear CREB: the involvement of protein kinases A and C.

Hyperglycemia-induced alterations in mesangial (MES) cell function and extracellular matrix protein accumulation are seen in diabetic glomerulopathy. Recent studies have demonstrated that some of the effects of high glucose (HG) on cellular metabolism are mediated by the hexosamine biosynthesis pathway (HBP), in which fructose-6-phosphate is converted to glucosamine 6-phosphate by the rate-liming enzyme glutamine:fructose-6-phosphate amidotransferase (GFA). In this study, we investigated the role of HBP on HG-stimulated fibronectin protein synthesis, a matrix component, in SV-40-transformed rat kidney MES cells. Treatment of MES cells with 25 mmol/l glucose (HG) for 48 h increases cellular fibronectin levels by two- to threefold on Western blots when compared with low glucose (5 mmol/l). Glucosamine (GlcN; 1.5 mmol/l), which enters the hexosamine pathway distal to GFA action, also increases fibronectin synthesis. Azaserine (AZA; 0.5 micromol/l), an inhibitor of GFA, blocks the HG- but not the GlcN-induced fibronectin synthesis. Fibronectin contains cAMP responsive element (CRE) consensus sequences in its promoter and the phosphorylation of CRE-binding protein (CREB) may regulate its expression. On Western blots, HG and GlcN stimulate two- to threefold the phosphorylation of CREB at Ser 133, whereas CREB protein content was unaltered by either HG or GlcN. In addition, nuclear CREB activity was increased by HG and GlcN on gel-shift assays using (32)P-CRE oligonucleotides. AZA impeded the HG-enhanced CREB phosphorylation and CRE binding but had no effect on GlcN-mediated CREB phosphorylation and CRE binding. Pharmacologic inhibition of protein kinase C (PKC) and protein kinase A (PKA), which are involved in hexosamine-mediated matrix production, blocked the CREB phosphorylation and fibronectin synthesis seen in HG and GlcN conditions. We conclude that the effects of HG on fibronectin synthesis in the mesangium are mediated by the HBP possibly via hexosamine regulation of CREB and PKC/PKA signaling pathways. These results support the hypothesis that the HBP is a sensor and regulator of the actions of glucose in the kidney.

Animals↗
PubMed1992

Insulin regulation of pyruvate kinase activity in isolated adipocytes. Crucial role of glucose and the hexosamine biosynthesis pathway in the expression of insulin action.

We recently identified glutamine:fructose-6-phosphate amidotransferase (GFAT) as an insulin-regulated enzyme in adipocytes. Moreover, we found that loss of GFAT activity is not due to a direct action of insulin but rather is mediated by enhanced glucose uptake and the subsequent routing of glucose through the hexosamine biosynthesis pathway. To assess whether other cytosolic enzymes are controlled through formation of hexosamine products, we treated adipocytes for 5 h with physiological concentrations of insulin (ED50 = 0.33 ng/ml), glucose (ED50 = 4.5 mM), and glutamine (ED50 = 4.4 mM) and then measured pyruvate kinase (PK) activity. Combined treatment resulted in a progressive (t 1/2 of 2.5 h) and marked (3-fold) increase in PK activity, whereas omission of one or more of these components failed to alter enzyme activity. Several lines of additional evidence implicated the hexosamine biosynthesis pathway in PK regulation; therefore, it appears that the M2 isoform of pyruvate kinase represents another enzyme regulated by insulin through stimulation of glucose uptake and formation of hexosamine products. Related studies revealed that enhancement of PK activity is dependent upon ongoing mRNA synthesis and de novo protein synthesis and is mediated by an increase in enzyme content. Considered together, these findings provide new insights into the cascade of metabolic events triggered by insulin and implicated a novel metabolic pathway in the pretranslational control of enzyme function.

Adipose Tissue↗
PubMedDate not supplied

[Effect of hydrocortisone on the metabolic indices of hexosamine-containing biopolymers in the stomach].

The experimental findings showed that hydrocortisone effect on metabolism of hexosamine-containing biopolymers of the stomach was dose-dependent. When administered in a small dose (0.2 mg/kg body weight) it increased the activity of biosynthesis of hexosamines, which are necessary for the formation of hexosamine-containing biopolymers, and also increased the total content in the gastric wall of biopolymers, glycosaminoglycans and glycoproteins soluble in perchloric acid. Administration of a large dose of the hormone (50 mg/kg) produced opposite changes in the studied tissue. In patients with peptic ulcer of the stomach and duodenum, exacerbation of which occurred against the background of stress-induced hypercorticosteroidemia, there was observed a decrease of glycosaminoglycan content in the gastric juice and mucosa. A decrease of hexosamine content in glycoproteins was noted.

11-Hydroxycorticosteroids↗
PubMedDate not supplied

Hexosamine induction of oxidative stress, hypertrophy and laminin expression in renal mesangial cells: effect of the anti-oxidant alpha-lipoic acid.

We have previously shown that one of the potential mediators of the deleterious effects of high glucose on extracellular matrix protein (ECM) expression in renal mesangial cells is its metabolic flux through the hexosamine biosynthesis pathway (HBP). Here, we investigate further whether the hexosamines induce oxidative stress, cell-cycle arrest and ECM expression using SV-40-transformed rat mesangial (MES) cells and whether the anti-oxidant alpha-lipoic acid will reverse some of these effects. Culturing renal MES cells with high glucose (HG, 25 mM) or glucosamine (GlcN, 1.5 mM) for 48 h stimulates laminin gamma1 subunit expression significantly approximately 1.5 +/- 0.2- and 1.9 +/- 0.3-fold, respectively, when compared to low glucose (LG, 5 mM). Similarly, HG and GlcN increase the level of G0/G1 cell-cycle progression factor cyclin D1 significantly approximately 1.7 +/- 0.2- and 1.4 +/- 0.04-fold, respectively, versus LG (p < 0.01 for both). Azaserine, an inhibitor of glutamine:fruc-6-PO(4) amidotransferase (GFAT) in the HBP, blocks the HG-induced expression of laminin gamma1 and cyclin D1, but not GlcN's effect because it exerts its metabolic function distal to GFAT. HG and GlcN also elevate reactive oxygen species (ROS) generation, pro-apoptotic caspase-3 activity, and lead to mesangial cell death as revealed by TUNEL and Live/Dead assays. FACS analysis of cell-cycle progression shows that the cells are arrested at G1 phase; however, they undergo cell growth and hypertrophy as the RNA/DNA ratio is significantly (p < 0.05) increased in HG or GlcN-treated cells relative to LG. The anti-oxidant alpha-lipoic acid (150 microM) reverses ROS generation and mesangial cell death induced by HG and GlcN. Alpha-lipoic acid also reduces HG and GlcN-induced laminin gamma1 and cyclin D1 expression in MES cells. In addition, induction of diabetes in rats by streptozotocin (STZ) increases both laminin gamma1 and cyclin D1 expression in the renal cortex and treatment of the diabetic rats with alpha-lipoic acid (400 mg kg(-1) body weight) reduces the level of both proteins significantly (p < 0.05) when compared to untreated diabetic rats. These results support the hypothesis that the hexosamine pathway mediates mesangial cell oxidative stress, ECM expression and apoptosis. Anti-oxidant alpha-lipoic acid reverses the effects of high glucose, hexosamine and diabetes on oxidative stress and ECM expression in mesangial cells and rat kidney.

Animals↗
PubMedDate not supplied

Relaxant effects of hexosamines on isolated small human placental arteries.

Wharton's jelly contains large amounts of hyaluronic acid, and glucosamine is an important constituent of this macromolecule. In order to evaluate the placental vascular effects of this aminosugar, small chorionic and stem villous arteries were dissected from placental specimens obtained at normal term vaginal deliveries (n = 15). Ring preparations were mounted in organ baths, and isometric wall tensions were measured. Glucosamine and its epimer galactosamine (5 X 10(-4) to 10(-2) M) produced marked relaxation of contractions induced by PGF2 alpha (10(-5) M) in both chorionic and stem villous arteries. The effect was unchanged after pretreatment with atropin, propranolol and indomethacin. The relaxant effect of the neutral sugar mannose was less pronounced compared with that of the hexosamines. Total tissue concentrations of placental hexosamines have been reported within the range needed to produce placental vascular relaxation in the present study. However, the major part of these compounds is integrated in macromolecules, and the tissue level of free hexosamine is probably far below the total concentrations. Accordingly, the effects of hexosamines demonstrated in the present study might not be of physiological importance in the regulation of fetal placental medial smooth muscle tension.

Arteries↗
PubMed1980

Regulation of the hexosamine biosynthetic pathway in the water mold Blastocladiella emersonii: Sensitivity to endproduct inhibition is dependent upon the life cycle phase.

Chitin, a homopolymer of N-acetylglucosamine (GlcNAc), is the major macromolecular constituent of Blastocladiella emersonii cell walls. Zoospores do not possess a wall nor do they contain sufficient total hexosamine to account for the chitin content of the wall abruptly formed during germination. UDPGlcNAc, both the endproduct of hexosamine biosynthesis and the substrate for chitin synthesis, is present in zoospores in sufficient concentration to inhibit the first hexosamine pathway-specific enzyme activity. Net chitin accumulates in register with dry weight during exponential growth, but does not accumulate appreciably during the succeeding sporulation phase. Predicted relationships among net rates of chitin synthesis, UDPGlcNAc concentrations, and UDP plus UTP concentrations throughout the life cycle are explored, as are the assumptions upon which the predictions were based. We find that the sensitivity of the first hexosamine pathway-specific enzyme to endproduct inhibition is not constant throughout the life cycle; sensitivity is very high in the zoospore phase, decreases dramatically during germination, remains very low through the growth phase, and increases gradually to the zoospore level during sporulation. The organism appears to have evolved endproduct regulation in this case as an adaptation to "hard-times" phases of the life cycle-i.e., as a safeguard against overproduction of end product (UDPGlcNAc) when its utilization in cell wall (specifically chitin) synthesis is curtailed. Conversely, the organism effectively discards this mode of regulation during "good times," when the demands for end product are evidently greater than endproduct inhibition would otherwise permit.

Journal Article↗
PubMed1988

Mass spectrometry of hexosamine containing oligosaccharides as permethylated N-trifluoroacetyl derivatives.

Permethylated N-trifluoroacetyl hexosamine containing oligosaccharide alditols are favorable for analysis by mass spectrometry. Electron impact and fast atom bombardment mass spectra of these derivatives are characterized by strong primary and secondary fragments in which a positive charge is localized on the N-trifluoroacetyl hexosamine residue. From the mass spectra the monosaccharide sequence and the position(s) of substitution of a N-trifluoroacetyl hexosamine can be determined.

Carbohydrate Sequence↗