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PubMed2005

In vivo effect of piperine on serum and tissue glycoprotein levels in benzo(a)pyrene induced lung carcinogenesis in Swiss albino mice.

In recent years, considerable emphasis has been focused on identifying new cancer chemopreventive agents, which could be useful for the human population. Piperine is a pure, pungent alkaloid constituent of black and long peppers (Piper nigrum and Piper longum), that acts as an antioxidant and anticancer agent by its numerous macromolecules associated with them. In the present study, piperine was found to suppress benzo(a)pyrene (B(a)p) induced lung cancer in Swiss albino mice. In lung cancer bearing mice, altered levels of total protein and protein bound carbohydrate components (hexose, hexosamine and sialic acid) were observed in serum, lung and liver tissues. Dietary supplementation of piperine (50 mg/kg body weight) to B(a)p administered animals decreased the total protein and protein bound carbohydrate levels of lung cancer bearing animals in during initiation and post-initiation phases. Our data suggest that piperine may extend its chemopreventive effect through modulating the protein bound carbohydrate levels, as they are one of the indicators of tumorigenesis.

Alkaloids↗
PubMed2006

Diabetes and mitochondrial function: role of hyperglycemia and oxidative stress.

Hyperglycemia resulting from uncontrolled glucose regulation is widely recognized as the causal link between diabetes and diabetic complications. Four major molecular mechanisms have been implicated in hyperglycemia-induced tissue damage: activation of protein kinase C (PKC) isoforms via de novo synthesis of the lipid second messenger diacylglycerol (DAG), increased hexosamine pathway flux, increased advanced glycation end product (AGE) formation, and increased polyol pathway flux. Hyperglycemia-induced overproduction of superoxide is the causal link between high glucose and the pathways responsible for hyperglycemic damage. In fact, diabetes is typically accompanied by increased production of free radicals and/or impaired antioxidant defense capabilities, indicating a central contribution for reactive oxygen species (ROS) in the onset, progression, and pathological consequences of diabetes. Besides oxidative stress, a growing body of evidence has demonstrated a link between various disturbances in mitochondrial functioning and type 2 diabetes. Mutations in mitochondrial DNA (mtDNA) and decreases in mtDNA copy number have been linked to the pathogenesis of type 2 diabetes. The study of the relationship of mtDNA to type 2 diabetes has revealed the influence of the mitochondria on nuclear-encoded glucose transporters, glucose-stimulated insulin secretion, and nuclear-encoded uncoupling proteins (UCPs) in beta-cell glucose toxicity. This review focuses on a range of mitochondrial factors important in the pathogenesis of diabetes. We review the published literature regarding the direct effects of hyperglycemia on mitochondrial function and suggest the possibility of regulation of mitochondrial function at a transcriptional level in response to hyperglycemia. The main goal of this review is to include a fresh consideration of pathways involved in hyperglycemia-induced diabetic complications.

Animals↗
PubMed2004

Biodegradable organic matter in municipal solid waste incineration bottom ash.

For investigation of the behavior of municipal solid waste incineration bottom ash in landfill, we have analysed bottom ash samples taken after the quench tank as well as after five months of storage in the laboratory for elements and organic constituents. Water extractable organic carbon, particulate organic carbon, amino acids, hexosamines and carbohydrates considerably decreased during the five months of storage and their spectra revealed microbial reworking. This shows that the organic matter present in the bottom ash after incineration can provide a substrate for microbial activity. The resulting changes of the physico-chemical environment may effect the short-term behavior of the bottom ash in landfill.

Biodegradation, Environmental↗
PubMed2004

Molecular screening of the human glutamine-fructose-6-phosphate amidotransferase 1 (GFPT1) gene and association studies with diabetes and diabetic nephropathy.

Increased glucose metabolism through the hexosamine pathway may result in insulin resistance, impaired insulin secretion, and diabetic nephropathy. We hypothesized that variants of GFPT1 encoding glutamine-fructose-6-phosphate amidotransferase, the rate limiting enzyme in this pathway, could increase GFPT1 gene expression and thus susceptibility to diabetes and diabetic nephropathy. To test this hypothesis, we screened for variation in the GFPT1 and flanking regions in Caucasian and African-American individuals. We tested each variant with over 5% allele frequency for an association with type 2 diabetes in Caucasian and African-American populations, and for an association with diabetic nephropathy in African-American subjects. We measured allele specific levels of GFPT1 mRNA and we compared mRNA levels across diagnostic categories for each ethnic group using RNA derived from transformed lymphocytes. None of the 8 variants detected altered the coding sequence or was present in a known regulatory region. We found a marginal association (p = 0.044) of 1/6 variants with diabetes in Caucasian subjects, and marginal associations of 2/7 variants with diabetic nephropathy among African-American subjects (p = 0.025, p = 0.041). Alleles marked by a variant in the 3' untranslated region were equally expressed, but in a small sample, GFPT1 mRNA levels were increased by 60% in Caucasians with diabetic nephropathy compared to diabetic individuals without nephropathy. Variants in the GFPT1 gene show suggestive evidence of an association with diabetic nephropathy among African-American individuals, and increased GFPT1 gene expression may characterize Caucasian subjects with diabetic nephropathy. Both findings need to be confirmed in other populations.

Black or African American↗
PubMed2005

Validation of a heparan sulfate-derived disaccharide as a marker of accumulation in murine mucopolysaccharidosis type IIIA.

Mucopolysaccharidosis type IIIA (MPS IIIA) is a neurodegenerative lysosomal storage disorder resulting from sulfamidase deficiency, which leads to accumulation of heparan sulfate within lysosomes. We have determined the time-course of accumulation of a disaccharide [hexosamine-N-sulfate[alpha-1,4]hexuronic acid; HNS-UA] marker of heparan sulfate storage within the brain, liver, and spleen of a naturally occurring mouse model of MPS IIIA. HNS-UA is detectable in the brain of affected mice on the day of birth, when it is significantly increased compared to normal control mice. As mice age, this compound steadily accumulates until a plateau is reached at approximately 20-weeks. A similar rate of accumulation of HNS-UA is seen in the liver and spleen of affected mice. Intracerebral delivery of recombinant human sulfamidase reduced the amount of HNS-UA present in segments of the brain receiving the correcting enzyme, thus demonstrating the effectiveness of enzyme replacement therapy within the central nervous system of affected mice. This finding therefore provides evidence for the use of the disaccharide HNS-UA to monitor the effect of therapies for this condition in humans, when treatment strategies are devised.

Age Factors↗
PubMed1980

Changes in glycosaminoglycan composition of normal human placentas with maturation.

Crude glycosaminoglycan preparations were isolated from acetone-powder of first-, second-, and third-trimester human placentas. Glycosaminoglycan composition was examined by electrophoresis and densitometric scanning before and after treatment with testicular hyaluronidase and chondroitinase ABC. Hexosamines were determined in electrophoretic fractions in order to identify the individual glycosaminoglycans. The results showed a decrease in glycosaminoglycans and an increase in protein contents in the preparations as the placenta matured. The main glycosaminoglycans in all placentas were dermatan sulfate, chondroitin sulfates, hyaluronic acid, and heparan sulfate. With aging of the placenta, the proportion of hyaluronic acid remained unchanged and that of chondroitin sulfate decreased, whereas the proportions of dermatan and heparan sulfates increased. Age-dependent changes in the glycosaminoglycan composition of the placenta appear to follow a pattern similar to that reported for other mammalian tissues.

Chondroitin Sulfates↗
PubMed1980

Glycosaminoglycan patterns in diabetic and toxemic term placentas.

Crude glycosaminoglycans were prepared from acetone powder of diabetic, toxemic, and normal term placentas. Glycosaminoglycan composition was determined by electrophoresis and densitometric scanning with and without treatment with testicular hyaluronidase and chondroitinase ABC. The identity of individual glycosaminoglycans was confirmed by the nature of their hexosamine. Glycosaminoglycan content was found to be significantly increased in diabetic placentas and increased to a lesser degree in the toxemic placentas. The amount of hyaluronic acid was elevated in both abnormal tissues, and heparan sulfate was slightly higher in diabetes, while unchanged in toxemia. Dermatan sulfate was markedly reduced in the abnormal placentas while chondroitin 4/6 sulfate was unaltered. An attempt was made to correlate the histopathologic changes reported to occur in these conditions with the alterations in the glycosaminoglycans patterns of placentas.

Chondroitin Sulfates↗
PubMed2002

Phosphoinositide 3-kinase mediates protein kinase C beta II mRNA destabilization in rat A10 smooth muscle cell cultures exposed to high glucose.

High-glucose exposure down-regulates protein kinaseC beta II posttranscriptionally in rat and human vascular smooth muscle cells and contributes to increased cell proliferation. High-glucose-induced mRNA destabilization is specific for PKC beta II mRNA, while PKC beta I and other PKC mRNA are not affected. This study focused on whether glucose metabolism was required. The effect was blocked by cytochalasin B, suggesting a requirement for glucose uptake. Glucosamine did not mimic the effect, indicating that metabolism via hexosamine pathway was not involved. The effect was hexokinase-independent since 3-O-methylglucose, in a dose-dependent manner, mimicked high-glucose effects. Cycloheximide did not block the effect excluding dependency on new protein synthesis. Wortmannin and LY294002, phosphoinositide 3-kinase (PI3-kinase) inhibitors, blocked glucose effects in the presence of 5,6-dichloro-1-beta-d-ribofuranosylbenzimidazole. Glucose and 3-O-methylglucose activated PI3-kinase, and LY294002 blocked glucose effects on Akt phosphorylation. In these cells, high-glucose concentrations activated a metabolically linked signaling pathway independent of glucose metabolism to regulate mRNA processing.

Androstadienes↗
PubMed2003

Mitochondrial and nucleocytoplasmic isoforms of O-linked GlcNAc transferase encoded by a single mammalian gene.

O-Linked N-acetylglucosamine (GlcNAc) transferase (OGT) mediates a novel hexosamine-dependent signal transduction pathway. Yet, little is known about the regulation of ogt gene expression in mammals. We report the sequence and characterization of the mouse ogt locus and provide a comparison with the human and rat ogt genes. The mammalian ogt genes are similar in structure and exhibit approximately 80% sequence identity. The mouse and human ogt genes contain two potential promoters producing four major transcripts. By analyzing 56 human cDNA clones and other existing expressed sequence tags, we found that at least three protein products differing at their amino terminus result from alternative splicing. We used OGT-specific antisera to demonstrate the presence of these isoforms in HeLa cells. The longest form is a nucleocytoplasmic OGT (ncOGT) with 12 tetratricopeptide repeats (TPRs); a shorter form of OGT encodes a mitochondrially sequestered enzyme with 9 TPRs and an N-terminal mitochondrion-targeting sequence (mOGT). An even shorter form of OGT (sOGT) contains only 2 TPRs. The genomic organization of OGT appears to be highly conserved throughout metazoan evolution. These results provide the basis for a more detailed analysis of the significance and regulation of the nucleocytoplasmic and mitochondrial isoforms of OGT in mammals.

Amino Acid Sequence↗
PubMed1998

Biochemical and connective tissue changes in cyclophosphamide-induced lung fibrosis in rats.

The present investigation was designed to characterize the biochemical and connective tissue components and to correlate the significance of morphological and biochemical perturbations in cyclophosphamide (CP)-induced lung fibrosis in rats. Lung fibrosis was induced in male Wistar rats by intraperitoneal injection of 20 mg/100 g body weight of CP, and their pneumotoxic derangements were characterized during an early destructive phase followed by a proliferative and synthetic phase. Serum angiotensin-converting enzyme (ACE) activity was higher in CP-treated rats at days 2, 3, 5, 7, and 11, but there was a significant decrease in lung ACE activity during the same time period. Elevated levels of beta-glucuronidase activity were observed in the lung lavage fluid of CP-administered rats days 2, 3, 5, and 7. Lung myeloperoxidase activity was higher in CP rats. Of significance was the presence of collagenase and collagenolytic cathepsin in the lavage fluid of CP rats, when compared with the barely detectable levels in controls. A similar increase in these enzyme activities was also noticed in the lung tissue of CP rats during the same experimental period. Lavage fluid hydroxyproline content was higher in CP rats when compared with controls. Similarly, lung protein and DNA levels were elevated significantly after treatment with CP. The pulmonary histamine and serotonin contents were significantly higher in CP rats. The incorporation of [3H]thymidine into lung total DNA, [3H]proline into lung hydroxyproline, and [35S]sulphate into lung glycosaminoglycan, measured as indicators of lung DNA, collagen, and glycosaminoglycan synthesis, respectively, was also higher in CP groups. Increased levels of hydroxyproline, elastin, hexosamine, total hexose, fucose, sialic acid, and uronic acid in the lungs of rats 14, 28, and 42 days after CP insult were characterized as biomarkers of CP-induced interstitial changes. These findings indicate that CP-induced lung fibrosis results in alterations not only in collagen synthesis and accumulation, but also in glycosaminoglycan and glycoprotein content.

Animals↗
PubMed1982

Secondary structure in glycosaminoglycuronans: N.M.R. spectra in dimethyl sulphoxide of disaccharides related to hyaluronic acid and chondroitin sulphate.

1H-N.m.r.spectra for solutions in dimethyl sulphoxide-d6 of disaccharides related to hyaluronate and chondroitin sulphate are compared with those of their methylated derivatives. All resonances, including those of HO and HN groups, have been assigned. The temperature and concentration dependences suggest that HO-4 of the hexosamine residue in hyalobiouronate (but not that in chondrosinate) is hydrogen-bonded to O-5 of the uronic acid residue. The resonance of HO-2 of the uronate residue of chondrosinate also shows anomalies that may arise from intra-residue hydrogen-bonding. These findings confirm the existence of some features previously suggested to be present in glycosaminoglycuronan polymers. The resonance of HO-4 of the uronate residue in the disaccharides and in sodium (methyl alpha-D-glucopyranosid)uronate behaves as though there was a hydrogen bond between the carboxylate group and HO-4.

Carbohydrate Conformation↗
PubMed1977

Gas-liquid chromatographic analysis of the monosaccharide composition of acid glycosaminoglycans (mucopolysaccharides) derived from animal tissues.

Quantitative, gas-liquid chromatography was investigated for analysis of the monosaccharide composition of acid mucopolysaccharides from animal tissues. The method entailed the analysis of the trimethylsillyl (Me3Si) derivatives of methyl glycosides on two liquid phases. Good resolution of monosaccharides was achieved by use of columns of SE-30 and Apiezon-M. The procedure was tested with chondroitin 4-sulfate, and the results were slightly different from those of Mathews et al. When the analysis is performed according to this method, important points are: (1) absolutely anhydrous, methanolic hydrogen chloride is necessary, to ensure detection of hexosamines and sialic acid; and (2) high moisture in the air obstructs high recovery of methyl glycosides and their Me3Si derivatives, except in the case of neutral sugars.

Animals↗
PubMed1994

A reversed phase HPLC method for the simultaneous determination of all monosaccharides contained in galactosaminoglycan isomers from human aorta proteoglycans.

Monosaccharides obtained by reduction and hydrolysis of galactosaminoglycan isomers, are entirely determined as their perbenzoyl derivatives by reversed phase HPLC, without removal of hexosamines prior to benzoylation. The method is suitable for the analysis of arterial proteoglycan constituent galactosaminoglycans, providing specific, precise and reproducible results. Moreover, synthesis and characterization of tri-O-benzoyl-1,6-L-anhydroidose and N-benzoyl-tetra-O-benzoyl-alpha- and -beta-D-galactosamine have been accomplished.

Adult↗
PubMed2002

Determination of the composition of the oligosaccharide phosphate fraction of Pichia (Hansenula) holstii NRRL Y-2448 phosphomannan by capillary electrophoresis and HPLC.

The promising new anticancer agent, PI-88, is prepared by the sulfonation of the oligosaccharide phosphate fraction of the extracellular phosphomannan produced by the yeast Pichia (Hansenula) holstii NRRL Y-2448. The composition of the oligosaccharide phosphate fraction was determined by capillary electrophoresis (CE) with indirect UV detection using 6 mM potassium sorbate at pH 10.3 as the background electrolyte. Further confirmation of the composition was obtained by HPLC analysis of a sample dephosphorylated by treatment with alkaline phosphatase. The structure of the hexasaccharide component has been determined by isolation and NMR spectroscopic analysis of its dephosphorylated derivative. Additionally, the structure of a second, previously undetected tetrasaccharide component (a hexosamine) has been determined by isolation and NMR spectroscopic analysis of the acetate of its dephosphorylated derivative. It is demonstrated that CE is an ideal method for the quality control of the oligosaccharide phosphate fraction for use in the production of PI-88.

Antineoplastic Agents↗
PubMed2001

Overexpression of glutamine:fructose-6-phosphate-amidotransferase induces transforming growth factor-beta1 synthesis in NIH-3T3 fibroblasts.

Increased flux through the hexosamine biosynthetic pathway with glutamine:fructose-6-phosphate-amidotransferase (GFAT) as rate-limiting enzyme has been linked to the enhanced bioactivity of the prosclerotic cytokine transforming growth factor beta1 (TGF-beta1) in fibrotic complications, particularly in diabetic kidney disease. Here, we investigate in a stable transfection system the effect of overexpression of GFAT on TGF-beta1 synthesis in NIH-3T3 fibroblasts. We demonstrate a 1.8-fold stimulation of TGF-beta1 mRNA and a 1.9-fold increased protein expression, whereas TGF-beta2 production was not upregulated. The 1.5-fold enhanced TGF-beta1 promoter activity suggests a transcriptional regulation. The elevated TGF-beta1 protein is biologically active since GFAT-overexpressing cells exhibit a 2-fold fibronectin production. The results indicate a GFAT-dependent induction of TGF-beta1 synthesis.

3T3 Cells↗
PubMed1998

Pancreatic duct obstruction is an aggravating factor in the canine model of chronic alcoholic pancreatitis.

BACKGROUND & AIMS: Chronic alcoholic pancreatitis occurs in only a limited number of heavy drinkers. Other factors than alcohol are necessary for the occurrence of chronic alcoholic pancreatitis. The aim of this study was to examine whether pancreatic duct obstruction resulted in increased alcohol-induced parenchymal cell damage. METHODS: Four groups of adult mongrel dogs were used. In group A, 2. 0 g . kg-1 . day-1 of ethanol was administered via a gastric cannula. In group O, after ligation of the minor pancreatic duct, a polyethylene tube was inserted transduodenally into the major duct. In group AO, the protocols used in groups A and O were combined. Laparotomy was repeated after 3 months in each group. RESULTS: Three of the 9 dogs in group AO had pancreatic calculi in the main pancreatic duct. Moderate interlobular fibrosis, parenchymal cell loss, and inflammatory cell infiltration resembling human chronic alcoholic pancreatitis were observed in group AO. Little change was observed in groups A and O. Exocrine function assessed by secretin test in group AO was significantly reduced. Total protein, hexosamine, and calcium contents of the pancreatic juice in group AO were significantly increased. CONCLUSIONS: Pancreatic duct obstruction is an aggravating factor in chronic alcoholic pancreatitis.

Acute Disease↗
PubMed2001

Glucosamine enhances platelet-derived growth factor-induced DNA synthesis via phosphatidylinositol 3-kinase pathway in rat aortic smooth muscle cells.

Vascular smooth muscle cells play a key role in the development of atherosclerosis. Culture of vascular smooth muscle A10 cells with high glucose for 4 weeks enhanced platelet-derived growth factor (PDGF)-induced BrdU incorporation. Since a long period of high glucose incubation was required for the effect, and it was inhibited by co-incubation with azaserine, the role of hexosamine biosynthesis in the development of atherosclerosis in diabetes was studied in A10 cells. Addition of glucosamine to the culture media enhanced PDGF-stimulated BrdU incorporation, and PDGF-induced tyrosine phosphorylation of the PDGF beta-receptor was increased by glucosamine treatment. Of the subsequent intracellular signaling pathways, PDGF-induced PDGF beta-receptor association with PLC gamma was not affected, whereas tyrosine phosphorylation of Shc, subsequent association of Shc with Grb2, and MAP kinase activation were relatively decreased. In contrast, PDGF-induced PDGF beta-receptor association with the p85 regulatory subunit of PI3-kinase and PI3-kinase activation were increased by 20% (P<0.01) and 36% (P<0.01), respectively. The intracellular signaling molecules responsible for the glucosamine effect were further examined using pharmacological inhibitors. Pretreatment with PLC inhibitor (U73122) had negligible effects, and MEK1 inhibitor (PD98059) showed only a slight inhibitory effect on the PDGF-induced BrdU incorporation. In contrast, pretreatment with PI3-kinase inhibitor (LY294002) significantly inhibited glucosamine enhancement of PDGF-induced BrdU incorporation. These findings suggest that glucosamine is involved in the development of atherosclerosis by enhancing PDGF-induced mitogenesis specifically via the PI3-kinase pathway.

Adaptor Proteins, Signal Transducing↗
PubMed1979

Methylation analysis in glycoprotein chemistry. General procedure for quantification of the products of solvolysis of permethylated glycopeptides and glycoproteins.

A technique for the gas chromatographic analysis of the products of solvolysis of permethylated glycopeptides and glycoproteins has been developed. It involves methanolysis of a permethylated compound, quantitative transformation of methyl ethers of methyl glycosides into the corresponding O-trimethylsilyl(TMS)-O-methylalditols [2-deoxy-2-(N-methyl)acetamido-O-TMS-O-methylalditols in the case of hexosamine derivatives] and gas chromatographic quantification using a single column packed with 0.4% OV-225 on surface-modified Chromosorb.

Acetylglucosamine↗