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Cells have several sensory systems that detect energy and metabolic status and adjust flux through metabolic pathways accordingly. Many of these sensors and signaling pathways are conserved from yeast to mammals. In this review, we bring together information about five different nutrient-sensing pathways (AMP kinase, mTOR, PAS kinase, hexosamine biosynthesis and Sir2), highlighting their similarities, differences and roles in disease.
The preventive effect of teprenone (6,10,14,18-teramethyl-5,9,13,17-nonadecatetaene-2-one), an anti-ulcer drug, on acute gastric mucosal lesion progression was examined in rats with a single intraperitoneal (i.p.) injection of compound 48/80 (0.75 mg/kg). Teprenone (20, 100 or 200 mg/kg), which was orally administered 0.5 h after compound 48/80 treatment at which time gastric mucosal lesions appeared, prevented gastric mucosal lesion development at 3 h after the treatment dose-dependently. Gastric mucosal tissues of compound 48/80-treated rats showed increases in myeloperoxidase (an index of neutrophil infiltration) and xanthine oxidase activities and thiobarbituric acid reactive substances (an index of lipid peroxidation) content and decreases in Se-glutathione peroxidase activity and hexosamine and vitamin E contents at 3 h after the treatment. Post-administered teprenone attenuated all these changes dose-dependently. These results indicate that teprenone prevents acute gastric mucosal lesion progression in compound 48/80-treated rats possibly by suppressing gastric mucus depletion, neutrophil infiltration and oxidative stress in the gastric mucosal tissue.
The effect of Sulforaphane on the inhibition of lung metastasis induced by B16F-10 melanoma cells was studied in C57BL/6 mice by three different modalities of administration-simultaneous, prophylactic and after tumour developed. Of this simultaneous mode of Sulforaphane administration was found to be most effective. There was 95.5% inhibition of lung tumour nodule formation and 94.06% increase in the life span of metastatic tumour bearing animals. Highly elevated levels of lung hydroxyproline, lung uronic acid, lung hexosamine, serum sialic acid and serum gamma-glutamyl transpeptidase (GGT) in the metastatic control animals was found to be significantly lowered in the Sulforaphane treated animals. Histopathological analysis of lung tissues also correlated with these results. In the in vitro system Sulforaphane showed a significant inhibition in the invasion of B16F-10 melanoma cells across the collagen matrix. (3)H-thymidine proliferation assay showed that Sulforaphane could inhibit the proliferation of B16F-10 melanoma cells in vitro. Gelatin zymographic analysis showed that Sulforaphane could inhibit the activation of matrix metalloproteinases. These findings suggest that Sulforaphane reduced the invasion of B16F-10 melanoma cells by the inhibition of activation of matrix metalloproteinases, thereby inhibiting lung metastasis.
Dermatan sulfate (DS) is a member of the family of structurally complex, sulfated, linear heteropolysaccharides called glycosaminoglycans (GAGs). It has a similar structure to heparin and heparan sulfate (HS), but with acetylgalactosamine replacing glucosamine, and the uronic acid moiety, mainly iduronic, joined 1-->3 to the hexosamine. We are studying the relationships between structure and activities of dermatan sulfate, in particular those associated with the thrombin inhibition mediated by heparin cofactor II (HCII). As we have demonstrated with heparin, a small fraction of dermatan sulfate was isolated by precipitation with the first component of the complement system, under very specific conditions of low ionic strength, and the presence of calcium ions. The sulfate content and the anticoagulant activity of the dermatan sulfate fraction isolated in the precipitate were three and four times greater respectively than the starting material. Our in vivo studies showed that this fraction has threefold higher thrombolytic activity than the DS. All these results suggest that this fraction could be used as a therapeutic agent for thrombi dissolution.
The mucopolysaccharides produced by B16 mouse melanoma cells have been isolated in milligram quantities from the spent media in which the cells were grown in the presence of 2-amino-2-deoxy-D-glucose-t and [35S]-sulfate. The mucopolysaccharides obtained by precipitation with cetylpyridinium chloride from the Pronase digest of the media were further purified by gel filtration, ion-exchange chromatography, and treatment with nucleases. The major components were identified as chondroitin-4-sulfates by identification of the hexosamine as 2-amino-2-deoxy-D-galactose, and by digestibility with hyaluronidases, chondroitinase AC, and chondro-4-sulfatase. The o.r.d. curve and i.r. spectra of these components also confirmed their similarity to chondroitin-4-sulfate from cartilage. The molecular weight of the polysaccharide chains was estimated to be in the range 90,000-120,000 by sedimentation equilibrium analysis.
The carbohydrate content (neutral hexoses, fucose, sialic acid, and hexosamine) of human erythrocytes is significantly higher in young than in old erythrocytes. The differences observed in the carbohydrate content of surface glycopeptides, obtained after incubation with either Pronase or trypsin, is still more striking, suggesting important modifications of the carbohydrate moeties of the erythrocyte membrane during in vivo ageing.
We have reported that neutrophil infiltration into gastric mucosa is closely related to gastric mucosal lesion development in rats with water immersion restraint stress. In this study, we examined the effect of teprenone, which is known to prevent gastric mucosal injury through stimulation of gastric mucus synthesis and secretion, on neutrophil infiltration into the gastric mucosa of rats with water immersion restraint stress. Pre- and post-administration of teprenone (200 mg/kg, p.o.) significantly attenuated the neutrophil infiltration into the gastric mucosa and the lesion development found at 6 h of water immersion restraint stress with preservation of gastric mucosal hexosamine and adherent mucus levels. These results indicate that teprenone exerts protective and preventive actions against water immersion restraint stress-induced gastric mucosal lesions in rats and suggest that these actions could be related to the preservation of gastric mucus synthesis and secretion and inhibition of neutrophil infiltration into the gastric mucosal tissue.
In rats with polyvinyl rings implanted under the dorsal skin, the formation of granulation tissue was found to be stimulated by application of brain extract with fibroblast growth factor (FGF) S3 activity which had been obtained from cattle. This stimulating effect on wound healing proved to depend on doses and was detectable in rats aged two and six months on the third and seventh postoperative days. The desired action could be induced only by repetitive administration of FGF S3 or by coupling of the latter to SYSpur-derm, a synthetic dermatoplastic material. More fractions with potential action upon formation of granulation tissue proved to be obtainable from further biochemical separation of FGF S3. One of such fractions was successfully concentrated to a potentiality by which one tenth of the normal dose yielded the same effect as the full dose. Hexosamine and hydroxyproline levels were measured, at the same time, and found to stimulate fibroblasts. The findings are discussed.
Roots of Hemidesmus indicus var. indicus are used for various ailments in Indian traditional medicines. The present study evaluated the antiulcerogenic property of aqueous ethanolic extracts of the roots in animal models. Modified pyloric ligated (Shay) rat model and aspirin-induced ulcerogenesis in pylorus ligated rat models were used for this study and analysed for gastric volume, ulcer score, pH, free and total acidity and sodium and potassium ion output. Bio-chemical estimations like total proteins, total hexoses, hexosamine, fucose, sialic acid and pepsin were also made. Ulcer score was calculated for cysteamine-induced duodenal ulcer model. Roots collected during flowering season were found to be more effective than that collected during vegetative seasons.
The positive influence of Aloe vera, a tropical cactus, on the healing of full-thickness wounds in diabetic rats is reported. Full-thickness excision/incision wounds were created on the back of rats, and treated either by topical application on the wound surface or by oral administration of the Aloe vera gel to the rat. Wound granulation tissues were removed on various days and the collagen, hexosamine, total protein and DNA contents were determined, in addition to the rates of wound contraction and period of epithelialization. Measurements of tensile strength were made on treated/untreated incision wounds. The results indicated that Aloe vera treatment of wounds in diabetic rats may enhance the process of wound healing by influencing phases such as inflammation, fibroplasia, collagen synthesis and maturation, and wound contraction. These effects may be due to the reported hypoglycemic effects of the aloe gel.
Pretreatment with the butanol extract of the water fraction of Phyllanthus emblica fruits at the dose of 100 mg/kg body-weight, orally administered to rats for 10 consecutive days, was found to enhance secretion of gastric mucus and hexosamine (P<0.001) in the indomethacin induced ulceration of rats. The morphological observations also supported a protective effect of the stomach wall from lesion. The indomethacin treatment of the premedicated animals with the drug hardly affected either the malondialdehyde (MDA) or superoxide dismutase (SOD) level in gastric tissue while the ulcerative agent itself significantly enhanced both the levels. An antioxidant property appears to be predominantly responsible for this cytoprotective action of the drug.
In Kluyveromyces lactis, the cell wall compositions of Kl (ATCC 96897), a wild sensitive strain, and Klm (ATCC 96896), a strain resistant to amphotericin B (AmB), were shown to be very different, since the walls in the latter were significantly enriched in hexosamine, but had a reduced content in phosphate and amino acid. In both strains, the cell walls limited their sensitivity to this antifungal agent. The absence of cell wall increased the sensitivity of the cells to this polyene by 5 to 10-fold. When the cells were treated with enzymes such as pronase and chitinase in order to change the cell wall structure just before inoculation, the yeasts appeared more resistant to the antibiotic. However, treatments with chymopapain and phospholipase C did not significantly change the sensitivity of the two strains to this agent. Cells treated with acid phosphatase displayed a longer lag phase than the control cells. In addition, when cultured in the presence of AmB, the cells were less sensitive to this agent. The present results reveal that both a change in the ionic charges of the cell wall and an alteration in the cell wall structure modified the sensitivity of these yeast strains to AmB.
Clear distinctions in morphology and proteoglycan composition have been described in regions of adult tendon that pass under bone and are subjected to compressive as well as tensional forces. In this study, developing bovine deep flexor tendon from early fetal stages through 6 months of age was examined biochemically and by light and electron microscopy. Longitudinal collagen fibers were seen in the tensional region of tendon throughout development; whereas a well established network arrangement of collagen fibers with wide interfibrillar spaces was seen in the compressed region by 7 months of fetal age. Collagen fibril diameters of both regions increased with age with the mean diameter in tensional tissue always greater than in compressed tissue. Glycosaminoglycan hexosamine content of the tensional region remained low throughout development (approximately 0.2% of dry tissue weight), but increased in the compressed region from 0.4% of dry weight at the 7-month fetal stage, to 1.0% dry weight at 6 months. Keratan sulfate was not detectable in tensional tendon at any age as measured by inhibition ELISA, but was found in increasing quantities in the pressure bearing region of tendon from young calves. Small proteoglycans predominated in both tensional and compressed regions throughout fetal and early neonatal development, and were of both PG I (biglycan) and PG II (decorin) types. Large proteoglycans represented only a small proportion of total proteoglycans in both regions of fetal tendon. By SDS/PAGE analysis, immunoreactivity, and molecular sieve chromatography, large proteoglycans of fetal compressed tendon were similar to large proteoglycans of adult tensional tendon in that they contained only chondroitin-6-sulfate, with little if any KS, and appeared to be slightly smaller than cartilage large proteoglycans.(ABSTRACT TRUNCATED AT 250 WORDS)
Semicarbazide-sensitive amine oxidase (EC 1.4.3.6; amine:oxygen oxidoreductase (deaminating) (copper-containing); SSAO) is a multifunctional protein. It acts under inflammatory conditions as a vascular-adhesion protein (VAP-1), mediating the adhesion of lymphocytes to vascular endothelial cells. The relationships, if any, between this adhesion function and the enzymatic functions (amine-substrate specificity and catalysis) of SSAO have not yet been defined. Since cell surface amino sugars and their derivatives are known to be involved in cell-to-cell recognition, we have investigated their possible effects on the enzyme activity of SSAO. The aminohexoses galactosamine, glucosamine and mannosamine were not oxidatively deaminated by SSAO. However, their presence during the assay of benzylamine oxidation resulted in a time-dependent inhibition. This inhibition was shown to follow saturation kinetics with respect to hexosamine concentration. Although time-dependent, the inhibition of SSAO activity was found to be reversible by dilution. In contrast, there is no such inhibition when the N-acetylamino sugar derivatives or the parent sugars (galactose, glucose and mannose) replaced the amino sugars in the reaction mixture. These results suggest that the interactions between SSAO and aminohexoses are specific and, therefore, that the cell-adhesion functions and amine-recognition functions of VAP-1/SSAO may be interlinked.
A human glycoprotein was isolated from the urine of a patient with plasma cell leukemia. It appears pure and homogeneous when examined by immunoelectrophoresis, sodium dodecyl sulfate (NaDodSO4)-polyacrylamide gel electrophoresis, gel filtration in 6 M guanidine hydrochloride (Gdn.HCl), and NH2-terminal amino acid sequence analysis. It has a brown color due to a tightly (most likely covalently) bound chromophore group(s) and migrates to the alpha1 region in immunoelectrophoresis. A molecular weight (mol wt) of 27 000 was obtained for the glycoprotein by gel filtration in 6 M Gdn.HCl. Its approximate mol wt determined by Na-DodSO4-polyacrylamide gel electrophoresis is 29 000 on 5% and 7.5% and 10% gels. Amino acid and hexosamine analyses showed that it is a glycoprotein and indicated that it contains four half-cystine residues per molecule. Based on the above observations we designated it "alpha1-microglycoprotein" (alpha1-MGP). Isoelectric focusing of alpha1-MGP showed a significant charge heterogeneity, although only a single NH2-terminal amino acid sequence was obtained for alpha1-MGP, i.e., Gly-Pro-Val-Pro-( )-Pro-Pro-Asx-Asx-Ile-Glx-Val-Glx-Glx-Asx-Phe-Phe-Ile-(Ser or Ala)-Arg. The alpha1-MGP was found in significant concentrations in the urine of many patients with neoplastic diseases.
The three morphologically and functionally distinct jelly coat layers of Xenopus laevis eggs, J1, J2, and J3, were separated by manual dissection, solubilized with dithiothreitol, and physicochemically analyzed. The chemical composition of the three jelly layers varied from 37 to 48% protein and 63 to 52% carbohydrate. The carbohydrate consisted of hexosamines, galactose, and fucose. Some of the carbohydrate in each of the jelly layers was covalently linked to protein through O-glycosidic bonds as beta elimination of the carbohydrate moiety in the presence of alkali was observed. In agreement with a previous finding, covalently attached sulfate was localized within the innermost jelly coat layer, J1. Cellulose acetate electrophoresis at pH 8.0 resolved a total of nine macromolecular components from the three jelly coat layers differentially staining for protein and carbohydrate: J1 yielded two anodically migrating components; the middle layer J2 yielded two cathodically migrating macromolecular components; the outermost layer J3 contained five species, three anodic and two cathodic. Sodium dodecyl sulfate agarose gel electrophoresis analysis yielded nine unique species, six of which stained coincidently for protein and carbohydrate. Immunoelectrophoresis and Ouchterlony double diffusion analyses using antiserum to total jelly components resolved nine different antigenic species with cross-reactivity between one or two macromolecules in layers J1 and J3. Analytical sedimentation velocity centrifugation revealed eight distinct species all of which exhibited hypersharp schlieren patterns and whose s20,w values were highly concentration dependent. On the basis of these analyses, Xenopus laevis egg jelly layers are composed of at least 8-9 distinct macromolecular species. The majority of these macromolecules are uniquely associated with different jelly coat layers.
Lysosomal enzymes play important roles in the inflammatory process. The pentacyclic triterpenes, lupeol and lupeol linoleate were administered orally (50 mg/kg) for 8 days to arthritic rats, after 11th day of adjuvant injection. The lysosomal enzymes were significantly increased in arthritic condition, which are involved in the destruction of structural macromolecules in connective tissue and cartilage in rheumatoid arthritis. Hence the level of collagen was significantly decreased and the excretion of urinary hydroxyproline, hexosamine, hexuronic acid and glycosaminoglycans were increased in arthritic rats. Treatment of arthritic rats with triterpenes reversed the above changes, which may be due to stabilization of the lysosomal membrane. Out of the two triterpenes tested, lupeol linoleate showed better ameliorating action than lupeol.
The relationship between the changes of active oxygen metabolism and blood flow and the formation, progression, and recovery of lesions was examined in the gastric mucosa of rats treated once with compound 48/80, a mast cell degranulator. Gastric mucosal lesions appeared 0.5 hr after compound 48/80 treatment, became worst at 3 hr, and recovered fairly well at 12 hr. Increases in gastric mucosal lipid peroxide content and xanthine oxidase and myeloperoxidase activities and decreases in gastric mucosal vitamin E and hexosamine contents and Se-dependent glutathione peroxidase activity occurred with the formation and progression of gastric mucosal lesions. These changes were attenuated with the recovery of the lesion. Gastric mucosal nonprotein SH content decreased with the formation of gastric mucosal lesions, and this decreased SH content returned to near the original level with lesion progression. No changes in gastric mucosal superoxide dismutase and catalase activities occurred with the formation, progression, and recovery of gastric mucosal lesions. Gastric mucosal blood flow decreased with the formation of gastric mucosal lesions, and this decreased blood flow recovered with lesion progression. Serum serotonin concentration, an index of mast cell degranulation, increased with the formation of gastric mucosal lesions, and this increased serotonin level was attenuated with lesion progression and recovery. Pretreatment with ketotifen, a connective tissue mast cell stabilizer, prevented the formation of gastric mucosal lesions, the increases of gastric mucosal lipid peroxide content, xanthine oxidase and myeloperoxidase activities, and serum serotonin level; and the decreases of gastric mucosal nonprotein SH content, glutathione peroxidase activity, and blood flow found at 0.5 hr after compound 48/80 treatment. These results indicate that the changes of gastric mucosal active oxygen metabolism and blood flow are closely related to the formation, progression, and recovery of gastric mucosal lesions in rats with a single compound 48/80 treatment. The present results also suggest that this compound 48/80-induced gastric mucosal injury could be a kind of ischemia-reperfusion-induced injury occurring through degranulation of connective tissue mast cells.