hymecromone and Body-Weight

This study was conducted to evaluate the effects of umbelliferone (UF) and 4-methylumbelliferone (mUF) on high-fat diet-induced hypertriglyceridemia and hyperglycemia in mice. The mice were assigned to normal control, high-fat control, and high-fat with UF or mUF groups. For UF or mUF groups, the high-fat diet was supplemented with UF or mUF at 0.02% (wt/wt) for 12weeks. Both UF and mUF significantly decreased plasma triglyceride, free fatty acid and glucose levels, adipocyte size, white adipose tissue weights, and hepatic phosphatidate phosphohydrolase activity and significantly increased plasma adiponectin levels and hepatic fatty acid β-oxidation activity compared with the high-fat control group. UF and mUF improved glucose intolerance and hepatic steatosis in the high-fat fed mice. Long-term high-fat diet intake induced an increase in hepatic CYP2E1 activity and lipid peroxide and cytosolic hydrogen peroxide contents and suppressed superoxide dismutase and glutathione peroxidase activities, which were reversed by UF and mUF supplementation. These results indicate that UF and mUF similarly ameliorate hypertriglyceridemia and hyperglycemia partly by modulating hepatic lipid metabolism and the antioxidant defense system along with increasing adiponectin levels.

Topics: Animals; Blood Glucose; Body Weight; Cytochrome P-450 CYP2E1; Dietary Fats; Dietary Supplements; Energy Intake; Gene Expression Regulation; Hymecromone; Hyperglycemia; Hypertriglyceridemia; Lipid Peroxidation; Lipids; Liver; Male; Mice; Mice, Inbred C57BL; Umbelliferones

Gaucher disease (GD), caused by a defect of acid β-glucosidase (β-Glu), is one of the most common sphingolipidoses. Recently, ambroxol, an FDA-approved drug used to treat airway mucus hypersecretion and hyaline membrane disease in newborns, was identified as a chemical chaperone for GD. In the present study, we investigated the chaperone activity and toxicity of ambroxol on both cultured GD patient cells and normal mice. We found that ambroxol treatment significantly increased N370S, F213I, N188S/G193W and R120W mutant β-Glu activities in GD fibroblasts with low cytotoxicity. Additionally, we measured the β-Glu activity in the tissues of normal mice which received water containing increasing concentrations of ambroxol ad libitum for one week. No serious adverse effect was observed during this experiment. Ambroxol significantly increased the β-Glu activity in the spleen, heart and cerebellum of the mice. This result showed its oral availability and wide distribution and chaperone activity in the tissues, including the brain, and its lack of acute toxicity. These characteristics of ambroxol would make it a potential therapeutic chaperone in the treatment of GD with neurological manifestations.

Topics: Ambroxol; Animals; beta-Glucosidase; Body Weight; Cells, Cultured; Colorimetry; Dose-Response Relationship, Drug; Drinking; Expectorants; Fibroblasts; Fluorescent Dyes; Galactosides; Gaucher Disease; Gene Expression Regulation, Enzymologic; Humans; Hymecromone; Mice; Mice, Inbred C57BL; Molecular Chaperones; Mutation; Skin; Time Factors

4-Methylumbelliferyl beta-D-xyloside was administered to 9-day-old chick embryos, and the morphological and chemical changes in the embryo were followed daily. Increases in wet weight, Na and Cl content, and visible edema were detectable at 10 days and fully apparent at 11 days. Dry weight increased to the same extent in control and treated embryos for four days, but then diverged. The degree of sulfation of chondroitin sulfate was slightly less in treated than control embryos at 10 days, and reached a steady low value at 11 days. Analysis of glycosaminoglycans in skin, muscle, and aorta showed an increase in chondroitin and its sulfates in the two former tissues but not the latter. In muscle and aorta, the degree of sulfation of chondroitin sulfate was markedly reduced; but in skin the results suggested a more complex picture in which the normal metabolism of glycosaminoglycans was altered. A possible physiological role is suggested for chondroitin sulfate in embryonic soft tissues.

Topics: Abnormalities, Drug-Induced; Animals; Body Weight; Chick Embryo; Chlorides; Chondroitin Sulfates; DNA; Edema; Glycosaminoglycans; Glycosides; Hymecromone; Kinetics; Sodium; Tissue Distribution; Umbelliferones

Wet weights and glycosaminoglycan content were determined for embryo, amnion, and allantois of control chick embryos and embryos injected with 4-methylumbelliferyl beta-D-xyloside at nine days of age. There was an immediate increase in total uronic acid content, but not in uronic acid concentration, in the embryo. No difference could be detected either in fluid volume, nor in content or type of glycosaminoglycan, in the amnion of the two groups. The fluid content of the allantois fo control eggs increased steadily between nine and 14 days, but in treated embryos the fluid content of the allantois remained low for at least a week. Less than 2 mg of uronic acid was present in allantoic fluid of control 16-day-old embryos, while treated embryos had accumulated more than 8 mg. More than 95% of the latter uronic acid was accounted for as chondroitin sulfate linked to methylumbelliferone and with a degree of sulfation of 50-60%. Thus beta-xyloside-treated embryos excrete large amounts of chondroitin sulfate and very little fluid.

Topics: Allantois; Amnion; Animals; Body Fluids; Body Weight; Chick Embryo; Chondroitin Sulfates; Glycosaminoglycans; Glycosides; Hymecromone; Umbelliferones; Uronic Acids

Nine-day chick embryos were treated with 4-methylumbelliferyl beta-D-xyloside or beta-aminopropionitrile fumarate, and their gross chemical composition was examined one week later. Total DNA was 10--20% less in embryos treated with either drug than it was in control embryos. Xyloside-treated embryos showed marked increases in percent wet weight and in sodium/DNA and chloride/DNA ratios, and small decreases in protein/DNA, hydroxyproline/DNA and sulfate/DNA. None of these parameters was affected in embryos treated with beta-aminopropionitrile. Approximately 85% of the uronic acid of control embryos was present as chondroitin sulfate, with a degree of sulfation of 80% and charge density of 1.8; all of this chondroitin sulfate was covalently linked to peptide and had a number-average molecular weight of 29,300. In embryos treated with beta-xyloside, 90% of the uronic acid was present as chondroitin sulfate, with a degree of sulfation of 40% and charge density ranging from 1 to 2; 27% of this chondroitin sulfate, with an average molecular weight of 25,400, was peptide linked, while 73% was linked to 4-methylumbelliferone and had an average molecular weight of 22,900. The chemical differences between embryos treated with the xyloside and embryos treated with the lathyrogen reinforce the conclusion on morphological grounds that these are distinct syndromes involving different aspects of the extracellular matrix.

Topics: Abnormalities, Drug-Induced; Aminopropionitrile; Animals; Body Weight; Chick Embryo; Chondroitin Sulfates; DNA; Extracellular Space; Glycosaminoglycans; Glycosides; Hymecromone; Lathyrism; Umbelliferones