benzofurans and Hypercholesterolemia

Allantoin is known as the agonist of imidazoline receptor, especially the I₂ subtype. Effect of allantoin on imidazoline I₁ receptor (I₁R) relating to reduction of blood pressure and its merit in steatosis are still obscure. Also, farnesoid X receptor (FXR) plays an important role in lipid homeostasis related to I₁R activation. Thus, we administered allantoin into high fat diet (HFD)-fed mice showing hypertriglyceridemia and hypercholesterolemia. Allantoin significantly improved hyperlipidemia in HFD mice after 4 weeks of administration. Pretreatment with efaroxan, at a dose sufficient to inhibit I₁R activation, attenuated the action of allantoin. In addition, in cultured HepG2 cells, allantoin increased the expression of farnesoid X receptor (FXR). The allantoin-induced FXR expression was blocked by efaroxan. Similar changes were observed in the expressions of FXR-targeted genes. Otherwise, allantoin also lowered systolic blood pressure (SBP) in HFD mice that can be blocked by efaroxan. Taken together, allantoin has an ability to activate I₁R for improvement of metabolic disorders.

Topics: Allantoin; Animals; Anticholesteremic Agents; Antihypertensive Agents; Benzofurans; Diet, High-Fat; Fatty Liver; Hep G2 Cells; Humans; Hypercholesterolemia; Hypertriglyceridemia; Hypolipidemic Agents; Imidazoles; Imidazoline Receptors; Liver; Male; Mice; Mice, Inbred C57BL; Receptors, Cytoplasmic and Nuclear; Receptors, LDL; Up-Regulation

Atherosclerosis and restenosis are inflammatory responses involving free radicals and lipid peroxidation and may be prevented/cured by antioxidant-mediated lipid peroxidation inhibition. Salvianolic acid (Sal B), a water-soluble antioxidant obtained from a Chinese medicinal herb, is believed to have multiple preventive and therapeutic effects against human vascular diseases. In this study the in vitro and in vivo inhibitory effects of Sal B on oxidative stress were determined.. In human aortic endothelial cells (HAECs), Sal B reduced oxidative stress, inhibited low-density lipoprotein (LDL) oxidation and reduced oxidised LDL-induced cytotoxicity. Sal B inhibited Cu(2+) -induced LDL oxidation in vitro (with a potency 16.3 times that of probucol) and attenuated HAEC-mediated LDL oxidation as well as reactive oxygen species (ROS) production. In cholesterol-fed New Zealand White rabbits (with probucol as positive control), Sal B intake reduced Cu(2+) -induced LDL oxidation, lipid deposition in the thoracic aorta, intimal thickness of the aortic arch and thoracic aorta and neointimal formation in the abdominal aorta.. The data obtained in this study suggest that Sal B protects HAECs from oxidative injury-mediated cell death via inhibition of ROS production. The antioxidant activity of Sal B may help explain its efficacy in the treatment of vascular diseases.

Topics: Animals; Antioxidants; Aorta; Benzofurans; Cholesterol, Dietary; Copper; Drugs, Chinese Herbal; Endothelial Cells; Humans; Hypercholesterolemia; Hyperplasia; Lipid Metabolism; Lipid Peroxidation; Lipoproteins, LDL; Oxidative Stress; Phytotherapy; Rabbits; Reactive Oxygen Species; Salvia miltiorrhiza; Tunica Intima; Vascular Diseases

Stimulatory effects of a novel isobenzofranone, MD-700, on low density lipoprotein (LDL) receptor activity were investigated in vitro and in vivo. MD-700 at 0.03 microg/ml elevated the expression of LDL receptor in HepG2 cells within 4 h. Corresponding to this, uptake of fluorescent labeled-LDL (3,3'-dioctadecylindocarbocyanine-LDL) by the cells increased linearly in time- and dose-dependent manner by MD-700 for up to 12 h. In the experiment using HepG2 cells transiently transfected with promoter-luciferase gene constructs, MD-700 increased luciferase activity in a dose-dependent manner from 0.03 to 0.1 microg/ml. In contrast, luciferase activity was not stimulated by MD-700 in construct with a deleted sterol regulatory element (SRE)-1, suggesting importance of SRE-1 in stimulation of the LDL receptor gene promoter by MD-700. Binding experiments on liver membranes from MD-700-treated hamsters showed about a 60% increase in 125I-labeled LDL binding. A Scatchard plot revealed that MD-700 increased the maximal binding without affecting binding affinity. In contrast to findings with an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, pravastatin, MD-700 had no effect on the sterol synthesis in hamster liver homogenates. These results suggest that MD-700 stimulates the expression of LDL receptor, presumably in a manner independent of change in sterol metabolism, and thereby promotes LDL clearance. Hypocholesterolemic actions of MD-700 in hamsters were then examined. MD-700 lowered serum cholesterol levels in hamsters fed normal chow or a high-fat diet. Fractionation of serum lipoproteins demonstrated that MD-700 selectively decreased LDL and very low density lipoprotein cholesterol. Dose-dependent decrease in serum cholesterol was also seen in hypercholesterolemic rats. Thus, the hypocholesterolemic action of MD-700 may be attributed to up-regulation of the LDL receptor, based on stimulation of the transcription of the LDL receptor gene. Although pravastatin stimulates LDL uptake and lowers serum cholesterol in a manner similar to that seen with MD-700, the mechanism responsible for hypocholesterolemic action appears to differ.

Topics: Animals; Benzofurans; Blotting, Northern; Carbocyanines; Carcinoma, Hepatocellular; Cell Membrane; Cholesterol; Cricetinae; Disease Models, Animal; DNA Primers; Fluorescent Dyes; Humans; Hypercholesterolemia; Lipoproteins, LDL; Lipoproteins, VLDL; Liver Neoplasms; Male; Promoter Regions, Genetic; Rats; Rats, Wistar; Receptors, LDL; RNA, Messenger; RNA, Neoplasm; Sterols; Transcription, Genetic; Tumor Cells, Cultured; Up-Regulation

Recent studies have shown that acyl-CoA:cholesterol acyltransferase (ACAT) plays an important role in the initiation of diabetes-associated hypercholesterolemia. To confirm this hypothesis, effects of a potent ACAT inhibitor, FR145237, on diet-induced hypercholesterolemia were examined in streptozotocin (STZ)-induced diabetic rats. One-week feeding of 1% cholesterol and 0.5% cholic acid to normal rats and STZ-induced diabetic rats increased plasma cholesterol levels in both groups, and the response was more remarkable in the STZ rats than in the normal ones (1266 +/- 476 mg/dl and 146 +/- 7 mg/dl, respectively). FR145237 dose-dependently reduced the rise in plasma cholesterol levels in the STZ rats and the levels were almost normalized by treatment with 1 mg/kg/day of the compound. These results suggest that hyperresponse to dietary cholesterol was induced in the STZ rats and that ACAT is involved in the hyperresponse. The effects of FR145237 on other plasma lipids such as high density lipoprotein (HDL) cholesterol and triglyceride (TG) levels were also examined.

Topics: Animals; Benzofurans; Blood Glucose; Body Weight; Cholesterol; Cholesterol, Dietary; Cholesterol, HDL; Diabetes Mellitus, Experimental; Eating; Enzyme Inhibitors; Hypercholesterolemia; Male; Phenylurea Compounds; Rats; Rats, Sprague-Dawley; Sterol O-Acyltransferase; Triglycerides

1. Aqueous celery extract was administered intraperitoneally to genetically hypercholesterolaemic (RICO) and normocholesterolaemic (RAIF) rats via Alzet osmotic pumps over a 13 day period. 2. The serum cholesterol concentration of the celery extract-treated RICO rats was found to be significantly lower (P < 0.05) than the control rats. Aqueous celery extract was effective in preventing the rise of cholesterol level in the RICO rats. However, no such observation was seen in the RAIF rats. The serum triglyceride level was unchanged in both strains of rats. 3. When 3-n-butylphthalide (BuPh), a unique component in celery, was administered in the same manner to the RICO and RAIF rats, it did not produce significant changes in the serum and liver lipid profiles of these rats. The activities of hepatic 3-hydroxy-3-methylglutaryl CoA reductase in both strains of rats were also not significantly different from their respective controls. 4. Together with our recently reported thin-layer chromatography findings that BuPh was not detected in the aqueous celery extract, this study suggests that the effect of celery extract on serum cholesterol levels in the RICO rats could be attributed to chemical constituents other than BuPh.

Topics: Animals; Benzofurans; Cholesterol; Cholesterol, HDL; Hydroxymethylglutaryl CoA Reductases; Hypercholesterolemia; Lipoproteins; Liver; Plant Extracts; Rats; Triglycerides; Vegetables

The hypocholesterolemic and antiatherosclerotic activities of FR145237, a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, were evaluated in cholesterol-fed and Watanabe heritable hyperlipidemic (WHHL) rabbits. In the first experiment, rabbits were fed a high cholesterol (1% cholesterol) diet for 2 weeks and further fed a high cholesterol diet containing FR145237 for 8 weeks. FR145237 (0.1, 0.32 and 1.0 mg/kg) dose-dependently lowered the plasma total cholestrol levels by 80%, 96% and 97%, respectively. and reduced aortic atherosclerosis by 44%, 90% and 90%, respectively. To clarify a direct effect of FR145237 at the aortic wall, a second experiment was performed. Rabbits were fed a high-cholesterol diet for 8 weeks to establish aortic atherosclerosis and then fed a normal diet with or without FR145237 for 8 weeks. Cholesterol content in the aorta and the liver was significantly reduced in the FR145237 group (10 mg/kg) by 50% and 43%, respectively, though plasma total cholesterol level did not differ from that in the control group. In the WHHL rabbits, FR145237 (10 mg/kg) did not affect plasma cholesterol level but significantly reduced the atherosclerotic lesion in the coronary arteries by 61%. These results suggest that FR145237 potently lowers the plasma cholesterol level in hypercholesterolemia induced by dietary cholesterol but not that by LDL receptor deficiency, and that FR145237 has a direct antiatherosclerotic activity on the arterial wall independent of its hypocholesterolemic activity.

Topics: Animals; Aorta; Arteriosclerosis; Benzofurans; Carrier Proteins; Cholesterol; Cholesterol, Dietary; Diet, Atherogenic; Disease Models, Animal; Enzyme Inhibitors; Hypercholesterolemia; Hyperlipidemias; Lipoproteins, HDL; Lipoproteins, LDL; Liver; Male; Molecular Structure; Phenylurea Compounds; Rabbits; Receptors, Lipoprotein; RNA-Binding Proteins; Sterol O-Acyltransferase