Glucosamine, a naturally occurring amino monosaccharide, is widely used to treat osteoarthritis in humans. Furthermore, glucosamine exhibits an anti-inflammatory action by inhibiting the activation of neutrophils, chondrocytes and synoviocytes. Recently, we revealed that glucosamine suppresses cytokine-induced activation of intestinal epithelial cells in vitro. In the present study therefore, we investigated whether glucosamine exhibits the anti-inflammatory effect in vivo, using dextran sulfate sodium (DSS)-induced colitis in rats, a model of inflammatory bowel diseases (IBD). The results indicated that glucosamine improved the clinical symptoms (evaluated by disease activity index), and suppressed colonic inflammation (evaluated by colon length and weight/length ratio) and tissue injury (evaluated by histological damage score) in DSS-induced colitis. Furthermore, glucosamine inhibited the activation of intestinal epithelial cells, as evidenced by the suppressed phosphorylation of NF-κB in the intestinal mucosa of DSS-induced colitis. Collectively, these observations suggest that glucosamine is likely to suppress the activation of intestinal epithelial cells in vivo, thereby possibly exhibiting anti-inflammatory action in a DSS-induced rat colitis model. Thus, glucosamine could prove to be a useful agent for IBD.
When carbohydrate metabolism is impaired, fatty acid metabolism is activated. Excess acetyl-coenzyme A (CoA) is generated from fatty acids by β-oxidation and is used for the formation of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) and subsequently for acetoacetate. High levels of secreted ketone bodies (acetoacetate and 3β-hydroxybutyrate) lower the pH of blood and urine, resulting in ketoacidosis. HMG-CoA lyase in hepatic cells is a rate-limiting enzyme catalyzing the cleavage of HMG-CoA to acetoacetate, and thus inhibition of this enzyme results in reduced acetoacetate production, in other words, impaired ketoacidosis. Inhibition of HMG-CoA lyase activity possibly prevents ketoacidosis and should be the therapeutic target. Polyphenols are common and abundant dietary constituents with beneficial effects on human health. We examined the inhibitory effects of dietary polyphenols on HMG-CoA lyase activity in cellular extracts of human hepatoma HepG2 cells. Of the nine representative dietary polyphenols tested, ( )-epigallocatechin (EGC), ( )-epigallocatechin gallate (EGCG), and gallic acid (GA) effectively inhibited HMG-CoA lyase activity. LineweaverBurk analysis revealed that EGC and EGCG are likely to be mixed-type noncompetitive inhibitors. Pyrogallol with the gallyl structure also inhibited HMG-CoA lyase activity, suggesting that the gallyl moiety of polyphenols is important for the inhibition of HMG-CoA lyase activity.Key words 3-hydroxy-3-methylglutaryl-CoA lyase; ketoacidosis; polyphenol; inhibition; (−)-epigallocatechin gallate Under normal conditions, glucose serves as the primary energy source in most human tissues. It is converted via glycolysis to pyruvate and then to acetyl-coenzyme A (CoA), which feeds into the tricarboxylic acid cycle to produce energy. During fasting and starvation on the other hand, ketone bodies converted from fatty acids are readily utilized as an energy source in the brain and muscular tissues. However, in patients with diabetes or soft drink ketosis-so-called "PET bottle syndrome"-which is caused by consuming excessive amounts of soft drinks in summer and/or after exercise, ketone bodies are overproduced due to impaired glucose metabolism.1-3) Long-term impairment of glucose metabolism induces ketoacidosis, which itself can induce a coma. 4)Fatty acid metabolism is activated when carbohydrate metabolism is impaired. Excess acetyl-CoA is generated from fatty acids by β-oxidation and is used for the formation of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) and subsequently acetoacetate. Some of the acetoacetate is converted to 3β-hydroxybutyrate through a reaction catalyzed by 3β-hydroxybutyrate dehydrogenase. In addition, acetoacetate is spontaneously converted into acetone by decarboxylation, albeit in small quantities. Acetoacetate, 3β-hydroxybutyrate, and acetone are ketone bodies, which in high levels lower the pH of blood and urine, resulting in ketoacidosis. Polyphenols are common and abundant dietary constituents with beneficial effects on human health. Recent research strongly...
Hypoglycemia is one of the serious adverse effects induced by cibenzoline (CBZ), an antiarrhythmic agent. In order to clarify the pharmacodynamics of CBZ-induced hypoglycemia, CBZ was administered intravenously to conscious rats at a dose of 5, 10 or 20 mg/kg and serum samples were collected periodically to determine the concentrations of CBZ, insulin and glucose. The pharmacokinetics of CBZ showed nonlinear characteristics and could be described by a two-compartment model with Michaelis-Menten elimination kinetics. CBZ induced a rapid increase in the serum concentration of insulin. As the CBZ dose was increased, a greater hypoglycemic effect occurred. The indirect response model was applied to account for the CBZ-induced increase in insulin secretion and the subsequent decrease in serum glucose. A linear relationship was assumed between the serum concentration of CBZ and its stimulating effect on insulin secretion. A nonlinear relationship was assumed between the serum concentration of insulin and its stimulating effect on the elimination of serum glucose. The time courses of serum concentrations of CBZ, insulin and glucose after intravenous injection of CBZ could be described by the pharmacokinetic and pharmacodynamic model developed. This approach will be useful for the identification of variable factors related to CBZ-induced hypoglycemia.
Abstract. Antioxidative flavonoids are used to reduce the risk of cardiovascular diseases in humans. However, the precise mechanism for the anti-atherosclerotic actions of flavonoids remains to be elucidated. In the present study, to assess the mechanism for the action of antioxidative flavonoids on atherosclerosis, we investigated the effect of flavangenol, one of the most potent antioxidants currently known, on spontaneously hyperlipidemic B6.KOR-Apoe shl mice. Flavangenol was orally administered to B6.KORApoe shl mice ad libitum (6 mg flavangenol/mouse/day). After 6 months, serum levels of lipids (total cholesterol, triglyceride, HDL-cholesterol and LDL-cholesterol) and lipid peroxide were measured, and histopathological changes (lipid accumulation and inflammatory cell infiltration) in the aortic root were evaluated. Serum levels of total cholesterol and LDL-cholesterol were markedly increased, and HDLcholesterol levels were decreased in B6
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