ABSTRACT
Two diacyldaucic acids (1 and 2), an α,ß-unsaturated γ-lactone-type lignan (3) and its derivatives (4-6), and 12 known compounds were isolated from a traditional East Asian vegetable, Oenanthe javanica. The absolute configuration of 1 was validated by obtaining (+)-osbeckic acid through acid hydrolysis. The absolute configurations of 3-5 were determined by comparing their experimental and computed ECD data. The conclusion was supported by applying the phenylglycine methyl ester method to 3. Compound 6 was obtained as an interconverting mixture of isomers in a 3:1 trans- cis ratio. Several water-soluble components (1, 3, and 6) showed concentration-dependent inhibitory effects on antigen-stimulated degranulation in RBL-2H3 cells without producing any direct cytotoxicity against RBL-2H3 or HeLa cells.
Subject(s)
Dicarboxylic Acids/pharmacology , Lactones/pharmacology , Lignans/pharmacology , Mast Cells/drug effects , Oenanthe/chemistry , Phenylpropionates/antagonists & inhibitors , Phenylpropionates/pharmacology , Sugar Acids/pharmacology , Animals , Dicarboxylic Acids/chemistry , Dicarboxylic Acids/isolation & purification , HeLa Cells , Humans , Lactones/chemistry , Lignans/chemistry , Lignans/isolation & purification , Mast Cells/chemistry , Phenylpropionates/chemistry , Sugar Acids/chemistry , Sugar Acids/isolation & purificationABSTRACT
OBJECTIVE: Mitochondrial enzymatic activity reductions in both myocardial and skeletal muscle tissues have been reported in a canine model of pacing-induced congestive heart failure (CHF). Endothelin-1 (ET-1), a vasoconstrictor peptide with diverse biological properties, has been implicated in CHF pathogenesis, and ET-1 receptor blockade has been shown to attenuate CHF progression. We hypothesized that the beneficial effect of ET-1 receptor blockade may be mediated in part by improved mitochondrial function. METHODS: Myocardium and skeletal muscle tissues were evaluated for respiratory complex I-V and citrate synthase activity levels in paced animals treated with and without LU 135252, a specific type A ET-1 receptor (ET(A)) antagonist. RESULTS: Specific activity levels of complex V and III, which were 65% to 85% lower in both cardiac and skeletal muscle in paced compared to unpaced animals, were significantly increased in ET(A) antagonist-treated animals (50%-300% compared to untreated paced animals). Levels of other mitochondrial respiratory complex activities including complex I, II, and IV as well as citrate synthase were not significantly changed. CONCLUSIONS: These findings suggest that endothelin activation may be involved in the myocardial dysfunction and mitochondrial enzyme deficiencies observed in pacing-induced CHF. Improvement of mitochondrial function may be a novel mechanism mediating the beneficial effect of ET(A) receptor blockade in CHF.
Subject(s)
Carrier Proteins , Endothelin Receptor Antagonists , Heart Failure/metabolism , Heart Failure/therapy , Mitochondria, Heart/drug effects , Adenosine Triphosphatases/drug effects , Animals , Cardiac Pacing, Artificial , Citrate (si)-Synthase/drug effects , Citric Acid Cycle/drug effects , Disease Models, Animal , Dogs , Hemodynamics/drug effects , Membrane Proteins/drug effects , Mitochondria, Heart/metabolism , Mitochondrial Proton-Translocating ATPases , Models, Cardiovascular , Multienzyme Complexes/drug effects , Muscle, Skeletal/cytology , Muscle, Skeletal/metabolism , Oxidative Phosphorylation/drug effects , Oxidative Stress/drug effects , Phenylpropionates/antagonists & inhibitors , Pyrimidines/antagonists & inhibitors , Treatment OutcomeABSTRACT
The reversible binding of lithocholate to human serum albumin determines a decrease of the binding of rac-ketoprofen. The process was followed by displacement chromatography using increasing concentrations of the competitor, i.e., lithocholate, in the mobile phase. The inhibition of rac-ketoprofen binding resulting was enantioselective and greater displacement was observed for the (S) enantiomer. The displacement process resulting was competitive in nature, the two enantiomers of ketoprofen binding to the same binding site as the modifier. The investigation was extended to other nonsteroidal antiinflammatory drugs. The enantioselective binding inhibition was larger in the case of rac-naproxen and rac-suprofen with respect to the phenomenon observed in the case of rac-ketoprofen. The difference in circular dichroism spectroscopy was also used to characterize the binding of lithocholate to human serum albumin. This bile acid was proven to bind to site II on human serum albumin. The results, as obtained by displacement chromatography and difference circular dichroism spectroscopy, strongly support the hypothesized role of bile acids in inducing the enantioselective inhibition of ketoprofen binding to human serum albumin in patients suffering from liver diseases.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/metabolism , Lithocholic Acid/pharmacology , Phenylpropionates/metabolism , Serum Albumin/metabolism , Anti-Inflammatory Agents, Non-Steroidal/antagonists & inhibitors , Binding Sites , Binding, Competitive , Chromatography , Circular Dichroism , Drug Interactions , Fenoprofen/antagonists & inhibitors , Fenoprofen/metabolism , Humans , Ketoprofen/antagonists & inhibitors , Ketoprofen/metabolism , Lithocholic Acid/metabolism , Naproxen/antagonists & inhibitors , Naproxen/metabolism , Phenylpropionates/antagonists & inhibitors , Stereoisomerism , Substrate Specificity , Suprofen/antagonists & inhibitors , Suprofen/metabolismABSTRACT
Investigations were performed in male Wistar rats to determine the effects of gamma-oryzanol on circadian rhythm of stress ulcer and on various kinds of experimental ulcers, and the modification of antiulcerogenic action of this drug when combined with the inhibitors or precursors of amine metabolism. Circadian rhythms were observed in stress ulceration with a peak at 2 : 00 p.m. and a reduction at 8 : 00 p.m. The inhibitory action of gamma-oryzanol was significant when stress was loaded for 6 hr from 2 : 00 a.m., 5 : 00 a.m., 11 : 00 a.m. or 2:00 p.m. An 8-day treatment with gamma-oryzanol, 100 mg/kg, s.c., showed a significant inhibition of fasting ulcer, while the 5-day pretreatment exerted slight effects on ulcers by pylorus-ligation or stress-atropine. A 10-day treatment with the same dose of gamma-oyzanol in acetic acid ulcers lowered the serum level of gastrin. Treatment with reserpine, alpha-MT or PCPA prior to stress loading abolished the anti-ulcer effect of gamma-oryzanol, 100 mg/kg, s.c. for 5 days in stress ulcer. Treatment with L-DOPA or 5-HTP revealed a tendency toward restoration of the anti-ulcer effect of gamma-oryzanol. It is suggested that the monoaminergic neuron system is involved in the anti-ulcer action of gamma-oryzanol.
