RESUMEN
Among 276 herbal extracts, a methanol extract of Castanopsis cuspidata var. sieboldii stems was selected as an experimental source for novel acetylcholinesterase (AChE) inhibitors. Five compounds were isolated from the extract by activity-guided screening, and their inhibitory activities against butyrylcholinesterase (BChE), monoamine oxidases (MAOs), and ß-site amyloid precursor protein cleaving enzyme 1 (BACE-1) were also evaluated. Of these compounds, 4'-O-(α-L-rhamnopyranosyl)-3,3',4-tri-O-methylellagic acid (3) and 3,3',4-tri-O-methylellagic acid (4) effectively inhibited AChE with IC50 values of 10.1 and 10.7 µM, respectively. Ellagic acid (5) inhibited AChE (IC50 = 41.7 µM) less than 3 and 4. In addition, 3 effectively inhibited MAO-B (IC50 = 7.27 µM) followed by 5 (IC50 = 9.21 µM). All five compounds weakly inhibited BChE and BACE-1. Compounds 3, 4, and 5 reversibly and competitively inhibited AChE, and were slightly or non-toxic to MDCK cells. The binding energies of 3 and 4 (- 8.5 and - 9.2 kcal/mol, respectively) for AChE were greater than that of 5 (- 8.3 kcal/mol), and 3 and 4 formed a hydrogen bond with Tyr124 in AChE. These results suggest 3 is a dual-targeting inhibitor of AChE and MAO-B, and that these compounds should be viewed as potential therapeutics for the treatment of Alzheimer's disease.
Asunto(s)
Inhibidores de la Colinesterasa/farmacología , Ácido Elágico/aislamiento & purificación , Ácido Elágico/farmacología , Fagaceae/química , Inhibidores de la Monoaminooxidasa/farmacología , Monoaminooxidasa/metabolismo , Animales , Bioensayo , Muerte Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Fraccionamiento Químico , Inhibidores de la Colinesterasa/farmacocinética , Diálisis , Perros , Electrophorus , Ácido Elágico/farmacocinética , Células HL-60 , Humanos , Enlace de Hidrógeno , Cinética , Células de Riñón Canino Madin Darby , Metanol , Simulación del Acoplamiento Molecular , Inhibidores de la Monoaminooxidasa/farmacocinética , Fitoquímicos/química , Fitoquímicos/farmacología , Extractos Vegetales/químicaRESUMEN
Ellagic acid (EA) is a polyphenolic active compound with antimalarial and other promising therapeutic activities. However, its solubility and its permeability are both low (BCS IV). These properties greatly compromise its oral bioavailability and clinical utilizations. To overcome these limitations of the physicochemical parameters, several formulation approaches, including particle size reduction, amorphization and lipid-based formulations, have been used. Although these strategies have not yet led to a clinical application, some of them have resulted in significant improvements in the solubility and bioavailability of EA. This critical review reports and analyses the different formulation approaches used by scientists to improve both the biopharmaceutical properties and the clinical use of EA.
Asunto(s)
Antimaláricos/farmacocinética , Composición de Medicamentos/métodos , Ácido Elágico/farmacocinética , Excipientes/química , Administración Oral , Animales , Antimaláricos/administración & dosificación , Antimaláricos/química , Disponibilidad Biológica , Química Farmacéutica , Evaluación Preclínica de Medicamentos , Ácido Elágico/administración & dosificación , Ácido Elágico/química , Voluntarios Sanos , Humanos , Lípidos/química , Modelos Animales , Tamaño de la Partícula , Solubilidad , Agua/químicaRESUMEN
Previously, we have reported the opposite effects of compounds isolated from Lagerstroemia speciosa leaves on a glucose transport (GLUT4) assay. Ellagitannins from L. speciosa activated GLUT4, while ellagic acid derivatives showed an inhibitory effect. As part of our continuing research on anti-diabetic nutritional supplements, we herein compared the anti-diabetic effects of several extracts (LE1-8) from leaves of L. speciosa using different manufacturing processes based on the contents of ellagitannins and ellagic acid derivatives. Their anti-diabetic effects were evaluated through glucose uptake and adipocyte differentiation in 3T3-L1 cells in vitro as well as alloxan induced diabetic mice in vivo. These extracts were given to mice by gavage at doses of 0.25, 1.0, and 4.0 g per kg body weight once a day for 21 consecutive days. Results showed that LE1 (1.0 g kg-1), LE3 (1.0 or 4.0 g kg-1), LE4 (1.0 or 4.0 g kg-1), LE5 (0.25 or 1.0 or 4.0 g kg-1) and LE7 (1.0 or 4.0 g kg-1) showed significant anti-diabetic effects in alloxan-induced diabetic mice as indicated by the decreased levels of fasting blood glucose, body weight, serum biomarkers, tissue weight and body fat, and increased final insulin levels. LE8 (1.0 g kg-1) showed a moderate anti-diabetic effect as illustrated by the reduced fasting blood glucose level while LE2 and LE6 showed slight effects in alloxan-induced diabetic mice. The potential correlation of the content of ellagitannins, ellagic acid derivatives, and corosolic acid with the anti-diabetic activity was discussed.
Asunto(s)
Ácido Elágico , Taninos Hidrolizables , Hipoglucemiantes , Lagerstroemia/química , Extractos Vegetales , Células 3T3-L1 , Adipocitos/efectos de los fármacos , Animales , Glucemia/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Diabetes Mellitus Experimental/metabolismo , Ácido Elágico/química , Ácido Elágico/farmacocinética , Ácido Elágico/farmacología , Taninos Hidrolizables/química , Taninos Hidrolizables/farmacocinética , Taninos Hidrolizables/farmacología , Hipoglucemiantes/química , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Masculino , Ratones , Ratones Endogámicos ICR , Extractos Vegetales/química , Extractos Vegetales/farmacocinética , Extractos Vegetales/farmacología , Hojas de la Planta/químicaRESUMEN
Wastes deriving from production of wines by yeast fermentation of Punica granatum (fermented pomegranate wastes, FPW) showed a marked antioxidant activity in a series of conventional chemical tests. HPLC/MS analysis of the methanol extract showed the presence of ellagic acid (EA) as the main phenolic component at levels up to 40% on a w/w basis. Experiments using murine macrophages showed that FPW extract is able to reduce the LPS-induced expression of pro-inflammatory genes IL-1ß, TNF-α and iNOS. A remarkable increase in the antioxidant properties and extractable EA content was observed following acid hydrolytic treatment of FPW. Under simulated gastrointestinal conditions, EA was slowly released from FPW up to 80% of the overall content over 2â¯h incubation at the slightly alkaline pHs simulating the small intestine environment, suggesting a potential of the material in nutraceuticals and other applications.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Antioxidantes/farmacología , Ácido Elágico/farmacocinética , Lythraceae/química , Residuos/análisis , Animales , Antioxidantes/análisis , Antioxidantes/farmacocinética , Preparaciones de Acción Retardada , Digestión , Ácido Elágico/análisis , Fermentación , Inflamación/tratamiento farmacológico , Inflamación/genética , Lipopolisacáridos/farmacología , Espectroscopía de Resonancia Magnética , Ratones , Fenoles/análisis , Extractos Vegetales/química , Extractos Vegetales/farmacología , Células RAW 264.7 , VinoRESUMEN
BACKGROUND: Cytochrome P450-2D6 (CYP2D6), a member of the CYP450 mixed function oxidase system, is an important CYP isoform with regard to herbal-drug interactions and is responsible for the metabolism of nearly 25% of drugs. Until now, studies on the effects of various phytochemicals on CYP2D6 activity in vivo have been very rare. Gallic acid and ellagic acid are natural polyphenols which are widely distributed in fruits and medicinal plants. In the present study, the effects of gallic acid and ellagic acid pretreatment on intestinal transport and oral bioavailability of metoprolol were investigated. METHODS: The intestinal transport of metoprolol was assessed by conducting an in situ single pass intestinal perfusion (SPIP) study. The bioavailability study was conducted to evaluate the pharmacokinetic parameters of orally administered metoprolol in rats. RESULTS: After pretreatment with gallic acid and ellagic acid, no significant change in effective permeability of metoprolol was observed at the ileum part of rat intestine. A significant improvement in the peak plasma concentration (Cmax) and area under the serum concentration-time profile (AUC) and decrease in clearance were observed in rats pretreated with gallic acid and ellagic acid. CONCLUSIONS: Gallic acid and ellagic acid significantly enhanced the oral bioavailability of metoprolol by inhibiting CYP2D6-mediated metabolism in the rat liver. Hence, adverse herbal-drug interactions may result with concomitant ingestion of gallic acid and ellagic acid supplements and drugs that are CYP2D6 substrates. The clinical assessment of these interactions should be further investigated in human volunteers.
Asunto(s)
Inhibidores del Citocromo P-450 CYP2D6/administración & dosificación , Inhibidores del Citocromo P-450 CYP2D6/farmacocinética , Citocromo P-450 CYP2D6/metabolismo , Ácido Elágico/farmacocinética , Ácido Gálico/farmacocinética , Hígado/metabolismo , Metoprolol/farmacocinética , Administración Oral , Animales , Disponibilidad Biológica , Relación Dosis-Respuesta a Droga , Ácido Elágico/administración & dosificación , Ácido Gálico/administración & dosificación , Hígado/enzimología , Masculino , Metoprolol/administración & dosificación , Microsomas Hepáticos/enzimología , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
The pomegranate, Punica granatum L., is an ancient, mystical, unique fruit borne on a small, long-living tree cultivated throughout the Mediterranean region, as far north as the Himalayas, in Southeast Asia, and in California and Arizona in the United States. In addition to its ancient historical uses, pomegranate is used in several systems of medicine for a variety of ailments. The synergistic action of the pomegranate constituents appears to be superior to that of single constituents. In the past decade, numerous studies on the antioxidant, anticarcinogenic, and anti-inflammatory properties of pomegranate constituents have been published, focusing on treatment and prevention of cancer, cardiovascular disease, diabetes, dental conditions, erectile dysfunction, bacterial infections and antibiotic resistance, and ultraviolet radiation-induced skin damage. Other potential applications include infant brain ischemia, male infertility, Alzheimer's disease, arthritis, and obesity.
Asunto(s)
Lythraceae/química , Fitoterapia , Extractos Vegetales/uso terapéutico , Animales , Antioxidantes/farmacocinética , Antioxidantes/uso terapéutico , Ácido Elágico/farmacocinética , Ácido Elágico/uso terapéutico , Femenino , Humanos , Masculino , Ratones , Extractos Vegetales/farmacocinética , RatasRESUMEN
The intake of polyphenols has been demonstrated to have health-promoting and disease-preventive effects. The pomegranate (Punica granatum L.), which is rich in several polyphenols, has been used for centuries in ancient cultures for its medicinal purposes. The potential health benefits of pomegranate polyphenols have been demonstrated in numerous in vitro studies and in vivo experiments. This study investigated the absorption and antioxidant effects of a standardized extract from pomegranate in healthy human volunteers after the acute consumption of 800 mg of extract. Results indicate that ellagic acid (EA) from the extract is bioavailable, with an observed C(max) of 33 ng/mL at t(max) of 1 h. The plasma metabolites urolithin A, urolithin B, hydroxyl-urolithin A, urolithin A-glucuronide, and dimethyl ellagic acid-glucuronide were identified by HPLC-MS. The antioxidant capacity measured with the oxygen radical absorbance capacity (ORAC) assay was increased with a maximum effect of 32% after 0.5 h, whereas the generation of reactive oxygen species (ROS) was not affected. The inflammation marker interleukin-6 (IL-6) was not significantly affected after 4 h after the consumption of the extract. Overall, this study demonstrated the absorbability of EA from a pomegranate extract high in ellagitannin content and its ex vivo antioxidant effects.
Asunto(s)
Antioxidantes/farmacocinética , Ácido Elágico/farmacocinética , Taninos Hidrolizables/farmacocinética , Lythraceae/química , Extractos Vegetales/farmacocinética , Adulto , Ácido Elágico/sangre , Femenino , Cromatografía de Gases y Espectrometría de Masas , Humanos , Taninos Hidrolizables/sangre , Masculino , Extractos Vegetales/sangreRESUMEN
Quantification of ellagic acid, the principal bioactive component of pomegranate leaf extract, in rats plasma following oral administration of pomegranate leaf extract was achieved by using a high-performance liquid chromatographic method. The calibration curve for ellagic acid was linear (r2=0.9998) ver the concentration range 0.026-1.3 microg/ml. The intra- and inter-day assays of ellagic acid from rat plasma were less than 6.52% at concentration range from 26 to 1300 ng/ml and good overall recoveries (94.5-102.4%) were found on same concentrations. The concentration-time profile was fitted with an open two-compartment system with lag time and its max concentration of ellagic acid in plasma was 213 ng/ml only 0.55 h after oral administration extract 0.8 g/kg. The pharmacokinetic profile indicates that ellagic acid has poor absorption and rapid elimination after oral administration pomegranate leaf extract, and part of it was absorbed from stomach.