RESUMEN
Hypercholesterolemia is one of the key risk factors for coronary heart disease, a major cause of death in developed countries. Suppression of NPC1L1-mediated dietary and biliary cholesterol absorption is predicted to be one of the most effective ways to reduce the risk of hypercholesterolemia. In a screen for natural products that inhibit ezetimibe glucuronide binding to NPC1L1, we found a novel compound, fomiroid A, in extracts of the mushroom Fomitopsis nigra. Fomiroid A is a lanosterone derivative with molecular formula C30H48O3. Fomiroid A inhibited ezetimibe glucuronide binding to NPC1L1, and dose-dependently prevented NPC1L1-mediated cholesterol uptake and formation of esterified cholesterol in NPC1L1-expressing Caco2 cells. Fomiroid A exhibited a pharmacological chaperone activity that corrected trafficking defects of the L1072T/L1168I mutant of NPC1L1. Because ezetimibe does not have such an activity, the binding site and mode of action of fomiroid A are likely to be distinct from those of ezetimibe.
Asunto(s)
Anticolesterolemiantes/farmacología , Colesterol/metabolismo , Coriolaceae/química , Ezetimiba/farmacología , Lanosterol/análogos & derivados , Proteínas de la Membrana/metabolismo , Anticolesterolemiantes/metabolismo , Azetidinas/metabolismo , Sitios de Unión , Unión Competitiva , Células CACO-2/efectos de los fármacos , Colesterol/farmacocinética , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Esterificación/efectos de los fármacos , Glucurónidos/metabolismo , Células HEK293/efectos de los fármacos , Humanos , Lanosterol/farmacología , Proteínas de la Membrana/genética , Proteínas de Transporte de Membrana , Estructura MolecularRESUMEN
The EtOH extract of tarragon Artemisia dracunculus, a perennial herb in the family Asteraceae, was found to potently inhibit α-melanocyte-stimulating hormone (α-MSH) induced melanin production in B16 mouse melanoma cells. Bioassay-guided fractionation led to the isolation of two alkamide compounds, isobutyl (1) and piperidiyl (2) amides of undeca-2E,4E-dien-8,10-dynoic acid. The respective EC(50) values for melanin biosynthesis inhibition were 1.8 and 2.3 µg/mL for 1 and 2.
Asunto(s)
Artemisia/química , Melaninas/antagonistas & inhibidores , Melanoma Experimental/tratamiento farmacológico , Extractos Vegetales/farmacología , Alcamidas Poliinsaturadas , Neoplasias Cutáneas/tratamiento farmacológico , alfa-MSH/antagonistas & inhibidores , Animales , Supervivencia Celular/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Melaninas/biosíntesis , Melanoma Experimental/patología , Ratones , Extractos Vegetales/química , Alcamidas Poliinsaturadas/química , Alcamidas Poliinsaturadas/aislamiento & purificación , Alcamidas Poliinsaturadas/farmacología , Neoplasias Cutáneas/patología , Células Tumorales Cultivadas , alfa-MSH/metabolismoRESUMEN
An EtOH extract of fruits of Piper longum was found to exhibit a potent inhibitory effect against alpha-melanocyte-stimulating hormone (alpha-MSH)-induced melanin production in B16 mouse melanoma cells. Bioassay-directed fractionation led to the isolation of prenylated phenolic compounds bakuchiol, bavachin, and isobavachalcone. These compounds and the crude extract of the fruits of P. longum may have suppressive effects against pigmentation by melanin in the skin.
Asunto(s)
Melaninas/biosíntesis , Melanoma Experimental/patología , Piper/química , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Chalconas/aislamiento & purificación , Chalconas/farmacología , Flavonoides/aislamiento & purificación , Flavonoides/farmacología , Ratones , Fenoles/aislamiento & purificación , Fenoles/farmacologíaRESUMEN
Amyloid beta (Abeta) is closely related to the onset of Alzheimer's disease (AD). To construct AD animal models, a bolus administration of a large dose of toxic Abeta into the cerebral ventricles of rodents has been performed in earlier studies. In parallel, a continuous infusion system via an osmotic pump into the cerebral ventricle has been developed to make a rat AD model. In this study, we developed a mouse AD model by repetitive administration of Abeta25-35 via a cannula implanted into the cerebral ventricle. Using this administration system, we reproducibly constructed a mouse with impaired spatial working memory. In accordance with the occurrence of the abnormal mouse behavior, we found that the number of choline acetyltransferase (ChAT)-positive neurons was reduced in paraventricular regions of brains of Abeta25-35-administered mice in a dose-dependent manner. Considering that the repetitive administration of a small dose of toxic Abeta via an implanted cannula leads to a brain status more resembling that of the AD patients than a bolus injection of a large dose of Abeta, and therapeutic as well as toxic agents are able to be repeatedly and reliably administered via an implanted cannula, we concluded that the implanted cannula-bearing AD mouse model is useful for development of new AD therapy.