RESUMEN
The triterpenes, alpha-amyrin (AA) and its palmitate (AAP) and linoleate esters (AAL), were tested on models of inflammatory and destructive arthritic processes and their effects were compared with the clinical antiarthritic drugs indomethacin (IN) and methotrexate (MTX). The triterpenes had no effect on the prostaglandin phase of carrageenin pedal edema in rats, which was reduced 28% by 100 microM IN. AAL caused a considerable reduction in the synthesis by human neutrophils of 5-lipoxygenase products--5-HETE (IC50 = 70 microM), LTB4, (62 microM), isomer I (30 microM) and isomer II (24 microM). Rat osteosarcoma cell growth was inhibited by all triterpenes with IC50's (microM) of < 10 (AAP), 14 (AA) and 27 (AAL) and were more effective than IN (35). MTX caused 100% inhibition at a concentration of 10 microM compared with 64% inhibition by AAP. Tadpole collagenase digestion of type I (bone) native collagen was completely inhibited by all the triterpenes as well as IN and MTX at 100 microM. The results indicate that the principal point of antiarthritic intervention by amyrin triterpenes lies in their local inhibition of joint destruction.
Asunto(s)
Artritis Experimental/tratamiento farmacológico , Triterpenos/farmacología , Animales , Artritis Experimental/metabolismo , División Celular/efectos de los fármacos , Colagenasas/efectos de los fármacos , Ésteres/farmacología , Femenino , Humanos , Ácidos Hidroxieicosatetraenoicos/biosíntesis , Indometacina/farmacología , Leucotrieno B4/biosíntesis , Metotrexato/farmacología , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Ácido Oleanólico/análogos & derivados , Ratas , Ratas Wistar , Células Tumorales CultivadasRESUMEN
The major component of the amyloid deposition that characterizes Alzheimer's disease is the 4-kDa beta A4 protein, which is derived from a much larger amyloid protein precursor (APP). A procedure for the complete purification of APP from human brain is described. The same amino terminal sequence of APP was found in two patients with Alzheimer's disease and one control subject. Two major forms of APP were identified in human brain with apparent molecular masses of 100-110 kDa and 120-130 kDa. Soluble and membrane fractions of brain contained nearly equal amounts of APP in both humans and rats. Immunoprecipitation with carboxyl terminus-directed antibodies indicates that the soluble forms of APP are truncated. Carboxyl terminus truncation of membrane-associated forms of human brain APP was also found to occur during postmortem autolysis. The availability of purified human brain APP will facilitate the investigation of its normal function and the events that lead to its abnormal cleavage in patients with Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Encéfalo/metabolismo , Anciano , Anciano de 80 o más Años , Precursor de Proteína beta-Amiloide/química , Precursor de Proteína beta-Amiloide/aislamiento & purificación , Femenino , Humanos , Solubilidad , Fracciones Subcelulares/metabolismo , Distribución TisularRESUMEN
A screening method is described for urinary 3-methoxy-4-hydroxy mandelic acid using an initial ion exchange procedure, vanillin formation and extraction into toluene. The technique, is simple, rapid and specific, with a reference value up to 35 mumol (7.0 mg)/day established on 92 normal human subjects. Over 200 patients' urines were analysed by the method of which 18 gave values above the reference range. The majority of these increased excretions are attributed to the metabolic effects of drugs, one patient suffered from phaeochromocytoma and only 2 results remaining unexplained.