RESUMEN
INTRODUCTION: There is evidence that supports a role for Vitamin D (Vit. D) in muscle. The exact mechanism by which Vit. D deficiency impairs muscle strength and function is not clear. METHODS: Three-week-old mice were fed diets with varied combinations of Vit. D and Ca2+ deficiency. Behavioral testing, genomic and protein analysis, and muscle histology were performed with a focus on neuromuscular junction (NMJ) -related genes. RESULTS: Vit. D and Ca2+ deficient mice performed more poorly on given behavioral tasks than animals with Vit. D deficiency alone. Genomic and protein analysis of the soleus and tibialis anterior muscles revealed changes in several Vit. D metabolic, NMJ-related, and protein chaperoning and refolding genes. CONCLUSIONS: These data suggest that detrimental effects of a Vit. D deficient or a Vit. D and Ca2+ deficient diet may be a result of differential alterations in the structure and function of the NMJ and a lack of a sustained stress response in muscles. Muscle Nerve 54: 1120-1132, 2016.
Asunto(s)
Deficiencia de Ácido Ascórbico/patología , Dieta/efectos adversos , Regulación de la Expresión Génica/fisiología , Miembro Posterior/patología , Fibras Musculares Esqueléticas/fisiología , Unión Neuromuscular/fisiopatología , Factores de Edad , Animales , Deficiencia de Ácido Ascórbico/sangre , Deficiencia de Ácido Ascórbico/etiología , Deficiencia de Ácido Ascórbico/metabolismo , Calcio/metabolismo , Modelos Animales de Enfermedad , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Locomoción , Masculino , Ratones , Ratones Endogámicos C57BL , Fuerza Muscular , Hormona Paratiroidea/sangre , Fósforo/sangre , Equilibrio Postural , Desempeño Psicomotor , Vitamina D/metabolismoRESUMEN
A selective estrogen receptor modulator (SERM) for the potential treatment of hot flushes is described. (R)-(+)-7,9-difluoro-5-[4-(2-piperidin-1-ylethoxy)phenyl]-5H-6-oxachrysen-2-ol, LSN2120310, potently binds ERalpha and ERbeta and is an antagonist in MCF-7 breast adenocarcinoma and Ishikawa uterine cancer cell lines. The compound is a potent estrogen antagonist in the rat uterus. In ovariectomized rats, the compound lowers cholesterol, maintains bone mineral density, and is efficacious in a morphine dependent rat model of hot flush efficacy.
Asunto(s)
Benzopiranos/síntesis química , Antagonistas de Estrógenos/síntesis química , Sofocos/tratamiento farmacológico , Naftalenos/síntesis química , Moduladores Selectivos de los Receptores de Estrógeno/síntesis química , Adenocarcinoma , Animales , Anticolesterolemiantes/síntesis química , Anticolesterolemiantes/química , Anticolesterolemiantes/farmacología , Benzopiranos/química , Benzopiranos/farmacología , Densidad Ósea/efectos de los fármacos , Neoplasias de la Mama , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Colesterol/sangre , Antagonistas de Estrógenos/química , Antagonistas de Estrógenos/farmacología , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/metabolismo , Femenino , Humanos , Morfina/farmacología , Naftalenos/química , Naftalenos/farmacología , Ovariectomía , Ratas , Ratas Sprague-Dawley , Moduladores Selectivos de los Receptores de Estrógeno/química , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Estereoisomerismo , Neoplasias Uterinas , Útero/efectos de los fármacos , Útero/crecimiento & desarrolloRESUMEN
We report the synthesis and characterization of novel 3-aryl indoles as potent and efficacious progesterone receptor (PR) antagonists with potential for the treatment of uterine fibroids. These compounds demonstrated excellent selectivity over other steroid nuclear hormone receptors such as the mineralocorticoid receptor (MR). They were prepared from 2-bromo-6-nitro indole in four to six steps using a Suzuki cross-coupling as the key step. Compound 8f was orally active in the complement 3 model of progesterone antagonism in the rat uterus and demonstrated partial antagonism in the McPhail model of progesterone activity.
RESUMEN
For selective estrogen receptor modulators (SERMs), the orientation of the basic side chain relative to the SERM core has a significant impact on function. The synthesis and biological evaluation of two series of SERMs are disclosed, where the ligand side chain is constrained to adopt a defined orientation. Compounds where the side chain is forced into the plane of the SERM core have a different profile compared to those compounds where the side chain is pseudo-orthogonal, particularly with regard to antagonism of estradiol action on an Ishikawa uterine cell line.