RESUMO
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.
Assuntos
Deficiência de Ácido Ascórbico/patologia , Dieta/efeitos adversos , Regulação da Expressão Gênica/fisiologia , Membro Posterior/patologia , Fibras Musculares Esqueléticas/fisiologia , Junção Neuromuscular/fisiopatologia , Fatores Etários , Animais , Deficiência de Ácido Ascórbico/sangue , Deficiência de Ácido Ascórbico/etiologia , Deficiência de Ácido Ascórbico/metabolismo , Cálcio/metabolismo , Modelos Animais de Doenças , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Locomoção , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Força Muscular , Hormônio Paratireóideo/sangue , Fósforo/sangue , Equilíbrio Postural , Desempenho Psicomotor , Vitamina D/metabolismoRESUMO
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.
RESUMO
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.
Assuntos
Benzopiranos/síntese química , Antagonistas de Estrogênios/síntese química , Fogachos/tratamento farmacológico , Naftalenos/síntese química , Moduladores Seletivos de Receptor Estrogênico/síntese química , Adenocarcinoma , Animais , Anticolesterolemiantes/síntese química , Anticolesterolemiantes/química , Anticolesterolemiantes/farmacologia , Benzopiranos/química , Benzopiranos/farmacologia , Densidade Óssea/efeitos dos fármacos , Neoplasias da Mama , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colesterol/sangue , Antagonistas de Estrogênios/química , Antagonistas de Estrogênios/farmacologia , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Feminino , Humanos , Morfina/farmacologia , Naftalenos/química , Naftalenos/farmacologia , Ovariectomia , Ratos , Ratos Sprague-Dawley , Moduladores Seletivos de Receptor Estrogênico/química , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Estereoisomerismo , Neoplasias Uterinas , Útero/efeitos dos fármacos , Útero/crescimento & desenvolvimentoRESUMO
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.
