RESUMO
In recent years, more and more attention of researchers has been paid to the study of dilated cardiomyopathy (DCMP). The prevalence of this disease in older age groups is higher than previously thought, and the course of the disease is associated with a worse prognosis and treatment difficulties. Researchers are considering various signaling molecules whose expression changes are associated with myocardial damage and the development of DCMP; evaluation of changes in the expression of melatonin and its receptors in DCMP requires further study. The aim of the study was to study the age-related features of the expression of melatonin and its receptors (MT1, MT2) in the myocardium and their changes depending on the presence of dilated cardiomyopathy. Immunocytochemical and immunohistochemical methods were used to evaluate the expression of melatonin and its MT1, MT2 receptors in myocardial autopsy material and cardiomyocyte cultures of people of different ages with and without cardiovascular pathology. The study revealed age-associated changes in the form of a decrease in the expression of melatonin and its MT1 and MT2 receptors in the myocardium. In individuals with DCMP of all age groups, a more significant decrease in expression was noted: melatonin by 1,6-1,7 times in old age and 3,2 times in old age; MT1 by 1,8 and 2 times, respectively; MT2 by 1,4 and 4 times, respectively. The relationship between the decrease in the expression of melatonin and its receptors in myocardial tissues with age and the presence of DCMP was revealed. The data obtained allow us to clarify age-dependent changes in melatonin and its receptors, as well as to assume their important role in the development of DCMP, which requires further study.
Assuntos
Cardiomiopatia Dilatada , Melatonina , Humanos , Idoso , Melatonina/metabolismo , Cardiomiopatia Dilatada/diagnóstico , Desoxicitidina Monofosfato , Receptor MT1 de Melatonina/metabolismo , Miocárdio/metabolismo , Receptor MT2 de Melatonina/metabolismoRESUMO
The aim of this work was to study the ability of some estrogen 8α-analogues, that have CH3-group in the C-3 position, exhibit osteoprotective and cholesterolemic effects. The properties of these analogues was comparisoned with effects of native estradiol and 17α-ethynylestradiol (EE). We showed that compounds 3 ((d,l)-17ß-acethoxy-3-methoxy-8α-estra-1,3,5(10)-triene) and 4 ((d,l)-3-methoxy-8α-estra-1,3,5(10)-triene-17-one) had the same osteoprotective and cholesterolemic effects as EE. The utherotropic effects of compound 3 and EE were the same, while the utherotropic activity of 17-keto derivative (compound 4) was higher than effect of EE. The osteoprotective and cholesterolemic effects of compounds 5 and 6 (d- or l-17ß-acethoxy-3-methoxy-13-ethyl-8α-gone-1,3,5(10)-triene) were approximately the same, however the utherotropic action of these compounds was different: the compound 5 had significantly lower activity, but the compound 6 had the same effect in comparison with EE. Thus, all studied estrogen 8α-analogues may be used as basic constructions for structural modifications which is necessary as medications with while spectrum of biological properties.
Assuntos
Congêneres do Estradiol , Hipercolesterolemia/tratamento farmacológico , Hipolipemiantes , Osteoporose/tratamento farmacológico , Animais , Congêneres do Estradiol/síntese química , Congêneres do Estradiol/química , Congêneres do Estradiol/farmacologia , Feminino , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patologia , Hipolipemiantes/síntese química , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Osteoporose/metabolismo , Osteoporose/patologia , Ratos , Ratos Sprague-DawleyRESUMO
A total synthesis of 8alpha analogues of steroid estrogens with fluorine in position 2 was achieved. Structural features of these compounds were studied by the example of 17beta-acetoxy-2-fluoro-3-methoxy-8alpha-estra-1,3,5(10)-triene. It was shown that the 8alpha analogues of 2-fluorosubstituted steroid estrogens have a low uterotropic activity and retain the osteoprotective and hypocholesterolemic activities.
Assuntos
Estrenos/síntese química , Estrogênios/síntese química , Flúor , Animais , Anticolesterolemiantes/síntese química , Anticolesterolemiantes/química , Anticolesterolemiantes/farmacologia , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/síntese química , Conservadores da Densidade Óssea/química , Conservadores da Densidade Óssea/farmacologia , Colesterol/sangue , Estrenos/química , Estrenos/farmacologia , Estrogênios/química , Estrogênios/farmacologia , Feminino , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Útero/efeitos dos fármacosRESUMO
All the signals in the 1H and 13C NMR spectra of some analogues of 7alpha-methyl-8alpha- and 6-oxa-8alpha-steroid estrogens were completely assigned. Considering the values of nuclear Overhauser effect and vicinal coupling constants, these steroids were shown to exhibit a fast, on the NMR time scale, conformational equilibrium arising due to the inversion of ring B. The conformer populations were obtained from a comparison of the experimental and theoretical values of the dihedral angles and the interproton distances. This conformational equilibrium was shown to depend on the nature of atom in position 6: for the 7alpha-methyl-6-oxa-8alpha analogues of the steroid estrogens, the population of the conformer with the pseudoaxial orientation of the 7alpha-methyl group was observed to be decreased compared with the 7alpha-methyl-8alpha analogue.
Assuntos
Estrogênios/química , Esteroides/química , Espectroscopia de Ressonância Magnética , Conformação Molecular , SoluçõesRESUMO
Modifications of 6-oxa-D-homo-8alpha-analogues of steroid estrogens were found to lead to a complete loss of the uterotropic and hypertriglyceridemic activities. These compounds may be promising for the design on their basis of inhibitors of the steroid hormone metabolism and transporters of other compounds to the estrogen target organs.