RESUMEN
Both obesity and malnutrition leading to cachexia and sarcopenia are relevant risk factors in the development of many diseases. They also increase mortality, also prolong hospitalisations and convalescence, and undoubtedly increase the cost of treatment, mostly in the elderly populations. The aim of the study was to assess the relationship between the levels of leptin and adiponectin with regard to insulin resistance and malnutrition status by studying a senior female population and to evaluate predictors of insulin resistance and malnutrition. A total of 88 elderly females were enrolled prospectively with a median age of 75 years. Anthropometric and biochemical parameters (fasting glucose, insulin, folic acid, vitamin B12 concentrations, lipid profile, complete blood count) were recorded along with a full geriatric assessment, have been made in all participants. A comprehensive nutritional phenotype has been established. Leptin and adiponectin concentrations were measured by applying immunoassay techniques. Lipid profile and other parameters were performed by biochemical methods. We observed significant decreases of albumin, alanine aminotransferase, insulin, and triglycerides concentrations with age. The risk of insulin resistance based on HOMA-IR index was decreased with age. Significantly higher concentrations of leptin, leptin-to-adiponectin ratio (LAR), hsCRP, fasting glucose, insulin in the insulin resistant subgroup in respect of normal sensitivity insulin cases were noted. The concentrations of albumin, aspartate aminotransferase, alanine aminotransferase and total cholesterol were significantly lower in those patients at risk of malnutrition than in the well-nourished subjects. LAR reached the most accurate AUCROC = 0.705 for insulin resistance prediction, with a cut-off value at 3.85. The greatest diagnostic power was presented by the albumin concentration with AUCROC = 0.761 and then LAR 0.718 in discriminating between well-nourished patients and those at risk of malnutrition. We suggest that the leptin-to-adiponectin ratio is suitable as a marker of insulin resistance and nutritional status in the elderly.
Asunto(s)
Adiponectina/sangre , Evaluación Geriátrica/métodos , Resistencia a la Insulina/fisiología , Leptina/sangre , Estado Nutricional/fisiología , Vigilancia de la Población , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Estudios Transversales , Diabetes Mellitus/sangre , Diabetes Mellitus/diagnóstico , Femenino , Humanos , Valor Predictivo de las Pruebas , Estudios ProspectivosRESUMEN
The solution conformations of two potent antagonists of bradykinin (Arg1-Pro2-Pro3-Gly4-Phe5-Ser6-Pro7-Phe8-Arg9), [Aca(-1),DArg0,Hyp3,Thi5,DPhe7,(N-Bzl)Gly8]BK (1) and [Aaa(-1),DArg0,Hyp3,Thi5,(2-DNal)7,Thi8]BK (2), were studied by using 2D NMR spectroscopy in DMSO-d6 and molecular dynamics simulations. The NMR spectra of peptide 1 reveals the existence of at least two isomers arising from isomerization across the DPhe7-(N-Bzl)Gly8 peptide bond. The more populated isomer possesses the cis peptide bond at this position. The ratio of cis/trans isomers amounted to 7:3. With both antagonists, the NMR data indicate a beta-turn structure for the Hyp3-Gly4 residues. In addition, for peptide 2, position 2,3 is likely to be occupied by turn-like structures. The cis peptide bond between DPhe7 and (N-Bzl)Gly8 in analogue 1 suggests type VI beta-turn at position 7,8. The molecular dynamics runs were performed on both peptides in DMSO solution. The results indicate that the structure of peptide 1 is characterized by type VIb beta-turn comprising residues Ser6-Arg9 and the betaI or betaII-turn involving the Pro2-Thi5 fragment, whereas peptide 2 shows the tendency towards the formation of type I beta-turn at position 2,3. The structures of both antagonists are stabilized by a salt bridge between the guanidine moiety of Arg1 and the carboxyl group of Arg9. Moreover, the side chain of DArg0 is apart of the rest of molecule and is not involved in structural elements except for a few calculated structures.
Asunto(s)
Antagonistas de los Receptores de Bradiquinina , Bradiquinina/química , Fragmentos de Péptidos/química , Fragmentos de Péptidos/farmacología , Receptores de Bradiquinina/fisiología , Simulación por Computador , Humanos , Modelos Moleculares , Conformación Molecular , Resonancia Magnética Nuclear Biomolecular , Conformación Proteica , Relación Estructura-ActividadRESUMEN
Molecular docking simulations are now fast developing area of research. In this work we describe an effective procedure of preparation of the receptor-ligand complexes. The amino-acid residues involved in ligand binding were identified and described.
Asunto(s)
Ligandos , Receptores de Oxitocina/química , Receptores de Oxitocina/metabolismo , Receptores de Vasopresinas/química , Receptores de Vasopresinas/metabolismo , Aminoácidos/química , Fenómenos Biofísicos , Biofisica , Humanos , Modelos Moleculares , Unión Proteica , TemperaturaRESUMEN
The nonapeptide hormones arginine vasopressin (CYFQNCPRG-NH2, AVP) and oxytocin (CYIQNCPLG-NH2, OT), control many essential functions in mammals. Their main activities include the urine concentration (via stimulation of AVP V2 receptors, V2R, in the kidneys), blood pressure regulation (via stimulation of vascular V1a AVP receptors, V1aR), ACTH control (via stimulation of V1b receptors, V1bR, in the pituitary) and labor and lactation control (via stimulation of OT receptors, OTR, in the uterus and nipples, respectively). All four receptor subtypes belong to the GTP-binding (G) protein-coupled receptor (GPCR) family. This work consists of docking of YM087, a potent non-peptide V1aR and V2R - but not OTR - antagonist, into the receptor models based on relatively new theoretical templates of rhodopsin (RD) and opiate receptors, proposed by Mosberg et al. (Univ. of Michigan, Ann Arbor, USA). It is simultaneously demonstrated that this RD template satisfactorily compares with the first historical GPCR structure of bovine rhodopsin (Palczewski et al., 2000) and that homology-modeling of V2R, V1aR and OTR using opiate receptors as templates is rational, based on relatively high (20-60%) sequence homology among the set of 4 neurophyseal and 4 opiate receptors. YM087 was computer-docked to V1aR, V2R and OTR using the AutoDock (Olson et al., Scripps Research Institute, La Jolla, USA) and subsequently relaxed using restrained simulated annealing and molecular dynamics, as implemented in AMBER program (Kollman et al., University of California, San Francisco, USA). From about 80 diverse configurations, sampled for each of the three ligand/receptor systems, 3 best energy-relaxed complexes were selected for mutual comparisons. Similar docking modes were found for the YM087/V1aR and YM087/V2R complexes, diverse from those of the YM087/OTR complexes, in agreement with the molecular affinity data.
Asunto(s)
Antagonistas de los Receptores de Hormonas Antidiuréticas , Benzazepinas/química , Receptores de Oxitocina/antagonistas & inhibidores , Secuencia de Aminoácidos , Simulación por Computador , Diseño Asistido por Computadora , Diseño de Fármacos , Humanos , Técnicas In Vitro , Modelos Moleculares , Datos de Secuencia Molecular , Receptores de Oxitocina/química , Receptores de Oxitocina/genética , Receptores de Vasopresinas/química , Receptores de Vasopresinas/genética , Homología de Secuencia de AminoácidoRESUMEN
G protein-coupled receptors (GPCRs) transducing diverse external signals to cells via activation of heterotrimeric GTP-binding (G) proteins, estimated to mediate actions of 60% of drugs, had been resistant to structure determination until summer 2000. The first atomic-resolution experimental structure of a GPCR, that of dark (inactive) rhodopsin, thus provides a trustworthy 3D prototype for antagonist-bound forms of this huge family of proteins. In this work, our former theoretical GPCR models are evaluated against the new experimental template. Subsequently, a working hypothesis regarding the signal transduction mechanism by GPCRs is presented.
Asunto(s)
Receptores de Oxitocina/química , Rodopsina/química , Humanos , Ligandos , Modelos Moleculares , Unión Proteica , Estructura Terciaria de Proteína , Receptores de Superficie Celular/química , Receptores de Superficie Celular/metabolismo , Receptores de Vasopresinas/química , Transducción de SeñalRESUMEN
Introduction of the naphthylalanine residue into either position 3 of arginine vasopressin (AVP), or its analogs results in peptides with interesting pharmacological properties. The single substituted analog of AVP with L-2-Nal in position 3 causes moderate antiduretic activity, whereas [Mpa1, (L-1-Nal)3, (D-Arg)8] VP and [Mpa1, (L-2-Nal)3, (D-Arg)8] VP are potent and selective V2 agonists. Moreover [(L-2-Nal)3, (D-Arg)8] VP is among the most potent and selective antagonists of V1a receptors. In this study we carried out conformational calculations on [(L-1-Nal)3] AVP, [(L-2-Nal)3] AVP, [(L-1-Nal)3, (D-Arg)8] VP, [(L-2-Nal)3, (D-Arg)8] VP, [Mpa1, (L-1-Nal)3, (D-Arg)8] VP, [Mpa1, (L-2-Nal)3, (D-Arg)8] VP, using the ECEPP/3 force field with and without including hydration to simulate aqueous and nonpolar environments. It was found that in all six compound studied, the low-energy conformations have common geometry and relative energies. Therefore, the modifications of the Phe in position 3 influence the binding to the receptor by changing the size of the third residue, rather than by changing the conformational space. The lowest-energy conformations in the presence and absence of water had beta-turns at residues Phe3-Gln4 and Gln4-Asn5 and Gln4-Asn5, respectively. The conformation at the Gln4-Asn5 turn was most similar to the crystal structure of the pressinoic acid (the cyclic moiety of vasopressin).
Asunto(s)
Alanina/análogos & derivados , Alanina/química , Arginina Vasopresina/química , Amidas/química , Sitios de Unión , Hidrógeno/química , Modelos Químicos , Modelos Moleculares , Método de Montecarlo , Conformación Proteica , Relación Estructura-Actividad , Agua/metabolismoRESUMEN
St George's Respiratory Questionnaire (SGRQ) has been widely used in the assessment of health related quality of life (HRQOL) in patients with asthma and chronic obstructive pulmonary disease. Introduction of the new language version of the HRQOL questionnaire needs to be preceded by a highly structured process of validation. We aimed to validate the Polish version of SGRQ in the group of 83 patients with asthma. Following the comprehension study, we thus evaluated reliability, validity, reproducibility, responsiveness, and measurement equivalence of the Polish version of SGRQ. Disease severity and health status were also concurrently assessed. The reliability was good, with Cronbach's alpha coefficient exceeding 0.75 for global and all subscale scores. There have been highly significant correlations between spirometric parameters, intensity of symptoms, health status self-assessment, and the degree of depression, and quality of life scores. Reproducibility, stability and responsiveness were confirmed in the follow-up study. Minimal clinically important difference was found to be 5.3 points. Polish version of SGRQ was found to be psychometrically equivalent to four other versions of SGRQ, which underscores its validity in the population of Polish asthmatics.