Identification of bioactive peptides from a Brazilian kefir sample, and their anti-Alzheimer potential in Drosophila melanogaster.

Alzheimer's disease (AD) is the most common form of dementia in the elderly, affecting cognitive, intellectual, and motor functions. Different hypotheses explain AD's mechanism, such as the amyloidogenic hypothesis. Moreover, this disease is multifactorial, and several studies have shown that gut dysbiosis and oxidative stress influence its pathogenesis. Knowing that kefir is a probiotic used in therapies to restore dysbiosis and that the bioactive peptides present in it have antioxidant properties, we explored its biotechnological potential as a source of molecules capable of modulating the amyloidogenic pathway and reducing oxidative stress, contributing to the treatment of AD. For that, we used Drosophila melanogaster model for AD (AD-like flies). Identification of bioactive peptides in the kefir sample was made by proteomic and peptidomic analyses, followed by in vitro evaluation of antioxidant and acetylcholinesterase inhibition potential. Flies were treated and their motor performance, brain morphology, and oxidative stress evaluated. Finally, we performed molecular docking between the peptides found and the main pathology-related proteins in the flies. The results showed that the fraction with the higher peptide concentration was positive for the parameters evaluated. In conclusion, these results revealed these kefir peptide-rich fractions have therapeutic potential for AD.

10-hydroxy-2E-decenoic acid (10HDA) does not promote caste differentiation in Melipona scutellaris stingless bees.

In bees from genus Melipona, differential feeding is not enough to fully explain female polyphenism. In these bees, there is a hypothesis that in addition to the environmental component (food), a genetic component is also involved in caste differentiation. This mechanism has not yet been fully elucidated and may involve epigenetic and metabolic regulation. Here, we verified that the genes encoding histone deacetylases HDAC1 and HDAC4 and histone acetyltransferase KAT2A were expressed at all stages of Melipona scutellaris, with fluctuations between developmental stages and castes. In larvae, the HDAC genes showed the same profile of Juvenile Hormone titers-previous reported-whereas the HAT gene exhibited the opposite profile. We also investigated the larvae and larval food metabolomes, but we did not identify the putative queen-fate inducing compounds, geraniol and 10-hydroxy-2E-decenoic acid (10HDA). Finally, we demonstrated that the histone deacetylase inhibitor 10HDA-the major lipid component of royal jelly and hence a putative regulator of honeybee caste differentiation-was unable to promote differentiation in queens in Melipona scutellaris. Our results suggest that epigenetic and hormonal regulations may act synergistically to drive caste differentiation in Melipona and that 10HDA is not a caste-differentiation factor in Melipona scutellaris.

NOTCH1 is critical for fibroblast-mediated induction of cardiomyocyte specialization into ventricular conduction system-like cells in vitro.

Cardiac fibroblasts are present throughout the myocardium and are enriched in the microenvironment surrounding the ventricular conduction system (VCS). Several forms of arrhythmias are linked to VCS abnormalities, but it is still unclear whether VCS malformations are cardiomyocyte autonomous or could be linked to crosstalk between different cell types. We reasoned that fibroblasts influence cardiomyocyte specialization in VCS cells. We developed 2D and 3D culture models of neonatal rat cardiac cells to assess the influence of cardiac fibroblasts on cardiomyocytes. Cardiomyocytes adjacent to cardiac fibroblasts showed a two-fold increase in expression of VCS markers (NAV1.5 and CONTACTIN 2) and calcium transient duration, displaying a Purkinje-like profile. Fibroblast-conditioned media (fCM) was sufficient to activate VCS-related genes (Irx3, Scn5a, Connexin 40) and to induce action potential prolongation, a hallmark of Purkinge phenotype. fCM-mediated response seemed to be spatially-dependent as cardiomyocyte organoids treated with fCM had increased expression of connexin 40 and NAV1.5 primarily on its outer surface. Finally, NOTCH1 activation in both cardiomyocytes and fibroblasts was required for connexin 40 up-regulation (a proxy of VCS phenotype). Altogether, we provide evidence that cardiac fibroblasts influence cardiomyocyte specialization into VCS-like cells via NOTCH1 signaling in vitro.

Potential Biomarkers of the Turnover, Mineralization, and Volume Classification: Results Using NMR Metabolomics in Hemodialysis Patients.

Bone biopsy is still the gold standard to assess bone turnover (T), mineralization (M), and volume (V) in CKD patients, and serum biomarkers are not able to replace histomorphometry. Recently, metabolomics has emerged as a new technique that could allow for the identification of new biomarkers useful for disease diagnosis or for the understanding of pathophysiologic mechanisms, but it has never been assessed in the chronic kidney disease-mineral and bone disorder (CKD-MBD) scenario. In this study, we investigated the association between serum metabolites and the bone TMV classification in patients with end-stage renal disease by using serum NMR spectroscopy and bone biopsy of 49 hemodialysis patients from a single center in Brazil. High T was identified in 21 patients and was associated with higher levels of dimethylsulfone, glycine, citrate, and N-acetylornithine. The receiver-operating characteristic curve for the combination of PTH and these metabolites provided an area under the receiver-operating characteristic curve (AUC) of 0.86 (0.76 to 0.97). Abnormal M was identified in 30 patients and was associated with lower ethanol. The AUC for age, diabetes mellitus, and ethanol was 0.83 (0.71 to 0.96). Low V was identified in 17 patients and was associated with lower carnitine. The association of age, phosphate, and carnitine provided an AUC of 0.83 (0.70 to 0.96). Although differences among the curves by adding selected metabolites to traditional models were not statistically significant, the accuracy of the diagnosis according to the TMV classification seemed to be improved. This is the first study to evaluate the TMV classification system in relation to the serum metabolome assessed by NMR spectroscopy, showing that selected metabolites may help in the evaluation of bone phenotypes in CKD-MBD. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Myosin Sequestration Regulates Sarcomere Function, Cardiomyocyte Energetics, and Metabolism, Informing the Pathogenesis of Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is caused by pathogenic variants in sarcomere protein genes that evoke hypercontractility, poor relaxation, and increased energy consumption by the heart and increased patient risks for arrhythmias and heart failure. Recent studies show that pathogenic missense variants in myosin, the molecular motor of the sarcomere, are clustered in residues that participate in dynamic conformational states of sarcomere proteins. We hypothesized that these conformations are essential to adapt contractile output for energy conservation and that pathophysiology of HCM results from destabilization of these conformations. METHODS: We assayed myosin ATP binding to define the proportion of myosins in the super relaxed state (SRX) conformation or the disordered relaxed state (DRX) conformation in healthy rodent and human hearts, at baseline and in response to reduced hemodynamic demands of hibernation or pathogenic HCM variants. To determine the relationships between myosin conformations, sarcomere function, and cell biology, we assessed contractility, relaxation, and cardiomyocyte morphology and metabolism, with and without an allosteric modulator of myosin ATPase activity. We then tested whether the positions of myosin variants of unknown clinical significance that were identified in patients with HCM, predicted functional consequences and associations with heart failure and arrhythmias. RESULTS: Myosins undergo physiological shifts between the SRX conformation that maximizes energy conservation and the DRX conformation that enables cross-bridge formation with greater ATP consumption. Systemic hemodynamic requirements, pharmacological modulators of myosin, and pathogenic myosin missense mutations influenced the proportions of these conformations. Hibernation increased the proportion of myosins in the SRX conformation, whereas pathogenic variants destabilized these and increased the proportion of myosins in the DRX conformation, which enhanced cardiomyocyte contractility, but impaired relaxation and evoked hypertrophic remodeling with increased energetic stress. Using structural locations to stratify variants of unknown clinical significance, we showed that the variants that destabilized myosin conformations were associated with higher rates of heart failure and arrhythmias in patients with HCM. CONCLUSIONS: Myosin conformations establish work-energy equipoise that is essential for life-long cellular homeostasis and heart function. Destabilization of myosin energy-conserving states promotes contractile abnormalities, morphological and metabolic remodeling, and adverse clinical outcomes in patients with HCM. Therapeutic restabilization corrects cellular contractile and metabolic phenotypes and may limit these adverse clinical outcomes in patients with HCM.

The chronic effects of muscle-resistance training in arterial pressure of hypertensive older adults: a meta-analysis / Os efeitos crônicos do treinamento de resistência muscular na pressão arterial de idosos hipertensos: uma metanálise / Los efectos crónicos del entrenamiento de resistencia muscular en la presión arterial de los ancianos hipertensos: una metanálisis

Abstract Introduction: Little research has been done on the effects of muscle-resistance training (RT) in hypertensive older adults. Objective: The aim of this meta-analysis was to verify the efficacy of RT, on a chronic basis, on the systolic (SBP) and diastolic blood pressure (DBP) of hypertensive older adults. Method: Several literature databases were explored to find studies on controlled and randomized trials that evaluated the effects of RT in hypertensive older adults for more than 10 weeks. Profile of the participants, sample size, intervention protocol, and results of SBP and DBP were analyzed. The PEDro scale and the Cochrane tool were used to analyze the methodological quality of the studies and the risk of bias, respectively. The RevMan5.3 program was used to analyze the results on the SBP and DBP after the RT intervention and in the control groups. Results: The meta-analysis of five studies considering 96 hypertensive individuals who underwent RT and 104 hypertensive control subjects showed that the regular practice of RT from 12 to 16 weeks, three times a week, with three sets from 8 to 12 repetitions at an intensity of 60% to 80% of one-repetition maximum (1-RM), significantly reduced SBP by 7.26 mmHg (95%CI = -9.16 - 5.37) and DBP by 4.84 mmHg (95%CI = -5.89 - 3.79). Conclusion: The muscle-resistance training was effective in reducing, chronically, the blood pressure of hypertensive older adults. It can also decrease the need for medication inherent to hypertension.

Resumo Introdução: Pouca pesquisa foi realizada sobre os efeitos do treinamento de resistência muscular (TR) em adultos idosos hipertensos. Objetivo: O objetivo da presente metanálise foi verificar a eficácia da TR, de forma crônica, na pressão arterial sistólica (PAS) e diastólica (PAD) de idosos com hipertensão controlada. Método: Várias bases de dados da literatura foram exploradas para encontrar estudos que examinaram ensaios clínicos controlados e randomizados que avaliaram os efeitos do TR em idosos hipertensos por um período de mais de 10 semanas. Foi analisado o perfil dos participantes, o tamanho da amostra, o protocolo de intervenção e os resultados da PAS e PAD. A Escala PEDro e a ferramenta Cochrane foram utilizadas para analisar a qualidade metodológica dos estudos e o risco de viés, respectivamente. O programa RevMan5.3 foi usado para analisar os resultados na PAS e PAD após a intervenção TR e nos grupos de controle. Resultados: A metanálise de cinco estudos incluiu que, considerando os 96 indivíduos hipertensos submetidos à TR e 104 sujeitos de controle hipertensos, a prática regular de TR por 12 a 16 semanas, três vezes por semana, com três séries de 8 a 12 repetições em uma intensidade de 60% a 80% do teste de uma repetição máxima (1-RM), reduziram significativamente a PAS em 7,26 mmHg (IC 95% = -9,16 - 5,37) e PAD por 4,84 mmHg (IC 95% = -5,89 - 3,79). Conclusão: O treinamento resistido muscular foi eficaz na redução crônica da pressão arterial de idosos hipertensos controlados, podendo diminuir a necessidade de medicação anti-hipertensiva. Estes resultados implicam uma maior sobrevivência para esta população, bem como uma possível diminuição da necessidade de medicamentos inerentes à hipertensão.

Resumen Introducción: Poca investigación se realizó sobre los efectos del entrenamiento de resistencia muscular (ER) en adultos mayores hipertensos. Objectivo: El objetivo del presente metanálisis fue verificar la eficacia del ET, de forma crónica, en la presión arterial sistólica (PAS) y diastólica (PAD) de ancianos con hipertensión controlada. Método: Varias bases de datos de la literatura se exploraron para encontrar estudios que examinaron ensayos clínicos controlados y aleatorizados que evaluaron los efectos del ER en ancianos hipertensos por un período de más de 10 semanas. Se analizó el perfil de los participantes, el tamaño de la muestra, el protocolo de intervención y los resultados de la PAS y PAD. La Escala PEDro y la herramienta Cochrane se utilizaron para analizar la calidad metodológica de los estudios y el riesgo de sesgos, respectivamente. El programa RevMan5.3 fue utilizado para analizar los resultados en la PAS y PAD después de la intervención ER y en los grupos de control. Resultados: El metanálisis de cinco estudios incluyó que, considerando los 96 individuos hipertensos sometidos a ET y 104 sujetos de control hipertensos, la práctica regular de ET por 12 a 16 semanas, tres veces por semana, con tres series de 8 a 12 repeticiones en una intensidad del 60% al 80% de una repetición máxima (1-RM), redujo significativamente la PAS en 7,26 mmHg (IC 95% = -9,16 - 5,37) y DBP por 4,84 mmHg (IC 95% = -5,89 - 3,79). Conclusión: El entrenamiento resistido muscular fue eficaz en la reducción de la presión arterial de ancianos hipertensos controlados, crónicamente, y puede disminuir la necesidad de medicación antihipertensiva.

Dipeptidyl peptidase IV inhibition upregulates GLUT4 translocation and expression in heart and skeletal muscle of spontaneously hypertensive rats.

The purpose of the current study was to test the hypothesis that the dipeptidyl peptidase IV (DPPIV) inhibitor sitagliptin, which exerts anti-hyperglycemic and anti-hypertensive effects, upregulates GLUT4 translocation, protein levels, and/or mRNA expression in heart and skeletal muscle of spontaneously hypertensive rats (SHRs). Ten days of treatment with sitagliptin (40 mg/kg twice daily) decreased plasma DPPIV activity in both young (Y, 5-week-old) and adult (A, 20-week-old) SHRs to similar extents (~85%). However, DPPIV inhibition only lowered blood pressure in Y-SHRs (119 ± 3 vs. 136 ± 4 mmHg). GLUT4 translocation, total protein levels and mRNA expression were decreased in the heart, soleus and gastrocnemius muscle of SHRs compared to age-matched Wistar Kyoto (WKY) normotensive rats. These differences were much more pronounced between A-SHRs and A-WKY rats than between Y-SHRs and Y-WKY rats. In Y-SHRs, sitagliptin normalized GLUT4 expression in the heart, soleus and gastrocnemius. In A-SHRs, sitagliptin increased GLUT4 expression to levels that were even higher than those of A-WKY rats. Sitagliptin enhanced the circulating levels of the DPPIV substrate glucagon-like peptide-1 (GLP-1) in SHRs. In addition, stimulation of the GLP-1 receptor in cardiomyocytes isolated from SHRs increased the protein level of GLUT4 by 154 ± 13%. Collectively, these results indicate that DPPIV inhibition upregulates GLUT4 in heart and skeletal muscle of SHRs. The underlying mechanism of sitagliptin-induced upregulation of GLUT4 in SHRs may be, at least partially, attributed to GLP-1.

Efeito de diferentes frequências semanais de treinamento físico geral sobre a flexibilidade de mulheres de meia idade / Effect of different weekly amount of general physical training on flexibility in middle-aged women

O objetivo do presente estudo foi verificar a influência de um programa de 15 meses de exercício aeróbio, localizado e de alongamento, com diferentes frequências semanais sobre a flexibilidade em mulheres de meia idade. Participaram do estudo 107 mulheres, divididas aleatoriamente em três grupos, Grupo 1 (n=36, G1: 50,8 ± 12,5 anos) que treinou três vezes por semana; Grupo 2 (n=36, G2: 51,0 ± 14,0 anos) que treinou duas vezes por semana; Grupo Controle (GC: n=35, 52,1 ± 13,4 anos) que não foi submetido a qualquer treinamento. Durante 15 meses, os GE?? (1 e 2) foram submetidos a um programa de treinamento com exercícios localizados, aeróbio e flexibilidade com 60 minutos de duração. Foram realizadas avaliações a cada três meses para avaliar a progressão dos avaliados. Foi verificado que tanto o G1 quanto o G2 apresentaram melhoras nos valores da flexibilidade (teste de sentar e alcançar), no entanto, a partir da avaliação "1", até o pós teste, o G1 apresentou melhores resultados (20,16 ± 8,06; 23,61 ± 7,75; 25,22 ± 7,19; 26,76 ± 7,37; 27,71 ± 7,24; 29,47 ± 7,13) em relação ao G2 (17,69 ± 10,06; 18,58 ± 9,19; 19,44 ± 8,94; 20,67 ± 8,20; 21,17 ± 8,26; 23,17 ± 8,35). Conclui-se que os exercícios físicos combinados, realizados duas ou três vezes na semana, tendem a melhorar os níveis de flexibilidade e que são obtidos valores mais satisfatórios quando há volumes maiores de treinamento.

The objective of this study was to evaluate the influence of a 15-month program based on aerobic, stretching, and localized exercises at different weekly amounts on the flexibility of middle-aged women. The study included 107 women randomly divided into three groups: Group 1 (n = 36, G1: 50.8 ± 12.5 years) trained three times a week; Group 2 (n = 36, G2: 51.0 ± 14.0 years) trained twice a week; and the control group (CG: n = 35, 52.1 ± 13.4 years) did not practice any exercise. During 15 months, G1 and G2 underwent a training program including aerobic, stretching, and localized exercises for 60 minutes. Participants were assessed every three months to check their progression. We found that both G1 and G2 showed improvement in flexibility (sit and reach test). However, from assessment "1" to post-test, G1 showed better results (20.16 ± 8.06; 23.61 ± 7.75; 25.22 ± 7.19; 26.76 ± 7.37; 27.71 ± 7.24; 29.47 ± 7.13) compared with G2 (17.69 ± 10.06; 18.58 ± 9.19; 19.44 ± 8.94; 20.67 ± 8.20; 21.17 ± 8.26; 23.17 ± 8.35). We concluded that practicing combined physical exercises two or three times a week tend to improve the levels of flexibility and that more satisfactory values are achieved when the amount of training is larger.

Influência dos exercícios aeróbio e resistido sobre perfil hemodinâmico e lipídico em idosas hipertensas / Influence of aerobic exercise and resistance training on hemodynamic and lipid profile in hypertensive elderly

O envelhecimento é um processo caracterizado pela diminuição das funções fisiológicas e de todas as capacidades físicas. O objetivo do presente estudo foi verificar o efeito do exercício aeróbio e resistido sobre parâmetros hemodinâmicos, antropométricos e lipídicos de mulheres idosas hipertensas. Participaram do estudo 25 mulheres no grupo experimental (GE) (74,44 ± 6,3 anos) e 12 mulheres no grupo controle (GC) (75,25 ± 6,8 anos). O GE participou de sessões 60 minutos de exercícios físicos combinados com intensidade moderada que contemplaram alongamentos, exercícios localizados e caminhada, enquanto o GC manteve seus hábitos normais. Ao contrário do GC todas as variáveis analisadas no GE sofreram alterações significativa de (p<0,05) nos três momentos de intervenção, FCrep (85,0 ± 11,4 bpm; 80,1 ± 10,3 bpm; 79,4 ± 9,9 bpm), PAS (157,6 ± 13,9 mmHg; 142,8 ± 10,6 mmHg; 132,8 ± 8,4 mmHg), PAD (92,4 ± 7,2 mmHg; 88,0 ± 5,0 mmHg; 82,0 ± 4,1 mmHg), glicemia (110,2 ± 16,4 ml/dl; 101,3 ± 12,8 ml/dl; 95,3 ± 10,4 ml/dl), triglicerídeos (205,6 ± 37,7 ml/dl; 184,2 ± 32,5 ml/dl; 170,4 ± 29,2 ml/dl), colesterol total (223,2 ± 27,8 ml/dl; 205,3 ± 24,1 ml/dl; 196,4 ± 22,3 ml/dl), HDL (43,1 ± 1,5 ml/dl; 44,3 ± 1,5 ml/dl; 44,8 ± 1,4 ml/dl), VLDL (28,3 ± 3,2 ml/dl; 26,2 ± 2,5 ml/dl; 25,4 ± 2,2 ml/dl), LDL (151,8 ± 26,3 ml/dl; 134,9 ± 23,3 ml/dl; 126,2 ± 21,2 ml/dl). Concluiu-se que os exercícios físicos combinados foram eficientes nas melhorias das variáveis hemodinâmicas, antropométricas e lipídicas em idosas hipertensas.

Aging is a process characterized by decreased function physiological and all physical abilities. The purpose of this study was to assess the effect of aerobic exercise and resistance training on hemodynamic parameters, anthropometric and lipid in elderly hypertensive women. Participated in this study 25 women in experimental group (GE) (74,44 ± 6,3 years) and 12 women in control group (CG) (75,25 ± 6,8 years). GE participated in physical exercise sessions that included the combined practice of stretching, localized exercises and walking while CG remained normal daily habits. Unlike the CG all variables in the EG had significant changes in three moments of intervention, HRrest (85,0 ± 11,4 bpm; 80,1 ± 10,3 bpm; 79,4 ± 9,9 bpm), SBP (157,6 ± 13,9 mmHg; 142,8 ± 10,6 mmHg; 132,8 ± 8,4 mmHg), DBP (92,4 ± 7,2 mmHg; 88,0 ± 5,0 mmHg; 82,0 ± 4,1 mmHg), glucose (110,2 ± 16,4 ml/dl; 101,3 ± 12,8 ml/dl; 95,3 ± 10,4 ml/dl), triglycerides (205,6 ± 37,7 ml/dl; 184,2 ± 32,5 ml/dl; 170,4 ± 29,2 ml/dl), total cholesterol (223,2 ± 27,8 ml/dl; 205,3 ± 24,1 ml/dl; 196,4 ± 22,3 ml/dl), HDL (43,1 ± 1,5 ml/dl; 44,3 ± 1,5 ml/dl; 44,8 ± 1,4 ml/dl), VLDL (28,3 ± 3,2 ml/dl; 26,2 ± 2,5 ml/dl; 25,4 ± 2,2 ml/dl), LDL (151,8 ± 26,3 ml/dl; 134,9 ± 23,3 ml/dl; 126,2 ± 21,2 ml/dl). We concluded that exercise combination were effective in improvement of hemodynamic, anthropometric and lipid levels in elderly hypertensive.

Estructura de la demanda de un servicio de urgencia en situación de catástrofe / Estructure of the demand of an emergency service in disasters situation

Se presentan las variaciones ocurridas en la estructura de la demanda del servicio de urgencia de un hospital general de la Región Metropolitana, en el día de ocurrencia y siguientes al sismo de marzo de 1985. En la comparación con igual período del año anterior 1984, se evidencian diferencias en los grupos de patologías en cuyo origen tiene influencia el stress, tales como son los trastornos neurofuncionales, el síndrome anginosos, la hemorragia digestiva alta y el asma bronquial, siendo estas diferencias estadísticamente significativas. A la inversa las patologías de consulta habitual en un servicio de urgencia, y cuya frecuencia o agravación no tienen relación con el stress, no experimentaron variación significativa a raíz del terremoto comparadas con su ocurrencia en fecha similar del año anterior. Se analizan también las variaciones de las patologías relacionadas al stress en términos de sexo y edad, destacándose el predominio de consultantes mujeres afectadas por trastornos neurofuncionales y neurológicos. Se señalan la importancia de la información obtenida en la administración de los recursos de atención de salud en situaciones de emergencia como la en referencia y la posibilidad de preparar equipos profesionales para afrontar las exigencias particulares de la demanda en casos de catástrofes

Medicina tradicional como fuente de resolución de problemas de salud infantil: perspectiva para el autocuidad de la salud

Se presentan los resultados de las encuestas a 133 madres que consultaron en Consultorio sobre la utilización de la medicina tradicional como forma de resolución de problemas de salud infantil: un 71,0% de las madres utilizaba el Sistema Formal y la Medicina Tradicional; un 20,6% sólo el Sistema Formal y un 8,4% de preferencia la Medicina Tradicional. Los principales problemas de salud que llevaron a consultar a la medicina tradicional, correspondieron a patología respiratoria (71,3%) y digestiva (46,2%) y al signo de fiebre 34,0%. Se reseña la forma de resolución del problema de salud por medicina tradicional, correspondiendo: a resolución por las propias madres en el hogar en un 61,3%; consulta a profesional no médico 36,8% y consulta a familiar 32,1%. Las principales motivaciones que llevan a consultar a la medicina tradicional corresponden a "falta de número" 41,5%, "falta de explicación de enfermedad y desinterés del médico" 27%, como a "una atención" más rápida en el Sistema Informal", 43,4% y a que las enfermedades graves sanan solas, 37,7%