Physical Activity as a Preventive Lifestyle Intervention Acts Through Specific Exosomal miRNA Species-Evidence From Human Short- and Long-Term Pilot Studies

Exercise initiates systemic adaptation to promote health and prevent various lifestyle-related chronic diseases. Emerging evidence suggests that circulating exosomes mediate some of the beneficial effects of exercise via the transfer of microRNAs between tissues. Yet to date, a comprehensive profile of the exosomal miRNA (exomiR) content released following short-term (0.5 year in this study) and long-term (25 + years in this study) regular bouts of exercise is still lacking. However, a better understanding of these miRNA species would assist in clarifying the role of regular exercise at the molecular level in the prevention of chronic diseases. In the present pilot studies we analyzed serum exomiR expression in healthy young, sedentary participants (n = 14; age: 23 ± 2 years) at baseline and following a half year-long moderate-intensity regular exercise training. We also analyzed serum exomiR expression in older, healthy trained participants (seniors, n = 11; age: 62 ± 6 years) who engaged in endurance activities for at least 25 years. Following the isolation and enrichment of serum exosomes using Total Exosome Isolation Reagent (TEI) their exomiR levels were determined using the amplification-free Nanostring platform. Hierarchical cluster analysis revealed that the majority of exomiRs overlap for short-term (0.5 year in this study) and long-term (25 + years in this study) regular bouts of exercise. The top 12 significantly altered exomiRs (let-7a-5p; let-7g-5p; miR-130a-3p; miR-142-3p; miR-150-5p; miR-15a-5p; miR-15b-5p; miR-199a-3p; miR-199b-3p; miR-223-3p; miR-23a-3p, and miR-451a-3p) were used for further evaluation. According to KEGG pathway analysis a large portion of the exomiRs target chronic diseases including cancer, neurodegenerative and metabolic diseases, and viral infections. Our results provide evidence that exosomal miRNA modulation is the molecular mechanism through which regular exercise prevents various chronic diseases. The possibility of using such exomiRs to target diseases is of great interest. While further validation is needed, our comprehensive exomiR study presents, for the first time, the disease-preventive molecular pattern of both short and long-term regular exercise

New small-size peptides modulators of the exosite of BACE1 obtained from a structure-based design

We report here two new small-size peptides acting as modulators of the -site APP cleaving enzyme 1 (BACE1) exosite. Ac-YPYFDPL-NH2 and Ac-YPYDIPL-NH2 displayed a moderate but significant inhibitory effect on BACE1. These peptides were obtained from a molecular modeling study. By combining MD simulations with ab initio and DFT calculations, a simple and generally applicable procedure to evaluate the binding energies of small-size peptides interacting with the exosite of the BACE1 is reported here. The structural aspects obtained for the different complexes were analyzed providing a clear picture about the binding interactions of these peptides. These interactions have been investigated within the framework of the density functional theory and the quantum theory of atoms in molecules using a reduced model. Although the approach used here was traditionally applied to the study of noncovalent interactions in small molecules complexes in gas phase, we show, through in this work, that this methodology is also a very powerful tool for the study of biomolecular complexes, providing a very detailed description of the binding event of peptides modulators at the exosite of BACE1

Opposite effect of Ca2+/Mg2+ ions on the aggregation of native and precursor-derived Aβ42.

Work with the Alzheimer’s disease-related synthetic peptide beta-amyloid (Ab) is a challenging task because of its disadvantageous dissolution properties and high propensity for aggregation. Recently, a new synthetic derivative, iso-Ab42, has been introduced, which is a precursor of Ab42, and it offers advantages as concerns its synthesis and use for sample preparation. These two Ab forms showed high similarity in their biological effects, as well as in their main structural characteristics under wellchosen experimental circumstances. When we changed these conditions, considerable dissimilarities appeared in the aggregation properties of the two peptides. In the present study, the aggregation pathways of native and precursor- derived Ab42 oligomers were compared in a physiological buffer with and without divalent metal ions (Ca2?/Mg2?). The presence of these ions influenced the Ab conformations, the morphology as well as formation dynamics of aggregates in a different manner, as it was demonstrated by thioflavin-T-binding experiments, transmission electron microscopy and electronic circular dichroism measurements. Namely, the aggregation of native Ab42 to fibrils was facilitated, while the aggregation of precursor-derived Ab42 was hindered by these divalent metal ions. The observed differences in the aggregation had an impact also on the biological efficiency of native and precursor-derived Ab42 as it was elucidated by viability assays with enhanced sensitivity on primary endothelial cell cultures. Using replica exchange molecular dynamics, we modeled the conformational ensembles of the two investigated Ab variants evolving during preparation process. We found considerable differences in the probability distribution of the conformers that can explain the observed dissimilarities in their aggregation properties