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1.
Ex Vivo Molecular Rejuvenation Improves the Therapeutic Activity of Senescent Human Cardiac Stem Cells in a Mouse Model of Myocardial Infarction
Elisa Avolio, Giuseppe Gianfranceschi, Angela Caragnano, Emmanouil Athanasakis, Rajesh Katare, Daniela Cesselli, Marco Meloni, Anita Palma, Arianna Barchiesi, Carlo Vascotto, Barbara Toffoletto, Elisa Mazzega, Nicoletta Finato, Giuseppe Aresu, Ugolino Livi, Costanza Emanueli, Giacinto Scoles, Carlo Alberto Beltrami, Paolo Madeddu, Antonio Paolo Beltrami, 2014, original scientific article

Abstract: Cardiac stem cells (CSC) from explanted decompensated hearts (E-CSC) are, with respect to those obtained from healthy donors (D-CSC), senescent and functionally impaired. We aimed to identify alterations in signaling pathways that are associated with CSC senescence. Additionally, we inves- tigated if pharmacological modulation of altered pathways can reduce CSC senescence in vitro and enhance their reparative ability in vivo. Measurement of secreted factors showed that E-CSC release larger amounts of proinflammatory cytokine IL1b compared with D-CSC. Using blocking antibodies, we verified that IL1b hampers the paracrine protective action of E-CSC on cardiomyo- cyte viability. IL1b acts intracranially inducing IKKb signaling, a mechanism that via nuclear factor-jB upregulates the expression of IL1b itself. Moreover, E-CSC show reduced levels of AMP protein kinase (AMPK) activating phosphorylation. This latter event, together with enhanced IKKb signaling, increases TORC1 activity, thereby impairing the autophagic flux and inhibiting the phos- phorylation of Akt and cAMP response element-binding protein. The combined use of rapamycin and resveratrol enhanced AMPK, thereby restoring downstream signaling and reducing IL1b secretion. These molecular corrections reduced E-CSC senescence, re-establishing their protective activity on cardiomyocytes. Moreover ex vivo treatment with rapamycin and resveratrol improved E-CSC capacity to induce cardiac repair upon injection in the mouse infarcted heart, leading to reduced cardiomyocyte senescence and apoptosis and increased abundance of endog- enous c-Kit1 CSC in the peri-infarct area. Molecular rejuvenation of patient-derived CSC by short pharmacologic conditioning boosts their in vivo reparative abilities. This approach might prove useful for refinement of CSC-based therapies.
Keywords: Stem cells, Myocardial infarction, Cellular senescence, Heart failure
Published in RUNG: 21.03.2017; Views: 3945; Downloads: 0
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2.
In silico generation of peptides by replica exchange Monte Carlo: Docking-based optimization of maltose-binding-protein ligands
Anna Russo, Pasqualina Liana Scognamiglio, Rolando Pablo Hong Enriquez, Carlo Santambrogio, Rita Grandori, Daniela Marasco, Antonio Giordano, Giacinto Scoles, Sara Fortuna, 2015, original scientific article

Abstract: Short peptides can be designed in silico and synthesized through automated techniques, making them advantageous and versatile protein binders. A number of docking-based algorithms allow for a computational screening of peptides as binders. Here we developed ex-novo peptides targeting the maltose site of the Maltose Binding Protein, the prototypical system for the study of protein ligand recognition. We used a Monte Carlo based protocol, to computationally evolve a set of octapeptides starting from a polialanine sequence. We screened in silico the candidate peptides and characterized their binding abilities by surface plasmon resonance, fluorescence and electrospray ionization mass spectrometry assays. These experiments showed the designed binders to recognize their target with micromolar affinity. We finally discuss the obtained results in the light of further improvement in the ex-novo optimization of peptide based binders.
Keywords: peptides, docking, optimisation, computation, maltose binding protein, probe, ligand
Published in RUNG: 12.10.2016; Views: 3921; Downloads: 140
.pdf Full text (4,27 MB)

3.
Chelating effect in short polymers for the design of bidentate binders of increased affinity and selectivity
Sara Fortuna, Federico Fogolari, Giacinto Scoles, 2015, original scientific article

Abstract: The design of new strong and selective binders is a key step towards the development of new sensing devices and effective drugs. Both affinity and selectivity can be increased through chelation and here we theoretically explore the possibility of coupling two binders through a flexible linker. We prove the enhanced ability of double binders of keeping their target with a simple model where a polymer composed by hard spheres interacts with a spherical macromolecule, such as a protein, through two sticky spots. By Monte Carlo simulations and thermodynamic integration we show the chelating effect to hold for coupling polymers whose radius of gyration is comparable to size of the chelated particle. We show the binding free energy of flexible double binders to be higher than that of two single binders and to be maximized when the binding sites are at distances comparable to the mean free polymer end-to-end distance. The affinity of two coupled binders is therefore predicted to increase non linearly and in turn, by targeting two non-equivalent binding sites, this will lead to higher selectivity.
Keywords: chelation, polymer, multivalency, bidentate, free energy, thermodynamic integration, Monte Carlo
Published in RUNG: 11.10.2016; Views: 3981; Downloads: 151
.pdf Full text (1,68 MB)

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