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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.
Found in: osebi
Keywords: peptides, docking, optimisation, computation, maltose binding protein, probe, ligand
Published: 12.10.2016; Views: 2760; Downloads: 108
.pdf Fulltext (4,27 MB)

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.
Found in: osebi
Keywords: Stem cells, Myocardial infarction, Cellular senescence, Heart failure
Published: 21.03.2017; Views: 2786; Downloads: 0
.pdf Fulltext (1,48 MB)

Cardiac stem cell aging and heart failure
Daniela Cesselli, Aneta Aleksova, Elisa Mazzega, Angela Caragnano, Antonio Paolo Beltrami, 2017, review article

Abstract: A side effect of the medical improvements of the last centuries is the progressive aging of the world population, which is estimated to reach the impressive number of 2 billion people with more than 65 years by 2050. As a consequence, age-related diseases, such as heart failure, will affect more and more patients in the next years. To understand the biological bases of these diseases will be a crucial task in order to find better treatments, and possibly slow age-related morbidity and mortality. Cardiac stem cells have been at the center of a heated debate and their potential involvement in cardiac homeostasis has been questioned. In this review, we summarize evidence obtained by independent groups, on different animal models and humans, that strongly support the important role played by immature, cardiac resident cells in the cardioprotection against heart failure.
Found in: osebi
Keywords: Aging, Heart failure, Cardiomyocyte turnover, Stem cells, Cell senescence, cKit, Sca1, PDGFRα, Cardiospheres
Published: 28.03.2017; Views: 3050; Downloads: 0
.pdf Fulltext (1,43 MB)

Matrix Gla protein (MGP) is involved in elastic fiber calcification in the dermis of Pseudoxanthoma Elasticum (PXE) patients.
Federica Boraldi, Annovi Giulia, Paolinelli Devincenzi Chiara, Schurgers Leon J, Vermeer Cees, Quaglino Daniela, Pasquali Ronchetti Ivonne, Gheduzzi Dealba, 2007, original scientific article

Abstract: Mature MGP (Matrix g-carboxyglutamic acid protein) is known to inhibit soft connective tissues calcification. We investigated its possible involvement in pseudoxanthoma elasticum (PXE), a genetic disorder whose clinical manifestations are due to mineralization of elastic fibers. PXE patients have lower serum concentration of total MGP compared to controls (Po0.001). Antibodies specific for the noncarboxylated (Glu-MGP) and for the g-carboxylated (Gla-MGP) forms of MGP were assayed on ultrathin sections of dermis from controls and PXE patients. Normal elastic fibers in controls and patients were slightly positive for both forms of MGP, whereas Gla-MGP was more abundant within control’s than within patient’s elastic fibers (Po0.001). In patients’ calcified elastic fibers, Glu-MGP intensively colocalized with mineral precipitates, whereas Gla-MGP precisely localized at the mineralization front. Data suggest that MGP is present within elastic fibers and is associated with calcification of dermal elastic fibers in PXE.
Found in: osebi
Keywords: calcification, dermal fibroblast, elastic fiber, human skin, MGP, pseudoxanthoma elasticum
Published: 22.07.2019; Views: 2005; Downloads: 0
.pdf Fulltext (689,32 KB)

Hypoxia influences the cellular cross-talk of human dermal fibroblasts. A proteomic approach.
Naldini Antonella, Tiozzo Roberta, Sommer Pascal, Carraro Fabio, Annovi Giulia, Boraldi Federica, Quaglino Daniela, 2007, original scientific article

Abstract: The ability of cells to respond to changes in oxygen availability is critical for many physiological and pathological processes (i.e. development, aging, wound healing, hypertension, cancer). Changes in the protein profile of normal human dermal fibroblasts were investigated in vitro after 96 h in 5% CO2 and 21% O2 (pO2=140 mm Hg) or 2% O2 (pO2=14 mm Hg), these parameters representing a mild chronic hypoxic exposure which fibroblasts may undergo in vivo. The proliferation rate and the protein content were not significantly modified by hypoxia, whereas proteome analysis demonstrated changes in the expression of 56 proteins. Protein identification was performed by mass spectrometry. Data demonstrate that human fibroblasts respond to mild hypoxia increasing the expression of hypoxia inducible factor (HIF1a) and of the 150-kDa oxygen-regulated protein. Other differentially expressed proteins appeared to be related to stress response, transcriptional control, metabolism, cytoskeleton, matrix remodelling and angiogenesis. Furthermore, some of them, like galectin 1, 40S ribosomal protein SA, N-myc-downstream regulated gene-1 protein, that have been described in the literature as possible cancer markers, significantly changed their expression also in normal hypoxic fibroblasts. Interestingly, a bovine fetuin was also identified that appeared significantly less internalised by hypoxic fibroblasts. In conclusion, results indicate that human dermal fibroblasts respond to an in vitro mild chronic hypoxic exposure by modifying a number of multifunctional proteins. Furthermore, data highlight the importance of stromal cells in modulating the intercellular cross-talk occurring in physiological and in pathologic conditions.
Found in: osebi
Keywords: Human fibroblast, Primary cell culture, Hypoxia, Connective tissue, Proteome, 2D gel electrophoresis, Mass-spectrometry
Published: 22.07.2019; Views: 2014; Downloads: 0
.pdf Fulltext (919,07 KB)

The effect of serum withdrawal on the protein profile of quiescent human dermal fibroblasts in primary cell culture.
Quaglino Daniela, Tiozzo Roberta, Paolinelli Devincenzi Chiara, Annovi Giulia, Boraldi Federica, 2008, original scientific article

Abstract: The effect of serum deprivation on proliferating cells is well known, in contrast its role on primary cell cultures, at confluence, has not been deeply investigated. Therefore, in order to explore the response of quiescent cells to serum deprivation, ubiquitous mesenchymal cells, as normal human dermal fibroblasts, were grown, for 48 h after confluence, in the presence or absence of 10% FBS. Fibroblast behaviour (i.e. cell morphology, cell viability, ROS production and elastin synthesis) was evaluated morphologically and biochemically. Moreover, the protein profile was investigated by 2-DE and differentially expressed proteins were identified by MS. Serum withdrawal caused cell shrinkage but did not significantly modify the total cell number. ROS production, as evaluated by the dihydroethidium (DH2) probe, was increased after serum deprivation, whereas elastin synthesis, measured by a colorimetric method, was markedly reduced in the absence of serum. By proteome analysis, 41 proteins appeared to significantly change their expression, the great majority of protein changes were related to the cytoskeleton, the stress response and the glycolytic pathway. Data indicate that human dermal fibroblasts in primary cell culture can adapt themselves to environmental changes, without significantly altering cell viability, at least after a few days of treatment, even though serum withdrawal represents a stress condition capable to increase ROS production, to influence cell metabolism and to interfere with cell behaviour, favouring the expression of several age-related features.
Found in: osebi
Keywords: Dermal fibroblasts / Primary cell culture / ROS production / Serum withdrawal
Published: 22.07.2019; Views: 2043; Downloads: 0
.pdf Fulltext (462,68 KB)

A long-term study on female mice fed on a genetically modified soybean: effects on liver ageing.
Serafina Battistelli, Beatrice Baldelli, Giulia Annovi, Federica Boraldi, Manuela Malatesta, Marco Baggiogera, Daniela Quaglino, 2008, original scientific article

Abstract: Liver represents a suitable model for monitoring the effects of a diet, due to its key role in controlling the whole metabolism. Although no direct evidence has been reported so far that genetically modified (GM) food may affect health, previous studies on hepatocytes from young female mice fed on GM soybean demonstrated nuclear modifications involving transcription and splicing pathways. In this study, the effects of this diet were studied on liver of old female mice in order to elucidate possible interference with ageing. The morpho-functional characteristics of the liver of 24-month-old mice, fed from weaning on control or GM soybean, were investigated by combining a proteomic approach with ultrastructural, morphometrical and immunoelectron microscopical analyses. Several proteins belonging to hepatocyte metabolism, stress response, calcium signalling and mitochondria were differentially expressed in GM-fed mice, indicating a more marked expression of senescence markers in comparison to controls. Moreover, hepatocytes of GM-fed mice showed mitochondrial and nuclear modifications indicative of reduced metabolic rate. This study demonstrates that GM soybean intake can influence some liver features during ageing and, although the mechanisms remain unknown, underlines the importance to investigate the long-term consequences of GM-diets and the potential synergistic effects with ageing, xenobiotics and/or stress conditions.
Found in: osebi
Keywords: Genetically modified soybean, liver, mitochondria
Published: 23.08.2019; Views: 1900; Downloads: 0
.pdf Fulltext (514,70 KB)

New insights into autophagic cell death in the gypsy moth Lymantria dispar: a proteomic approach.
Enzo Ottaviani, Daniela Quaglino, Giulia Annovi, Federica Boraldi, Davide Malagoli, 2009, original scientific article

Abstract: Autophagy is an evolutionary ancient process based on the activity of genes conserved from yeast to metazoan taxa. Whereas its role as a mechanism to provide energy during cell starvation is commonly accepted, debate continues about the occurrence of autophagy as a means specifically activated to achieve cell death. The IPLB-LdFB insect cell line, derived from the larval fat body of the lepidoptera Lymantria dispar, represents a suitable model to address this question, as both autophagic and apoptotic cell death can be induced by various stimuli. Using morphological and functional approaches, we have observed that the culture medium conditioned by IPLB-LdFB cells committed to death by the ATPase inhibitor oligomycin A stimulates autophagic cell death in untreated IPLB-LdFB cells. Moreover, proteomic analysis of the conditioned media suggests that, in IPLB-LdFB cells, oligomycin A promotes a shift towards lipid metabolism, increases oxidative stress and specifically directs the cells towards autophagic activity.
Found in: osebi
Keywords: Autophagic cell death, Fat body, IDGF, IPLB-LdFB, Proteomics
Published: 23.08.2019; Views: 1739; Downloads: 0
.pdf Fulltext (2,33 MB)

Connective tissue and diseases: from morphology to proteomics towards the development of new therapeutic appproach
Daniela Quaglino, Federica Boraldi, Giulia Annovi, Deanna Guerra, Ivonne Pasquali Ronchetti, 2009, review article

Abstract: Connective tissue consists of cells separated by the extracellular matrix, whose composition and amount vary according to age, to functional requirements, and to the presence of pathologic conditions. Within this non-random macromolecular assembly, collagens, elastin, proteoglycans and structural glycoproteins are mutually interdependent and modifications of one component, by extrinsic (environmental) and/or intrinsic (systemic, genetic, age-related) factors, may have consequences on the tissue as a whole. Since decades, different microscopical techniques have been applied mainly for diagnostic purposes and for detailed descriptions of changes occurring in cells and in matrix components. More recently, in order to dissect the molecular complexity of the matrix network, to analyse the interactions between cells and matrix and to look for modulators of cell phenotype, histomorphologic investigations have been implemented with proteomic studies that allow to identify possible diagnostic markers, and to better understand patho-mechanisms enabling the design of novel therapeutic strategies. Therefore, the progressively expanding, although incomplete, knowledge on connective tissue biology, sheds new light on the pathogenesis of diseases affecting single molecules (i.e. collagenopathies, mucopolysaccharidoses, elastinopathies) and discloses the importance of matrix components as fundamental regulators of cell phenotype, in relation, for instance, to the aging process and/or to cancer development and progression. Few examples will be presented demonstrating the promises of proteomics as a technique leading to the discovery of new therapies and possibly to the development of individualized treatments for a better patient care.
Found in: osebi
Keywords: pathology, proteomics, fibrosis, rheumatology, cancer
Published: 23.08.2019; Views: 1672; Downloads: 0
.pdf Fulltext (967,65 KB)

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