San Raffaele Institute Sulmona

San Raffaele Cimena, Italy

San Raffaele Institute Sulmona

San Raffaele Cimena, Italy
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Datan E.,Queens College, City University of New York | Shirazian A.,Queens College, City University of New York | Shirazian A.,Profectus Biosciences, Inc. | Benjamin S.,Queens College, City University of New York | And 8 more authors.
Virology | Year: 2014

Autophagy, a stress response activated in influenza A virus infection helps the cell avoid apoptosis. However, in the absence of apoptosis infected cells undergo vastly expanded autophagy and nevertheless die in the presence of necrostatin but not of autophagy inhibitors. Combinations of inhibitors indicate that the controls of protective and lethal autophagy are different. Infection that triggers apoptosis also triggers canonical autophagy signaling exhibiting transient PI3K and mTORC1 activity. In terminal autophagy phospho-mTOR(Ser2448) is suppressed while mTORC1, PI3K and mTORC2 activities increase. mTORC1 substrate p70S6K becomes highly phosphorylated while its activity, now regulated by mTORC2, is required for LC3-II formation. Inhibition of mTORC2/p70S6K, unlike that of PI3K/mTORC1, blocks expanded autophagy in the absence of apoptosis but not moderate autophagy. Inhibitors of expanded autophagy limit virus reproduction. Thus expanded, lethal autophagy is activated by a signaling mechanism different from autophagy that helps cells survive toxic or stressful episodes. © 2014 Elsevier Inc.


Mattei V.,Sabina Universitas | Matarrese P.,Instituto Superiore Of Sanita | Garofalo T.,University of Rome La Sapienza | Tinari A.,Instituto Superiore Of Sanita | And 8 more authors.
Molecular Biology of the Cell | Year: 2011

We examined the possibility that cellular prion protein (PrP C) plays a role in the receptor-mediated apoptotic pathway. We first found that CD95/Fas triggering induced a redistribution of PrP C to the mitochondria of T lymphoblastoid CEM cells via a mechanism that brings into play microtubular network integrity and function. In particular, we demonstrated that PrP C was redistributed to raft-like microdomains at the mitochondrial membrane, as well as at endoplasmic reticulum-mitochondria- associated membranes. Our in vitro experiments also demonstrated that, although PrP C had such an effect on mitochondria, it induced the loss of mitochondrial membrane potential and cytochrome c release only after a contained rise of calcium concentration. Finally, the involvement of PrP C in apoptosis execution was also analyzed in PrP C-small interfering RNA-transfected cells, which were found to be significantly less susceptible to CD95/Fas-induced apoptosis. Taken together, these results suggest that PrP C might play a role in the complex multimolecular signaling associated with CD95/Fas receptor-mediated apoptosis. © 2011 Mattei et al.


Sgarbi G.,University of Bologna | Matarrese P.,Instituto Superiore Of Sanita | Pinti M.,University of Modena and Reggio Emilia | Lanzarini C.,University of Bologna | And 16 more authors.
Aging | Year: 2014

Mitochondria have been considered for long time as important determinants of cell aging because of their role in the production of reactive oxygen species. In this study we investigated the impact of mitochondrial metabolism and biology as determinants of successful aging in primary cultures of fibroblasts isolated from the skin of long living individuals (LLI) (about 100 years old) compared with those from young (about 27 years old) and old (about 75 years old) subjects. We observed that fibroblasts from LLI displayed significantly lower complex I-driven ATP synthesis and higher production of H2O2 in comparison with old subjects. Despite these changes, bioenergetics of these cells appeared to operate normally. This lack of functional consequences was likely due to a compensatory phenomenon at the level of mitochondria, which displayed a maintained supercomplexes organization and an increased mass. This appears to be due to a decreased mitophagy, induced by hyperfused, elongated mitochondria. The overall data indicate that longevity is characterized by a preserved bioenergetic function likely attained by a successful mitochondria remodeling that can compensate for functional defects through an increase in mass, i.e. a sort of mitochondrial "hypertrophy". © Sgarbi et al.


Colasanti T.,Instituto Superiore Of Sanita | Colasanti T.,San Raffaele Institute Pisana | Vomero M.,Instituto Superiore Of Sanita | Alessandri C.,University of Rome La Sapienza | And 17 more authors.
Cell Death and Disease | Year: 2014

It has been demonstrated that α-synuclein can aggregate and contribute to the pathogenesis of some neurodegenerative diseases and it is capable of hindering autophagy in neuronal cells. Here, we investigated the implication of α-synuclein in the autophagy process in primary human T lymphocytes. We provide evidence that: (i) knocking down of the α-synuclein gene resulted in increased autophagy, (ii) autophagy induction by energy deprivation was associated with a significant decrease of α-synuclein levels, (iii) autophagy inhibition by 3-methyladenine or by ATG5 knocking down led to a significant increase of α-synuclein levels, and (iv) autophagy impairment, constitutive in T lymphocytes from patients with systemic lupus erythematosus, was associated with abnormal accumulation of α-synuclein aggregates. These results suggest that α-synuclein could be considered as an autophagy-related marker of peripheral blood lymphocytes, potentially suitable for use in the clinical practice. © 2014 Macmillan Publishers Limited. All rights reserved.


Pennarun B.,Beth Israel Deaconess Medical Center | Gaidos G.,Dartmouth College | Bucur O.,Beth Israel Deaconess Medical Center | Tinari A.,Instituto Superiore Of Sanita | And 10 more authors.
Cell Death and Disease | Year: 2013

One of the objectives in the development of effective cancer therapy is induction of tumor-selective cell death. Toward this end, we have identified a small peptide that, when introduced into cells via a TAT cell-delivery system, shows a remarkably potent cytoxicity in a variety of cancer cell lines and inhibits tumor growth in vivo, whereas sparing normal cells and tissues. This fusion peptide was named killerFLIP as its sequence was derived from the C-terminal domain of c-FLIP, an anti-apoptotic protein. Using structure activity analysis, we determined the minimal bioactive core of killerFLIP, namely killerFLIP-E. Structural analysis of cells using electron microscopy demonstrated that killerFLIP-E triggers cell death accompanied by rapid (within minutes) plasma membrane permeabilization. Studies of the structure of the active core of killerFLIP (-E) indicated that it possesses amphiphilic properties and self-assembles into micellar structures in aqueous solution. The biochemical properties of killerFLIP are comparable to those of cationic lytic peptides, which participate in defense against pathogens and have also demonstrated anticancer properties.We show that the pro-cell death effects of killerFLIP are independent of its sequence similarity with c-FLIPL as killerFLIP-induced cell death was largely apoptosis and necroptosis independent. A killerFLIP-E variant containing a scrambled c-FLIPL motif indeed induced similar cell death, suggesting the importance of the c-FLIPL residues but not of their sequence. Thus, we report the discovery of a promising synthetic peptide with novel anticancer activity in vitro and in vivo. © 2013 Macmillan Publishers Limited. All rights reserved.


Berry A.,Instituto Superiore Of Sanita | Vacirca D.,Instituto Superiore Of Sanita | Capoccia S.,Instituto Superiore Of Sanita | Bellisario V.,Instituto Superiore Of Sanita | And 5 more authors.
Journal of Alzheimer's Disease | Year: 2013

Previous studies have suggested a pathogenetic role of autoantibodies (Abs) against ATP synthase (ATPs) in patients with Alzheimer's disease (AD). Using a mouse model, we found that intracerebroventricular administration of anti-ATPs-Abs, purified from AD patients, leads to poor cognitive performance and pronounced cell damage in the hippocampus, a brain region specifically involved in learning and memory processes, which is severely affected in AD. Our results are suggestive of a role of anti-ATPs-Abs in the onset and progression of AD and also provide a fruitful model for the study of memory disturbances in neurodegenerative diseases. © 2013 - IOS Press and the authors. All rights reserved.

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