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San Fedele Superiore, Italy

Straface E.,Section of Cell Aging and Degeneration | Brandani M.,University of Florence | Malorni W.,San Raffaele Institute
Handbook of Experimental Pharmacology | Year: 2012

Different pathways involved in the complex machinery implicated in determining cell fate have been investigated in the recent years. Different forms of cell death have been described: apart from the classical form of death known as necrosis, a well characterized traumatic injury of the cell, several additional forms of cell death have been identified. Among these, apoptosis has been characterized in detail. These studies stem from the implication that the apoptotic process plays a key role in a plethora of human pathologies, including cardiovascular diseases. In fact, defects in the mechanisms of cell death, i.e., both an increase or a decrease of apoptosis, have been associated with the pathogenesis of vessel and myocardial diseases. Some new insights also derived from the study of autophagy, a less characterized form of cell damage mainly associated with cell survival strategies but that also leads, as final event, to the death of the cell. Interestingly, very recently, a gender difference has been found in this respect: cells from males and females can behave differently. In fact, they seem to display several different features, including those determining their fate. These gender cytology differences are briefly described here. The study of this gender disparity is of great relevance in cardiovascular disease pathogenesis and pharmacology. The comprehension of the gender-related mechanisms of cell demise can in fact disclose new scenarios in preclinical and clinical management of cardiovascular diseases. © 2012 Springer-Verlag Berlin Heidelberg. Source

Pietraforte D.,Istituto Superiore di Sanita | Malorni W.,Section of Cell Aging and Degeneration | Malorni W.,University of LAquila
Antioxidants and Redox Signaling | Year: 2014

Redox signaling plays a fundamental role in tissue physiological metabolism. A fine balance between reactive oxidizing species (ROS) generation and antioxidant levels allows either the cross talk between cells or the control of fundamental intracellular functions, such as cell-cell interactions, cell division, migration, and contraction. A deregulation of this balance, for example, leading to oxidative stress, has been implicated in many pathological conditions, including cardiovascular-, neuronal-, and immunological-related diseases, as well as in cancer. A key role of ROS generation has also been associated with a variety of cell death processes, including necrosis, apoptosis, and autophagy. More recently, the discovery that autophagy, formerly considered as a cell death program, mainly represents an important cytoprotection mechanism, led to a series of studies aimed at the comprehension of the role of ROS generation in regulating intracellular signals leading to the activation of survival mechanisms or triggering cell death. However, different cell types, for example, neuronal cells, muscle cells, lymphocytes, or epithelial cells, seem to display different redox sensitivities, different signaling pathways, and different defense mechanisms. In few words, as illustrated in detail in the present Forum, the future challenge on this matter will be represented by the comprehension of the histotype-associated or histotype-dependent intracellular mechanisms of ROS management. Antioxid. Redox Signal. 21, 52-55. © Copyright 2014, Mary Ann Liebert, Inc. 2014. Source

Sorice M.,University of Rome La Sapienza | Garofalo T.,University of Rome La Sapienza | Misasi R.,University of Rome La Sapienza | Manganelli V.,University of Rome La Sapienza | And 3 more authors.
Anti-Cancer Agents in Medicinal Chemistry | Year: 2012

Subcellular organelles such as mitochondria, endoplasmic reticulum and the Golgi complex are involved in the progression of cell death program. Recent evidence unveils that Fas ligand-mediated apoptosis induces scrambling of mitochondrial and secretory organelles via a global alteration of membrane traffic that is modulated by apical caspases. On the basis of the biochemical nature of lipid rafts, composed by sphingolipids, including gangliosides and sphingomyelin, cholesterol and signaling proteins, it has been suggested that they are part of this traffic and can participate in cell remodelling leading to cell death program execution. Although detected in various cell types, the role of lipid rafts in apoptosis has been mostly studied in T cells, where the physiological apoptotic program occurs through CD95/Fas. In this review, the possible contribution of lipid rafts to the cascade of events leading to T cell apoptosis after CD95/Fas ligation is summarized. We focused on the paradigmatic component of rafts GD3, which can proceed from the cell plasma membrane (and/or from trans Golgi network) to the mitochondria via a microtubule-dependent mechanism. This transport may be regulated by CLIPR-59, a new CLIP-170-related protein, involved in the regulation of microtubule dynamics. Particular attention has been given to mitochondrial raft-like microdomains, which may represent preferential sites where key reactions take place. Indeed, GD3, by interacting with mitochondrial raft-like microdomains, may trigger specific events involved in the apoptogenic program, including mitochondria hyperpolarization and depolarization, fission-associated changes, megapore formation and release of apoptogenic factors. These findings introduce an additional task for identifying new molecular target(s) of anti-cancer agents. © 2012 Bentham Science Publishers. Source

Straface E.,Section of Cell Aging and Degeneration | Gambardella L.,Section of Cell Aging and Degeneration | Metere A.,Section of Biomarkers in Degenerative Diseases | Marchesi A.,Bambino Gesu Hospital | And 7 more authors.
Biochemical and Biophysical Research Communications | Year: 2010

Kawasaki disease (KD) is a rare and often undiagnosed disease, at least in the western countries. It is characterized by an inflammatory acute febrile vasculitis of medium sized arteries with a propensity to damage the coronary arteries. It normally occurs in the early childhood and the diagnosis is based on clinical symptoms. During the progression of the disease thrombocytosis is usually detected. This can exert a pathogenetic role in the cardiovascular complications occurring in KD. In the present work peripheral blood plasma and platelets from twelve naïve patients with KD were analyzed in order to detect possible pathogenetic determinants or progression markers. Morphological, biochemical and flow cytometrical methods have been used. With respect to age-matched healthy donors, we found an increase of platelet activation markers, i.e. degranulation, phosphatidylserine (PS) externalization and leukocyte-red cell-platelet aggregates. Some significant alterations that could represent suitable diagnostic determinants have also been detected in patient plasma: (i) decreased antioxidant power, (ii) decreased levels of asymmetric dymethylarginine (ADMA), a naturally occurring chemical interfering with the production of nitric oxide, and (iii) increased levels of soluble P-Selectin and soluble annexin V. Since PS externalizing platelets are known to exert a pro-coagulant activity, our data suggest the hypothesis that increased risk of vascular complications in KD could depend on platelet stimulation and defective apoptosis probably related to nitrosative stress. © 2010 Elsevier Inc. All rights reserved. Source

Ciarlo L.,Section of Cell Aging and Degeneration | Manganelli V.,University of Rome La Sapienza | Matarrese P.,Section of Cell Aging and Degeneration | Garofalo T.,University of Rome La Sapienza | And 8 more authors.
Journal of Lipid Research | Year: 2012

Huntington's disease (HD) is a genetic neurodegenerative disease characterized by an exceedingly high number of contiguous glutamine residues in the translated protein, huntingtin (Htt). The primary site of cell toxicity is the nucleus, but mitochondria have been identified as key components of cell damage. The present work has been carried out in immortalized lymphocytes from patients with HD. These cells, in comparison with lymphoid cells from healthy subjects, displayed: i) a redistribution of mitochondria, forming large aggregates; ii) a constitutive hyperpolarization of mitochondrial membrane; and iii) a constitutive alteration of mitochondrial fission machinery, with high apoptotic susceptibility. Moreover, mitochondrial fission molecules, e.g., protein dynamin-related protein 1, as well as Htt, associated with mitochondrial raft-like microdomains, glycosphingolipid-enriched structures detectable in mitochondria. These findings, together with the observation that a ceramide synthase inhibitor and a raft disruptor are capable of impairing the peculiar mitochondrial remodeling in HD cells, suggest that mitochondrial alterations occurring in these cells could be due to raft-mediated defects of mitochondrial fission/fusion machinery. Copyright © 2012 by the American Society for Biochemistry and Molecular Biology, Inc. Source

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