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Ascenzi P.,Third University of Rome | Ascenzi P.,National Institute For Infectious Diseases Irccs Lazzaro Spallanzani | Di Masi A.,Third University of Rome | Sciorati C.,San Raffaele Scientific Institute | And 2 more authors.
BioFactors | Year: 2010

Cellular damage occurring under oxidative conditions has been ascribed mainly to the formation of peroxynitrite (ONOOH/ONOO-) that originates from the reaction of NO• with O2 •-. The detrimental effects of peroxynitrite are exacerbated by the reaction with CO2 that leads to ONOOC(O)O-, which further decays to the strong oxidant radicals NO2 • and CO3 •-. The reaction with CO2, however, may redirect peroxynitrite specificity. An excessive formation of peroxynitrite represents an important mechanism contributing to the DNA damage, the inactivation of metabolic enzymes, ionic pumps, and structural proteins, and the disruption of cell membranes. Because of its ability to oxidize biomolecules, peroxynitrite is implicated in an increasing list of diseases, including neurodegenerative and cardiovascular disorders, inflammation, pain, autoimmunity, cancer, and aging. However, peroxynitrite displays also protective activities: (i) at high concentrations, it shows anti-viral, anti-microbial, and anti-parasitic actions; and (ii) at low concentrations, it stimulates protective mechanisms in the cardiovascular, nervous, and respiratory systems. The detrimental effects of peroxynitrite and related reactive species are impaired by (pseudo-) enzymatic systems, mainly represented by heme-proteins (e.g., hemoglobin and myoglobin). Here, we report biochemical aspects of peroxynitrite actions being at the root of its biomedical effects. Copyright © 2010 International Union of Biochemistry and Molecular Biology, Inc. Source


Rossin F.,University of Rome Tor Vergata | D'Eletto M.,University of Rome Tor Vergata | MacDonald D.,CHDI Management CHDI Foundation | Farrace M.G.,University of Rome Tor Vergata | And 2 more authors.
Amino Acids | Year: 2012

Tissue transglutaminase (TG2) activity has been implicated in inflammatory disease processes such as Celiac disease, infectious diseases, cancer, and neurodegenerative diseases, such as Huntington's disease. Furthermore, four distinct biochemical activities have been described for TG2 including protein crosslinking via transamidation, GTPase, kinase and protein disulfide isomerase activities. Although the enzyme plays a complex role in the regulation of cell death and autophagy, the molecular mechanisms and the putative biochemical activity involved in each is unclear. Therefore, the goal of the present study was to determine how TG2 modulates autophagy and/or apoptosis and which of its biochemical activities is involved in those processes. To address this question, immortalized embryonic fibroblasts obtained from TG2 knock-out mice were reconstituted with either wild-type TG2 or TG2 lacking its transamidating activity and these were subjected to different treatments to induce autophagy or apoptosis. We found that knock out of the endogenous TG2 resulted in a significant exacerbation of caspase 3 activity and PARP cleavage in MEF cells subjected to apoptotic stimuli. Interestingly, the same cells showed the accumulation of LC3 II isoform following autophagy induction. These findings strongly suggest that TG2 transamidating activity plays a protective role in the response of MEF cells to death stimuli, because the expression of the wild-type TG2, but not its transamidation inactive C277S mutant, resulted in a suppression of caspase 3 as well as PARP cleavage upon apoptosis induction. Additionally, the same mutant was unable to catalyze the final steps in autophagosome formation during autophagy. Our findings clearly indicate that the TG2 transamidating activity is the primary biochemical function involved in the physiological regulation of both apoptosis and autophagy. These data also indicate that TG2 is a key regulator of cross-talk between autophagy and apoptosis. © Springer-Verlag 2011. Source


Gullotta F.,Third University of Rome | de Marinis E.,Third University of Rome | Ascenzi P.,Third University of Rome | Ascenzi P.,National Institute For Infectious Diseases Irccs Lazzaro Spallanzani | di Masi A.,Third University of Rome
Current Medicinal Chemistry | Year: 2010

Among several types of DNA lesions, the DNA double strand breaks (DSBs) are one of the most deleterious and harmful. Mammalian cells mount a coordinated response to DSBs with the aim of appropriately repair the DNA damage. Indeed, failure of the DNA damage response (DDR) can lead to the development of cancer-prone genetic diseases. The identification and development of drugs targeting proteins involved in the DDR is even more investigated, as it gives the possibility to specifically target cancer cells. Indeed, the administration of DNA repair inhibitors could be combined with chemo- and radiotherapy, thus improving the eradication of tumor cells. Here, we provide an overview about DSBs damage response, focusing on the role of the DSBs repair mechanisms, of chromatin modifications, and of the cancer susceptibility gene BRCA1 which plays a multifunctional role in controlling genome integrity. Moreover, the most investigated DSBs enzyme inhibitors tested as potential therapeutic agents for anti-cancer therapy are reported. © 2010 Bentham Science Publishers Ltd. Source


Ascenzi P.,Third University of Rome | Ascenzi P.,National Institute For Infectious Diseases Irccs Lazzaro Spallanzani | Fasano M.,University of Insubria
Biophysical Chemistry | Year: 2010

Human serum albumin (HSA), the most prominent protein in plasma, binds different classes of ligands at multiple sites. The globular domain structural organization of monomeric HSA is at the root of its allosteric properties which are reminiscent of those of multimeric proteins. Here, both functional and structural aspects of the allosteric modulation of heme and drug (e.g., warfarin and ibuprofen) binding to HSA and of the drug-dependent reactivity of HSA-heme are reviewed. © 2010 Elsevier B.V. Source


Mastroberardino P.G.,Erasmus University Rotterdam | Mastroberardino P.G.,University of Pittsburgh | Piacentini M.,University of Rome Tor Vergata | Piacentini M.,National Institute For Infectious Diseases Irccs Lazzaro Spallanzani
Journal of Internal Medicine | Year: 2010

Huntington's disease (HD) is a dominant genetic neurodegenerative disorder. The pathology affects principally neurons in the basal ganglia circuits and terminates invariably in death. There is compelling necessity for safe and effective therapeutic strategies to arrest, or even retard the progression of the pathogenesis. Recent findings indicate the autophagy-lysosome systems as appealing targets for pharmacological intervention. Autophagy exerts a critical role in controlling neuronal protein homeostasis, which is perturbed in HD, and is compromised in the pathogenesis of several neurodegenerative diseases. Type 2 transglutaminase (TG2) plays an important role both in apoptosis and autophagy regulation, and accumulates at high levels in cells under stressful conditions. TG2 inhibition, achieved either via drug treatments or genetic approaches, has been shown to be beneficial for the treatment of HD in animal models. In this review we will discuss the relevance of TG2 to the pathogenesis of HD, in an effort to define novel therapeutic avenues. © 2010 The Association for the Publication of the Journal of Internal Medicine. Source

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