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Considerazioni sull'età scheletrica e sull'età dentale rispetto a quella cronologica in pazienti con morbo di Cooley
No full textIron regulatory proteins : from molecular mechanisms to drug development
No full textEukaryotic cells require iron for survival but, as an excess of poorly liganded iron can lead to the catalytic production of toxic radicals that can damage cell structures, regulatory mechanisms have been developed to maintain appropriate cell and body iron levels. The interactions of iron responsive elements (IREs) with iron regulatory proteins (IRPs) coordinately regulate the expression of the genes involved in iron uptake, use, storage, and export at the post-transcriptional level, and represent the main regulatory network controlling cell iron homeostasis. IRP1 and IRP2 are similar (but not identical) proteins with partially overlapping and complementary functions, and control cell iron metabolism by binding to IREs (i.e., conserved RNA stem-loops located in the untranslated regions of a dozen mRNAs directly or indirectly related to iron metabolism). The discovery of the presence of IREs in a number of other mRNAs has extended our knowledge of the influence of the IRE/IRP regulatory network to new metabolic pathways, and it has been recently learned that an increasing number of agents and physiopathological conditions impinge on the IRE/IRP system. This review focuses on recent findings concerning the IRP-mediated regulation of iron homeostasis, its alterations in disease, and new research directions to be explored in the near future
The iron regulatory proteins: Targets and modulators of free radical reactions and oxidative damage
No full textIron acquisition is a fundamental requirement for many aspects of life, but excess iron may result in formation of free radicals that damage cellular constituents. For this reason, the amount of iron within the cell is carefully regulated in order to provide an adequate level of a micronutrient while preventing its accumulation and toxicity. A major mechanism for the regulation of iron homeostasis relies on the post-transcriptional control of ferritin and transferrin receptor mRNAs, which are recognized by two cytoplasmic iron regulatory proteins (IRP-1 and IRP-2) that modulate their translation and stability, respectively. IRP-1 can function as a mRNA binding protein or as an aconitase, depending on whether it disassembles or assembles an iron-sulfur cluster in response to iron deficiency or abundancy, respectively. IRP-2 is structurally and functionally similar to IRP-1, but does not assemble a cluster nor exhibits aconitase activity. Here we briefly review the role of IRP in iron-mediated damage induced by oxygen radicals, nitrogen-centered reactive species, and xenobiotics of pharmacological and clinical interest
Glia-neuron interplay in health and disease: pharmacological evidence for this required teamwork
Full text linkGlia is a cell population highly present in the central nervous system (CNS) with the purpose, among other functions, to support neurons. In fact, many of these cells are closely in contact with neurons, actively participating to homeostatic support and synaptic transmission. For instance, astrocytes are considered integral part of the tripartite synapse. By this way, recent discoveries made possible to change perspective regarding the neuro-centric view of chronic neurodegenerative disorders, expanding the horizon to new players involved in the physiological and/or pathologic processes that take place in CNS. Better understanding the contribution of non-neuronal cells to these processes will be crucial for the development of new therapeutic approaches to counteract neurodegeneration.
Moving from these assumptions, my studies focused on evaluating the role of glial cells in inducing and triggering the inflammatory processes during neurodegeneration and, in particular, on the events that lead these cells to an activated state named reactive gliosis. Moreover, the consequences caused by these processes on neuronal survival, and in a macroscopic manner, on learning and memory, were evaluated.
To achieve such goals, I worked with different preclinical models of AD, both in vitro and in vivo, attempting to recreate at best the pathological hallmarks of pathology. In addition, since the crucial role of glial cells in the maintenance of brain homeostasis and their close connection with neuronal functioning and survival, the action of different molecules on neuroinflammation, as well as on neuronal survival, were tested
An introduction to the metabolic determinants of anthracycline cardiotoxicity
No full textAntitumor therapy with doxorubicin and other anthracyclines is limited by the possible development of cardiomyopathy upon chronic administration. Several lines of evidence suggest that a close link exists between cardiotoxicity and the amount of anthracycline that accumulates in the heart and then undergoes one- or two- electron reduction to toxic metabolites or by-products. Alternative metabolic pathways lead to an oxidative degradation of anthracyclines, possibly counteracting anthracycline accumulation and reductive bioactivation; unfortunately, however, the actual role of anthracycline oxidation is only partially characterized. Here, we briefly review the biochemical foundations of reductive versus oxidative anthracycline metabolism. We show that multiple links exist between one pathway of toxic biactivation and another, limiting the search and clinical development of "better anthracyclines" that retain antitumor activity but induce less cardiotoxicity than the available analogues
Doxorubicin paradoxically protects cardiomyocytes against iron-mediated toxicity : role of reactive oxygen species and ferritin
No full textThe cardiotoxicity induced by the anticancer anthracycline doxorubicin (DOX) is attributed to reactions between iron and reactive oxygen species (ROS) that lead to oxidative damage. We found that DOX forms ROS in H9c2 cardiomyocytes, as shown by dichlorodihydrofluorescein oxidation and the expression of stress-responsive genes such as catalase or aldose reductase. DOX also increased ferritin levels in these cells, particularly the H subunit. A considerable increase in ferritin mRNA levels showed that DOX acted at transcriptional level, but an additional potential mechanism was identified as the down-regulation of iron regulatory protein-2, post-transcriptional inhibitor of ferritin synthesis. Pretreatment with DOX protected H9c2 cells against the damage induced by subsequent exposure to ferric ammonium citrate, and experiments with 55Fe revealed that the protection was due to the deposition of iron in ferritin. Cytoprotection was also observed when DOX was replaced by glucose/glucose oxidase, a source of H2O2, thus suggesting that DOX increases ferritin synthesis through the action of ROS. This concept was supported by three more lines of evidence. (i) DOX-induced ferritin synthesis was blocked by N-acetylcysteine, a scavenger of ROS. (ii) Mitoxantrone, a ROS-forming analogue, similarly induced ferritin expression and protected the cells against iron toxicity. (iii) 5-Iminodaunorubicin, an analogue lacking ROS-forming activity, did not induce ferritin synthesis or protect the cells against iron toxicity. These results characterize a paradoxically beneficial link between anthracycline-derived ROS, increased ferritin synthesis, and resistance to iron-mediated damage. The role of iron and ROS in anthracycline-induced cardiotoxicity may, therefore, be more complex than previously believed
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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