212 results on '"RIGOLIO, ROBERTA"'
Search Results
2. V-ATPase Proton Pump May Take Part to Drug-Resistance Phenotype of Glioma Stem Cells
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Giambra, Martina, primary, Di Cristofori, Andrea, additional, Raimondo, Francesca, additional, Rigolio, Roberta, additional, Conconi, Donatella, additional, Chiarello, Gaia, additional, Tabano, Silvia Maria, additional, Antolini, Laura, additional, Nicolini, Gabriella, additional, Bua, Miriam, additional, Ferlito, Davide, additional, Carrabba, Giorgio, additional, Giussani, Carlo Giorgio, additional, Lavitrano, Marialuisa, additional, and Bentivegna, Angela, additional
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- 2024
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3. Vacuolar Proton-Translocating ATPase May Take Part in the Drug Resistance Phenotype of Glioma Stem Cells
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Giambra, M, Di Cristofori, A, Raimondo, F, Rigolio, R, Conconi, D, Chiarello, G, Tabano, S, Antolini, L, Nicolini, G, Bua, M, Ferlito, D, Carrabba, G, Giussani, C, Lavitrano, M, Bentivegna, A, Giambra, Martina, Di Cristofori, Andrea, Raimondo, Francesca, Rigolio, Roberta, Conconi, Donatella, Chiarello, Gaia, Tabano, Silvia Maria, Antolini, Laura, Nicolini, Gabriella, Bua, Miriam, Ferlito, Davide, Carrabba, Giorgio, Giussani, Carlo Giorgio, Lavitrano, Marialuisa, Bentivegna, Angela, Giambra, M, Di Cristofori, A, Raimondo, F, Rigolio, R, Conconi, D, Chiarello, G, Tabano, S, Antolini, L, Nicolini, G, Bua, M, Ferlito, D, Carrabba, G, Giussani, C, Lavitrano, M, Bentivegna, A, Giambra, Martina, Di Cristofori, Andrea, Raimondo, Francesca, Rigolio, Roberta, Conconi, Donatella, Chiarello, Gaia, Tabano, Silvia Maria, Antolini, Laura, Nicolini, Gabriella, Bua, Miriam, Ferlito, Davide, Carrabba, Giorgio, Giussani, Carlo Giorgio, Lavitrano, Marialuisa, and Bentivegna, Angela
- Abstract
The vacuolar proton-translocating ATPase (V-ATPase) is a transmembrane multi-protein complex fundamental in maintaining a normal intracellular pH. In the tumoral contest, its role is crucial since the metabolism underlying carcinogenesis is mainly based on anaerobic glycolytic reactions. Moreover, neoplastic cells use the V-ATPase to extrude chemotherapy drugs into the extra-cellular compartment as a drug resistance mechanism. In glioblastoma (GBM), the most malignant and incurable primary brain tumor, the expression of this pump is upregulated, making it a new possible therapeutic target. In this work, the bafilomycin A1-induced inhibition of V-ATPase in patient-derived glioma stem cell (GSC) lines was evaluated together with temozolomide, the first-line therapy against GBM. In contrast with previous published data, the proposed treatment did not overcome resistance to the standard therapy. In addition, our data showed that nanomolar dosages of bafilomycin A1 led to the blockage of the autophagy process and cellular necrosis, making the drug unusable in models which are more complex. Nevertheless, the increased expression of V-ATPase following bafilomycin A1 suggests a critical role of the proton pump in GBM stem components, encouraging the search for novel strategies to limit its activity in order to circumvent resistance to conventional therapy.
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- 2024
4. Artificial apolipoprotein corona enables nanoparticle brain targeting
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Dal Magro, Roberta, Albertini, Barbara, Beretta, Silvia, Rigolio, Roberta, Donzelli, Elisabetta, Chiorazzi, Alessia, Ricci, Maurizio, Blasi, Paolo, and Sancini, Giulio
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- 2018
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5. Oxaliplatin-induced neuropathy occurs through impairment of haemoglobin proton buffering and is reversed by carbonic anhydrase inhibitors
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Potenzieri, Alberto, Riva, Beatrice, Rigolio, Roberta, Chiorazzi, Alessia, Pozzi, Eleonora, Ballarini, Elisa, Cavaletti, Guido, and Genazzani, Armando A.
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- 2020
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6. Another Brick to Confirm the Efficacy of Rigosertib as Anticancer Agent
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Malacrida, Alessio, primary, Deschamps-Wright, Marie, additional, Rigolio, Roberta, additional, Cavaletti, Guido, additional, and Miloso, Mariarosaria, additional
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- 2023
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7. Oxaliplatin induces pH acidification in dorsal root ganglia neurons
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Riva, Beatrice, Dionisi, Marianna, Potenzieri, Alberto, Chiorazzi, Alessia, Cordero-Sanchez, Celia, Rigolio, Roberta, Carozzi, Valentina Alda, Lim, Dmitry, Cavaletti, Guido, Marmiroli, Paola, Distasi, Carla, and Genazzani, Armando A.
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- 2018
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8. Multiple Sclerosis Drug Therapy: From the Classical Pharmaceutical Down to Cellular and Molecular Approach
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Rigolio, Roberta, primary, Ballarini, Elisa, additional, Grimoldi, Maria, additional, Gardinetti, Margherita, additional, and Di Sante, Gabriele, additional
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- 2016
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9. Functionalization of liposomes with ApoE-derived peptides at different density affects cellular uptake and drug transport across a blood-brain barrier model
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Re, Francesca, Cambianica, Ilaria, Zona, Cristiano, Sesana, Silvia, Gregori, Maria, Rigolio, Roberta, La Ferla, Barbara, Nicotra, Francesco, Forloni, Gianluigi, Cagnotto, Alfredo, Salmona, Mario, Masserini, Massimo, and Sancini, Giulio
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- 2011
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10. Anti-Multiple Myeloma Potential of Secondary Metabolites from Hibiscus sabdariffa—Part 2
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Malacrida, Alessio, primary, Cavalloro, Valeria, additional, Martino, Emanuela, additional, Costa, Giosuè, additional, Ambrosio, Francesca Alessandra, additional, Alcaro, Stefano, additional, Rigolio, Roberta, additional, Cassetti, Arianna, additional, Miloso, Mariarosaria, additional, and Collina, Simona, additional
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- 2021
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11. Multimodal Analysis in Acute and Chronic Experimental Autoimmune Encephalomyelitis
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Giatti, Silvia, Boraso, Mariaserena, Abbiati, Federico, Ballarini, Elisa, Calabrese, Donato, Santos-Galindo, Maria, Rigolio, Roberta, Pesaresi, Marzia, Caruso, Donatella, Viviani, Barbara, Cavaletti, Guido, Garcia-Segura, Luis Miguel, and Melcangi, Roberto Cosimo
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- 2013
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12. In Vitro Evaluation of Rigosertib Antitumoral and Radiosensitizing Effects against Human Cholangiocarcinoma Cells
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Malacrida, Alessio, primary, Rigolio, Roberta, additional, Celio, Luigi, additional, Damian, Silvia, additional, Cavaletti, Guido, additional, Mazzaferro, Vincenzo, additional, and Miloso, Mariarosaria, additional
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- 2021
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13. Neuroinflammatory Process Involved in Different Preclinical Models of Chemotherapy-Induced Peripheral Neuropathy
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Fumagalli, G, Monza, L, Cavaletti, G, Rigolio, R, Meregalli, C, Fumagalli, Giulia, Monza, Laura, Cavaletti, Guido, Rigolio, Roberta, Meregalli, Cristina, Fumagalli, G, Monza, L, Cavaletti, G, Rigolio, R, Meregalli, C, Fumagalli, Giulia, Monza, Laura, Cavaletti, Guido, Rigolio, Roberta, and Meregalli, Cristina
- Abstract
Peripheral neuropathies are characterized by nerves damage and axonal loss, and they could be classified in hereditary or acquired forms. Acquired peripheral neuropathies are associated with several causes, including toxic agent exposure, among which the antineoplastic compounds are responsible for the so called Chemotherapy-Induced Peripheral Neuropathy (CIPN). Several clinical features are related to the use of anticancer drugs which exert their action by affecting different mechanisms and structures of the peripheral nervous system: the axons (axonopathy) or the dorsal root ganglia (DRG) neurons cell body (neuronopathy/ganglionopathy). In addition, antineoplastic treatments may affect the blood brain barrier integrity, leading to cognitive impairment that may be severe and long-lasting. CIPN may affect patient quality of life leading to modification or discontinuation of the anticancer therapy. Although the mechanisms of the damage are not completely understood, several hypotheses have been proposed, among which neuroinflammation is now emerging to be relevant in CIPN pathophysiology. In this review, we consider different aspects of neuro-immune interactions in several CIPN preclinical studies which suggest a critical connection between chemotherapeutic agents and neurotoxicity. The features of the neuroinflammatory processes may be different depending on the type of drug (platinum derivatives, taxanes, vinca alkaloids and proteasome inhibitors). In particular, recent studies have demonstrated an involvement of the immune response (both innate and adaptive) and the stimulation and secretion of mediators (cytokines and chemokines) that may be responsible for the painful symptoms, whereas glial cells such as satellite and Schwann cells might contribute to the maintenance of the neuroinflammatory process in DRG and axons respectively. Moreover, neuroinflammatory components have also been shown in the spinal cord with microglia and astrocytes playing an important rol
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- 2021
14. Actively induced EAE in Lewis rats: Characterization of spleen and spinal cord infiltrating lymphocytes by flow cytometry during the course of the disease
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Rigolio, Roberta, Biffi, Alessandro, Oggioni, Norberto, and Cavaletti, Guido
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- 2008
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15. Neuroinflammatory Process Involved in Different Preclinical Models of Chemotherapy-Induced Peripheral Neuropathy
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Fumagalli, Giulia, primary, Monza, Laura, additional, Cavaletti, Guido, additional, Rigolio, Roberta, additional, and Meregalli, Cristina, additional
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- 2021
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16. A new device to study ex-vivo the effects of extracorporeal photochemotherapy on the immune system
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Rigolio, Roberta, Perseghin, Paolo, Jonsson, Svante, Petersson, Jesper, Cavaletti, Guido, and Cilio, Corrado Maria
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- 2007
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17. Differential Exchange of Multifunctional Liposomes Between Glioblastoma Cells and Healthy Astrocytes via Tunneling Nanotubes
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Formicola, Beatrice, primary, D'Aloia, Alessia, additional, Dal Magro, Roberta, additional, Stucchi, Simone, additional, Rigolio, Roberta, additional, Ceriani, Michela, additional, and Re, Francesca, additional
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- 2019
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18. Differential Exchange of Multifunctional Liposomes Between Glioblastoma Cells and Healthy Astrocytes via Tunneling Nanotubes
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Formicola, B, D'Aloia, A, Dal Magro, R, Stucchi, S, Rigolio, R, Ceriani, M, Re, F, Formicola, Beatrice, D'Aloia, Alessia, Dal Magro, Roberta, Stucchi, Simone, Rigolio, Roberta, Ceriani, Michela, Re, Francesca, Formicola, B, D'Aloia, A, Dal Magro, R, Stucchi, S, Rigolio, R, Ceriani, M, Re, F, Formicola, Beatrice, D'Aloia, Alessia, Dal Magro, Roberta, Stucchi, Simone, Rigolio, Roberta, Ceriani, Michela, and Re, Francesca
- Abstract
Despite advances in cancer therapies, nanomedicine approaches including the treatment of glioblastoma (GBM), the most common, aggressive brain tumor, remains inefficient. These failures are likely attributable to the complex and not yet completely known biology of this tumor, which is responsible for its strong invasiveness, high degree of metastasis, high proliferation potential, and resistance to radiation and chemotherapy. The intimate connection through which the cells communicate between them plays an important role in these biological processes. In this scenario, tunneling nanotubes (TnTs) are recently gaining importance as a key feature in tumor progression and in particular in the re-growth of GBM after surgery. In this context, we firstly identified structural differences of TnTs formed by U87-MG cells, as model of GBM cells, in comparison with those formed by normal human astrocytes (NHA), used as a model of healthy cells. Successively, we have studied the possibility to exploit U87-MG TnTs as drug-delivery channels in cancer therapy, using liposomes composed of cholesterol/sphingomyelin and surface functionalized with mApoE and chlorotoxin peptides (Mf-LIP) as nanovehicle model. The results showed that U87-MG cells formed almost exclusively thick and long protrusions, whereas NHA formed more thin and short TnTs. Considering that thick TnTs are more efficient in transport of vesicles and organelles, we showed that fluorescent-labeled Mf-LIP can be transported via TnTs between U87-MG cells and with less extent through the protrusions formed by NHA cells. Our results demonstrate that nanotubes are potentially useful as drug-delivery channels for cancer therapy, facilitating the intercellular redistribution of this drug in close and far away cells, thus reaching isolated tumor niches that are hardly targeted by simple drug diffusion in the brain parenchyma. Moreover, the differences identified in TnTs formed by GBM and NHA cells can be exploited to increase t
- Published
- 2019
19. Oxaliplatin-induced neuropathy occurs through impairment of haemoglobin proton buffering and is reversed by carbonic anhydrase inhibitors
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Potenzieri, Alberto, primary, Riva, Beatrice, additional, Rigolio, Roberta, additional, Chiorazzi, Alessia, additional, Pozzi, Eleonora, additional, Ballarini, Elisa, additional, Cavaletti, Guido, additional, and Genazzani, Armando A., additional
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- 2019
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20. Correlative Synchrotron Micro-CT and FIB-SEM Imaging for the Analysis of Multifocal Pathologies
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Parlanti, Paola, primary, Rigolio, Roberta, additional, Tromba, Giuliana, additional, Manzini, Chiara, additional, Popratiloff, Anastas, additional, and Cappello, Valentina, additional
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- 2019
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21. Anti-Multiple Myeloma Potential of Secondary Metabolites from Hibiscus sabdariffa
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Malacrida, Alessio, primary, Cavalloro, Valeria, additional, Martino, Emanuela, additional, Cassetti, Arianna, additional, Nicolini, Gabriella, additional, Rigolio, Roberta, additional, Cavaletti, Guido, additional, Mannucci, Barbara, additional, Vasile, Francesca, additional, Giacomo, Marcello Di, additional, Collina, Simona, additional, and Miloso, Mariarosaria, additional
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- 2019
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22. De novo UBE2A mutations are recurrently acquired during chronic myeloid leukemia progression and interfere with myeloid differentiation pathways
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Magistroni, Vera, primary, Mauri, Mario, additional, D’Aliberti, Deborah, additional, Mezzatesta, Caterina, additional, Crespiatico, Ilaria, additional, Nava, Miriam, additional, Fontana, Diletta, additional, Sharma, Nitesh, additional, Parker, Wendy, additional, Schreiber, Andreas, additional, Yeung, David, additional, Pirola, Alessandra, additional, Readelli, Sara, additional, Massimino, Luca, additional, Wang, Paul, additional, Khandelwal, Praveen, additional, Citterio, Stefania, additional, Viltadi, Michela, additional, Bombelli, Silvia, additional, Rigolio, Roberta, additional, Perego, Roberto, additional, Boultwood, Jacqueline, additional, Morotti, Alessandro, additional, Saglio, Giuseppe, additional, Kim, Dong-Wook, additional, Branford, Susan, additional, Gambacorti-Passerini, Carlo, additional, and Piazza, Rocco, additional
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- 2019
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23. Synchrotron-based technique: a new high resolution imaging of nervous system
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Barbone, Giacomo, Ceresa, Cecilia, Monfrini, Marianna, Eckermann, Marina, Chiorazzi, Alessia, Canta, Annalisa, Bossi, Mario, Mittone, Alberto, Bravin, Alberto, Coan, Paola, Parlanti, Paola, Rigolio, Roberta, Cappello, Valentina, Gemmi, Mauro, Marmiroli, Paola, and Cavaletti, Guido
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Imaging, synchrotron, phase contrast micro-tomography, nervous system - Abstract
X-ray phase contrast micro-tomography (μPCI-CT) is a high resolution technique that can be used to investigate vascular and neurodegenerative disorders overcoming the limitations of the conventional imaging modalities. In fact, currently available neuroimaging techniques are based on sample-invasive imaging protocols involving dissections, staining or labeling of nervous system structures. On the other hand, μPCI-CT permits to visualize the spinal cord micro-vasculature, to detect single neuronal cells in the vertebral column and even cells infiltrating the nervous system in pathological conditions. These properties make μPCI-CT a potential powerful instrument in the study of vascular and neurodegenerative disorders as well as in the patient evaluation during medical treatment. Moreover, it would be a powerful instrument to localize in preclinical model of immune mediated diseases ectopic cells infiltrating the nervous system in a multifocal and unpredictable way. To optimize tissue fixation protocols for μPCI-CT analysis, several attempts were performed combining different protein and lipid fixation procedures and time points. The high-resolution synchrotron μPCI-CT setup allowed recognition of full-organ spinal cord anatomy of healthy rats, including anterior/posterior gray horns, the dorsal/ventral roots and ganglions, the central canal and the meninges, was clearly depicted. Superficial and deep vessels were visualized without need of any contrast-agent. At the highest resolution used, single neuronal cells perfused by surrounding vasculature were recognized allowing the detection of specific structure such as bundles of nerve fibers, single motor neurons and neuro-glial cells, cell bodies and axons as well as intra-cellular structure (i.e. cell nuclei and nucleoli). Moreover, in preclinical studies, the optimization of protocol for μPCI-CT allowed to localize ectopic infiltrating cells in nervous system organs in both mouse and rat models of Krabbe disease and Multiple Sclerosis which would allow a further accurate analysis of the areas and cell-parenchima fine interaction., Italian Journal of Anatomy and Embryology, Vol. 122, No. 1 (Supplement) 2017
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- 2017
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24. Animal Models for the Study of Human Central and Peripheral Nervous System Diseases
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MONZA, LAURA, FUMAGALLI, GIULIA, POZZI, ELEONORA, ALBERTI, PAOLA, CANTA, ANNALISA ROSANNA, CHIORAZZI, ALESSIA, MEREGALLI, CRISTINA, CAROZZI, VALENTINA ALDA, RIGOLIO, ROBERTA, OGGIONI, NORBERTO, MARMIROLI, PAOLA LORENA, CAVALETTI, GUIDO ANGELO, Monza, L, Fumagalli, G, Pozzi, E, Alberti, P, Canta, A, Chiorazzi, A, Meregalli, C, Carozzi, V, Rigolio, R, Oggioni, N, Marmiroli, P, and Cavaletti, G
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anima models, peripheral and central nervous diseases - Published
- 2017
25. Multimodal experimental approach to the study of human neurological diseases
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CHIORAZZI, ALESSIA, MEREGALLI, CRISTINA, CANTA, ANNALISA ROSANNA, CAROZZI, VALENTINA ALDA, OGGIONI, NORBERTO, RIGOLIO, ROBERTA, POZZI, ELEONORA, MONZA, LAURA, FUMAGALLI, GIULIA, MARMIROLI, PAOLA LORENA, CAVALETTI, GUIDO ANGELO, Alberti, A, Chiorazzi, A, Meregalli, C, Canta, A, Carozzi, V, Oggioni, N, Rigolio, R, Pozzi, E, Monza, L, Fumagalli, G, Alberti, A, Marmiroli, P, and Cavaletti, G
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experimental approach to human neurological diseases - Published
- 2017
26. Size and specimen-dependent strategy for x-ray micro-ct and tem correlative analysis of nervous system samples
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Parlanti, P, Cappello, V, Brun, F, Tromba, G, Rigolio, R, Tonazzini, I, Cecchini, M, Piazza, V, Gemmi, M, Gemmi, M., RIGOLIO, ROBERTA, Parlanti, P, Cappello, V, Brun, F, Tromba, G, Rigolio, R, Tonazzini, I, Cecchini, M, Piazza, V, Gemmi, M, Gemmi, M., and RIGOLIO, ROBERTA
- Abstract
Correlative approaches are a powerful tool in the investigation of biological samples, but require specific preparation procedures to maintain the strength of the employed methods. Here we report the optimization of the embedding protocol of nervous system samples for a correlative synchrotron X-ray computed microtomography (micro-CT) and transmission electron microscopy (TEM) approach. We demonstrate that it is possible to locate, with the micrometric resolution of micro-CT, specific volumes of interest for a further ultrastructural characterization to be performed with TEM. This approach can be applied to samples of different size and morphology up to several cm. Our optimized method represents an invaluable tool for investigating those pathologies in which microscopic alterations are localized in few confined regions, rather than diffused in entire tissues, organs or systems. We present a proof of concept of our method in a mouse model of Globoid Cells Leukodistrophy.
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- 2017
27. ApoE-modified solid lipid nanoparticles: A feasible strategy to cross the blood-brain barrier
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DAL MAGRO, R, Ornaghi, F, Cambianica, I, Beretta, S, Re, F, Musicanti, C, Rigolio, R, Donzelli, E, Canta, A, Ballarini, E, Cavaletti, G, Gasco, P, Sancini, G, DAL MAGRO, ROBERTA, ORNAGHI, FRANCESCA, CAMBIANICA, ILARIA NADIA, RE, FRANCESCA, RIGOLIO, ROBERTA, DONZELLI, ELISABETTA, CANTA, ANNALISA ROSANNA, BALLARINI, ELISA, CAVALETTI, GUIDO ANGELO, SANCINI, GIULIO ALFREDO, DAL MAGRO, R, Ornaghi, F, Cambianica, I, Beretta, S, Re, F, Musicanti, C, Rigolio, R, Donzelli, E, Canta, A, Ballarini, E, Cavaletti, G, Gasco, P, Sancini, G, DAL MAGRO, ROBERTA, ORNAGHI, FRANCESCA, CAMBIANICA, ILARIA NADIA, RE, FRANCESCA, RIGOLIO, ROBERTA, DONZELLI, ELISABETTA, CANTA, ANNALISA ROSANNA, BALLARINI, ELISA, CAVALETTI, GUIDO ANGELO, and SANCINI, GIULIO ALFREDO
- Abstract
Solid lipid nanoparticles (SLN) are colloidal drug delivery systems characterized by higher entrapment efficiency, good scalability of the preparation process and increased sustained prolonged release of the payload compared to other nanocarriers. The possibility to functionalize the surface of SLN with ligands to achieve a site specific targeting makes them attractive to overcome the limited blood-brain barrier (BBB) penetration of therapeutic compounds. SLN are prepared for brain targeting by exploiting the adaptability of warm microemulsion process for the covalent surface modification with an Apolipoprotein E-derived peptide (SLN-mApoE). Furthermore, the influence of the administration route on SLN-mApoE brain bioavailability is here evaluated. SLN-mApoE are able to cross intact a BBB in vitro model. The pulmonary administration of SLN-mApoE is related to a higher confinement in the brain of Balb/c mice compared to the intravenous and intraperitoneal administration routes, without inducing any acute inflammatory reaction in the lungs. These results promote the pulmonary administration of brain-targeted SLN as a feasible strategy for improving brain delivery of therapeutics.
- Published
- 2017
28. Animal Models for the Study of Human Central and Peripheral Nervous System Diseases
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Monza, L, Fumagalli, G, Pozzi, E, Alberti, P, Canta, A, Chiorazzi, A, Meregalli, C, Carozzi, V, Rigolio, R, Oggioni, N, Marmiroli, P, Cavaletti, G, MONZA, LAURA, FUMAGALLI, GIULIA, POZZI, ELEONORA, ALBERTI, PAOLA, CANTA, ANNALISA ROSANNA, CHIORAZZI, ALESSIA, MEREGALLI, CRISTINA, CAROZZI, VALENTINA ALDA, RIGOLIO, ROBERTA, OGGIONI, NORBERTO, MARMIROLI, PAOLA LORENA, CAVALETTI, GUIDO ANGELO, Monza, L, Fumagalli, G, Pozzi, E, Alberti, P, Canta, A, Chiorazzi, A, Meregalli, C, Carozzi, V, Rigolio, R, Oggioni, N, Marmiroli, P, Cavaletti, G, MONZA, LAURA, FUMAGALLI, GIULIA, POZZI, ELEONORA, ALBERTI, PAOLA, CANTA, ANNALISA ROSANNA, CHIORAZZI, ALESSIA, MEREGALLI, CRISTINA, CAROZZI, VALENTINA ALDA, RIGOLIO, ROBERTA, OGGIONI, NORBERTO, MARMIROLI, PAOLA LORENA, and CAVALETTI, GUIDO ANGELO
- Published
- 2017
29. Multimodal experimental approach to the study of human neurological diseases
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Chiorazzi, A, Meregalli, C, Canta, A, Carozzi, V, Oggioni, N, Rigolio, R, Pozzi, E, Monza, L, Fumagalli, G, Alberti, A, Marmiroli, P, Cavaletti, G, CHIORAZZI, ALESSIA, MEREGALLI, CRISTINA, CANTA, ANNALISA ROSANNA, CAROZZI, VALENTINA ALDA, OGGIONI, NORBERTO, RIGOLIO, ROBERTA, POZZI, ELEONORA, MONZA, LAURA, FUMAGALLI, GIULIA, MARMIROLI, PAOLA LORENA, CAVALETTI, GUIDO ANGELO, Chiorazzi, A, Meregalli, C, Canta, A, Carozzi, V, Oggioni, N, Rigolio, R, Pozzi, E, Monza, L, Fumagalli, G, Alberti, A, Marmiroli, P, Cavaletti, G, CHIORAZZI, ALESSIA, MEREGALLI, CRISTINA, CANTA, ANNALISA ROSANNA, CAROZZI, VALENTINA ALDA, OGGIONI, NORBERTO, RIGOLIO, ROBERTA, POZZI, ELEONORA, MONZA, LAURA, FUMAGALLI, GIULIA, MARMIROLI, PAOLA LORENA, and CAVALETTI, GUIDO ANGELO
- Published
- 2017
30. Human Mesenchymal Stem Cells and Endothelial Progenitor Cells exert a neuroprotective effect on rat cortical neurons injured by oxygen and glucose deprivation
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Donzelli, Elisabetta, Nicolini, Gabriella, Scuteri, Arianna, De Cristofaro, Valentina, Rigolio, Roberta, Ceresa, Cecilia, and Miloso, Mariarosaria
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nervous system ,Mesenchymal stem cells ,endothelial progenitor cells: oxygen and glucose deprivation ,embryonic cortical neurons - Abstract
Oxygen and glucose deprivation (OGD) due to ischemic events or trauma in the brain result in neuronal loss. The therapeutic approaches available inadequate and often the outcome is unfavorable for the patient or at least unpredictable. Stem cells could be useful for the treatment of OGD injured-neurons. Mesenchymal Stem Cells (MSCs), isolated from bone marrow as well as from various tissues, have poor immunogenicity and neuroprotective properties being able to alleviate ischemic brain injuries in animal models. The Endothelial Progenitor Cells (EPCs) are present at low frequencies both in the bone marrow and in the peripheral blood. They are thought to play a role in the recovery of cerebrovasculature integrity after stroke. In the present study we evaluated the potential neuroprotective effect of human MSCs and human EPCs on rat embryonic cortical neurons injured by OGD. OGD was induced by incubating the cortical neurons in a hypoxia chamber in a 95% N2 + 5% CO2 atmosphere at 37°C without glucose. To set up the experimental protocol, OGD was maintained for 1, 2 and 3 hours. The neurons were returned in normoxic atmosphere and after 2 and 5 days neuronal survival was evaluated by MTT assay, LDH assay and viable cellular counting. The 2 hours OGD was able to reduce neuronal viability by 50% and was chosen for the subsequent experiments. To assess MSCs and EPCs neuroprotective action, after 2 hours-long OGD the neurons were 1) co-cultured with either MSCs or EPCs seeded on a cell culture insert avoiding direct contact while sharing the same medium, or 2) cultured in a medium previously conditioned by either MSCs or EPCs. Neuronal survival was evaluated by MTT assay after 2 and 5 days. Both MSCs and EPCs increased neuronal survival after ODG. The effect was observed in absence of a direct contact between MSCs or EPCs and the injured neurons, suggesting that the release of soluble factors may be involved in their neuroprotective action. In conclusion both MSCs and EPCs could represent a potential therapeutic approach for the treatment of brain ischemic injury. Further studies are needed to identify the specific molecules and pathways that play a role in the neuroprotective effect of MSCs and EPCs., Italian Journal of Anatomy and Embryology, Vol. 120, No. 1 (Supplement) 2015
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- 2015
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31. Anti-inflammatory properties of a testosterone metabolite in an experimental model of multiple sclerosis
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Romano, S, Giatti, S, Viviani, B, Garcia Segura, L, Melcangi, R., RIGOLIO, ROBERTA, CAVALETTI, GUIDO ANGELO, Romano, S, Giatti, S, Rigolio, R, Viviani, B, Cavaletti, G, Garcia Segura, L, and Melcangi, R
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BIO/16 - ANATOMIA UMANA ,Multiple sclerosis,Experimental autoimmune encephalomyelitis, neurosteroids, dihydrotestosterone, neuroinflammation - Abstract
Multiple sclerosis (MS) is an autoimmune disease affecting the CNS and characterized by neuroinflammation. Clinical observations revealed different incidence between males and females, suggesting a possible influence of sex steroids. These molecules, produced by peripheral steroidogenic glands, can exert their actions into the CNS, directly, or after metabolic conversion, and, for this reason, they are also called neuroactive steroids. Observations on experimental autoimmune encephalomyelitis (EAE) rodents, the most used animal model for MS, also suggest an involvement for neuroactive steroids in the pathology. In particular, castration worsen, while testosterone or its metabolite dihydrotestosterone (DHT) improve the pathological course of the disease. Based on these evidences, male Dark Agouti rats were induced with EAE in order to develop a relapsing-remitting pathology, similar to the most common human form of MS. EAE animals were treated with DHT or vehicle (sesame oil) and monitored through the experiment. After 45 days post induction, we evaluated inflammatory parameters in spinal cord tissues. The pathological course was improved in EAE rats treated with DHT compared to vehicle. Moreover, neuroinflammatory parameters such as microglial and astrocytes markers as well as cytokine expression and thiobarbituric acid-reactive substances, that were increased in the EAE-vehicle group, are significantly reduced after treatment with DHT. In conclusion, DHT treatment ameliorates not only the pathological course of the disease but also neuroinflammatory parameters in spinal cord tissues. These observations may suggest DHT as potential therapeutic option for male MS patients.
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- 2015
- Full Text
- View/download PDF
32. Synergistic activity of ALK and mTOR inhibitors for the treatment of NPM-ALK positive lymphoma
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Redaelli, S, Ceccon, M, Antolini, L, Rigolio, R, Pirola, A, Peronaci, M, GAMBACORTI PASSERINI, C, Mologni, L, REDAELLI, SARA, CECCON, MONICA, ANTOLINI, LAURA, RIGOLIO, ROBERTA, PIROLA, ALESSANDRA, PERONACI, MARCO, GAMBACORTI PASSERINI, CARLO, MOLOGNI, LUCA, Redaelli, S, Ceccon, M, Antolini, L, Rigolio, R, Pirola, A, Peronaci, M, GAMBACORTI PASSERINI, C, Mologni, L, REDAELLI, SARA, CECCON, MONICA, ANTOLINI, LAURA, RIGOLIO, ROBERTA, PIROLA, ALESSANDRA, PERONACI, MARCO, GAMBACORTI PASSERINI, CARLO, and MOLOGNI, LUCA
- Abstract
ALK-positive Anaplastic Large Cell Lymphoma (ALCL) represents a subset of Non-Hodgkin Lymphoma whose treatment benefited from crizotinib development, a dual ALK/MET inhibitor. Crizotinib blocks ALK-triggered pathways such as PI3K/AKT/ mTOR, indispensable for survival of ALK-driven tumors. Despite the positive impact of targeted treatment in ALCL, resistant clones are often selected during therapy. Strategies to overcome resistance include the design of second generation drugs and the use of combined therapies that simultaneously target multiple nodes essential for cells survival. We investigated the effects of combined ALK/mTOR inhibition. We observed a specific synergistic effect of combining ALK inhibitors with an mTOR inhibitor (temsirolimus), in ALK+ lymphoma cells. The positive cooperation resulted in an increased inhibition of mTOR effectors, compared to single treatments, a block in G0/G1 phase and induction of apoptosis. The combination was able to prevent the selection of resistant clones, while longterm exposure to single agents led to the establishment of resistant cell lines, with either ALK inhibitor or temsirolimus. In vivo, mice injected with Karpas 299 cells and treated with low dose combination showed complete regression of tumors, while only partial inhibition was obtained in single agents-treated mice. Upon treatment stop the combination was able to significantly delay tumor relapses. Re-challenge of relapsed tumors at a higher dose led to full regression of xenografts in the combination group, but not in mice treated with lorlatinib alone. In conclusion, our data suggest that the combination of ALK and mTOR inhibitors could be a valuable therapeutic option for ALK+ ALCL patients.
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- 2016
33. Excess of NPM-ALK oncogenic signaling promotes cellular apoptosis and drug dependency
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Ceccon, M, Merlo, M, Mologni, L, Poggio, T, Varesio, L, Menotti, M, Bombelli, S, Rigolio, R, Manazza, A, Di Giacomo, F, Ambrogio, C, Giudici, G, Casati, C, Mastini, C, Compagno, M, Turner, S, GAMBACORTI PASSERINI, C, Chiarle, R, Voena, C, CECCON, MONICA, MOLOGNI, LUCA, BOMBELLI, SILVIA, RIGOLIO, ROBERTA, CASATI, COSTANZA, MASTINI, CRISTINA, GAMBACORTI PASSERINI, CARLO, Voena, C., Ceccon, M, Merlo, M, Mologni, L, Poggio, T, Varesio, L, Menotti, M, Bombelli, S, Rigolio, R, Manazza, A, Di Giacomo, F, Ambrogio, C, Giudici, G, Casati, C, Mastini, C, Compagno, M, Turner, S, GAMBACORTI PASSERINI, C, Chiarle, R, Voena, C, CECCON, MONICA, MOLOGNI, LUCA, BOMBELLI, SILVIA, RIGOLIO, ROBERTA, CASATI, COSTANZA, MASTINI, CRISTINA, GAMBACORTI PASSERINI, CARLO, and Voena, C.
- Abstract
Most of the anaplastic large-cell lymphoma (ALCL) cases carry the t(2;5; p23;q35) that produces the fusion protein NPM-ALK (nucleophosmin-anaplastic lymphoma kinase). NPM-ALK-deregulated kinase activity drives several pathways that support malignant transformation of lymphoma cells. We found that in ALK-rearranged ALCL cell lines, NPM-ALK was distributed in equal amounts between the cytoplasm and the nucleus. Only the cytoplasmic portion was catalytically active in both cell lines and primary ALCL, whereas the nuclear portion was inactive because of heterodimerization with NPM1. Thus, about 50% of the NPMALK is not active and sequestered as NPM-ALK/NPM1 heterodimers in the nucleus. Overexpression or relocalization of NPM-ALK to the cytoplasm by NPM genetic knockout or knockdown caused ERK1/2 (extracellular signal-regulated protein kinases 1 and 2) increased phosphorylation and cell death through the engagement of an ATM/Chk2-and ãH2AX (phosphorylated H2A histone family member X)-mediated DNA-damage response. Remarkably, human NPM-ALK-amplified cell lines resistant to ALK tyrosine kinase inhibitors (TKIs) underwent apoptosis upon drug withdrawal as a consequence of ERK1/2 hyperactivation. Altogether, these findings indicate that an excess of NPM-ALK activation and signaling induces apoptosis via oncogenic stress responses. A 'drug holiday' where the ALK TKI treatment is suspended could represent a therapeutic option in cells that become resistant by NPM-ALK amplification.
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- 2016
34. Multiple Neuroprotective Mechanisms of Mesenchymal Stem Cells
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SCUTERI, ARIANNA, MONFRINI, MARIANNA, DONZELLI, ELISABETTA, BALLARINI, ELISA, RIGOLIO, ROBERTA, CHIORAZZI, ALESSIA, MEREGALLI, CRISTINA, TREDICI, GIOVANNI, Scuteri, A, Monfrini, M, Donzelli, E, Ballarini, E, Rigolio, R, Chiorazzi, A, Meregalli, C, and Tredici, G
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BIO/16 - ANATOMIA UMANA ,Mesenchymal Stem Cells ,Neurodegenerative disease - Abstract
Neurodegenerative diseases are different and many-sided disorders affecting both the Central and the Peripheral Nervous System. Despite the very different peculiar features, all the neurodegenerative diseases are characterized by the neuronal degeneration, which may be the consequence of different processes, such as an altered protein accumulation, an axonal damage, or the exposure to toxic agents. The progressive neuronal death leads to disease progression, which is not effectively counteracted by the current symptomatic therapies. Among the newly proposed therapeutic approaches, encouraging results have been obtained with Mesenchymal Stem Cells (MSCs), adult stem cells initially proposed for their differentiation potential and for their immune-modulatory abilities. Here we first verified in vivo the protective potential of MSCs into an in vivo model of Multiple Sclerosis (MS), represented by Experimental Autoimmune Encephalomyelitis (EAE), demonstrating that intravenous administration of MSCs are able to ameliorate the clinical score and the functional skills, and to reduce demyelinated lesions. We then investigated in vitro the possible molecular mechanisms of MSC protective action, thus demonstrating that, besides immunomodulation, MSCs are able to support neuronal survival after toxic stimuli exposure by reducing the apoptosis and by inhibiting the Metalloprotease pathway, which is supposed to be involved in neurodegenerative disease progression. Moreover, MSCs are able to promote the axonal myelination through the modulation of p75 receptor. For all these abilities, MSCs can represent a promising therapeutic approach for the treatment of neurodegenerative disorders.
- Published
- 2014
35. 3 alpha-diol, a testosterone metabolite, has anti-inflammatory properties in the experimental autoimmune encephalomyelitis model
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Giatti, S, Romano, S, Calabrese, D, Carrero, P, Abbiati, F, Boraso, M, Viviani, B, Caruso, D, Garcia Segura, L, Melcangi, R., RIGOLIO, ROBERTA, CAVALETTI, GUIDO ANGELO, Giatti, S, Romano, S, Rigolio, R, Calabrese, D, Carrero, P, Abbiati, F, Boraso, M, Viviani, B, Cavaletti, G, Caruso, D, Garcia Segura, L, and Melcangi, R
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BIO/16 - ANATOMIA UMANA ,neurosteroids, 3 alpha-diol, experimental autoimmune encephalomyelitis, multiple sclerosis, inflammation - Abstract
Multiple sclerosis (MS) is an autoimmune pathology characterized by inflammatory and demyelinating phases. Clinical observations indicate an involvement for sex hormones in thepathology, so that, recently, a therapy for MS based on hormones has been proposed. A clinicaltrial, involving male MS patients, revealed improvement in cognitive performances after one yeartreatment with testosterone (Sicotte et al., 2007). In the experimental autoimmune encephalomyelitis (EAE) mice, a MS animal model, neuroprotective effects of testosterone, and of its metabolite dihydrotestosterone (DHT), were observed (Dalal et al., 1997; Palaszynski et al.,2004). In the same model, castration has deleterious effects on clinical course, suggesting a protective role for androgens (Bebo et al., 1998). Moreover, in vitro evidences showed that testosterone is able to reduce inflammatory cytokines produced by human macrophages (D’Agostino et al., 1999) and monocytes (Li et al., 1993; Liva and Voskuhl, 2001). These antiinflammatory properties may be mediated by the conversion of testosterone into estradiol, or, alternatively, by some direct effects on androgen receptor (AR), mediated by DHT. This steroid can be subsequently converted into 3 alpha-diol, a GABAA receptor agonist, acting as antiinflammatory agent. Based on these evidences, we were interested in explore the protective effects of androgens treatment in a rat EAE model characterized by acute inflammatory events. We induced male Lewis rats with myelin basic protein in order to develop EAE; animals were treated with 3 alpha-diol or vehicle (sesame oil) every other day for two weeks, whereas control rats (i.e., rats not induced with EAE) received in same days only vehicle. Neurological deficits were assessed throughout the experiment (i.e., until 15 days post induction; dpi), and, at 15dpi, spinal cords were dissected. The clinical course and the weight loss of EAE rats treated with 3 alpha-diol were not different when compared to vehicle treated animals. Significant differences between these two groups were instead observed in the spinal cord after immunostaining analysis for the glial fibrillary acidic protein and the major histocompatibility complex class II, where 3 alpha-diol treatment was able to reduce the inflammatory parameters. In agreement with this observation, gene expression for tumor necrosis factor alpha, a pro-inflammatory cytokine, was decreased after 3 alpha-diol administration compared to oil-treated EAE animals. This effect seems specific for proinflammatory cytokine, because the expression of transforming growth factor beta 1, an antiinflammatory cytokine, was not different between vehicle and 3 alpha-diol treated EAE rats. To asses the metabolic fate of the injected 3 alpha-diol, liquid chromatography tandem mass spectrometry analysis were performed in spinal cord from all groups. 3 alpha-diol levels were significantly increased in steroid treated animals; moreover, a significant raise in DHT levels was observed in the same animals, indicating a retroconversion of 3 alpha-diol into DHT. The data we obtained may suggest that the reduction of inflammatory parameters could be due by both the action of DHT on AR and/or of 3 alpha-diol on GABAA receptor. These observations pointed out, for the first time, the effects of 3 alpha-diol on inflammatory parameters in EAE Lewis rats. Future studies will be aimed to elucidate the involvement of androgen and/or GABAA receptors on the observed effects.
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- 2014
36. Anti-proliferative and anti-migratory effects of baicalin on cholangiocarcinoma cell line egi-1
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Rigolio, Roberta, Cadamuro, Massimiliano, Caramia, Grazia, Malacrida, Alessio, Maggioni, Daniele, Foudah, Dana, Miloso, Mariarosaria, Rigolio, R, Cadamuro, M, Caramia, G, Malacrida, A, Maggioni, D, Foudah, D, and Miloso, M
- Subjects
BIO/16 - ANATOMIA UMANA ,Cholangiocarcinoma, EGI-1 cells, Baicalin, cell viability, cell migration ,Cholangiocarcinoma ,EGI-1 cells ,Baicalin ,cell viability ,cell migration - Abstract
Cholangiocarcinoma (CCA) is the second most frequent primary liver neoplasia. It mainly arises from the malignant transformation of biliary epithelial cells, although it might originate from either hepatic progenitor cells at the Hering canals or transformed hepatocytes. CCA is a highly aggressive tumor with extremely poor prognosis and limited therapeutic approaches. Baicalin (BA) is one of the main bioactive flavonoids identified in the Scutellaria Baicalensis Georgi root dried extract which is extensively used in the Chinese traditional medicine. Together with the anti-inflammatory effect, the anti-neoplastic action is the most relevant BA property demonstrated on cancer cells of different origin. Being aware of the need of new therapeutic weapons for CCA treatment, we investigated whether Baicalin could exert anti-proliferative and anti-migratory effect on EGI-1 cells, a highly metastatic CCA cell line derived from bile duct carcinoma. We first tested different BA concentrations (from 5 to 200μM) in limiting EGI-1 viability using MTT assay. After 24h and 48h treatment, 5 and 10μM BA had no effect while rising from 25μM to 200μM (i.e. 25, 50, 100 and 200μM) BA exerted a significant cell viability reduction already at 24h and increased after 48h BA exposure. This reduction well correlated with the adherent absolute cell number decrease and it cannot be due to BA induced cell cycle impairment after neither 24 nor 48h treatment. We also evaluated the anti-migratory BA potential by a wound healing assay adding different BA concentrations (5, 25, 50,100 and 200μM) to the culture medium immediately after performing a wound on confluent cell cultures. All BA concentrations but 5μM induced a significant reduction in the EGI-1 migration rate after 24h treatment. Moreover 25, 50 and 10μM BA showed similar migration inhibition extent at 24 and 48h whilst 200μM BA exerted a stronger inhibitory effect already after 24h exposure which increased with time in a significant way. Taken together our preliminary results demonstrate that BA impairs CCA cell viability and migration suggesting a promising adjuvant therapeutic use for BA as antitumoral agent., Italian Journal of Anatomy and Embryology, Vol 119, No 1 (Supplement) 2014
- Published
- 2014
37. In Vitro and in Vivo Characterization of Bosutinib as Substrate of the Pglycoprotein Efflux Transporter
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REDAELLI, SARA, PERINI, PIETRO, CECCON, MONICA, PIAZZA, ROCCO GIOVANNI, RIGOLIO, ROBERTA, GAMBACORTI PASSERINI, CARLO, Boschelli, F, Giannoudis, A, Redaelli, S, Perini, P, Ceccon, M, Piazza, R, Rigolio, R, Boschelli, F, Giannoudis, A, and GAMBACORTI PASSERINI, C
- Subjects
BIO/16 - ANATOMIA UMANA ,CML, Drug resistance, drug transporters ,MED/15 - MALATTIE DEL SANGUE - Published
- 2014
38. Functional Magnetic Resonance Imaging Reveals Brain Cortex Remodeling in a Rat Model of Chronic Multiple Sclerosis
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Tambalo, S, Fiorini, S, Bontempi, P, Sbarbati, A, Pluchino, S, Marzola, P., RIGOLIO, ROBERTA, CAVALETTI, GUIDO ANGELO, MARMIROLI, PAOLA LORENA, Tambalo, S, Fiorini, S, Rigolio, R, Bontempi, P, Sbarbati, A, Cavaletti, G, Marmiroli, P, Pluchino, S, and Marzola, P
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BIO/16 - ANATOMIA UMANA ,Experimental Autoimmune Encephalomyelitis, functional MRI, brain activation - Abstract
Experimental Autoimmune Encephalomyelitis (EAE) is a good model of Multiple Sclerosis in rodents. We have applied fMRI to invesigate the alteration in functional response in rats induced with EAE. Cortical activation is altered in EAE rat brain, compared to controls. fMRI showed an increase in the activated volume involving also the cortex ipsilateral and some extra-cortical areas at the observed time points. These results demonstrate brain cortex remodeling in EAE, a remakable feature of MS. The present model seems to be a relevant tool in preclinical MS studies.
- Published
- 2014
39. Synergistic activity of ALK and mTOR inhibitors for the treatment of NPM-ALK positive lymphoma
- Author
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Redaelli, Sara, primary, Ceccon, Monica, additional, Antolini, Laura, additional, Rigolio, Roberta, additional, Pirola, Alessandra, additional, Peronaci, Marco, additional, Gambacorti-Passerini, Carlo, additional, and Mologni, Luca, additional
- Published
- 2016
- Full Text
- View/download PDF
40. Therapeutic Administration of Mesenchymal Stem Cells Abrogates the Relapse Phase in Chronic Relapsing-Remitting EAE
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Scuteri, A, Donzelli, E, Rigolio, R, Ballarini, E, Monfrini, M, Crippa, L, Chiorazzi, A, Carozzi, V, Meregalli, C, Canta, A, Oggioni, N, Tredici, G, Cavaletti, G, SCUTERI, ARIANNA, DONZELLI, ELISABETTA, RIGOLIO, ROBERTA, BALLARINI, ELISA, MONFRINI, MARIANNA, CHIORAZZI, ALESSIA, CAROZZI, VALENTINA ALDA, MEREGALLI, CRISTINA, CANTA, ANNALISA ROSANNA, OGGIONI, NORBERTO, TREDICI, GIOVANNI, CAVALETTI, GUIDO ANGELO, Scuteri, A, Donzelli, E, Rigolio, R, Ballarini, E, Monfrini, M, Crippa, L, Chiorazzi, A, Carozzi, V, Meregalli, C, Canta, A, Oggioni, N, Tredici, G, Cavaletti, G, SCUTERI, ARIANNA, DONZELLI, ELISABETTA, RIGOLIO, ROBERTA, BALLARINI, ELISA, MONFRINI, MARIANNA, CHIORAZZI, ALESSIA, CAROZZI, VALENTINA ALDA, MEREGALLI, CRISTINA, CANTA, ANNALISA ROSANNA, OGGIONI, NORBERTO, TREDICI, GIOVANNI, and CAVALETTI, GUIDO ANGELO
- Abstract
Multiple Sclerosis (MS) is a neuroinflammatory and immune-mediated chronic disease of the Central Nervous System which progressively damages the axonal myelin sheath, leading to axonal transmission impairment and to the development of neurological symptoms. Most MS cases are characterized by a relapsing-remitting course, and current therapies rely only on the use of immunomodulating drugs which are, however, unable to reverse disease progression. Among the newly proposed alternative therapies, Mesenchymal Stem Cells (MSCs) are considered suitable for MS treatment due to their capacity to modulate the immune response and to modify the pattern of the released cytokines. So far, encouraging results have been obtained with the administration of MSCs before disease onset, mainly in animal models of acute Experimental Autoimmune Encephalomyelitis (EAE) in which MSCs were able to reduce inflammation, thus ameliorating also the disease’s clinical symptoms. On the contrary, only a very small number of studies have investigated the effect of MSCs on relapsing-remitting models of the disease. Here, we investigated the therapeutic potential of MSC administration, both before and after the disease’s onset, in an animal model of MS represented by Dark Agouti rats affected by chronic Relapsing-Remitting EAE. Our results demonstrated that in chronic Relapsing-Remitting EAE the administration of MSCs after the clinical disease’s appearance is able to completely abrogate the relapsing phase and to strongly reduce spinal cord demyelination. These encouraging results have demonstrated that MSCs can provide a protective and reparative strategy for MS treatment.
- Published
- 2015
41. In vitro and in vivo identification of ABCB1 as an efflux transporter of bosutinib
- Author
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Redaelli, S, Perini, P, Ceccon, M, Piazza, R, Rigolio, R, Mauri, M, Boschelli, F, Giannoudis, A, GAMBACORTI PASSERINI, C, REDAELLI, SARA, PERINI, PIETRO, CECCON, MONICA, PIAZZA, ROCCO GIOVANNI, RIGOLIO, ROBERTA, MAURI, MARIO, GAMBACORTI PASSERINI, CARLO, Redaelli, S, Perini, P, Ceccon, M, Piazza, R, Rigolio, R, Mauri, M, Boschelli, F, Giannoudis, A, GAMBACORTI PASSERINI, C, REDAELLI, SARA, PERINI, PIETRO, CECCON, MONICA, PIAZZA, ROCCO GIOVANNI, RIGOLIO, ROBERTA, MAURI, MARIO, and GAMBACORTI PASSERINI, CARLO
- Abstract
Background: Bosutinib is a recently approved ABL inhibitor. In spite of the well-documented effectiveness of BCR-ABL inhibitors in treating chronic myeloid leukemia, development of resistance is a continuous clinical challenge. Transporters that facilitate drug uptake and efflux have been proposed as one potential source of resistance to tyrosine kinase inhibitor treatment. Our aim was to determine which carriers are responsible for bosutinib transport. Methods: K562S cells overexpressing the drug transporters ABCB1, ABCG2, and SLC22A1 were generated, characterized and used in proliferation assay and intracellular uptake and retention assay (IUR). In vivo experiments were performed in nude mice injected with K562S, K562DOX cells (overexpressing ABCB1), and K562DOX silenced for ABCB1 (K562DOX/sh P-GP). Results: The IUR assay using C-14 bosutinib showed that only ABCB1 was responsible for active bosutinib transport. K562DOX cells showed the lowest intracellular level of bosutinib, while K562DOX cells treated with the ABCB1 inhibitor verapamil showed intracellular bosutinib levels comparable with parental K562S. Proliferation assays demonstrated that K562DOX are resistant to bosutinib treatment while verapamil is able to restore the sensitivity to the drug. Nude mice injected with K562DOX and treated with bosutinib showed very limited response and quickly relapsed after stopping treatment while K562S as well as K562DOX/sh P-GP remained tumor-free. Conclusions: Our data suggest that the analysis of ABCB1 expression levels might help determine treatment options for patients exhibiting resistance to bosutinib.
- Published
- 2015
42. Functional Magnetic Resonance Imaging of Rats with Experimental Autoimmune Encephalomyelitis Reveals Brain Cortex Remodeling
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Tambalo, S, Peruzzotti Jametti, L, Rigolio, R, Fiorini, S, Bontempi, P, Mallucci, G, Balzarotti, B, Marmiroli, P, Sbarbati, A, Cavaletti, G, Pluchino, S, Marzola, P, RIGOLIO, ROBERTA, MARMIROLI, PAOLA LORENA, CAVALETTI, GUIDO ANGELO, Marzola, P., Tambalo, S, Peruzzotti Jametti, L, Rigolio, R, Fiorini, S, Bontempi, P, Mallucci, G, Balzarotti, B, Marmiroli, P, Sbarbati, A, Cavaletti, G, Pluchino, S, Marzola, P, RIGOLIO, ROBERTA, MARMIROLI, PAOLA LORENA, CAVALETTI, GUIDO ANGELO, and Marzola, P.
- Abstract
Cortical reorganization occurring in multiple sclerosis(MS)patients isthoughtto playakeyrole in limiting the effect of structural tissuedamage. Conversely, its exhaustionmaycontribute to the irreversible disability that accumulates with disease progression. Several aspects of MS-related cortical reorganization, including the overall functional effect and likely modulation by therapies, still remain to be elucidated. The aim of this work was to assess the extent of functional cortical reorganization and its brain structural/pathological correlates in Dark Agouti rats with experimental autoimmune encephalomyelitis (EAE), a widely accepted preclinical model of chronic MS. Morphological and functional MRI (fMRI) were performed before disease induction and during the relapsing and chronic phases of EAE. During somatosensory stimulation of the right forepaw, fMRI demonstrated that cortical reorganization occurs in both relapsing and chronic phases of EAE with increased activated volume and decreased laterality index versus baseline values. Voxel-based morphometry demonstrated gray matter (GM) atrophy in the cerebral cortex, and both GM and white matter atrophy were assessed by ex vivo pathology of the sensorimotor cortex and corpus callosum. Neuroinflammation persisted in the relapsing and chronic phases, with dendritic spine density in the layer IV sensory neurons inversely correlating with the number of cluster of differentiation 45-positive inflammatory lesions. Our work provides an innovative experimental platform that may be pivotal for the comprehension of key mechanisms responsible for the accumulation of irreversible brain damage and for the development of innovative therapies to reduce disability in EAE/MS.
- Published
- 2015
43. Evaluation of brain activity changes occurring in an animal model for multiple sclerosis: a functional Magnetic Resonance Imaging study
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RIGOLIO, ROBERTA, MARMIROLI, PAOLA LORENA, CAVALETTI, GUIDO ANGELO, RODRIGUEZ MENENDEZ, VIRGINIA, Fiorini, S, Tambalo, S, Marzola, P., Rigolio, R, Marmiroli, P, Cavaletti, G, RODRIGUEZ MENENDEZ, V, Fiorini, S, Tambalo, S, and Marzola, P
- Subjects
Experimental Autoimmune Encephalomyelitis (EAE) ,functional MRI (fMRI) ,brain plasticity ,Multiple sclerosis, experimental autoimmune encephalomyelitis, functional MRI (fMRI), brain activity ,BIO/16 - ANATOMIA UMANA - Abstract
Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Magnetic Resonance Imaging (MRI), showing the extent of the involvement of CNS, plays a major role in the assessment of patients with MS. Further information can be obtained with functional MRI (fMRI) which may be used in MS patients to investigate the functional reorganization of cortical areas. fMRI observations in MS are already available in humans, but deeper knowledge on its usefulness might be gained using reliable animal models. We investigated by means of fMRI the brain plasticity in a chronic model of MS, i.e. Experimental Autoimmune Encephalomyelitis (EAE) in the Dark Agouti (DA) rat strain. Serial fMRI acquisitions were performed before, 30 and 60 days after EAE induction. fMRI with somatosensory stimulation was performed according to ref [1]. Briefly electrical stimulation (a train of squared pulses with frequency=3Hz, current=2mA, duration=0.5ms) was delivered to the left forepaw during acquisition of MR images sensitive to Blood-Volume. A single stimulation protocol was composed of 30 images under rest condition and 10 images acquired during stimulation. After appropriate image analysis, performed using the FSL software package [2], the brain region activated by the applied stimulus was determined. Prior to EAE induction, electrical stimulation resulted in a localized response in the contralateral sensory motor cortex according to previously reported results [1]. Thirty and 60 days after EAE Induction, the activated area was greatly increased covering large regions of both contra and ipsilateral somatosensory cortex and extending also to extra-cortical regions. Our results show that the experimental model of EAE in DA rats reproduces a remarkable findings observed in MS patients, i.e. the functional reorganization of motor cortex. It remains to be investigated whether this effect could represent an innovative platform for testing new therapeutic approaches for MS., Italian Journal of Anatomy and Embryology, Vol 117, No 2 (Supplement) 2012
- Published
- 2013
- Full Text
- View/download PDF
44. Effectiveness of MSC therapeutic administration on rats affected by chronic Experimental Autoimmune Encephalomyelitis
- Author
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SCUTERI, ARIANNA, DONZELLI, ELISABETTA, RIGOLIO, ROBERTA, BALLARINI, ELISA, MONFRINI, MARIANNA, CHIORAZZI, ALESSIA, SALA, BARBARA, MEREGALLI, CRISTINA, TREDICI, GIOVANNI, CAVALETTI, GUIDO ANGELO, Scuteri, A, Donzelli, E, Rigolio, R, Ballarini, E, Monfrini, M, Chiorazzi, A, Sala, B, Meregalli, C, Cavaletti, G, and Tredici, G
- Subjects
BIO/16 - ANATOMIA UMANA ,Multiple Sclerosi ,Mesenchymal STem Cells - Abstract
Multiple sclerosis (MS) is a severe chronic disease characterized by the presence of immuno-mediated demyelinating lesions and impairment of axonal transmission, which cause the reduction of nerve conduction velocity and lead to the development of neurological symptoms. Current therapy for MS is based on immunosuppressant agents, but recently Mesenchymal Stem Cells (MSCs) have been proposed as therapeutic treatment for MS, demonstrating a positive effect when administered before disease onset, mainly due to their immunomodulatory properties. Here, we investigate the therapeutic potential of MSCs into an animal model of multiple sclerosis, represented by Dark Agouti rats affected by chronic Relapsing-Remitting experimental autoimmune encephalomyelitis (EAE). In order to assess their putative effectiveness, 106 MSC were intravenously injected in EAE rats before disease onset (7 days after disease induction), to test the “preventive” schedule, or after disease onset (14 days after MSC induction), to test the “therapeutic” schedule with MSCs. Clinical score was assessed daily, and after 45 days rats were sacrificed and histological analysis of spinal cords were performed to evaluate the demyelinating lesions. Clinical score analysis demonstrated that the “preventive” schedule of treatment had no effect on EAE clinical course, while the therapeutic schedule was able to hamper relapsing phase from day 19 and till the end of the experiment (day 45) with respect to EAE group. At day 45, histological analysis performed on spinal cords of EAE rats demonstrated the presence of demyelinated plaques, assessed by Luxol fast Blue staining and by immunohystochemistry for MBP. The same lesions were present in spinal cords of rats treated with the preventive MSC administration. On the contrary the therapeutic schedule with MSCs was able to significantly reduce the extension of demyelinated areas in the spinal cords, thus confirming clinical score evaluations. These results suggested that MSCs are able to ameliorate the clinical course of EAE animals and to hamper the disease relapsing by reducing the areas of demyelinated lesions. We are now evaluating the possible mechanism of MSCs action by investigating some putative myelinating properties of MSCs.
- Published
- 2013
45. Positive effect of Mesenchymal Stem Cells therapeutic administration on chronic Experimental Autoimmune Encephalomyelitis
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Scuteri, Arianna, Donzelli, Elisabetta, Rigolio, Roberta, Ballarini, Elisa, Monfrini, Marianna, Ravasi, Maddalena, Chiorazzi, Alessia, Sala, Barbara, Meregalli, Cristina, Tredici, Giovanni, Scuteri, A, Donzelli, E, Rigolio, R, Ballarini, E, Monfrini, M, Ravasi, M, Chiorazzi, A, Sala, B, Meregalli, C, and Tredici, G
- Subjects
Mesenchymal stem cells, chronic EAE, demyelination ,BIO/16 - ANATOMIA UMANA ,mesenchymal stem cells ,chronic EAE ,demyelination - Abstract
Multiple Sclerosis (MS) is a crippling chronic disease of the Central Nervous System caused by the presence of self-antibodies which progressively damage axonal myelin sheath, leading to axonal transmission impairment and to the development of neurological symptoms. MS is characterized by a Relapsing-Remitting course, and current therapies rely only on the use of immunosuppressive drugs, which are however unable to reverse disease progression. Encouraging results have been obtained in preclinical studies with the administration of Mesenchymal Stem Cells (MSCs) before disease onset (Zappia et al., 2005). Here, we investigate the therapeutic potential of MSC administration after disease onset into an animal model of MS, represented by Dark Agouti rats affected by chronic Relapsing-Remitting Experimental Autoimmune Encephalomyelitis (EAE) (Cavaletti et al., 2004). 106 MSC were intravenously injected in EAE rats after disease onset. Clinical score was assessed daily, and after 45 days rats were sacrificed and histological analysis of spinal cords performed to evaluate the demyelinating lesions. After the first peak of disease, no further relapses were observed in EAE rats treated with MSCs, differently from what observed in EAE group. Histological analysis demonstrated the presence of demyelinated plaques in spinal cords of EAE rats, (Luxol fast Blue staining and anti-MBP immunohystochemistry). On the contrary the therapeutic schedule with MSCs significantly reduces the number and the extension of demyelinated areas in the spinal cords, confirming clinical score evaluations. These results demonstrated that MSCs ameliorate the clinical course of EAE and hamper the disease relapsing by reducing the areas of demyelinated lesions. Granted by MIUR – FIRB Futuro in Ricerca 2008 Prot. N° RBFR08VSVI_001., Italian Journal of Anatomy and Embryology, Vol 118, No 2 (Supplement) 2013
- Published
- 2013
46. Anti-inflammatory properties for a testosterone metabolite in acute experimental model of multiple sclerosis
- Author
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Giatti, S, Calabrese, D, Carrero, P, Abbiati, F, Boraso, M, Viviani, B, Caruso, D, Garcia Segura, L, Melcangi, RC, RIGOLIO, ROBERTA, CAVALETTI, GUIDO ANGELO, Giatti, S, Rigolio, R, Calabrese, D, Carrero, P, Abbiati, F, Boraso, M, Viviani, B, Cavaletti, G, Caruso, D, Garcia Segura, L, and Melcangi, R
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BIO/16 - ANATOMIA UMANA ,Multiple sclerosis, experimental autoimmune encephalomyelitis, neurosteroids, neuroinflammation - Published
- 2013
47. MSCs effect on Dark Agouti rats affected by chronic EAE
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BALLARINI, ELISA, SCUTERI, ARIANNA, RIGOLIO, ROBERTA, DONZELLI, ELISABETTA, MONFRINI, MARIANNA, CAROZZI, VALENTINA ALDA, CHIORAZZI, ALESSIA, MEREGALLI, CRISTINA, SALA, BARBARA, CAVALETTI, GUIDO ANGELO, TREDICI, GIOVANNI, Ballarini, E, Scuteri, A, Rigolio, R, Donzelli, E, Monfrini, M, Carozzi, V, Chiorazzi, A, Meregalli, C, Sala, B, Cavaletti, G, and Tredici, G
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BIO/16 - ANATOMIA UMANA ,EAE, MSCs - Abstract
Besides the immunomodulatory action, Mesenchymal Stem Cells (MSCs) are able to promote neuronal and glial survival both by releasing trophic factors and through cell to cell contact. For these features MSCs are a promising tool for the treatment of inflammatory and demyelinating diseases such as Multiple Sclerosis (MS). Here we reported a pre-clinical study on Dark Agouti rats affected by a Relapsing-Remitting form of Experimental Autoimmune Encephalomyelitis (RR-EAE), one of the most suitable models for the study of RR-MS. In order to assess the possible preventive or therapeutic effect, 106 MSCs were injected i.v. (intra venous) at day 7 or at day 14 post EAE induction (p.i.) and clinical score was evaluated daily. The preventive schedule of treatment (day 7 p.i.) had no effect on EAE clinical course but the therapeutic one (day 14 p.i.) was able to hamper the relapsing phase from day 19 p.i. and till the end of the experiment (day 45 p.i.) with respect to EAE group. At day 45 p.i., histological analysis performed on spinal cord of EAE rats revealed a substantial absence of inflammatory infiltration and the presence of demyelinated plaques, assessed by Luxol fast Blue staining and by immunohistochemistry for MBP (Myelin Basic Protein). Moreover the analysis performed on serial paraffin sections revealed that the therapeutic schedule with MSCs was able to significantly reduce the extension of demyelinated areas in the spinal cord white matter with respect to EAE and EAE+MSCs day 7 p.i. groups, thus confirming clinical score evaluations. These results suggested that MSCs are able to ameliorate the clinical course of EAE animals by reducing the areas of demyelinated lesions. We are now evaluating the possible mechanism of MSCs action by investigating in vitro some putative myelinating and immunomodulating properties of MSCs. This study was granted by MIUR – FIRB Futuro in Ricerca 2008 RBFR08VSVI_001.
- Published
- 2013
48. Neutrophil depletion affects Dark Agouti Experimental Autoimmune Encephalomyelitis
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RIGOLIO, ROBERTA, BALLARINI, ELISA, MEREGALLI, CRISTINA, CHIORAZZI, ALESSIA, SALA, BARBARA, AVEZZA, FEDERICA, CANTA, ANNALISA ROSANNA, CAROZZI, VALENTINA ALDA, CAVALETTI, GUIDO ANGELO, Magni, A, Crippa, L, Rigolio, R, Magni, A, Ballarini, E, Meregalli, C, Chiorazzi, A, Sala, B, Avezza, F, Canta, A, Carozzi, V, Crippa, L, and Cavaletti, G
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Experimental Autoimmune Encephalomyelitis, neutrophils, clinical score - Abstract
Objective: Neutrophils have been shown to own several immunoregulatory properties. Nevertheless few attention has been given to their contribution to both Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis (EAE) etiopathogenesis and progression. We aim to investigate the potential role of neutrophils during EAE sensitization and chronic phase in Dark Agouti (DA) EAE. Methods: Chronic EAE was induced in DA rats by intrafootpad injection of syngenic spinal cord homogenate in incomplete Freund's adjuvant. Neutrophils were depleted by means of intraperitoneal injection of anti-rat neutrophil serum (aNEU) at different disease time course, i.e. either during the sensitization and the chronic phase of the disease. The animals were weighted weekly and aNEU effect was first evaluated on clinical score while deeper analysis were performed on blood formula, spleen morphology and spinal cord cytokine, chemokine and myelin basic protein expression. Results: aNEU had no effect on clinical score when neutrophil depletion was performed during the chronic phase, i.e. from 14 to 35 days post EAE induction (dpi). When aNEU was administered during the EAE sensitization phase up to 8dpi, no difference in mean clinical score could be revealed between EAE and aNEU-treated EAE rats up to the disease peak, i.e. 14 dpi. However a significant improvement in clinical condition could be reported soon after the disease peak so that a chronic course was transformed into an acute/ monophasic one. aNEU treatment induced a faster body weight gain while it did not affect blood formula changes related to EAE course. Moreover while aNEU treatment did not counteract EAE effects on both spleen microscopic morphological changes and Treg (FoxP3) content, it mainly affected the expression of both pro- and anti-inflammatory cytokines in the three main spinal cord traits (cervical, thoracic, lumbar) while relative low effect was observed on both MCP-1 and myelin basic protein expression. Conclusions: Neutrophil depletion transformed a chronic EAE model into an acute/monophasic one and resulted in cytokine expression changes in spinal cord mainly referred to the cervical trait. Acknowledgment: This project was supported by FISM — Fondazione Italiana Sclerosi Multipla cod 2009/R/22. We wish to thank Mr. Oggioni for his support in animal management.
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- 2012
49. Brain activity changes in an animal model for multiple sclerosis can be highlighted by functional magnetic resonance imaging
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GRIMOLDI, MARIA, RIGOLIO, ROBERTA, MARMIROLI, PAOLA LORENA, CAVALETTI, GUIDO ANGELO, Tambalo, S, Fiorini, S, Marzola, P., Grimoldi, M, Rigolio, R, Tambalo, S, Marmiroli, P, Fiorini, S, Cavaletti, G, and Marzola, P
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BIO/16 - ANATOMIA UMANA ,Multiple scleorosis, experimental autoimmune encephalomyelitis, functional MRI (fMRI), brain activation - Abstract
Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Magnetic Resonance Imaging (MRI) is used for MS first diagnosis and the evaluation of CNS damage extension during disease course while information about cortical area functional reorganization can be obtained by means of functional MRI (fMRI). The clinical patterns of disease evolution are highly variable and scarcely correlate with structural MRI-detected CNS damage. This phenomenon has been referred to as clinical/MRI paradox. Experimental Autoimmune Encephalomyelitis (EAE) is the animal model for MS and can be induced in Dark Agouti (DA) rat reproducing the condition experienced by the most MS patients, i.e. the remitting-relapsing form. fMRI observations in MS are already available in humans, but deeper knowledge on its usefulness might be gained using reliable animal models. EAE was induced by syngenic spinal cord intrafootpad administration with clinical disease onset around 10 days post EAE induction (dpi) and the worst clinical condition reached on 14dpi without a complete symptom resolution in main animals up to 45dpi. The brain plasticity was investigated by means of serial fMRI acquisitions performed before, 30 and 60 days after EAE induction. A train of squared pulses electrical stimulation (frequency=3Hz, current=2mA, duration=0.5ms) was delivered to the left forepaw during acquisition of MRI sensitive to Blood-Volume. A single stimulation protocol was composed of 30 images under rest condition and 10 images acquired during stimulation. After appropriate image analysis, performed using the FSL software package, the brain region activated by the applied stimulus was determined. The week before EAE induction, electrical stimulation resulted in a localized response only in the contralateral sensory motor cortex according to previously reported results. Thirty and 60dpi, the activated area was greatly increased covering large regions of both contra and ipsilateral somatosensory cortex and extending also to extra-cortical regions. Our results show that the DA rat EAE model is a good model in reproducing the functional reorganization of cortex observed in MS patients. It remains to be investigated whether this effect could represent an innovative platform for testing new therapeutic approaches for MS. AKNOWLEDGMENTS: The present work was partially supported by Fondazione Italiana Sclerosi Multipla (FISM) grant code 10/12/F14. We thank Dr Elisa Ballarini and Dr Virginia Rodriguez-Menendez for the image supply.
- Published
- 2012
50. Neutrophil depletion during sensitization phase affects the chronic phase of Experimental Autoimmune Encephalomyelitis
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RIGOLIO, ROBERTA, BALLARINI, ELISA, MEREGALLI, CRISTINA, CHIORAZZI, ALESSIA, SALA, BARBARA, AVEZZA, FEDERICA, CANTA, ANNALISA ROSANNA, CAROZZI, VALENTINA ALDA, CAVALETTI, GUIDO ANGELO, Magni, A, Crippa, L, Rigolio, R, Magni, A, Ballarini, E, Meregalli, C, Chiorazzi, A, Sala, B, Avezza, F, Canta, A, Carozzi, V, Crippa, L, and Cavaletti, G
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BIO/16 - ANATOMIA UMANA ,Multiple sclerosis, xperimental autoimmune encephalomyelitis, innate immunity - Published
- 2012
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