121 results on '"Rigolio R"'
Search Results
2. Excess of NPM-ALK oncogenic signaling promotes cellular apoptosis and drug dependency
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Ceccon, M, Merlo, M E Boggio, Mologni, L, Poggio, T, Varesio, L M, Menotti, M, Bombelli, S, Rigolio, R, Manazza, A D, Di Giacomo, F, Ambrogio, C, Giudici, G, Casati, C, Mastini, C, Compagno, M, Turner, S D, Gambacorti-Passerini, C, Chiarle, R, and Voena, C
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- 2016
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3. Neuroprotective Effects of Progesterone in Chronic Experimental Autoimmune Encephalomyelitis
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Giatti, S., Caruso, D., Boraso, M., Abbiati, F., Ballarini, E., Calabrese, D., Pesaresi, M., Rigolio, R., Santos-Galindo, M., Viviani, B., Cavaletti, G., Garcia-Segura, L. M., and Melcangi, R. C.
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- 2012
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4. Resveratrol interference with the cell cycle protects human neuroblastoma SH-SY5Y cell from paclitaxel-induced apoptosis
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Rigolio, R., Miloso, M., Nicolini, G., Villa, D., Scuteri, A., Simone, M., and Tredici, G.
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- 2005
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5. PERIPHERAL NERVOUS SYSTEM INVOLVEMENT IN NIEMANN-PICK DISEASE TYPE A
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Rigolio, R, Vercelli, A, Gilardini, A, Bossi, M, Avezza, F, Tredici, G, Marmiroli, P, and Cavaletti, G
- Published
- 2005
6. Pixantrone (BBR2778) reduces the severity of experimental allergic encephalomyelitis
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Cavaletti, G, Cavalletti, E, Crippa, L, Di Luccio, E, Oggioni, N, Mazzanti, B, Biagioli, T, Sala, F, Sala, V, Frigo, M, Rota, S, Tagliabue, E, Stanzani, L, Galbiati, S, Rigolio, R, Zoia, C, Tredici, G, Perseghin, P, Dassi, M, Riccio, P, and Lolli, F
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- 2004
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7. Effect of trans-resveratrol on signal transduction pathways involved in paclitaxel-induced apoptosis in human neuroblastoma SH-SY5Y cells
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Nicolini, G., Rigolio, R., Scuteri, A., Miloso, M., Saccomanno, D., Cavaletti, G., and Tredici, G.
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- 2003
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8. Evaluation of in vitro antitumoral activity and neurotoxicity of a Hibiscus Sabdariffa ethyl acetate fraction against human multiple myeloma cells
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Malacrida, A, Rigolio, R, Nicolini, G, Cassetti, A, Cavaletti, G, Miloso, M, Malacrida, A, Rigolio, R, Nicolini, G, Cassetti, A, Cavaletti, G, and Miloso, M
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BIO/16 - ANATOMIA UMANA ,Hibiscus Sabdariffa, proliferation, neurotoxicity, multiple myeloma - Abstract
Background: Hibiscus Sabdariffa is a plant of the Malvacee family commonly used in Asian and African folk medicine and for Karkadè preparation. In our laboratory, we previously demonstrated that Hibiscus Sabdariffa total extract (HSE) exerted against human multiple myeloma cells a reversible cytostatic effect and reduced cell motility/invasiveness. In order to identify the molecule/s involved in HSE effects, in this study we evaluated the antitumoral activity of a fraction of HSE obtained after ethyl acetate separation (HEF). Material and methods: Human multiple myelomacell s RPMI8226 were treated with different HEF concentrations and cell viability was evaluated by MTT and Trypan blue vital count assays. Apoptosis cell death was evaluated by AnnexinV assay and Caspase3 western blot. Cells migration/invasion was assessed using Boyden Chamber assay. Rat embryo dorsal root ganglia cultures were used to assess HEF neurotoxicity in vitro. HEF and HSE activity was compared. Results: HEF was effective in reducing RPMI8226 cell viability in a dose and time dependent manner. HEF enhanced cell mortality, AnnexinV positive cells and Caspase3 activation. Moreover, HEF was effective in reducing cells migration/invasion and it was not neurotoxic in vitro. Conclusions: In this study we evaluated the in vitro effects of HEF against human multiple myeloma cells RPMI8226. Our results demonstrated that HEF treatment showed an increased effectiveness and Caspase3-dependent apoptosis, but not an increased neurotoxicity, compared to HSE. Considering evident anticancer properties of HEF, it can provide the basis for a further fractionation in order to isolate molecules responsible for Hibiscus sabdariffa effects.
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- 2016
9. Neutrophil contribution and immunoglobulin effect in Dark Agouti Experimental Autoimmune Encephalomyelitis
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Ballarini, E, Carozzi, V, Canta, A, Chiorazzi, A, Meregalli, C, Avezza, F, Crippa, L, Oggioni, N, Cavaletti, G, Rigolio, R, Ballarini, E, Carozzi, V, Canta, A, Chiorazzi, A, Meregalli, C, Avezza, F, Crippa, L, Oggioni, N, Cavaletti, G, and Rigolio, R
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Experimental autoimmune encephalomyelitis, innate immunity, neutrophils ,BIO/16 - ANATOMIA UMANA - Published
- 2010
10. Granulocytes in actively induced Lewis rat EAE
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Rigolio, R, Rodriguez-Menendez, V, Chiorazzi, A, Meregalli, C, Donzelli, E, Oggioni, N, Cavaletti, G, Rigolio, R, Rodriguez-Menendez, V, Chiorazzi, A, Meregalli, C, Donzelli, E, Oggioni, N, and Cavaletti, G
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Granulocytes, Lewis rat, induced EAE ,BIO/16 - ANATOMIA UMANA - Published
- 2008
11. Peripheral nervous system involvement in Niemann-Pick disease type A
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Rigolio, R., Vercelli, Alessandro, Gilardini, A., Bossi, M., Avezza, F., Tredici, G., and Marmiroli, P. Cavaletti G.
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- 2004
12. Targeting Cells With MR Imaging Probes: Cellular Interaction And Intracellular Magnetic Iron Oxide Nanoparticles Uptake In Brain Capillary Endothelial and Choroidal Plexus Epithelial Cells.
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Cambianica, I., Bossi, M., Gasco, P., Gonzalez, W., Idee, J. M., Miserocchi, G., Rigolio, R., Chanana, M., Morjan, I., Wang, D., and Sancini, G.
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MAGNETIC resonance imaging ,IRON oxides ,NANOPARTICLES ,EPITHELIAL cells ,CONFOCAL microscopy ,ENDOCYTOSIS ,NYSTATIN ,CONTRAST media - Abstract
Magnetic iron oxide nanoparticles (NPs) are considered for various diagnostic and therapeutic applications in brain including their use as contrast agent for magnetic resonance imaging. In delivery application, the critical step is the transport across cell layers and the internalization of NPs into specific cells, a process often limited by poor targeting specificity and low internalization efficiency. The development of the models of brain endothelial cells and choroidal plexus epithelial cells in culture has allowed us to investigate into these mechanisms. Our strategy is aimed at exploring different routes to the entrapment of iron oxide NPs in these brain related cells. Here we demonstrated that not only cells endowed with a good phagocytic activity like activated macrophages but also endothelial brain capillary and choroidal plexus epithelial cells do internalize iron oxide NPs. Our study of the intracellular trafficking of NPs by TEM, and confocal microscopy revealed that NPs are mainly internalized by the endocytic pathway. Iron oxide NPs were dispersed in water and coated with 3,4-dihydroxyl-L-phenylalanine (L-DOPA) using standard procedures. Magnetic lipid NPs were prepared by NANOVECTOR: water in oil in water (W/O/W) microemulsion process has been applied to directly coat different iron based NPs by lipid layer or to encapsulate them into Solid Lipid Nanoparticles (SLNs). By these coating/loading the colloidal stability was improved without strong alteration of the particle size distribution. Magnetic lipid NPs could be reconstituted after freeze drying without appreciable changes in stability. L-DOPA coated NPs are stable in PBS and in MEM (Modified Eagle Medium) medium. The magnetic properties of these NPs were not altered by the coating processes. We investigated the cellular uptake, cytotoxicity, and interaction of these NPs with rat brain capillary endothelial (REB4) and choroidal plexus epithelial (Z310) cells. By means of widefield, confocal microscopy and flow cytometry we studied the cell uptake of magnetic SLNs derivatized with a fluorescent reporter molecule and of L-DOPA-TRITC coated NPs. Inhibition of the caveolae-mediated pathway by preincubation with filipin and nystatin did not modify the cellular uptake of these NPs in both cell lines. Furthermore a mild decrease of the NPs cell uptake was obtained after chlorpromazine and NaN
3 pretreatment, which interferes with clathrin and energy-dependent endocytosis, and cytochalasin and amiloride pretreatment which interfere with macropinocytosis. NPs particle size as such can strongly affect the efficiency of cellular uptake and the mode of endocytosis. Considering that our L-DOPA and magnetic SLNs display a medium hydrodynamic size of 120 nm with a polydispersity index of 0.3, we can assume that the cell uptake process of these NPs may develop, depending the particle size, both via clathrin mediated endocytosis and macropinocytosis and only to less extent via the pathway of caveolae-mediated endocytosis. Taken together these results let us to conclude that SLNs iron loaded and iron based L-DOPA coated NPs are internalized into brain endothelial and choroidal plexus epithelial cells and this might provide the first step of an intracellular trafficking to transport these NPs between blood and brain. [ABSTRACT FROM AUTHOR]- Published
- 2010
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13. Sex dimorphism in an animal model of multiple sclerosis: Focus on pregnenolone synthesis.
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Giatti, S., Rigolio, R., Diviccaro, S., Falvo, E., Caruso, D., Garcia-Segura, L.M., Cavaletti, G., and Melcangi, R.C.
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MULTIPLE sclerosis , *PERIPHERAL nervous system , *SPINAL cord , *CHOLESTEROL metabolism , *HYDROXYCHOLESTEROLS , *STEROIDS , *SEXUAL dimorphism , *ANIMAL disease models - Abstract
• Synthesis of PREG in the EAE spinal cord is altered by the pathology in a sex dimorphic way. • Synthesis of PREG in the EAE spinal cord is altered depending on the pathological progression. • The study of neurosteroidogenic processes could be relevant to better understand the sexual dimorphism of MS. • Metabolism of cholesterol and oxysterol may be interconnected with neuroactive steroid production. Neuroactive steroids, molecules produced from cholesterol in steroidogenic cells (i.e., peripheral glands and nervous system) are physiological modulators and protective agents of nervous function. A possible role for neuroactive steroids in the sex-dimorphic clinical manifestation, onset and progression of Multiple Sclerosis (MS) has been recently suggested. To explore this possibility, we assessed the synthesis of the first steroidogenic product (pregnenolone; PREG) in the spinal cord of experimental autoimmune encephalomyelitis rats, a MS model. Data obtained indicate that the synthesis of PREG in the spinal cord is altered by the pathology in a sex-dimorphic way and depending on the pathological progression. Indeed, in male spinal cord the synthesis was already decreased at the acute phase of the disease (i.e., 14 days post induction - dpi) and maintained low during the chronic phase (i.e., 45 dpi), while in females this effect was observed only at the chronic phase. Substrate availability had also a role in the sex-dimorphic kinetics. Indeed, at the chronic phase, male animals showed a reduction in the levels of free cholesterol coupled to alteration of cholesterol metabolism into oxysterols; these effects were not observed in female animals. These findings suggest that the comprehension of the neurosteroidogenic processes could be relevant to better understand the sexual dimorphism of MS and to possibly design sex-oriented therapeutic strategies based on neuroactive steroids. [ABSTRACT FROM AUTHOR]
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- 2020
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14. PACLITAXEL NEUROTOXICITY: ANTI-APOPTOTIC EFFECT OF RESVERATROL.
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Miloso, M., Rigolio, R., Nicolini, G., Crimi, M., Donzelli, E., Di Silvestro, A., Cavaletti, G., and Tredici, G
- Abstract
We have demonstrated in the SH-SY5Y human neuroblastoma cell line that the antineoplastic drug paclitaxel induces apoptosis associated with the phosphorylation of c-raf and Bcl-2, thus causing Bcl-2 inactivation. In addition, we have observed the cleavage of caspase 7 and PARP, and the involvement of JNK/SAPK cascade. In this study, we investigated the possible anti-apoptotic effect of resveratrol on paclitaxel-induced apoptosis. Resveratrol is a natural antioxidant occurring in grapes and wine that as been shown to have anticancer and anti-inflammatory effects. Studies on the effect(s) of resveratrol on nervous cells are very few and limited to testing its ability in preventing oxidative stress in rat pheocromocytoma PC12 cells. However, the biological and pharmacological properties of resveratrol suggest that this natural compound might act on neuronal cells with a mode of action that is different from the antioxidant ones. To confirm this hypothesis, we studied the possible antagonist effect(s) of resveratrol on paclitaxel-induced apoptosis pathways. Our results indicate that the simultaneous treatment of 50M resveratrol and 1M paclitaxel induces a significant reduction of the percentage of apoptotic cells in comparison with 1M paclitaxel alone. Furthermore, we have demonstrated that resveratrol treatment determines a significant reduction of the phosphorylation of c-raf and Bcl-2 and a partial reduction of cleavage of caspase 7 and PARP. Finally, we observed an evident reduction of activation of JNK/SAPK in the presence of resveratrol. On the contrary, resveratrol does not affect the tubulin polymerization induced by paclitaxel. In conclusion, our results suggest that resveratrol is able to partially antagonize a nonoxidative stress apoptotic stimulus by influencing the typical signal pathways involved in apoptosis. [ABSTRACT FROM AUTHOR]
- Published
- 2000
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15. ChemInform Abstract: A Novel Synthesis of 3-Halo-2-phenylquinoline-4-carboxylic Acids.
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RAVEGLIA, L. F., GIARDINA, G. A. M., GRUGNI, M., RIGOLIO, R., and FARINA, C.
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- 1997
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16. ChemInform Abstract: A Reliable and Efficient Synthesis of SR 142801.
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GIARDINA, G. A. M., GRUGNI, M., RIGOLIO, R., VASSALLO, M., ERHARD, K., and FARINA, C.
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- 1997
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17. Size and specimen-dependent strategy for x-ray micro-ct and tem correlative analysis of nervous system samples
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Francesco Brun, Ilaria Tonazzini, Vincenzo Piazza, Paola Parlanti, Mauro Gemmi, Marco Cecchini, Roberta Rigolio, Valentina Cappello, Giuliana Tromba, Parlanti, P, Cappello, V, Brun, F, Tromba, G, Rigolio, R, Tonazzini, I, Cecchini, M, Piazza, V, Gemmi, M, Parlanti, P., Cappello, V., Brun, F., Tromba, G., Rigolio, R., Tonazzini, I., Cecchini, M., Piazza, V., and Gemmi, M.
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0301 basic medicine ,Correlative ,Nervous system ,Pathology ,medicine.medical_specialty ,Science ,Biology ,x-ray micro-ct, TEM, nervous system ,Nervous System ,Article ,law.invention ,03 medical and health sciences ,Mice ,Imaging, Three-Dimensional ,Microscopy, Electron, Transmission ,law ,Microscopy ,medicine ,Animals ,Multidisciplinary ,Animal ,Resolution (electron density) ,X-ray ,X-Ray Microtomography ,Synchrotron ,Characterization (materials science) ,Leukodystrophy, Globoid Cell ,Rats ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Spinal Cord ,Transmission electron microscopy ,Rat ,Medicine ,Biomedical engineering - 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
18. Artificial apolipoprotein corona enables nanoparticle brain targeting
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Maurizio Ricci, Roberta Dal Magro, Barbara Albertini, Paolo Blasi, Elisabetta Donzelli, Giulio Sancini, Silvia Beretta, Roberta Rigolio, Alessia Chiorazzi, Dal Magro, R, Albertini, B, Beretta, S, Rigolio, R, Donzelli, E, Chiorazzi, A, Ricci, M, Blasi, P, Sancini, G, Dal Magro R., Albertini B., Beretta S., Rigolio R., Donzelli E., Chiorazzi A., Ricci M., Blasi P., and Sancini G.
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0301 basic medicine ,Male ,Apolipoprotein B ,Endothelium ,Apolipoprotein E4 ,Biomedical Engineering ,Pharmaceutical Science ,Medicine (miscellaneous) ,Nanoparticle ,Lipid nanoparticle ,Bioengineering ,Nanotechnology ,Protein Corona ,02 engineering and technology ,Blood–brain barrier ,03 medical and health sciences ,Blood brain barrier ,Brain targeting ,Lipid nanoparticles ,Protein corona ,Animals ,Apolipoproteins ,Biological Transport ,Blood-Brain Barrier ,Brain ,Mice ,Mice, Inbred BALB C ,Nanoparticles ,Drug Delivery Systems ,BIO/09 - FISIOLOGIA ,Parenchyma ,medicine ,General Materials Science ,Apolipoprotein e4 ,Inbred BALB C ,biology ,Animal ,Chemistry ,021001 nanoscience & nanotechnology ,Apolipoprotein ,030104 developmental biology ,medicine.anatomical_structure ,Biophysics ,biology.protein ,Molecular Medicine ,0210 nano-technology - Abstract
Many potential therapeutic compounds for brain diseases fail to reach their molecular targets due to the impermeability of the blood-brain barrier, limiting their clinical development. Nanotechnology-based approaches might improve compounds pharmacokinetics by enhancing binding to the cerebrovascular endothelium and translocation into the brain. Adsorption of apolipoprotein E4 onto polysorbate 80-stabilized nanoparticles to produce a protein corona allows the specific targeting of cerebrovascular endothelium. This strategy increased nanoparticle translocation into brain parenchyma, and improved brain nanoparticle accumulation 3-fold compared to undecorated particles (119.8 vs 40.5 picomoles). Apolipoprotein decorated nanoparticles have high clinical translational potential and may improve the development of nanotechnology-based medicine for a variety of neurological diseases. (C) 2017 Elsevier Inc. All rights reserved.
- Published
- 2018
19. Neuroinflammatory Process Involved in Different Preclinical Models of Chemotherapy-Induced Peripheral Neuropathy
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Giulia Fumagalli, Laura Monza, Guido Cavaletti, Roberta Rigolio, Cristina Meregalli, Fumagalli, G, Monza, L, Cavaletti, G, Rigolio, R, and Meregalli, C
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0301 basic medicine ,lcsh:Immunologic diseases. Allergy ,Neuroimmunomodulation ,Immunology ,Axonal loss ,Antineoplastic Agents ,Review ,Blood–brain barrier ,neuroinflammation ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,medicine ,Humans ,Immunology and Allergy ,Cognitive Dysfunction ,immune cell activation ,Vinca Alkaloids ,Neuroinflammation ,Inflammation ,neuropathic pain ,immune modulation ,Microglia ,business.industry ,Neurotoxicity ,Peripheral Nervous System Diseases ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Peripheral neuropathy ,Chemotherapy-induced peripheral neuropathy ,nervous system ,Peripheral nervous system ,Quality of Life ,Cytokines ,Neuralgia ,Taxoids ,Chemokines ,Cisplatin ,business ,lcsh:RC581-607 ,Neuroscience ,Proteasome Inhibitors ,030217 neurology & neurosurgery ,Signal Transduction ,chemotherapy-induced peripheral neuropathy - 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 role in CIPN development. Taking together, better understanding of these aspects would permit the development of possible strategies in order to improve the management of CIPN.
- Published
- 2021
20. Anti-Multiple Myeloma Potential of Secondary Metabolites from Hibiscus sabdariffa
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Francesca Vasile, Mariarosaria Miloso, Valeria Cavalloro, Marcello Di Giacomo, Simona Collina, Arianna Cassetti, Gabriella Nicolini, Guido Cavaletti, Alessio Malacrida, Emanuela Martino, Barbara Mannucci, Roberta Rigolio, Malacrida, A, Cavalloro, V, Martino, E, Cassetti, A, Nicolini, G, Rigolio, R, Cavaletti, G, Mannucci, B, Vasile, F, Di Giacomo, M, Collina, S, and Miloso, M
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Hibiscu ,Pharmaceutical Science ,Secondary Metabolism ,Pharmacology ,Chemical Fractionation ,Mass Spectrometry ,Analytical Chemistry ,0302 clinical medicine ,Multiple myeloma ,Drug Discovery ,Chromatography, High Pressure Liquid ,0303 health sciences ,biology ,Molecular Structure ,Hibiscus sabdariffa ,In vitro toxicology ,Cell migration ,Hibiscus ,Chemistry (miscellaneous) ,030220 oncology & carcinogenesis ,nature-aided drug discovery ,Molecular Medicine ,Human ,bioguided assay fractionation ,Spectrometry, Mass, Electrospray Ionization ,Article ,Plant Extract ,lcsh:QD241-441 ,03 medical and health sciences ,lcsh:Organic chemistry ,Cell Line, Tumor ,medicine ,Humans ,Viability assay ,Physical and Theoretical Chemistry ,Hib-ester ,030304 developmental biology ,business.industry ,Plant Extracts ,Hib-carbaldehyde ,Organic Chemistry ,Neurotoxicity ,medicine.disease ,biology.organism_classification ,Antineoplastic Agents, Phytogenic ,Cell culture ,business - Abstract
Multiple myeloma (MM) belongs to hematological cancers and its incidence is increasing worldwide. Despite recent advances in its therapy, MM still causes many deaths every year. In fact, current therapies sometimes fail and are associated with severe adverse effects, including neurotoxicity. As a part of our ongoing efforts to discover new potential therapies against MM, we prepared Hibiscus sabdariffa extracts obtained by a microwave-assisted solvent extraction and investigate their activity by in vitro assays on the RPMI-8226 cell line. The bioguided fractionation of the crude ethanolic extract allowed the identification of HsFC as the most effective extract. We assessed cell viability (MTT and Tripan blue test), cell migration (Boyden chamber assay), and neurotoxicity (DRG neurotoxicity assay). The promising results prompted us to further fractionate HsFC and we obtained two molecules effective against RPMI-8226 cells without neurotoxic effects at their active concentrations. Moreover, both compounds are able to significantly reduce cell migration.
- Published
- 2019
21. De novo UBE2A mutations are recurrently acquired during chronic myeloid leukemia progression and interfere with myeloid differentiation pathways
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Caterina Mezzatesta, David T Yeung, Miriam Nava, Alessandro Morotti, Carlo Gambacorti-Passerini, Jacqueline Boultwood, Deborah D'Aliberti, Roberta Rigolio, Luca Massimino, Wendy T Parker, Rocco Piazza, Diletta Fontana, Alessandra Pirola, Sara Readelli, Dong-Wook Kim, Nitesh Sharma, Andreas W. Schreiber, Mario Mauri, Ilaria Crespiatico, Susan Branford, Vera Magistroni, Giuseppe Saglio, R Perego, Praveen Khandelwal, Michela Viltadi, Paul Wang, Silvia Bombelli, Stefania Citterio, Magistroni, V, Mauri, M, D'Aliberti, D, Mezzatesta, C, Crespiatico, I, Nava, M, Fontana, D, Sharma, N, Parker, W, Schreiber, A, Yeung, D, Pirola, A, Redaelli, S, Massimino, L, Wang, P, Khandelwal, P, Citterio, S, Viltadi, M, Bombelli, S, Rigolio, R, Perego, R, Boultwood, J, Morotti, A, Saglio, G, Dong-Wook, K, Branford, S, Gambacorti Passerini, C, Piazza, R, Magistroni, Vera, Mauri, Mario, D'Aliberti, Deborah, Mezzatesta, Caterina, Branford, Susan, and Piazza, Rocco
- Subjects
Myeloid ,Blast Crisis progression ,kinase ,bcr-abl ,Chronic Myeloid Leukemia ,Article ,gene ube2a cause ,Molecular Genetics ,03 medical and health sciences ,Myelogenous ,0302 clinical medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,medicine ,Humans ,Chronic Myelogenous Leukemia ,business.industry ,Ubiquitination ,Myeloid leukemia ,Imatinib ,Hematology ,organization ,medicine.disease ,blast crisis ,3. Good health ,Hematopoiesis ,Ematologia, leucemia mieloide cronica, crisi blastica, mutazioni ,inhibitor ,Leukemia ,chronic myelogenous leukemia ,enzyme ,medicine.anatomical_structure ,resistant ,Leukemia, Myeloid ,repair ,Mutation ,Atypical chronic myeloid leukemia ,Cancer research ,business ,030215 immunology ,K562 cells ,Chronic myelogenous leukemia ,medicine.drug - Abstract
Despite the advent of tyrosine kinase inhibitors, a proportion of chronic myeloid leukemia patients in chronic phase fails to respond to Imatinib or to second generation inhibitors and progress to blast crisis. Limited improvements in the understanding of the molecular mechanisms responsible for chronic myeloid leukemia transformation from chronic phase to the aggressive blast crisis were achieved until now. We present here a massive parallel sequencing analysis of 10 blast crisis samples and of the corresponding autologous chronic phase controls which reveals, for the first time, recurrent mutations affecting the ubiquitin-conjugating enzyme E2A gene (UBE2A, formerly RAD6A). Additional analyses on a cohort of 24 blast crisis, 41 chronic phase as well as 40 acute myeloid leukemia and 38 atypical chronic myeloid leukemia patients at onset confirmed that UBE2A mutations are specifically acquired during chronic myeloid leukemia progression with a frequency of 16.7% in advanced phases. In vitro studies show that the mutations here described cause a decrease in UBE2A activity, leading to an impairment of myeloid differentiation in chronic myeloid leukemia cells.
- Published
- 2019
22. Oxaliplatin induces pH acidification in dorsal root ganglia neurons
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Valentina Alda Carozzi, Roberta Rigolio, Armando A. Genazzani, Celia Cordero-Sanchez, Alessia Chiorazzi, Alberto Potenzieri, Beatrice Riva, Dmitry Lim, Paola Marmiroli, Guido Cavaletti, Marianna Dionisi, Carla Distasi, Riva, B, Dionisi, M, Potenzieri, A, Chiorazzi, A, Cordero-Sanchez, C, Rigolio, R, Carozzi, V, Lim, D, Cavaletti, G, Marmiroli, P, Distasi, C, and Genazzani, A
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0301 basic medicine ,Dorsum ,Sensory Receptor Cells ,Intracellular Space ,lcsh:Medicine ,Action Potentials ,Antineoplastic Agents ,Pharmacology ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,In vivo ,Ganglia, Spinal ,medicine ,Animals ,Humans ,lcsh:Science ,TRPA1 Cation Channel ,Sensitization ,Multidisciplinary ,Chemistry ,Oxalic Acid ,lcsh:R ,Neurotoxicity ,Hydrogen-Ion Concentration ,medicine.disease ,Peripheral ,Oxaliplatin ,Electrophysiological Phenomena ,Cytosol ,030104 developmental biology ,medicine.anatomical_structure ,Toxicity ,lcsh:Q ,oxaliplatin, side effects, pH ,Cisplatin ,030217 neurology & neurosurgery ,Biomarkers ,medicine.drug - Abstract
Oxaliplatin induced peripheral neurotoxicity is characterized by an acute cold-induced syndrome characterized by cramps, paresthesias/dysesthesias in the distal limbs and perioral region, that develops rapidly and lasts up to one week affecting nearly all the patients as well as by long-lasting symptoms. It has been previously shown that pharmacological or genetic ablation of TRPA1 responses reduces oxaliplatin-induced peripheral neurotoxicity in mouse models. In the present report, we show that treatment with concentrations of oxaliplatin similar to those found in plasma of treated patients leads to an acidification of the cytosol of mouse dorsal root ganglia neurons in culture and this in turn is responsible for sensitization of TRPA1 channels, thereby providing a mechanistic explanation to toxicity of oxaliplatin. Reversal of the acidification indeed leads to a significantly reduced activity of TRPA1 channels. Last, acidification occurs also in vivo after a single injection of therapeutically-relevant doses of oxaliplatin.
- Published
- 2018
23. 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
24. 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
25. Excess of NPM-ALK oncogenic signaling promotes cellular apoptosis and drug dependency
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C Casati, Roberta Rigolio, Giovanni Giudici, Lydia Varesio, M E Boggio Merlo, Luca Mologni, Andrea D. Manazza, Roberto Chiarle, Silvia Bombelli, F Di Giacomo, Carlo Gambacorti-Passerini, Monica Ceccon, Mara Compagno, Claudia Voena, Matteo Menotti, Suzanne D. Turner, Chiara Ambrogio, Cristina Mastini, Teresa Poggio, 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, Turner, Suzanne [0000-0002-8439-4507], and Apollo - University of Cambridge Repository
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0301 basic medicine ,Cancer Research ,Oncogene Proteins, Fusion ,Pyridines ,Apoptosis ,Mice, SCID ,Histones ,0302 clinical medicine ,Mice, Inbred NOD ,hemic and lymphatic diseases ,Extracellular Signal-Regulated MAP Kinases ,Cells, Cultured ,Mice, Knockout ,Microscopy, Confocal ,integumentary system ,Kinase ,Drug Synergism ,Cell cycle ,Protein-Tyrosine Kinases ,Hydrazines ,030220 oncology & carcinogenesis ,Lymphoma, Large-Cell, Anaplastic ,RNA Interference ,Signal transduction ,Tyrosine kinase ,Nucleophosmin ,medicine.drug ,Signal Transduction ,Programmed cell death ,Cell Survival ,Blotting, Western ,Transplantation, Heterologous ,Biology ,Article ,03 medical and health sciences ,Molecular Biology ,Genetics ,Crizotinib ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Kinase activity ,Protein Kinase Inhibitors ,Dose-Response Relationship, Drug ,Triazoles ,030104 developmental biology ,Cytoplasm ,Immunology ,Cancer research ,Pyrazoles - 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 NPM-ALK 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 γH2AX (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.
- Published
- 2016
26. 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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Francesco Nicotra, Giulio Sancini, Barbara La Ferla, Francesca Re, Silvia Sesana, Alfredo Cagnotto, Mario Salmona, Massimo Masserini, Cristiano Zona, Gianluigi Forloni, Maria Gregori, Ilaria Cambianica, Roberta Rigolio, Re, F, Cambianica, I, Zona, C, Sesana, M, Gregori, M, Rigolio, R, LA FERLA, B, Nicotra, F, Forloni, G, Cagnotto, A, Salmona, M, Masserini, M, and Sancini, G
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Pharmaceutical Science ,Medicine (miscellaneous) ,Peptide ,02 engineering and technology ,environment and public health ,law.invention ,Drug Delivery Systems ,law ,BIO/09 - FISIOLOGIA ,CHIM/06 - CHIMICA ORGANICA ,General Materials Science ,chemistry.chemical_classification ,0303 health sciences ,Liposome ,Microscopy, Confocal ,medicine.diagnostic_test ,Brain ,Cell sorting ,021001 nanoscience & nanotechnology ,Flow Cytometry ,brain endothelial cell ,medicine.anatomical_structure ,Biochemistry ,Blood-Brain Barrier ,Molecular Medicine ,0210 nano-technology ,Materials science ,Curcumin ,nanoliposome ,Biomedical Engineering ,Bioengineering ,Blood–brain barrier ,Permeability ,Flow cytometry ,Cell Line ,03 medical and health sciences ,Apolipoproteins E ,Confocal microscopy ,medicine ,NLS ,Animals ,Humans ,ApoE-peptide ,030304 developmental biology ,Endothelial Cells ,Biological Transport ,Rats ,chemistry ,Liposomes ,Biophysics ,Nanoparticles ,Nanocarriers - Abstract
A promising strategy to enhance blood-brain barrier penetration by drugs is the functionalization of nanocarriers with uptake-facilitating ligands. We studied the cellular uptake, by cultured RBE4 brain capillary endothelial cells, of nanoliposomes (NLs) covalently coupled with monomer or tandem dimer of apolipoprotein E (ApoE)-derived peptides (residues 141-150), at various densities. NLs without functionalization did not show either relevant membrane accumulation or cellular uptake, as monitored by confocal microscopy and quantified by fluorescence-activated cell sorting. Functionalization with peptides mediated an efficient NLs uptake that increased with peptide density; NLs carrying monomeric peptide performed the best. Moreover, we studied the ability of ApoE-NLs to enhance the transport of a drug payload through a RBE4 cell monolayer. The permeability of a tritiated curcumin derivative was enhanced after its entrapment into ApoE-NLs, in particular those functionalized with the dimer (+83% with respect to free drug, P < 0.01). Thus, these NLs appear particularly suitable for implementing further strategies for drug brain targeting. From the Clinical Editor: Re and her collaborators present a method for delivering nanoliposomes via the blood brain barrier by utilizing peptide fragments including monomers or tandem dimers ApoE. This method may enable enhanced nanoliposome associated drug delivery via the blood-brain barrier, which would have enormous significance in neurodegenerative and other CNS disorders
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- 2011
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27. Functional Magnetic Resonance Imaging of Rats with Experimental Autoimmune Encephalomyelitis Reveals Brain Cortex Remodeling
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Stefano Pluchino, Pasquina Marzola, Pietro Bontempi, Silvia Fiorini, Guido Cavaletti, Paola Marmiroli, Beatrice Balzarotti, Andrea Sbarbati, Stefano Tambalo, Giulia Mallucci, Roberta Rigolio, Luca Peruzzotti-Jametti, 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, Tambalo, Stefano [0000-0003-2562-1324], Peruzzotti-Jametti, Luca [0000-0002-9396-5607], Marmiroli, Paola [0000-0002-7590-7649], Cavaletti, Guido [0000-0003-4128-2406], and Apollo - University of Cambridge Repository
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Male ,Pathology ,medicine.medical_specialty ,Encephalomyelitis, Autoimmune, Experimental ,brain plasticity ,cortical reorganization ,experimental autoimmune encephalomyelitis ,functional magnetic resonance imaging ,multiple sclerosis ,neuroimmunology ,Nerve Tissue Proteins ,Brain damage ,experimental autoimmune encephalomyeliti ,Corpus callosum ,Somatosensory system ,Corpus Callosum ,BIO/16 - ANATOMIA UMANA ,Neuroplasticity ,medicine ,Image Processing, Computer-Assisted ,Animals ,Cerebral Cortex ,Neurons ,Afferent Pathways ,medicine.diagnostic_test ,General Neuroscience ,Multiple sclerosis ,Experimental autoimmune encephalomyelitis ,Articles ,Dendrites ,medicine.disease ,Magnetic Resonance Imaging ,Electric Stimulation ,Hindlimb ,Rats ,Oxygen ,Disease Models, Animal ,medicine.anatomical_structure ,Cerebral cortex ,multiple sclerosi ,Cytokines ,medicine.symptom ,Functional magnetic resonance imaging ,Psychology ,Neuroscience ,brain plasticity,cortical reorganization,experimental autoimmune encephalomyelitis,functional magnetic resonance imaging,multiple sclerosis,neuroimmunology - Abstract
UNLABELLED: Cortical reorganization occurring in multiple sclerosis (MS) patients is thought to play a key role in limiting the effect of structural tissue damage. Conversely, its exhaustion may contribute 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. SIGNIFICANCE STATEMENT: Since the early 2000s, functional MRI (fMRI) has demonstrated profound modifications in the recruitment of cortical areas during motor, cognitive, and sensory tasks in multiple sclerosis (MS) patients. Experimental autoimmune encephalomyelitis (EAE) represents a reliable model of the chronic-progressive variant of MS. fMRI studies in EAE have not been performed extensively up to now. This paper reports fMRI studies in a rat model of MS with somatosensory stimulation of the forepaw. We demonstrated modifications in the recruitment of cortical areas consistent with data from MS patients. To the best of our knowledge, this is the first report of cortical remodeling in a preclinical in vivo model of MS.
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- 2015
28. Therapeutic Administration of Mesenchymal Stem Cells Abrogates the Relapse Phase in Chronic Relapsing-Remitting EAE
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Alessia Chiorazzi, Annalisa Canta, Luca Crippa, M Monfrini, Cristina Meregalli, Valentina Alda Carozzi, Elisa Ballarini, Guido Cavaletti, Arianna Scuteri, Norberto Oggioni, Giovanni Tredici, Elisabetta Donzelli, Roberta Rigolio, Scuteri, A, Donzelli, E, Rigolio, R, Ballarini, E, Monfrini, M, Crippa, L, Chiorazzi, A, Carozzi, V, Meregalli, C, Canta, A, Oggioni, N, Tredici, G, and Cavaletti, G
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Clinical score ,business.industry ,Multiple sclerosis ,Experimental autoimmune encephalomyelitis ,Central nervous system ,Mesenchymal stem cell ,Inflammation ,Disease ,medicine.disease ,Active microglia ,MSC ,Relapsing-Remitting EAE ,medicine.anatomical_structure ,Immune system ,BIO/16 - ANATOMIA UMANA ,Recovery ,Immunology ,medicine ,Relapse phase ,medicine.symptom ,Demyelination ,business - 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.
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- 2015
29. 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
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30. 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
31. 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
32. 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
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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
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- 2014
33. 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
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BIO/16 - ANATOMIA UMANA ,CML, Drug resistance, drug transporters ,MED/15 - MALATTIE DEL SANGUE - Published
- 2014
34. 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
35. 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
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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
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36. Effectiveness of MSC therapeutic administration on rats affected by chronic Experimental Autoimmune Encephalomyelitis
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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
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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.
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- 2013
37. 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
38. Apigenin impairs oral squamous cell carcinoma growth in vitro inducing cell cycle arrest and apoptosis
- Author
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Lorenzo Pignataro, Renato Maria Gaini, Daniele Maggioni, Gabriella Nicolini, Werner Garavello, Roberta Rigolio, Maggioni, D, Garavello, W, Rigolio, R, Pignataro, L, Gaini, R, and Nicolini, G
- Subjects
Keratinocytes ,Cancer Research ,Cell cycle checkpoint ,in vitro, oral carcinoma ,Cell ,Blotting, Western ,Apoptosis ,Cell Cycle Proteins ,Biology ,In Vitro Techniques ,chemistry.chemical_compound ,medicine ,Humans ,Propidium iodide ,Apigenin ,Cells, Cultured ,Cell Proliferation ,Cyclin-dependent kinase 1 ,Cell growth ,Cell Cycle Checkpoints ,Cell cycle ,BIO/17 - ISTOLOGIA ,Tongue Neoplasms ,HaCaT ,medicine.anatomical_structure ,Oncology ,chemistry ,Cancer research ,Carcinoma, Squamous Cell - Abstract
In the present study, we investigated the effect of apigenin, a flavonoid widely present in fruits and vegetables, on a tongue oral cancer-derived cell line (SCC-25) and on a keratinocyte cell line (HaCaT), with the aim of unveiling its antiproliferative mechanisms. The effect of apigenin on cell growth was evaluated by MTT assay, while apoptosis was investigated by phosphatidyl serine membrane translocation and cell cycle distribution by propidium iodide DNA staining through flow cytometry. In addition the expression of cyclins and cyclin-dependent kinases was evaluated by western blotting. A reduction of apigenin-induced cell growth was found in both cell lines, although SCC-25 cells were significantly more sensitive than the immortalized keratinocytes, HaCaT. Moreover, apigenin induced apoptosis and modulated the cell cycle in SCC-25 cells. Apigenin treatment resulted in cell cycle arrest at both G0/G1 and G2/M checkpoints, while western blot analysis revealed the decreased expression of cyclin D1 and E, and inactivation of CDK1 upon apigenin treatment. These results demonstrate the anticancer potential of apigenin in an oral squamous cell carcinoma cell line, suggesting that it may be a very promising chemopreventive agent due to its cancer cell cytotoxic activity and its ability to act as a cell cycle modulating agent at multiple levels.
- Published
- 2013
39. Multimodal Analysis in Acute and Chronic Experimental Autoimmune Encephalomyelitis
- Author
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Guido Cavaletti, Donatella Caruso, Luis M. Garcia-Segura, María Santos-Galindo, Mariaserena Boraso, Donato Calabrese, Elisa Ballarini, Marzia Pesaresi, Roberto Cosimo Melcangi, Roberta Rigolio, Federico Abbiati, Barbara Viviani, Silvia Giatti, Giatti, S, Boraso, M, Abbiati, F, Ballarini, E, Calabrese, D, Santos Galindo, M, Rigolio, R, Pesaresi, M, Caruso, D, Viviani, B, Cavaletti, G, Garcia Segura, L, and Melcangi, R
- Subjects
Male ,medicine.medical_specialty ,Neuroactive steroid ,Proteolipid protein 1 ,Encephalomyelitis, Autoimmune, Experimental ,CD3 ,medicine.medical_treatment ,Immunology ,Genes, MHC Class II ,Neuroscience (miscellaneous) ,Nuclease Protection Assays ,Real-Time Polymerase Chain Reaction ,Mass Spectrometry ,EAE, assessment ,Myelin ,Ribonucleases ,Internal medicine ,medicine ,Immunology and Allergy ,Animals ,Fluorometry ,Pharmacology ,Neurons ,biology ,Microglia ,business.industry ,Experimental autoimmune encephalomyelitis ,medicine.disease ,Immunohistochemistry ,Myelin basic protein ,Blood Cell Count ,Rats ,medicine.anatomical_structure ,Endocrinology ,Cytokine ,Neutrophil Infiltration ,Acute Disease ,Chronic Disease ,biology.protein ,Disease Progression ,Cytokines ,Steroids ,Sodium-Potassium-Exchanging ATPase ,business ,Myelin Proteins ,Signal Transduction - Abstract
Different experimental autoimmune encephalomyelitis models (EAE) have been developed. However, due to the different experimental conditions applied, observations simultaneously considering different pathological targets are still scarce. Using EAE induced in Dark Agouti rats with syngenic whole spinal cord homogenate suspended in incomplete Freund's adjuvant, we here analyze neurosteroidogenic machinery, cytokine levels, microglial cells, infiltration of inflammatory cells, myelin proteins and Na(+), K(+)-ATPase pump activity in the spinal cord. Data obtained in the acute phase of the disease confirmed that neurological signs were accompanied by the presence of perivascular infiltrating T cells (CD3(+) cells) and activated monocytic/microglial cells (ED1(+) and MHC-II(+)) in the spinal cord. In particular, the number of MHC-II(+) cells was significantly increased in association with increased expression of pro- (i.e., TNF-α, IL-1β) and anti-inflammatory (i.e., TGF-β) cytokines as well as with decreased expression of proteolipid protein and myelin basic protein. During the chronic phase of the disease, the number of MHC-II(+) cells was still increased, although less than in the acute phase. Changes in the number of MHC-II(+) cells were associated with decreased Na(+),K(+)-ATPase enzymatic activity. A general decrease in the levels of neuroactive steroids, with the exception of an increase in tetrahydroprogesterone and 17β-estradiol, was detected in the acute phase. These changes were maintained or reverted in the chronic phase of EAE. In conclusion, we report that modifications in the neuroimmune response in the acute and chronic phases of EAE are associated with specific changes in myelin proteins, Na(+),K(+)-ATPase pump and in the levels of neuroactive steroids.
- Published
- 2013
40. 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
- Subjects
BIO/16 - ANATOMIA UMANA ,Multiple sclerosis, experimental autoimmune encephalomyelitis, neurosteroids, neuroinflammation - Published
- 2013
41. MSCs effect on Dark Agouti rats affected by chronic EAE
- Author
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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
- Subjects
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
42. Neutrophil depletion affects Dark Agouti Experimental Autoimmune Encephalomyelitis
- Author
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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
- Subjects
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.
- Published
- 2012
43. Brain activity changes in an animal model for multiple sclerosis can be highlighted by functional magnetic resonance imaging
- Author
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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
- Subjects
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
44. Neuroprotective Effects of Progesterone in Chronic Experimental Autoimmune Encephalomyelitis
- Author
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S, Giatti, D, Caruso, M, Boraso, F, Abbiati, E, Ballarini, D, Calabrese, M, Pesaresi, R, Rigolio, M, Santos-Galindo, B, Viviani, G, Cavaletti, L M, Garcia-Segura, R C, Melcangi, Giatti, S, Caruso, D, Boraso, M, Abbiati, F, Ballarini, E, Calabrese, D, Pesaresi, M, Rigolio, R, Santos galindo, M, Viviani, B, Cavaletti, G, Garcia Segura, L, and Melcangi, R
- Subjects
Male ,Disease Models, Animal ,Encephalomyelitis, Autoimmune, Experimental ,Neuroprotective Agents ,Spinal Cord ,Chronic Disease ,Animals ,neuroprotective effects of progesterone ,Progesterone ,Rats - Abstract
Observations so far obtained in experimental autoimmune encephalomyelitis (EAE) have revealed the promising neuroprotective effects exerted by progesterone (PROG). The findings suggest that this neuroactive steroid may potentially represent a therapeutic tool for multiple sclerosis (MS). However, up to now, the efficacy of PROG has been only tested in the acute phase of the disease, whereas it is well known that MS expresses different features depending on the phase of the disease. Accordingly, we have evaluated the effect of PROG treatment in EAE induced in Dark Agouti rats (i.e. an experimental model showing a protracted relapsing EAE). Data obtained 45days after EAE induction show that PROG treatment exerts a beneficial effect on clinical score, confirming surrogate parameters of spinal cord damage in chronic EAE (i.e. reactive microglia, cytokine levels, activity of the Na +,K +-ATPase pump and myelin basic protein expression). An increase of the levels of dihydroprogesterone and isopregnanolone (i.e. two PROG metabolites) was also observed in the spinal cord after PROG treatment. Taken together, these results indicate that PROG is effective in reducing the severity of chronic EAE and, consequently, may have potential with respect to MS treatment. © 2012 The Authors. Journal of Neuroendocrinology © 2012 Blackwell Publishing Ltd.
- Published
- 2012
45. Neutrophil depletion during sensitization phase affects the chronic phase of Experimental Autoimmune Encephalomyelitis
- Author
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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
- Subjects
BIO/16 - ANATOMIA UMANA ,Multiple sclerosis, xperimental autoimmune encephalomyelitis, innate immunity - Published
- 2012
46. Changes in neuroactive steroids in experimental autoimmune encephalomyelitis
- Author
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CAVALETTI, GUIDO ANGELO, BALLARINI, ELISA, RIGOLIO, ROBERTA, Giatti, S, Caruso, D, Viviani, B, Abbiati, E, Boraso, M, Calabrese, D, Pesaresi, M, Santos Galindo, L, Garcia Segura, M, Melcangi, R., Cavaletti, G, Giatti, S, Caruso, D, Viviani, B, Abbiati, E, Ballarini, E, Boraso, M, Calabrese, D, Pesaresi, M, Rigolio, R, Santos Galindo, L, Garcia Segura, M, and Melcangi, R
- Subjects
BIO/16 - ANATOMIA UMANA ,Multiple sclerosis, experimental autoimmune enephalomyelitis, neurosteroids, cell infiltration, Na+K+ ATPase activity, microglia activation - Published
- 2011
47. Paclitaxel: Chemotherapy and Neurotoxicity – The Two sides of the Coin
- Author
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CHIORAZZI, ALESSIA, BALLARINI, ELISA, CANTA, ANNALISA ROSANNA, CAROZZI, VALENTINA ALDA, CERESA, CECILIA, MAGGIONI, DANIELE, NICOLINI, GABRIELLA, RIGOLIO, ROBERTA, RODRIGUEZ MENENDEZ, VIRGINIA, SALA, BARBARA, CAVALETTI, GUIDO ANGELO, Chiorazzi, A, Ballarini, E, Canta, A, Carozzi, V, Ceresa, C, Maggioni, D, Nicolini, G, Rigolio, R, RODRIGUEZ MENENDEZ, V, Sala, B, and Cavaletti, G
- Subjects
Neurotoxicity, paclitaxel - Published
- 2011
48. MSCs ameliorate clinical course in rats with experimental autoimmune encephalomyelitis
- Author
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SCUTERI, ARIANNA, DONZELLI, ELISABETTA, RIGOLIO, ROBERTA, MAGGIONI, DANIELE, RAVASI, MADDALENA, CHIORAZZI, ALESSIA, MEREGALLI, CRISTINA, SALA, BARBARA, AVEZZA, FEDERICA, CAVALETTI, GUIDO ANGELO, TREDICI, GIOVANNI, Scuteri, A, Donzelli, E, Rigolio, R, Maggioni, D, Ravasi, M, Chiorazzi, A, Meregalli, C, Sala, B, Avezza, F, Cavaletti, G, and Tredici, G
- Subjects
BIO/16 - ANATOMIA UMANA ,Multiple Sclerosi ,Mesenchymal STem Cells - Abstract
Multiple sclerosis (MS) is a chronic immuno-mediated inflammatory and demyelinating disease characterised by both demyelinating lesions and axonal degeneration, leading to the reduction of nerve conduction velocity and the development of neurological deficits. Recently, some in vivo studies have proposed Mesenchymal Stem Cells (MSCs) as promising therapeutic treatment for MS mainly for their capacity to modulate the immune response, although it is not yet known if other mechanisms, different from immune modulation, are involved in MSCs positive. We investigate the therapeutic potential and the clinical effects of MSCs by using an animal model of multiple sclerosis, represented by Lewis rats affected by acute experimental autoimmune encephalomyelitis (EAE). MSCs were intravenously administered immediately after EAE induction (T0) or one week later (T7), in both the cases before disease onset. The clinical course of acute EAE was ameliorated only in EAE animals in which MSCs were injected one week after disease induction, while EAE rats and EAE rats with MSCs injected at T0 showed similar clinical scores. Moreover, the EAE rats which received MSCs at T7 displayed a cytokines pattern expression comparable to untreated control rats, while both EAE group and EAE+MSCs (T0) group showed an increased expression of pro-inflammatory cytokines. These results evidenced that the intravenous administration of MSCs one week after EAE induction (and before disease onset) induces the amelioration of the clinical scores of EAE-rats, thus supporting the potential role for MSCs in cell therapy in multiple sclerosis. We are now investigating the molecular mechanisms of this positive effect, focusing our attention on the Metalloproteinases pathway, involved in multiple sclerosis and modulated by MSCs.
- Published
- 2011
49. Preventive treatment with anti-rat neutrophil serum affects the relapsing phase in Dark Agouti EAE rats
- Author
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RIGOLIO, ROBERTA, BALLARINI, ELISA, MEREGALLI, CRISTINA, CHIORAZZI, ALESSIA, SALA, BARBARA, CAROZZI, VALENTINA ALDA, CANTA, ANNALISA ROSANNA, AVEZZA, FEDERICA, OGGIONI, NORBERTO, CAVALETTI, GUIDO ANGELO, Magni, A, Crippa, L, Rigolio, R, Magni, A, Ballarini, E, Meregalli, C, Chiorazzi, A, Sala, B, Carozzi, V, Canta, A, Avezza, F, Oggioni, N, Crippa, L, and Cavaletti, G
- Subjects
BIO/16 - ANATOMIA UMANA ,experimental autoimmune encephalomyelitis, innate immunity, neutrophil depletion - Published
- 2011
50. Organic cation transporter 2 mRNA expression in dorsal root ganglia neurons
- Author
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CAVALETTI, GUIDO ANGELO, NICOLINI, GABRIELLA, CERESA, CECILIA, OGGIONI, NORBERTO, SALA, BARBARA, RIGOLIO, ROBERTA, CHIORAZZI, ALESSIA, TREDICI, GIOVANNI, Cavaletti, G, Nicolini, G, Ceresa, C, Oggioni, N, Sala, B, Rigolio, R, Chiorazzi, A, and Tredici, G
- Subjects
BIO/16 - ANATOMIA UMANA ,organic cation transporter, dorsal root ganglia neurons, developmental expression ,Organic cation transporter ,dorsal root ganglia neurons ,developmental expression - Abstract
Organic cation transporters (OCTs) play an important role in transporting cationic xeno- and endobiotics across biological membranes. In particular their role in platinum drugs transport, such as cisplatin and oxaliplatin, has recently been studied in many normal tissues and cancer cells. It has become increasingly clear the role of these transporters in key tissues responsible for drug absorption and disposition: kidney, liver and intestine. However, only limited information is available regarding their distribution and activity in nervous system. This study was aimed to investigate (1) the expression of OCT2 in rat DRG and (2) to quantify the developmental changes in the mRNA expression of OCT2 in DRG neurons isolated from embryonic E15 and young adult Wistar rats. OCT2 mRNA expression in rat DRG was localized by in situ hybridization experiments and quantified by TaqMan Real Time PCR. Our results demonstrated the expression of OCT2 mRNA in rat DRG and its neuronal localization. In order to verify possible developmental changes in the OCT2 expression we quantified by TaqMan Real Time PCR the OCT2 mRNA using in vitro models of DRG neurons obtained from embryonic E15 rats and from young adult rats. OCT2 mRNA expression was lower in embryonic neuron cultures with respect to the one obtained from young adult rats, demonstrating a developmental change in the expression of this transporter in rat DRG neurons. The OCT2 mRNA expression in 4 weeks of age rats approached adult expression levels. Furthermore in literature is reported that the OCT2 mRNA expression in the kidney is gender dependent. Our preliminary data obtained in DRG of adult Wistar rats did not demonstrate the gender difference in OCT2 mRNA expression observed in the kidney. Key words: organic cation transporter, dorsal root ganglia neurons, developmental expression Supported in part by an unrestricted research grant from the “Fondazione Banca del Monte di Lombardia”
- Published
- 2010
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