82 results on '"Falvo, E."'
Search Results
2. Gut Steroids and Microbiota: Effect of Gonadectomy and Sex
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Diviccaro, S., Fitzgerald, J.A., Cioffi, L., Falvo, E., Crispie, F., Cotter, P.D., O'Mahony, S.M., Giatti, S., Caruso, D., and Melcangi, R.
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Ribosomal ,Male ,16S ,gut microbiota ,branched- and short-chain fatty acids ,gastrointestinal tract ,mucosa ,pregnenolone ,sex dimorphism ,sex steroids ,stool ,Animals ,Castration ,Female ,Gas Chromatography-Mass Spectrometry ,Pregnanolone ,Progesterone ,RNA, Ribosomal, 16S ,Rats ,Microbiota ,Pregnenolone ,Settore MED/13 - Endocrinologia ,Settore BIO/10 - Biochimica ,RNA - Abstract
Sex steroids, derived mainly from gonads, can shape microbiota composition; however, the impact of gonadectomy and sex on steroid production in the gut (i.e., gut steroids), and its interaction with microbiota composition, needs to be clarified. In this study, steroid environment and gut steroidogenesis were analysed by liquid chromatography tandem mass spectrometry and expression analyses. Gut microbiota composition as branched- and short-chain fatty acids were determined by 16S rRNA gene sequence analysis and gas chromatography flame ionisation detection, respectively. Here, we first demonstrated that levels of pregnenolone (PREG), progesterone (PROG), and isoallopregnanolone (ISOALLO) were higher in the female rat colon, whereas the level of testosterone (T) was higher in males. Sexual dimorphism on gut steroidogenesis is also reported after gonadectomy. Sex, and more significantly, gonadectomy, affects microbiota composition. We noted that a number of taxa and inferred metabolic pathways were associated with gut steroids, such as positive associations between
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- 2022
3. PHOTOGRAMMETRIC AND FLUORESCENCE SOLUTIONS FOR MONITORING OF HABITAT FORMING ORGANISMS
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Rossi, P., primary, Righi, S., additional, Parente, L., additional, Castagnetti, C., additional, Cattini, S., additional, Di Loro, G., additional, Falvo, E., additional, Grassi, F., additional, Mancini, F., additional, Rovati, L., additional, Simonini, R., additional, and Capra, A., additional
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- 2022
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4. Selective targeting of melanoma by PEG-masked protein-based multifunctional nanoparticles
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Vannucci L, Falvo E, Fornara M, Di Micco P, Benada O, Krizan J, Svoboda J, Hulikova-Capkova K, Morea V, Boffi A, and Ceci P
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Medicine (General) ,R5-920 - Abstract
Luca Vannucci1,*, Elisabetta Falvo2,*, Manuela Fornara3, Patrizio Di Micco4, Oldrich Benada1, Jiri Krizan1, Jan Svoboda1, Katarina Hulikova-Capkova1, Veronica Morea3, Alberto Boffi4,5, Pierpaolo Ceci3 1Institute of Microbiology, Academy of Sciences of the Czech Republic, VVI, Prague, Czech Republic; 2Regina Elena Cancer Institute, Pharmacokinetic/Pharmacogenomic Unit, 3National Research Council of Italy, Institute of Molecular Biology and Pathology, 4Department of Biochemical Sciences “A Rossi Fanelli”, University of Rome “Sapienza”, 5Center for Life Nano Science at Sapienza, Italian Institute of Technology, Rome, Italy *These two authors contributed equally to this workBackground: Nanoparticle-based systems are promising for the development of imaging and therapeutic agents. The main advantage of nanoparticles over traditional systems lies in the possibility of loading multiple functionalities onto a single molecule, which are useful for therapeutic and/or diagnostic purposes. These functionalities include targeting moieties which are able to recognize receptors overexpressed by specific cells and tissues. However, targeted delivery of nanoparticles requires an accurate system design. We present here a rationally designed, genetically engineered, and chemically modified protein-based nanoplatform for cell/tissue-specific targeting.Methods: Our nanoparticle constructs were based on the heavy chain of the human protein ferritin (HFt), a highly symmetrical assembly of 24 subunits enclosing a hollow cavity. HFt-based nanoparticles were produced using both genetic engineering and chemical functionalization methods to impart several functionalities, ie, the α-melanocyte-stimulating hormone peptide as a melanoma-targeting moiety, stabilizing and HFt-masking polyethylene glycol molecules, rhodamine fluorophores, and magnetic resonance imaging agents. The constructs produced were extensively characterized by a number of physicochemical techniques, and assayed for selective melanoma-targeting in vitro and in vivo.Results: Our HFt-based nanoparticle constructs functionalized with the α-melanocyte-stimulating hormone peptide moiety and polyethylene glycol molecules were specifically taken up by melanoma cells but not by other cancer cell types in vitro. Moreover, experiments in melanoma-bearing mice indicate that these constructs have an excellent tumor-targeting profile and a long circulation time in vivo.Conclusion: By masking human HFt with polyethylene glycol and targeting it with an α-melanocyte-stimulating hormone peptide, we developed an HFt-based melanoma-targeting nanoplatform for application in melanoma diagnosis and treatment. These results could be of general interest, because the same strategy can be exploited to develop ad hoc nanoplatforms for specific delivery towards any cell/tissue type for which a suitable targeting moiety is available.Keywords: multifunctional nanoparticles, ferritin, nanoplatform, cancer-targeting, melanoma
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- 2012
5. Gene variants associated to malignant thyroid disease in familial adenomatous polyposis: A novel APC germline mutation
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Martayan, A., Sanchez-Mete, L., Baldelli, R., Falvo, E., Barnabei, A., Conti, L., Giacomini, P., Appetecchia, M., and Stigliano, V.
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- 2010
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6. Physiopathological role of the enzymatic complex 5α-reductase and 3α/β-hydroxysteroid oxidoreductase in the generation of progesterone and testosterone neuroactive metabolites
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Giatti, S., Diviccaro, Silvia, Falvo, E., García-Segura, Luis M., Melcangi, R. C., Ministero dell'Istruzione, dell'Università e della Ricerca, Università degli Studi di Milano, Post-Finasteride Syndrome Foundation, Agencia Estatal de Investigación (España), Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (España), Instituto de Salud Carlos III, and European Commission
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Translocator protein of 18kd ,Finasteride ,Neuroactive steroids ,Neurodegenerative disorders ,Psychiatric disorders ,Neuroprotection - Abstract
The enzymatic complex 5α-reductase (5α-R) and 3α/3β-hydroxysteroid oxidoreductase (HSOR) is expressed in the nervous system, where it transforms progesterone (PROG) and testosterone (T) into neuroactive metabolites. These metabolites regulate myelination, brain maturation, neurotransmission, reproductive behavior and the stress response. The expression of 5α-R and 3α-HSOR and the levels of PROG and T reduced metabolites show regional and sex differences in the nervous system and are affected by changing physiological conditions as well as by neurodegenerative and psychiatric disorders. A decrease in their nervous tissue levels may negatively impact the course and outcome of some pathological events. However, in other pathological conditions their increased levels may have a negative impact. Thus, the use of synthetic analogues of these steroids or 5α-R modulation have been proposed as therapeutic approaches for several nervous system pathologies. However, further research is needed to fully understand the consequences of these manipulations, in particular with 5α-R inhibitors. We acknowledge support from MIUR Progetto Eccellenza and Intramural Grant Line-B from Università degli Studi di Milano to SG and Post-Finasteride Foundation to RCM. We also acknowledge support from Agencia Estatal de Investigación, Spain (grant number BFU2017-82754-R), Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain and Fondos Feder to LM G-S.
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- 2020
7. Steroidogenic machinery in the adult rat colon
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Diviccaro, S., primary, Giatti, S., additional, Borgo, F., additional, Falvo, E., additional, Caruso, D., additional, Garcia-Segura, L.M., additional, and Melcangi, R.C., additional
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- 2020
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8. Alterations of gut microbiota composition in post-finasteride patients: a pilot study
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Borgo, F., primary, Macandog, A. D., additional, Diviccaro, S., additional, Falvo, E., additional, Giatti, S., additional, Cavaletti, G., additional, and Melcangi, R. C., additional
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- 2020
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9. Sex dimorphism in an animal model of multiple sclerosis: Focus on pregnenolone synthesis
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Giatti, S., primary, Rigolio, R., additional, Diviccaro, S., additional, Falvo, E., additional, Caruso, D., additional, Garcia-Segura, L.M., additional, Cavaletti, G., additional, and Melcangi, R.C., additional
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- 2020
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10. Sensing the quantum behaviour of magnetic nanoparticles by electron magnetic resonance
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Fittipaldi, M., Mercatelli, R., Sottini, S., Ceci, P., Falvo, E., and Gatteschi, D.
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Physics::General Physics ,Materials science ,Spin states ,Population ,General Physics and Astronomy ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,Quantitative Biology::Cell Behavior ,law.invention ,chemistry.chemical_compound ,law ,Physical and Theoretical Chemistry ,Spin (physics) ,Spectroscopy ,education ,Electron paramagnetic resonance ,education.field_of_study ,Condensed matter physics ,ferritin ,021001 nanoscience & nanotechnology ,0104 chemical sciences ,chemistry ,magnetism ,Excited state ,Magnetic nanoparticles ,EPR ,0210 nano-technology ,Iron oxide nanoparticles - Abstract
We have investigated Magnetic Nanoparticles (MNPs) of spinel type iron oxide (of approximately 8 nm) mineralized in the internal cavity of the bioreactor ferritin nanocage. In particular, we have used Electron Magnetic Resonance, EMR, spectroscopy and taken advantage of the capacity of the protein shells to control the size of the MNPs. EMR measurements in perpendicular and parallel configurations have been recorded at various temperatures. A model based on the giant spin is used to interpret the experimental results. The analysis indicates that the observed quantum behaviour has to be ascribed to the whole MNP and that the thermal population of excited spin states has a strong influence in the EMR behaviour of MNPs.
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- 2016
11. PO-207 Ferritin-engineered nanoparticles as targeted drug delivery system for cancer treatment
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Damiani, V., primary, Falvo, E., additional, Pitea, M., additional, Fracasso, G., additional, Rossi, C., additional, Sala, G., additional, De Laurenzi, V., additional, and Ceci, P., additional
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- 2018
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12. Nanoconstructs for targeting the tumor microenvironment
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Vannucci, L, Rajsiglová, I, Stakeheev, D, Ceci, P, Falvo, E, Babic, M, Kostiv, U, Caja, F, Krizan, J, Vrba, J, Vrba, J. Jr, Vrba, D, Farina, Laura, Lopresto, V, and Ruvio, G.
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- 2016
13. Antibody-drug conjugates: targeting melanoma with cisplatin encapsulated in protein-cage nanoparticles based on human ferritin. Nanoscale
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Falvo E, Tremante E, Fraioli R, Leonetti C, Zamparelli C, Boffi A, Morea V, Ceci P, and Giacomini P.
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- 2013
14. Intra- and interparticle magnetism of cobalt-doped iron-oxide nanoparticles encapsulated in a synthetic ferritin cage
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Skoropata, E., primary, Desautels, R. D., additional, Falvo, E., additional, Ceci, P., additional, Kasyutich, O., additional, Freeland, J. W., additional, and van Lierop, J., additional
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- 2014
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15. Reassessment of Protein Stability, DNA Binding, and Protection of Mycobacterium smegmatis Dps
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Ceci P, Ilari A, Falvo E, Giangiacomo L, and Chiancone E.
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The structure and function of Mycobacterium smegmatis Dps (DNA-binding proteins from starved cells) and of the protein studied by Gupta and Chatterji ( Gupta, S., and Chatterji, D. ( 2003) J. Biol. Chem. 278, 5235 - 5241), in which the C terminus that is used for binding DNA contains a histidine tag, have been characterized in parallel. The native dodecamer dissociated reversibly into dimers above pH 7.5 and below pH 6.0, with apparent pK(a) values of similar to 7.65 and 4.75; at pH similar to 4.0, dimers formed monomers. Based on structural analysis, the two dissociation steps have been attributed to breakage of the salt bridges between Glu(157) and Arg(99) located at the 3-fold symmetry axes and to protonation of Asp(66) hydrogen-bonded to Lys(36) across the dimer interface, respectively. The C-terminal tag did not affect subunit dissociation, but altered DNA binding dramatically. At neutral pH, protonation of the histidine tag promoted DNA condensation, whereas in the native C terminus, compensation of negative and positive charges led to DNA binding without condensation. This different mode of interaction with DNA has important functional consequences as indicated by the failure of the native protein to protect DNA from DNase-mediated cleavage and by the efficiency of the tagged protein in doing so as a result of DNA sequestration in the condensates. Chemical protection of DNA from oxidative damage is realized by Dps proteins in a multistep iron oxidation/ uptake/ mineralization process. Dimers have a decreased protection efficiency due to disruption of the dodecamer internal cavity, where iron is deposited and mineralized after oxidation at the ferroxidase center.
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- 2005
16. DNA condensation and self-aggregation of Escherichia coli Dps are coupled phenomena related to the properties of the N-terminus
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Ceci P, Cellai S, Falvo E, Rivetti C, Rossi GL, and Chiancone E.
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- 2004
17. The Dps protein of Agrobacterium tumefaciens does not bind to DNA but protects it toward oxidative cleavage: x-ray crystal structure, iron binding, and hydroxyl-radical scavenging properties
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Ceci P., Ilari A, Falvo E., and Chiancone E.
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Agrobacterium tumefaciens Dps (DNA-binding proteins from starved cells), encoded by the dps gene located on the circular chromosome of this plant pathogen, was cloned, and its structural and functional properties were determined in vitro. In Escherichia coli Dps, the family prototype, the DNA binding properties are thought to be associated with the presence of the lysine-containing N-terminal tail that extends from the protein surface into the solvent. The x-ray crystal structure of A. tumefaciens Dps shows that the positively charged N-terminal tail, which is 11 amino acids shorter than in the E. coli protein, is blocked onto the protein surface. This feature accounts for the lack of interaction with DNA. The intersubunit ferroxidase center characteristic of Dps proteins is conserved and confers to the A. tumefaciens protein a ferritin-like activity that manifests itself in the capacity to oxidize and incorporate iron in the internal cavity and to release it after reduction. In turn, sequestration of Fe(II) correlates with the capacity of A. tumefaciens Dps to reduce the production of hydroxyl radicals from H2O2 through Fenton chemistry. These data demonstrate conclusively that DNA protection from oxidative damage in vitro does not require formation of a Dps-DNA complex. In vivo, the hydroxyl radical scavenging activity of A. tumefaciens Dps may be envisaged to act in concert with catalase A to counteract the toxic effect of H2O2, the major component of the plant defense system when challenged by the bacterium.
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- 2003
18. P1.20 CDX2 VDR Polymorphism Impinges on the Response of Cultured Breast Cancer Cell Lines to Vitamin D
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Pulito, C., primary, Terrenato, I., additional, Sacconi, A., additional, Biagioni, F., additional, Mottolese, M., additional, Blandino, G., additional, Muti, P., additional, Falvo, E., additional, and Strano, S., additional
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- 2012
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19. Diagnostics
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Einert, T. R., primary, Schmidt, G., additional, Binnig, G., additional, Balacescu, O., additional, Balacescu, L., additional, Rus, M., additional, Buiga, R., additional, Tudoran, O., additional, Todor, N., additional, Nagy, V., additional, Irimie, A., additional, Neagoe, I., additional, Yacobi, R., additional, Ustaev, E., additional, Berger, R. R., additional, Barshack, I., additional, Kaur, K., additional, Henderson, S., additional, Cutts, A., additional, Domingo, E., additional, Woods, J., additional, Motley, C., additional, Dougherty, B., additional, Middleton, M., additional, Hassan, B., additional, Wang, Y., additional, Beasley, E., additional, Naley, M., additional, Schuh, A., additional, Tomlinson, I., additional, Taylor, J., additional, Planchard, D., additional, Lueza, B., additional, Rahal, A., additional, Lacroix, L., additional, Ngocamus, M., additional, Auger, N., additional, Saulnier, P., additional, Dorfmuller, P., additional, Le Chevalier, T., additional, Celebic, A., additional, Pignon, J. P., additional, Soria, J. C., additional, Besse, B., additional, Sun, Y. H., additional, Wang, R., additional, Li, C. G., additional, Pan, Y. J., additional, Chen, H. Q., additional, Chouchane, L., additional, Shan, J., additional, Kizhakayil, D., additional, Aigha, I., additional, Dsouza, S., additional, Noureddine, B., additional, Gabbouj, S., additional, Mathew, R., additional, Hassen, E., additional, Shan, S., additional, al-Rumaihi, K., additional, al-Bozom, I., additional, al-Said, S., additional, Rabah, D., additional, Farhat, K., additional, Jakobsen Falk, I. A., additional, Green, K. H. Z., additional, Lotfi, K., additional, Fyrberg, A., additional, Pejovic, T., additional, Li, H., additional, Mhawech-Fauceglia, P., additional, Hoatlin, M., additional, Guo, M. G., additional, Huang, M., additional, Ge, Y., additional, Hess, K., additional, Wei, C., additional, Zhang, W., additional, Bogush, T. A., additional, Dudko, E. A., additional, Nureev, M. V., additional, Kamensky, A. A., additional, Polotsky, B. E., additional, Tjulandin, S. A., additional, Davydov, M. I., additional, Caballero, M., additional, Hasmats, J., additional, Green, H., additional, Quanz, M., additional, Buhler, C., additional, Sun, J. S., additional, Dutreix, M., additional, Cebotaru, C. L., additional, Placintar, A. N., additional, Ghilezan, N., additional, Balogh, Z. B., additional, Reiniger, L., additional, Rajnai, H., additional, Csomor, J., additional, Szepesi, A., additional, Balogh, A., additional, Deak, L., additional, Gagyi, E., additional, Bodor, C., additional, Matolcsy, A., additional, Bozhenko, V. K., additional, Rozhkova, N. I., additional, Kudinova, E. A., additional, Bliznyukov, O. P., additional, Vaskevich, E. N., additional, Trotsenko, I. D., additional, Kharchenko, N. V., additional, Kiandarian, I. V., additional, Pulito, C., additional, Terrenato, I., additional, Sacconi, A., additional, Biagioni, F., additional, Mottolese, M., additional, Blandino, G., additional, Muti, P., additional, Falvo, E., additional, Strano, S., additional, Mori, F., additional, Ganci, F., additional, Covello, R., additional, Zoccali, C., additional, Biagini, R., additional, Palmer, G. A., additional, Wegdam, W., additional, Meijer, D., additional, Kramer, G., additional, Langridge, J., additional, Moerland, P. D., additional, de Jong, S. M., additional, Vissers, J. P., additional, Kenter, G. G., additional, Buist, M. R., additional, Aerts, J. M. F. G., additional, Milione, M., additional, de Braud, F., additional, Buzzoni, R., additional, Pusceddu, S., additional, Mazzaferro, V., additional, Damato, A., additional, Pelosi, G., additional, Garassino, M., additional, Broggini, M., additional, Marabese, M., additional, Veronese, S., additional, Ganzinelli, M., additional, Martelli, O., additional, Bossel, N., additional, Fontemaggi, G., additional, Manciocco, V., additional, Sperduti, I., additional, Strigari, L., additional, Spriano, G., additional, Domany, E., additional, Donzelli, S., additional, Bellissimo, T., additional, Alessandrini, G., additional, Carosi, M. A., additional, Pescarmona, E., additional, Facciolo, F., additional, Telera, S., additional, Pompili, A., additional, de Vriendt, V., additional, de Roock, W., additional, di Narzo, A. F., additional, Tian, S., additional, Biesmans, B., additional, Jacobs, B., additional, de Schutter, J., additional, Budzinska, E., additional, Sagaert, X., additional, Delorenzi, M., additional, Simon, I., additional, Tejpar, S., additional, Zhu, Y., additional, Wang, H. K., additional, Ye, D. W., additional, Denisov, E., additional, Tsyganov, M., additional, Tashireva, L., additional, Zavyalova, M., additional, Perelmuter, V., additional, Cherdyntseva, N., additional, Kim, Y. C., additional, Jang, T., additional, Oh, I. J., additional, Kim, K. S., additional, Ban, H., additional, Na, K. J., additional, Ahn, S. J., additional, Kang, H., additional, Kim, W. J., additional, Park, C., additional, Abousamra, N. K., additional, El-Din, M. S., additional, and Azmy, E. A., additional
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- 2012
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20. P1.26 Micrornas' Expression Profile and their Correlation with Clinical Outcome in head and Neck Squamous Cell Carcinoma
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Ganci, F., primary, Bossel, N., additional, Sacconi, A., additional, Fontemaggi, G., additional, Manciocco, V., additional, Sperduti, I., additional, Falvo, E., additional, Strigari, L., additional, Covello, R., additional, Muti, P., additional, Strano, S., additional, Spriano, G., additional, Domany, E., additional, and Blandino, G., additional
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- 2012
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21. X-ray structure of Dps from Mycobacterium smegmatis
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Ilari, A., primary, Ceci, P., additional, Falvo, E., additional, and Chiancone, E., additional
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- 2005
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22. CDX2 VDR POLYMORPHISM IMPINGES ON THE RESPONSE OF CULTURED BREAST CANCER CELL LINES TO VITAMIN D
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Pulito, C., Terrenato, I., andrea sacconi, Biagioni, F., Mottolese, M., Blandino, G., Muti, P., Falvo, E., and Strano, S.
23. Nanoconstructs for targeting the tumor microenvironment
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Vannucci, L., Rajsiglova, L., Stakheev, D., Ceez, P., Falvo, E., Babic, M., Kostiv, U., Caja, F., Krizan, S., Jan Vrba, Vrba, D., Farina, L., Lopresto, V., and Ruvio, G.
24. Gut microbiota composition is altered in a preclinical model of type 1 diabetes mellitus: Influence on gut steroids, permeability, and cognitive abilities
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Silvia Diviccaro, Eva Falvo, Rocco Piazza, Lucia Cioffi, Monika Herian, Paola Brivio, Francesca Calabrese, Silvia Giatti, Donatella Caruso, Roberto Cosimo Melcangi, Diviccaro, S, Falvo, E, Piazza, R, Cioffi, L, Herian, M, Brivio, P, Calabrese, F, Giatti, S, Caruso, D, and Melcangi, R
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Pharmacology ,Akkermansia ,Allopregnanolone ,Blautia ,Claudin-1 ,NOR test ,Pregnenolone ,Cellular and Molecular Neuroscience ,Settore BIO/10 - Biochimica ,Settore BIO/14 - Farmacologia ,Settore MED/13 - Endocrinologia - Abstract
Sex steroid hormones are not only synthesized from the gonads but also by other tissues, such as the brain (i.e., neurosteroids) and colon (i.e., gut steroids). Gut microbiota can be shaped from sex steroid hormones synthesized from the gonads and locally interacts with gut steroids as in turn modulates neurosteroids. Type 1 diabetes mellitus (T1DM) is characterized by dysbiosis and also by diabetic encephalopathy. However, the interactions of players of gut-brain axis, such as gut steroids, gut permeability markers and microbiota, have been poorly explored in this pathology and, particularly in females. On this basis, we have explored, in streptozotocin (STZ)induced adult female rats, whether one month of T1DM may alter (I) gut microbiome composition and diversity by 16S next-generation sequencing, (II) gut steroid levels by liquid chromatography-tandem mass spectrometry, (III) gut permeability markers by gene expression analysis, (IV) cognitive behavior by the novel object recognition (NOR) test and whether correlations among these aspects may occur. Results obtained reveal that T1DM alters gut beta-, but not alpha-diversity. The pathology is also associated with a decrease and an increase in colonic pregnenolone and allopregnanolone levels, respectively. Additionally, diabetes alters gut permeability and worsens cognitive behavior. Finally, we reported a significant correlation of pregnenolone with Blautia, claudin-1 and the NOR index and of allopregnanolone with Parasutterella, Gammaproteobacteria and claudin-1. Altogether, these results suggest new putative roles of these two gut steroids related to cognitive deficit and dysbiosis in T1DM female experimental model.
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- 2023
25. Alterations of gut microbiota composition in post-finasteride patients: a pilot study
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Silvia Diviccaro, A D Macandog, Eva Falvo, Silvia Giatti, Francesca Borgo, Roberto Cosimo Melcangi, Guido Cavaletti, Borgo, F, Macandog, A, Diviccaro, S, Falvo, E, Giatti, S, Cavaletti, G, and Melcangi, R
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0301 basic medicine ,Male ,Endocrinology, Diabetes and Metabolism ,Physiology ,Disease ,Gut flora ,Gut microbiota-brain axi ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,5-alpha Reductase Inhibitors ,RNA, Ribosomal, 16S ,Correlation of Data ,education.field_of_study ,biology ,Depression ,Finasteride ,Biodiversity ,Middle Aged ,Physical Functional Performance ,Major depressive disorder ,Original Article ,Sample collection ,medicine.symptom ,Androgenic alopecia ,Drug-Related Side Effects and Adverse Reactions ,Fecal microbiota ,Population ,Sexual dysfunction ,digestive system ,03 medical and health sciences ,medicine ,Humans ,Cognitive Dysfunction ,education ,Feces ,business.industry ,Alopecia ,Sequence Analysis, DNA ,medicine.disease ,biology.organism_classification ,Gastrointestinal Microbiome ,Sexual Dysfunction, Physiological ,030104 developmental biology ,chemistry ,Gut microbiota-brain axis ,5alpha-reductase ,business ,030217 neurology & neurosurgery - Abstract
Purpose Post-finasteride syndrome (PFS) has been reported in a subset of patients treated with finasteride (an inhibitor of the enzyme 5alpha-reductase) for androgenetic alopecia. These patients showed, despite the suspension of the treatment, a variety of persistent symptoms, like sexual dysfunction and cognitive and psychological disorders, including depression. A growing body of literature highlights the relevance of the gut microbiota-brain axis in human health and disease. For instance, alterations in gut microbiota composition have been reported in patients with major depressive disorder. Therefore, we have here analyzed the gut microbiota composition in PFS patients in comparison with a healthy cohort. Methods Fecal microbiota of 23 PFS patients was analyzed by 16S rRNA gene sequencing and compared with that reported in ten healthy male subjects. Results Sexual dysfunction, psychological and cognitive complaints, muscular problems, and physical alterations symptoms were reported in more than half of the PFS patients at the moment of sample collection. The quality sequence check revealed a low library depth for two fecal samples. Therefore, the gut microbiota analyses were conducted on 21 patients. The α-diversity was significantly lower in PFS group, showing a reduction of richness and diversity of gut microbiota structure. Moreover, when visualizing β-diversity, a clustering effect was found in the gut microbiota of a subset of PFS subjects, which was also characterized by a reduction in Faecalibacterium spp. and Ruminococcaceae UCG-005, while Alloprevotella and Odoribacter spp were increased compared to healthy control. Conclusion Gut microbiota population is altered in PFS patients, suggesting that it might represent a diagnostic marker and a possible therapeutic target for this syndrome.
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- 2021
26. Sex dimorphism in an animal model of multiple sclerosis: Focus on pregnenolone synthesis
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Luis M. Garcia-Segura, Roberta Rigolio, Silvia Giatti, Roberto Cosimo Melcangi, Eva Falvo, Guido Cavaletti, Silvia Diviccaro, Donatella Caruso, Agencia Estatal de Investigación (España), Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (España), Instituto de Salud Carlos III, European Commission, Giatti, S, Rigolio, R, Diviccaro, S, Falvo, E, Caruso, D, Garcia-Segura, L, Cavaletti, G, and Melcangi, R
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0301 basic medicine ,Nervous system ,Male ,medicine.medical_specialty ,Neuroactive steroid ,Encephalomyelitis, Autoimmune, Experimental ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Biochemistry ,Substrate Specificity ,Multiple sclerosis ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,Oxysterol ,Internal medicine ,medicine ,Animals ,Humans ,Multiple sclerosi ,Molecular Biology ,Sex Characteristics ,Spinal cord ,business.industry ,Cholesterol ,Experimental autoimmune encephalomyelitis ,Cell Biology ,Oxysterols ,medicine.disease ,Rats ,Sexual dimorphism ,Disease Models, Animal ,Kinetics ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,030220 oncology & carcinogenesis ,Pregnenolone ,Molecular Medicine ,Female ,business ,Neurosteroids ,medicine.drug - Abstract
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., We also acknowledge support from Agencia Estatal de Investigación, Spain (grant number BFU2017-82754-R), Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain and Fondos Feder to LM.G-S.
- Published
- 2020
27. The presence of glutamate residues on the PAS sequence of the stimuli-sensitive nano-ferritin improves in vivo biodistribution and mitoxantrone encapsulation homogeneity
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Roberta Opri, Francesco Fazi, Gianni Colotti, Elisa Tremante, Aldo Braca, Francesca Malagrinò, Elisabetta Falvo, Patrizio Di Micco, Giulio Fracasso, Alessandro Arcovito, Pierpaolo Ceci, Alessandro Giuffrè, Falvo, E., Malagrino, Francesca., Arcovito, A., Fazi, F., Colotti, G., Tremante, E., Di Micco, P., Braca, A., Opri, R., Giuffre, A., Fracasso, G., and Ceci, P.
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0301 basic medicine ,Biodistribution ,Proteases ,Glutamic Acid ,Pharmaceutical Science ,Antineoplastic Agents ,02 engineering and technology ,Serine ,03 medical and health sciences ,Doxorubicin (PubChem CID:31703) ,In vivo ,Cell Line, Tumor ,Protein-cage nanocarrier ,Pasylated ferritin ,Humans ,Tissue Distribution ,cancer ,drug-delivery ,drug-encapsulation ,mitoxantrone ,pasylated ferritin ,protein-cage nanocarrier ,3003 ,Settore BIO/10 - BIOCHIMICA ,Peptide sequence ,Cancer ,Drug Carriers ,Chemistry ,Mitoxantrone (PubChem CID:4212) ,Drug-delivery ,Drug-encapsulation ,Mitoxantrone ,021001 nanoscience & nanotechnology ,In vitro ,030104 developmental biology ,Biochemistry ,Doxorubicin ,Apoferritins ,Cancer cell ,Drug delivery ,Nanoparticles ,0210 nano-technology - Abstract
A genetically engineered human ferritin heavy chain (HFt)-based construct has been recently shown by our group to efficiently entrap and deliver doxorubicin to cancer cells. This construct, named HFt-MP-PAS, contained a tumor-selective sequence (MP) responsive to proteolytic cleavage by tumor proteases (MMPs), located between each HFt subunit and an outer shielding polypeptide sequence rich in proline (P), serine (S) and alanine (A) residues (PAS). HFt-MP-PAS displayed excellent therapeutic efficacy in xenogenic pancreatic and head and neck cancer models in vivo, leading to a significant increase in overall animal survivals. Here we report a new construct obtained by the genetic insertion of two glutamate residues in the PAS sequence of HFt-MP-PAS. Such new construct, named HFt-MP-PASE, is characterized by improved performances as drug biodistribution in a xenogenic pancreatic cancer model in vivo. Moreover, HFt-MP-PASE efficiently encapsulates the anti-cancer drug mitoxantrone (MIT), and the resulting MIT-loaded nanoparticles proved to be more soluble and monodispersed than the HFt-MP-PAS counterparts. Importantly, in vitro MIT-loaded HFt-MP-PASE kills several cancer cell lines of different origin (colon, breast, sarcoma and pancreas) at least as efficiently as the free drug. Finally, our MIT loaded protein nanocages allowed in vivo an impressive incrementing of the drug accumulation in the tumor with respect to the free drug.
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- 2018
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28. Postinfectious Functional Gastrointestinal Disorders in Children: A Multicenter Prospective Study
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Federica Altomare, Francesca Graziano, Mariateresa Sanseviero, Antonio Marseglia, Antonella Falvo, Valentina Talarico, Carlo Di Lorenzo, Elvira Cozza, V. Rutigliano, Domenico Ciliberto, Annamaria Staiano, Daniela Concolino, Elisabetta Gatta, Angelo Campanozzi, Domenica De Venuto, Teresa Gentile, Bianca Virginia Palermo, Licia Pensabene, Silvia Salvatore, A. Ripepi, Rossella Turco, Pensabene, L., Talarico, V., Concolino, D., Ciliberto, D., Campanozzi, A., Gentile, T., Rutigliano, V., Salvatore, S., Staiano, A., Lorenzo, Di, Graziano, C., Palermo, F., Sanseviero, B. V., Altomare, M., Cozza, F., Falvo, E., Marseglia, A., Gatta, A., Venuto, De, Ripepi, D., and Turco, A.
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Male ,medicine.medical_specialty ,Adolescent ,Gastrointestinal Diseases ,medicine.disease_cause ,Infections ,Gastroenterology ,Functional gastrointestinal disorder ,Internal medicine ,Rotavirus ,Surveys and Questionnaires ,medicine ,Humans ,Prospective Studies ,Prospective cohort study ,Child ,Irritable bowel syndrome ,business.industry ,Incidence (epidemiology) ,Incidence ,medicine.disease ,Relative risk ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Etiology ,Norovirus ,Female ,business ,Follow-Up Studies - Abstract
Objectives To prospectively investigate the occurrence of postinfectious functional gastrointestinal disorders (FGIDs), diagnosed according to the Rome III criteria, in children with acute diarrhea of different infectious etiology. Study design This was a prospective cohort multicenter study. Children 4-17 years of age presenting with acute diarrhea who tested positive for an enteric infection were recruited within 1 month from the episode and matched with control subjects of similar age and sex. Symptoms were evaluated with a validated questionnaire for FGIDs at the time of enrollment in the study and after 3 and 6 months. Results A total of 64 patients (36 boys; median age 5.3 years; age range 4.1-14.1 years) were recruited, 32 subjects in each arm. Infections included rotavirus (56.8%), salmonella (30%), adenovirus (6.6%), norovirus (3.3%), and Giardia lamblia (3.3%). FGIDs were significantly more common in exposed patients compared with controls within 1 month from acute diarrhea (40.6% vs 12.5% [ P = .02, relative risk (RR) = 1.9]), 3 months (53% vs 15.6% [ P = .003, RR = 2.2]), and 6 months (46.8% vs 15.6% [ P = .01, RR = 1.9]) later. No correlation was found between different etiologies, age, or sex, and any type of FGIDs. Among exposed children, abdominal pain–related FGIDs were significantly more frequent compared with controls after 6 months from infection ( P = .04, RR = 1.7). Conclusion This prospective cohort multicenter study supports postinfectious FGIDs as a true entity in children. There seems to be a significant increase in abdominal pain–related FGIDs after acute diarrhea in children within 1 month and 3 and 6 months later.
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- 2015
29. Dose and polymorphic genes xrcc1, xrcc3, gst play a role in the risk of developing erythema in breast cancer patients following single shot partial breast irradiation after conservative surgery
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Lidia Strigari, Antonella Soriani, Paola Pinnarò, Stefano Arcangeli, Isabella Sperduti, Carolina Giordano, Daniela D'Alessio, Elisabetta Falvo, Giovanni Blandino, Gennaro Citro, Paola Muti, Falvo, E, Strigari, L, Citro, G, Giordano, C, Arcangeli, S, Soriani, A, D'Alessio, D, Muti, P, Blandino, G, Sperduti, I, and Pinnarò, P
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Cancer Research ,medicine.medical_specialty ,DNA Repair ,Genotype ,Erythema ,DNA repair ,Breast Neoplasms ,Polymorphism, Single Nucleotide ,lcsh:RC254-282 ,polymorphic genes xrcc1, xrcc3 ,XRCC1 ,Breast cancer ,XRCC3 ,Risk Factors ,Surgical oncology ,Genetics ,Humans ,Medicine ,Genetic Predisposition to Disease ,Prospective Studies ,skin and connective tissue diseases ,Prospective cohort study ,Aged ,Glutathione Transferase ,Aged, 80 and over ,integumentary system ,business.industry ,Partial Breast Irradiation ,Radiotherapy Dosage ,Middle Aged ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Surgery ,PARTIAL BREAST RADIOTHERAPY ,DNA-Binding Proteins ,Oxidative Stress ,Logistic Models ,X-ray Repair Cross Complementing Protein 1 ,Glutathione S-Transferase pi ,Oncology ,Multivariate Analysis ,SINGLE FRACTION RADIOTHERAPY ,Female ,Rad51 Recombinase ,Radiotherapy, Conformal ,medicine.symptom ,business ,Research Article - Abstract
Background To evaluate the association between polymorphisms involved in DNA repair and oxidative stress genes and mean dose to whole breast on acute skin reactions (erythema) in breast cancer (BC) patients following single shot partial breast irradiation (SSPBI) after breast conservative surgery. Materials and Methods Acute toxicity was assessed using vers.3 criteria. single nucleotides polymorphisms(SNPs) in genes: XRCC1(Arg399Gln/Arg194Trp), XRCC3 (A4541G-5'UTR/Thr241Met), GSTP1(Ile105Val), GSTA1 and RAD51(untranslated region). SNPs were determined in 57 BC patients by the Pyrosequencing analysis. Univariate(ORs and 95% CI) and logistic multivariate analyses (MVA) were performed to correlate polymorphic genes with the risk of developing acute skin reactions to radiotherapy. Results After SSPBI on the tumour bed following conservative surgery, grade 1 or 2 acute erythema was observed in 19 pts(33%). Univariate analysis indicated a higher significant risk of developing erythema in patients with polymorphic variant wt XRCC1Arg194Trp, mut/het XRCC3Thr241Met, wt/het XRCC3A4541G-5'UTR. Similarly a higher erythema rate was also found in the presence of mut/het of XRCC1Arg194Trp or wt of GSTA1. Whereas, a lower erythema rate was observed in patients with mut/het of XRCC1Arg194Trp or wt of XRCC1Arg399Gln. The mean dose to whole breast(p = 0.002), the presence of either mut/het XRCC1Arg194Trp or wt XRCC3Thr241Met (p = 0.006) and the presence of either mut/het XRCC1Arg194Trp or wt GSTA1(p = 0.031) were confirmed as predictors of radiotherapy-induced erythema by MVA. Conclusions The Whole breast mean dose together with the presence of some polymorphic genes involved in DNA repair or oxidative stress could explain the erythema observed after SSPBI, but further studies are needed to confirm these results in a larger cohort. Trial Registration ClinicalTrials.gov Identifier: NCT01316328
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- 2011
30. Nose-to-brain selective drug delivery to glioma via ferritin-based nanovectors reduces tumor growth and improves survival rate.
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Marrocco F, Falvo E, Mosca L, Tisci G, Arcovito A, Reccagni A, Limatola C, Bernardini R, Ceci P, D'Alessandro G, and Colotti G
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- Animals, Mice, Survival Rate, Brain, Blood-Brain Barrier, Ferritins, Glioma drug therapy
- Abstract
Gliomas are among the most fatal tumors, and the available therapeutic options are very limited. Additionally, the blood-brain barrier (BBB) prevents most drugs from entering the brain. We designed and produced a ferritin-based stimuli-sensitive nanocarrier with high biocompatibility and water solubility. It can incorporate high amounts of the potent topoisomerase 1 inhibitor Genz-644282. Here, we show that this nanocarrier, named The-0504, can cross the BBB and specifically deliver the payload to gliomas that express high amounts of the ferritin/transferrin receptor TfR1 (CD71). Intranasal or intravenous administration of The-0504 both reduce tumor growth and improve the survival rate of glioma-bearing mice. However, nose-to-brain administration is a simpler and less invasive route that may spare most of the healthy tissues compared to intravenous injections. For this reason, the data reported here could pave the way towards a new, safe, and direct ferritin-based drug delivery method for brain diseases, especially brain tumors., (© 2024. The Author(s).)
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- 2024
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31. Widespread in vivo efficacy of The-0504: A conditionally-activatable nanoferritin for tumor-agnostic targeting of CD71-expressing cancers.
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Fracasso G, Falvo E, Tisci G, Sala G, Colotti G, Cingarlini S, Tito C, Bibbo S, Frusteri C, Tremante E, Giordani E, Giacomini P, and Ceci P
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Background: Cancer is still among the leading causes of death all over the world. Improving chemotherapy and minimizing associated toxicities are major unmet medical needs. Recently, we provided a preliminary preclinical evaluation of a human ferritin (HFt)-based drug carrier (The-0504) that selectively delivers the wide-spectrum topoisomerase I inhibitor Genz-644282 to CD71-expressing tumors. The-0504 has so far been evaluated on four different human tumor xenotransplant models (breast, colorectal, pancreatic and liver cancers)., Methods: Herein, we extend our studies, by: (a) testing DNA damage in vitro, (b) treating eight additional tumor xenograft models in vivo with The-0504; (c) performing pharmacokinetic (PK) studies in rats; and (d) evaluating The-0504 anti-tumor xenotransplant efficacy by optimizing its administration schedule based on PK considerations., Results: Immunofluorescence demonstrated that The-0504 induces foci expressing the DNA double-strand break marker γH2AX. Expression increases up to 4-fold and is more persistent as compared to free Genz-644282. In vivo studies confirmed a remarkable anti-tumor activity of The-0504, resulting in tumor eradication in most murine xenograft models, regardless of embryological origin (e.g. epithelial, mesenchymal or neuroendocrine), and molecular subtypes. PK studies demonstrated a long persistence of The-0504 in rat serum (half-life of about 40 h as compared to 15 h of the free drug), with a 400-fold increase in peak concentrations as compared to the free drug. On this basis, we reduced The-0504 administration frequency from twice to once per week, with no appreciable loss in therapeutic efficacy in mice., Conclusion: The results presented here confirm that The-0504 is highly active against several human tumor xenotransplants, even when administered less frequently than previously reported. The-0504 may be a good candidate for further clinical development in a tumor histotype-agnostic setting., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Pierpaolo Ceci and Elisabetta Falvo are inventors on patent application EP3186192B1 held by Thena Biotech that covers fusion proteins based on human ferritins and methods of use thereof. Pierpaolo Ceci is a member (free of charge) of the Scientific Advisory Committee of Thena Biotech. All the authors declare no conflict of interest., (© 2023 The Authors.)
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- 2023
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32. Gut microbiota composition is altered in a preclinical model of type 1 diabetes mellitus: Influence on gut steroids, permeability, and cognitive abilities.
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Diviccaro S, Falvo E, Piazza R, Cioffi L, Herian M, Brivio P, Calabrese F, Giatti S, Caruso D, and Melcangi RC
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- Rats, Female, Animals, Dysbiosis, Claudin-1, Pregnanolone, Gonadal Steroid Hormones metabolism, Cognition, Permeability, Pregnenolone, Gastrointestinal Microbiome, Diabetes Mellitus, Type 1, Neurosteroids
- Abstract
Sex steroid hormones are not only synthesized from the gonads but also by other tissues, such as the brain (i.e., neurosteroids) and colon (i.e., gut steroids). Gut microbiota can be shaped from sex steroid hormones synthesized from the gonads and locally interacts with gut steroids as in turn modulates neurosteroids. Type 1 diabetes mellitus (T1DM) is characterized by dysbiosis and also by diabetic encephalopathy. However, the interactions of players of gut-brain axis, such as gut steroids, gut permeability markers and microbiota, have been poorly explored in this pathology and, particularly in females. On this basis, we have explored, in streptozotocin (STZ)-induced adult female rats, whether one month of T1DM may alter (I) gut microbiome composition and diversity by 16S next-generation sequencing, (II) gut steroid levels by liquid chromatography-tandem mass spectrometry, (III) gut permeability markers by gene expression analysis, (IV) cognitive behavior by the novel object recognition (NOR) test and whether correlations among these aspects may occur. Results obtained reveal that T1DM alters gut β-, but not α-diversity. The pathology is also associated with a decrease and an increase in colonic pregnenolone and allopregnanolone levels, respectively. Additionally, diabetes alters gut permeability and worsens cognitive behavior. Finally, we reported a significant correlation of pregnenolone with Blautia, claudin-1 and the NOR index and of allopregnanolone with Parasutterella, Gammaproteobacteria and claudin-1. Altogether, these results suggest new putative roles of these two gut steroids related to cognitive deficit and dysbiosis in T1DM female experimental model. This article is part of the Special Issue on "Microbiome & the Brain: Mechanisms & Maladies"., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
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- 2023
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33. Diabetic Encephalopathy in a Preclinical Experimental Model of Type 1 Diabetes Mellitus: Observations in Adult Female Rat.
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Falvo E, Giatti S, Diviccaro S, Cioffi L, Herian M, Brivio P, Calabrese F, Caruso D, and Melcangi RC
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- Female, Rats, Male, Animals, Neuroinflammatory Diseases, Maze Learning, Brain metabolism, Hippocampus metabolism, Oxidative Stress, Diabetes Mellitus, Type 1 complications, Diabetes Mellitus, Type 1 metabolism
- Abstract
Patients affected by diabetes mellitus (DM) show diabetic encephalopathy with an increased risk of cognitive deficits, dementia and Alzheimer's disease, but the mechanisms are not fully explored. In the male animal models of DM, the development of cognitive impairment seems to be the result of the concomitance of different processes such as neuroinflammation, oxidative stress, mitochondrial dysfunction, and aberrant synaptogenesis. However, even if diabetic encephalopathy shows some sex-dimorphic features, no observations in female rats have been so far reported on these aspects. Therefore, in an experimental model of type 1 DM (T1DM), we explored the impact of one month of pathology on memory abilities by the novel object recognition test and on neuroinflammation, synaptogenesis and mitochondrial functionality. Moreover, given that steroids are involved in memory and learning, we also analysed their levels and receptors. We reported that memory dysfunction can be associated with different features in the female hippocampus and cerebral cortex. Indeed, in the hippocampus, we observed aberrant synaptogenesis and neuroinflammation but not mitochondrial dysfunction and oxidative stress, possibly due to the results of locally increased levels of progesterone metabolites (i.e., dihydroprogesterone and allopregnanolone). These observations suggest specific brain-area effects of T1DM since different alterations are observed in the cerebral cortex.
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- 2023
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34. Gut Inflammation Induced by Finasteride Withdrawal: Therapeutic Effect of Allopregnanolone in Adult Male Rats.
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Diviccaro S, Giatti S, Cioffi L, Falvo E, Herian M, Caruso D, and Melcangi RC
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- Animals, Rats, Male, Pregnenolone, Receptors, GABA-A, Inflammation drug therapy, Inflammation chemically induced, Finasteride pharmacology, Pregnanolone pharmacology
- Abstract
The treatment with finasteride (i.e., an inhibitor of 5α-reductase) may be associated with different side effects (i.e., depression, anxiety, cognitive impairment and sexual dysfunction) inducing the so-called post finasteride syndrome (PFS). Moreover, previous observations in PFS patients and an experimental model showed alterations in gut microbiota populations, suggesting an inflammatory environment. To confirm this hypothesis, we have explored the effect of chronic treatment with finasteride (i.e., for 20 days) and its withdrawal (i.e., for 1 month) on the levels of steroids, neurotransmitters, pro-inflammatory cytokines and gut permeability markers in the colon of adult male rat. The obtained data demonstrate that the levels of allopregnanolone (ALLO) decreased after finasteride treatment and after its withdrawal. Following the drug suspension, the decrease in ALLO levels correlates with an increase in IL-1β and TNF-α, serotonin and a decrease in dopamine. Importantly, ALLO treatment is able to counteract some of these alterations. The relation between ALLO and GABA-A receptors and/or pregnenolone (ALLO precursor) could be crucial in their mode of action. These observations provide an important background to explore further the protective effect of ALLO in the PFS experimental model and the possibility of its translation into clinical therapy.
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- 2022
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35. Paroxetine effects in adult male rat colon: Focus on gut steroidogenesis and microbiota.
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Diviccaro S, Giatti S, Cioffi L, Falvo E, Piazza R, Caruso D, and Melcangi RC
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- Animals, Colon, Humans, Male, Rats, Selective Serotonin Reuptake Inhibitors pharmacology, Selective Serotonin Reuptake Inhibitors therapeutic use, Steroids, Microbiota, Paroxetine pharmacology, Paroxetine therapeutic use
- Abstract
Paroxetine, a selective serotonin reuptake inhibitor (SSRI), is prescribed to treat psychiatric disorders, although an off-label SSRI use is also for functional gastrointestinal disorders. The mutual correlation between serotonin and peripheral sex steroids has been reported, however little attention to sex steroids synthesized by gut, has been given so far. Indeed, whether SSRIs, may also influence the gut steroid production, immediately after treatment and/or after suspension, is still unclear. The finding that gut possesses steroidogenic capability is of particular relevance, also for the existence of the gut-microbiota-brain axis, where gut microbiota represents a key orchestrator. On this basis, adult male rats were treated daily for two weeks with paroxetine or vehicle and, 24 h after treatment and at 1 month of withdrawal, steroid environment and gut microbiota were evaluated. Results obtained reveal that paroxetine significantly affects steroid levels, only in the colon but not in plasma. In particular, steroid modifications observed immediately after treatment are not overlap with those detected at withdrawal. Additionally, paroxetine treatment and its withdrawal impact gut microbiota populations differently. Altogether, these results suggest a biphasic effect of the drug treatment in the gut both on steroidogenesis and microbiota., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
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- 2022
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36. Allopregnanolone: An overview on its synthesis and effects.
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Diviccaro S, Cioffi L, Falvo E, Giatti S, and Melcangi RC
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- Progesterone, Neurosteroids, Pregnanolone
- Abstract
Allopregnanolone, a 3α,5α-progesterone metabolite, acts as a potent allosteric modulator of the γ-aminobutyric acid type A receptor. In the present review, the synthesis of this neuroactive steroid occurring in the nervous system is discussed with respect to physiological and pathological conditions. In addition, its physiological and neuroprotective effects are also reported. Interestingly, the levels of this neuroactive steroid, as well as its effects, are sex-dimorphic, suggesting a possible gender medicine based on this neuroactive steroid for neurological disorders. However, allopregnanolone presents low bioavailability and extensive hepatic metabolism, limiting its use as a drug. Therefore, synthetic analogues or a different therapeutic strategy able to increase allopregnanolone levels have been proposed to overcome any pharmacokinetic issues., (© 2021 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.)
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- 2022
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37. Image-Based Monitoring of Cracks: Effectiveness Analysis of an Open-Source Machine Learning-Assisted Procedure.
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Parente L, Falvo E, Castagnetti C, Grassi F, Mancini F, Rossi P, and Capra A
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The proper inspection of a cracks pattern over time is a critical diagnosis step to provide a thorough knowledge of the health state of a structure. When monitoring cracks propagating on a planar surface, adopting a single-image-based approach is a more convenient (costly and logistically) solution compared to subjective operators-based solutions. Machine learning (ML)- based monitoring solutions offer the advantage of automation in crack detection; however, complex and time-consuming training must be carried out. This study presents a simple and automated ML-based crack monitoring approach implemented in open sources software that only requires a single image for training. The effectiveness of the approach is assessed conducting work in controlled and real case study sites. For both sites, the generated outputs are significant in terms of accuracy (~1 mm), repeatability (sub-mm) and precision (sub-pixel). The presented results highlight that the successful detection of cracks is achievable with only a straightforward ML-based training procedure conducted on only a single image of the multi-temporal sequence. Furthermore, the use of an innovative camera kit allowed exploiting automated acquisition and transmission fundamental for Internet of Things (IoTs) for structural health monitoring and to reduce user-based operations and increase safety.
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- 2022
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38. Mitoxantrone-Loaded Nanoferritin Slows Tumor Growth and Improves the Overall Survival Rate in a Subcutaneous Pancreatic Cancer Mouse Model.
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Conti G, Pitea M, Ossanna R, Opri R, Tisci G, Falvo E, Innamorati G, Ghanem E, Sbarbati A, Ceci P, and Fracasso G
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Pancreatic cancer (PC) represents an intriguing topic for researchers. To date, the prognosis of metastasized PC is poor with just 7% of patients exceeding a five-year survival period. Thus, molecular modifications of existing drugs should be developed to change the course of the disease. Our previously generated nanocages of Mitoxantrone (MIT) encapsulated in human H-chain Ferritin (HFt), designated as HFt-MP-PASE-MIT, has shown excellent tumor distribution and extended serum half-life meriting further investigation for PC treatment. Thus, in this study, we used the same nano-formulation to test its cytotoxicity using both in vitro and in vivo assays. Interestingly, both encapsulated and free-MIT drugs demonstrated similar killing capabilities on PaCa44 cell line. Conversely, in vivo assessment in a subcutaneous PaCa44 tumor model of PC demonstrated a remarkable capability for encapsulated MIT to control tumor growth and improve mouse survival with a median survival rate of 65 vs. 33 days for loaded and free-MIT, respectively. Interestingly, throughout the course of mice treatment, MIT encapsulation did not present any adverse side effects as confirmed by histological analysis of various murine tissue organs and body mass weights. Our results are promising and pave the way to effective PC targeted chemotherapy using our HFt nanodelivery platforms.
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- 2021
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39. Effects of paroxetine treatment and its withdrawal on neurosteroidogenesis.
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Giatti S, Diviccaro S, Cioffi L, Falvo E, Caruso D, and Melcangi RC
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- Animals, Hippocampus, Male, Paroxetine adverse effects, Rats, Selective Serotonin Reuptake Inhibitors adverse effects, Neurosteroids, Sexual Dysfunction, Physiological
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Selective serotonin reuptake inhibitors (SSRI) show high efficacy in treating depression, however during treatment side effects, like for instance sexual dysfunction, may appear, decreasing compliance. In some cases, this condition will last after drug discontinuation, leading to the so-called post-SSRI sexual dysfunction (PSSD). The etiology of PSSD is still unknown, however a role for neuroactive steroids may be hypothesized. Indeed, these molecules are key physiological regulators of the nervous system, and their alteration has been associated with several neuropathological conditions, including depression. Additionally, neuroactive steroids are also involved in the control of sexual function. Interestingly, sexual dysfunction induced by SSRI treatment has been also observed in animal models. On this basis, we have here evaluated whether a subchronic treatment with paroxetine for two weeks and/or its withdrawal (i.e., a month) may affect the levels of neuroactive steroids in brain areas (i.e., hippocampus, hypothalamus, and cerebral cortex) and/or in plasma and cerebrospinal fluid of male rats. Data obtained indicate that the SSRI treatment alters neuroactive steroid levels and the expression of key enzymes of the steroidogenesis in a brain tissue- and time-dependent manner. Indeed, these observations with the finding that plasma levels of neuroactive steroids are not affected suggest that the effect of paroxetine treatment is directly on neurosteroidogenesis. In particular, a negative impact on the expression of steroidogenic enzymes was observed at the withdrawal. Therefore, it is possible to hypothesize that altered neurosteroidogenesis may also occur in PSSD and consequently it may represent a possible pharmacological target for this disorder., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
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- 2021
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40. Three-Dimensional Proteome-Wide Scale Screening for the 5-Alpha Reductase Inhibitor Finasteride: Identification of a Novel Off-Target.
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Giatti S, Di Domizio A, Diviccaro S, Falvo E, Caruso D, Contini A, and Melcangi RC
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- 5-alpha Reductase Inhibitors metabolism, 5-alpha Reductase Inhibitors pharmacology, Animals, Binding Sites, Binding, Competitive, Catecholamines analysis, Catecholamines metabolism, Chromatography, High Pressure Liquid, Databases, Protein, Epinephrine metabolism, Finasteride metabolism, Finasteride pharmacology, Humans, Male, Molecular Docking Simulation, Molecular Dynamics Simulation, Phenylethanolamine N-Methyltransferase chemistry, Protein Binding, Rats, Rats, Sprague-Dawley, Tandem Mass Spectrometry, Thermodynamics, 5-alpha Reductase Inhibitors chemistry, Finasteride chemistry, Phenylethanolamine N-Methyltransferase metabolism
- Abstract
Finasteride, a 5-alpha reductase (5α-R) inhibitor, is a widely used drug for treating androgen-dependent conditions. However, its use is associated with sexual, psychological, and physical complaints, suggesting that other mechanisms, in addition to 5α-R inhibition, may be involved. Here, a multidisciplinary approach has been used to identify potential finasteride off-target proteins. SPILLO-PBSS software suggests an additional inhibitory activity of finasteride on phenylethanolamine N -methyltransferase (PNMT), the limiting enzyme in formation of the stress hormone epinephrine. The interaction of finasteride with PNMT was supported by docking and molecular dynamics analysis and by in vitro assay, confirming the inhibitory nature of the binding. Finally, this inhibition was also confirmed in an in vivo rat model. Literature data indicate that PNMT activity perturbation may be correlated with sexual and psychological side effects. Therefore, results here obtained suggest that the binding of finasteride to PNMT might have a role in producing the side effects exerted by finasteride treatment.
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- 2021
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41. High activity and low toxicity of a novel CD71-targeting nanotherapeutic named The-0504 on preclinical models of several human aggressive tumors.
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Falvo E, Damiani V, Conti G, Boschi F, Messana K, Giacomini P, Milella M, De Laurenzi V, Morea V, Sala G, Fracasso G, and Ceci P
- Subjects
- Animals, Cell Line, Tumor, Female, Humans, Mice, Mice, Nude, Rats, Antigens, CD metabolism, Biomarkers, Tumor metabolism, Ferritins metabolism, Nanostructures chemistry, Neoplasms genetics, Receptors, Transferrin metabolism
- Abstract
Background: Ferritin receptor (CD71) is an example of a very attractive cancer target, since it is highly expressed in virtually all tumor types, including metastatic loci. However, this target can be considered to be inaccessible to conventional target therapies, due to its presence in many healthy tissues. Here, we describe the preclinical evaluation of a tumor proteases-activatable human ferritin (HFt)-based drug carrier (The-0504) that is able to selectively deliver the wide-spectrum topoisomerase I inhibitor Genz-644282 to CD71-expressing tumors, preventing the limiting toxic effects associated with CD71-targeting therapies., Methods: CD71 expression was evaluated using flow cytometry and immunohistochemistry techniques. The-0504 antiproliferative activity towards several cancer cell lines was assessed in vitro. The-0504 antitumor efficacy and survival benefit were evaluated in different human tumors, which had been grown either as xenografts or patient-derived xenografts in mice. The-0504 toxicology profile was investigated in multiple-cycle repeat-dose study in rodents., Results: In vitro studies indicate that The-0504 is highly specific for CD71 expressing cells, and that there is a relationship between CD71 levels and The-0504 anticancer activity. In vivo treatments with The-0504 showed a remarkable efficacy, eradicating several human tumors of very diverse and aggressive histotypes, such as pancreas, liver and colorectal carcinomas, and triple-negative breast cancer., Conclusions: Durable disease-free survival, persistent antitumor responses after discontinuation of treatment and favorable toxicology profile make The-0504 an ideal candidate for clinical development as a novel, CD71-targeted, low-toxicity alternative to chemotherapy.
- Published
- 2021
- Full Text
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42. Physiopathological Role of Neuroactive Steroids in the Peripheral Nervous System.
- Author
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Falvo E, Diviccaro S, Melcangi RC, and Giatti S
- Subjects
- Animals, Humans, Models, Biological, Neuroprotective Agents pharmacology, Neuroprotective Agents therapeutic use, Neurosteroids chemistry, Neurosteroids therapeutic use, Peripheral Nervous System drug effects, Peripheral Nervous System Diseases drug therapy, Peripheral Nervous System Diseases pathology, Peripheral Nervous System Diseases physiopathology, Neurosteroids metabolism, Peripheral Nervous System physiopathology
- Abstract
Peripheral neuropathy (PN) refers to many conditions involving damage to the peripheral nervous system (PNS). Usually, PN causes weakness, numbness and pain and is the result of traumatic injuries, infections, metabolic problems, inherited causes, or exposure to chemicals. Despite the high prevalence of PN, available treatments are still unsatisfactory. Neuroactive steroids (i.e., steroid hormones synthesized by peripheral glands as well as steroids directly synthesized in the nervous system) represent important physiological regulators of PNS functionality. Data obtained so far and here discussed, indeed show that in several experimental models of PN the levels of neuroactive steroids are affected by the pathology and that treatment with these molecules is able to exert protective effects on several PN features, including neuropathic pain. Of note, the observations that neuroactive steroid levels are sexually dimorphic not only in physiological status but also in PN, associated with the finding that PN show sex dimorphic manifestations, may suggest the possibility of a sex specific therapy based on neuroactive steroids.
- Published
- 2020
- Full Text
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43. Engineered Human Nanoferritin Bearing the Drug Genz-644282 for Cancer Therapy.
- Author
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Falvo E, Arcovito A, Conti G, Cipolla G, Pitea M, Morea V, Damiani V, Sala G, Fracasso G, and Ceci P
- Abstract
Gastrointestinal tumors, including pancreatic and colorectal cancers, represent one of the greatest public health issues worldwide, leading to a million global deaths. Recent research demonstrated that the human heavy chain ferritin (HFt) can encapsulate different types of drugs in its cavity and can bind to its receptor, CD71, in several solid and hematological tumors, thus highlighting the potential use of ferritin for tumor-targeting therapies. Here, we describe the development and characterization of a novel nanomedicine based on the HFt that is named The-0504. In particular, this novel system is a nano-assembly comprising an engineered version of HFt that entraps about 80 molecules of a potent, wide-spectrum, non-camptothecin topoisomerase I inhibitor (Genz-644282). The-0504 can be produced by a standardized pre-industrial process as a pure and homogeneously formulated product with favourable lyophilization properties. The preliminary anticancer activity was evaluated in cultured cancer cells and in a mouse model of pancreatic cancer. Overall results reported here make The-0504 a candidate for further preclinical development against CD-71 expressing deadly tumors.
- Published
- 2020
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44. Physiopathological role of the enzymatic complex 5α-reductase and 3α/β-hydroxysteroid oxidoreductase in the generation of progesterone and testosterone neuroactive metabolites.
- Author
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Giatti S, Diviccaro S, Falvo E, Garcia-Segura LM, and Melcangi RC
- Subjects
- 3-Hydroxysteroid Dehydrogenases genetics, Animals, Brain enzymology, Cholestenone 5 alpha-Reductase genetics, Female, Gene Expression, Humans, Male, Mental Disorders enzymology, Neurodegenerative Diseases enzymology, Neuroprotective Agents, Sex Characteristics, 3-Hydroxysteroid Dehydrogenases physiology, Cholestenone 5 alpha-Reductase physiology, Progesterone metabolism, Testosterone metabolism
- Abstract
The enzymatic complex 5α-reductase (5α-R) and 3α/3β-hydroxysteroid oxidoreductase (HSOR) is expressed in the nervous system, where it transforms progesterone (PROG) and testosterone (T) into neuroactive metabolites. These metabolites regulate myelination, brain maturation, neurotransmission, reproductive behavior and the stress response. The expression of 5α-R and 3α-HSOR and the levels of PROG and T reduced metabolites show regional and sex differences in the nervous system and are affected by changing physiological conditions as well as by neurodegenerative and psychiatric disorders. A decrease in their nervous tissue levels may negatively impact the course and outcome of some pathological events. However, in other pathological conditions their increased levels may have a negative impact. Thus, the use of synthetic analogues of these steroids or 5α-R modulation have been proposed as therapeutic approaches for several nervous system pathologies. However, further research is needed to fully understand the consequences of these manipulations, in particular with 5α-R inhibitors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
- Full Text
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45. Increasing the Magnetic Anisotropy of a Natural System: Co-Doped Magnetite Mineralized in Ferritin Shells.
- Author
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Fantechi E, Innocenti C, Ferretti AM, Falvo E, Ceci P, Pineider F, and Sangregorio C
- Abstract
Iron oxide nanoparticles mineralized within the internal cavity of Ferritin protein cage are extremely appealing for the realization of multifunctional therapeutic and diagnostic agents for cancer treatment by drug delivery, magnetic fluid hyperthermia (MFH) and magnetic resonance imaging. Being the maximum mean size imposed by the internal diameter of the protein shell (ca. 8 nm) too small for the use of these systems in MFH, a valuable strategy for the improvement of the hyperthermic efficiency is increasing the magnetic anisotropy by doping the iron oxide with divalent Co ions. This strategy has been demonstrated to be highly efficient in the case of iron oxide nanoparticles mineralized in Human Ferritin (HFt). However, a deterioration of nanoparticles crystallinity and consequently a reduction of the hyperthermic efficiency were observed with increasing Co-doping. In this contribution, we compare two series of Co-doped iron oxide nanoparticles (Co-doping level up to 15%) mineralized into HFt and into Ferritin from the archaea Pirococcus Furiosus (PfFt), the protein structure of which differs for the nucleation sites, with the aim of increasing the crystalline quality of the inorganic cores for larger Co doping. Highly monodisperse nanoparticles of 6-7 nm were obtained in both series. The structural and magnetic characterization indicate that the PfFt series is less subjected to crystallinity deterioration with increasing Co content with respect to the HFt one. Such difference is reflected in the hyperthermic efficiency, which reaches the maximum value for different intermediate Co-doping (10% and 5% for PfFt and HFt, respectively), and goes to zero for further Co-doping increments.
- Published
- 2019
- Full Text
- View/download PDF
46. Cryo-EM structure of the human ferritin-transferrin receptor 1 complex.
- Author
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Montemiglio LC, Testi C, Ceci P, Falvo E, Pitea M, Savino C, Arcovito A, Peruzzi G, Baiocco P, Mancia F, Boffi A, des Georges A, and Vallone B
- Subjects
- Antigens, CD genetics, Antigens, CD metabolism, Apoferritins genetics, Apoferritins metabolism, Arenaviruses, New World genetics, Arenaviruses, New World metabolism, Binding Sites, Cloning, Molecular, Cryoelectron Microscopy, Escherichia coli genetics, Escherichia coli metabolism, Gene Expression, Genetic Vectors chemistry, Genetic Vectors metabolism, HeLa Cells, Hemochromatosis Protein chemistry, Hemochromatosis Protein genetics, Hemochromatosis Protein metabolism, Humans, Plasmodium vivax genetics, Plasmodium vivax metabolism, Protein Binding, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Protein Interaction Domains and Motifs, Protozoan Proteins genetics, Protozoan Proteins metabolism, Receptors, Transferrin genetics, Receptors, Transferrin metabolism, Receptors, Virus genetics, Receptors, Virus metabolism, Recombinant Proteins chemistry, Recombinant Proteins genetics, Recombinant Proteins metabolism, Substrate Specificity, Transferrin genetics, Transferrin metabolism, Viral Envelope Proteins genetics, Viral Envelope Proteins metabolism, Antigens, CD chemistry, Apoferritins chemistry, Protozoan Proteins chemistry, Receptors, Transferrin chemistry, Receptors, Virus chemistry, Transferrin chemistry, Viral Envelope Proteins chemistry
- Abstract
Human transferrin receptor 1 (CD71) guarantees iron supply by endocytosis upon binding of iron-loaded transferrin and ferritin. Arenaviruses and the malaria parasite exploit CD71 for cell invasion and epitopes on CD71 for interaction with transferrin and pathogenic hosts were identified. Here, we provide the molecular basis of the CD71 ectodomain-human ferritin interaction by determining the 3.9 Å resolution single-particle cryo-electron microscopy structure of their complex and by validating our structural findings in a cellular context. The contact surfaces between the heavy-chain ferritin and CD71 largely overlap with arenaviruses and Plasmodium vivax binding regions in the apical part of the receptor ectodomain. Our data account for transferrin-independent binding of ferritin to CD71 and suggest that select pathogens may have adapted to enter cells by mimicking the ferritin access gate.
- Published
- 2019
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47. Very low intensity ultrasounds as a new strategy to improve selective delivery of nanoparticles-complexes in cancer cells.
- Author
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Loria R, Giliberti C, Bedini A, Palomba R, Caracciolo G, Ceci P, Falvo E, Marconi R, Falcioni R, Bossi G, and Strigari L
- Subjects
- Antineoplastic Agents pharmacology, Cell Line, Tumor, Colonic Neoplasms pathology, Humans, Antineoplastic Agents therapeutic use, Colonic Neoplasms diagnostic imaging, Colonic Neoplasms drug therapy, Drug Delivery Systems methods, Nanoparticles metabolism, Ultrasonography methods
- Abstract
Background: The possibility to combine Low Intensity UltraSound (LIUS) and Nanoparticles (NP) could represent a promising strategy for drugs delivery in tumors difficult to treat overcoming resistance to therapies. On one side the NP can carry drugs that specifically target the tumors on the other the LIUS can facilitate and direct the delivery to the tumor cells. In this study, we investigated whether Very Low Intensity UltraSound (VLIUS), at intensities lower than 120 mW/cm
2 , might constitute a novel strategy to improve delivery to tumor cells. Thus, in order to verify the efficacy of this novel modality in terms of increase selective uptake in tumoral cells and translate speedily in clinical practice, we investigated VLIUS in three different in vitro experimental tumor models and normal cells adopting three different therapeutic strategies., Methods: VLIUS at different intensities and exposure time were applied to tumor and normal cells to evaluate the efficiency in uptake of labeled human ferritin (HFt)-based NP, the delivery of NP complexed Firefly luciferase reported gene (lipoplex-LUC), and the tumor-killing of chemotherapeutic agent., Results: Specifically, we found that specific VLIUS intensity (120 mW/cm2 ) increases tumor cell uptake of HFt-based NPs at specific concentration (0.5 mg/ml). Similarly, VLIUS treatments increase significantly tumor cells delivery of lipoplex-LUC cargos. Furthermore, of interest, VLIUS increases tumor killing of chemotherapy drug trabectedin in a time dependent fashion. Noteworthy, VLIUS treatments are well tolerated in normal cells with not significant effects on cell survival, NPs delivery and drug-induced toxicity, suggesting a tumor specific fashion., Conclusions: Our data shed novel lights on the potential application of VLIUS for the design and development of novel therapeutic strategies aiming to efficiently deliver NP loaded cargos or anticancer drugs into more aggressive and unresponsive tumors niche.- Published
- 2019
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- View/download PDF
48. Study of manganese binding to the ferroxidase centre of human H-type ferritin.
- Author
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Ardini M, Howes BD, Fiorillo A, Falvo E, Sottini S, Rovai D, Lantieri M, Ilari A, Gatteschi D, Spina G, Chiancone E, Stefanini S, and Fittipaldi M
- Subjects
- Electron Spin Resonance Spectroscopy, Humans, Protein Binding, Apoferritins chemistry, Apoferritins metabolism, Ceruloplasmin chemistry, Ceruloplasmin metabolism, Manganese chemistry, Manganese metabolism
- Abstract
Ferritins are ubiquitous and conserved proteins endowed with enzymatic ferroxidase activity, that oxidize Fe(II) ions at the dimetal ferroxidase centre to form a mineralized Fe(III) oxide core deposited within the apo-protein shell. Herein, the in vitro formation of a heterodimetal cofactor constituted by Fe and Mn ions has been investigated in human H ferritin (hHFt). Namely, Mn and Fe binding at the hHFt ferroxidase centre and its effects on Fe(II) oxidation have been investigated by UV-Vis ferroxidation kinetics, fluorimetric titrations, multifrequency EPR, and preliminary Mössbauer spectroscopy. Our results show that in hHFt, both Fe(II) and Mn(II) bind the ferroxidase centre forming a Fe-Mn cofactor. Moreover, molecular oxygen seems to favour Mn(II) binding and increases the ferroxidation activity of the Mn-loaded protein. The data suggest that Mn influences the Fe binding and the efficiency of the ferroxidation reaction. The higher efficiency of the Mn-Fe heterometallic centre may have a physiological relevance in specific cell types (i.e. glia cells), where the concentration of Mn is the same order of magnitude as iron., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
49. The presence of glutamate residues on the PAS sequence of the stimuli-sensitive nano-ferritin improves in vivo biodistribution and mitoxantrone encapsulation homogeneity.
- Author
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Falvo E, Malagrinò F, Arcovito A, Fazi F, Colotti G, Tremante E, Di Micco P, Braca A, Opri R, Giuffrè A, Fracasso G, and Ceci P
- Subjects
- Cell Line, Tumor, Humans, Tissue Distribution, Antineoplastic Agents administration & dosage, Apoferritins administration & dosage, Doxorubicin administration & dosage, Drug Carriers administration & dosage, Glutamic Acid administration & dosage, Mitoxantrone administration & dosage, Nanoparticles administration & dosage
- Abstract
A genetically engineered human ferritin heavy chain (HFt)-based construct has been recently shown by our group to efficiently entrap and deliver doxorubicin to cancer cells. This construct, named HFt-MP-PAS, contained a tumor-selective sequence (MP) responsive to proteolytic cleavage by tumor proteases (MMPs), located between each HFt subunit and an outer shielding polypeptide sequence rich in proline (P), serine (S) and alanine (A) residues (PAS). HFt-MP-PAS displayed excellent therapeutic efficacy in xenogenic pancreatic and head and neck cancer models in vivo, leading to a significant increase in overall animal survivals. Here we report a new construct obtained by the genetic insertion of two glutamate residues in the PAS sequence of HFt-MP-PAS. Such new construct, named HFt-MP-PASE, is characterized by improved performances as drug biodistribution in a xenogenic pancreatic cancer model in vivo. Moreover, HFt-MP-PASE efficiently encapsulates the anti-cancer drug mitoxantrone (MIT), and the resulting MIT-loaded nanoparticles proved to be more soluble and monodispersed than the HFt-MP-PAS counterparts. Importantly, in vitro MIT-loaded HFt-MP-PASE kills several cancer cell lines of different origin (colon, breast, sarcoma and pancreas) at least as efficiently as the free drug. Finally, our MIT loaded protein nanocages allowed in vivo an impressive incrementing of the drug accumulation in the tumor with respect to the free drug., (Copyright © 2018 Elsevier B.V. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
50. Therapeutic Efficacy of the Novel Stimuli-Sensitive Nano-Ferritins Containing Doxorubicin in a Head and Neck Cancer Model.
- Author
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Damiani V, Falvo E, Fracasso G, Federici L, Pitea M, De Laurenzi V, Sala G, and Ceci P
- Subjects
- Cell Line, Tumor, Cell Proliferation drug effects, Doxorubicin chemical synthesis, Doxorubicin chemistry, Doxorubicin pharmacology, Humans, Peptides chemistry, Receptors, Transferrin metabolism, Squamous Cell Carcinoma of Head and Neck, Treatment Outcome, Apoferritins chemistry, Carcinoma, Squamous Cell drug therapy, Doxorubicin therapeutic use, Head and Neck Neoplasms drug therapy, Nanoparticles chemistry
- Abstract
Doxorubicin is employed alone or in combination for the treatment of several hematological and solid malignancies; despite its efficacy, there are associated cardiotoxicity limits both in its application in patients with heart disease risk factors and also in its long-term use. HFt-MP-PAS40 is a genetically engineered human ferritin heavy chain (HFt)-based construct able to efficiently entrap and deliver doxorubicin to cancer cells. HF-MP-PAS contains a short motif sequence (defined as MP) responsive to proteolytic cleavage by tumor matrix metalloproteases (MMPs), located between each HFt subunit and a masking polypeptide sequence rich in proline (P), alanine (A), and serine (S) residues (PAS). This carrier displayed excellent therapeutic efficacy in a xenogenic pancreatic cancer model in vivo, leading to a significant increase in overall animal survival in treated mice. Herein, we describe the HFt-MP-PAS40-Dox efficacy against squamous cell carcinomas of the head and neck (HNSCC) with the goal of validating the application of our nano-drug for the treatment of different solid tumors. In addition, a tolerability study in healthy mice was also performed. The results indicate that HFt-MP-PAS40-Dox produced increased anti-tumor effects both in vitro and in vivo in comparison to the free drug in several HNSCC cell lines. In the acute toxicity studies, the maximum tolerated dose (MTD) of HFt-MP-PAS40-Dox was about 3.5 higher than the free drug: 25 mg/kg versus 7 mg/kg doxorubicin equivalents. Importantly, evaluation of heart tissues provided evidence that doxorubicin is less cardio-toxic when encapsulated inside the ferritin carrier. In conclusion, HFt-MP-PAS40-Dox may be administered safely at higher doses compared with the free drug, resulting in superior efficacy to control HNSCC malignancies., Competing Interests: The authors declare no conflict of interest.
- Published
- 2017
- Full Text
- View/download PDF
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