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149 results on '"Bucciantini, M"'

1. Interaction of an anticancer peptide fragment of azurin with p53 and its isolated domains studied by atomic force spectroscopy

Author

Bizzarri AR, Santini S, Coppari E, Bucciantini M, Di Agostino S, Yamada T, Beattie CW, and Cannistraro S

Subjects
Medicine (General), R5-920
Abstract

Anna Rita Bizzarri1, Simona Santini1, Emilia Coppari1, Monica Bucciantini2, Silvia Di Agostino3, Tohru Yamada4, Craig W Beattie4, Salvatore Cannistraro11Biophysics and Nanoscience Centre, CNISM, Facoltà di Scienze, Università della Tuscia, Viterbo, 2Department of Biochemical Sciences, University of Florence, Florence, 3Molecular Oncogenesis Laboratory, Experimental Oncology Department, Regina Elena Cancer Institute, Rome, Italy; 4Department of Surgical Oncology, University of Illinois College of Medicine, Chicago, IL, USAAbstract: p28 is a 28-amino acid peptide fragment of the cupredoxin azurin derived from Pseudomonas aeruginosa that preferentially penetrates cancerous cells and arrests their proliferation in vitro and in vivo. Its antitumor activity reportedly arises from post-translational stabilization of the tumor suppressor p53 normally downregulated by the binding of several ubiquitin ligases. This would require p28 to specifically bind to p53 to inhibit specific ligases from initiating proteosome-mediated degradation. In this study, atomic force spectroscopy, a nanotechnological approach, was used to investigate the interaction of p28 with full-length p53 and its isolated domains at the single molecule level. Analysis of the unbinding forces and the dissociation rate constant suggest that p28 forms a stable complex with the DNA-binding domain of p53, inhibiting the binding of ubiquitin ligases other than Mdm2 to reduce proteasomal degradation of p53.Keywords: AFS, cancer physics, unbinding forces

Published
2011

2. Anti-Aging and Neuroprotective Properties of Grifola frondosa and Hericium erinaceus Extracts

Author

Tripodi, F, Falletta, E, Leri, M, Angeloni, C, Beghelli, D, Giusti, L, Milanesi, R, Sampaio-Marques, B, Ludovico, P, Goppa, L, Rossi, P, Savino, E, Bucciantini, M, Coccetti, P, Tripodi, Farida, Falletta, Ermelinda, Leri, Manuela, Angeloni, Cristina, Beghelli, Daniela, Giusti, Laura, Milanesi, Riccardo, Sampaio-Marques, Belém, Ludovico, Paula, Goppa, Lorenzo, Rossi, Paola, Savino, Elena, Bucciantini, Monica, Coccetti, Paola, Tripodi, F, Falletta, E, Leri, M, Angeloni, C, Beghelli, D, Giusti, L, Milanesi, R, Sampaio-Marques, B, Ludovico, P, Goppa, L, Rossi, P, Savino, E, Bucciantini, M, Coccetti, P, Tripodi, Farida, Falletta, Ermelinda, Leri, Manuela, Angeloni, Cristina, Beghelli, Daniela, Giusti, Laura, Milanesi, Riccardo, Sampaio-Marques, Belém, Ludovico, Paula, Goppa, Lorenzo, Rossi, Paola, Savino, Elena, Bucciantini, Monica, and Coccetti, Paola

Published
2022

6. Garcinoic acid prevents beta-amyloid (Abeta) deposition in the mouse brain

Author

Marinelli R, Torquato P, Bartolini D, Mas-Bargues C, Bellezza G, Gioiello A, Borras C, De Luca A, Fallarino F, Sebastiani B, Mani S, Sidoni A, Vina J, Leri M, Bucciantini M, Nardiello P, Casamenti F, and Galli F

Abstract

Garcinoic acid (GA or delta-T3-13'COOH), is a natural vitamin E metabolite that has preliminarily been identified as a modulator of nuclear receptors involved in beta-amyloid (Abeta) metabolism and progression of Alzheimer's disease (AD). In this study, we investigated GA's effects on Abeta oligomer formation and deposition. Specifically, we compared them with those of other vitamin E analogs and the soy isoflavone genistein, a natural agonist of peroxisome proliferator-activated receptor gamma (PPARgamma) that has therapeutic potential for managing AD. GA significantly reduced Abeta aggregation and accumulation in mouse cortical astrocytes. Similarly to genistein, GA up-regulated PPARgamma expression and apolipoprotein E (ApoE) efflux in these cells with an efficacy that was comparable to that of its metabolic precursor delta-tocotrienol and higher than those of alpha-tocopherol metabolites. Unlike for genistein and the other vitamin E compounds, the GA-induced restoration of ApoE efflux was not affected by pharmacological inhibition of PPARgamma activity, and specific activation of pregnane X receptor (PXR) was observed together with ApoE and multidrug resistance protein 1 (MDR1) membrane transporter up-regulation in both the mouse astrocytes and brain tissue. These effects of GA were associated with reduced Abeta deposition in the brain of TgCRND8 mice, a transgenic AD model. In conclusion, GA holds potential for preventing Abeta oligomerization and deposition in the brain. The mechanistic aspects of GA's properties appear to be distinct from those of other vitamin E metabolites and of genistein. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

Published
2020

8. The polyphenol Oleuropein aglycone hinders the growth of toxic transthyretin amyloid assemblies

Author

Leri, M, Nosi, D, Natalello, A, Porcari, R, Ramazzotti, M, Chiti, F, Bellotti, V, Doglia, S, Stefani, M, Bucciantini, M, NATALELLO, ANTONINO, DOGLIA, SILVIA MARIA, Bucciantini, M., Leri, M, Nosi, D, Natalello, A, Porcari, R, Ramazzotti, M, Chiti, F, Bellotti, V, Doglia, S, Stefani, M, Bucciantini, M, NATALELLO, ANTONINO, DOGLIA, SILVIA MARIA, and Bucciantini, M.

Abstract

Transthyretin (TTR) is involved in a subset of familial or sporadic amyloid diseases including senile systemic amyloidosis (SSA), familial amyloid polyneuropathy and cardiomyopathy (FAP/FAC) for which no effective therapy has been found yet. These conditions are characterized by extracellular deposits primarily found in the heart parenchyma and in peripheral nerves whose main component are amyloid fibrils, presently considered the main culprits of cell sufferance. The latter are polymeric assemblies grown from misfolded TTR, either wt or carrying one out of many identified mutations. The recent introduction in the clinical practice of synthetic TTR-stabilizing molecules that reduce protein aggregation provides the rationale to search natural effective molecules able to interfere with TTR amyloid aggregation by hindering the appearance of toxic species or by favoring the growth of harmless aggregates. Here we carried out an in depth biophysical and morphological study on the molecular features of the aggregation of wt- and L55P-TTR involved in SSA or FAP/FAC, respectively, and on the interference with fibril aggregation, stability and toxicity to cardiac HL-1 cells to demonstrate the ability of Oleuropein aglycone (OleA), the main phenolic component of the extra virgin olive oil. We describe the molecular basis of such interference and the resulting reduction of TTR amyloid aggregate cytotoxicity. Our data offer the possibility to validate and optimize the use of OleA or its molecular scaffold to rationally design promising drugs against TTR-related pathologies that could enter a clinical experimental phase.

Published
2016

9. A FTIR microspectroscopy study of the structural and biochemical perturbations induced by natively folded and aggregated transthyretin in HL-1 cardiomyocytes

Author

Ami, D, Mereghetti, P, Leri, M, Giorgetti, S, Natalello, A, Doglia, S, Stefani, M, Bucciantini, M, Ami, Diletta, Mereghetti, Paolo, Leri, Manuela, Giorgetti, Sofia, Natalello, Antonino, Doglia, Silvia Maria, Stefani, Massimo, Bucciantini, Monica, Ami, D, Mereghetti, P, Leri, M, Giorgetti, S, Natalello, A, Doglia, S, Stefani, M, Bucciantini, M, Ami, Diletta, Mereghetti, Paolo, Leri, Manuela, Giorgetti, Sofia, Natalello, Antonino, Doglia, Silvia Maria, Stefani, Massimo, and Bucciantini, Monica

Abstract

Protein misfolding and aggregation are associated with a number of human degenerative diseases. In spite of the enormous research efforts to develop effective strategies aimed at interfering with the pathogenic cascades induced by misfolded/aggregated peptides/proteins, the necessary detailed understanding of the molecular bases of amyloid formation and toxicity is still lacking. To this aim, approaches able to provide a global insight in amyloid-mediated physiological alterations are of importance. In this study, we exploited Fourier transform infrared microspectroscopy, supported by multivariate analysis, to investigate in situ the spectral changes occurring in cultured intact HL-1 cardiomyocytes exposed to wild type (WT) or mutant (L55P) transthyretin (TTR) in native, or amyloid conformation. The presence of extracellular deposits of amyloid aggregates of WT or L55P TTR, respectively, is a key hallmark of two pathological conditions, known as senile systemic amyloidosis and familial amyloid polyneuropathy. We found that the major effects, associated with modifications in lipid properties and in the cell metabolic/phosphorylation status, were observed when natively folded WT or L55P TTR was administered to the cells. The effects induced by aggregates of TTR were milder and in some cases displayed a different timing compared to those elicited by the natively folded protein.

Published
2018

10. 1610. Avvisi stellari

Author

Bucciantini, M., Camerota, Michele, and Giudice, Franco Salvatore

Subjects
telescopio, Galileo, Sidereus Nuncius, Paesi Bassi, Settore M-STO/05 - STORIA DELLA SCIENZA E DELLE TECNICHE, Paesi Bassi, telescopio, Galileo, Sidereus Nuncius, scoperte astronomiche, scoperte astronomiche
Published
2017

13. Biochemical and Electrophysiological Modification of Amyloid Transthyretin on Cardiomyocytes

Author

Sartiani, L, Bucciantini, M, Spinelli, V, Leri, M, Natalello, A, Nosi, D, Doglia, S, Relini, A, Penco, A, Giorgetti, S, Gerace, E, Mannaioni, G, Bellotti, V, Rigacci, S, Cerbai, E, Stefani, M, NATALELLO, ANTONINO, DOGLIA, SILVIA MARIA, Stefani, M., Sartiani, L, Bucciantini, M, Spinelli, V, Leri, M, Natalello, A, Nosi, D, Doglia, S, Relini, A, Penco, A, Giorgetti, S, Gerace, E, Mannaioni, G, Bellotti, V, Rigacci, S, Cerbai, E, Stefani, M, NATALELLO, ANTONINO, DOGLIA, SILVIA MARIA, and Stefani, M.

Abstract

Transthyretin (TTR) amyloidoses are familial or sporadic degenerative conditions that often feature heavy cardiac involvement. Presently, no effective pharmacological therapy for TTR amyloidoses is available, mostly due to a substantial lack of knowledge about both the molecular mechanisms of TTR aggregation in tissue and the ensuing functional and viability modifications that occur in aggregate-exposed cells. TTR amyloidoses are of particular interest regarding the relation between functional and viability impairment in aggregate-exposed excitable cells such as peripheral neurons and cardiomyocytes. In particular, the latter cells provide an opportunity to investigate in parallel the electrophysiological and biochemical modifications that take place when the cells are exposed for various lengths of time to variously aggregated wild-type TTR, a condition that characterizes senile systemic amyloidosis. In this study, we investigated biochemical and electrophysiological modifications in cardiomyocytes exposed to amyloid oligomers or fibrils of wild-type TTR or to its T4-stabilized form, which resists tetramer disassembly, misfolding, and aggregation. Amyloid TTR cytotoxicity results in mitochondrial potential modification, oxidative stress, deregulation of cytoplasmic Ca2+ levels, and Ca2+ cycling. The altered intracellular Ca2+ cycling causes a prolongation of the action potential, as determined by whole-cell recordings of action potentials on isolated mouse ventricular myocytes, which may contribute to the development of cellular arrhythmias and conduction alterations often seen in patients with TTR amyloidosis. Our data add information about the biochemical, functional, and viability alterations that occur in cardiomyocytes exposed to aggregated TTR, and provide clues as to the molecular and physiological basis of heart dysfunction in sporadic senile systemic amyloidosis and familial amyloid cardiomyopathy forms of TTR amyloidoses.

Published
2016

14. Journals under threat. A joint response from History of Science, Technology and Medicine editors

Author

Fox, R., Andersen, H., Ariew, R., Feingold, M., Bag, A. K., Barrow-Green, J., Dalen, B., Benson, K., Beretta, M., Blay, M., Cornelius Borck, Bowker, G., Star, S. L., Bucciantini, M., Camerota, M., Buchwald, J., Gray, J., Cappelletti, V., Cimino, G., Clark, M., Keller, A., Cline, R., Clucas, S., Gaukroger, S., Cook, H., Hardy, A., Corry, L., Métraux, A., Renn, J., Dolan, B., Luckin, B., Duerbeck, H., Orchiston, W., Epple, M., Hård, M., Rheinberger, H. J., Roelcke, V., French, S., Farber, P., Fissell, M., Packard, R., Good, J., Hackmann, W., Halleux, R., Holmqvist, B., Hoskin, M., Inkster, I., Spada, M. F., Jardine, N., Levere, T., Lightman, B., Lüthy, C., Lynch, M., Mccluskey, S., Ruggles, C., Morris, P., Nelson, E. C., Nicholson, I., Olesko, K., Peréz, L., Morus, I. R., Rigden, J., Stuewer, R. H., Samsó, J., Schaffer, S., Schappacher, N., Strom, C., Unschuld, P., Weingart, P., Zamecki, S., and Zuidervaart, H.

Subjects
Europe, Humans, Periodicals as Topic, Netherlands
Published
2012

15. Does azurin bind to the transactivation domain of p53? A Trp phosphorescence study

Author

Gabellieri E, Bucciantini M, Stefani M, and Cioni P

Abstract

The bacterial redox protein azurin has been shown to be able to enter into cancer cells and induce apoptosis by stabilizing p53. Although the formation of a complex between the two proteins has been demonstrated, little is known about their binding features. We investigated the interaction between the transcription activation domain of p53 (p53(1-63)) and Pseudomonas aeruginosa azurin using fluorescence and phosphorescence spectroscopic techniques. Trp phosphorescence lifetime measurements revealed conformational changes in azurin induced by the interaction with p53(1-63). Acrylamide quenching of Trp phosphorescence also indicated a significant increase in the overall flexibility of azurin upon binding to p53(1-63). We show that azurin binds to the N-terminal region of p53 with a dissociation constant in the 5-10 ¼M range. No change in the fluorescence and phosphorescence emission of p53(1-63) was detected in the presence of azurin. This result indicated that no Trp residue of p53(1-63) is located in the interaction site with azurin and therefore suggested that the azurin binding site does not overlap that of MDM2, the protein that plays a crucial role in the p53 regulation. The present results may assist in the design of novel cancer treatments based on p53 stabilization by azurin

Published
2011

18. Journals under threat: a joint response from history of science, technology and medicine editors

Author

Cook, H., Hardy, A., Andersen, H., Ariew, R., Feingold, M., Bag, A. K., Barrow-Green, J., Dalen, B., Benson, K., Beretta, M., Blay, M., Bleker, J., Stolberg, M., Cornelius Borck, Bowker, G., Star, S. L., Bucciantini, M., Camerota, M., Buchwald, J., Gray, J., Cappelletti, V., Cimino, G., Carson, C., Clark, M., Keller, A., Cline, R., Clucas, S., Gaukroger, S., Corry, L., Métraux, A., Renn, J., Dolan, B., Luckin, B., Duerbeck, H., Orchiston, W., Epple, M., Hård, M., Rheinberger, H. J., Roelcke, V., Farber, P., Fissell, M., Packard, R., Fox, R., Frasca-Spada, M., French, S., Good, J., Hackmann, W., Halleux, R., Holmqvist, B., Home, R., Hoskin, M., Inkster, I., Jardine, N., Levere, T., Lightman, B., Lüthy, C., Lynch, M., Mccluskey, S., Ruggles, C., Morris, P., Morus, I. R., Nelson, E. C., Nicholson, I., Olesko, K., Pérez, L., Rigden, J., Stuewer, R. H., Samsó, J., Schaffer, S., Schappacher, N., Staudenmaier, J., Strom, C., Unschuld, P., Weingart, P., Zamecki, S., and Zuidervaart, H.

Subjects
Technology, Germany, Science, Humans, History of Medicine, Journal Impact Factor, Periodicals as Topic, Editorial Policies
Published
2009

22. Different ataxin-3 amyloid aggregates induce intracellular Ca2+ deregulation by different mechanisms in cerebellar granule cells

Author

Pellistri, F, Bucciantini, M, Invernizzi, G, Gatta, E, Penco, A, Frana, A, Nosi, D, Relini, A, Regonesi, M, Gliozzi, A, Tortora, P, Robello, M, Stefani, M, Frana, AM, Stefani, M., REGONESI, MARIA ELENA, TORTORA, PAOLO, Pellistri, F, Bucciantini, M, Invernizzi, G, Gatta, E, Penco, A, Frana, A, Nosi, D, Relini, A, Regonesi, M, Gliozzi, A, Tortora, P, Robello, M, Stefani, M, Frana, AM, Stefani, M., REGONESI, MARIA ELENA, and TORTORA, PAOLO

Published
2013

25. Sunday, 18 July 2010

Author

Schuchardt, M., primary, Toelle, M., additional, Huang, T., additional, Wiedon, A., additional, Van Der Giet, M., additional, Mill, C., additional, George, S., additional, Jeremy, J., additional, Santulli, G., additional, Illario, M., additional, Cipolletta, E., additional, Sorriento, D., additional, Del Giudice, C., additional, Anastasio, A., additional, Trimarco, B., additional, Iaccarino, G., additional, Jobs, A., additional, Wagner, C., additional, Kurtz, A., additional, De Wit, C., additional, Koller, A., additional, Suvorava, T., additional, Weber, M., additional, Dao, V., additional, Kojda, G., additional, Tsaousi, A., additional, Lyon, C., additional, Williams, H., additional, Barth, N., additional, Loot, A., additional, Fleming, I., additional, Keul, P., additional, Lucke, S., additional, Graeler, M., additional, Heusch, G., additional, Levkau, B., additional, Biessen, E., additional, De Jager, S., additional, Bermudez-Pulgarin, B., additional, Bot, I., additional, Abia, R., additional, Van Berkel, T., additional, Renger, A., additional, Noack, C., additional, Zafiriou, M., additional, Dietz, R., additional, Bergmann, M., additional, Zelarayan, L., additional, Hammond, J., additional, Hamelet, J., additional, Van Assche, T., additional, Belge, C., additional, Vanderper, A., additional, Langin, D., additional, Herijgers, P., additional, Balligand, J., additional, Perrot, A., additional, Neubert, M., additional, Posch, M., additional, Oezcelik, C., additional, Waldmuller, S., additional, Berger, F., additional, Scheffold, T., additional, Bouvagnet, P., additional, Ozcelik, C., additional, Lebreiro, A., additional, Martins, E., additional, Lourenco, P., additional, Cruz, C., additional, Martins, M., additional, Bettencourt, P., additional, Maciel, M., additional, Abreu-Lima, C., additional, Pilichou, K., additional, Bauce, B., additional, Rampazzo, A., additional, Carturan, E., additional, Corrado, D., additional, Thiene, G., additional, Basso, C., additional, Piccini, I., additional, Fortmueller, L., additional, Kuhlmann, M., additional, Schaefers, M., additional, Carmeliet, P., additional, Kirchhof, P., additional, Fabritz, L., additional, Sanchez, J., additional, Rodriguez-Sinovas, A., additional, Agullo, E., additional, Garcia-Dorado, D., additional, Lymperopoulos, A., additional, Rengo, G., additional, Gao, E., additional, Zincarelli, C., additional, Koch, W., additional, Morgan, P., additional, Diez, A., additional, Perez, N., additional, Cingolani, H., additional, Zahradnikova, A., additional, Polakova, E., additional, Zahradnik, I., additional, Fluschnik, N., additional, Sossalla, S., additional, Ort, K., additional, Neef, S., additional, Hasenfuss, G., additional, Maier, L., additional, Weinert, S., additional, Poitz, D., additional, Herold, J., additional, Schmeisser, A., additional, Strasser, J., additional, Braun-Dullaeus, R., additional, Nazari-Jahantigh, M., additional, Weber, C., additional, Schober, A., additional, Leuner, A., additional, Eichhorn, B., additional, Ravens, U., additional, Morawietz, H., additional, Babes, E., additional, Babes, V., additional, Popescu, M., additional, Ardelean, A., additional, Rus, M., additional, Bustea, C., additional, Gwozdz, P., additional, Csanyi, G., additional, Luzak, B., additional, Gajda, M., additional, Mateuszuk, L., additional, Chmura-Skirlinska, A., additional, Watala, C., additional, Chlopicki, S., additional, Kierzkowska, I., additional, Sulicka, J., additional, Kwater, A., additional, Strach, M., additional, Surdacki, A., additional, Siedlar, M., additional, Grodzicki, T., additional, Olieslagers, S., additional, Pardali, L., additional, Tchaikovski, V., additional, Ten Dijke, P., additional, Waltenberger, J., additional, Renner, M., additional, Redwan, B., additional, Winter, M., additional, Panzenboeck, A., additional, Jakowitsch, J., additional, Sadushi-Kolici, R., additional, Bonderman, D., additional, Lang, I., additional, Toso, A., additional, Tanini, L., additional, Pizzetti, T., additional, Leoncini, M., additional, Maioli, M., additional, Tedeschi, D., additional, Oliviero, C., additional, Bellandi, F., additional, Casprini, P., additional, Amato, M., additional, Molins, B., additional, Pena, E., additional, Badimon, L., additional, Ferreiro Gutierrez, J., additional, Ueno, M., additional, Alissa, R., additional, Dharmashankar, K., additional, Capodanno, D., additional, Desai, B., additional, Bass, T., additional, Angiolillo, D., additional, Chabielska, E., additional, Gromotowicz, A., additional, Szemraj, J., additional, Stankiewicz, A., additional, Zakrzeska, A., additional, Mohammed, S., additional, Molla, F., additional, Soldo, A., additional, Russo, I., additional, Germano, G., additional, Balconi, G., additional, Staszewsky, L., additional, Latini, R., additional, Lynch, F., additional, Austin, C., additional, Prendergast, B., additional, Keenan, D., additional, Malik, R., additional, Izzard, A., additional, Heagerty, A., additional, Czikora, A., additional, Lizanecz, E., additional, Rutkai, I., additional, Boczan, J., additional, Porszasz, R., additional, Papp, Z., additional, Edes, I., additional, Toth, A., additional, Colantuoni, A., additional, Vagnani, S., additional, Lapi, D., additional, Maroz-Vadalazhskaya, N., additional, Koslov, I., additional, Shumavetz, V., additional, Glibovskaya, T., additional, Ostrovskiy, Y., additional, Koutsiaris, A., additional, Tachmitzi, S., additional, Kotoula, M., additional, Giannoukas, A., additional, Tsironi, E., additional, Darago, A., additional, Orosz, P., additional, Megyesi, Z., additional, Schudeja, S., additional, Matschke, K., additional, Deussen, A., additional, Castro, M., additional, Cena, J., additional, Walsh, M., additional, Schulz, R., additional, Poddar, K., additional, Rha, S., additional, Ramasamy, S., additional, Park, J., additional, Choi, C., additional, Seo, H., additional, Park, C., additional, Oh, D., additional, Almeida, J., additional, Pimenta, S., additional, Bernardes, J., additional, Machado, J., additional, Sabatasso, S., additional, Laissue, J., additional, Hlushchuk, R., additional, Brauer-Krisch, E., additional, Bravin, A., additional, Blattmann, H., additional, Michaud, K., additional, Djonov, V., additional, Hirschberg, K., additional, Tarcea, V., additional, Pali, S., additional, Korkmaz, S., additional, Loganathan, S., additional, Merkely, B., additional, Karck, M., additional, Szabo, G., additional, Pagliani, L., additional, Faggin, E., additional, Rattazzi, M., additional, Puato, M., additional, Presta, M., additional, Grego, F., additional, Deriu, G., additional, Pauletto, P., additional, Kaiser, R., additional, Albrecht, K., additional, Schgoer, W., additional, Theurl, M., additional, Beer, A., additional, Wiedemann, D., additional, Steger, C., additional, Bonaros, N., additional, Kirchmair, R., additional, Kharlamov, A., additional, Cabaravdic, M., additional, Breuss, J., additional, Uhrin, P., additional, Binder, B., additional, Fiordaliso, F., additional, Maggioni, M., additional, Biondi, A., additional, Masson, S., additional, Cervo, L., additional, Francke, A., additional, Soenke, W., additional, Strasser, R., additional, Hecht, N., additional, Vajkoczy, P., additional, Woitzik, J., additional, Hackbusch, D., additional, Gatzke, N., additional, Duelsner, A., additional, Tsuprykov, O., additional, Slavic, S., additional, Buschmann, I., additional, Kappert, K., additional, Massaro, M., additional, Scoditti, E., additional, Carluccio, M., additional, Storelli, C., additional, Distante, A., additional, De Caterina, R., additional, Barandi, L., additional, Harmati, G., additional, Simko, J., additional, Horvath, B., additional, Szentandrassy, N., additional, Banyasz, T., additional, Magyar, J., additional, Nanasi, P., additional, Kaya, A., additional, Uzunhasan, I., additional, Yildiz, A., additional, Yigit, Z., additional, Turkoglu, C., additional, Doisne, N., additional, Zannad, N., additional, Hivert, B., additional, Cosnay, P., additional, Maupoil, V., additional, Findlay, I., additional, Virag, L., additional, Kristof, A., additional, Koncz, I., additional, Szel, T., additional, Jost, N., additional, Biliczki, P., additional, Papp, J., additional, Varro, A., additional, Bukowska, A., additional, Skopp, K., additional, Hammwoehner, M., additional, Huth, C., additional, Bode-Boeger, S., additional, Goette, A., additional, Workman, A., additional, Dempster, J., additional, Marshall, G., additional, Rankin, A., additional, Revnic, C., additional, Ginghina, C., additional, Revnic, F., additional, Yakushev, S., additional, Petrushanko, I., additional, Makhro, A., additional, Segato Komniski, M., additional, Mitkevich, V., additional, Makarov, A., additional, Gassmann, M., additional, Bogdanova, A., additional, Rutkovskiy, A., additional, Mariero, L., additional, Stenslokken, K., additional, Valen, G., additional, Vaage, J., additional, Dizayee, S., additional, Kaestner, S., additional, Kuck, F., additional, Piekorz, R., additional, Hein, P., additional, Matthes, J., additional, Nurnberg, B., additional, Herzig, S., additional, Hertel, F., additional, Switalski, A., additional, Bender, K., additional, Kienitz, M.-C., additional, Pott, L., additional, Fornai, L., additional, Angelini, A., additional, Erika Amstalden Van Hove, E., additional, Fedrigo, M., additional, Heeren, R., additional, Kruse, M., additional, Pongs, O., additional, Lehmann, H., additional, Martens-Lobenhoffer, J., additional, Roehl, F., additional, Radicke, S., additional, Cotella, C., additional, Sblattero, D., additional, Schaefer, M., additional, Wettwer, E., additional, Santoro, C., additional, Seyler, C., additional, Kulzer, M., additional, Zitron, E., additional, Scholz, E., additional, Welke, F., additional, Thomas, D., additional, Karle, C., additional, Schmidt, K., additional, Dobrev, D., additional, Houshmand, N., additional, Menesi, D., additional, Cotella, D., additional, Szuts, V., additional, Puskas, L., additional, Kiss, I., additional, Deak, F., additional, Tereshchenko, S., additional, Gladyshev, M., additional, Kalachova, G., additional, Syshchik, N., additional, Gogolashvili, N., additional, Dedok, E., additional, Evert, L., additional, Wenzel, J., additional, Brandenburger, M., additional, Bogdan, R., additional, Richardt, D., additional, Reppel, M., additional, Hescheler, J., additional, Dendorfer, A., additional, Terlau, H., additional, Wiegerinck, R., additional, Galvez-Monton, C., additional, Jorge, E., additional, Martinez, R., additional, Ricart, E., additional, Cinca, J., additional, Bagavananthem Andavan, G., additional, Lemmens Gruber, R., additional, Brack, K., additional, Coote, J., additional, Ng, G., additional, Daimi, H., additional, Haj Khelil, A., additional, Neji, A., additional, Ben Hamda, K., additional, Maaoui, S., additional, Aranega, A., additional, Chibani, J., 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Dyer, E., additional, Leung, M.-C., additional, Monserrat, L., additional, Marston, S., additional, Fusco, A., additional, Paillard, M., additional, Liang, J., additional, Strub, G., additional, Gomez, L., additional, Hait, N., additional, Allegood, J., additional, Lesnefsky, E., additional, Spiegel, S., additional, Zuchi, C., additional, Coiro, S., additional, Bettini, M., additional, Ciliberti, G., additional, Mancini, I., additional, Tritto, I., additional, Becker, L., additional, Ambrosio, G., additional, Adam, T., additional, Sharp, S., additional, Opie, L., additional, Lecour, S., additional, Khaliulin, I., additional, Parker, J., additional, Halestrap, A., additional, Kandasamy, A., additional, Osterholt, M., additional, Miro-Casas, E., additional, Boengler, K., additional, Menazza, S., additional, Canton, M., additional, Sheeran, F., additional, Di Lisa, F., additional, Pepe, S., additional, Borchi, E., additional, Manni, M., additional, Bargelli, V., additional, Giordano, C., additional, D'amati, G., additional, Nediani, C., additional, Raimondi, L., additional, Micova, P., additional, Balkova, P., additional, Kolar, F., additional, Neckar, J., additional, Novak, F., additional, Novakova, O., additional, Schuchardt, M., additional, Pruefer, N., additional, Pruefer, J., additional, Jankowski, V., additional, Jankowski, J., additional, Su, Y., additional, Zervou, S., additional, Seidel, B., additional, Radovits, T., additional, Barnucz, E., additional, Aggeli, I., additional, Kefaloyianni, E., additional, Beis, I., additional, Gaitanaki, C., additional, Lacerda, L., additional, Somers, S., additional, Paur, H., additional, Nikolaev, V., additional, Lyon, A., additional, Silva, S., additional, Gomes, M., additional, Ferreira, P., additional, Capuano, V., additional, Ferron, L., additional, Ruchon, Y., additional, Ben Mohamed, F., additional, Renaud, J.-F., additional, Goncalves, N., additional, Gavina, C., additional, Pinho, S., additional, Moura, C., additional, Amorim, M., additional, Pinho, P., additional, Christ, T., additional, Molenaar, P., additional, Kaumann, A., additional, Kletsiou, E., additional, Giannakopoulou, M., additional, Bozas, E., additional, Iliodromitis, E., additional, Anastasiou-Nana, M., additional, Papathanassoglou, E., additional, Chottova Dvorakova, M., additional, Mistrova, E., additional, Slavikova, J., additional, Hynie, S., additional, Sida, P., additional, Klenerova, V., additional, Zakrzewicz, A., additional, Hoffmann, C., additional, Hohberg, M., additional, Chlench, S., additional, Maroski, J., additional, Drab, M., additional, Siegel, G., additional, Pries, A., additional, Schrot, G., additional, Wilck, N., additional, Fechner, M., additional, Arias, A., additional, Meiners, S., additional, Baumann, G., additional, Stangl, V., additional, Stangl, K., additional, Ludwig, A., additional, Christ, A., additional, Eijgelaar, W., additional, Daemen, M., additional, Penfold, M., additional, Schall, T., additional, Hintenberger, R., additional, Kaun, C., additional, Pfaffenberger, S., additional, Maurer, G., additional, Huber, K., additional, Wojta, J., additional, Demyanets, S., additional, Titov, V., additional, Chin-Dusting, J., additional, Vaisman, B., additional, Khong, S., additional, Remaley, A., additional, Andrews, K., additional, Hoeper, A., additional, Khalid, A., additional, Fuglested, B., additional, Aasum, E., additional, Larsen, T., additional, Diebold, I., additional, Petry, A., additional, Djordjevic, T., additional, Belaiba, R., additional, Fratz, S., additional, Hess, J., additional, Kietzmann, T., additional, Goerlach, A., additional, Chess, D., additional, Walsh, K., additional, Van Der Velden, J., additional, Moreira-Goncalves, D., additional, Paulus, W., additional, Niessen, H., additional, Perlini, S., additional, Azibani, F., additional, Tournoux, F., additional, Fazal, L., additional, Polidano, E., additional, Merval, R., additional, Chatziantoniou, C., additional, Samuel, J., additional, Delcayre, C., additional, Mgandela, P., additional, Brooksbank, R., additional, Maswanganyi, T., additional, Woodiwiss, A., additional, Norton, G., additional, Makaula, S., additional, Bucciantini, M., additional, Spinelli, V., additional, Coppini, R., additional, Russo, E., additional, Stefani, M., additional, Sukumaran, V., additional, Watanabe, K., additional, Ma, M., additional, Thandavarayan, R., additional, Azrozal, W., additional, Sari, F., additional, Shimazaki, H., additional, Kobayashi, Y., additional, Roleder, T., additional, Golba, K., additional, Deja, M., additional, Malinowski, M., additional, Wos, S., additional, Grebe, M., additional, Preissner, K., additional, Ercan, E., additional, Guven, A., additional, Asgun, F., additional, Ickin, M., additional, Ercan, F., additional, Kaplan, A., additional, Yavuz, O., additional, Bagla, S., additional, Kuka, J., additional, Vilskersts, R., additional, Vavers, E., additional, Liepins, E., additional, Dambrova, M., additional, Duerr, G., additional, Suchan, G., additional, Heuft, T., additional, Klaas, T., additional, Zimmer, A., additional, Welz, A., additional, Fleischmann, B., additional, Dewald, O., additional, Voelkl, J., additional, Haubner, B., additional, Kremser, C., additional, Mayr, A., additional, Klug, G., additional, Reiner, M., additional, Pachinger, O., additional, Metzler, B., additional, Pisarenko, O., additional, Shulzhenko, V., additional, Pelogeykina, Y., additional, Khatri, D., additional, Studneva, I., additional, Bencsik, P., additional, Kocsis, G., additional, Shamloo, M., additional, Woodburn, K., additional, Szucs, G., additional, Kupai, K., additional, Csont, C., additional, Kocsisne Fodor, G., additional, Monostori, P., additional, and Turi, S., additional

Published
2010
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30. pp60v-src phosphorylates and activates low molecular weight phosphotyrosine-protein phosphatase.

Author

Rigacci, S, Degl'Innocenti, D, Bucciantini, M, Cirri, P, Berti, A, and Ramponi, G

Abstract

Low M(r) phosphotyrosine-protein phosphatase belongs to the non-receptor cytosolic phosphotyrosine-protein phosphatase subfamily. It has been demonstrated that this enzyme dephosphorylates receptor tyrosine kinases, namely the epidermal growth factor receptor in vitro and the platelet-derived growth factor receptor in vivo. Low M(r) phosphotyrosine-protein phosphatase is constitutively tyrosine-phosphorylated in NIH/3T3 cells transformed by pp60v-src. The same tyrosine kinase, previously immunoprecipitated, phosphorylates this enzyme in vitro as well. Phosphorylation is enhanced using phosphatase inhibitors and phenylarsine oxide-inactivated phosphatase, consistently with the existence of an auto-dephosphorylation process. Intermolecular dephosphorylation is demonstrated adding the active enzyme in a solution containing the inactivated and previously phosphorylated one. This tyrosine phosphorylation correlates with an increase in catalytic activity. Our results provide evidence of a physiological mechanism of low M(r) phosphotyrosine-protein phosphatase activity regulation.

Published
1996

32. Expression, purification and preliminary crystal analysis of the human low Mrphosphotyrosine protein phosphatase isoform 1

Author

Marzocchini, R, Bucciantini, M, Stefani, M, Taddei, N, Thunnissen, M.G.M.M, Nordlund, P, and Ramponi, G

Abstract

The genes of the human low Mrphosphotyrosine protein phosphatase (PTPase) isoforms 1 (IF1) and 2 (IF2) were isolated by screening a human placenta cDNA library, cloned in pGEX and expressed in E. colias fusion proteins with glutathione S‐transferase. The recombinant proteins were purified by a rapid one‐step procedure allowing each enzyme to purify with high final yield and specific activity. This result is important for IF1, whose purification from natural sources is difficult, due to precipitation propensity, thus hindering structural studies. The enzymes obtained showed kinetic parameters very similar to those previously determined for the enzymes purified by classical procedures from both human erythrocytes and rat liver. These recombinant enzymes can therefore be used in place of those purified from natural sources for every purpose. IF1 and IF2 crystals were also grown. IF1 crystals were X‐ray‐grade, diffracted to better than 2.4 Å and were suitable for high resolution X‐ray structure determination.

Published
1998
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41. Protective effect of Vigna unguiculata extract against aging and neurodegeneration

Author

Farida Tripodi 1, Linda Lombardi 1, Lorenzo Guzzetti 1, Davide Panzeri 1, Riccardo Milanesi 1, Manuela Leri 2 3, Monica Bucciantini 2, Cristina Angeloni 4, Daniela Beghelli 5, Silvana Hrelia 6, Giada Onorato 7, Elia Di Schiavi 7, Ermelinda Falletta 8, Simona Nonnis 9, Gabriella Tedeschi 9, Massimo Labra 1, Paola Coccetti 1, Tripodi, F, Lombardi, L, Guzzetti, L, Panzeri, D, Milanesi, R, Leri, M, Bucciantini, M, Angeloni, C, Beghelli, D, Hrelia, S, Onorato, G, Di Schiavi, E, Falletta, E, Nonnis, S, Tedeschi, G, Labra, M, Coccetti, P, and Tripodi F, Lombardi L, Guzzetti L, Panzeri D, Milanesi R, Leri M, Bucciantini M, Angeloni C, Beghelli D, Hrelia S, Onorato G, Di Schiavi E, Falletta E, Nonnis S, Tedeschi G, Labra M, Coccetti P.

Subjects
human ?-synuclein, BIO/01 - BOTANICA GENERALE, Parkinson's disease (PD), Drosophila melanogaster, human α-synuclein, food and beverages, Saccharomyces cerevisiae, human alpha-synuclein, Caenorhabditis elegans, Parkinson’s disease (PD), BIO/10 - BIOCHIMICA, Caenorhabditis elegan, Research Paper
Abstract

Aging and age-related neurodegeneration are among the major challenges in modern medicine because of the progressive increase in the number of elderly in the world population. Nutrition, which has important long-term consequences for health, is an important way to prevent diseases and achieve healthy aging. The beneficial effects of Vigna unguiculata on metabolic disorders have been widely documented. Here, we show that an aqueous extract of V. unguiculata beans delays senescence both in Saccharomyces cerevisiae and Drosophila melanogaster, in a Snf1/AMPK-dependent manner. Consistently, an increased expression of FOXO, SIRT1, NOTCH and heme oxygenase (HO) genes, already known to be required for the longevity extension in D. melanogaster, is also shown. Preventing ?-synuclein self-assembly is one of the most promising approaches for the treatment of Parkinson's disease (PD), for which aging is a risk factor. In vitro aggregation of ?-synuclein, its toxicity and membrane localization in yeast and neuroblastoma cells are strongly decreased in the presence of bean extract. In a Caenorhabditis elegans model of PD, V. unguiculata extract substantially reduces the number of the age-dependent degeneration of the cephalic dopaminergic neurons. Our findings support the role of V. unguiculata beans as a functional food in age-related disorders.

Published
2020
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42. Anti-Aging and Neuroprotective Properties of Grifola frondosa and Hericium erinaceus Extracts

Author

Farida Tripodi, Ermelinda Falletta, Manuela Leri, Cristina Angeloni, Daniela Beghelli, Laura Giusti, Riccardo Milanesi, Belém Sampaio-Marques, Paula Ludovico, Lorenzo Goppa, Paola Rossi, Elena Savino, Monica Bucciantini, Paola Coccetti, Tripodi, Farida, Falletta, Ermelinda, Leri, Manuela, Angeloni, Cristina, Beghelli, Daniela, Giusti, Laura, Milanesi, Riccardo, Sampaio-Marques, Belém, Ludovico, Paula, Goppa, Lorenzo, Rossi, Paola, Savino, Elena, Bucciantini, Monica, Coccetti, Paola, Tripodi, F, Falletta, E, Leri, M, Angeloni, C, Beghelli, D, Giusti, L, Milanesi, R, Sampaio-Marques, B, Ludovico, P, Goppa, L, Rossi, P, Savino, E, Bucciantini, M, Coccetti, P, and Universidade do Minho

Subjects
Hericium erinaceus, Aging, Nutrition and Dietetics, Science & Technology, medicinal mushrooms, Grifola frondosa, Agaricale, Heat-Shock Protein, Saccharomyces cerevisiae, α-synuclein, Parkinson’s disease (PD), Drosophila melanogaster, Settore CHIM/04 - Chimica Industriale, BIO/10 - BIOCHIMICA, beta-Glucan, medicinal mushroom, alpha-Synuclein, Protein Aggregate, Reactive Oxygen Specie, Food Science, Hericium erinaceu, Human, Grifola
Abstract

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/nu14204368/s1. Table S1. Analytes identified by GC/MS on the basis of match with NIST2014 library and the corresponding target ions used to quantify them. Table S2. Yeast strains used in this study. Figure S1 Calibration curve and linear regression curve for ET. Figure S2 Evaluation of interference of fungal extracts on ThT assay. Figure S3. High fungal extract concentrations are toxic for adult flies., Nutrition has relevant consequences for human health and increasing pieces of evidence indicate that medicinal mushrooms have several beneficial effects. One of the main issues in Western countries is represented by the challenges of aging and age-related diseases, such as neurodegenerative disorders. Among these, Parkinson’s disease (PD) affects 10 million people worldwide and is associated with α-synuclein misfolding, also found in other pathologies collectively called synucleinopathies. Here, we show that aqueous extracts of two edible mushrooms, Grifola frondosa and Hericium erinaceus, represent a valuable source of β-glucans and exert anti-aging effects in yeast. Their beneficial effects are mediated through the inhibition of the Ras/PKA pathway, with increased expression of heat shock proteins, along with a consistent increase of both mean and maximal lifespans. These fungal extracts also reduce the toxicity of α-synuclein heterologously expressed in yeast cells, resulting in reduced ROS levels, lower α-synuclein membrane localization, and protein aggregation. The neuroprotective activity of G. frondosa extract was also confirmed in a PD model of Drosophila melanogaster. Taken together, our data suggest the use of G. frondosa and H. erinaceus as functional food to prevent aging and age-related disorders, further supporting the neuro-healthy properties of these medicinal mushroom extracts., We acknowledge financial support from the Italian Ministry of University and Research (MUR) through grant “Dipartimenti di Eccellenza 2017” to University of Milano-Bicocca, Department of Biotechnology and Biosciences. This research was also supported by the Italian Ministry of University and Research (MUR): Dipartimenti di Eccellenza Program (2018–2022) Dept. of Biology and Biotechnology “L. Spallanzani”, and Fondo di Ricerca e Giovani (FRG, University of Pavia). M.L. was supported by a fellowship from Fondazione Umberto Veronesi. R.M. was supported by a fellowship from the Italian Ministry of University and Research (MUR).

Published
2022

43. The polyphenol Oleuropein aglycone hinders the growth of toxic transthyretin amyloid assemblies

Author

Monica Bucciantini, Manuela Leri, Matteo Ramazzotti, Riccardo Porcari, Vittorio Bellotti, Daniele Nosi, Fabrizio Chiti, Silvia Maria Doglia, Massimo Stefani, Antonino Natalello, Leri, M, Nosi, D, Natalello, A, Porcari, R, Ramazzotti, M, Chiti, F, Bellotti, V, Doglia, S, Stefani, M, and Bucciantini, M

Subjects
0301 basic medicine, Amyloid, Endocrinology, Diabetes and Metabolism, Iridoid Glucosides, Clinical Biochemistry, FIS/07 - FISICA APPLICATA (A BENI CULTURALI, AMBIENTALI, BIOLOGIA E MEDICINA), Protein aggregation, Fibril, Transthyretin, Biochemistry, Cell Line, Familial amyloid cardiomyopathy, Mice, 03 medical and health sciences, Amyloid disease, 0302 clinical medicine, Spectroscopy, Fourier Transform Infrared, Nutrition and Dietetic, medicine, Animals, Prealbumin, Iridoids, FAC, Cytotoxicity, Molecular Biology, Nutrition and Dietetics, biology, Chemistry, Amyloidosis, FAP, nutritional and metabolic diseases, medicine.disease, Oleuropein aglycone, 030104 developmental biology, biology.protein, 030217 neurology & neurosurgery
Abstract

Transthyretin (TTR) is involved in a subset of familial or sporadic amyloid diseases including senile systemic amyloidosis (SSA), familial amyloid polyneuropathy and cardiomyopathy (FAP/FAC) for which no effective therapy has been found yet. These conditions are characterized by extracellular deposits primarily found in the heart parenchyma and in peripheral nerves whose main component are amyloid fibrils, presently considered the main culprits of cell sufferance. The latter are polymeric assemblies grown from misfolded TTR, either wt or carrying one out of many identified mutations. The recent introduction in the clinical practice of synthetic TTR-stabilizing molecules that reduce protein aggregation provides the rationale to search natural effective molecules able to interfere with TTR amyloid aggregation by hindering the appearance of toxic species or by favoring the growth of harmless aggregates. Here we carried out an in depth biophysical and morphological study on the molecular features of the aggregation of wt- and L55P-TTR involved in SSA or FAP/FAC, respectively, and on the interference with fibril aggregation, stability and toxicity to cardiac HL-1 cells to demonstrate the ability of Oleuropein aglycone (OleA), the main phenolic component of the extra virgin olive oil. We describe the molecular basis of such interference and the resulting reduction of TTR amyloid aggregate cytotoxicity. Our data offer the possibility to validate and optimize the use of OleA or its molecular scaffold to rationally design promising drugs against TTR-related pathologies that could enter a clinical experimental phase.

Published
2016
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44. Oleuropein aglycone and hydroxytyrosol interfere differently with toxic Aβ 1-42 aggregation

Author

Massimo Stefani, Antonino Natalello, Monica Bucciantini, Elena Bruzzone, Manuela Leri, Leri, M, Natalello, A, Bruzzone, E, Stefani, M, and Bucciantini, M

Subjects
Amyloid, Metabolite, Congo Red (PubChem CID: 11313), FIS/07 - FISICA APPLICATA (A BENI CULTURALI, AMBIENTALI, BIOLOGIA E MEDICINA), 1-42, Toxicology, Fibril, 03 medical and health sciences, chemistry.chemical_compound, 0404 agricultural biotechnology, Oleuropein, Hydroxytyrosol, Sodium Dodecil Sulfate (PubChem CID: 3423265), Oleuropein Aglycone (PubChem CID: 56842347), MTT (PubChem CID: 64965), 030304 developmental biology, Aβ, 0303 health sciences, biology, Hydroxythyrosol (PubChem: 82755) Dimethylsulfoxide (PubChem CID: 679), N,N-dimethylformamide (PubChem CID: 6228), 04 agricultural and veterinary sciences, General Medicine, Alzheimer's disease, biology.organism_classification, 040401 food science, peptide, Oleuropein aglycone, Aglycone, chemistry, Biochemistry, Olea, Polyphenol, Acrylamide (PubChem CID: 6579), Food Science
Abstract

Oleuropein aglycone (OleA), the most abundant polyphenol in extra virgin olive oil (EVOO), and Hydroxythyrosol (HT), the OleA main metabolite, have attracted our interest due to their multitarget effects, including the interference with amyloid aggregation path. However, the mechanistic details of their anti-amyloid effect are not known yet. We report here a broad biophysical approach and cell biology techniques that enabled us to characterize the different molecular mechanisms by which OleA and HT modulate the A beta(1-42) fibrillation, a main histopathological feature of Alzheimer's disease (AD). In particular, OleA prevents the growth of toxic A beta(1-42) oligomers and blocks their successive growth into mature fibrils following its interaction with the peptide N terminus, while HT speeds up harmless fibril formation. Our data demonstrate that, by stabilizing oligomers and fibrils, both polyphenols reduce their seeding activity and aggregate/membrane interaction on human neuroblastoma SH SY5Y cells. These findings highlight the great potential of EVOO polyphenols and offer the possibility to validate and to optimize their use for possible AD prevention and therapy.

Published
2019

45. A FTIR microspectroscopy study of the structural and biochemical perturbations induced by natively folded and aggregated transthyretin in HL-1 cardiomyocytes

Author

Paolo Mereghetti, Massimo Stefani, Sofia Giorgetti, Silvia Maria Doglia, Manuela Leri, Monica Bucciantini, Diletta Ami, Antonino Natalello, Ami, D, Mereghetti, P, Leri, M, Giorgetti, S, Natalello, A, Doglia, S, Stefani, M, and Bucciantini, M

Subjects
0301 basic medicine, Amyloid, Protein Folding, Cell Survival, Mutant, lcsh:Medicine, FIS/07 - FISICA APPLICATA (A BENI CULTURALI, AMBIENTALI, BIOLOGIA E MEDICINA), Protein aggregation, Article, 03 medical and health sciences, Membrane Lipids, Protein Aggregates, 0302 clinical medicine, Spectroscopy, Fourier Transform Infrared, Extracellular, Humans, Prealbumin, Myocytes, Cardiac, Phosphorylation, lcsh:Science, Cells, Cultured, Multidisciplinary, biology, Chemistry, lcsh:R, Infrared (micro)spectroscopy, amyloids, protein aggregation, TTR, Wild type, Cell biology, Transthyretin, 030104 developmental biology, Multivariate Analysis, Mutation, biology.protein, Protein folding, Calcium, lcsh:Q, Reactive Oxygen Species, 030217 neurology & neurosurgery
Abstract

Protein misfolding and aggregation are associated with a number of human degenerative diseases. In spite of the enormous research efforts to develop effective strategies aimed at interfering with the pathogenic cascades induced by misfolded/aggregated peptides/proteins, the necessary detailed understanding of the molecular bases of amyloid formation and toxicity is still lacking. To this aim, approaches able to provide a global insight in amyloid-mediated physiological alterations are of importance. In this study, we exploited Fourier transform infrared microspectroscopy, supported by multivariate analysis, to investigate in situ the spectral changes occurring in cultured intact HL-1 cardiomyocytes exposed to wild type (WT) or mutant (L55P) transthyretin (TTR) in native, or amyloid conformation. The presence of extracellular deposits of amyloid aggregates of WT or L55P TTR, respectively, is a key hallmark of two pathological conditions, known as senile systemic amyloidosis and familial amyloid polyneuropathy. We found that the major effects, associated with modifications in lipid properties and in the cell metabolic/phosphorylation status, were observed when natively folded WT or L55P TTR was administered to the cells. The effects induced by aggregates of TTR were milder and in some cases displayed a different timing compared to those elicited by the natively folded protein.

Published
2018

46. S-Homocysteinylation effects on transthyretin: worsening of cardiomyopathy onset

Author

Monica Bucciantini, Anna Caselli, Sofia Giorgetti, Paolo De Paoli, Manuela Leri, Massimo Stefani, Paola Rebuzzini, Loredana Marchese, Silvia Garagna, Simone Luti, Antonino Natalello, Leri, M, Rebuzzini, P, Caselli, A, Luti, S, Natalello, A, Giorgetti, S, Marchese, L, Garagna, S, Stefani, M, Paoli, P, and Bucciantini, M

Subjects
Amyloid disease, 0301 basic medicine, endocrine system, medicine.medical_specialty, Homocysteine, Protein Conformation, Mutant, Biophysics, Cardiomyopathy, FIS/07 - FISICA APPLICATA (A BENI CULTURALI, AMBIENTALI, BIOLOGIA E MEDICINA), medicine.disease_cause, Biochemistry, L55P-TTR, Structure-Activity Relationship, 03 medical and health sciences, chemistry.chemical_compound, Methionine, Internal medicine, medicine, Humans, Prealbumin, Myocytes, Cardiac, FAC, Molecular Biology, Amyloid Neuropathies, Familial, Mutation, 030102 biochemistry & molecular biology, biology, Protein Stability, Chemistry, Cardiomiopathy Amyloid disease FAP FAC L55P-TTR Homocysteine, Cardiac muscle, FAP, nutritional and metabolic diseases, medicine.disease, Cardiomiopathy, Stroke, Transthyretin, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, Diabetes Mellitus, Type 2, Cardiovascular Diseases, biology.protein, Cardiomyopathies
Abstract

Background L-Homocysteine (Hcy) is a non-proteinogenic α-amino acid synthesized from dietary methionine. In healthy humans, high Hcy levels are a risk factor for cardiovascular diseases, stroke and type 2 diabetes. A recent study reports that Hcy reacts with Cys10 of transthyretin (TTR), generating a stable covalent adduct. However, to date the effect of S-homocysteinylation on TTR conformational stability remains unknown. Methods The effect of Hcy on the conformational properties of wt- and L55P-TTR were analysed using a set of biophysical techniques. The cytotoxicity of S-homocysteinylated L55P-TTR was also evaluated in the HL-1 cardiomyocyte cell line, while the effects of the assemblies on kinematic and dynamics properties of cardiac muscle cells were analysed in cardiomyocyte syncytia. Results We found that Hcy stabilizes tetrameric wt-TTR, while it destabilizes the tetrameric structure of the L55P mutant, promoting the accumulation of self-assembly-prone monomeric species. Conclusions Our study demonstrated that S-homocysteinylation of the L55P-TTR mutant impairs protein stability, favouring the appearance of toxic monomers. Interestingly, S-homocysteinylation affected only mutant, not wt-TTR. Moreover, we also show that assemblies of S-homocysteinylated L55P-TTR impair cardiomyocytes functional parameters. General significance Our study offers new insights on the negative impact of S-homocysteinylation on L55P-TTR stability, whose aggregation is considered the causative agent of a form of early-onset familial amyloid polyneuropathy and cardiomyopathy. Our results suggest that high homocysteine levels are a further risk factor for TTR cardiomyopathy in patients harbouring the L55P-TTR mutation.

Published
2020
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47. Biochemical and Electrophysiological Modification of Amyloid Transthyretin on Cardiomyocytes

Author

Annalisa Relini, Monica Bucciantini, Guido Mannaioni, Vittorio Bellotti, Elisabetta Cerbai, Laura Sartiani, Daniele Nosi, Valentina Spinelli, Elisabetta Gerace, Massimo Stefani, Sofia Giorgetti, Amanda Penco, Silvia Maria Doglia, Manuela Leri, Stefania Rigacci, Antonino Natalello, Sartiani, L, Bucciantini, M, Spinelli, V, Leri, M, Natalello, A, Nosi, D, Doglia, S, Relini, A, Penco, A, Giorgetti, S, Gerace, E, Mannaioni, G, Bellotti, V, Rigacci, S, Cerbai, E, and Stefani, M

Subjects
0301 basic medicine, Amyloid, Cytoplasm, endocrine system, Heart Ventricles, Biophysics, FIS/07 - FISICA APPLICATA (A BENI CULTURALI, AMBIENTALI, BIOLOGIA E MEDICINA), Nanotechnology, Protein aggregation, transgenic mice, Fibril, cellular death, Familial amyloid cardiomyopathy, Mice, Protein Aggregates, 03 medical and health sciences, Aberrant protein oligomers, GM1 ganglioside, Alzheimer's disease, calcium influx, oxidative stress, action potential, atomic force microscopy, 0302 clinical medicine, medicine, Animals, Humans, Prealbumin, Myocyte, Myocytes, Cardiac, Amyloid, Biophysics, biology, Chemistry, Amyloidosis, nutritional and metabolic diseases, medicine.disease, Electrophysiological Phenomena, Cell biology, Mice, Inbred C57BL, Transthyretin, 030104 developmental biology, Cell Biophysics, biology.protein, Calcium, Transtiretina, Amiloidosi, Transthyretin, Amyloidosis, 030217 neurology & neurosurgery, Intracellular
Abstract

Transthyretin (TTR) amyloidoses are familial or sporadic degenerative conditions that often feature heavy cardiac involvement. Presently, no effective pharmacological therapy for TTR amyloidoses is available, mostly due to a substantial lack of knowledge about both the molecular mechanisms of TTR aggregation in tissue and the ensuing functional and viability modifications that occur in aggregate-exposed cells. TTR amyloidoses are of particular interest regarding the relation between functional and viability impairment in aggregate-exposed excitable cells such as peripheral neurons and cardiomyocytes. In particular, the latter cells provide an opportunity to investigate in parallel the electrophysiological and biochemical modifications that take place when the cells are exposed for various lengths of time to variously aggregated wild-type TTR, a condition that characterizes senile systemic amyloidosis. In this study, we investigated biochemical and electrophysiological modifications in cardiomyocytes exposed to amyloid oligomers or fibrils of wild-type TTR or to its T4-stabilized form, which resists tetramer disassembly, misfolding, and aggregation. Amyloid TTR cytotoxicity results in mitochondrial potential modification, oxidative stress, deregulation of cytoplasmic Ca2+ levels, and Ca2+ cycling. The altered intracellular Ca2+ cycling causes a prolongation of the action potential, as determined by whole-cell recordings of action potentials on isolated mouse ventricular myocytes, which may contribute to the development of cellular arrhythmias and conduction alterations often seen in patients with TTR amyloidosis. Our data add information about the biochemical, functional, and viability alterations that occur in cardiomyocytes exposed to aggregated TTR, and provide clues as to the molecular and physiological basis of heart dysfunction in sporadic senile systemic amyloidosis and familial amyloid cardiomyopathy forms of TTR amyloidoses.

Published
2016

50. Different ataxin-3 amyloid aggregates induce intracellular Ca2+ deregulation by different mechanisms in cerebellar granule cells

Author

Paolo Tortora, Gaetano Invernizzi, Elena Gatta, Monica Bucciantini, Massimo Stefani, Mauro Robello, Annalisa Relini, Amanda Penco, Daniele Nosi, Maria Elena Regonesi, Alessandra Gliozzi, Francesca Pellistri, Anna Maria Frana, Pellistri, F, Bucciantini, M, Invernizzi, G, Gatta, E, Penco, A, Frana, A, Nosi, D, Relini, A, Regonesi, M, Gliozzi, A, Tortora, P, Robello, M, and Stefani, M

Subjects
Amyloid, Time Factors, Cell, Intracellular Space, Apoptosis, Nerve Tissue Proteins, G(M1) Ganglioside, Microscopy, Atomic Force, Fibril, Oligomer toxicity, Rats, Sprague-Dawley, Cerebellum, Amyloid aggregate, medicine, Animals, Receptors, AMPA, Protein Structure, Quaternary, Receptor, Cytotoxicity, Ataxin-3, Molecular Biology, Fibril toxicity, Voltage-dependent calcium channel, Chemistry, Cell Membrane, Membrane disassembly, Cell Biology, BIO/10 - BIOCHIMICA, Rats, Intracellular Ca2+ level, Spectrometry, Fluorescence, medicine.anatomical_structure, Biochemistry, Ataxin, amyloid aggregate, intracellular Ca2+ level, oligomer toxicity, fibril toxicity, Biophysics, 2-amino-5-phosphonopentanoic acid, 8-anilino-1-naphthalenesulfonic acid, AMPA-R, ANS, APV, Amyloid aggregate, Ataxin-3, BSA, CGNs, CNQX, Fibril toxicity, GM1, Intracellular Ca(2+) level, JD, N-methyl-d-aspartate receptor, N-terminal Josephin domain, NMDA-R, Oligomer toxicity, SBMA, SCA3, ThT, Thioflavin T, VGCCs, bovine serum albumin, cyano-nitroquinoxaline-dione, monosialotetrahexosylganglioside, rat cerebellar granule neurons, spinobulbar muscular atrophy, spinocerebellar ataxia type 3, voltage-gated calcium channels, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, Calcium, Calcium Channels, Intracellular, Protein Binding
Abstract

This work aims at elucidating the relation between morphological and physicochemical properties of different ataxin-3 (ATX3) aggregates and their cytotoxicity. We investigated a non-pathological ATX3 form (ATX3Q24), a pathological expanded form (ATX3Q55), and an ATX3 variant truncated at residue 291 lacking the polyQ expansion (ATX3/291Δ). Solubility, morphology and hydrophobic exposure of oligomeric aggregates were characterized. Then we monitored the changes in the intracellular Ca2 + levels and the abnormal Ca2 + signaling resulting from aggregate interaction with cultured rat cerebellar granule cells. ATX3Q55, ATX3/291Δ and, to a lesser extent, ATX3Q24 oligomers displayed similar morphological and physicochemical features and induced qualitatively comparable time-dependent intracellular Ca2 + responses. However, only the pre-fibrillar aggregates of expanded ATX3 (the only variant which forms bundles of mature fibrils) triggered a characteristic Ca2 + response at a later stage that correlated with a larger hydrophobic exposure relative to the two other variants. Cell interaction with early oligomers involved glutamatergic receptors, voltage-gated channels and monosialotetrahexosylganglioside (GM1)-rich membrane domains, whereas cell interaction with more aged ATX3Q55 pre-fibrillar aggregates resulted in membrane disassembly by a mechanism involving only GM1-rich areas. Exposure to ATX3Q55 and ATX3/291Δ aggregates resulted in cell apoptosis, while ATX3Q24 was substantially innocuous. Our findings provide insight into the mechanisms of ATX3 aggregation, aggregate cytotoxicity and calcium level modifications in exposed cerebellar cells.

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