329 results on '"Boletta A"'
Search Results
2. Inhibition of asparagine synthetase effectively retards polycystic kidney disease progression
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Sara Clerici, Christine Podrini, Davide Stefanoni, Gianfranco Distefano, Laura Cassina, Maria Elena Steidl, Laura Tronci, Tamara Canu, Marco Chiaravalli, Daniel Spies, Thomas A Bell, Ana SH Costa, Antonio Esposito, Angelo D’Alessandro, Christian Frezza, Angela Bachi, and Alessandra Boletta
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ADPKD ,Glutamine Metabolism ,Metabolic Reprogramming ,Antisense Oligonucleotides ,Glycolysis ,Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Abstract
Abstract Polycystic kidney disease (PKD) is a genetic disorder characterized by bilateral cyst formation. We showed that PKD cells and kidneys display metabolic alterations, including the Warburg effect and glutaminolysis, sustained in vitro by the enzyme asparagine synthetase (ASNS). Here, we used antisense oligonucleotides (ASO) against Asns in orthologous and slowly progressive PKD murine models and show that treatment leads to a drastic reduction of total kidney volume (measured by MRI) and a prominent rescue of renal function in the mouse. Mechanistically, the upregulation of an ATF4–ASNS axis in PKD is driven by the amino acid response (AAR) branch of the integrated stress response (ISR). Metabolic profiling of PKD or control kidneys treated with Asns-ASO or Scr-ASO revealed major changes in the mutants, several of which are rescued by Asns silencing in vivo. Indeed, ASNS drives glutamine-dependent de novo pyrimidine synthesis and proliferation in cystic epithelia. Notably, while several metabolic pathways were completely corrected by Asns-ASO, glycolysis was only partially restored. Accordingly, combining the glycolytic inhibitor 2DG with Asns-ASO further improved efficacy. Our studies identify a new therapeutic target and novel metabolic vulnerabilities in PKD.
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- 2024
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3. Fibrocystin/Polyductin releases a C-terminal fragment that translocates into mitochondria and suppresses cystogenesis
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Walker, Rebecca V, Yao, Qin, Xu, Hangxue, Maranto, Anthony, Swaney, Kristen F, Ramachandran, Sreekumar, Li, Rong, Cassina, Laura, Polster, Brian M, Outeda, Patricia, Boletta, Alessandra, Watnick, Terry, and Qian, Feng
- Published
- 2023
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4. Fibrocystin/Polyductin releases a C-terminal fragment that translocates into mitochondria and suppresses cystogenesis
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Rebecca V Walker, Qin Yao, Hangxue Xu, Anthony Maranto, Kristen F Swaney, Sreekumar Ramachandran, Rong Li, Laura Cassina, Brian M Polster, Patricia Outeda, Alessandra Boletta, Terry Watnick, and Feng Qian
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Science - Abstract
Abstract Fibrocystin/Polyductin (FPC), encoded by PKHD1, is associated with autosomal recessive polycystic kidney disease (ARPKD), yet its precise role in cystogenesis remains unclear. Here we show that FPC undergoes complex proteolytic processing in developing kidneys, generating three soluble C-terminal fragments (ICDs). Notably, ICD15, contains a novel mitochondrial targeting sequence at its N-terminus, facilitating its translocation into mitochondria. This enhances mitochondrial respiration in renal epithelial cells, partially restoring impaired mitochondrial function caused by FPC loss. FPC inactivation leads to abnormal ultrastructural morphology of mitochondria in kidney tubules without cyst formation. Moreover, FPC inactivation significantly exacerbates renal cystogenesis and triggers severe pancreatic cystogenesis in a Pkd1 mouse mutant Pkd1 V/V in which cleavage of Pkd1-encoded Polycystin-1 at the GPCR Proteolysis Site is blocked. Deleting ICD15 enhances renal cystogenesis without inducing pancreatic cysts in Pkd1 V/V mice. These findings reveal a direct link between FPC and a mitochondrial pathway through ICD15 cleavage, crucial for cystogenesis mechanisms.
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- 2023
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5. Oxidative stress enhances the therapeutic action of a respiratory inhibitor in MYC‐driven lymphoma
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Giulio Donati, Paola Nicoli, Alessandro Verrecchia, Veronica Vallelonga, Ottavio Croci, Simona Rodighiero, Matteo Audano, Laura Cassina, Aya Ghsein, Giorgio Binelli, Alessandra Boletta, Nico Mitro, and Bruno Amati
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lymphoma ,mitochondria ,MYC ,ROS ,targeted therapy ,Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Abstract
Abstract MYC is a key oncogenic driver in multiple tumor types, but concomitantly endows cancer cells with a series of vulnerabilities that provide opportunities for targeted pharmacological intervention. For example, drugs that suppress mitochondrial respiration selectively kill MYC‐overexpressing cells. Here, we unravel the mechanistic basis for this synthetic lethal interaction and exploit it to improve the anticancer effects of the respiratory complex I inhibitor IACS‐010759. In a B‐lymphoid cell line, ectopic MYC activity and treatment with IACS‐010759 added up to induce oxidative stress, with consequent depletion of reduced glutathione and lethal disruption of redox homeostasis. This effect could be enhanced either with inhibitors of NADPH production through the pentose phosphate pathway, or with ascorbate (vitamin C), known to act as a pro‐oxidant at high doses. In these conditions, ascorbate synergized with IACS‐010759 to kill MYC‐overexpressing cells in vitro and reinforced its therapeutic action against human B‐cell lymphoma xenografts. Hence, complex I inhibition and high‐dose ascorbate might improve the outcome of patients affected by high‐grade lymphomas and potentially other MYC‐driven cancers.
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- 2023
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6. Disruption of polycystin-1 cleavage leads to cardiac metabolic rewiring in mice
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Amaral, Andressa G., da Silva, Camille C.C., Serna, Julian D.C., Honorato-Sampaio, Kinulpe, Freitas, Jéssica A., Duarte-Neto, Amaro N., Bloise, Antonio C., Cassina, Laura, Yoshinaga, Marcos Y., Chaves-Filho, Adriano B., Qian, Feng, Miyamoto, Sayuri, Boletta, Alessandra, Bordin, Silvana, Kowaltowski, Alicia J., and Onuchic, Luiz F.
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- 2022
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7. Targeting mitochondrial respiration and the BCL2 family in high‐grade MYC‐associated B‐cell lymphoma
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Giulio Donati, Micol Ravà, Marco Filipuzzi, Paola Nicoli, Laura Cassina, Alessandro Verrecchia, Mirko Doni, Simona Rodighiero, Federica Parodi, Alessandra Boletta, Christopher P. Vellano, Joseph R. Marszalek, Giulio F. Draetta, and Bruno Amati
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BCL2 ,chemotherapy ,DLBCL ,Integrated Stress Response ,MYC ,OxPhos ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Multiple molecular features, such as activation of specific oncogenes (e.g., MYC, BCL2) or a variety of gene expression signatures, have been associated with disease course in diffuse large B‐cell lymphoma (DLBCL), although their relationships and implications for targeted therapy remain to be fully unraveled. We report that MYC activity is closely correlated with—and most likely a driver of—gene signatures related to oxidative phosphorylation (OxPhos) in DLBCL, pointing to OxPhos enzymes, in particular mitochondrial electron transport chain (ETC) complexes, as possible therapeutic targets in high‐grade MYC‐associated lymphomas. In our experiments, indeed, MYC sensitized B cells to the ETC complex I inhibitor IACS‐010759. Mechanistically, IACS‐010759 triggered the integrated stress response (ISR) pathway, driven by the transcription factors ATF4 and CHOP, which engaged the intrinsic apoptosis pathway and lowered the apoptotic threshold in MYC‐overexpressing cells. In line with these findings, the BCL2‐inhibitory compound venetoclax synergized with IACS‐010759 against double‐hit lymphoma (DHL), a high‐grade malignancy with concurrent activation of MYC and BCL2. In BCL2‐negative lymphoma cells, instead, killing by IACS‐010759 was potentiated by the Mcl‐1 inhibitor S63845. Thus, combining an OxPhos inhibitor with select BH3‐mimetic drugs provides a novel therapeutic principle against aggressive, MYC‐associated DLBCL variants.
- Published
- 2022
- Full Text
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8. Políticas públicas dos EUA e da China para a pandemia: tensões geopolíticas, competição tecnológica e modelos de desenvolvimento
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Italo Barreto Poty and Caroline Boletta de O. Aguiar
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china ,estados unidos ,5g ,tecnologia ,covid-19 ,International relations ,JZ2-6530 ,Colonies and colonization. Emigration and immigration. International migration ,JV1-9480 - Abstract
Este artigo tem como objetivo analisar as respostas dos Estados Unidos e da China em termos de políticas públicas de combate à pandemia da COVID-19, com ênfase no contexto atual de acirramento das tensões geopolíticas, na competição tecnológica e nos modelos de desenvolvimento de ambos os países. Considerando a importância da internet na contemporaneidade para áreas essenciais como economia, política, segurança e defesa, daremos destaque à corrida pela liderança no desenvolvimento das redes 5G. A questão principal que propomos é: qual foi o papel da pandemia na disputa geopolítica entre China e Estados Unidos, considerando sua dimensão tecnológica? A metodologia de pesquisa adotada é a análise qualitativa de documentos oficiais e bibliografia especializada sobre o tema. Nossa hipótese é que a pandemia pode ter conferido vantagem à China na corrida pela liderança no 5G, considerando o maior foco dado pelo governo chinês aos investimentos nessa tecnologia e sua importância no combate à pandemia no país asiático, em que a internet foi essencial para o controle do isolamento social como forma de conter a disseminação do vírus. Os Estados Unidos, por sua vez, concentraram seus esforços no setor de biotecnologia para combater a pandemia.
- Published
- 2021
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9. Primary cilia sense glutamine availability and respond via asparagine synthetase
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Maria Elena Steidl, Elisa A. Nigro, Anne Kallehauge Nielsen, Roberto Pagliarini, Laura Cassina, Matteo Lampis, Christine Podrini, Marco Chiaravalli, Valeria Mannella, Gianfranco Distefano, Ming Yang, Mariam Aslanyan, Giovanna Musco, Ronald Roepman, Christian Frezza, Alessandra Boletta, Podrini, Christine [0000-0002-5391-3378], Musco, Giovanna [0000-0002-0469-2994], Frezza, Christian [0000-0002-3293-7397], Boletta, Alessandra [0000-0002-4704-4006], and Apollo - University of Cambridge Repository
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All institutes and research themes of the Radboud University Medical Center ,Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] ,Glutamine ,Physiology (medical) ,Endocrinology, Diabetes and Metabolism ,Internal Medicine ,Aspartate-Ammonia Ligase ,Cilia ,Cell Biology ,Signal Transduction - Abstract
Acknowledgements: The authors are grateful to the other members of the Boletta laboratory for useful discussions and to L. Tronci for helpful suggestions on data analysis. This work was supported by the Italian Ministry of Health (RF-2018-12368254; RF-2016-02361267 to A.B.; GR-2016-02364851 to C.P. and R.P.), the Italian association of patients with PKD (AIRP to A.B.), the PKD Foundation (218G18 to A.B.), the European Community (H-2020-MSCA-ITN-2019#SCiLS to A.B. and R.R.), by the Italian association for research on cancer (AIRC, IG2019-23513 to A.B.), by Q12 grant (MRC_MC_UU_12022/6 to C.F.), the European Research Council (ERC819920 to C.F.), and the CRUK Programme Foundation (Award C51061/A27453 to C.F.). The authors are grateful to S. Bramani for her continuous support. Part of this work was carried out in ALEMBIC, an advanced microscopy laboratory established by IRCCS Ospedale San Raffaele and Università Vita-Salute San Raffaele. Part of the present work was performed by M.E.S. and A.K.N. in fulfilment of the requirements for obtaining a PhD degree at Vita-Salute San Raffaele University, Milano, Italy., Funder: EC | EC Seventh Framework Programm | FP7 People: Marie-Curie Actions (FP7-PEOPLE - Specific Programme "People" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011264; Grant(s): H2020-MSCA-ITN-2019#SCiLS, H2020-MSCA-ITN-2019#SCiLS, Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): ERC819920, Depriving cells of nutrients triggers an energetic crisis, which is resolved by metabolic rewiring and organelle reorganization. Primary cilia are microtubule-based organelles at the cell surface, capable of integrating multiple metabolic and signalling cues, but their precise sensory function is not fully understood. Here we show that primary cilia respond to nutrient availability and adjust their length via glutamine-mediated anaplerosis facilitated by asparagine synthetase (ASNS). Nutrient deprivation causes cilia elongation, mediated by reduced mitochondrial function, ATP availability and AMPK activation independently of mTORC1. Of note, glutamine removal and replenishment is necessary and sufficient to induce ciliary elongation or retraction, respectively, under nutrient stress conditions both in vivo and in vitro by restoring mitochondrial anaplerosis via ASNS-dependent glutamate generation. Ift88-mutant cells lacking cilia show reduced glutamine-dependent mitochondrial anaplerosis during metabolic stress, due to reduced expression and activity of ASNS at the base of cilia. Our data indicate a role for cilia in responding to, and possibly sensing, cellular glutamine levels via ASNS during metabolic stress.
- Published
- 2023
10. P1563: INTRACELLULAR IRON OVERLOAD IMPAIRS HSC FUNCTION BY AFFECTING MITOCHONDRIAL FITNESS IN ΒETA-THALASSEMIA
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S. Sighinolfi, A. Aprile, L. Cassina, M. Panzeri, S. Beretta, M. Storto, A. Boletta, I. Merelli, and G. Ferrari
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2022
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11. Mechanosensory Genes Pkd1 and Pkd2 Contribute to the Planar Polarization of Brain Ventricular Epithelium.
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Ohata, Shinya, Herranz-Pérez, Vicente, Nakatani, Jin, Boletta, Alessandra, García-Verdugo, José, and Álvarez-Buylla, Arturo
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cilia ,ependymal cell ,epithelium ,neural stem cell ,planar cell polarity ,polycystin ,Animals ,Cell Polarity ,Cerebral Ventricles ,Cilia ,Ependyma ,Ependymoglial Cells ,Mice ,Mice ,Knockout ,TRPP Cation Channels - Abstract
UNLABELLED: Directional beating of ependymal (E) cells cilia in the walls of the ventricles in the brain is essential for proper CSF flow. E cells display two forms of planar cell polarity (PCP): rotational polarity of individual cilium and translational polarity (asymmetric positioning of cilia in the apical area). The orientation of individual E cells varies according to their location in the ventricular wall (location-specific PCP). It has been hypothesized that hydrodynamic forces on the apical surface of radial glia cells (RGCs), the embryonic precursors of E cells, could guide location-specific PCP in the ventricular epithelium. However, the detection mechanisms for these hydrodynamic forces have not been identified. Here, we show that the mechanosensory proteins polycystic kidney disease 1 (Pkd1) and Pkd2 are present in primary cilia of RGCs. Ablation of Pkd1 or Pkd2 in Nestin-Cre;Pkd1(flox/flox) or Nestin-Cre;Pkd2(flox/flox) mice, affected PCP development in RGCs and E cells. Early shear forces on the ventricular epithelium may activate Pkd1 and Pkd2 in primary cilia of RGCs to properly polarize RGCs and E cells. Consistently, Pkd1, Pkd2, or primary cilia on RGCs were required for the proper asymmetric localization of the PCP protein Vangl2 in E cells apical area. Analyses of single- and double-heterozygous mutants for Pkd1 and/or Vangl2 suggest that these genes function in the same pathway to establish E cells PCP. We conclude that Pkd1 and Pkd2 mechanosensory proteins contribute to the development of brain PCP and prevention of hydrocephalus. SIGNIFICANCE STATEMENT: This study identifies key molecules in the development of planar cell polarity (PCP) in the brain and prevention of hydrocephalus. Multiciliated ependymal (E) cells within the brain ventricular epithelium generate CSF flow through ciliary beating. E cells display location-specific PCP in the orientation and asymmetric positioning of their cilia. Defects in this PCP can result in hydrocephalus. Hydrodynamic forces on radial glial cells (RGCs), the embryonic progenitors of E cells, have been suggested to guide PCP. We show that the mechanosensory proteins Pkd1 and Pkd2 localize to primary cilia in RGCs, and their ablation disrupts the development of PCP in E cells. Early shear forces on RGCs may activate Pkd1 and Pkd2 in RGCs primary cilia to properly orient E cells. This study identifies key molecules in the development of brain PCP and prevention of hydrocephalus.
- Published
- 2015
12. The anti-inflammatory cytokine interleukin-37 is an inhibitor of trained immunity
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Giulio Cavalli, Isak W. Tengesdal, Mark Gresnigt, Travis Nemkov, Rob J.W. Arts, Jorge Domínguez-Andrés, Raffaella Molteni, Davide Stefanoni, Eleonora Cantoni, Laura Cassina, Silvia Giugliano, Kiki Schraa, Taylor S. Mills, Eric M. Pietras, Elan Z. Eisenmensser, Lorenzo Dagna, Alessandra Boletta, Angelo D’Alessandro, Leo A.B. Joosten, Mihai G. Netea, and Charles A. Dinarello
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trained immunity ,innate immunity ,cytokines ,IL-1 family ,cell energy metabolism ,immunometabolism ,Biology (General) ,QH301-705.5 - Abstract
Summary: Trained immunity (TI) is a de facto innate immune memory program induced in monocytes/macrophages by exposure to pathogens or vaccines, which evolved as protection against infections. TI is characterized by immunometabolic changes and histone post-translational modifications, which enhance production of pro-inflammatory cytokines. As aberrant activation of TI is implicated in inflammatory diseases, tight regulation is critical; however, the mechanisms responsible for this modulation remain elusive. Interleukin-37 (IL-37) is an anti-inflammatory cytokine that curbs inflammation and modulates metabolic pathways. In this study, we show that administration of recombinant IL-37 abrogates the protective effects of TI in vivo, as revealed by reduced host pro-inflammatory responses and survival to disseminated candidiasis. Mechanistically, IL-37 reverses the immunometabolic changes and histone post-translational modifications characteristic of TI in monocytes, thus suppressing cytokine production in response to infection. IL-37 thereby emerges as an inhibitor of TI and as a potential therapeutic target in immune-mediated pathologies.
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- 2021
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13. Características do melanoma em idosos
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Kátia Sheylla Malta Purim, João Pedro Ceccon Bonetti, Juliane Yumi Furuta Silva, Laura Boletta Marques, Maria Catarino Simões Pinto, and Leandro Carvalho Ribeiro
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Melanoma ,Cirurgia Oncológica ,Saúde do Idoso ,Surgery ,RD1-811 - Abstract
RESUMO Objetivo: Avaliar características do melanoma em idosos. Método: Pesquisa retrospectiva mediante revisão de prontuários de idosos diagnosticados com melanoma cutâneo primário, no período de 2013 a 2017, atendidos no Hospital Erasto Gaertner, em Curitiba-Paraná. Resultados: Amostra com 139 pacientes, mulheres (52,5%), média de 70,3 anos de idade, com lesão em membro superior ou membro inferior (32,3%) e cabeça (24,4%), sinais de ulceração (33,8%) e classificação em tipo histológico nodular (29,5%), extensivo superficial (27,3%) e acral (11,5%). Média do índice de Breslow de 3,7 mm. Metástases ocorreram em 33% dos pacientes, para linfonodos (36%) e sistema nervoso central (20%). Pesquisa do linfonodo sentinela foi realizada em 41,7% e tratamento cirúrgico isolado em 70% dos casos. Houve recidiva em 34,5% pacientes e 17,9% evoluíram com óbito. Esses achados apontam características prognósticas sombrias relacionadas ao diagnóstico e tratamento tardio da neoplasia. Conclusões: Melanoma em membros e cabeça, índice de Breslow intermediário, metastático para linfonodos e sistema nervoso central, recidiva e tem desfecho fatal. Há necessidade de direcionar estratégias para melhor abordagem da doença em idosos, como prevenção, detecção precoce e oferta de tratamento uniforme e adequado.
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- 2020
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14. Oxidative stress enhances the therapeutic action of a respiratory inhibitor in MYC ‐driven lymphoma
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Donati, Giulio, primary, Nicoli, Paola, additional, Verrecchia, Alessandro, additional, Vallelonga, Veronica, additional, Croci, Ottavio, additional, Rodighiero, Simona, additional, Audano, Matteo, additional, Cassina, Laura, additional, Ghsein, Aya, additional, Binelli, Giorgio, additional, Boletta, Alessandra, additional, Mitro, Nico, additional, and Amati, Bruno, additional
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- 2023
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15. Cleavage of Polycystin-1 Requires the Receptor for Egg Jelly Domain and Is Disrupted by Human Autosomal-Dominant Polycystic Kidney Disease 1-Associated Mutations
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Qian, Feng, Boletta, Alessandra, Bhunia, Anil K., Xu, Hangxue, Liu, Lijuan, Ahrabi, Ali K., Watnick, Terry J., Zhou, Fang, and Germino, Gregory G.
- Published
- 2002
16. Polycystin-1 Regulates Actomyosin Contraction and the Cellular Response to Extracellular Stiffness
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Nigro, Elisa Agnese, Distefano, Gianfranco, Chiaravalli, Marco, Matafora, Vittoria, Castelli, Maddalena, Pesenti Gritti, Angela, Bachi, Angela, and Boletta, Alessandra
- Published
- 2019
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17. Oxidative stress enhances the therapeutic action of a respiratory inhibitor in <scp>MYC</scp> ‐driven lymphoma
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Giulio Donati, Paola Nicoli, Alessandro Verrecchia, Veronica Vallelonga, Ottavio Croci, Simona Rodighiero, Matteo Audano, Laura Cassina, Aya Ghsein, Giorgio Binelli, Alessandra Boletta, Nico Mitro, and Bruno Amati
- Subjects
Molecular Medicine - Published
- 2023
18. The centrosomal OFD1 protein interacts with the translation machinery and regulates the synthesis of specific targets
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Daniela Iaconis, Maria Monti, Mario Renda, Arianne van Koppen, Roberta Tammaro, Marco Chiaravalli, Flora Cozzolino, Paola Pignata, Claudia Crina, Piero Pucci, Alessandra Boletta, Vincenzo Belcastro, Rachel H. Giles, Enrico Maria Surace, Simone Gallo, Mario Pende, and Brunella Franco
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Medicine ,Science - Abstract
Abstract Protein synthesis is traditionally associated with specific cytoplasmic compartments. We now show that OFD1, a centrosomal/basal body protein, interacts with components of the Preinitiation complex of translation (PIC) and of the eukaryotic Initiation Factor (eIF)4F complex and modulates the translation of specific mRNA targets in the kidney. We demonstrate that OFD1 cooperates with the mRNA binding protein Bicc1 to functionally control the protein synthesis machinery at the centrosome where also the PIC and eIF4F components were shown to localize in mammalian cells. Interestingly, Ofd1 and Bicc1 are both involved in renal cystogenesis and selected targets were shown to accumulate in two models of inherited renal cystic disease. Our results suggest a possible role for the centrosome as a specialized station to modulate translation for specific functions of the nearby ciliary structures and may provide functional clues for the understanding of renal cystic disease.
- Published
- 2017
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19. Primary cilia sense glutamine availability and respond via asparagine synthetase.
- Author
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Steidl, M.E., Nigro, E.A., Nielsen, A.K.S., Pagliarini, R., Cassina, L., Lampis, M., Podrini, C., Chiaravalli, M., Mannella, V., Distefano, G., Yang, M., Aslanyan, M.G., Musco, G., Roepman, R., Frezza, C., Boletta, A., Steidl, M.E., Nigro, E.A., Nielsen, A.K.S., Pagliarini, R., Cassina, L., Lampis, M., Podrini, C., Chiaravalli, M., Mannella, V., Distefano, G., Yang, M., Aslanyan, M.G., Musco, G., Roepman, R., Frezza, C., and Boletta, A.
- Abstract
Item does not contain fulltext, Depriving cells of nutrients triggers an energetic crisis, which is resolved by metabolic rewiring and organelle reorganization. Primary cilia are microtubule-based organelles at the cell surface, capable of integrating multiple metabolic and signalling cues, but their precise sensory function is not fully understood. Here we show that primary cilia respond to nutrient availability and adjust their length via glutamine-mediated anaplerosis facilitated by asparagine synthetase (ASNS). Nutrient deprivation causes cilia elongation, mediated by reduced mitochondrial function, ATP availability and AMPK activation independently of mTORC1. Of note, glutamine removal and replenishment is necessary and sufficient to induce ciliary elongation or retraction, respectively, under nutrient stress conditions both in vivo and in vitro by restoring mitochondrial anaplerosis via ASNS-dependent glutamate generation. Ift88-mutant cells lacking cilia show reduced glutamine-dependent mitochondrial anaplerosis during metabolic stress, due to reduced expression and activity of ASNS at the base of cilia. Our data indicate a role for cilia in responding to, and possibly sensing, cellular glutamine levels via ASNS during metabolic stress.
- Published
- 2023
20. mTORC1-driven accumulation of the oncometabolite fumarate as a potential critical step in renal cancer progression
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Luca Drusian and Alessandra Boletta
- Subjects
renal carcinoma ,oncometabolite ,fumarate hydratase ,mtor ,fumarate ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Modeling renal cancer in the mouse has been challenging. We recently showed that upregulation of mechanistic target of rapamycin complex 1 (mTORC1) in a restricted segment of the renal tubule leads to downregulation of the tricarboxylic acid (TCA) cycle enzyme fumarate hydratase, to accumulation of the oncometabolite fumarate, and gradual transformation from benign cysts into cystadenomas and papillary carcinomas.
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- 2019
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21. Role of the KEAP1-NRF2 Axis in Renal Cell Carcinoma
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Sara Clerici and Alessandra Boletta
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NRF2 ,KEAP1 ,ccRCC ,PRCC ,kidney injury ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
NRF2 is a transcription factor that coordinates the antioxidant response in many different tissues, ensuring cytoprotection from endogenous and exogenous stress stimuli. In the kidney, its function is essential in appropriate cellular response to oxidative stress, however its aberrant activation supports progression, metastasis, and resistance to therapies in renal cell carcinoma, similarly to what happens in other nonrenal cancers. While at the moment direct inhibitors of NRF2 are not available, understanding the molecular mechanisms that regulate its hyperactivation in specific tumor types is crucial as it may open new therapeutic perspectives. Here, we focus our attention on renal cell carcinoma, describing how NRF2 hyperactivation can contribute to tumor progression and chemoresistance. Furthermore, we highlight the mechanism whereby the many pathways that are generally altered in these tumors converge to dysregulation of the KEAP1-NRF2 axis.
- Published
- 2020
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22. Dissection of metabolic reprogramming in polycystic kidney disease reveals coordinated rewiring of bioenergetic pathways
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Podrini, Christine, Rowe, Isaline, Pagliarini, Roberto, Costa, Ana S. H., Chiaravalli, Marco, Di Meo, Ivano, Kim, Hyunho, Distefano, Gianfranco, Tiranti, Valeria, Qian, Feng, di Bernardo, Diego, Frezza, Christian, and Boletta, Alessandra
- Published
- 2018
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23. mTORC1-mediated inhibition of polycystin-1 expression drives renal cyst formation in tuberous sclerosis complex
- Author
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Monika Pema, Luca Drusian, Marco Chiaravalli, Maddalena Castelli, Qin Yao, Sara Ricciardi, Stefan Somlo, Feng Qian, Stefano Biffo, and Alessandra Boletta
- Subjects
Science - Abstract
Polycystic kidney disease (PKD) is a ciliopathy resulting from defective localization of membrane proteins such as PC-1 to the primary cilium, resulting in renal cysts, and is associated with another cystic genetic disease called tuberous sclerosis complex (TSC). Here the authors use kidney-specific Tsc1 and Pkd1 mice to show that mTORC1 signalling inhibits PC-1 biogenesis as a potential mechanism of TSC/PKD contiguous gene syndrome.
- Published
- 2016
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24. Targeting the Mitochondrial Protease Clpp Unveils Mitochondrial Vulnerabilities in Multiple Myeloma
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Perini, Tommaso, primary, Oliva, Laura, additional, Materozzi, Maria, additional, Del Pizzo, Rossella, additional, Cassina, Laura, additional, Samur, Mehmet K., additional, Orfanelli, Ugo, additional, Milan, Enrico, additional, Boletta, Alessandra, additional, Munshi, Nikhil C, additional, and Cenci, Simone, additional
- Published
- 2022
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25. Intracellular Iron Overload Induces Metabolic Switching in Active Hematopoietic Stem Cells in Beta-Thalassemia
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Aprile, Annamaria, primary, Sighinolfi, Silvia, additional, Cassina, Laura, additional, Panzeri, Mariacarla, additional, Storto, Mariangela, additional, Beretta, Stefano, additional, Merelli, Ivan, additional, Boletta, Alessandra, additional, and Ferrari, Giuliana, additional
- Published
- 2022
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26. Targeting mitochondrial respiration and the BCL2 family in high‐grade MYC‐associated B‐cell lymphoma
- Author
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Federica Parodi, Alessandra Boletta, Giulio Donati, Bruno Amati, Christopher P. Vellano, Giulio Draetta, Micol Ravà, Joseph R. Marszalek, Alessandro Verrecchia, Paola Nicoli, Mirko Doni, Simona Rodighiero, Marco Filipuzzi, and Laura Cassina
- Subjects
Cancer Research ,medicine.medical_treatment ,Biology ,CHOP ,Targeted therapy ,Proto-Oncogene Proteins c-myc ,chemistry.chemical_compound ,immune system diseases ,hemic and lymphatic diseases ,Genetics ,medicine ,Humans ,Integrated stress response ,B-cell lymphoma ,Transcription factor ,Venetoclax ,Respiration ,Intrinsic apoptosis ,Oncogenes ,General Medicine ,medicine.disease ,Lymphoma ,Proto-Oncogene Proteins c-bcl-2 ,Oncology ,chemistry ,Cancer research ,Molecular Medicine ,Lymphoma, Large B-Cell, Diffuse - Abstract
Multiple molecular features, such as activation of specific oncogenes (e.g., MYC, BCL2) or a variety of gene expression signatures, have been associated with disease course in diffuse large B-cell lymphoma (DLBCL), although their relationships and implications for targeted therapy remain to be fully unraveled. We report that MYC activity is closely correlated with-and most likely a driver of-gene signatures related to oxidative phosphorylation (OxPhos) in DLBCL, pointing to OxPhos enzymes, in particular mitochondrial electron transport chain (ETC) complexes, as possible therapeutic targets in high-grade MYC-associated lymphomas. In our experiments, indeed, MYC sensitized B cells to the ETC complex I inhibitor IACS-010759. Mechanistically, IACS-010759 triggered the integrated stress response (ISR) pathway, driven by the transcription factors ATF4 and CHOP, which engaged the intrinsic apoptosis pathway and lowered the apoptotic threshold in MYC-overexpressing cells. In line with these findings, the BCL2-inhibitory compound venetoclax synergized with IACS-010759 against double-hit lymphoma (DHL), a high-grade malignancy with concurrent activation of MYC and BCL2. In BCL2-negative lymphoma cells, instead, killing by IACS-010759 was potentiated by the Mcl-1 inhibitor S63845. Thus, combining an OxPhos inhibitor with select BH3-mimetic drugs provides a novel therapeutic principle against aggressive, MYC-associated DLBCL variants.
- Published
- 2021
27. Il Registro Italiano del Rene Policistico Autosomico Dominante
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P. Carrera, L. Palmieri, F. Caruso, D. Lodi, F. Rigo, L. Furci, M. Granito, F. Damiano, R. Iatrino, A. Boletta, M. Ferrari, G. Aguiari, and R. Magistroni
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Internal medicine ,RC31-1245 ,Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Abstract non disponibile
- Published
- 2018
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28. Role of the Polycystins in Cell Migration, Polarity, and Tissue Morphogenesis
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Elisa Agnese Nigro, Maddalena Castelli, and Alessandra Boletta
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polycystin ,polycystic kidney disease ,epithelial morphogenesis ,cell migration ,cell polarity ,cilia ,renal cyst ,planar cell polarity ,Cytology ,QH573-671 - Abstract
Cystic kidney diseases (CKD) is a class of disorders characterized by ciliary dysfunction and, therefore, belonging to the ciliopathies. The prototype CKD is autosomal dominant polycystic kidney disease (ADPKD), whose mutated genes encode for two membrane-bound proteins, polycystin-1 (PC-1) and polycystin-2 (PC-2), of unknown function. Recent studies on CKD-associated genes identified new mechanisms of morphogenesis that are central for establishment and maintenance of proper renal tubular diameter. During embryonic development in the mouse and lower vertebrates a convergent-extension (CE)-like mechanism based on planar cell polarity (PCP) and cellular intercalation is involved in “sculpting” the tubules into a narrow and elongated shape. Once the appropriate diameter is established, further elongation occurs through oriented cell division (OCD). The polycystins (PCs) regulate some of these essential processes. In this review we summarize recent work on the role of PCs in regulating cell migration, the cytoskeleton, and front-rear polarity. These important properties are essential for proper morphogenesis of the renal tubules and the lymphatic vessels. We highlight here several open questions and controversies. Finally, we try to outline some of the next steps required to study these processes and their relevance in physiological and pathological conditions.
- Published
- 2015
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29. Role of the polycystins as mechanosensors of extracellular stiffness
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Alessandra Boletta and Elisa Agnese Nigro
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0301 basic medicine ,TRPP Cation Channels ,Protein Conformation ,Physiology ,Autosomal dominant polycystic kidney disease ,Biology ,Kidney ,Mechanotransduction, Cellular ,Structure-Activity Relationship ,03 medical and health sciences ,Extracellular ,Polycystic kidney disease ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,030102 biochemistry & molecular biology ,Mechanosensation ,PKD1 ,Genetic disorder ,Polycystic Kidney, Autosomal Dominant ,medicine.disease ,Transmembrane protein ,Extracellular Matrix ,Phenotype ,030104 developmental biology ,Cellular Microenvironment ,Mutation ,Neuroscience ,Function (biology) - Abstract
Polycystin-1 (PC-1) is a transmembrane protein, encoded by the PKD1 gene, mutated in autosomal dominant polycystic kidney disease (ADPKD). This common genetic disorder, characterized by cyst formation in both kidneys, ultimately leading to renal failure, is still waiting for a definitive treatment. The overall function of PC-1 and the molecular mechanism responsible for cyst formation are slowly coming to light, but they are both still intensively studied. In particular, PC-1 has been proposed to act as a mechanosensor, although the precise signal that activates the mechanical properties of this protein has been long debated and questioned. In this review, we report studies and evidence of PC-1 function as a mechanosensor, starting from the peculiarity of its structure, through the long journey that progressively shed new light on the potential initiating events of cystogenesis, concluding with the description of PC-1 recently shown ability to sense the mechanical stimuli provided by the stiffness of the extracellular environment. These new findings have potentially important implications for the understanding of ADPKD pathophysiology and potentially for designing new therapies.NEW & NOTEWORTHY Polycystin-1 has recently emerged as a possible receptor able to sense extracellular stiffness and to negatively control the cellular actomyosin contraction machinery. Here, we revisit a large body of literature on autosomal dominant polycystic kidney disease providing a new possible mechanistic view on the topic.
- Published
- 2021
30. Targeting the Mitochondrial Protease Clpp Unveils Mitochondrial Vulnerabilities in Multiple Myeloma
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Tommaso Perini, Laura Oliva, Maria Materozzi, Rossella Del Pizzo, Laura Cassina, Mehmet K. Samur, Ugo Orfanelli, Enrico Milan, Alessandra Boletta, Nikhil C Munshi, and Simone Cenci
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
31. Intracellular Iron Overload Induces Metabolic Switching in Active Hematopoietic Stem Cells in Beta-Thalassemia
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Annamaria Aprile, Silvia Sighinolfi, Laura Cassina, Mariacarla Panzeri, Mariangela Storto, Stefano Beretta, Ivan Merelli, Alessandra Boletta, and Giuliana Ferrari
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
32. P1563: INTRACELLULAR IRON OVERLOAD IMPAIRS HSC FUNCTION BY AFFECTING MITOCHONDRIAL FITNESS IN ΒETA-THALASSEMIA
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Sighinolfi, S., primary, Aprile, A., additional, Cassina, L., additional, Panzeri, M., additional, Beretta, S., additional, Storto, M., additional, Boletta, A., additional, Merelli, I., additional, and Ferrari, G., additional
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- 2022
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33. https://www.puntoorginternationaljournal.org/index.php/PIJ/article/view/90
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Francesco Boletta, Giancarlo Giudici, and Daniele Giuffrida
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Curse ,Incentive ,Work (electrical) ,Short run ,Equity (finance) ,Revenue ,General Medicine ,Equity crowdfunding ,Monetary economics ,Business - Abstract
Equity crowdfunding platforms allow small ventures to raise money and find new investors among retail individuals. In this work we aim at analysing the relationship between the number of equity investors registered in the crowdfunding round and the follow-up growth of revenues reported by investee firms. We find support for the ‘curse of the crowd’ hypothesis, according to which a larger number of investors registered at the end of the equity crowdfunding campaign is associated to lower growth in the revenues, in the short run. We posit that this effect is attributable to coordination costs, possible conflicts and low incentive for investors to spend efforts in value-adding activities.
- Published
- 2021
34. Increased mitochondrial fragmentation in polycystic kidney disease acts as a modifier of disease progression
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Laura Cassina, Marco Chiaravalli, and Alessandra Boletta
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0301 basic medicine ,medicine.medical_specialty ,Cellular respiration ,Autosomal dominant polycystic kidney disease ,Mitochondrion ,Biology ,Biochemistry ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Genetics ,medicine ,Polycystic kidney disease ,Animals ,MFN1 ,Fragmentation (cell biology) ,Molecular Biology ,Cell Proliferation ,Mice, Knockout ,Polycystic Kidney Diseases ,Kidney ,PKD1 ,Cysts ,Pyruvate Dehydrogenase Acetyl-Transferring Kinase ,medicine.disease ,Mitochondria ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Disease Progression ,030217 neurology & neurosurgery ,Biotechnology - Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenic disorder, characterized by bilateral renal cyst formation. Multiple pathways are de-regulated in cystic epithelia offering good opportunities for therapy. Others and we have previously reported that metabolic reprogramming, including alterations of the TCA cycle, are prominent features of ADPKD. Several lines of evidence suggest that mitochondrial impairment might be responsible for the metabolic alterations. Here, we performed morphologic and morphometric evaluation of mitochondria by TEM in an orthologous mouse model of PKD caused by mutations in the Pkd1 gene (Ksp-Cre;Pkd1flox/- ). Furthermore, we measured mitochondrial respiration by COX and SDH enzymatic activity in situ. We found several alterations including reduced mitochondrial mass, altered structure and fragmentation of the mitochondrial network in cystic epithelia of Ksp-Cre;Pkd1flox/- mice. At the molecular level, we found reduced expression of the pro-fusion proteins OPA1 and MFN1 and up-regulation of the pro-fission protein DRP1. Importantly, administration of Mdivi-1, which interferes with DRP1 rescuing mitochondrial fragmentation, significantly reduced kidney/body weight, cyst formation, and improved renal function in Ksp-Cre;Pkd1flox/- mice. Our data indicate that impaired mitochondrial structure and function play a role in disease progression, and that their improvement can significantly modify the course of the disease.
- Published
- 2020
35. The anti-inflammatory cytokine interleukin-37 is an inhibitor of trained immunity
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Davide Stefanoni, Silvia Giugliano, Eleonora Cantoni, Giulio Cavalli, Elan Z. Eisenmensser, Isak W. Tengesdal, Kiki Schraa, Lorenzo Dagna, Mihai G. Netea, Laura Cassina, Angelo D'Alessandro, Travis Nemkov, Leo A. B. Joosten, Eric M. Pietras, Jorge Domínguez-Andrés, Mark S. Gresnigt, Rob J.W. Arts, Taylor S. Mills, Raffaella Molteni, Alessandra Boletta, Charles A. Dinarello, Cavalli, Giulio, Tengesdal, I W, Gresnigt, M, Nemkov, T, Arts, R J W, Dominguez-Andres, J, Molteni, R, Stefanoni, D, Cantoni, E, Cassina, L, Giugliano, S, Schraa, K, Mills, T, Pietras, E M, Eisenmensser, E Z, Dagna, L, Boletta, A, D'Alessandro, A, Joosten, L A B, Netea, M G, and Dinarello, C A
- Subjects
0301 basic medicine ,Male ,Neutrophils ,medicine.medical_treatment ,immunometabolism ,Anti-Inflammatory Agents ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,Epigenesis, Genetic ,trained immunity ,0302 clinical medicine ,Medicine ,lcsh:QH301-705.5 ,innate immunity ,biology ,cell energy metabolism ,Candidiasis ,Interleukin ,3. Good health ,Histone ,Cytokine ,regulatory cytokine ,Host-Pathogen Interactions ,medicine.symptom ,Glycolysis ,medicine.drug_class ,Inflammation ,General Biochemistry, Genetics and Molecular Biology ,Anti-inflammatory ,IL-1 family ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,Immunity ,Animals ,Humans ,Epigenetics ,Innate immune system ,epigenetics ,business.industry ,cytokines ,infection ,Immunity, Innate ,Mice, Inbred C57BL ,030104 developmental biology ,lcsh:Biology (General) ,inflammation ,Immunology ,biology.protein ,business ,030217 neurology & neurosurgery ,Interleukin-1 - Abstract
Summary Trained immunity (TI) is a de facto innate immune memory program induced in monocytes/macrophages by exposure to pathogens or vaccines, which evolved as protection against infections. TI is characterized by immunometabolic changes and histone post-translational modifications, which enhance production of pro-inflammatory cytokines. As aberrant activation of TI is implicated in inflammatory diseases, tight regulation is critical; however, the mechanisms responsible for this modulation remain elusive. Interleukin-37 (IL-37) is an anti-inflammatory cytokine that curbs inflammation and modulates metabolic pathways. In this study, we show that administration of recombinant IL-37 abrogates the protective effects of TI in vivo, as revealed by reduced host pro-inflammatory responses and survival to disseminated candidiasis. Mechanistically, IL-37 reverses the immunometabolic changes and histone post-translational modifications characteristic of TI in monocytes, thus suppressing cytokine production in response to infection. IL-37 thereby emerges as an inhibitor of TI and as a potential therapeutic target in immune-mediated pathologies.
- Published
- 2021
36. Oncogene-induced maladaptive activation of trained immunity in the pathogenesis and treatment of Erdheim-Chester disease
- Author
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Mihai G. Netea, Riccardo Biavasco, Lorenzo Dagna, Simone Cenci, Travis Nemkov, Giulio Cavalli, Philippe Maksud, Claudio Doglioni, Gianfranco Distefano, Daniela Cesana, Charles A. Dinarello, Eleonora Cantoni, Anna Kajaste-Rudnitski, Corrado Campochiaro, Simone Cardaci, Daniela Gnani, Isak W. Tengesdal, Julien Haroche, Samuel Zambrano, Alessandro Tomelleri, Giacomo De Luca, Davide Stefanoni, Francesco Piras, Ivan Merelli, Angelo D'Alessandro, Maddalena Panigada, Davide Mazza, Rob J.W. Arts, Jorge Domínguez-Andrés, Alessia Loffreda, Laura Cassina, Raffaella Molteni, Eugenio Montini, Alessandra Boletta, Leo A. B. Joosten, Elisabetta Ferrero, Marina Ferrarini, Biavasco, Riccardo, Molteni, Raffaella, Stefanoni, Davide, Nemkov, Travi, Netea, Mihai G., Domínguez-Andrés, Jorge, Arts, Rob JW, Merelli, Ivan, Mazza, Davide, Zambrano, S, Panigada, Maddalena, Cantoni, Eleonora, Tengesdal, Isak, Maksud, Philippe, Piras, Francesco, De Luca, Giacomo, Cassina, Laura, Distefano, Gianfranco, Loffreda, Alessia, Gnani, Daniela, Doglioni, Claudio, Tomelleri, Alessandro, Campochiaro, Corrado, Joosten, Leo, Dinarello, Charles A, Kajaste-Rudnitski, Anna, Haroche, Julien, Cardaci, Simone, Cenci, Simone, Dagna, Lorenzo, Ferrarini, Marina, Ferrero, Elisabetta, Boletta, Alessandra, D'Alessandro, Angelo, Montini, Eugenio, and Cavalli, Giulio
- Subjects
Proto-Oncogene Proteins B-raf ,Erdheim-Chester Disease ,Myeloid ,medicine.medical_treatment ,Immunology ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,Inflammation ,Biochemistry ,Myeloid Neoplasm ,Proinflammatory cytokine ,Epigenesis, Genetic ,Pathogenesis ,medicine ,Humans ,Point Mutation ,Protein kinase B ,Cells, Cultured ,business.industry ,Monocyte ,Macrophages ,Immunity ,Cell Biology ,Hematology ,Oncogenes ,Cytokine ,medicine.anatomical_structure ,Cancer research ,medicine.symptom ,business - Abstract
Trained immunity (TI) is a proinflammatory program induced in monocyte/macrophages upon sensing of specific pathogens and is characterized by immunometabolic and epigenetic changes that enhance cytokine production. Maladaptive activation of TI (ie, in the absence of infection) may result in detrimental inflammation and development of disease; however, the exact role and extent of inappropriate activation of TI in the pathogenesis of human diseases is undetermined. In this study, we uncovered the oncogene-induced, maladaptive induction of TI in the pathogenesis of a human inflammatory myeloid neoplasm (Erdheim-Chester disease, [ECD]), characterized by the BRAFV600E oncogenic mutation in monocyte/macrophages and excess cytokine production. Mechanistically, myeloid cells expressing BRAFV600E exhibit all molecular features of TI: activation of the AKT/mammalian target of rapamycin signaling axis; increased glycolysis, glutaminolysis, and cholesterol synthesis; epigenetic changes on promoters of genes encoding cytokines; and enhanced cytokine production leading to hyperinflammatory responses. In patients with ECD, effective therapeutic strategies combat this maladaptive TI phenotype; in addition, pharmacologic inhibition of immunometabolic changes underlying TI (ie, glycolysis) effectively dampens cytokine production by myeloid cells. This study revealed the deleterious potential of inappropriate activation of TI in the pathogenesis of human inflammatory myeloid neoplasms and the opportunity for inhibition of TI in conditions characterized by maladaptive myeloid-driven inflammation.
- Published
- 2021
37. Políticas públicas dos EUA e da China para a pandemia: tensões geopolíticas, competição tecnológica e modelos de desenvolvimento
- Author
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Poty, Italo Barreto, primary and Aguiar, Caroline Boletta de O., additional
- Published
- 2021
- Full Text
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38. Targeting mitochondrial respiration and the BCL2 family in high‐grade MYC‐associated B‐cell lymphoma
- Author
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Donati, Giulio, primary, Ravà, Micol, additional, Filipuzzi, Marco, additional, Nicoli, Paola, additional, Cassina, Laura, additional, Verrecchia, Alessandro, additional, Doni, Mirko, additional, Rodighiero, Simona, additional, Parodi, Federica, additional, Boletta, Alessandra, additional, Vellano, Christopher P., additional, Marszalek, Joseph R., additional, Draetta, Giulio F., additional, and Amati, Bruno, additional
- Published
- 2021
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39. Disruption of polycystin-1 cleavage leads to cardiac metabolic rewiring in mice
- Author
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Andressa G. Amaral, Camille C.C. da Silva, Julian D.C. Serna, Kinulpe Honorato-Sampaio, Jéssica A. Freitas, Amaro N. Duarte-Neto, Antonio C. Bloise, Laura Cassina, Marcos Y. Yoshinaga, Adriano B. Chaves-Filho, Feng Qian, Sayuri Miyamoto, Alessandra Boletta, Silvana Bordin, Alicia J. Kowaltowski, and Luiz F. Onuchic
- Subjects
Mice ,TRPP Cation Channels ,Mutation ,Molecular Medicine ,Animals ,Heart ,Polycystic Kidney, Autosomal Dominant ,Molecular Biology ,Mitochondria - Abstract
Cardiovascular manifestations account for marked morbi-mortality in autosomal dominant polycystic kidney disease (ADPKD). Pkd1- and Pkd2-deficient mice develop cardiac dysfunction, however the underlying mechanisms remain largely unclear. It is unknown whether impairment of polycystin-1 cleavage at the G-protein-coupled receptor proteolysis site, a significant ADPKD mutational mechanism, is involved in this process. We analyzed the impact of polycystin-1 cleavage on heart metabolism using Pkd1
- Published
- 2021
40. TWEAK Signaling Pathway Blockade Slows Cyst Growth and Disease Progression in Autosomal Dominant Polycystic Kidney Disease
- Author
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Cordido, Adrian, primary, Nuñez-Gonzalez, Laura, additional, Martinez-Moreno, Julio M., additional, Lamas-Gonzalez, Olaya, additional, Rodriguez-Osorio, Laura, additional, Perez-Gomez, Maria Vanessa, additional, Martin-Sanchez, Diego, additional, Outeda, Patricia, additional, Chiaravalli, Marco, additional, Watnick, Terry, additional, Boletta, Alessandra, additional, Diaz, Candido, additional, Carracedo, Angel, additional, Sanz, Ana B., additional, Ortiz, Alberto, additional, and Garcia-Gonzalez, Miguel A., additional
- Published
- 2021
- Full Text
- View/download PDF
41. Defective glucose metabolism in polycystic kidney disease identifies a new therapeutic strategy
- Author
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Rowe, Isaline, Chiaravalli, Marco, Mannella, Valeria, Ulisse, Valeria, Quilici, Giacomo, Pema, Monika, Song, Xuewen W., Xu, Hangxue, Mari, Silvia, Qian, Feng, Pei, York, Musco, Giovanna, and Boletta, Alessandra
- Subjects
Glucose metabolism -- Health aspects -- Research -- Analysis ,Polycystic kidney disease -- Health aspects -- Research -- Analysis -- Care and treatment ,Biological sciences ,Health - Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder characterized by bilateral renal cyst formation (1). Recent identification of signaling cascades deregulated in ADPKD has led to the initiation of several clinical trials, but an approved therapy is still lacking (2), (3). Using a metabolomic approach, we identify a pathogenic pathway in this disease that can be safely targeted for therapy. We show that mutation of PKD1 results in enhanced glycolysis in cells in a mouse model of PKD and in kidneys from humans with ADPKD. Glucose deprivation resulted in lower proliferation and higher apoptotic rates in PKD1-mutant cells than in nondeprived cells. Notably, two distinct PKD mouse models treated with 2-deoxyglucose (2DG), to inhibit glycolysis, had lower kidney weight, volume, cystic index and proliferation rates as compared to nontreated mice. These metabolic alterations depend on the extracellular signal-related kinase (ERK) pathway acting in a dual manner by inhibiting the liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) axis on the one hand while activating the mTOR complex 1 (mTORC1)-glycolytic cascade on the other. Enhanced metabolic rates further inhibit AMPK. Forced activation of AMPK acts in a negative feedback loop, restoring normal ERK activity. Taken together, these data indicate that defective glucose metabolism is intimately involved in the pathobiology of ADPKD. Our findings provide a strong rationale for a new therapeutic strategy using existing drugs, either individually or in combination., ADPKD is a chronic progressive disease (1). Cysts originate from any segment of the renal tubule in only 1-5% of the nephrons, a condition that should be compatible with a [...]
- Published
- 2013
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42. Mitochondrial Transmembrane Potential (ψm) Assay Using TMRM
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Isaline Rowe and Alessandra Boletta
- Subjects
Biology (General) ,QH301-705.5 - Abstract
During cellular respiration, nutrients are oxidized to generate energy through a mechanism called oxidative phosphorylation, which occurs in the mitochondria. During oxidative phosphorylation, the gradual degradation of molecules through the TCA cycle releases electrons from the covalent bonds that are broken. These electrons are captured by NAD+ through its reduction into NADH. Finally, NADH transports the electrons to the complexes of the electron chain in the internal membrane of mitochondria. These complexes use the energy released by the electrons to pump protons into the intermembrane space, generating an electrochemical gradient across the internal membrane of mitochondria, which provides energy for the ATP-synthase complex, ultimately producing adenosine triphosphate (ATP). We assessed the mitochondrial membrane potential (ψm) using tetramethylrhodamine methyl ester (TMRM), a cell-permeant, cationic, red fluorescent dye. To measure specifically the mitochondrial membrane potential (ψm) we quantified the fluorescence intensity before and after applying FCCP, a mitochondrial electron chain uncoupler. The difference of intensity before and after applying FCCP corresponds specifically to the mitochondrial membrane potential. We analyzed mitochondrial membrane potential (ψm) by cytofluorimetry. The ratio between the total level of signal and the signal generated after uncoupling provided a normalized value for the difference in cell size. Furthermore, to normalize for the different size of cells that we were analyzing we have analyzed TMRM in live imaging using IN Cell Analyzer, so that the level of mitochondrial membrane potential could be detected per unit of mitochondrial membrane area measured. Thus, our protocol can also be used to compare the mitochondrial membrane potential of cells that are different in size.
- Published
- 2013
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43. ATP and Lactate Quantification
- Author
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Isaline Rowe, Marco Chiaravalli, and Alessandra Boletta
- Subjects
Biology (General) ,QH301-705.5 - Abstract
Cells use glucose to generate energy by two different metabolic processes: lactic fermentation and aerobic respiration. In the first common series of reactions, glucose is converted into pyruvate. In anaerobic conditions, pyruvate is transformed into lactate, this process yields to 2 ATP molecules per glucose molecule. In the presence of oxygen, pyruvate is imported into mitochondria where it is used in the Krebs (or TCA) cycle and oxydative phosphorylation. The global process of oxydative phosphorylation yields to 32 ATP per glucose molecule. For reasons not fully understood, in some pathological cases like cancer, cells use anaerobic glycolysis even in the presence of oxygen, in which case the process is called aerobic glycolysis (or Warburg effect). This results in an increased uptake of glucose and lactate production. Measure of intracellular ATP content and lactate concentrations can provide a readout of aerobic glycolyis.
- Published
- 2013
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44. Difetti nel metabolismo del glucosio nel rene policistico: primi studi e prospettive future
- Author
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Isaline Rowe, Marco Chiaravalli, and Alessandra Boletta
- Subjects
Rene policistico ,Glucosio ,Ciglia ,Cisti ,Internal medicine ,RC31-1245 ,Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Il rene policistico autosomico dominante (ADPKD) è una malattia genetica molto comune, caratterizzata dalla formazione di cisti in entrambi i reni. Diverse considerazioni circa i meccanismi genetici e molecolari che stanno alla base della formazione delle cisti in questa malattia sono ancora controverse, ma c'è oggi un ampio consenso sul fatto che la ADPKD sia dovuta alla perdita di funzionalità di uno dei due geni mutati nella malattia, PKD1 o PKD2. In questo breve articolo parleremo in particolare di due aspetti: 1) cercheremo di dare una panoramica sullo stato dell'arte di quanto a oggi compreso sulle basi genetiche e molecolari della malattia, cercando di fornire una visione integrata dei diversi modelli di cistogenesi proposti; 2) forniremo una descrizione dettagliata e un'ampia discussione sui recenti risultati riportati dal nostro laboratorio su un difetto a livello del metabolismo del glucosio nella ADPKD e sulle sue potenziali implicazioni terapeutiche, evidenziando anche la necessità di un'ulteriore validazione dei nostri risultati in altri modelli animali di malattia a esordio tardivo e a progressione lenta.
- Published
- 2013
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45. Oncogene-induced maladaptive activation of trained immunity in the pathogenesis and treatment of Erdheim-Chester disease
- Author
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Biavasco, Riccardo, primary, Molteni, Raffaella, additional, Stefanoni, Davide, additional, Nemkov, Travis, additional, Netea, Mihai G., additional, Domínguez-Andrés, Jorge, additional, Arts, Rob JW, additional, Merelli, Ivan, additional, Mazza, Davide, additional, Zambrano, Samuel, additional, Panigada, Maddalena, additional, Cantoni, Eleonora, additional, Tengesdal, Isak, additional, Maksud, Philippe, additional, Piras, Francesco, additional, De Luca, Giacomo, additional, Cassina, Laura, additional, Distefano, Gianfranco, additional, Loffreda, Alessia, additional, Gnani, Daniela, additional, Doglioni, Claudio, additional, Tomelleri, Alessandro, additional, Campochiaro, Corrado, additional, Joosten, Leo, additional, Dinarello, Charles A, additional, Kajaste-Rudnitski, Anna, additional, Haroche, Julien, additional, Cardaci, Simone, additional, Cenci, Simone, additional, Dagna, Lorenzo, additional, Ferrarini, Marina, additional, Ferrero, Elisabetta, additional, Boletta, Alessandra, additional, D'Alessandro, Angelo, additional, Montini, Eugenio, additional, and Cavalli, Giulio, additional
- Published
- 2021
- Full Text
- View/download PDF
46. Role of the polycystins as mechanosensors of extracellular stiffness
- Author
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Nigro, Elisa A., primary and Boletta, Alessandra, additional
- Published
- 2021
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47. Oncogene-induced maladaptive activation of trained immunity in the pathogenesis and treatment of Erdheim-Chester disease.
- Author
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Molteni, R., Biavasco, R., Stefanoni, D., Nemkov, T., Dominguez Andres, J., Arts, R.J.W., Merelli, I., Mazza, D., Zambrano, S., Panigada, M., Cantoni, E., Tengesdal, I.W., Maksud, P., Piras, F., Cesana, D., Cassina, L., Distefano, G., Loffreda, A., Gnani, D., Luca, G. De, Tomelleri, A., Campochiaro, C., Joosten, L.A.B., Dinarello, C.A., Kajaste-Rudnitski, A., Haroche, J., Cardaci, S., Cenci, S., Dagna, L., Doglioni, C., Ferrarini, M., Ferrero, E., Boletta, A., d'Alessandro, A., Montini, E., Netea, M.G., Cavalli, G.C., Molteni, R., Biavasco, R., Stefanoni, D., Nemkov, T., Dominguez Andres, J., Arts, R.J.W., Merelli, I., Mazza, D., Zambrano, S., Panigada, M., Cantoni, E., Tengesdal, I.W., Maksud, P., Piras, F., Cesana, D., Cassina, L., Distefano, G., Loffreda, A., Gnani, D., Luca, G. De, Tomelleri, A., Campochiaro, C., Joosten, L.A.B., Dinarello, C.A., Kajaste-Rudnitski, A., Haroche, J., Cardaci, S., Cenci, S., Dagna, L., Doglioni, C., Ferrarini, M., Ferrero, E., Boletta, A., d'Alessandro, A., Montini, E., Netea, M.G., and Cavalli, G.C.
- Abstract
Item does not contain fulltext, Trained immunity (TI) is a proinflammatory program induced in monocyte/macrophages upon sensing of specific pathogens and is characterized by immunometabolic and epigenetic changes that enhance cytokine production. Maladaptive activation of TI (ie, in the absence of infection) may result in detrimental inflammation and development of disease; however, the exact role and extent of inappropriate activation of TI in the pathogenesis of human diseases is undetermined. In this study, we uncovered the oncogene-induced, maladaptive induction of TI in the pathogenesis of a human inflammatory myeloid neoplasm (Erdheim-Chester disease, [ECD]), characterized by the BRAFV600E oncogenic mutation in monocyte/macrophages and excess cytokine production. Mechanistically, myeloid cells expressing BRAFV600E exhibit all molecular features of TI: activation of the AKT/mammalian target of rapamycin signaling axis; increased glycolysis, glutaminolysis, and cholesterol synthesis; epigenetic changes on promoters of genes encoding cytokines; and enhanced cytokine production leading to hyperinflammatory responses. In patients with ECD, effective therapeutic strategies combat this maladaptive TI phenotype; in addition, pharmacologic inhibition of immunometabolic changes underlying TI (ie, glycolysis) effectively dampens cytokine production by myeloid cells. This study revealed the deleterious potential of inappropriate activation of TI in the pathogenesis of human inflammatory myeloid neoplasms and the opportunity for inhibition of TI in conditions characterized by maladaptive myeloid-driven inflammation.
- Published
- 2021
48. Targeting mitochondrial respiration and the BCL2 family in MYC-associated B-cell lymphoma
- Author
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Alessandro Verrecchia, Joseph R. Marszalek, Mirko Doni, Micol Ravà, Marco Filipuzzi, Bruno Amati, Alessandra Boletta, Federica Parodi, Simona Rodighiero, Christopher P. Vellano, Paola Nicoli, Giulio Draetta, Laura Cassina, and Giulio Donati
- Subjects
Transcription Factor CHOP ,Venetoclax ,Intrinsic apoptosis ,Biology ,medicine.disease ,Lymphoma ,chemistry.chemical_compound ,chemistry ,immune system diseases ,Apoptosis ,hemic and lymphatic diseases ,Gene expression ,medicine ,Cancer research ,Integrated stress response ,B-cell lymphoma - Abstract
Multiple molecular features, such as activation of specific oncogenes (e. g.MYC,BCL2) or a variety of gene expression signatures, have been associated with disease course in diffuse large B-cell lymphoma (DLBCL). Understanding the relationships between these features and their possible exploitation toward disease classification and therapy remains a major priority in the field. Here, we report that MYC activity in DLBCL is closely correlated with – and most likely a driver of – gene signatures related to Oxidative Phosphorylation (OxPhos). On this basis, we hypothesized that enzymes involved in Oxidative Phosphorylation, and in particular electron-transport chain (ETC) complexes, might constitute tractable therapeutic targets in MYC-associated lymphoma. Indeed, our data show that MYC sensitizes B-cells to IACS-010759, a selective inhibitor of ETC complex I. Mechanistically, IACS-010759 activates an ATF4-driven Integrated Stress Response (ISR), engaging the intrinsic apoptosis pathway through the transcription factor CHOP. In line with these findings, IACS-010759 shows synergy with the BCL2 inhibitor venetoclax against double-hit lymphoma (DHL), a high-grade form of DLBCL with concurrent activation ofMYCandBCL2. Similarly, in BCL2-negative lymphoma cell lines, inhibition of the BCL2-related protein Mcl-1 potentiates killing by IACS-010759. Altogether, ETC complex I inhibition engages the ISR to lower the apoptotic threshold in MYC-driven lymphomas and, in combination with select BCL2-family inhibitors, provides a novel therapeutic principle against this aggressive DLBCL subset.Statement of significanceThis work points to OxPhos as a key MYC-activated process and a tractable therapeutic target toward personalized treatment of high-grade DLBCL, providing strong context-dependent cooperation with BH3-mimetic compounds.
- Published
- 2020
49. Role of the KEAP1-NRF2 Axis in Renal Cell Carcinoma
- Author
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Alessandra Boletta and Sara Clerici
- Subjects
0301 basic medicine ,Cancer Research ,Review ,lcsh:RC254-282 ,Metastasis ,NRF2 ,03 medical and health sciences ,0302 clinical medicine ,Renal cell carcinoma ,Medicine ,PRCC ,Transcription factor ,Kidney ,business.industry ,Mechanism (biology) ,ccRCC ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Cytoprotection ,KEAP1 ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Tumor progression ,030220 oncology & carcinogenesis ,Cancer research ,kidney injury ,business - Abstract
Simple Summary Renal cancers are common types of tumors affecting humans. While many different genes have been found to be mutated and to drive the initiation and progression of these lethal cancers, a fine molecular understanding of the process is still lacking. One important pathway that emerges central in many different types of renal cancers is one called KEAP-NRF2. This axis is very important in normal kidneys as a defense against oxidative stress. Here, we summarize a large body of literature suggesting that this axis is exploited by tumor cells to escape control and to transform, and thus it could represent a good target for therapy. Abstract NRF2 is a transcription factor that coordinates the antioxidant response in many different tissues, ensuring cytoprotection from endogenous and exogenous stress stimuli. In the kidney, its function is essential in appropriate cellular response to oxidative stress, however its aberrant activation supports progression, metastasis, and resistance to therapies in renal cell carcinoma, similarly to what happens in other nonrenal cancers. While at the moment direct inhibitors of NRF2 are not available, understanding the molecular mechanisms that regulate its hyperactivation in specific tumor types is crucial as it may open new therapeutic perspectives. Here, we focus our attention on renal cell carcinoma, describing how NRF2 hyperactivation can contribute to tumor progression and chemoresistance. Furthermore, we highlight the mechanism whereby the many pathways that are generally altered in these tumors converge to dysregulation of the KEAP1-NRF2 axis.
- Published
- 2020
50. Defective metabolism in polycystic kidney disease: potential for therapy and open questions
- Author
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Rowe, Isaline and Boletta, Alessandra
- Published
- 2014
- Full Text
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