78 results on '"Bonacina, F."'
Search Results
2. Unraveling the metabolic pattern of angiopoietin-like 3 knock-out mouse models under fasting and fed conditions
- Author
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Terenghi, O, primary, Da Dalt, L, additional, Fantini, F, additional, Moregola, A, additional, Bonacina, F, additional, and Norata, G D, additional
- Published
- 2024
- Full Text
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3. Modulation of mitochondrial dynamism in kupffer cells impacts systemic metabolism
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Fantini, F, primary, Da Dalt, L, additional, Moregola, A, additional, Vingiani, G B, additional, Svecla, M, additional, Terenghi, O, additional, Nour, J, additional, Bellini, R, additional, Bonacina, F, additional, and Norata, G D, additional
- Published
- 2024
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4. Impact of immune system humanization on atherosclerosis in dyslipidemic immunocompromised mice
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Bonacina, F, primary, Moreola, A, additional, Nour, J, additional, Greco, S, additional, Vingiani, G B, additional, and Norata, G D, additional
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- 2024
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5. Monocarboxylate transporter 1 deficiency impacts CD8+ T lymphocytes proliferation and recruitment to adipose tissue during obesity
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Macchi, C., Moregola, A., Greco, M.F., Svecla, M., Bonacina, F., Dhup, S., Dadhich, R.K., Audano, M., Sonveaux, P., Mauro, C., Mitro, N., Ruscica, M., and Norata, G.D.
- Published
- 2022
- Full Text
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6. SOROPREVALÊNCIA DE SÍFILIS EM DOADORES DE SANGUE DE UM HOSPITAL TERCIÁRIO DE PORTO ALEGRE
- Author
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Janzen, PH, primary, Rosa, AG, additional, Cohen, CR, additional, Bohem, RE, additional, Bonacina, F, additional, Sekine, L, additional, and Wagner, SC, additional
- Published
- 2023
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- View/download PDF
7. PREVALÊNCIA DE INFECÇÃO POR TRYPANOSOMA CRUZI EM DOADORES DE SANGUE DE UM HOSPITAL TERCIÁRIO DO SUL DO PAÍS
- Author
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Rosa, AG, primary, Janzen, PH, additional, Cohen, CR, additional, Boehm, RE, additional, Bonacina, F, additional, Sekine, L, additional, and Wagner, SC, additional
- Published
- 2023
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8. Editorial: Exploiting cellular immunometabolism as a strategy for innovative cardiovascular therapies.
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Bonacina, F. and Della-Morte, D.
- Published
- 2024
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9. Immunotherapy: GENERATION OF HUMANIZED IMMUNOCOMPROMISED DYSLIPIDEMIC RAG2-KO/IL2RG-KO/CD47-KO/LDL-R KO MICE FOR THE STUDY OF IMMUNOMODULATORY THERAPIES FOR THE TREATMENT OF ATHEROSCLEROSIS
- Author
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Bonacina, F., primary, Moregola, A., additional, Nour, J., additional, and Norata, G., additional
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- 2023
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10. Internal Combustion Engine sensor network analysis using graph modeling
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Corsini, A., Bonacina, F., Feudo, S., Marchegiani, A., and Venturini, P.
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- 2017
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11. Multivariate KPI for Energy Management of Cooling Systems in Food Industry
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Corsini, A., Bonacina, F., Feudo, S., Lucchetta, F., and Marchegiani, A.
- Published
- 2016
- Full Text
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12. FREQUÊNCIA DE TESTES RÁPIDOS POSITIVOS PARA SARS-COV-2 ENTRE DOADORES DE SANGUE
- Author
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Silva, MB, primary, Boehm, RE, additional, Cohen, CR, additional, Bonacina, F, additional, Farinon, J, additional, Correa, GG, additional, Fontana, C, additional, Corrêa, JARA, additional, Mattos, EMA, additional, Arbo, BD, additional, and Sekine, L, additional
- Published
- 2022
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13. VALIDAÇÃO DO PROTOCOLO DE CENTRIFUGAÇÃO PARA TRIAGEM SOROLÓGICA DE DOADORES DE SANGUE
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Cohen, CR, primary, Boehm, RE, additional, Silva, MB, additional, Bonacina, F, additional, Fontana, C, additional, Farinon, J, additional, and Sekine, L, additional
- Published
- 2022
- Full Text
- View/download PDF
14. Monocarboxylate transporter 1 deficiency impacts CD8 T lymphocytes proliferation and recruitment to adipose tissue during obesity
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Macchi, C, Moregola, A, Greco, MF, Svecla, M, Bonacina, F, Dhup, Suveera, Dadhich, Rakesh K, Audano, M, Sonveaux, Pierre, Mauro, C, Mitro, N, Ruscica, M, Norata, GD, and UCL - SSS/IREC/FATH - Pôle de Pharmacologie et thérapeutique
- Subjects
Proteomics ,Biological sciences ,Immunology ,Metabolomics - Abstract
Lactate sits at the crossroad of metabolism, immunity, and inflammation. The expression of cellular lactate transporter MCT1 (known as Slc16a1) increases during immune cell activation to cope with the metabolic reprogramming. We investigated the impact of MCT1 deficiency on CD8 T cell function during obesity-related inflammatory conditions. The absence of MCT1 impaired CD8 T cell proliferation with a shift of ATP production to mitochondrial oxidative phosphorylation. In mice fed a high-fat diet, a reduction in the number of CD8 T cells, which infiltrated epididymal visceral adipose tissue (epiWAT) or subcutaneous adipose tissue, was observed. Adipose tissue weight and adipocyte area were significantly reduced together with downregulation of adipogenic genes only in the epiWAT. Our findings highlight a distinct effect of MCT1 deficiency in CD8 T cells in the crosstalk with adipocytes and reinforce the concept that targeting immunometabolic reprogramming in lymphocyte could impact the immune-adipose tissue axis in obesity.
- Published
- 2022
15. IMPLEMENTAÇÃO E VALIDAÇÃO DE EQUIPAMENTOS E KITS DE TRIAGEM SOROLÓGICA
- Author
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Cohen, CR, primary, Boehm, RE, additional, Bonacina, F, additional, Silva, MB, additional, Fontana, C, additional, Rosa, AM, additional, and Sekine, L, additional
- Published
- 2021
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16. TAXA DE RETORNO DE CONVOCAÇÃO DE DOADORES DE SANGUE COM SOROLOGIA REAGENTE
- Author
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Boehm, RE, primary, Silva, MB, additional, Cohen, CR, additional, Bonacina, F, additional, Fontana, C, additional, and Sekine, L, additional
- Published
- 2021
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17. REDUÇÃO DA PREVALÊNCIA DE HIV ENTRE DOADORES DE SANGUE NO HOSPITAL DE CLÍNICAS DE PORTO ALEGRE
- Author
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Boehm, RE, primary, Cohen, CR, additional, Bonacina, F, additional, Silva, MB, additional, Fontana, C, additional, and Sekine, L, additional
- Published
- 2021
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18. AVALIAÇÃO DE PROTOCOLOS DE CENTRIFUGAÇÃO PARA TRIAGEM SOROLÓGICA DE DOADORES DE SANGUE
- Author
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Boehm, RE, primary, Silva, MB, additional, Cohen, CR, additional, Bonacina, F, additional, Fontana, C, additional, and Sekine, L, additional
- Published
- 2021
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19. PERFIL DOS DOADORES DE SANGUE DO HOSPITAL DE CLÍNICAS DE PORTO ALEGRE: ANÁLISE DE 2005 A 2020
- Author
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Cohen, CR, primary, Bonacina, F, additional, Boehm, RE, additional, Silva, MB, additional, and Sekine, L, additional
- Published
- 2021
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20. ANÁLISE COMPARATIVA ENTRE DOADORES DE SANGUE QUE SOROCONVERTERAM PARA HIV NO BANCO DE SANGUE DO HOSPITAL DE CLÍNICAS DE PORTO ALEGRE
- Author
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Bonacina, F, primary, Cohen, CR, additional, Boehm, RE, additional, Farinon, J, additional, Silva, MB, additional, Fontana, C, additional, and Sekine, L, additional
- Published
- 2021
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21. Corrigendum to “Vascular pentraxin 3 controls arterial thrombosis by targeting collagen and fibrinogen induced platelets aggregation” [Biochim. Biophys. Acta, 1862 (2016) 1182–1190]
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Bonacina, F., primary, Barbieri, S.S., additional, Cutuli, L., additional, Amadi, P., additional, Don, A., additional, Sironi, M., additional, Tartari, S., additional, Mantovani, A., additional, Bottazzi, B., additional, Garlanda, C., additional, Tremoli, E., additional, Catapano, A.L., additional, and Norata, G.D., additional
- Published
- 2019
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22. 5206PCSK9 deficiency results in altered insulin secretion and glucose intolerance: the role of the LDL-receptor
- Author
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Da Dalt, L, primary, Balzarotti, G, additional, Ruscica, M, additional, Bonacina, F, additional, Macchi, C, additional, Perego, C, additional, Catapano, A L, additional, and Norata, G D, additional
- Published
- 2018
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23. Vascular pentraxin 3 controls arterial thrombosis by targeting collagen and fibrinogen induced platelets aggregation
- Author
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Bonacina, F., primary, Barbieri, S.S., additional, Cutuli, L., additional, Amadio, P., additional, Doni, A., additional, Sironi, M., additional, Tartari, S., additional, Mantovani, A., additional, Bottazzi, B., additional, Garlanda, C., additional, Tremoli, E., additional, Catapano, A.L., additional, and Norata, G.D., additional
- Published
- 2016
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24. HDL in innate and adaptive immunity
- Author
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Catapano, A. L., primary, Pirillo, A., additional, Bonacina, F., additional, and Norata, G. D., additional
- Published
- 2014
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25. A multiple network approach to corporate governance
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Enrico Moretto, Giovanni Zambruno, Fausto Bonacina, Marco D'Errico, Silvana Stefani, Anna Torriero, Bonacina, F, D’Errico, M, Moretto, E, Stefani, S, Torriero, A, Zambruno, G, University of Zurich, and D'Errico, Marco
- Subjects
Statistics and Probability ,Theoretical computer science ,Computer science ,Multiple networks ,Context (language use) ,3300 General Social Sciences ,Social Sciences (all) ,Tensor analysi ,Order (exchange) ,Operations management ,Corporate governance ,Tensor analysis ,SECS-S/06 - METODI MATEMATICI DELL'ECONOMIA E DELLE SCIENZE ATTUARIALI E FINANZIARIE ,Tensor ,2613 Statistics and Probability ,Multiple network ,Structure (mathematical logic) ,Financial market ,Perspective (graphical) ,Univariate ,General Social Sciences ,Settore SECS-S/06 - METODI MATEMATICI DELL'ECONOMIA E DELLE SCIENZE ATTUARIALI E FINANZIARIE ,10003 Department of Banking and Finance ,330 Economics - Abstract
In this work, we consider corporate governance (CG) ties among companies from a multiple network perspective. Such a structure naturally arises from the close interrelation between the Shareholding network and the Board of Directors network. In order to capture the simultaneous effects of both networks on CG, we propose to model the CG multiple network structure via tensor analysis. In particular, we consider the TOPHITS model, based on the PARAFAC tensor decomposition, to show that tensor techniques can be successfully applied in this context. By providing some empirical results from the Italian financial market in the univariate case, we then show that a tensor–based multiple network approach can reveal important information.
- Published
- 2015
26. The optimal generation mix for an electricity producer: the case of Italy
- Author
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BONACINA, FAUSTO, Bonacina, F, and STEFANI, SILVANA
- Subjects
Renewable energy, Energy policy, Portfolio optimization ,SECS-S/06 - METODI MATEMATICI DELL'ECONOMIA E DELLE SCIENZE ATTUARIALI E FINANZIARIE - Abstract
In this work we extend the model of Roques et al. (2008) for the construction of the optimal electricity generation portfolio. In our analysis we consider an electricity producer, who can choose to invest both in renewable and conventional sources. We build portfolios based on the Net Present Value generated by the investment in a particular technology. We use Monte Carlo simulations in order to compute the NPV distributions. As an extension to Roques et al. (2008), we consider the presence of incentives for renewable technologies. We apply our model to Italian data.
- Published
- 2013
27. ASGR1 deficiency diverts lipids toward adipose tissue but results in liver damage during obesity.
- Author
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Svecla M, Da Dalt L, Moregola A, Nour J, Baragetti A, Uboldi P, Donetti E, Arnaboldi L, Beretta G, Bonacina F, and Norata GD
- Subjects
- Animals, Humans, Mice, Adipose Tissue metabolism, Diet, High-Fat, Inflammation metabolism, Lipids, Liver metabolism, Mice, Inbred C57BL, Obesity complications, Asialoglycoprotein Receptor genetics, Metabolic Syndrome complications
- Abstract
Background: Asialoglycoprotein receptor 1 (ASGR1), primarily expressed on hepatocytes, promotes the clearance and the degradation of glycoproteins, including lipoproteins, from the circulation. In humans, loss-of-function variants of ASGR1 are associated with a favorable metabolic profile and reduced incidence of cardiovascular diseases. The molecular mechanisms by which ASGR1 could affect the onset of metabolic syndrome and obesity are unclear. Therefore, here we investigated the contribution of ASGR1 in the development of metabolic syndrome and obesity., Methods: ASGR1 deficient mice (ASGR1
-/- ) were subjected to a high-fat diet (45% Kcal from fat) for 20 weeks. The systemic metabolic profile, hepatic and visceral adipose tissue were characterized for metabolic and structural alterations, as well as for immune cells infiltration., Results: ASGR1-/- mice present a hypertrophic adipose tissue with 41% increase in fat accumulation in visceral adipose tissue (VAT), alongside with alteration in lipid metabolic pathways. Intriguingly, ASGR1-/- mice exhibit a comparable response to an acute glucose and insulin challenge in circulation, coupled with notably decreased in circulating cholesterol levels. Although the liver of ASGR1-/- have similar lipid accumulation to the WT mice, they present elevated levels of liver inflammation and a decrease in mitochondrial function., Conclusion: ASGR1 deficiency impacts energetic homeostasis during obesity leading to improved plasma lipid levels but increased VAT lipid accumulation and liver damage., (© 2024. The Author(s).)- Published
- 2024
- Full Text
- View/download PDF
28. Dendritic cell immunoreceptor 2 (DCIR2) deficiency decreases hepatic conventional dendritic cell content but not the progression of diet-induced obesity.
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Bellini R, Moregola A, Nour J, Uboldi P, Bonacina F, and Norata GD
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- Animals, Mice, Dendritic Cells, Diet, High-Fat adverse effects, Inflammation metabolism, Liver pathology, Insulins metabolism, Obesity etiology, Obesity pathology
- Abstract
Aims: Inflammatory pathways and immune system dysregulation participate in the onset and progression of cardiometabolic diseases. The dendritic cell immunoreceptor 2 (DCIR2) is a C-type lectin receptor mainly expressed by conventional type 2 dendritic cells, involved in antigen recognition and in the modulation of T cell response. Here, we investigated the effect of DCIR2 deficiency during the development of obesity., Methods: DCIR2 KO mice and the WT counterpart were fed with high-fat diet (HFD) for 20 weeks. Weight gain, glucose and insulin tolerance were assessed, parallel to immune cell subset profiling and histological analysis., Results: After HFD feeding, DCIR2 KO mice presented altered conventional dendritic cell distribution within the liver without affecting markers of hepatic inflammation. These observations were liver restricted, since immune profile of metabolic and lymphoid organs-namely adipose tissue, spleen and mesenteric lymph nodes-did not show differences between the two groups. This reflected in a similar metabolic profile of DCIR2 KO compared to WT mice, characterized by comparable body weight gain as well as adipose tissues, spleen, Peyer's patches and mesenteric lymph nodes weight at sacrifice. Also, insulin response was similar in both groups., Conclusion: Our data show that DCIR2 has a redundant role in the progression of diet-induced obesity and inflammation., (© 2023 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)
- Published
- 2023
- Full Text
- View/download PDF
29. Fibronectin extra domain a limits liver dysfunction and protects mice during acute inflammation.
- Author
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Venu VKP, Moregola A, Da Dalt L, Uboldi P, Bonacina F, Muro AF, and Norata GD
- Abstract
Background and Aim: The primary transcript of fibronectin (FN) undergoes alternative splicing to generate different isoforms, including FN containing the Extra Domain A (FN_EDA+), whose expression is regulated spatially and temporarily during developmental and disease conditions including acute inflammation. The role of FN_EDA+ during sepsis, however, remains elusive., Methods: Mice constitutively express the EDA domain of fibronectin (EDA
+/+ ); lacking the FN EDA domain (EDA-/- ) or with a conditional ablation of EDA + inclusion only in liver produced FN (alb-CRE+ EDA floxed mice) thus expressing normal plasma FN were used. Systemic inflammation and sepsis were induced by either LPS injection (70 mg/kg) or by cecal ligation and puncture (CLP) Neutrophils isolated from septic patients were tested for neutrophil binding ability., Results: We observed that EDA+/+ were protected toward sepsis as compared to EDA-/- mice. Also alb-CRE+ EDA floxed mice presented reduced survival, thus indicating a key role for EDA in protecting toward sepsis. This phenotype was associated with improved liver and spleen inflammatory profile. Ex vivo experiments showed that neutrophils bind to a larger extent to an FN_EDA + coated surface as compared to FN, thus potentially limiting their over-reactivity., Conclusions: Our study demonstrates that the inclusion of the EDA domain in fibronectin dampens the nflammatoryi consequences of sepsis., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)- Published
- 2023
- Full Text
- View/download PDF
30. Global patterns and drivers of influenza decline during the COVID-19 pandemic.
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Bonacina F, Boëlle PY, Colizza V, Lopez O, Thomas M, and Poletto C
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- Humans, Pandemics, North America, Weather, Influenza, Human epidemiology, COVID-19 epidemiology
- Abstract
Objectives: The influenza circulation reportedly declined during the COVID-19 pandemic in many countries. The occurrence of this change has not been studied worldwide nor its potential drivers., Methods: The change in the proportion of positive influenza samples reported by country and trimester was computed relative to the 2014-2019 period using the FluNet database. Random forests were used to determine predictors of change from demographical, weather, pandemic preparedness, COVID-19 incidence, and pandemic response characteristics. Regression trees were used to classify observations according to these predictors., Results: During the COVID-19 pandemic, the influenza decline relative to prepandemic levels was global but heterogeneous across space and time. It was more than 50% for 311 of 376 trimesters-countries and even more than 99% for 135. COVID-19 incidence and pandemic preparedness were the two most important predictors of the decline. Europe and North America initially showed limited decline despite high COVID-19 restrictions; however, there was a strong decline afterward in most temperate countries, where pandemic preparedness, COVID-19 incidence, and social restrictions were high; the decline was limited in countries where these factors were low. The "zero-COVID" countries experienced the greatest decline., Conclusion: Our findings set the stage for interpreting the resurgence of influenza worldwide., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
31. Neutral effect of SGLT2 inhibitors on lipoprotein metabolism: From clinical evidence to molecular mechanisms.
- Author
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Osto E, Bonacina F, Pirillo A, and Norata GD
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- Humans, Triglycerides, Cholesterol, LDL, Lipoproteins, Glucose, Sodium-Glucose Transporter 2 Inhibitors therapeutic use, Sodium-Glucose Transporter 2 Inhibitors pharmacology, Diabetes Mellitus, Type 2 drug therapy, Atherosclerosis drug therapy, Cardiovascular Diseases drug therapy, Cardiovascular Diseases prevention & control
- Abstract
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are effective, well-tolerated, and safe glucose-lowering compounds for patients with type 2 diabetes mellitus (T2DM). SGLT2i benefit encompasses protection from heart and kidney failure, independently of the presence of diabetes. In addition, SGLT2i consistently reduce the risk of hospitalization for heart failure and, although with some heterogeneity between specific members of the class, favourably affect the risk of cardiovascular outcomes. The molecular mechanisms underlying the cardiovascular favourable effect are not fully clarified. Studies testing the efficacy of SGLT2i in human cohorts and experimental models of atherosclerotic cardiovascular disease (ASCVD) have reported significant differences in circulating levels and composition of lipoprotein classes. In randomized clinical trials, small but significant increases in low-density lipoprotein cholesterol (LDL-C) levels have been observed, with a still undefined clinical significance; on the other hand, favourable (although modest) effects on high-density lipoprotein cholesterol (HDL-C) and triglycerides have been reported. At the molecular level, glycosuria may promote a starving-like state that ultimately leads to a metabolic improvement through the mobilization of fatty acids from the adipose tissue and their oxidation for the production of ketone bodies. This, however, may also fuel hepatic cholesterol synthesis, thus inhibiting atherogenic lipoprotein uptake from the liver. Long-term studies collecting detailed information on lipid-lowering therapies at baseline and during the trials with SGLT2i, as well as regularly monitoring lipid profiles are warranted to disentangle the potential implications of SGLT2i in modulating lipoprotein-mediated atherosclerotic cardiovascular risk., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2023
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32. Vinculin phosphorylation modulates endothelial cell permeability: a new target for cardiovascular disease?
- Author
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Bonacina F and Danilo Norata G
- Subjects
- Humans, Phosphorylation, Vinculin metabolism, Endothelial Cells metabolism, Permeability, Cardiovascular Diseases, Atherosclerosis
- Abstract
Competing Interests: Conflict of interest: The authors declare to have not any conflict of interest.
- Published
- 2023
- Full Text
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33. Dendritic cell marker Clec4a4 deficiency limits atherosclerosis progression.
- Author
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Bellini R, Moregola A, Nour J, Rombouts Y, Neyrolles O, Uboldi P, Bonacina F, and Norata GD
- Abstract
Background and Aims: Atherogenesis results from altered lipid metabolism and impaired immune response. Emerging evidence has suggested that dendritic cells (DCs) participate to atherosclerosis-related immune response, but their impact is scarcely characterized. Clec4a4 or DCIR2 (Dendritic cell immunoreceptor 2) is a C-type lectin receptor, mainly expressed by CD8α
- DCs, able to modulate T cell immunity. However, whether this DC subset could play a role in the atherogenesis is still poorly understood. Thus, the aim of this study is to investigate whether the absence of Clec4a4 could affect atherosclerosis-related immune response and atherosclerosis itself., Methods: Dcir2-/- Ldlr-/- and Ldlr-/- mice were fed a standard diet or cholesterol-enriched diet for 12 weeks. Subsequently, the profile of circulating and lymph nodes-resident immune cells was investigated together with the analysis of plasma lipid levels and atherosclerotic plaque extension in the aorta., Results: Here, we show that Clec4a4 expression is downregulated under hypercholesterolemia and its deficiency in Ldlr-/- mice results in the reduction of atherosclerotic plaque formation, together with altered lipid metabolism and impaired myeloid immune cell distribution., Conclusions: Our findings suggest a pro-atherosclerotic role of Clec4a4 in experimental atherosclerosis., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)- Published
- 2022
- Full Text
- View/download PDF
34. Mannose Receptor Deficiency Impacts Bone Marrow and Circulating Immune Cells during High Fat Diet Induced Obesity.
- Author
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Nour J, Moregola A, Svecla M, Da Dalt L, Bellini R, Neyrolles O, Fadini GP, Rombouts Y, Albiero M, Bonacina F, and Norata GD
- Abstract
The mannose receptor C-type 1 (Mrc1) is a C-type lectin receptor expressed on the immune cells and sinusoidal endothelial cells (ECs) of several tissues, including the bone marrow (BM). Parallel to systemic metabolic alterations and hematopoietic cell proliferation, high-fat diet (HFD) feeding increases the expression of Mrc1 in sinusoidal ECs, thus calling for the investigation of its role in bone marrow cell reprogramming and the metabolic profile during obesity. Mrc1
-/- mice and wild-type (WT) littermates were fed an HFD (45% Kcal/diet) for 20 weeks. Weight gain was monitored during the diet regimen and glucose and insulin tolerance were assessed. Extensive flow cytometry profiling, histological, and proteomic analyses were performed. After HFD feeding, Mrc1-/- mice presented impaired medullary hematopoiesis with reduced myeloid progenitors and mature cells in parallel with an increase in BM adipocytes compared to controls. Accordingly, circulating levels of neutrophils and pro-inflammatory monocytes decreased in Mrc1-/- mice together with reduced infiltration of macrophages in the visceral adipose tissue and the liver compared to controls. Liver histological profiling coupled with untargeted proteomic analysis revealed that Mrc1-/- mice presented decreased liver steatosis and the downregulation of proteins belonging to pathways involved in liver dysfunction. This profile was reflected by improved glucose and insulin response and reduced weight gain during HFD feeding in Mrc1-/- mice compared to controls. Our data show that during HFD feeding, mannose receptor deficiency impacts BM and circulating immune cell subsets, which is associated with reduced systemic inflammation and resistance to obesity development., Competing Interests: The authors declare no conflict of interest.- Published
- 2022
- Full Text
- View/download PDF
35. The low-density lipoprotein receptor-mTORC1 axis coordinates CD8+ T cell activation.
- Author
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Bonacina F, Moregola A, Svecla M, Coe D, Uboldi P, Fraire S, Beretta S, Beretta G, Pellegatta F, Catapano AL, Marelli-Berg FM, and Norata GD
- Subjects
- Animals, Cytokines metabolism, Granzymes metabolism, Humans, Hyperlipoproteinemia Type II, Interferon-gamma metabolism, Mice, Mice, Knockout, Perforin, RNA, Messenger genetics, CD8-Positive T-Lymphocytes metabolism, Cholesterol metabolism, Lymphocyte Activation, Mechanistic Target of Rapamycin Complex 1 genetics, Mechanistic Target of Rapamycin Complex 1 metabolism, Receptors, LDL genetics, Receptors, LDL metabolism
- Abstract
Activation of T cells relies on the availability of intracellular cholesterol for an effective response after stimulation. We investigated the contribution of cholesterol derived from extracellular uptake by the low-density lipoprotein (LDL) receptor in the immunometabolic response of T cells. By combining proteomics, gene expression profiling, and immunophenotyping, we described a unique role for cholesterol provided by the LDLR pathway in CD8+ T cell activation. mRNA and protein expression of LDLR was significantly increased in activated CD8+ compared to CD4+ WT T cells, and this resulted in a significant reduction of proliferation and cytokine production (IFNγ, Granzyme B, and Perforin) of CD8+ but not CD4+ T cells from Ldlr -/- mice after in vitro and in vivo stimulation. This effect was the consequence of altered cholesterol routing to the lysosome resulting in a lower mTORC1 activation. Similarly, CD8+ T cells from humans affected by familial hypercholesterolemia (FH) carrying a mutation on the LDLR gene showed reduced activation after an immune challenge., (© 2022 Bonacina et al.)
- Published
- 2022
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36. Crosstalk between dendritic cells and T lymphocytes during atherogenesis: Focus on antigen presentation and break of tolerance.
- Author
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Bellini R, Bonacina F, and Norata GD
- Abstract
Atherosclerosis is a chronic disease resulting from an impaired lipid and immune homeostasis, where the interaction between innate and adaptive immune cells leads to the promotion of atherosclerosis-associated immune-inflammatory response. Emerging evidence has suggested that this response presents similarities to the reactivity of effector immune cells toward self-epitopes, often as a consequence of a break of tolerance . In this context, dendritic cells, a heterogeneous population of antigen presenting cells, play a key role in instructing effector T cells to react against foreign antigens and T regulatory cells to maintain tolerance against self-antigens and/or to patrol for self-reactive effector T cells. Alterations in this delicate balance appears to contribute to atherogenesis. The aim of this review is to discuss different DC subsets, and their role in atherosclerosis as well as in T cell polarization. Moreover, we will discuss how loss of T cell tolerogenic phenotype participates to the immune-inflammatory response associated to atherosclerosis and how a better understanding of these mechanisms might result in designing immunomodulatory therapies targeting DC-T cell crosstalk for the treatment of atherosclerosis-related inflammation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bellini, Bonacina and Norata.)
- Published
- 2022
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37. Lack of ApoA-I in ApoEKO Mice Causes Skin Xanthomas, Worsening of Inflammation, and Increased Coronary Atherosclerosis in the Absence of Hyperlipidemia.
- Author
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Busnelli M, Manzini S, Colombo A, Franchi E, Bonacina F, Chiara M, Arnaboldi F, Donetti E, Ambrogi F, Oleari R, Lettieri A, Horner D, Scanziani E, Norata GD, and Chiesa G
- Subjects
- Animals, Apolipoprotein A-I, Apolipoproteins E genetics, Cholesterol metabolism, Inflammation complications, Inflammation genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Atherosclerosis metabolism, Coronary Artery Disease complications, Coronary Artery Disease genetics, Hyperlipidemias complications, Hyperlipidemias genetics, Xanthomatosis
- Abstract
Background: HDL (high-density lipoprotein) and its major protein component, apoA-I (apolipoprotein A-I), play a unique role in cholesterol homeostasis and immunity. ApoA-I deficiency in hyperlipidemic, atheroprone mice was shown to drive cholesterol accumulation and inflammatory cell activation/proliferation. The present study was aimed at investigating the impact of apoA-I deficiency on lipid deposition and local/systemic inflammation in normolipidemic conditions., Methods: ApoE deficient mice, apoE/apoA-I double deficient (DKO) mice, DKO mice overexpressing human apoA-I, and C57Bl/6J control mice were fed normal laboratory diet until 30 weeks of age. Plasma lipids were quantified, atherosclerosis development at the aortic sinus and coronary arteries was measured, skin ultrastructure was evaluated by electron microscopy. Blood and lymphoid organs were characterized through histological, immunocytofluorimetric, and whole transcriptome analyses., Results: DKO were characterized by almost complete HDL deficiency and by plasma total cholesterol levels comparable to control mice. Only DKO showed xanthoma formation and severe inflammation in the skin-draining lymph nodes, whose transcriptome analysis revealed a dramatic impairment in energy metabolism and fatty acid oxidation pathways. An increased presence of CD4
+ T effector memory cells was detected in blood, spleen, and skin-draining lymph nodes of DKO. A worsening of atherosclerosis at the aortic sinus and coronary arteries was also observed in DKO versus apoE deficient. Human apoA-I overexpression in the DKO background was able to rescue the skin phenotype and halt atherosclerosis development., Conclusions: HDL deficiency, in the absence of hyperlipidemia, is associated with severe alterations of skin morphology, aortic and coronary atherosclerosis, local and systemic inflammation.- Published
- 2022
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38. Loss of voltage-gated hydrogen channel 1 expression reveals heterogeneous metabolic adaptation to intracellular acidification by T cells.
- Author
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Coe D, Poobalasingam T, Fu H, Bonacina F, Wang G, Morales V, Moregola A, Mitro N, Cheung KC, Ward EJ, Nadkarni S, Aksentijevic D, Bianchi K, Norata GD, Capasso M, and Marelli-Berg FM
- Subjects
- Hydrogen-Ion Concentration, Lymphocyte Count, Signal Transduction, Hydrogen, Protons
- Abstract
Voltage-gated hydrogen channel 1 (Hvcn1) is a voltage-gated proton channel, which reduces cytosol acidification and facilitates the production of ROS. The increased expression of this channel in some cancers has led to proposing Hvcn1 antagonists as potential therapeutics. While its role in most leukocytes has been studied in depth, the function of Hvcn1 in T cells remains poorly defined. We show that Hvcn1 plays a nonredundant role in protecting naive T cells from intracellular acidification during priming. Despite sharing overall functional impairment in vivo and in vitro, Hvcn1-deficient CD4+ and CD8+ T cells display profound differences during the transition from naive to primed T cells, including in the preservation of T cell receptor (TCR) signaling, cellular division, and death. These selective features result, at least in part, from a substantially different metabolic response to intracellular acidification associated with priming. While Hvcn1-deficient naive CD4+ T cells reprogram to rescue the glycolytic pathway, naive CD8+ T cells, which express high levels of this channel in the mitochondria, respond by metabolically compensating mitochondrial dysfunction, at least in part via AMPK activation. These observations imply heterogeneity between adaptation of naive CD4+ and CD8+ T cells to intracellular acidification during activation.
- Published
- 2022
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39. PCSK9 deficiency rewires heart metabolism and drives heart failure with preserved ejection fraction.
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Da Dalt L, Castiglioni L, Baragetti A, Audano M, Svecla M, Bonacina F, Pedretti S, Uboldi P, Benzoni P, Giannetti F, Barbuti A, Pellegatta F, Indino S, Donetti E, Sironi L, Mitro N, Catapano AL, and Norata GD
- Subjects
- Animals, Male, Mice, Mice, Knockout, Receptors, LDL genetics, Stroke Volume, Heart Failure genetics, Proprotein Convertase 9 genetics
- Abstract
Aims: PCSK9 is secreted into the circulation, mainly by the liver, and interacts with low-density lipoprotein receptor (LDLR) homologous and non-homologous receptors, including CD36, thus favouring their intracellular degradation. As PCSK9 deficiency increases the expression of lipids and lipoprotein receptors, thus contributing to cellular lipid accumulation, we investigated whether this could affect heart metabolism and function., Methods and Results: Wild-type (WT), Pcsk9 KO, Liver conditional Pcsk9 KO and Pcsk9/Ldlr double KO male mice were fed for 20 weeks with a standard fat diet and then exercise resistance, muscle strength, and heart characteristics were evaluated. Pcsk9 KO presented reduced running resistance coupled to echocardiographic abnormalities suggestive of heart failure with preserved ejection fraction (HFpEF). Heart mitochondrial activity, following maximal coupled and uncoupled respiration, was reduced in Pcsk9 KO mice compared to WT mice and was coupled to major changes in cardiac metabolism together with increased expression of LDLR and CD36 and with lipid accumulation. A similar phenotype was observed in Pcsk9/Ldlr DKO, thus excluding a contribution for LDLR to cardiac impairment observed in Pcsk9 KO mice. Heart function profiling of the liver selective Pcsk9 KO model further excluded the involvement of circulating PCSK9 in the development of HFpEF, pointing to a possible role locally produced PCSK9. Concordantly, carriers of the R46L loss-of-function variant for PCSK9 presented increased left ventricular mass but similar ejection fraction compared to matched control subjects., Conclusion: PCSK9 deficiency impacts cardiac lipid metabolism in an LDLR independent manner and contributes to the development of HFpEF., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)
- Published
- 2021
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40. Purification and In Vitro Evaluation of an Anti-HER2 Affibody-Monomethyl Auristatin E Conjugate in HER2-Positive Cancer Cells.
- Author
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Damiani I, Castiglioni S, Sochaj-Gregorczyk A, Bonacina F, Colombo I, Rusconi V, Otlewski J, Corsini A, and Bellosta S
- Abstract
A promising approach for the development of high-affinity tumor targeting ADCs is the use of engineered protein drugs, such as affibody molecules, which represent a valuable alternative to monoclonal antibodies (mAbs) in cancer-targeted therapy. We developed a method for a more efficient purification of the Z
HER2:2891 DCS affibody conjugated with the cytotoxic antimitotic agent auristatin E (MMAE), and its efficacy was tested in vitro on cell viability, proliferation, migration, and apoptosis. The effects of ZHER2:2891 DCS-MMAE were compared with the clinically approved monoclonal antibody trastuzumab (Herceptin® ). To demonstrate that ZHER2:2891 DCS-MMAE can selectively target HER2 overexpressing tumor cells, we used three different cell lines: the human adenocarcinoma cell lines SK-BR-3 and ZR-75-1, both overexpressing HER2, and the triple-negative breast cancer cell line MDA-MB-231. MTT assay showed that ZHER2:2891 DCS-MMAE induces a significant time-dependent toxic effect in SK-BR-3 cells. A 30% reduction of cell viability was already found after 10 min exposure at a concentration of 7 nM (IC50 of 80.2 nM). On the contrary, MDA-MB-231 cells, which express basal levels of HER2, were not affected by the conjugate. The cytotoxic effect of the ZHER2:2891 DCS-MMAE was confirmed by measuring apoptosis by flow cytometry. In SK-BR-3 cells, increasing concentrations of conjugated affibody induced cell death starting from 10 min of treatment, with the strongest effect observed after 48 h. Overall, these results demonstrate that the ADC, formed by the anti-HER2 affibody conjugated to monomethyl auristatin E, efficiently interacts with high affinity with HER2 positive cancer cells in vitro, allowing the selective and specific delivery of the cytotoxic payload.- Published
- 2021
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41. Adoptive transfer of CX3CR1 transduced-T regulatory cells improves homing to the atherosclerotic plaques and dampens atherosclerosis progression.
- Author
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Bonacina F, Martini E, Svecla M, Nour J, Cremonesi M, Beretta G, Moregola A, Pellegatta F, Zampoleri V, Catapano AL, Kallikourdis M, and Norata GD
- Subjects
- Adult, Animals, Aortic Diseases immunology, Aortic Diseases metabolism, Aortic Diseases pathology, Atherosclerosis immunology, Atherosclerosis metabolism, Atherosclerosis pathology, CX3C Chemokine Receptor 1 genetics, Cells, Cultured, Disease Models, Animal, Disease Progression, Female, Humans, Hyperlipoproteinemia Type II immunology, Hyperlipoproteinemia Type II metabolism, Male, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Prospective Studies, Receptors, LDL genetics, Receptors, LDL metabolism, Retrospective Studies, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory metabolism, Mice, Adoptive Transfer, Aortic Diseases prevention & control, Atherosclerosis prevention & control, CX3C Chemokine Receptor 1 metabolism, Genetic Therapy, Plaque, Atherosclerotic, T-Lymphocytes, Regulatory transplantation, Transduction, Genetic
- Abstract
Aim: Loss of immunosuppressive response supports inflammation during atherosclerosis. We tested whether adoptive cell therapy (ACT) with Tregulatory cells (Tregs), engineered to selectively migrate in the atherosclerotic plaque, would dampen the immune-inflammatory response in the arterial wall in animal models of familial hypercholesterolaemia (FH)., Methods and Results: FH patients presented a decreased Treg suppressive function associated to an increased inflammatory burden. A similar phenotype was observed in Ldlr -/- mice accompanied by a selective increased expression of the chemokine CX3CL1 in the aorta but not in other districts (lymph nodes, spleen, and liver). Treg overexpressing CX3CR1 were thus generated (CX3CR1+-Tregs) to drive Tregs selectively to the plaque. CX3CR1+-Tregs were injected (i.v.) in Ldlr -/- fed high-cholesterol diet (western type diet, WTD) for 8 weeks. CX3CR1+-Tregs were detected in the aorta, but not in other tissues, of Ldlr -/- mice 24 h after ACT, corroborating the efficacy of this approach. After 4 additional weeks of WTD, ACT with CX3CR1+-Tregs resulted in reduced plaque progression and lipid deposition, ameliorated plaque stability by increasing collagen and smooth muscle cells content, while decreasing the number of pro-inflammatory macrophages. Shotgun proteomics of the aorta showed a metabolic rewiring in CX3CR1+-Tregs treated Ldlr -/- mice compared to controls that was associated with the improvement of inflammation-resolving pathways and disease progression., Conclusion: ACT with vasculotropic Tregs appears as a promising strategy to selectively target immune activation in the atherosclerotic plaque., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2021
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- View/download PDF
42. HDL in Immune-Inflammatory Responses: Implications beyond Cardiovascular Diseases.
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Bonacina F, Pirillo A, Catapano AL, and Norata GD
- Subjects
- Animals, Humans, Immune System Diseases genetics, Immunity, Innate, Lymphocytes immunology, Macrophages immunology, Cardiovascular Diseases metabolism, Immune System Diseases immunology, Lipoproteins, HDL immunology
- Abstract
High density lipoproteins (HDL) are heterogeneous particles composed by a vast array of proteins and lipids, mostly recognized for their cardiovascular (CV) protective effects. However, evidences from basic to clinical research have contributed to depict a role of HDL in the modulation of immune-inflammatory response thus paving the road to investigate their involvement in other diseases beyond those related to the CV system. HDL-C levels and HDL composition are indeed altered in patients with autoimmune diseases and usually associated to disease severity. At molecular levels, HDL have been shown to modulate the anti-inflammatory potential of endothelial cells and, by controlling the amount of cellular cholesterol, to interfere with the signaling through plasma membrane lipid rafts in immune cells. These findings, coupled to observations acquired from subjects carrying mutations in genes related to HDL system, have helped to elucidate the contribution of HDL beyond cholesterol efflux thus posing HDL-based therapies as a compelling interventional approach to limit the inflammatory burden of immune-inflammatory diseases.
- Published
- 2021
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43. Caloric Restriction Promotes Immunometabolic Reprogramming Leading to Protection from Tuberculosis.
- Author
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Palma C, La Rocca C, Gigantino V, Aquino G, Piccaro G, Di Silvestre D, Brambilla F, Rossi R, Bonacina F, Lepore MT, Audano M, Mitro N, Botti G, Bruzzaniti S, Fusco C, Procaccini C, De Rosa V, Galgani M, Alviggi C, Puca A, Grassi F, Rezzonico-Jost T, Norata GD, Mauri P, Netea MG, de Candia P, and Matarese G
- Subjects
- Animals, Caloric Restriction, Female, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Mycobacterium tuberculosis immunology, Mycobacterium tuberculosis metabolism, Tuberculosis immunology, Tuberculosis metabolism, Tuberculosis prevention & control
- Abstract
There is a strong relationship between metabolic state and susceptibility to Mycobacterium tuberculosis (MTB) infection, with energy metabolism setting the basis for an exaggerated immuno-inflammatory response, which concurs with MTB pathogenesis. Herein, we show that controlled caloric restriction (CR), not leading to malnutrition, protects susceptible DBA/2 mice against pulmonary MTB infection by reducing bacterial load, lung immunopathology, and generation of foam cells, an MTB reservoir in lung granulomas. Mechanistically, CR induced a metabolic shift toward glycolysis, and decreased both fatty acid oxidation and mTOR activity associated with induction of autophagy in immune cells. An integrated multi-omics approach revealed a specific CR-induced metabolomic, transcriptomic, and proteomic signature leading to reduced lung damage and protective remodeling of lung interstitial tightness able to limit MTB spreading. Our data propose CR as a feasible immunometabolic manipulation to control MTB infection, and this approach offers an unexpected strategy to boost immunity against MTB., Competing Interests: Declaration of Interests Authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2021
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44. Fenretinide treatment accelerates atherosclerosis development in apoE-deficient mice in spite of beneficial metabolic effects.
- Author
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Busnelli M, Manzini S, Bonacina F, Soldati S, Barbieri SS, Amadio P, Sandrini L, Arnaboldi F, Donetti E, Laaksonen R, Paltrinieri S, Scanziani E, and Chiesa G
- Subjects
- Animals, Aorta metabolism, Aorta pathology, Aortic Diseases genetics, Aortic Diseases metabolism, Aortic Diseases pathology, Atherosclerosis genetics, Atherosclerosis metabolism, Atherosclerosis pathology, Blood Glucose drug effects, Blood Glucose metabolism, Diet, Western, Disease Models, Animal, Disease Progression, Female, Lipids blood, Liver drug effects, Liver metabolism, Liver pathology, Mice, Inbred C57BL, Mice, Knockout, ApoE, Plaque, Atherosclerotic, Spleen drug effects, Spleen metabolism, Spleen pathology, Weight Loss drug effects, Antineoplastic Agents toxicity, Aorta drug effects, Aortic Diseases chemically induced, Atherosclerosis chemically induced, Energy Metabolism drug effects, Fenretinide toxicity
- Abstract
Background and Purpose: Fenretinide, a synthetic retinoid derivative first investigated for cancer prevention and treatment, has been shown to ameliorate glucose tolerance, improve plasma lipid profile and reduce body fat mass. These effects, together with its ability to inhibit ceramide synthesis, suggest that fenretinide may have an anti-atherosclerotic action., Experimental Approach: To this aim, nine-week-old apoE-knockout (EKO) female mice were fed for twelve weeks a Western diet, without (control) or with (0.1% w/w) fenretinide. As a reference, wild-type (WT) mice were treated similarly. Growth and metabolic parameters were monitored throughout the study. Atherosclerosis development was evaluated in the aorta and at the aortic sinus. Blood and lymphoid organs were further characterized with thorough cytological/histological and immunocytofluorimetric analyses., Key Results: Fenretinide treatment significantly lowered body weight, glucose levels and plasma levels of total cholesterol, triglycerides, and phospholipids. In the liver, fenretinide remarkably reduced hepatic glycogenosis and steatosis driven by the Western diet. Treated spleens were abnormally enlarged, with severe follicular atrophy and massive extramedullary haematopoiesis. Severe renal hemosiderin deposition was observed in treated EKO mice. Treatment resulted in a threefold increase of total leukocytes (WT and EKO) and raised the activated/resting monocyte ratio in EKO mice. Finally, atherosclerosis development was markedly increased at the aortic arch, thoracic and abdominal aorta of fenretinide-treated mice., Conclusions and Implications: We provide the first evidence that, despite beneficial metabolic effects, fenretinide treatment may enhance the development of atherosclerosis., (© 2019 The British Pharmacological Society.)
- Published
- 2020
- Full Text
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45. Pentraxin 3 deficiency protects from the metabolic inflammation associated to diet-induced obesity.
- Author
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Bonacina F, Moregola A, Porte R, Baragetti A, Bonavita E, Salatin A, Grigore L, Pellegatta F, Molgora M, Sironi M, Barbati E, Mantovani A, Bottazzi B, Catapano AL, Garlanda C, and Norata GD
- Subjects
- Adipogenesis, Adiposity, Aged, Animals, C-Reactive Protein genetics, Cell Plasticity, Cells, Cultured, Disease Models, Animal, Female, Haplotypes, Humans, Inflammation immunology, Inflammation metabolism, Inflammation physiopathology, Inflammation Mediators immunology, Intra-Abdominal Fat immunology, Macrophages immunology, Macrophages metabolism, Male, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Neovascularization, Physiologic, Nerve Tissue Proteins genetics, Obesity immunology, Obesity physiopathology, Obesity, Abdominal epidemiology, Obesity, Abdominal genetics, Obesity, Abdominal physiopathology, Phenotype, Serum Amyloid P-Component genetics, Signal Transduction, Subcutaneous Fat immunology, Weight Gain, C-Reactive Protein deficiency, Diet, High-Fat, Energy Metabolism, Immunity, Innate, Inflammation prevention & control, Inflammation Mediators metabolism, Intra-Abdominal Fat blood supply, Intra-Abdominal Fat metabolism, Nerve Tissue Proteins deficiency, Obesity metabolism, Subcutaneous Fat blood supply, Subcutaneous Fat metabolism
- Abstract
Aims: Low-grade chronic inflammation characterizes obesity and metabolic syndrome. Here, we aim at investigating the impact of the acute-phase protein long pentraxin 3 (PTX3) on the immune-inflammatory response occurring during diet-induced obesity., Methods and Results: PTX3 deficiency in mice fed a high-fat diet for 20 weeks protects from weight gain and adipose tissue deposition in visceral and subcutaneous depots. This effect is not related to changes in glucose homeostasis and lipid metabolism but is associated with an improved immune cell phenotype in the adipose tissue of Ptx3 deficient animals, which is characterized by M2-macrophages polarization and increased angiogenesis. These findings are recapitulated in humans where carriers of a PTX3 haplotype (PTX3 h2/h2 haplotype), resulting in lower PTX3 plasma levels, presented with a reduced prevalence of obesity and decreased abdominal adiposity compared with non-carriers., Conclusion: Our results support a critical role for PTX3 in the onset of obesity by promoting inflammation and limiting adipose tissue vascularization and delineate PTX3 targeting as a valuable strategy for the treatment of adipose tissue-associated inflammatory response., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2019
- Full Text
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46. Immunometabolic function of cholesterol in cardiovascular disease and beyond.
- Author
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Yvan-Charvet L, Bonacina F, Guinamard RR, and Norata GD
- Subjects
- Animals, Cardiovascular Diseases metabolism, Cardiovascular Diseases physiopathology, Cardiovascular System metabolism, Cardiovascular System physiopathology, Cholesterol metabolism, Humans, Immune System metabolism, Immune System physiopathology, Inflammation metabolism, Inflammation physiopathology, Inflammation Mediators metabolism, Signal Transduction, Cardiovascular Diseases immunology, Cardiovascular System immunology, Cholesterol immunology, Energy Metabolism immunology, Immune System immunology, Immunomodulation, Inflammation immunology, Inflammation Mediators immunology
- Abstract
Inflammation represents the driving feature of many diseases, including atherosclerosis, cancer, autoimmunity and infections. It is now established that metabolic processes shape a proper immune response and within this context the alteration in cellular cholesterol homeostasis has emerged as a culprit of many metabolic abnormalities observed in chronic inflammatory diseases. Cholesterol accumulation supports the inflammatory response of myeloid cells (i.e. augmentation of toll-like receptor signalling, inflammasome activation, and production of monocytes and neutrophils) which is beneficial in the response to infections, but worsens diseases associated with chronic metabolic inflammation including atherosclerosis. In addition to the innate immune system, cells of adaptive immunity, upon activation, have also been shown to undergo a reprogramming of cellular cholesterol metabolism, which results in the amplification of inflammatory responses. Aim of this review is to discuss (i) the molecular mechanisms linking cellular cholesterol metabolism to specific immune functions; (ii) how cellular cholesterol accumulation sustains chronic inflammatory diseases such as atherosclerosis; (iii) the immunometabolic profile of patients with defects of genes affecting cholesterol metabolism including familial hypercholesterolaemia, cholesteryl ester storage disease, Niemann-Pick type C, and immunoglobulin D syndrome/mevalonate kinase deficiency. Available data indicate that cholesterol immunometabolism plays a key role in directing immune cells function and set the stage for investigating the repurposing of existing 'metabolic' drugs to modulate the immune response., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2019
- Full Text
- View/download PDF
47. Comparison of Two Ginkgo biloba L. Extracts on Oxidative Stress and Inflammation Markers in Human Endothelial Cells.
- Author
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Piazza S, Pacchetti B, Fumagalli M, Bonacina F, Dell'Agli M, and Sangiovanni E
- Subjects
- Acetone, Active Transport, Cell Nucleus, Anti-Inflammatory Agents pharmacology, Antioxidants pharmacology, Atherosclerosis drug therapy, Cyclic AMP metabolism, E-Selectin metabolism, Ethanol, Gene Expression Regulation, Ginkgo biloba, Human Umbilical Vein Endothelial Cells metabolism, Humans, Inflammation drug therapy, NF-kappa B metabolism, Phosphorylation, Reactive Oxygen Species metabolism, Tumor Necrosis Factor-alpha metabolism, Vascular Cell Adhesion Molecule-1 metabolism, Endothelium, Vascular drug effects, Human Umbilical Vein Endothelial Cells drug effects, Oxidative Stress drug effects, Plant Extracts pharmacology
- Abstract
Atherosclerosis is characterized by interaction between immune and vascular endothelial cells which is mediated by adhesion molecules occurring on the surface of the vascular endothelium leading to massive release of proinflammatory mediators. Ginkgo biloba L. (Ginkgoaceae) standardized extracts showing beneficial effects are commonly prepared by solvent extraction, and acetone is used according to the European Pharmacopoeia recommendations; the well-known Ginkgo biloba acetone extract EGb761® is the most clinically investigated. However, in some countries, the allowed amount of solvent is limited to ethanol, thus implying that the usage of a standardized Ginkgo biloba ethanol extract may be preferred in all those cases, such as for food supplements. The present paper investigates if ethanol and acetone extracts, with comparable standardization, may be considered comparable in terms of biological activity, focusing on the radical scavenging and anti-inflammatory activities. Both the extracts showed high inhibition of TNF α -induced VCAM-1 release (41.1-43.9 μ g/mL), which was partly due to the NF- κ B pathway impairment. Besides ROS decrease, cAMP increase following treatment with ginkgo extracts was addressed and proposed as further molecular mechanism responsible for the inhibition of endothelial E-selectin. No statistical difference was observed between the extracts. The present study demonstrates for the first time that ethanol and acetone extracts show comparable biological activities in human endothelial cell, thus providing new insights into the usage of ethanol extracts in those countries where restrictions in amount of acetone are present.
- Published
- 2019
- Full Text
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48. PCSK9 deficiency reduces insulin secretion and promotes glucose intolerance: the role of the low-density lipoprotein receptor.
- Author
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Da Dalt L, Ruscica M, Bonacina F, Balzarotti G, Dhyani A, Di Cairano E, Baragetti A, Arnaboldi L, De Metrio S, Pellegatta F, Grigore L, Botta M, Macchi C, Uboldi P, Perego C, Catapano AL, and Norata GD
- Subjects
- Animals, Apoptosis, Diabetes Mellitus, Type 2 metabolism, Diabetes Mellitus, Type 2 pathology, Mice, Mice, Knockout, Pancreas metabolism, Pancreas pathology, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2 genetics, Glucose Intolerance metabolism, Insulin Secretion physiology, Proprotein Convertase 9 metabolism, Receptors, LDL metabolism
- Abstract
Aims: PCSK9 loss of function genetic variants are associated with lower low-density lipoprotein cholesterol but also with higher plasma glucose levels and increased risk of Type 2 diabetes mellitus. Here, we investigated the molecular mechanisms underlying this association., Methods and Results: Pcsk9 KO, WT, Pcsk9/Ldlr double KO (DKO), Ldlr KO, albumin AlbCre+/Pcsk9LoxP/LoxP (liver-selective Pcsk9 knock-out mice), and AlbCre-/Pcsk9LoxP/LoxP mice were used. GTT, ITT, insulin and C-peptide plasma levels, pancreas morphology, and cholesterol accumulation in pancreatic islets were studied in the different animal models. Glucose clearance was significantly impaired in Pcsk9 KO mice fed with a standard or a high-fat diet for 20 weeks compared with WT animals; insulin sensitivity, however, was not affected. A detailed analysis of pancreas morphology of Pcsk9 KO mice vs. controls revealed larger islets with increased accumulation of cholesteryl esters, paralleled by increased insulin intracellular levels and decreased plasma insulin, and C-peptide levels. This phenotype was completely reverted in Pcsk9/Ldlr DKO mice implying the low-density lipoprotein receptor (LDLR) as the proprotein convertase subtilisin/kexin Type 9 (PCSK9) target responsible for the phenotype observed. Further studies in albumin AlbCre+/Pcsk9LoxP/LoxP mice, which lack detectable circulating PCSK9, also showed a complete recovery of the phenotype, thus indicating that circulating, liver-derived PCSK9, the principal target of monoclonal antibodies, does not impact beta-cell function and insulin secretion., Conclusion: PCSK9 critically controls LDLR expression in pancreas perhaps contributing to the maintenance of a proper physiological balance to limit cholesterol overload in beta cells. This effect is independent of circulating PCSK9 and is probably related to locally produced PCSK9.
- Published
- 2019
- Full Text
- View/download PDF
49. Author Correction: Cluster-assembled zirconia substrates promote long-term differentiation and functioning of human islets of Langerhans.
- Author
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Galli A, Maffioli E, Sogne E, Moretti S, Di Cairano ES, Negri A, Nonnis S, Norata GD, Bonacina F, Borghi F, Podestà A, Bertuzzi F, Milani P, Lenardi C, Tedeschi G, and Perego C
- Abstract
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
- Published
- 2018
- Full Text
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50. Myeloid apolipoprotein E controls dendritic cell antigen presentation and T cell activation.
- Author
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Bonacina F, Coe D, Wang G, Longhi MP, Baragetti A, Moregola A, Garlaschelli K, Uboldi P, Pellegatta F, Grigore L, Da Dalt L, Annoni A, Gregori S, Xiao Q, Caruso D, Mitro N, Catapano AL, Marelli-Berg FM, and Norata GD
- Subjects
- Animals, Apolipoprotein E4 genetics, Bone Marrow Cells cytology, Cell Differentiation, Cell Movement, Cholesterol metabolism, Dendritic Cells cytology, Fatty Acids metabolism, Female, Hematopoietic Stem Cells cytology, Histocompatibility Antigens Class II, Humans, Hypercholesterolemia metabolism, Major Histocompatibility Complex, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Oxysterols chemistry, Oxysterols metabolism, Phospholipids chemistry, Antigen Presentation, Apolipoproteins E genetics, Dendritic Cells metabolism, Lymphocyte Activation, Myeloid Cells metabolism, T-Lymphocytes metabolism
- Abstract
Cholesterol homeostasis has a pivotal function in regulating immune cells. Here we show that apolipoprotein E (apoE) deficiency leads to the accumulation of cholesterol in the cell membrane of dendritic cells (DC), resulting in enhanced MHC-II-dependent antigen presentation and CD4
+ T-cell activation. Results from WT and apoE KO bone marrow chimera suggest that apoE from cells of hematopoietic origin has immunomodulatory functions, regardless of the onset of hypercholesterolemia. Humans expressing apoE4 isoform (ε4/3-ε4/4) have increased circulating levels of activated T cells compared to those expressing WT apoE3 (ε3/3) or apoE2 isoform (ε2/3-ε2/2). This increase is caused by enhanced antigen-presentation by apoE4-expressing DCs, and is reversed when these DCs are incubated with serum containing WT apoE3. In summary, our study identifies myeloid-produced apoE as a key physiological modulator of DC antigen presentation function, paving the way for further explorations of apoE as a tool to improve the management of immune diseases.- Published
- 2018
- Full Text
- View/download PDF
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