26 results on '"Arici, Martina"'
Search Results
2. A dynamic clamping approach using in silico IK1 current for discrimination of chamber-specific hiPSC-derived cardiomyocytes
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Altomare, Claudia, Bartolucci, Chiara, Sala, Luca, Balbi, Carolina, Burrello, Jacopo, Pietrogiovanna, Nicole, Burrello, Alessio, Bolis, Sara, Panella, Stefano, Arici, Martina, Krause, Rolf, Rocchetti, Marcella, Severi, Stefano, and Barile, Lucio
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- 2023
- Full Text
- View/download PDF
3. Liraglutide preserves CD34+ stem cells from dysfunction Induced by high glucose exposure
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Sforza, Annalisa, Vigorelli, Vera, Rurali, Erica, Perrucci, Gianluca Lorenzo, Gambini, Elisa, Arici, Martina, Metallo, Alessia, Rinaldi, Raffaella, Fiorina, Paolo, Barbuti, Andrea, Raucci, Angela, Sacco, Elena, Rocchetti, Marcella, Pompilio, Giulio, Genovese, Stefano, and Vinci, Maria Cristina
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- 2022
- Full Text
- View/download PDF
4. Targeting GRP receptor: Design, synthesis and preliminary biological characterization of new non-peptide antagonists of bombesin
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Palmioli, Alessandro, Nicolini, Gabriella, Tripodi, Farida, Orsato, Alexandre, Ceresa, Cecilia, Donzelli, Elisabetta, Arici, Martina, Coccetti, Paola, Rocchetti, Marcella, La Ferla, Barbara, and Airoldi, Cristina
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- 2021
- Full Text
- View/download PDF
5. Selective SERCA2a activator as a candidate for chronic heart failure therapy
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Arici, M, Hsu, S, Ferrandi, M, Barassi, P, Ronchi, C, Torre, E, Luraghi, A, Chang, G, Ferrari, P, Bianchi, G, Peri, F, Zaza, A, Rocchetti, M, Arici, Martina, Hsu, Shih-Che, Ferrandi, Mara, Barassi, Paolo, Ronchi, Carlotta, Torre, Eleonora, Luraghi, Andrea, Chang, Gwo-Jyh, Ferrari, Patrizia, Bianchi, Giuseppe, Peri, Francesco, Zaza, Antonio, Rocchetti, Marcella, Arici, M, Hsu, S, Ferrandi, M, Barassi, P, Ronchi, C, Torre, E, Luraghi, A, Chang, G, Ferrari, P, Bianchi, G, Peri, F, Zaza, A, Rocchetti, M, Arici, Martina, Hsu, Shih-Che, Ferrandi, Mara, Barassi, Paolo, Ronchi, Carlotta, Torre, Eleonora, Luraghi, Andrea, Chang, Gwo-Jyh, Ferrari, Patrizia, Bianchi, Giuseppe, Peri, Francesco, Zaza, Antonio, and Rocchetti, Marcella
- Abstract
Background: The sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA2a) depression substantially contributes to diastolic dysfunction in heart failure (HF), suggesting that SERCA2a stimulation may be a mechanism-based HF therapy. Istaroxime is a drug endowed with both a SERCA2a stimulatory activity and a Na+/K+ pump inhibitory activity for acute HF treatment. Its main metabolite PST3093 shows a more favorable therapeutic profile as compared to the parent drug, but it is still unsuitable for chronic usage. Novel PST3093 derivatives have been recently developed for oral (chronic) HF treatment; compound 8 was selected among them and here characterized. Methods: Effects of compound 8 were evaluated in a context of SERCA2a depression, by using streptozotocin-treated rats, a well-known model of diastolic dysfunction. The impact of SERCA2a stimulation by compound 8 was assessed at the cellular level ad in vivo, following i.v. infusion (acute effects) or oral administration (chronic effects). Results: As expected from SERCA2a stimulation, compound 8 induced SR Ca2+ compartmentalization in STZ myocytes. In-vivo echocardiographic analysis during i.v. infusion and after repeated oral administration of compound 8, detected a significant improvement of diastolic function. Moreover, compound 8 did not affect electrical activity of healthy guinea-pig myocytes, in line with the absence of off-target effects. Finally, compound 8 was well tolerated in mice with no evidence of acute toxicity. Conclusions: The pharmacological evaluation of compound 8 indicates that it may be a safe and selective drug for a mechanism-based treatment of chronic HF by restoring SERCA2a activity.
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- 2024
6. The long-lasting istaroxime metabolite PST3093 stimulates SERCA2a and reverses disease-induced changes in cardiac function
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Arici, Martina, primary, Ferrandi, Mara, additional, Hsu, Shih-Che, additional, Torre, Eleonora, additional, Barassi, Paolo, additional, Luraghi, Andrea, additional, Ronchi, Carlotta, additional, Chang, Gwo-Jyh, additional, Peri, Franchesco, additional, Ferrari, Patrizia, additional, Bianchi, Giuseppe, additional, Rocchetti, Marcella, additional, and Zaza, Antonio, additional
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- 2024
- Full Text
- View/download PDF
7. Selective SERCA2a activator as a candidate for chronic heart failure therapy
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Arici, Martina, primary, Hsu, Shih-Che, additional, Ferrandi, Mara, additional, Barassi, Paolo, additional, Ronchi, Carlotta, additional, Torre, Eleonora, additional, Luraghi, Andrea, additional, Chang, Gwo-Jyh, additional, Ferrari, Patrizia, additional, Bianchi, Giuseppe, additional, Peri, Francesco, additional, Zaza, Antonio, additional, and Rocchetti, Marcella, additional
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- 2023
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- View/download PDF
8. In-vitro studies of the NaV1.5 S805L Brugada mutation: The resting cell voltage is a critical element in determining the pathological or physiological phenotype of the current
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Molla, David, Frosio, Anthony, Bertoli, Giorgia, Piantoni, Chiara, Arici, Martina, Bartolucci, Chiara, Marchese, Procolo, Bazzini, Claudia, Barbuti, Andrea, Rocchetti, Marcella, Severi, Stefano, Bucchi, Annalisa, and Baruscotti, Mirko
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- 2024
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9. Intracellular Ca2+ dynamics modulation by istaroxime and its metabolite in pulmonary artery smooth muscle cells
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Metallo, Alessia, D'Angeli, Virginia, Arici, Martina, and Rocchetti, Marcella
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- 2024
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10. Istaroxime follow-on compounds: A new class of selective SERCA2a activators for chronic heart failure treatment
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Arici, Martina, Hsu, Shih-Che, Ferrandi, Mara, Barassi, Paolo, Ronchi, Carlotta, Torre, Eleonora, Luraghi, Andrea, Metallo, Alessia, Chang, Gwo-Jyh, Ferrari, Patrizia, Bianchi, Giuseppe, Regonesi, Maria Elena, Airoldi, Cristina, Peri, Francesco, Zaza, Antonio, and Rocchetti, Marcella
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- 2024
- Full Text
- View/download PDF
11. A dynamic clamping approach using in silico IK1 current for discrimination of chamber-specific hiPSC-derived cardiomyocytes
- Author
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Altomare, C, Bartolucci, C, Sala, L, Balbi, C, Burrello, J, Pietrogiovanna, N, Burrello, A, Bolis, S, Panella, S, Arici, M, Krause, R, Rocchetti, M, Severi, S, Barile, L, Altomare, Claudia, Bartolucci, Chiara, Sala, Luca, Balbi, Carolina, Burrello, Jacopo, Pietrogiovanna, Nicole, Burrello, Alessio, Bolis, Sara, Panella, Stefano, Arici, Martina, Krause, Rolf, Rocchetti, Marcella, Severi, Stefano, Barile, Lucio, Altomare, C, Bartolucci, C, Sala, L, Balbi, C, Burrello, J, Pietrogiovanna, N, Burrello, A, Bolis, S, Panella, S, Arici, M, Krause, R, Rocchetti, M, Severi, S, Barile, L, Altomare, Claudia, Bartolucci, Chiara, Sala, Luca, Balbi, Carolina, Burrello, Jacopo, Pietrogiovanna, Nicole, Burrello, Alessio, Bolis, Sara, Panella, Stefano, Arici, Martina, Krause, Rolf, Rocchetti, Marcella, Severi, Stefano, and Barile, Lucio
- Abstract
Human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CM) constitute a mixed population of ventricular-, atrial-, nodal-like cells, limiting the reliability for studying chamber-specific disease mechanisms. Previous studies characterised CM phenotype based on action potential (AP) morphology, but the classification criteria were still undefined. Our aim was to use in silico models to develop an automated approach for discriminating the electrophysiological differences between hiPSC-CM. We propose the dynamic clamp (DC) technique with the injection of a specific IK1 current as a tool for deriving nine electrical biomarkers and blindly classifying differentiated CM. An unsupervised learning algorithm was applied to discriminate CM phenotypes and principal component analysis was used to visualise cell clustering. Pharmacological validation was performed by specific ion channel blocker and receptor agonist. The proposed approach improves the translational relevance of the hiPSC-CM model for studying mechanisms underlying inherited or acquired atrial arrhythmias in human CM, and for screening anti-arrhythmic agents.
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- 2023
12. Selective SERCA2a stimulation: a new promising therapeutic approach for heart failure treatment
- Author
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Arici, M, ROCCHETTI, MARCELLA, ARICI, MARTINA, Arici, M, ROCCHETTI, MARCELLA, and ARICI, MARTINA
- Abstract
Lo scompenso cardiaco è una delle principali cause di morte improvvisa nei paesi sviluppati ed è noto che il cuore scompensato sia caratterizzato da una ridotta contrattilità causata da un’alterazione della dinamica del calcio tra il sarcoplasma e il reticolo sarcoplasmatico. In questo ambito, istaroxime è un farmaco in fase 2 preclinica che combina l’inibizione della pompa Na+/K+ e la stimolazione di SERCA2a, mostrando effetti promettenti per il trattamento dello scompenso cardiaco acuto. Tuttavia, l’uso di istaroxime è limitato al trattamento i.v. a causa della sua breve emivita (⁓ 1 h) e dalla sua estensiva metabolizzazione a livello epatico portando alla formazione di una molecola chiamata PST3093. Il primo obiettivo del mio progetto di tesi mirava allo studio del PST3093, il principale metabolita di istaroxime, per capire se fosse dotato di attività farmacologica e per comprendere meglio gli effetti in vivo dell’istaroxime. Sulla base dei risultati ottenuti, il secondo obiettivo era quello di sviluppare degli analoghi del PST3093, stimolatori di SERCA2a e dotati di un gruppo metabolicamente stabile per la somministrazione orale. Effetti in vivo e in vitro dei derivati del PST3093 venivano valutati in un modello di ratto con cardiomiopatia diabetica indotta da streptozotocina (STZ), in quanto caratterizzato da disfunzione diastolica associata a down-regolazione di SERCA2a. Innanzitutto, venivano studiati gli effetti del PST3093 sull’attività di SERCA2a e della pompa Na+/K+, sulla dinamica del calcio intracellulare in miociti ventricolari isolati e sull’emodinamica nei ratti STZ. A differenza di istaroxime, il PST3093 risultava uno stimolatore “selettivo” di SERCA2a, privo di effetti sulla pompa Na+/K+ ̧ con un profilo meno aritmogenico del composto di origine. Il PST3093 risultava attivo a concentrazioni nanomolari in preparazioni cardiache di cavia e di ratto STZ e, similmente a istaroxime, stimolava SERCA2a solo in presenza del fosfolambano, diminuendon, Heart failure (HF) is one of the leading causes of sudden death in developed countries and it is known that failing hearts are characterized by reduced contractile properties caused by impaired Ca2+ cycling between the sarcoplasm and sarcoplasmic reticulum (SR). In this field, istaroxime is a small-molecule drug under phase 2 clinical trial that, combining inhibition of Na+/K+ ATPase and SERCA2a stimulation, shows an interesting profile for acute HF treatment. However, istaroxime use is restricted to acute i.v. infusion because of its plasma half-life of about 1 hour in humans and its extensive hepatic metabolism to a molecule, named PST3093. The first aim of my thesis project dealt with the investigation whether PST3093, the main metabolite of istaroxime, may, on its own, be endowed with pharmacological activity and at least partially explain in vivo istaroxime effects. In light of the results, the second aim was to develop PST3093 analogues with metabolically stable groups, with the purpose to generate orally administrable SERCA2a stimulators. In vivo and in vitro effects of PST3093 follow-on compounds were evaluated by using streptozotocin (STZ)-treated rats developing diabetic cardiomyopathy with diastolic dysfunction associated to SERCA2a downregulation. Firstly, we characterized PST3093 effects on SERCA2a and Na+/K+ ATPase activities, intracellular Ca2+ dynamics in isolated ventricular myocytes and in vivo hemodynamic effects in STZ rats. At variance with its parent compound, PST3093 is a “selective” (i.e. devoid of Na+/K+ ATPase inhibition) SERCA2a stimulator, showing a safer profile than istaroxime. It is active at nanomolar concentrations in cardiac preparations from normal guinea pig and STZ rats and, similarly to istaroxime, it stimulates SERCA2a only in the presence of phospholamban (PLN), thus relieving its inhibitory activity on SERCA2a. In-vivo PST3093 i.v. infusion (acute effects) in STZ rats improved overall cardiac performance and reversed most STZ
- Published
- 2023
13. Selective SERCA2a stimulation: a new promising therapeutic approach for heart failure treatment
- Author
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ARICI, MARTINA, Arici, M, and ROCCHETTI, MARCELLA
- Subjects
Heart Failure ,BIO/09 - FISIOLOGIA ,Scompenso cardiaco ,Fosfolambano ,Istaroxime ,Dinamica del calcio ,Calcium handling ,SERCA2a ,Phospholamban - Abstract
Lo scompenso cardiaco è una delle principali cause di morte improvvisa nei paesi sviluppati ed è noto che il cuore scompensato sia caratterizzato da una ridotta contrattilità causata da un’alterazione della dinamica del calcio tra il sarcoplasma e il reticolo sarcoplasmatico. In questo ambito, istaroxime è un farmaco in fase 2 preclinica che combina l’inibizione della pompa Na+/K+ e la stimolazione di SERCA2a, mostrando effetti promettenti per il trattamento dello scompenso cardiaco acuto. Tuttavia, l’uso di istaroxime è limitato al trattamento i.v. a causa della sua breve emivita (⁓ 1 h) e dalla sua estensiva metabolizzazione a livello epatico portando alla formazione di una molecola chiamata PST3093. Il primo obiettivo del mio progetto di tesi mirava allo studio del PST3093, il principale metabolita di istaroxime, per capire se fosse dotato di attività farmacologica e per comprendere meglio gli effetti in vivo dell’istaroxime. Sulla base dei risultati ottenuti, il secondo obiettivo era quello di sviluppare degli analoghi del PST3093, stimolatori di SERCA2a e dotati di un gruppo metabolicamente stabile per la somministrazione orale. Effetti in vivo e in vitro dei derivati del PST3093 venivano valutati in un modello di ratto con cardiomiopatia diabetica indotta da streptozotocina (STZ), in quanto caratterizzato da disfunzione diastolica associata a down-regolazione di SERCA2a. Innanzitutto, venivano studiati gli effetti del PST3093 sull’attività di SERCA2a e della pompa Na+/K+, sulla dinamica del calcio intracellulare in miociti ventricolari isolati e sull’emodinamica nei ratti STZ. A differenza di istaroxime, il PST3093 risultava uno stimolatore “selettivo” di SERCA2a, privo di effetti sulla pompa Na+/K+¸ con un profilo meno aritmogenico del composto di origine. Il PST3093 risultava attivo a concentrazioni nanomolari in preparazioni cardiache di cavia e di ratto STZ e, similmente a istaroxime, stimolava SERCA2a solo in presenza del fosfolambano, diminuendone l’inibizione su SERCA2a. L’infusione del composto (effetto acuto) nei ratti STZ migliorava complessivamente le prestazioni cardiache e revertiva molte anomalie causate da STZ. Grazie alla collaborazione con un gruppo di chimici del nostro dipartimento, sono stati sintetizzati dei derivati del PST3093 privi di attività inibitoria sulla pompa Na+/K+ e formulati per essere utilizzati nel trattamento cronico (orale) dello scompenso cardiaco. Molti di loro mantenevano l’azione stimolatoria su SERCA2a a dosi nanomolari. Il composto 5 e il composto 8 venivano selezionati per ulteriori analisi in cardiomiociti isolati e in vivo (in acuto). Entrambi i composti, stimolando SERCA2a, promuovevano la compartimentalizzazione nel calcio intracellulare e, in seguito a infusione, ripristinavano la funzione diastolica nei ratti STZ. Infine, venivano valutati gli effetti cronici in vivo del composto 8 nei ratti STZ dopo somministrazione orale. Venivano testate due diverse dosi (40 o 80 mg/kg) e gli effetti venivano valutati dopo 1 o 4 somministrazioni (1 al giorno), per valutare eventuali effetti dose-dipendenti e, indirettamente, esplorare la sua farmacocinetica. Il composto 8 migliorava in maniera dose-dipendente la disfunzione diastolica causata da STZ e la sua farmacocinetica risultava comparabile a quella del PST3093. Analisi delle interazioni molecolari con 50 diversi ligandi escludevano effetti off-target del composto 8. Infine, veniva valutata la tossicità in topo. Il composto 8 risultava meno tossico di PST3093 e istaroxime In conclusione, PST3093 e i suoi derivati agivano come stimolatori “selettivi” di SERCA2a. Mentre il PST3093 prolungava gli effetti benefici dati dall’infusione dell’istaroxime, i suoi derivati possono essere considerati il prototipo di una nuova classe farmacodinamica per la terapia dello scompenso cardiaco. In particolare, il composto 8 risultava un possibile candidato per la terapia cronica. Heart failure (HF) is one of the leading causes of sudden death in developed countries and it is known that failing hearts are characterized by reduced contractile properties caused by impaired Ca2+ cycling between the sarcoplasm and sarcoplasmic reticulum (SR). In this field, istaroxime is a small-molecule drug under phase 2 clinical trial that, combining inhibition of Na+/K+ ATPase and SERCA2a stimulation, shows an interesting profile for acute HF treatment. However, istaroxime use is restricted to acute i.v. infusion because of its plasma half-life of about 1 hour in humans and its extensive hepatic metabolism to a molecule, named PST3093. The first aim of my thesis project dealt with the investigation whether PST3093, the main metabolite of istaroxime, may, on its own, be endowed with pharmacological activity and at least partially explain in vivo istaroxime effects. In light of the results, the second aim was to develop PST3093 analogues with metabolically stable groups, with the purpose to generate orally administrable SERCA2a stimulators. In vivo and in vitro effects of PST3093 follow-on compounds were evaluated by using streptozotocin (STZ)-treated rats developing diabetic cardiomyopathy with diastolic dysfunction associated to SERCA2a downregulation. Firstly, we characterized PST3093 effects on SERCA2a and Na+/K+ ATPase activities, intracellular Ca2+ dynamics in isolated ventricular myocytes and in vivo hemodynamic effects in STZ rats. At variance with its parent compound, PST3093 is a “selective” (i.e. devoid of Na+/K+ ATPase inhibition) SERCA2a stimulator, showing a safer profile than istaroxime. It is active at nanomolar concentrations in cardiac preparations from normal guinea pig and STZ rats and, similarly to istaroxime, it stimulates SERCA2a only in the presence of phospholamban (PLN), thus relieving its inhibitory activity on SERCA2a. In-vivo PST3093 i.v. infusion (acute effects) in STZ rats improved overall cardiac performance and reversed most STZ-induced abnormalities. Thanks to a collaboration with chemists of our Department, we synthesized a panel of PST3093 derivatives devoid of Na+/K+ ATPase inhibitory activity to develop a class of compounds suitable for chronic (oral) HF treatment. Most of them retained SERCA2a stimulatory action with nanomolar potency. Two selected PST3093 analogues, compound 5 and compound 8, were further characterized in isolated cardiomyocytes and their acute in vivo effects were firstly evaluated after i.v. infusion in STZ rats. Both compounds, stimulating SERCA2a, improved intracellular Ca2+ handling (promoting SR Ca2+ compartmentalization) and restored diastolic function following acute i.v. infusion in STZ rats. Finally, we evaluated chronic in vivo effects of compound 8 in STZ rats after oral administration at two dosages (40 or 80 mg/kg) at 1 or 4 daily doses to evaluate potential dose-dependent effects and to indirectly explore its pharmacokinetic in rats. Compound 8 dose-dependently ameliorated STZ-induced diastolic dysfunction and its pharmacokinetic was comparable to that of PST3093, i.e. longer than istaroxime one. Off-target effects of compound 8 were excluded based on the analysis of its molecular interaction with a panel of 50 ligands. Acute toxicity in mice was finally evaluated, showing a safer profile of compound 8 than PST3093 and istaroxime. In conclusion, PST3093 and its derivatives act as “selective” SERCA2a stimulators. While PST3093 is suitable to prolong the cardiac beneficial effect of istaroxime infusion, PST3093 derivatives can be considered the prototype of a novel pharmacodynamic class for the ino-lusitropic approach of HF. In particular, compound 8 seems to be a favourable drug candidate for chronic HF therapy.
- Published
- 2023
14. Istaroxime metabolite PST3093 selectively stimulates SERCA2a and reverses disease-induced changes in cardiac function
- Author
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Arici, Martina, primary, Ferrandi, Mara, additional, Hsu, Shih-Che, additional, Torre, Eleonora, additional, Barassi, Paolo, additional, Luraghi, Andrea, additional, Ronchi, Carlotta, additional, Chang, Gwo-Jyh, additional, Peri, Francesco, additional, Ferrari, Patrizia, additional, Bianchi, Giuseppe, additional, Rocchetti, Marcella, additional, and Zaza, Antonio, additional
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- 2022
- Full Text
- View/download PDF
15. Highly Selective SERCA2a Activators: Preclinical Development of a Congeneric Group of First-in-Class Drug Leads against Heart Failure
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Luraghi, Andrea, primary, Ferrandi, Mara, additional, Barassi, Paolo, additional, Arici, Martina, additional, Hsu, Shih-Che, additional, Torre, Eleonora, additional, Ronchi, Carlotta, additional, Romerio, Alessio, additional, Chang, Gwo-Jyh, additional, Ferrari, Patrizia, additional, Bianchi, Giuseppe, additional, Zaza, Antonio, additional, Rocchetti, Marcella, additional, and Peri, Francesco, additional
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- 2022
- Full Text
- View/download PDF
16. SERCA2a stimulation by istaroxime improves intracellular Ca2+ handling and diastolic dysfunction in a model of diabetic cardiomyopathy
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Torre, E, Arici, M, Lodrini, A, Ferrandi, M, Barassi, P, Hsu, S, Chang, G, Boz, E, Sala, E, Vagni, S, Altomare, C, Mostacciuolo, G, Bussadori, C, Ferrari, P, Bianchi, G, Rocchetti, M, Torre, Eleonora, Arici, Martina, Lodrini, Alessandra Maria, Ferrandi, Mara, Barassi, Paolo, Hsu, Shih-Che, Chang, Gwo-Jyh, Boz, Elisabetta, Sala, Emanuela, Vagni, Sara, Altomare, Claudia, Mostacciuolo, Gaspare, Bussadori, Claudio, Ferrari, Patrizia, Bianchi, Giuseppe, Rocchetti, Marcella, Torre, E, Arici, M, Lodrini, A, Ferrandi, M, Barassi, P, Hsu, S, Chang, G, Boz, E, Sala, E, Vagni, S, Altomare, C, Mostacciuolo, G, Bussadori, C, Ferrari, P, Bianchi, G, Rocchetti, M, Torre, Eleonora, Arici, Martina, Lodrini, Alessandra Maria, Ferrandi, Mara, Barassi, Paolo, Hsu, Shih-Che, Chang, Gwo-Jyh, Boz, Elisabetta, Sala, Emanuela, Vagni, Sara, Altomare, Claudia, Mostacciuolo, Gaspare, Bussadori, Claudio, Ferrari, Patrizia, Bianchi, Giuseppe, and Rocchetti, Marcella
- Abstract
Aims: Diabetic cardiomyopathy is a multifactorial disease characterized by an early onset of diastolic dysfunction (DD) that precedes the development of systolic impairment. Mechanisms that can restore cardiac relaxation improving intracellular Ca2+ dynamics represent a promising therapeutic approach for cardiovascular diseases associated to DD. Istaroxime has the dual properties to accelerate Ca2+ uptake into sarcoplasmic reticulum (SR) through the SR Ca2+ pump (SERCA2a) stimulation and to inhibit Na+/K+ ATPase (NKA). This project aims to characterize istaroxime effects at a concentration (100 nmol/L) marginally affecting NKA, in order to highlight its effects dependent on the stimulation of SERCA2a in an animal model of mild diabetes. Methods and results: Streptozotocin (STZ) treated diabetic rats were studied at 9 weeks after STZ injection in comparison to controls (CTR). Istaroxime effects were evaluated in vivo and in left ventricular (LV) preparations. STZ animals showed 1) marked DD not associated to cardiac fibrosis, 2) LV mass reduction associated to reduced LV cell dimension and T-tubules loss, 3) reduced LV SERCA2 protein level and activity and 4) slower SR Ca2+ uptake rate, 5) LV action potential (AP) prolongation and increased short-term variability (STV) of AP duration, 6) increased diastolic Ca2+, and 7) unaltered SR Ca2+ content and stability in intact cells. Acute istaroxime infusion (0.11 mg/kg/min for 15 min) reduced DD in STZ rats. Accordingly, in STZ myocytes istaroxime (100 nmol/L) stimulated SERCA2a activity and blunted STZ-induced abnormalities in LV Ca2+ dynamics. In CTR myocytes, istaroxime increased diastolic Ca2+ level due to NKA blockade albeit minimal, while its effects on SERCA2a were almost absent. Conclusions: SERCA2a stimulation by istaroxime improved STZ-induced DD and intracellular Ca2+ handling anomalies. Thus, SERCA2a stimulation can be considered a promising therapeutic approach for DD treatment. Translational perspective: Defi
- Published
- 2022
17. Stress-induced premature senescence is associated with a prolonged QT interval and recapitulates features of cardiac aging
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Lazzarini, Edoardo, primary, Lodrini, Alessandra Maria, additional, Arici, Martina, additional, Bolis, Sara, additional, Vagni, Sara, additional, Panella, Stefano, additional, Rendon-Angel, Azucena, additional, Saibene, Melissa, additional, Metallo, Alessia, additional, Torre, Tiziano, additional, Vassalli, Giuseppe, additional, Ameri, Pietro, additional, Altomare, Claudia, additional, Rocchetti, Marcella, additional, and Barile, Lucio, additional
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- 2022
- Full Text
- View/download PDF
18. Liraglutide Preserves CD34 + Stem Cells from Dysfunction Induced by High Glucose Exposure
- Author
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Sforza, Annalisa, primary, Vigorelli, Vera, additional, Rurali, Erica, additional, Gambini, Elisa, additional, Arici, Martina, additional, Rinaldi, Raffaella, additional, Fiorina, Paolo, additional, Barbuti, Andrea, additional, Raucci, Angela, additional, Rocchetti, Marcella, additional, Pompilio, Giulio, additional, Genovese, Stefano, additional, and Vinci, Maria Cristina, additional
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- 2021
- Full Text
- View/download PDF
19. Istaroxime metabolite PST3093 selectively stimulates SERCA2a and reverses disease-induced changes in cardiac function
- Author
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Arici, Martina, primary, Ferrandi, Mara, additional, Barassi, Paolo, additional, Hsu, Shih-Che, additional, Torre, Eleonora, additional, Luraghi, Andrea, additional, Ronchi, Carlotta, additional, Chang, Gwo-Jyh, additional, Peri, Francesco, additional, Ferrari, Patrizia, additional, Bianchi, Giuseppe, additional, Rocchetti, Marcella, additional, and Zaza, Antonio, additional
- Published
- 2021
- Full Text
- View/download PDF
20. Targeting GRP receptor: design, synthesis and preliminary biological characterization of new non-peptide antagonists of bombesin
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Palmioli, A, Nicolini, G, Tripodi, F, Orsato, A, Ceresa, C, Donzelli, E, Arici, M, Coccetti, P, Rocchetti, M, La Ferla, B, Airoldi, C, Palmioli, Alessandro, Nicolini, Gabriella, Tripodi, Farida, Orsato, Alexandre, Ceresa, Cecilia, Donzelli, Elisabetta, Arici, Martina, Coccetti, Paola, Rocchetti, Marcella, La Ferla, Barbara, Airoldi, Cristina, Palmioli, A, Nicolini, G, Tripodi, F, Orsato, A, Ceresa, C, Donzelli, E, Arici, M, Coccetti, P, Rocchetti, M, La Ferla, B, Airoldi, C, Palmioli, Alessandro, Nicolini, Gabriella, Tripodi, Farida, Orsato, Alexandre, Ceresa, Cecilia, Donzelli, Elisabetta, Arici, Martina, Coccetti, Paola, Rocchetti, Marcella, La Ferla, Barbara, and Airoldi, Cristina
- Abstract
We report the rational design, synthesis, and in vitro preliminary evaluation of a new small library of non-peptide ligands of Gastrin Releasing Peptide Receptor (GRP-R), able to antagonize its natural ligand bombesin (BN) in the nanomolar range of concentration. GRP-R is a transmembrane G-protein coupled receptor promoting the stimulation of cancer cell proliferation. Being overexpressed on the surface of different human cancer cell lines, GRP-R is ideal for the selective delivery to tumor cells of both anticancer drug and diagnostic devices. What makes very challenging the design of non-peptide BN analogues is that the 3D structure of the GRP-R is not available, which is the case for many membrane-bound receptors. Thus, the design of GRP-R ligands has to be based on the structure of its natural ligands, BN and GRP. We recently mapped the BN binding epitope by NMR and here we exploited the same spectroscopy, combined with MD, to define BN conformation in proximity of biological membranes, where the interaction with GRP-R takes place. The gained structural information was used to identify a rigid C-galactosidic scaffold able to support pharmacophore groups mimicking the BN key residues’ side chains in a suitable manner for binding to GRP-R. Our BN antagonists represent hit compounds for the rational design and synthesis of new ligands and modulators of GRP-R. The further optimization of the pharmacophore groups will allow to increase the biological activity. Due to their favorable chemical properties and stability, they could be employed for the active receptor-mediated targeting of GRP-R positive tumors.
- Published
- 2021
21. Structural and Electrophysiological Changes in a Model of Cardiotoxicity Induced by Anthracycline Combined With Trastuzumab
- Author
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Altomare, Claudia, primary, Lodrini, Alessandra Maria, additional, Milano, Giuseppina, additional, Biemmi, Vanessa, additional, Lazzarini, Edoardo, additional, Bolis, Sara, additional, Pernigoni, Nicolò, additional, Torre, Eleonora, additional, Arici, Martina, additional, Ferrandi, Mara, additional, Barile, Lucio, additional, Rocchetti, Marcella, additional, and Vassalli, Giuseppe, additional
- Published
- 2021
- Full Text
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22. SERCA2a stimulation by istaroxime improves intracellular Ca2+ handling and diastolic dysfunction in a model of diabetic cardiomyopathy
- Author
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Torre, Eleonora, primary, Arici, Martina, additional, Lodrini, Alessandra Maria, additional, Ferrandi, Mara, additional, Barassi, Paolo, additional, Hsu, Shih-Che, additional, Chang, Gwo-Jyh, additional, Boz, Elisabetta, additional, Sala, Emanuela, additional, Vagni, Sara, additional, Altomare, Claudia, additional, Mostacciuolo, Gaspare, additional, Bussadori, Claudio, additional, Ferrari, Patrizia, additional, Bianchi, Giuseppe, additional, and Rocchetti, Marcella, additional
- Published
- 2021
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- View/download PDF
23. Liraglutide preserves CD34+ stem cells from dysfunction Induced by high glucose exposure.
- Author
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Sforza, Annalisa, Vigorelli, Vera, Rurali, Erica, Perrucci, Gianluca Lorenzo, Gambini, Elisa, Arici, Martina, Metallo, Alessia, Rinaldi, Raffaella, Fiorina, Paolo, Barbuti, Andrea, Raucci, Angela, Sacco, Elena, Rocchetti, Marcella, Pompilio, Giulio, Genovese, Stefano, and Vinci, Maria Cristina
- Subjects
STEM cells ,TYPE 2 diabetes ,HEMATOPOIETIC stem cells ,LIRAGLUTIDE ,GLUCOSE - Abstract
Background: Glucagon like peptide-1 receptor agonists (GLP-1RAs) have shown to reduce mortality and cardiovascular events in patients with type 2 diabetes mellitus (T2DM). Since the impairment in number and function of vasculotrophic circulating CD34
+ hematopoietic stem progenitor cells (HSPCs) in T2D has been reported to increase cardiovascular (CV) risk, we hypothesized that one of the mechanisms whereby GLP-1 RAs exert CV protective effects may be related to the ability to improve CD34+ HSPC function. Methods: In cord blood (CB)-derived CD34+ HSPC, the expression of GLP-1 receptor (GLP-1R) mRNA, receptor protein and intracellular signaling was evaluated by RT-qPCR and Western Blot respectively. CD34+ HSPCs were exposed to high glucose (HG) condition and GLP-1RA liraglutide (LIRA) was added before as well as after functional impairment. Proliferation, CXCR4/SDF-1α axis activity and intracellular ROS production of CD34+ HSPC were evaluated. Results: CD34+ HSPCs express GLP-1R at transcriptional and protein level. LIRA treatment prevented and rescued HSPC proliferation, CXCR4/SDF-1α axis activity and metabolic imbalance from HG-induced impairment. LIRA stimulation promoted intracellular cAMP accumulation as well as ERK1/2 and AKT signaling activation. The selective GLP-1R antagonist exendin (9–39) abrogated LIRA-dependent ERK1/2 and AKT phosphorylation along with the related protective effects. Conclusion: We provided the first evidence that CD34+ HSPC express GLP-1R and that LIRA can favorably impact on cell dysfunction due to HG exposure. These findings open new perspectives on the favorable CV effects of GLP-1 RAs in T2DM patients. [ABSTRACT FROM AUTHOR]- Published
- 2022
- Full Text
- View/download PDF
24. SERCA2a stimulation by istaroxime improves intracellular Ca2+ handling and diastolic dysfunction in a model of diabetic cardiomyopathy.
- Author
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Torre, Eleonora, Arici, Martina, Lodrini, Alessandra Maria, Ferrandi, Mara, Barassi, Paolo, Hsu, Shih-Che, Chang, Gwo-Jyh, Boz, Elisabetta, Sala, Emanuela, Vagni, Sara, Altomare, Claudia, Mostacciuolo, Gaspare, Bussadori, Claudio, Ferrari, Patrizia, Bianchi, Giuseppe, and Rocchetti, Marcella
- Subjects
- *
DIABETIC cardiomyopathy , *ANIMAL models of diabetes , *CALCIUM ions , *LABORATORY rats , *ACTION potentials , *HEART cells - Abstract
Aims Diabetic cardiomyopathy is a multifactorial disease characterized by an early onset of diastolic dysfunction (DD) that precedes the development of systolic impairment. Mechanisms that can restore cardiac relaxation improving intracellular Ca2+ dynamics represent a promising therapeutic approach for cardiovascular diseases associated to DD. Istaroxime has the dual properties to accelerate Ca2+ uptake into sarcoplasmic reticulum (SR) through the SR Ca2+ pump (SERCA2a) stimulation and to inhibit Na+/K+ ATPase (NKA). This project aims to characterize istaroxime effects at a concentration (100 nmol/L) marginally affecting NKA, in order to highlight its effects dependent on the stimulation of SERCA2a in an animal model of mild diabetes. Methods and results Streptozotocin (STZ) treated diabetic rats were studied at 9 weeks after STZ injection in comparison to controls (CTR). Istaroxime effects were evaluated in vivo and in left ventricular (LV) preparations. STZ animals showed (i) marked DD not associated to cardiac fibrosis, (ii) LV mass reduction associated to reduced LV cell dimension and T-tubules loss, (iii) reduced LV SERCA2 protein level and activity and (iv) slower SR Ca2+ uptake rate, (v) LV action potential (AP) prolongation and increased short-term variability (STV) of AP duration, (vi) increased diastolic Ca2+, and (vii) unaltered SR Ca2+ content and stability in intact cells. Acute istaroxime infusion (0.11 mg/kg/min for 15 min) reduced DD in STZ rats. Accordingly, in STZ myocytes istaroxime (100 nmol/L) stimulated SERCA2a activity and blunted STZ-induced abnormalities in LV Ca2+ dynamics. In CTR myocytes, istaroxime increased diastolic Ca2+ level due to NKA blockade albeit minimal, while its effects on SERCA2a were almost absent. Conclusions SERCA2a stimulation by istaroxime improved STZ-induced DD and intracellular Ca2+ handling anomalies. Thus, SERCA2a stimulation can be considered a promising therapeutic approach for DD treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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25. A dynamic clamping approach using in silico IK1 current for discrimination of chamber-specific hiPSC-derived cardiomyocytes
- Author
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Claudia Altomare, Chiara Bartolucci, Luca Sala, Carolina Balbi, Jacopo Burrello, Nicole Pietrogiovanna, Alessio Burrello, Sara Bolis, Stefano Panella, Martina Arici, Rolf Krause, Marcella Rocchetti, Stefano Severi, Lucio Barile, Altomare, C, Bartolucci, C, Sala, L, Balbi, C, Burrello, J, Pietrogiovanna, N, Burrello, A, Bolis, S, Panella, S, Arici, M, Krause, R, Rocchetti, M, Severi, S, Barile, L, Altomare, Claudia, Bartolucci, Chiara, Sala, Luca, Balbi, Carolina, Burrello, Jacopo, Pietrogiovanna, Nicole, Burrello, Alessio, Bolis, Sara, Panella, Stefano, Arici, Martina, Krause, Rolf, Rocchetti, Marcella, Severi, Stefano, and Barile, Lucio
- Subjects
dynamic clamp, IK1, atrial myocytes, modeling, hiPSC ,Medicine (miscellaneous) ,dynamic clamping, hiPSC-derived cardiomyocytes, in silico IK1 current ,General Agricultural and Biological Sciences ,General Biochemistry, Genetics and Molecular Biology - Abstract
Human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CM) constitute a mixed population of ventricular-, atrial-, nodal-like cells, limiting the reliability for studying chamber-specific disease mechanisms. Previous studies characterised CM phenotype based on action potential (AP) morphology, but the classification criteria were still undefined. Our aim was to use in silico models to develop an automated approach for discriminating the electrophysiological differences between hiPSC-CM. We propose the dynamic clamp (DC) technique with the injection of a specific IK1 current as a tool for deriving nine electrical biomarkers and blindly classifying differentiated CM. An unsupervised learning algorithm was applied to discriminate CM phenotypes and principal component analysis was used to visualise cell clustering. Pharmacological validation was performed by specific ion channel blocker and receptor agonist. The proposed approach improves the translational relevance of the hiPSC-CM model for studying mechanisms underlying inherited or acquired atrial arrhythmias in human CM, and for screening anti-arrhythmic agents.
- Published
- 2023
26. Istaroxime Metabolite PST3093 Selectively Stimulates SERCA2a and Reverses Disease-Induced Changes in Cardiac Function.
- Author
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Arici M, Ferrandi M, Barassi P, Hsu SC, Torre E, Luraghi A, Ronchi C, Chang GJ, Peri F, Ferrari P, Bianchi G, Rocchetti M, and Zaza A
- Subjects
- Animals, Humans, Rats, Adenosine Triphosphatases metabolism, Adenosine Triphosphatases pharmacology, Adenosine Triphosphatases therapeutic use, Etiocholanolone pharmacology, Etiocholanolone therapeutic use, Myocytes, Cardiac metabolism, Sarcoplasmic Reticulum Calcium-Transporting ATPases metabolism, Sarcoplasmic Reticulum Calcium-Transporting ATPases therapeutic use, Heart, Heart Failure drug therapy
- Abstract
Heart failure (HF) therapeutic toolkit would strongly benefit from the availability of ino-lusitropic agents with a favorable pharmacodynamics and safety profile. Istaroxime is a promising agent, which combines Na
+ /K+ pump inhibition with sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) stimulation; however, it has a very short half-life and extensive metabolism to a molecule named PST3093. The present work aims to investigate whether PST3093 still retains the pharmacodynamic and pharmacokinetic properties of its parent compound. We studied PST3093 for its effects on SERCA2a and Na+ /K+ ATPase activities, Ca2+ dynamics in isolated myocytes, and hemodynamic effects in an in vivo rat model of diabetic [streptozotocin (STZ)-induced] cardiomyopathy. Istaroxime infusion in HF patients led to accumulation of PST3093 in the plasma; clearance was substantially slower for PST3093 than for istaroxime. In cardiac rat preparations, PST3093 did not inhibit the Na+ /K+ ATPase activity but retained SERCA2a stimulatory activity. In in vivo echocardiographic assessment, PST3093 improved overall cardiac performance and reversed most STZ-induced abnormalities. PST3093 intravenous toxicity was considerably lower than that of istaroxime, and it failed to significantly interact with 50 off-targets. Overall, PST3093 is a "selective" SERCA2a activator, the prototype of a novel pharmacodynamic category with a potential in the ino-lusitropic approach to HF with prevailing diastolic dysfunction. Its pharmacodynamics are peculiar, and its pharmacokinetics are suitable to prolong the cardiac beneficial effect of istaroxime infusion. SIGNIFICANCE STATEMENT: Heart failure (HF) treatment would benefit from the availability of ino-lusitropic agents with favourable profiles. PST3093 is the main metabolite of istaroxime, a promising agent combining Na+ /K+ pump inhibition and sarcoplasmic reticulum Ca2+ ATPase2a (SERCA2a) stimulation. PST3093 shows a longer half-life in human circulation compared to istaroxime, selectively activates SERCA2a, and improves cardiac performance in a model of diabetic cardiomyopathy. Overall, PST3093 as a selective SERCA2a activator can be considered the prototype of a novel pharmacodynamic category for HF treatment., (Copyright © 2022 by The Author(s).)- Published
- 2023
- Full Text
- View/download PDF
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