Glyceraldehyde-induced metabolic defects in cortical astrocytes: implication for Alzheimer's disease pathogenesis and therapy
Anno: 2026
Rivista: BIOMÉDECINE & PHARMACOTHÉRAPIE
Autori/autrici: Piccirillo, Silvia; Preziuso, Alessandra; Serfilippi, Tiziano; Terenzi, Valentina; Castaldo, Pasqualina; Lariccia, Vincenzo; Secondo, Agnese; Magi, Simona
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/357516
Citazioni:
Glyceraldehyde-induced metabolic defects in cortical astrocytes: implication for Alzheimer's disease pathogenesis and therapy / Piccirillo, S., Preziuso, A., Serfilippi, T., Terenzi, V., Castaldo, P., Lariccia, V., Secondo, A., Magi, S.. - In: BIOMÉDECINE & PHARMACOTHÉRAPIE. - ISSN 0753-3322. - 199:(2026). [10.1016/j.biopha.2026.119473]
Abstract:
A growing body of evidence suggests that reduced metabolic activity in astrocytes may compromise their normal supportive role for neurons and trigger pathophysiological pathways that contribute to the progression of Alzheimer's disease (AD). Due to the complexity of AD pathophysiology, it is cr...ucial to study the disease not only within those contexts traditionally viewed from a neuron-centric perspective. In this study, we settled up a new model of AD by exposing primary rat cortical astrocytes to glyceraldehyde (GA), an inhibitor of glycolytic pathway able to induce a significant hypometabolism and recapitulate several AD pathomechanisms. Accordingly, GA-induced hypometabolism produced (a) astrocytosis, as revealed by the increase in GFAP and Glutamine Synthase (GS) immunosignals, (b) mitochondrial dysfunction, detected as reduced ATP level, mitochondrial ROS hyperproduction and Ca2 + dyshomeostasis at both cytosolic and mitochondrial level (c) inflammation, measured as NF-κB activation, TNFα release, AGEs hyperproduction/RAGE hyperexpression and increase in S100β immunosignal, and, finally (d) autophagy impairment, characterized by the p62 and LC3II protein accumulation. By virtue of glutamate ability to stimulate cell metabolism, we examined the effect of the neurotransmitter supplementation on cell damage and those correlated mechanisms in the proposed AD model. Of interest, metabolic, inflammatory and autophagy defects were mitigated when astrocytes were exposed to glutamate as metabolic boosting substrate. The protective effect of glutamate was counteracted by the pharmacological inhibition of astrocytic glutamate transporters, thus highlighting the relevance of glutamate intracellular action. Collectively, these results highlight the importance of considering astrocyte-targeted therapies as potential strategy in AD.
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Organelles storing Ca2+ in the brain cells: New druggable targets in neurodegenerative diseases
Anno: 2026
Rivista: NEURAL REGENERATION RESEARCH
Autori/autrici: Tedeschi, Valentina; Ciancio, Raffaella; Piccirillo, Silvia; Preziuso, Alessandra; Serfilippi, Tiziano; Terenzi, Valentina; Magi, Simona; Lariccia, Vincenzo; Castaldo, Pasqualina; Vinciguerra, Antonio; Piccialli, Ilaria; Canzoniero, Lorella Maria Teresa; Pannaccione, Anna; Secondo, Agnese
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/357515
Citazioni:
Organelles storing Ca2+ in the brain cells: New druggable targets in neurodegenerative diseases / Tedeschi, V., Ciancio, R., Piccirillo, S., Preziuso, A., Serfilippi, T., Terenzi, V., Magi, S., Lariccia, V., Castaldo, P., Vinciguerra, A., Piccialli, I., Canzoniero, L.M.T., Pannaccione, A., Secondo, A.. - In: NEURAL REGENERATION RESEARCH. - ISSN 1673-5374. - 21:11(2026), pp. 5142-5151. [10.4103/nrr.nrr-d-25-01754]
Abstract:
Several lines of evidence suggest that targeting dysfunctional calcium (Ca2+)-storing organelles and their defective connections may represent a promising therapeutic strategy counteracting neurodegeneration. Dysfunction in these compartments converges to promote oxidative and endoplasmic reticulum ...stress, energy failure, autophagy blockade or hyperactivation, and progressive neurodegeneration. Within the intracellular scenario, several dysfunctional organelles have been characterized in terms of their capability to hijack Ca2+ signaling during neurodegeneration to deadly impact on neuronal tasks in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, brain ischemia, and neonatal hypoxic injury. This review has focused on the endoplasmic reticulum, mitochondria, and lysosomes, as well as their functional interconnection able to maintain the physiological processes such as lysosomal-dependent autophagy and function, lipid trafficking, and protein quality control. Clinically, looking ahead from the already existing therapies, drugs that enhance mitochondrial Ca2+ efflux or modulate mitochondrial Ca2+ uniporter regulation at mitochondria-associated membranes-endoplasmic reticulum sites represent innovative opportunities for next-generation strategies aimed at restoring mitochondrial homeostasis and protecting dopaminergic neurons in Parkinson's disease. Furthermore, functional stabilization of the lysosomal channel transient receptor potential mucolipin 1 by the lipid-based formulation of PI(3,5)P2 may extend the lifespan of amyotrophic lateral sclerosis mice by stimulating the nuclear translocation of the master regulator of autophagy activated by lysosomal Ca2+ release, namely transcription factor EB. Moreover, dysfunction of lysosomal-dependent autophagy can cause mutant huntingtin accumulation in Huntington's disease through the repression of transcription factor EB and lysophagy induction. Collectively, this growing focus may highlight a shift toward recognizing mitochondria, lysosomes, and endoplasmic reticulum, as well as their ionic machinery and interconnections, as a unifying strategy to maintain neuronal viability and mitigate the neurodegeneration progression in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, lysosomal storage diseases, brain ischemia, and neonatal hypoxic insult.
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Allosteric Activation of GDH/TCA Pathway Reduces Pathological Build-Up and Promotes Neuronal Survival in an In Vitro Model of Alzheimer’s Disease
Anno: 2026
Rivista: BIOMOLECULES
Autori/autrici: Serfilippi, Tiziano; Piccirillo, Silvia; Preziuso, Alessandra; Terenzi, Valentina; Ciancio, Raffaella; Magi, Simona; Lariccia, Vincenzo; Secondo, Agnese
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/357972
Citazioni:
Allosteric Activation of GDH/TCA Pathway Reduces Pathological Build-Up and Promotes Neuronal Survival in an In Vitro Model of Alzheimer’s Disease / Serfilippi, T., Piccirillo, S., Preziuso, A., Terenzi, V., Ciancio, R., Magi, S., Lariccia, V., Secondo, A.. - In: BIOMOLECULES. - ISSN 2218-273X. - ELETTRONICO. - 16:5(2026). [10.3390/biom16050667]
Abstract:
Mitochondrial dysfunction is a relevant hallmark of Alzheimer’s disease (AD), contributing to the impaired metabolic homeostasis involved in neuronal loss and cognitive decline. In this study, we target the metabolic dysfunction occurring in AD through a novel pharmacological approach involvin...g the modulation of glutamate dehydrogenase (GDH), which converts glutamate to α-ketoglutarate and supports the tricarboxylic acid (TCA) cycle. In our experimental models (i.e., differentiated SH-SY5Y cells and primary rat cortical neurons exposed to glyceraldehyde and amyloid-beta peptide 1-42, respectively), the allosteric GDH activator 2-Aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) increased mitochondrial ATP production, improved cellular bioenergetics, and reduced oxidative stress, ultimately promoting neuronal survival. Ionic dysfunctions in AD are linked to disrupted calcium homeostasis and organelle storing properties. In this context, GDH activation potentiated mitochondrial and endoplasmic reticulum calcium buffering capacity by enhancing store-operated calcium entry. Oxidative stress, largely driven by mitochondrial ROS overproduction, represents another major contributor to AD pathology. In our AD models BCH-mediated GDH activation reduced ROS formation and restored mitochondrial membrane potential (ΔΨm). Importantly, these metabolic and ionic improvements were associated with decreased accumulation of amyloid-β (Aβ1-42) and phosphorylated tau (pTau), two key AD biomarkers. Overall, modulation of the GDH/TCA pathway represents a promising approach for restoring metabolic dysfunctions and counteracting oxidative stress and ionic dysregulation and therefore AD neurodegeneration.
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Switching to levomethadone improves methadone-induced hyperhidrosis: A case report
Anno: 2025
Rivista: JOURNAL OF ADDICTIVE DISEASES
Autori/autrici: Serfilippi, Tiziano; Piccirillo, Silvia; Romagnoli, Francesca; Tarini, Marella; Lariccia, Vincenzo; Magi, Simona
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/343932
Citazioni:
Switching to levomethadone improves methadone-induced hyperhidrosis: A case report / Serfilippi, T., Piccirillo, S., Romagnoli, F., Tarini, M., Lariccia, V., Magi, S.. - In: JOURNAL OF ADDICTIVE DISEASES. - ISSN 1055-0887. - 44:1(2025), pp. 101-105. [10.1080/10550887.2024.2443696]
Abstract:
Methadone maintenance therapy is the cornerstone of treatment for heroin addiction. Hyperhidrosis is a common and often-overlooked side effect of methadone. Different medications, such as antihistamines and anticholinergic drugs, have been reported to be effective against opioid-induced sweating, bu...t there is no standardized therapy. A 51-year-old patient under methadone maintenance therapy reported long-standing hyperhidrosis, which worsened each time the methadone dosage was increased. After substituting methadone with levomethadone, while maintaining equivalent dosages, the patient reported a stark reduction in sweating. Therefore, levomethadone could be a promising alternative for patients in methadone maintenance therapy who suffer from methadone-induced hyperhidrosis.
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Identification of glutamate-related disease-dependent alterations in subventricular NSCs of the 3xTg Alzheimer’s disease model, could they be involved in attempting damage repair?
Anno: 2025
Rivista: CELL AND TISSUE RESEARCH
Autori/autrici: Cerqueni, Giorgia; Terenzi, Valentina; Preziuso, Alessandra; Serfilippi, Tiziano; Piccirillo, Silvia; Di Vincenzo, Mariangela; Ambrogini, Patrizia; Amoroso, Salvatore; Orciani, Monia; Lariccia, Vincenzo; Magi, Simona
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/343933
Citazioni:
Identification of glutamate-related disease-dependent alterations in subventricular NSCs of the 3xTg Alzheimer’s disease model, could they be involved in attempting damage repair? / Cerqueni, G., Terenzi, V., Preziuso, A., Serfilippi, T., Piccirillo, S., Di Vincenzo, M., Ambrogini, P., Amoroso, S., Orciani, M., Lariccia, V., Magi, S.. - In: CELL AND TISSUE RESEARCH. - ISSN 0302-766X. - 400:(2025), pp. 241-253. [10.1007/s00441-025-03954-6]
Abstract:
Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterised by several factors, such as impaired glutamate neurotransmission affecting crucial functions. Neural stem cells (NSCs) are present in the adult brains of all mammalian species and contribute to the continuous g...eneration of neural cells throughout life. The disruption of glutamate levels during the development of AD could impact NSCs’ functionality, influencing their response to the microenvironment. In this work, we isolated adult neural stem cells from both triple transgenic (3xTg)-AD mice and age-matched wild type (WT) mice in order to gather information on any differences between them, particularly concerning the potential mechanisms involved in the internalisation of glutamate and its utilisation for energy production. The 3xTg model offers the ability to recapitulate human pathology with both plaque and tangle hallmarks that are involved in the process of glutamate release. In vitro culture 3xTg NSCs showed a slight morphological difference compared to WT cells and a massive reduction of proliferation and viability. Furthermore, 3xTg NSCs displayed an increase in the expression of glutamate transporters and glutamine synthetase, while glutamate dehydrogenase did not show any reduction, which is typical in AD brains. Data obtained from this basic research study suggest a possible involvement of glutamate in the cellular energy balance, indicating an attempted response of NSCs to the cytotoxic microenvironment in the early stage of AD pathology. This finding is of great interest, as it corroborates the hypothesis that targeting the glutamatergic system could be an extremely promising strategy for new therapeutics in AD.
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Adjuvant treatment with Capecitabine in patients who received orthotopic liver transplantation with incidental diagnosis of intrahepatic cholangiocarcinoma. Implications on DPYD polymorphisms assessment: report of two cases and review of the literature
Anno: 2025
Rivista: CANCER CHEMOTHERAPY AND PHARMACOLOGY
Autori/autrici: Liguori, Carolina; Magi, Simona; Mandolesi, Alessandra; Agostini, Andrea; Svegliati-Baroni, Gianluca; Benedetti Cacciaguerra, Andrea; Parisi, Alessandro; Tiberi, Elisa; Vivarelli, Marco; Giovagnoni, Andrea; Goteri, Gaia; Castaldo, Pasqualina; Berardi, Rossana; Giampieri, Riccardo
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/342001
Citazioni:
Adjuvant treatment with Capecitabine in patients who received orthotopic liver transplantation with incidental diagnosis of intrahepatic cholangiocarcinoma. Implications on DPYD polymorphisms assessment: report of two cases and review of the literature / Liguori, C., Magi, S., Mandolesi, A., Agostini, A., Svegliati-Baroni, G., Benedetti Cacciaguerra, A., Parisi, A., Tiberi, E., Vivarelli, M., Giovagnoni, A., Goteri, G., Castaldo, P., Berardi, R., Giampieri, R.. - In: CANCER CHEMOTHERAPY AND PHARMACOLOGY. - ISSN 0344-5704. - 95:1(2025). [10.1007/s00280-025-04756-x]
Abstract:
In recent years, assessing dihydropyrimidine dehydrogenase (DPD) activity has become crucial for cancer patients undergoing 5-fluorouracil (5FU)-based chemotherapy due to the life-threatening toxicity associated with reduced DPD function. The methods for evaluating DPD activity have evolved, with th...e analysis of DPYD polymorphisms in blood samples becoming the preferred approach. As the indications for liver transplantation are increasing—particularly due to a rise in cases of cholangiocarcinoma (CCA) and non-resectable colorectal liver metastasis—more cancer patients with a history of liver transplantation may experience disease relapse. Furthermore, 5-fluorouracil chemotherapy is a standard treatment for both cancers. This growing need to evaluate DPD activity in transplanted livers arises because standard tests conducted on blood samples reflect the activity of native liver tissue and may produce misleading results. This paper presents two clinical cases from 2022 to 2023 involving patients who underwent successful liver transplants but were later diagnosed with intrahepatic CCA in the explanted liver. Both patients were subsequently prescribed capecitabine as adjuvant chemotherapy, making it essential to assess DPD activity in donor liver tissue to ensure safe treatment protocols. However, there are currently no established guidelines for this specific patient group. If we follow standard clinical practice, this critical analysis will be insufficient, as it only describes the DPD activity of the native liver. It is imperative to determine the DPD activity of the transplanted liver. In summary, this case report highlights the importance of managing this complex situation effectively
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The Impact and Performance of the Molecular Tumor Board: Three-Year Activity in Precision Medicine for Treatment of Patients with Cancer from the Marche Region, in Italy
Anno: 2025
Rivista: ONCOLOGY AND THERAPY
Autori/autrici: Agostinelli, Veronica; Torresi, Giada; Tarantino, Valentina; Goteri, Gaia; Filosa, Alessandra; Barbisan, Francesca; Bartoli, Elisa; Bianchi, Francesca; Chiodi, Natalia; Ambrosini, Elisa; Ricci, Giulia; Lucarelli, Alessandra; Burattini, Michela; Biagioni, Alice; Chiariotti, Sara; Magi, Simona; Mentrasti, Giulia; Morgese, Francesca; Papa, Roberto; Petrelli, Riccardo; Berardi, Rossana
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/341999
Citazioni:
The Impact and Performance of the Molecular Tumor Board: Three-Year Activity in Precision Medicine for Treatment of Patients with Cancer from the Marche Region, in Italy / Agostinelli, V., Torresi, G., Tarantino, V., Goteri, G., Filosa, A., Barbisan, F., Bartoli, E., Bianchi, F., Chiodi, N., Ambrosini, E., Ricci, G., Lucarelli, A., Burattini, M., Biagioni, A., Chiariotti, S., Magi, S., Mentrasti, G., Morgese, F., Papa, R., Petrelli, R., et al.. - In: ONCOLOGY AND THERAPY. - ISSN 2366-1070. - 13:1(2025), pp. 201-215. [10.1007/s40487-025-00325-7]
Abstract:
Introduction: Cancer incidence is rising in Italy, making it harder for researchers to search for innovative and comprehensive treatment strategies. The advancement of precision medicine, the hunt for molecular targets, and the development of drugs that may operate on a specific target have all beco...me increasingly important aspects of the oncological treatment strategy in recent years. The aim of this study is to analyze the activity and performance of the Oncology and Research Center of the Marche Region (CORM) and its Molecular Tumor Board (MTB) in implementing precision medicine to improve cancer treatment. Methods: CORM was established to provide multidisciplinary diagnostic and therapeutic services, promoting early diagnosis, innovative treatments, and continuous patients support. The MTB, including various specialists, facilitates the interpretation of genomic profiles to identify targeted therapies. Results: From June 2021 to May 2024, 118 patients were evaluated at the MTB of the Marche Region, with 77 undergoing molecular profiling. This study highlights the efficacy of the MTB in selecting appropriate molecular tests, interpreting results, and recommending personalized treatment strategies, leading to improved patient outcomes. Conclusion: Challenges such as the complexity of genomic data interpretation and the need for more computational tools to assist clinicians were also identified. Still, constant multidisciplinary collaboration between experts and the finest possible innovative technological support are required to achieve the best outcomes in cancer treatment
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A non‐redundant role of EAAT3 for ATP synthesis mediated by GDH in dopaminergic neuronal cells: a new avenue for glutamate metabolism and protection in Parkinson's disease
Anno: 2025
Rivista: THE FEBS JOURNAL
Autori/autrici: Preziuso, Alessandra; Serfilippi, Tiziano; Toujani, Marwa; Terenzi, Valentina; Amoroso, Salvatore; Magi, Simona; Lariccia, Vincenzo; Piccirillo, Silvia
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/343777
Citazioni:
A non‐redundant role of EAAT3 for ATP synthesis mediated by GDH in dopaminergic neuronal cells: a new avenue for glutamate metabolism and protection in Parkinson's disease / Preziuso, A., Serfilippi, T., Toujani, M., Terenzi, V., Amoroso, S., Magi, S., Lariccia, V., Piccirillo, S.. - In: THE FEBS JOURNAL. - ISSN 1742-464X. - 292:12(2025), pp. 3224-3241. [10.1111/febs.70053]
Abstract:
Parkinson's disease (PD) is a devastating neurodegenerative disorder with a distinct loss of the nigrostriatal dopaminergic pathway. Despite the multiplicity in etiology, alterations that disrupt neuronal integrity can be traced back to defects in fundamental processes that typically run under ...mitochondrial inputs. Evidence indicates that mitochondrial activities are hierarchically integrated with the energetic performance of these organelles, so that an interesting perspective holds that interventions aimed at improving mitochondrial bioenergetics can potentially mitigate the severity of PD phenotype expression. In this mechanistic framework, approaches that facilitate the mitochondrial anaplerotic use of glutamate (Glut) might counteract the detrimental shift from Glut metabolism, which is typically altered in PD, to excessive Glut transmission that feeds excitotoxicity and the neurodegenerative spiral. In this study, we investigated whether the enhancement of glutamate dehydrogenase (GDH) activity, by using the GDH activator 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH), has neuroprotective potential against PD injury. In both retinoic acid-differentiated SH-SY5Y cells and primary rat mesencephalic neurons challenged with α-synuclein plus rotenone to mimic PD, BCH-dependent GDH activation significantly ameliorated cell viability, improved mitochondrial ATP synthesis and lessened to control levels the cellular redox burden. Strikingly, we collected evidence for the existence of a functional axis connecting GDH activity to a specific intracellular pool of the Excitatory Amino Acid Transporters (EAATs), namely the EAAT3. Overall, our results reveal a novel and non-redundant role of EAAT3 for GDH-dependent protection against PD injury, which may inspire new pharmacological approaches against PD pathology.
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Moringa oleifera Extracts as Strategic Phyto-Therapy for Alzheimer's Disease
Anno: 2025
Rivista: FOOD SCIENCE & NUTRITION
Autori/autrici: Carrotta, Rita; Vilasi, Silvia; Costa, Maria Assunta; Librizzi, Fabio; Martorana, Vincenzo; Passantino, Rosa; Buzzanca, Carla; di Stefano, Vita; Ortore, Maria Grazia; Piccirillo, Silvia; Preziuso, Alessandra; Magi, Simona; Mangione, Maria Rosalia
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/343035
Citazioni:
Moringa oleifera Extracts as Strategic Phyto-Therapy for Alzheimer's Disease / Carrotta, R., Vilasi, S., Costa, M.A., Librizzi, F., Martorana, V., Passantino, R., Buzzanca, C., di Stefano, V., Ortore, M.G., Piccirillo, S., Preziuso, A., Magi, S., Mangione, M.R.. - In: FOOD SCIENCE & NUTRITION. - ISSN 2048-7177. - 13:4(2025). [10.1002/fsn3.70007]
Abstract:
In the last decades, plant extracts have received great attention. In particular, many studies pointed out the potential neuroprotective effect of polyphenols-rich extracts from plants. Evidence indeed highlights the action of polyphenols, both as antioxidants and as inhibitors in the formation of a...myloid protein aggregates, known to be involved in neurodegenerative diseases. In this work, aqueous extracts obtained at high and room temperature from leaves of Moringa oleifera (MO) harvested in Sicily were characterized for polyphenolic content, anti-oxidative and free radical scavenging capacity. UHPLC-HESI-MS analysis shows that both water extracts are rich in terms of polyphenols. Then, MO aqueous extracts were tested as inhibitors in the amyloid aggregation process of Amyloid β-peptide 1–42 (Aβ1-42). This peptide is strongly involved in Alzheimer's disease (AD), its overproduction and aggregated species being considered a hallmark of AD. Results show that MO extracts cause a strong inhibition on the amyloid process. Biophysical characterization of the extracts reveals the presence of stable polyphenol assemblies. Both free and aggregated polyphenols elicit an efficient inhibition mechanism held up by their ability to interact with metastable species, strongly hindering autocatalytic amyloid growth. Finally, the effects of the MO room temperature extract have been tested on an AD cell model, retinoic acid-differentiated SH-SY5Y cells challenged with glyceraldehyde (GA). Cell pretreatment with MO extract results in an improved cell viability in comparison with the control and furthermore in the reduction of both mitochondrial reactive oxygen species and GA-stimulated Aβ1-42 production.
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Exploring the Role of NCX1 and NCX3 in an In Vitro Model of Metabolism Impairment: Potential Neuroprotective Targets for Alzheimer's Disease
Anno: 2023
Rivista: BIOLOGY
Autori/autrici: Preziuso, Alessandra; Piccirillo, Silvia; Cerqueni, Giorgia; Serfilippi, Tiziano; Terenzi, Valentina; Vinciguerra, Antonio; Orciani, Monia; Amoroso, Salvatore; Magi, Simona; Lariccia, Vincenzo
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/321551
Citazioni:
Exploring the Role of NCX1 and NCX3 in an In Vitro Model of Metabolism Impairment: Potential Neuroprotective Targets for Alzheimer's Disease / Preziuso, A., Piccirillo, S., Cerqueni, G., Serfilippi, T., Terenzi, V., Vinciguerra, A., Orciani, M., Amoroso, S., Magi, S., Lariccia, V.. - In: BIOLOGY. - ISSN 2079-7737. - 12:7(2023). [10.3390/biology12071005]
Abstract:
Simple Summary Alzheimer's disease (AD) is a progressive neurodegenerative disorder and represents the most common cause of dementia among elderly people. It is characterized by the deterioration of brain cells and is linked to problems with energy production, cell metabolism, and harmful oxida...tive stress. Our study focused on two proteins called NCX1 and NCX3, which play a role in controlling calcium and sodium levels in cells. We wanted to understand whether these proteins may be involved in AD development when brain cells are exposed to metabolic impairment. To investigate this, we used a laboratory cell model and treated the cells with a substance called glyceraldehyde (GA) to mimic the metabolic dysfunction seen in AD. We used a technique called RNA interference to silence the expression of either NCX1 or NCX3 in the cells. We found that when NCX3 was silenced, the cells showed improved viability, increased energy production, and reduced damage from oxidative stress. Additionally, the levels of abnormal proteins associated with AD, such as A & beta; and pTau, were decreased. However, silencing NCX1 did not have the same positive effects, except for increased energy production. These findings suggest that targeting NCX3 may be a potential strategy to prevent the development of AD associated with metabolic dysfunction. Considering the paucity of pharmacological therapies, this knowledge could be valuable for identifying new potential treatments for AD. Alzheimer's disease (AD) is a widespread neurodegenerative disorder, affecting a large number of elderly individuals worldwide. Mitochondrial dysfunction, metabolic alterations, and oxidative stress are regarded as cooperating drivers of the progression of AD. In particular, metabolic impairment amplifies the production of reactive oxygen species (ROS), resulting in detrimental alterations to intracellular Ca2+ regulatory processes. The Na+/Ca2+ exchanger (NCX) proteins are key pathophysiological determinants of Ca2+ and Na+ homeostasis, operating at both the plasma membrane and mitochondria levels. Our study aimed to explore the role of NCX1 and NCX3 in retinoic acid (RA) differentiated SH-SY5Y cells treated with glyceraldehyde (GA), to induce impairment of the default glucose metabolism that typically precedes A & beta; deposition or Tau protein phosphorylation in AD. By using an RNA interference-mediated approach to silence either NCX1 or NCX3 expression, we found that, in GA-treated cells, the knocking-down of NCX3 ameliorated cell viability, increased the intracellular ATP production, and reduced the oxidative damage. Remarkably, NCX3 silencing also prevented the enhancement of A & beta; and pTau levels and normalized the GA-induced decrease in NCX reverse-mode activity. By contrast, the knocking-down of NCX1 was totally ineffective in preventing GA-induced cytotoxicity except for the increase in ATP synthesis. These findings indicate that NCX3 and NCX1 may differently influence the evolution of AD pathology fostered by glucose metabolic dysfunction, thus providing a potential target for preventing AD.
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A strategic tool to improve the study of molecular determinants of Alzheimer's disease: The role of glyceraldehyde
Anno: 2023
Rivista: BIOCHEMICAL PHARMACOLOGY
Autori/autrici: Piccirillo, Silvia; Preziuso, Alessandra; Cerqueni, Giorgia; Serfilippi, Tiziano; Terenzi, Valentina; Vinciguerra, Antonio; Amoroso, Salvatore; Lariccia, Vincenzo; Magi, Simona
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/325811
Citazioni:
A strategic tool to improve the study of molecular determinants of Alzheimer's disease: The role of glyceraldehyde / Piccirillo, S., Preziuso, A., Cerqueni, G., Serfilippi, T., Terenzi, V., Vinciguerra, A., Amoroso, S., Lariccia, V., Magi, S.. - In: BIOCHEMICAL PHARMACOLOGY. - ISSN 1873-2968. - ELETTRONICO. - 218:(2023). [10.1016/j.bcp.2023.115869]
Abstract:
Alzheimer's disease (AD) is the most prevalent form of dementia and is characterized by progressive neurodegeneration leading to severe cognitive, memory, and behavioral impairments. The onset of AD involves a complex interplay among various factors, including age, genetics, chronic inflammatio...n, and impaired energy metabolism. Despite significant efforts, there are currently no effective therapies capable of modifying the course of AD, likely owing to an excessive focus on the amyloid hypothesis and a limited consideration of other intracellular pathways. In the present review, we emphasize the emerging concept of AD as a metabolic disease, where alterations in energy metabolism play a critical role in its development and progression. Notably, glucose metabolism impairment is associated with mitochondrial dysfunction, oxidative stress, Ca2+ dyshomeostasis, and protein misfolding, forming interconnected processes that perpetuate a detrimental self-feeding loop sustaining AD progression. Advanced glycation end products (AGEs), neurotoxic compounds that accumulate in AD, are considered an important consequence of glucose metabolism disruption, and glyceraldehyde (GA), a glycolytic intermediate, is a key contributor to AGEs formation in both neurons and astrocytes. Exploring the impact of GA-induced glucose metabolism impairment opens up exciting possibilities for creating an easy-to-handle in vitro model that recapitulates the early stage of the disease. This model holds great potential for advancing the development of novel therapeutics targeting various intracellular pathways implicated in AD pathogenesis. In conclusion, looking beyond the conventional amyloid hypothesis could lead researchers to discover promising targets for intervention, offering the possibility of addressing the existing medical gaps in AD treatment.
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Taurine Stabilizing Effect on Lysozyme
Anno: 2022
Rivista: LIFE
Autori/autrici: Mastrella, Leonardo; Moretti, Paolo; Pieraccini, Silvia; Magi, Simona; Piccirillo, Silvia; Ortore, Maria Grazia
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/294781
Citazioni:
Taurine Stabilizing Effect on Lysozyme / Mastrella, L., Moretti, P., Pieraccini, S., Magi, S., Piccirillo, S., Ortore, M.G.. - In: LIFE. - ISSN 2075-1729. - STAMPA. - 12:1(2022). [10.3390/life12010133]
Abstract:
Taurine is an important organic osmolyte in mammalian cells, and it weakens inflammationand oxidative stress mediated injuries in some diseases. Recently, taurine has been demonstratedto play a therapeutic role against neurodegenerative disorders, although its parallel involvement inseveral biochemi...cal mechanisms makes not clear taurine specific role in these diseases. Furthermore,the stabilizing effect of this molecule in terms of protein stability is known, but not deeply investigated.In this work we explore by Circular Dichroism the stabilizing impact of taurine in lysozyme thermaldenaturation and its influence in lysozyme aggregation into amyloid fibrils. Taurine even at lowconcentration modifies protein-protein interactions in lysozyme native state, as revealed by SmallAngle X-ray Scattering experiments, and alters the amyloid aggregation pattern without completelyinhibiting it, as confirmed by UV/Vis spectroscopy with Congo Red and by Atomic Force Microscopy.Evaluation of the cytotoxicities of the amyloid fibrils grown in presence or in absence of taurine isinvestigated on SH-SY5Y neuroblastoma cells.
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A new K+channel-independent mechanism is involved in the antioxidant effect of XE-991 in an in vitro model of glucose metabolism impairment: implications for Alzheimer’s disease
Anno: 2022
Rivista: CELL DEATH DISCOVERY
Autori/autrici: Piccirillo, Silvia; Preziuso, Alessandra; Amoroso, Salvatore; Serfilippi, Tiziano; Miceli, Francesco; Magi, Simona; Lariccia, Vincenzo
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/306060
Citazioni:
A new K+channel-independent mechanism is involved in the antioxidant effect of XE-991 in an in vitro model of glucose metabolism impairment: implications for Alzheimer’s disease / Piccirillo, S., Preziuso, A., Amoroso, S., Serfilippi, T., Miceli, F., Magi, S., Lariccia, V.. - In: CELL DEATH DISCOVERY. - ISSN 2058-7716. - 8:1(2022). [10.1038/s41420-022-01187-y]
Abstract:
Alzheimer's disease (AD) is a neurodegenerative disorder that represents the first cause of dementia. Although there has been significant progress in AD research, the actual mechanisms underlying this pathology remain largely unknown. There is increasing evidence that oxidative stress, metaboli...c alterations, and mitochondrial dysfunction are key players in the development and worsening of AD. As a result, in the past few years, remarkable attempts have been made to develop neuroprotective strategies against the impairment of mitochondrial dynamics and cell redox status. In the present study, we reveal a novel antioxidant K+ channel-independent effect of the M-current inhibitor XE-991 in SH-SY5Y cells differentiated with retinoic acid (RA) and primary rat cortical neurons exposed to the glycolysis inhibitor glyceraldehyde (GA). This experimental approach aimed to create a condition of hypometabolism accompanied by mitochondrial dysfunction and redox imbalance, as frequently observed in the beginning stage of the disease. We found that XE-991 exerted a neuroprotective action most likely through the resumption of superoxide dismutase (SOD) activity, which was significantly compromised during GA challenge. We also observed that the enhancement of SOD activity was accompanied by a sequence of positive effects; these included the reduction in basal Ca2+ levels within cytoplasmic and mitochondrial compartments, the decrease in mitochondrial reactive oxygen species (ROS) production, the modulation of AMPK/mTOR pathway, the recovery of ΔΨm collapse, the increase in the intracellular ATP content and the decrease in amyloid-β (Aβ) and hyperphosphorylated form of tau protein (pTau) levels. Collectively, our study reveals an off-target antioxidant effect of XE-991 and paves the way toward the further evaluation of new therapeutic uses of already existing molecules to accelerate the process of developing an effective therapy to counteract AD.
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Mesenchymal Stem Cells Profile in Adult Atopic Dermatitis and Effect of IL4-IL13 Inflammatory Pathway Inhibition In Vivo: Prospective Case-Control Study
Anno: 2022
Rivista: JOURNAL OF CLINICAL MEDICINE
Autori/autrici: Campanati, Anna; Orciani, Monia; Marani, Andrea; Di Vincenzo, Mariangela; Magi, Simona; Gregoriou, Stamatios; Diotallevi, Federico; Martina, Emanuela; Radi, Giulia; Offidani, Annamaria
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/314437
Citazioni:
Mesenchymal Stem Cells Profile in Adult Atopic Dermatitis and Effect of IL4-IL13 Inflammatory Pathway Inhibition In Vivo: Prospective Case-Control Study / Campanati, A., Orciani, M., Marani, A., Di Vincenzo, M., Magi, S., Gregoriou, S., Diotallevi, F., Martina, E., Radi, G., Offidani, A.. - In: JOURNAL OF CLINICAL MEDICINE. - ISSN 2077-0383. - 11:16(2022). [10.3390/jcm11164759]
Abstract:
Atopic dermatitis (AD) is an inflammatory disease that typically begins in childhood and may persist into adulthood, becoming a lifelong condition. The major inflammatory mediators of AD are known to be interleukin IL4 and IL13, so Dupilumab, which is able to inhibit both interleukins by blocking th...e shared IL4R alpha subunit, has become an attractive option for treating AD. Mesenchymal stem cells (MSCs) are involved in the onset and development of AD by secreting specific interleukins. The aim of this study was to isolate MSCs from healthy controls (C-MSCs) and patients with AD before (AD-MSCs T0) and after 16 weeks of treatment with Dupilumab (AD-MSCs T16); to evaluate the expression mainly of IL4 and IL13 and of other inflammatory cytokines in C-MSCs, AD-MSCs at T0 and at T16; and to evaluate the efficacy of Dupilumab on MSCs immunobiology. C- and AD-MSCs (T0, T16) were isolated from skin specimens and characterized; the expression/secretion of IL4 and IL13 was evaluated using immuno-cytochemistry (ICC), indirect immune-fluorescence (IIF) and an ELISA test; secretion of IL2, IL4, IL5, IL6, IL10, IL12, IL13, IL17A, Interferon gamma (IFN gamma), Tumor necrosis factor alpha (TNF alpha), Granulocyte Colony-Stimulating Factor (G-CSF), and Transforming Growth Factor beta1 (TGF beta 1) were measured with ELISA. IL13 and IL6 were over-expressed, while IL4 was down-regulated in AD-MSCs at T0 compared to C-MSCs. IL6 and IL13 expression was restored after 16 weeks of Dupilumab treatment, while no significant effects on IL4 expression were noted. Finally, IL2, IL5, IL10, IL12, IL17A, INF gamma, TNF alpha, G-CSF, and TGF beta 1 were similarly secreted by C- and AD-MSCs. Although Dupilumab blocks the IL4R alpha subunit shared by IL4 and IL13, it is evident that its real target is IL13, and its ability to target IL13 in MSCs reinforces the evidence, already known in differentiated cells, of the central role IL13 rather than IL4 in the development of AD. The inflammatory cascade in AD begins at the mesenchymal level, so an upstream therapeutic intervention, able to modify the immunobiology of atopic MSCs, could potentially change the natural history of the disease.
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The Hidden Notes of Redox Balance in Neurodegenerative Diseases
Anno: 2022
Rivista: ANTIOXIDANTS
Autori/autrici: Piccirillo, Silvia; Magi, Simona; Preziuso, Alessandra; Serfilippi, Tiziano; Cerqueni, Giorgia; Orciani, Monia; Amoroso, Salvatore; Lariccia, Vincenzo
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/305542
Citazioni:
The Hidden Notes of Redox Balance in Neurodegenerative Diseases / Piccirillo, S., Magi, S., Preziuso, A., Serfilippi, T., Cerqueni, G., Orciani, M., Amoroso, S., Lariccia, V.. - In: ANTIOXIDANTS. - ISSN 2076-3921. - 11:8(2022). [10.3390/antiox11081456]
Abstract:
Reactive oxygen species (ROS) are versatile molecules that, even if produced in the background of many biological processes and responses, possess pleiotropic roles categorized in two interactive yet opposite domains. In particular, ROS can either function as signaling molecules that shape physiolog...ical cell functions, or act as deleterious end products of unbalanced redox reactions. Indeed, cellular redox status needs to be tightly regulated to ensure proper cellular functioning, and either excessive ROS accumulation or the dysfunction of antioxidant systems can perturb the redox homeostasis, leading to supraphysiological concentrations of ROS and potentially harmful outcomes. Therefore, whether ROS would act as signaling molecules or as detrimental factors strictly relies on a dynamic equilibrium between free radical production and scavenging resources. Of notice, the mammalian brain is particularly vulnerable to ROS-mediated toxicity, because it possesses relatively poor antioxidant defenses to cope with the redox burden imposed by the elevated oxygen consumption rate and metabolic activity. Many features of neurodegenerative diseases can in fact be traced back to causes of oxidative stress, which may influence both the onset and progression of brain demise. This review focuses on the description of the dual roles of ROS as double-edge sword in both physiological and pathological settings, with reference to Alzheimer's and Parkinson's diseases.
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Control of Ca2+ and metabolic homeostasis by the Na+/Ca2+ exchangers (NCXs) in health and disease
Anno: 2022
Rivista: BIOCHEMICAL PHARMACOLOGY
Autori/autrici: Rodrigues, Tiago; Piccirillo, Silvia; Magi, Simona; Preziuso, Alessandra; Dos Santos Ramos, Vyctória; Serfilippi, Tiziano; Orciani, Monia; Maciel Palacio Alvarez, Marcela; Luis Dos Santos Tersariol, Ivarne; Amoroso, Salvatore; Lariccia, Vincenzo
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/304502
Citazioni:
Control of Ca2+ and metabolic homeostasis by the Na+/Ca2+ exchangers (NCXs) in health and disease / Rodrigues, T., Piccirillo, S., Magi, S., Preziuso, A., Dos Santos Ramos, V., Serfilippi, T., Orciani, M., Maciel Palacio Alvarez, M., Luis Dos Santos Tersariol, I., Amoroso, S., Lariccia, V.. - In: BIOCHEMICAL PHARMACOLOGY. - ISSN 0006-2952. - 203:(2022), p. 115163. [10.1016/j.bcp.2022.115163]
Abstract:
Spatial and temporal control of calcium (Ca2+) levels is essential for the background rhythms and responses of living cells to environmental stimuli. Whatever other regulators a given cellular activity may have, localized and wider scale Ca2+ events (sparks, transients, and waves) are hierarchical d...eterminants of fundamental processes such as cell contraction, excitability, growth, metabolism and survival. Different cell types express specific channels, pumps and exchangers to efficiently generate and adapt Ca2+ patterns to cell requirements. The Na+/Ca2+ exchangers (NCXs) in particular contribute to Ca2+ homeostasis by buffering intracellular Ca2+ loads according to the electrochemical gradients of substrate ions - i.e., Ca2+ and sodium (Na+) - and under a dynamic control of redundant regulatory processes. An interesting feature of NCX emerges from the strict relationship that connects transporter activity with cell metabolism: on the one hand NCX operates under constant control of ATP-dependent regulatory processes, on the other hand the ion fluxes generated through NCX provide mechanistic support for the Na+-driven uptake of glutamate and Ca2+ influx to fuel mitochondrial respiration. Proof of concept evidence highlights therapeutic potential of preserving a timed and balanced NCX activity in a growing rate of diseases (including excitability, neurodegenerative, and proliferative disorders) because of an improved ability of stressed cells to safely maintain ion gradients and mitochondrial bioenergetics. Here, we will summarize and review recent works that have focused on the pathophysiological roles of NCXs in balancing the two-way relationship between Ca2+ signals and metabolism.
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The Neuroprotective Effect of L-Carnitine against Glyceraldehyde-Induced Metabolic Impairment: Possible Implications in Alzheimer's Disease
Anno: 2021
Rivista: CELLS
Autori/autrici: Magi, Simona; Preziuso, Alessandra; Piccirillo, Silvia; Giampieri, Francesca; Cianciosi, Danila; Orciani, Monia; Amoroso, Salvatore
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/291830
Citazioni:
The Neuroprotective Effect of L-Carnitine against Glyceraldehyde-Induced Metabolic Impairment: Possible Implications in Alzheimer's Disease / Magi, S., Preziuso, A., Piccirillo, S., Giampieri, F., Cianciosi, D., Orciani, M., Amoroso, S.. - In: CELLS. - ISSN 2073-4409. - STAMPA. - 10:8(2021), p. 2109. [10.3390/cells10082109]
Abstract:
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive regression and memory loss. Dysfunctions of both glucose metabolism and mitochondrial dynamics have been recognized as the main upstream events of the degenerative processes leading to AD. It has bee...n recently found that correcting cell metabolism by providing alternative substrates can prevent neuronal injury by retaining mitochondrial function and reducing AD marker levels. Here, we induced an AD-like phenotype by using the glycolysis inhibitor glyceraldehyde (GA) and explored whether L-carnitine (4-N-trimethylamino-3-hydroxybutyric acid, LC) could mitigate neuronal damage, both in SH-SY5Y neuroblastoma cells and in rat primary cortical neurons. We have already reported that GA significantly modified AD marker levels; here we demonstrated that GA dramatically compromised cellular bioenergetic status, as revealed by glycolysis and oxygen consumption rate (OCR) evaluation. We found that LC ameliorated cell survival, improved OCR and ATP synthesis, prevented the loss of the mitochondrial membrane potential (Delta psi(m)) and reduced the formation of reactive oxygen species (ROS). Of note, the beneficial effect of LC did not rely on the glycolytic pathway rescue. Finally, we noticed that LC significantly reduced the increase in pTau levels induced by GA. Overall, these findings suggest that the use of LC can promote cell survival in the setting of the metabolic impairments commonly observed in AD. Our data suggest that LC may act by maintaining mitochondrial function and by reducing the pTau level.
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Gateways for Glutamate Neuroprotection in Parkinson's Disease (PD): Essential Role of EAAT3 and NCX1 Revealed in an In Vitro Model of PD
Anno: 2020
Rivista: CELLS
Autori/autrici: Piccirillo, S.; Magi, S.; Preziuso, A.; Castaldo, P.; Amoroso, S.; Lariccia, V.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/284539
Citazioni:
Gateways for Glutamate Neuroprotection in Parkinson's Disease (PD): Essential Role of EAAT3 and NCX1 Revealed in an In Vitro Model of PD / Piccirillo, S., Magi, S., Preziuso, A., Castaldo, P., Amoroso, S., Lariccia, V.. - In: CELLS. - ISSN 2073-4409. - ELETTRONICO. - 9:9(2020), p. 2037. [10.3390/cells9092037]
Abstract:
Increasing evidence suggests that metabolic alterations may be etiologically linked to neurodegenerative disorders such as Parkinson's disease (PD) and in particular empathizes the possibility of targeting mitochondrial dysfunctions to improve PD progression. Under different pathological condit...ions (i.e., cardiac and neuronal ischemia/reperfusion injury), we showed that supplementation of energetic substrates like glutamate exerts a protective role by preserving mitochondrial functions and enhancing ATP synthesis through a mechanism involving the Na+-dependent excitatory amino acid transporters (EAATs) and the Na+/Ca2+ exchanger (NCX). In this study, we investigated whether a similar approach aimed at promoting glutamate metabolism would be also beneficial against cell damage in an in vitro PD-like model. In retinoic acid (RA)-differentiated SH-SY5Y cells challenged with α-synuclein (α-syn) plus rotenone (Rot), glutamate significantly improved cell viability by increasing ATP levels, reducing oxidative damage and cytosolic and mitochondrial Ca2+ overload. Glutamate benefits were strikingly lost when either EAAT3 or NCX1 expression was knocked down by RNA silencing. Overall, our results open the possibility of targeting EAAT3/NCX1 functions to limit PD pathology by simultaneously favoring glutamate uptake and metabolic use in dopaminergic neurons.
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NCX1 and EAAC1 transporters are involved in the protective action of glutamate in an in vitro Alzheimer's disease-like model
Anno: 2020
Rivista: CELL CALCIUM
Autori/autrici: Magi, S.; Piccirillo, S.; Maiolino, M.; Lariccia, V.; Amoroso, S.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/284540
Citazioni:
NCX1 and EAAC1 transporters are involved in the protective action of glutamate in an in vitro Alzheimer's disease-like model / Magi, S., Piccirillo, S., Maiolino, M., Lariccia, V., Amoroso, S.. - In: CELL CALCIUM. - ISSN 0143-4160. - ELETTRONICO. - 91:(2020), p. 102268. [10.1016/j.ceca.2020.102268]
Abstract:
Increasing evidence suggests that metabolic dysfunctions are at the roots of neurodegenerative disorders such as Alzheimer's disease (AD). In particular, defects in cerebral glucose metabolism, which have been often noted even before the occurrence of clinical symptoms and histopathological les...ions, are now regarded as critical contributors to the pathogenesis of AD. Hence, the stimulation of energy metabolism, by enhancing the availability of specific metabolites, might be an alternative way to improve ATP synthesis and to positively affect AD progression. For instance, glutamate may serve as an intermediary metabolite for ATP synthesis through the tricarboxylic acid (TCA) cycle and the oxidative phosphorylation. We have recently shown that two transporters are critical for the anaplerotic use of glutamate: the Na+-dependent Excitatory Amino Acids Carrier 1 (EAAC1) and the Na+-Ca2+ exchanger 1 (NCX1). Therefore, in the present study, we established an AD-like phenotype by perturbing glucose metabolism in both primary rat cortical neurons and retinoic acid (RA)-differentiated SH-SY5Y cells, and we explored the potential of glutamate to halt cell damage by monitoring neurotoxicity, AD markers, ATP synthesis, cytosolic Ca2+ levels and EAAC1/NCX1 functional activities. We found that glutamate significantly increased ATP production and cell survival, reduced the increase of AD biomarkers (amyloid β protein and the hyperphosphorylated form of tau protein), and recovered the increase of NCX reverse-mode activity. The RNA silencing of either EAAC1 or NCX1 caused the loss of the beneficial effects of glutamate, suggesting the requirement of a functional interplay between these transporters for glutamate-induced protection. Remarkably, our results indicate, as proof-of-principle, that facilitating the use of alternative fuels, like glutamate, may be an effective approach to overcome deficits in glucose utilization and significantly slow down neuronal degenerative process in AD.
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Cracking the code of sodium/calcium exchanger (NCX) gating: old and new complexities surfacing from the deep web of secondary regulations
Anno: 2020
Rivista: CELL CALCIUM
Autori/autrici: Lariccia, Vincenzo; Piccirillo, Silvia; Preziuso, Alessandra; Amoroso, Salvatore; Magi, Simona
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/273467
Citazioni:
Cracking the code of sodium/calcium exchanger (NCX) gating: old and new complexities surfacing from the deep web of secondary regulations / Lariccia, V., Piccirillo, S., Preziuso, A., Amoroso, S., Magi, S.. - In: CELL CALCIUM. - ISSN 0143-4160. - 87:(2020). [10.1016/j.ceca.2020.102169]
Abstract:
Cell membranes spatially define gradients that drive the complexity of biological signals. To guarantee movements and exchanges of solutes between compartments, membrane transporters negotiate the passages of ions and other important molecules through lipid bilayers. The Na+/Ca2+ exchangers (NCXs) i...n particular play central roles in balancing Na+ and Ca2+ fluxes across diverse proteolipid borders in all eukaryotic cells, influencing cellular functions and fate by multiple means. To prevent progression from balance to disease, redundant regulatory mechanisms cooperate at multiple levels (transcriptional, translational, and post-translational) and guarantee that the activities of NCXs are finely-tuned to cell homeostatic requirements. When this regulatory network is disturbed by pathological forces, cells may approach the end of life. In this review, we will discuss the main findings, controversies and open questions about regulatory mechanisms that control NCX functions in health and disease.
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Mitochondrial localization of NCXs: Balancing calcium and energy homeostasis
Anno: 2020
Rivista: CELL CALCIUM
Autori/autrici: Magi, S.; Piccirillo, S.; Preziuso, A.; Amoroso, S.; Lariccia, V.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/273464
Citazioni:
Mitochondrial localization of NCXs: Balancing calcium and energy homeostasis / Magi, S., Piccirillo, S., Preziuso, A., Amoroso, S., Lariccia, V.. - In: CELL CALCIUM. - ISSN 0143-4160. - 86:(2020). [10.1016/j.ceca.2020.102162]
Abstract:
It is well established that mitochondria are the main source of ATP production within cells. However, mitochondria have other remarkable functions, serving as important modulators of cellular Ca2+ signaling, and it is now generally recognized that control over Ca2+ homeostasis is intrinsically inter...woven with mitochondrial abilities to adjust and tune ATP production. In this review, we describe the mechanisms that mitochondria use to balance Ca2+ homeostasis maintenance and cell energy metabolism. In recent years, the knowledge on the molecular machinery mediating Ca2+ influx/efflux has been improved and, albeit still open to further investigations, several lines of evidence converge on the hypothesis that plasma membrane Na+/Ca2+ exchanger (NCX) isoforms are also expressed at the mitochondrial level, where they contribute to the Ca2+ and Na+ homeostasis maintenance. In particular, the connection between mitochondrial NCX activity and metabolic substrates utilization is further discussed here. We also briefly focus on the alterations of both mitochondrial Ca2+ handling and cellular bioenergetics in neurodegenerative diseases, such as Parkinson's and Alzheimer's disease.
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Challenges and Opportunities from Targeting Inflammatory Responses to SARS-CoV-2 Infection: A Narrative Review
Anno: 2020
Rivista: JOURNAL OF CLINICAL MEDICINE
Autori/autrici: Lariccia, Vincenzo; Magi, Simona; Serfilippi, Tiziano; Toujani, Marwa; Gratteri, Santo; Amoroso, Salvatore
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/285998
Citazioni:
Challenges and Opportunities from Targeting Inflammatory Responses to SARS-CoV-2 Infection: A Narrative Review / Lariccia, V., Magi, S., Serfilippi, T., Toujani, M., Gratteri, S., Amoroso, S.. - In: JOURNAL OF CLINICAL MEDICINE. - ISSN 2077-0383. - 9:12(2020), p. 4021. [10.3390/jcm9124021]
Abstract:
The novel coronavirus disease 2019 (COVID-19) is a global pandemic that continues to sweep across the world, posing an urgent need for effective therapies and prevention of the spread of the severe acute respiratory syndrome related to coronavirus-2 (SARS-CoV-2). A major hypothesis that is currently... guiding research and clinical care posits that an excessive and uncontrolled surge of pro-inflammatory cytokines (the so-called "cytokine storm") drives morbidity and mortality in the most severe cases. In the overall efforts made to develop effective and safe therapies (including vaccines) for COVID-19, clinicians are thus repurposing ready-to-use drugs with direct or indirect anti-inflammatory and immunomodulatory activities. Speculatively, there are many opportunities and challenges in targeting immune/inflammatory processes in the evolving settings of COVID-19 disease because of the need to safely balance the fight against virus and aggressive inflammation versus the suppression of host immune defenses and the risk of additional harms in already compromised patients. To this end, many studies are globally underway to weigh the pros and cons of tailoring drugs used for inflammatory-driven conditions to COVID-19 patient care, and the next step will be to summarize the growing clinical trial experience into clean clinical practice. Based on the current evidence, anti-inflammatory drugs should be considered as complementary approaches to anti-viral drugs that need to be timely introduced in the management of COVID-19 according to disease severity. While drugs that target SARS-CoV-2 entry or replication are expected to confer the greatest benefits at the early stage of the infection, anti-inflammatory drugs would be more effective in limiting the inflammatory processes that drive the worsening of the disease.
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NCX and EAAT transporters in ischemia: At the crossroad between glutamate metabolism and cell survival
Anno: 2020
Rivista: CELL CALCIUM
Autori/autrici: Piccirillo, S.; Magi, S.; Castaldo, P.; Preziuso, A.; Lariccia, V.; Amoroso, S.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/273463
Citazioni:
NCX and EAAT transporters in ischemia: At the crossroad between glutamate metabolism and cell survival / Piccirillo, S., Magi, S., Castaldo, P., Preziuso, A., Lariccia, V., Amoroso, S.. - In: CELL CALCIUM. - ISSN 0143-4160. - 86:(2020), p. 102160. [10.1016/j.ceca.2020.102160]
Abstract:
Energy metabolism impairment is a central event in the pathophysiology of ischemia. The limited availability of glucose and oxygen strongly affects mitochondrial activity, thus leading to ATP depletion. In this setting, the switch to alternative energy sources could ameliorate cells survival by enha...ncing ATP production, thus representing an attractive strategy for ischemic treatment. In this regard, some studies have recently re-evaluated the metabolic role of glutamate and its potential to promote cell survival under pathological conditions. In the present review, we discuss the ability of glutamate to exert an “energizing role” in cardiac and neuronal models of hypoxia/reoxygenation (H/R) injury, focusing on the Na+/Ca2+ exchanger (NCX) and the Na+-dependent excitatory amino acid transporters (EAATs) as key players in this metabolic pathway.
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Intracellular Calcium and Ischemic Damage: Dual Role of the Na+/Ca2+ Exchanger
Anno: 2020
Autori/autrici: Magi, Simona; Castaldo, Pasqualina; Lariccia, Vincenzo; Piccirillo, Silvia; Maiolino, Marta; Amoroso, Salvatore
Lingua: ENG
Classificazione IRIS: 2.1 Contributo in volume (Capitolo o Saggio)
Scheda completa IRIS: https://iris.univpm.it/handle/11566/284542
Citazioni:
Intracellular Calcium and Ischemic Damage: Dual Role of the Na+/Ca2+ Exchanger / Magi, S., Castaldo, P., Lariccia, V., Piccirillo, S., Maiolino, M., Amoroso, S.. - STAMPA. - (2020), pp. 361-372. [10.1007/978-3-030-33832-9_24]
Abstract:
Introduction The book describes the significant multidisciplinary research findings at the Università Politecnica delle Marche and the expected future advances. It addresses some of the most dramatic challenges posed by today’s fast-growing, global society and the changes it has caused.... It also discusses solutions to improve the wellbeing of human beings. The book covers the main research achievements in the various disciplines of the life sciences, and includes chapters that highlight mechanisms relevant to all aspects of human diseases, the molecular, cellular, and functional basis of therapy, and its translation into the management of people’s health needs. It also describes research on traditional and innovative foods to enhance quality, safety and functionality, and to develop bioactive/nutraceutical compounds. Further chapters address conservation and management of various environments, from the forests to the oceans, describing the studies on countermeasures against climate changes and terrestrial/aquatic pollutants, and on terrestrial/marine biodiversity, ecosystems and landscapes, erosion of genetic biodiversity, innovative aquaculture feed, sustainable crop production and management of forests. Lastly, the book reports the findings of research work on different classes of biomolecules, and on the molecular basis of antibiotic resistances and their diffusion.
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Excitatory amino acid transporters (Eaats): Glutamate transport and beyond
Anno: 2019
Rivista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Autori/autrici: Magi, S.; Piccirillo, S.; Amoroso, S.; Lariccia, V.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/273468
Citazioni:
Excitatory amino acid transporters (Eaats): Glutamate transport and beyond / Magi, S., Piccirillo, S., Amoroso, S., Lariccia, V.. - In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - ISSN 1661-6596. - 20:22(2019), p. 5674. [10.3390/ijms20225674]
Abstract:
Na+-dependent excitatory amino acid transporters (EAATs) are the major transport mechanisms for extracellular glutamate removal in the central nervous system (CNS). The primary function assigned to EAATs is the maintenance of low extracellular glutamate levels, thus allowing glutamate to be used as ...a signaling molecule in the brain and to avoid excitotoxicity. However, glutamate has other recognized functions. For instance, it is a key anaplerotic substrate for the tricarboxylic acid (TCA) cycle, as it can be converted to α-ketoglutarate by transaminases or glutamate dehydrogenase. Furthermore, glutamate is a precursor of the main antioxidant glutathione, which plays a pivotal role in preventing oxidative cell death. Therefore, glutamate signaling/use is at the crossroad of multiple metabolic pathways and accordingly, it can influence a plethora of cell functions, both in health and disease. Here, we provide an overview of the main functions of glutamate and its transport systems, analyzing its role as a neurotransmitter and at the same time, the possible metabolic fates it can undergo in the intracellular milieu. Specifically, the metabolic role of glutamate and the molecular machinery proposed to metabolically support its transport will be further analyzed.
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Low incidence of nephrotoxicity following intravenous administration of iodinated contrast media: a prospective study
Anno: 2019
Rivista: EUROPEAN RADIOLOGY
Autori/autrici: Castaldo, Pasqualina; Frasca', GIOVANNI MARIA; Brigante, Fabiana; Ferrante, Luigi; Magi, Simona; Pavani, Marianna; Skrami, Edlira; Giuseppetti, Gian Marco; Polonara, Gabriele; Amoroso, Salvatore
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/265725
Citazioni:
Low incidence of nephrotoxicity following intravenous administration of iodinated contrast media: a prospective study / Castaldo, P., Frasca', G.M., Brigante, F., Ferrante, L., Magi, S., Pavani, M., Skrami, E., Giuseppetti, G.M., Polonara, G., Amoroso, S.. - In: EUROPEAN RADIOLOGY. - ISSN 0938-7994. - STAMPA. - 29:7(2019), pp. 3927-3934. [10.1007/s00330-019-06147-2]
Abstract:
Objectives To estimate the incidence of contrast-induced acute kidney injury (CI-AKI) after intravenous (iv) iodinated contrast material (ICM) exposure. Methods This prospective cohort study included all consecutive patients who underwent radiological investigations using lowosmolar iopamidol 370... mg/ml in a regional hospital over a period of 36 months, without any exclusion criteria. The estimated glomerular filtration rate (eGFR) was evaluated using the MRDR equation before (2–10 days) and after (24–36 h) radiological investigations. CI-AKI was defined as a ≥ 25% decrease in eGFR from baseline. CI-AKI incidence was estimated using a binomial distribution. The association between CI-AKI and demographic and clinical characteristics was modeled using logistic regression. Results The study included 1541 patients with a median age of 68 (1st–3rd quartiles 58–76) years with various comorbidities, 30% of whom had pre-existing CKD. Patients affected by stage III or IV chronic kidney disease (CKD) received an infusion of 0.9% normal saline (1.0–1.5 ml/kg/h) before and after iso-osmolar iodixanol administration. CI-AKI was observed in 33 patients (2.1%, 95% CI 1.5–3.0). The logistic regression analysis showed that antibiotic and statin therapies were significantly associated with CI-AKI. The probability of developing CI-AKI decreased by 80% in patients taking statins (OR = 0.20, 95% CI 0.03; 0.68) and increased approximately three times in patients with antibiotic therapy compared with those who did not take statins and antibiotics (OR = 2.92, 95% CI 1.21; 6.36). Conclusions Our data suggest that low-osmolar iopamidol carries a low incidence of nephrotoxicity, even in subjects with various comorbid conditions or reduced renal function.
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Effects of ticagrelor on the sodium/calcium exchanger 1 (NCX1) in cardiac derived H9c2 cells
Anno: 2019
Rivista: EUROPEAN JOURNAL OF PHARMACOLOGY
Autori/autrici: Lariccia, Vincenzo; Macrì, Maria Loredana; Matteucci, Alessandra; Maiolino, Marta; Amoroso, Salvatore; Magi, Simona
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/264124
Citazioni:
Effects of ticagrelor on the sodium/calcium exchanger 1 (NCX1) in cardiac derived H9c2 cells / Lariccia, V., Macrì, M.L., Matteucci, A., Maiolino, M., Amoroso, S., Magi, S.. - In: EUROPEAN JOURNAL OF PHARMACOLOGY. - ISSN 0014-2999. - 850:(2019), pp. 158-166. [10.1016/j.ejphar.2019.01.067]
Abstract:
Ticagrelor is a direct acting and reversibly binding P2Y12 antagonist approved for the prevention of thromboembolic events. Clinical effects of ticagrelor cannot be simply accounted for by pure platelet inhibition, and off-target mechanisms can potentially play a role. In particular, recent evidence... suggests that ticagrelor may also influence heart function and improve the evolution of myocardial ischemic injury by more direct effects on myocytes. The cardiac sodium/calcium exchanger 1 (NCX1) is a critical player in the generation and control of calcium (Ca2+) signals, which orchestrate multiple myocyte activities in health and disease. Altered expression and/or activity of NCX1 can have profound consequences for the function and fate of myocytes. Whether ticagrelor affects cardiac NCX1 has not been investigated yet. To explore this hypothesis, we analyzed the expression, localization and activity of NCX1 in the heart derived H9c2-NCX1 cells following ticagrelor exposure. We found that ticagrelor concentration- and time-dependently reduced the activity of the cardiac NCX1 in H9c2 cells. In particular, the inhibitory effect of ticagrelor on the Ca2+-influx mode of NCX1 was evident within 1 h and further developed after 24 h, when NCX1 activity was suppressed by about 55% in cells treated with 1 μM ticagrelor. Ticagrelor-induced inhibition of exchanger activity was reached at clinically relevant concentrations, without affecting the expression levels and subcellular distribution of NCX1. Collectively, these findings suggest that cardiac NCX1 is a new downstream target of ticagrelor, which may contribute to the therapeutic profile of ticagrelor in clinical practice.
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Selective inhibition of mitochondrial sodium-calcium exchanger protects striatal neurons from α-synuclein plus rotenone induced toxicity
Anno: 2019
Rivista: CELL DEATH & DISEASE
Autori/autrici: Bastioli, Guendalina; Piccirillo, Silvia; Castaldo, Pasqualina; Magi, Simona; Tozzi, Alessandro; Amoroso, Salvatore; Calabresi, Paolo
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/265727
Citazioni:
Selective inhibition of mitochondrial sodium-calcium exchanger protects striatal neurons from α-synuclein plus rotenone induced toxicity / Bastioli, G., Piccirillo, S., Castaldo, P., Magi, S., Tozzi, A., Amoroso, S., Calabresi, P.. - In: CELL DEATH & DISEASE. - ISSN 2041-4889. - 10:2(2019), p. 80. [10.1038/s41419-018-1290-6]
Abstract:
Progressive accumulation of α-synuclein (α-syn) and exposure to environmental toxins are risk factors that may both concur to Parkinson’s disease (PD) pathogenesis. Electrophysiological recordings of field postsynaptic potentials (fEPSPs) and Ca2+ measures in striatal brain slice...s and differentiated SH-SY5Y cells showed that co-application of α-syn and the neurotoxic pesticide rotenone (Rot) induced Ca2+ dysregulation and alteration of both synaptic transmission and cell function. Interestingly, the presence of the mitochondrial NCX inhibitor CGP-37157 prevented these alterations. The specific involvement of the mitochondrial NCX was confirmed by the inability of the plasma membrane inhibitor SN-6 to counteract such phenomenon. Of note, using a siRNA approach, we found that NCX1 was the isoform specifically involved. These findings suggested that NCX1, operating on the mitochondrial membrane, may have a critical role in the maintenance of ionic Ca2+ homeostasis in PD and that its inhibition most likely exerts a protective effect in the toxicity induced by α-syn and Rot.
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The dual face of glutamate: from a neurotoxin to a potential survival factor—metabolic implications in health and disease
Anno: 2019
Rivista: CELLULAR AND MOLECULAR LIFE SCIENCES
Autori/autrici: Magi, Simona; Piccirillo, Silvia; Amoroso, Salvatore
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/265728
Citazioni:
The dual face of glutamate: from a neurotoxin to a potential survival factor—metabolic implications in health and disease / Magi, S., Piccirillo, S., Amoroso, S.. - In: CELLULAR AND MOLECULAR LIFE SCIENCES. - ISSN 1420-682X. - 76:8(2019), pp. 1473-1488. [10.1007/s00018-018-3002-x]
Abstract:
Glutamate is the major excitatory neurotransmitter in the central nervous system. Beyond this function, glutamate also plays a key role in intermediary metabolism in all organs and tissues, linking carbohydrate and amino acid metabolism via the tricarboxylic acid cycle. Under both physiological an...d pathological conditions, we have recently found that the ability of glutamate to fuel cell metabolism selectively relies on the activity of two main transporters: the sodium–calcium exchanger (NCX) and the sodium-dependent excitatory amino-acid transporters (EAATs). In ischemic settings, when glutamate is administered at the onset of the reoxygenation phase, the coordinate activity of EAAT and NCX allows glutamate to improve cell viability by stimulating ATP production. So far, this phenomenon has been observed in both cardiac and neuronal models. In this review, we focus on the most recent findings exploring the unusual activity of glutamate as a potential survival factor in different settings.
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Lipid signaling to membrane proteins: From second messengers to membrane domains and adapter-free endocytosis
Anno: 2018
Rivista: JOURNAL OF GENERAL PHYSIOLOGY
Autori/autrici: Hilgemann, Donald W; Dai, Gucan; Collins, Anthony; Lariccia, Vincenzo; Magi, Simona; Deisl, Christine; Fine, Michael
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/252885
Citazioni:
Lipid signaling to membrane proteins: From second messengers to membrane domains and adapter-free endocytosis / Hilgemann, D.W., Dai, G., Collins, A., Lariccia, V., Magi, S., Deisl, C., Fine, M.. - In: JOURNAL OF GENERAL PHYSIOLOGY. - ISSN 0022-1295. - (2018), p. jgp.201711875. [10.1085/jgp.201711875]
Abstract:
Lipids influence powerfully the function of ion channels and transporters in two well-documented ways. A few lipids act as bona fide second messengers by binding to specific sites that control channel and transporter gating. Other lipids act nonspecifically by modifying the physical environment of c...hannels and transporters, in particular the protein-membrane interface. In this short review, we first consider lipid signaling from this traditional viewpoint, highlighting innumerable Journal of General Physiology publications that have contributed to our present understanding. We then switch to our own emerging view that much important lipid signaling occurs via the formation of membrane domains that influence the function of channels and transporters within them, promote selected protein-protein interactions, and control the turnover of surface membrane.
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Glutamate as a potential "survival factor" in an in vitro model of neuronal hypoxia/reoxygenation injury: Leading role of the Na + /Ca 2+ exchanger
Anno: 2018
Rivista: CELL DEATH & DISEASE
Autori/autrici: Piccirillo, Silvia; Castaldo, Pasqualina; Macrì, Maria Loredana; Amoroso, Salvatore; Magi, Simona
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/265729
Citazioni:
Glutamate as a potential "survival factor" in an in vitro model of neuronal hypoxia/reoxygenation injury: Leading role of the Na + /Ca 2+ exchanger / Piccirillo, S., Castaldo, P., Macrì, M.L., Amoroso, S., Magi, S.. - In: CELL DEATH & DISEASE. - ISSN 2041-4889. - 9:7(2018), p. 731. [10.1038/s41419-018-0784-6]
Abstract:
In brain ischemia, reduction in oxygen and substrates affects mitochondrial respiratory chain and aerobic metabolism, culminating in ATP production impairment, ionic imbalance, and cell death. The restoration of blood flow and reoxygenation are frequently associated with exacerbation of tissue inj...ury, giving rise to ischemia/reperfusion (I/R) injury. In this setting, the imbalance of brain bioenergetics induces important metabolic adaptations, including utilization of alternative energy sources, such as glutamate. Although glutamate has long been considered as a neurotoxin, it can also be used as intermediary metabolite for ATP synthesis, and both the Na+/Ca2+ exchanger (NCX) and the Na+-dependent excitatory amino-acid transporters (EAATs) are essential in this pathway. Here we analyzed the role of NCX in the potential of glutamate to improve metabolism and survival of neuronal cells subjected to hypoxia/ reoxygenation (H/R). In SH-SY5Y neuroblastoma cells differentiated into a neuron-like state, H/R produced a significant cell damage, a decrease in ATP cellular content, and intracellular Ca2+ alterations. Exposure to glutamate at the onset of the reoxygenation phase attenuated H/R-induced cell damage and evoked a significant raise in intracellular ATP levels. Furthermore, we found that in H/R cells NCX reverse-mode activity was reduced, and that glutamate limited such reduction. All the effects induced by glutamate supplementation were lost when cells were transfected with small interfering RNA against NCX1 and EAAT3, suggesting the need of a specific functional interplay between these proteins for glutamate-induced protection. Collectively, our results revealed the potential beneficial effect of glutamate in an in vitro model of H/R injury and focused on the essential role exerted by NCX1. Although preliminary, these findings could be a starting point to further investigate in in vivo systems such protective effect in ischemic settings, shedding a new light on the classical view of glutamate as detrimental factor.
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Sudden cardiac death: Focus on the genetics of channelopathies and cardiomyopathies
Anno: 2017
Rivista: JOURNAL OF BIOMEDICAL SCIENCE
Autori/autrici: Magi, Simona; Lariccia, Vincenzo; Maiolino, Marta; Amoroso, Salvatore; Gratteri, Santo
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/252519
Citazioni:
Sudden cardiac death: Focus on the genetics of channelopathies and cardiomyopathies / Magi, S., Lariccia, V., Maiolino, M., Amoroso, S., Gratteri, S.. - In: JOURNAL OF BIOMEDICAL SCIENCE. - ISSN 1021-7770. - 24:1(2017), p. 56. [10.1186/s12929-017-0364-6]
Abstract:
Sudden cardiac death (SCD) describes a natural and unexpected death from cardiac causes occurring within a short period of time (generally within 1 h of symptom onset) in the absence of any other potentially lethal condition. Most SCD-related diseases have a genetic basis; in particular congenital c...ardiac channelopathies and cardiomyopathies have been described as leading causes of SCD. Congenital cardiac channelopathies are primary electric disorders caused by mutations affecting genes encoding cardiac ion channels or associated proteins, whereas cardiomyopathies are related to mutations in genes encoding several categories of proteins, including those of sarcomeres, desmosomes, the cytoskeleton, and the nuclear envelope. The purpose of this review is to provide a general overview of the main genetic variants that have been linked to the major congenital cardiac channelopathies and cardiomyopathies. Functional alterations of the related proteins are also described.
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Na+/Ca2+ exchanger 1 inhibition abolishes ischemic tolerance induced by ischemic preconditioning in different cardiac models
Anno: 2017
Rivista: EUROPEAN JOURNAL OF PHARMACOLOGY
Autori/autrici: Castaldo, Pasqualina; Macrì, Maria Loredana; Lariccia, Vincenzo; Matteucci, Alessandra; Maiolino, Marta; Gratteri, Santo; Amoroso, Salvatore; Magi, Simona
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/241086
Citazioni:
Na+/Ca2+ exchanger 1 inhibition abolishes ischemic tolerance induced by ischemic preconditioning in different cardiac models / Castaldo, P., Macrì, M.L., Lariccia, V., Matteucci, A., Maiolino, M., Gratteri, S., Amoroso, S., Magi, S.. - In: EUROPEAN JOURNAL OF PHARMACOLOGY. - ISSN 0014-2999. - ELETTRONICO. - (2017). [10.1016/j.ejphar.2016.11.045]
Abstract:
Ca2+-handling disturbances play an important role in the genesis of myocardial ischemia/reperfusion (I/R) injury. Ischemic preconditioning (IPC) is a powerful strategy to induce tolerance against subsequent ischemic episodes. IPC signaling pathways may be triggered by Ca2+ ion. Since Na+/Ca2+ exch...anger 1 (NCX1) participates in modulating intracellular Ca2+ homeostasis, here we further defined its role in I/R and investigated its potential involvement in IPC-induced cardioprotection. In isolated ventricular cardiomyocytes, perfused rat heart and H9c2 cardiomyoblasts, I/R produced a significant cell injury, assessed by measuring extracellular lactate dehydrogenase (LDH) and, for the whole heart, also by estimating myocardial infarct size area. Characterization of cell death revealed the involvement of apoptotic processes. Interestingly, I/R challenge induced NCX1 protein upregulation. In NCX1-transfected H9c2 cells, exchanger protein upregulation was accompanied by an increase in its reverse mode activity. The effects of I/R on extracellular LDH and infarct size area were drastically reduced by 1 !M SN-6, a selective NCX1 inhibitor. Moreover, SN-6 also prevented I/R-induced increase of NCX1 reverse-mode activity and protein upregulation. These results suggested a deleterious role of NCX1 in I/R-induced cell damage. In both isolated cardiomyocytes and perfused heart, IPC followed by I/R afforded cardioprotection, reducing extracellular LDH release and limiting ischemic area extent. Interestingly, NCX1 blockade (1 !M SN-6) completely abolished IPC protection against I/R, leading to exacerbation of cell injury, massive infarct size area and restoration of NCX1 protein expression. These findings suggest that NCX1 is deleterious in I/R, whereas it may be beneficial in promoting IPCinduced cardioprotection
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The Biological Effects of Kambo: Is There a Relationship Between its Administration and Sudden Death?
Anno: 2017
Rivista: JOURNAL OF FORENSIC SCIENCES
Autori/autrici: Aquila, Isabella; Gratteri, Santo; Sacco, Matteo A.; Fineschi, Vittorio; Magi, Simona; Castaldo, Pasqualina; Viscomi, Graziella; Amoroso, Salvatore; Ricci, Pietrantonio
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/253815
Citazioni:
The Biological Effects of Kambo: Is There a Relationship Between its Administration and Sudden Death? / Aquila, I., Gratteri, S., Sacco, M.A., Fineschi, V., Magi, S., Castaldo, P., Viscomi, G., Amoroso, S., Ricci, P.. - In: JOURNAL OF FORENSIC SCIENCES. - ISSN 0022-1198. - (2017). [10.1111/1556-4029.13641]
Abstract:
Kambo is a substance obtained from the skin secretions of a frog, Phyllomedusa bicolor, popular in the Amazon region, which is administered via the transdermal route. We report a case of 42-year-old man found dead in his house. Near the corpse, a plastic box labeled as "Kambo sticks" was f...ound. The man was a chronic consumer of Kambo and no previous pathology or genetic disease emerged in clinical history from the declaration of his general practitioner. Autopsy investigations and toxicological analysis were performed. The histopathological examination showed left ventricular hypertrophy. Toxicological screening was negative for ethanol and other drugs. Phyllocaerulein, phyllokinin, and deltorphin A were isolated from the Kambo sticks but, only deltorphin A was detected in blood sample. We describe the first forensic case of death associated with Kambo administration. We attempt to explain how its use could be related to the cause of sudden death in this case.
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Essential role of the Na+-Ca2+exchanger (NCX) in glutamate-enhanced cell survival in cardiac cells exposed to hypoxia/reoxygenation
Anno: 2017
Rivista: SCIENTIFIC REPORTS
Autori/autrici: Maiolino, Marta; Castaldo, Pasqualina; Lariccia, Vincenzo; Piccirillo, Silvia; Amoroso, Salvatore; Magi, Simona
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/252520
Citazioni:
Essential role of the Na+-Ca2+exchanger (NCX) in glutamate-enhanced cell survival in cardiac cells exposed to hypoxia/reoxygenation / Maiolino, M., Castaldo, P., Lariccia, V., Piccirillo, S., Amoroso, S., Magi, S.. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - 7:1(2017), p. 13073. [10.1038/s41598-017-13478-x]
Abstract:
Myocardial ischemia culminates in ATP production impairment, ionic derangement and cell death. The provision of metabolic substrates during reperfusion significantly increases heart tolerance to ischemia by improving mitochondrial performance. Under normoxia, glutamate contributes to myocardial ener...gy balance as substrate for anaplerotic reactions, and we demonstrated that the Na+/Ca2+ exchanger1 (NCX1) provides functional support for both glutamate uptake and use for ATP synthesis. Here we investigated the role of NCX1 in the potential of glutamate to improve energy metabolism and survival of cardiac cells subjected to hypoxia/reoxygenation (H/R). Specifically, in H9c2-NCX1 myoblasts, ATP levels, mitochondrial activities and cell survival were significantly compromised after H/R challenge. Glutamate supplementation at the onset of the reoxygenation phase significantly promoted viability, improved mitochondrial functions and normalized the H/R-induced increase of NCX1 reverse-mode activity. The benefits of glutamate were strikingly lost in H9c2-WT (lacking NCX1 expression), or in H9c2-NCX1 and rat cardiomyocytes treated with either NCX or Excitatory Amino Acid Transporters (EAATs) blockers, suggesting that a functional interplay between these transporters is critically required for glutamate-induced protection. Collectively, these results revealed for the first time the key role of NCX1 for the beneficial effects of glutamate against H/R-induced cell injury.
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Intracellular Calcium Dysregulation: Implications for Alzheimer's Disease
Anno: 2016
Rivista: BIOMED RESEARCH INTERNATIONAL
Autori/autrici: Magi, Simona; Castaldo, Pasqualina; Macri', MARIA LOREDANA; Maiolino, M.; Matteucci, Alessandra; Bastioli, Guendalina; Gratteri, S.; Amoroso, Salvatore; Lariccia, Vincenzo
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/236359
Citazioni:
Intracellular Calcium Dysregulation: Implications for Alzheimer's Disease / Magi, S., Castaldo, P., Macri', M.L., Maiolino, M., Matteucci, A., Bastioli, G., Gratteri, S., Amoroso, S., Lariccia, V.. - In: BIOMED RESEARCH INTERNATIONAL. - ISSN 2314-6141. - ELETTRONICO. - (2016), pp. 1-14. [10.1155/2016/6701324]
Abstract:
Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by progressive neuronal loss. AD is associated with aberrant processing of the amyloid precursor protein, which leads to the deposition of amyloid-β plaques within the brain. Together with plaques deposition, the hyperp...hosphorylation of the microtubules associated protein tau and the formation of intraneuronal neurofibrillary tangles are a typical neuropathological feature in AD brains. Cellular dysfunctions involving specific subcellular compartments, such as mitochondria and endoplasmic reticulum (ER), are emerging as crucial players in the pathogenesis of AD, as well as increased oxidative stress and dysregulation of calcium homeostasis. Specifically, dysregulation of intracellular calcium homeostasis has been suggested as a common proximal cause of neural dysfunction in AD. Aberrant calcium signaling has been considered a phenomenon mainly related to the dysfunction of intracellular calcium stores, which can occur in both neuronal and nonneuronal cells. This review reports the most recent findings on cellular mechanisms involved in the pathogenesis of AD, with main focus on the control of calcium homeostasis at both cytosolic and mitochondrial level.
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Gram-negative endotoxin lipopolysaccharide induces cardiac hypertrophy: Detrimental role of Na+–Ca2+ exchanger
Anno: 2015
Rivista: EUROPEAN JOURNAL OF PHARMACOLOGY
Autori/autrici: Magi, Simona; Nasti, ANNAMARIA ASSUNTA; Santo, Gratteri; Castaldo, Pasqualina; Bompadre, Stefano; Amoroso, Salvatore; Lariccia, Vincenzo
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/200307
Citazioni:
Gram-negative endotoxin lipopolysaccharide induces cardiac hypertrophy: Detrimental role of Na+–Ca2+ exchanger / Magi, S., Nasti, A.A., Santo, G., Castaldo, P., Bompadre, S., Amoroso, S., Lariccia, V.. - In: EUROPEAN JOURNAL OF PHARMACOLOGY. - ISSN 0014-2999. - 746:(2015), pp. 31-40. [10.1016/j.ejphar.2014.10.054]
Abstract:
Several molecular pathways involved in the development of cardiac hypertrophy are triggered by perturbation of intracellular Ca2+ homeostasis. Within the heart, Na+/Ca2+ exchanger 1 (NCX1) is one of the main determinant in controlling Ca2+ homeostasis. In cardiac hypertrophy and heart failure NCX1 e...xpression and activity have been reported to be altered. It has been shown that chronic bacterial infections (sepsis, endocarditis, and myocarditis) can promote cardiac hypertrophy. Bacterial stressors, such as the Gram-negative endotoxin lipopolysaccharide (LPS), can directly or indirectly affect intracellular Ca2+ homeostasis in the heart and induce the development of cardiac hypertrophy. The present study aimed at evaluating the potential link between the signal pathways activated in LPS-exposed myocytes and NCX1. In the whole rat heart, LPS perfusion induced an early hypertrophy response during which NCX1 expression significantly increased. Notably, all these changes were completely prevented by the NCX inhibitor SN-6. We further dissect the role of NCX1 in the LPS-induced hypertrophic response in an in vitro cardiac model based on two H9c2 cardiomyoblast clones, namely H9c2-WT (lacking endogenous NCX1 expression) and H9c2-NCX1 (stably transfected with a functional NCX1). H9c2-NCX1 were more susceptible than H9c2-WT to develop a hypertrophic phenotype, and they displayed a significant increase in NCX1 expression and function after LPS treatment. SN-6 completely counteracted both hypertrophic response and exchanger alterations induced by LPS in H9c2-NCX1 cells, but it had no effects on H9c2-WT. Collectively, our results suggest that NCX1 plays a critical role in promoting myocardial hypertrophy triggered by LPS.
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Glutamate-induced ATP synthesis: relationship between plasma membrane Na+/Ca2+ exchanger and excitatory amino acid transporters in brain and heart cell models
Anno: 2013
Rivista: MOLECULAR PHARMACOLOGY
Autori/autrici: Magi, Simona; Arcangeli, Sara; Castaldo, Pasqualina; Nasti, A. A.; Berrino, L.; Piegari, E.; Bernardini, R.; Amoroso, Salvatore; Lariccia, Vincenzo
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/128474
Citazioni:
Glutamate-induced ATP synthesis: relationship between plasma membrane Na+/Ca2+ exchanger and excitatory amino acid transporters in brain and heart cell models / Magi, S., Arcangeli, S., Castaldo, P., Nasti, A.A., Berrino, L., Piegari, E., Bernardini, R., Amoroso, S., Lariccia, V.. - In: MOLECULAR PHARMACOLOGY. - ISSN 0026-895X. - STAMPA. - 84:4(2013), pp. 603-614. [10.1124/mol.113.087775]
Abstract:
It is known that glutamate (Glu), the major excitatory amino acid in the central nervous system, can be an essential source for cell energy metabolism. Here we investigated the role of the plasma membrane Na(+)/Ca(2+) exchanger (NCX) and the excitatory amino acid transporters (EAATs) in Glu uptake a...nd recycling mechanisms leading to ATP synthesis. We used different cell lines, such as SH-SY5Y neuroblastoma, C6 glioma and H9c2 as neuronal, glial, and cardiac models, respectively. We first observed that Glu increased ATP production in SH-SY5Y and C6 cells. Pharmacological inhibition of either EAAT or NCX counteracted the Glu-induced ATP synthesis. Furthermore, Glu induced a plasma membrane depolarization and an intracellular Ca(2+) increase, and both responses were again abolished by EAAT and NCX blockers. In line with the hypothesis of a mutual interplay between the activities of EAAT and NCX, coimmunoprecipitation studies showed a physical interaction between them. We expanded our studies on EAAT/NCX interplay in the H9c2 cells. H9c2 expresses EAATs but lacks endogenous NCX1 expression. Glu failed to elicit any significant response in terms of ATP synthesis, cell depolarization, and Ca(2+) increase unless a functional NCX1 was introduced in H9c2 cells by stable transfection. Moreover, these responses were counteracted by EAAT and NCX blockers, as observed in SH-SY5Y and C6 cells. Collectively, these data suggest that plasma membrane EAAT and NCX are both involved in Glu-induced ATP synthesis, with NCX playing a pivotal role.
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Physical and Functional Interaction of NCX1 and EAAC1 Transporters Leading to Glutamate-Enhanced ATP Production in Brain Mitochondria
Anno: 2012
Rivista: PLOS ONE
Autori/autrici: Magi, Simona; Lariccia, Vincenzo; Castaldo, Pasqualina; Arcangeli, Sara; Nasti, ANNAMARIA ASSUNTA; Giordano, Antonio; Amoroso, Salvatore
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/68017
Citazioni:
Physical and Functional Interaction of NCX1 and EAAC1 Transporters Leading to Glutamate-Enhanced ATP Production in Brain Mitochondria / Magi, S., Lariccia, V., Castaldo, P., Arcangeli, S., Nasti, A.A., Giordano, A., Amoroso, S.. - In: PLOS ONE. - ISSN 1932-6203. - (2012). [10.1371/journal.pone.0034015]
Abstract:
Glutamate is emerging as a major factor stimulating energy production in CNS. Brain mitochondria can utilize this neurotransmitter as respiratory substrate and specific transporters are required to mediate the glutamate entry into the mitochondrial matrix. Glutamate transporters of the Excitatory Am...ino Acid Transporters (EAATs) family have been previously well characterized on the cell surface of neuronal and glial cells, representing the primary players for glutamate uptake in mammalian brain. Here, by using western blot, confocal microscopy and immunoelectron microscopy, we report for the first time that the Excitatory Amino Acid Carrier 1 (EAAC1), an EAATs member, is expressed in neuronal and glial mitochondria where it participates in glutamate-stimulated ATP production, evaluated by a luciferase-luciferin system. Mitochondrial metabolic response is counteracted when different EAATs pharmacological blockers or selective EAAC1 antisense oligonucleotides were used. Since EAATs are Na(+)-dependent proteins, this raised the possibility that other transporters regulating ion gradients across mitochondrial membrane were required for glutamate response. We describe colocalization, mutual activity dependency, physical interaction between EAAC1 and the sodium/calcium exchanger 1 (NCX1) both in neuronal and glial mitochondria, and that NCX1 is an essential modulator of this glutamate transporter. Only NCX1 activity is crucial for such glutamate-stimulated ATP synthesis, as demonstrated by pharmacological blockade and selective knock-down with antisense oligonucleotides. The EAAC1/NCX1-dependent mitochondrial response to glutamate may be a general and alternative mechanism whereby this neurotransmitter sustains ATP production, since we have documented such metabolic response also in mitochondria isolated from heart. The data reported here disclose a new physiological role for mitochondrial NCX1 as the key player in glutamate-induced energy production.
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Clinical pharmacogenetics of methotrexate
Anno: 2011
Rivista: CURRENT DRUG METABOLISM
Autori/autrici: Castaldo, Pasqualina; Magi, Simona; Nasti, ANNAMARIA ASSUNTA; Arcangeli, Sara; Lariccia, Vincenzo; Alesi, N.; Tocchini, M.; Amoroso, Salvatore
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/57918
Citazioni:
Clinical pharmacogenetics of methotrexate / Castaldo, P., Magi, S., Nasti, A.A., Arcangeli, S., Lariccia, V., Alesi, N., Tocchini, M., Amoroso, S.. - In: CURRENT DRUG METABOLISM. - ISSN 1389-2002. - 2011:(2011), pp. 278-286. [10.2174/138920011795101840]
Abstract:
It is well known that interindividual variability can affect the response to many drugs in relation to age, gender, diet, and organ function. Pharmacogenomic studies have also documented that genetic polymorphisms can exert clinically significant effects in terms of drug resistance, efficacy and tox...icity by modifying the expression of critical gene products (drug-metabolizing enzymes, transporters, and target molecules) as well as pharmacokinetic and pharmacodynamic parameters. A growing body of in vitro and clinical evidence suggests that common polymorphisms in the folate gene pathway are associated with an altered response to methotrexate (MTX) in patients with malignancy and autoimmune disease. Such polymorphisms may also induce significant MTX toxicity requiring expensive monitoring and treatment. Although the available data are not conclusive, they suggest that in the future MTX pharmacogenetics could play a key role in clinical practice by improving and tailoring treatment. This review describes the genetic polymorphisms that significantly influence MTX resistance, efficacy, and toxicity.
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Massive calcium-activated endocytosis without involvement of classical endocytic proteins.
Anno: 2011
Rivista: JOURNAL OF GENERAL PHYSIOLOGY
Autori/autrici: Lariccia, Vincenzo; Fine, M.; Magi, Simona; Lin, M. J.; Yaradanakul, A.; Llaguno, M. C.; Hilgemann, D. W.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/54917
Citazioni:
Massive calcium-activated endocytosis without involvement of classical endocytic proteins / Lariccia, V., Fine, M., Magi, S., Lin, M.J., Yaradanakul, A., Llaguno, M.C., Hilgemann, D.W.. - In: JOURNAL OF GENERAL PHYSIOLOGY. - ISSN 0022-1295. - 137:(2011), pp. 111-132. [10.1085/jgp.201010468]
Abstract:
We describe rapid massive endocytosis (MEND) of >50% of the plasmalemma in baby hamster kidney (BHK) and HEK293 cells in response to large Ca transients. Constitutively expressed Na/Ca exchangers (NCX1) are used to generate Ca transients, whereas capacitance recording and a membrane tracer dy...e, FM 4-64, are used to monitor endocytosis. With high cytoplasmic adenosine triphosphate (ATP; >5 mM), Ca influx causes exocytosis followed by MEND. Without ATP, Ca transients cause only exocytosis. MEND can then be initiated by pipette perfusion of ATP, and multiple results indicate that ATP acts via phosphatidylinositol-bis 4,5-phosphate (PIP(2)) synthesis: PIP(2) substitutes for ATP to induce MEND. ATP-activated MEND is blocked by an inositol 5-phosphatase and by guanosine 5'-[γ-thio]triphosphate (GTPγS). Block by GTPγS is overcome by the phospholipase C inhibitor, U73122, and PIP(2) induces MEND in the presence of GTPγS. MEND can occur in the absence of ATP and PIP(2) when cytoplasmic free Ca is clamped to 10 µM or more by Ca-buffered solutions. ATP-independent MEND occurs within seconds during Ca transients when cytoplasmic solutions contain polyamines (e.g., spermidine) or the membrane is enriched in cholesterol. Although PIP(2) and cholesterol can induce MEND minutes after Ca transients have subsided, polyamines must be present during Ca transients. MEND can reverse over minutes in an ATP-dependent fashion. It is blocked by brief β-methylcyclodextrin treatments, and tests for involvement of clathrin, dynamins, calcineurin, and actin cytoskeleton were negative. Therefore, we turned to the roles of lipids. Bacterial sphingomyelinases (SMases) cause similar MEND responses within seconds, suggesting that ceramide may be important. However, Ca-activated MEND is not blocked by reagents that inhibit SMases. MEND is abolished by the alkylating phospholipase A(2) inhibitor, bromoenol lactone, whereas exocytosis remains robust, and Ca influx causes MEND in cardiac myocytes without preceding exocytosis. Thus, exocytosis is not prerequisite for MEND. From these results and two companion studies, we suggest that Ca promotes the formation of membrane domains that spontaneously vesiculate to the cytoplasmic side.
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Massive Endocytosis Activated by Perturbing the Outer Plasmalemmal Monolayer
Anno: 2010
Rivista: BIOPHYSICAL JOURNAL
Autori/autrici: Fine, Michael; Llaguno, Marc C.; Yaradanakul, Alp; Lariccia, Vincenzo; Magi, Simona; Lin, Mei Jung; Hilgemann, Donald W.
Lingua: ENG
Classificazione IRIS: 4.2 Abstract in Atti di convegno
Scheda completa IRIS: https://iris.univpm.it/handle/11566/228750
Citazioni:
Massive Endocytosis Activated by Perturbing the Outer Plasmalemmal Monolayer / Fine, M., Llaguno, M.C., Yaradanakul, A., Lariccia, V., Magi, S., Lin, M.J., Hilgemann, D.W.. - In: BIOPHYSICAL JOURNAL. - ISSN 0006-3495. - 98:(2010), pp. 502-502. [http://dx.doi.org/10.1016/j.bpj.2009.12.2735]
Abstract:
The roles played by lipids in endocytic processes are the subject of much ongoing debate. Using electrophysiological, optical, and ultrastructural methods, we describe massive endocytosis (MEND) of >50% of the plasmalemma in response to perturbing the outer plasmalemma monolayer of fibroblasts an...d cardiac myocytes by multiple means. Extracellular application of a bacterial sphingomyelinase causes MEND within seconds, and similar responses occur with the nonionic detergents, Triton X-100 and NP-40, proapoptotic drugs (e.g. edelfosine and tamoxifen), and an amphipathic phospholipase inhibitor, U73122. At the concentrations employed, the effective agents do not cause membrane permeability changes, and they are inactive from the cytoplasmic side. Ca transients that do not cause MEND decrease markedly the threshold concentrations of amphipaths that cause MEND, perhaps by generating a lipid catalyst of MEND. Noise analysis of NP-40 records suggests that the average vesicle size is initially small (<100nm). However, internalized vesicles evidently fuse rapidly, as horseradish peroxidase is found within seconds in large vacuoles and multi-lamellar bodies. These MEND responses do not require cytoplasmic ATP, Ca, or dynamins, and they can be repeated multiple times with reversal taking place over several minutes in the presence of ATP. For nonionic detergents, ongoing MEND stops within 2 to 4 seconds when detergent is removed. For dodecylsulfate and dodecylglucoside, MEND occurs only after detergent removal. These results suggest that endocytosis can be driven primarily by lipidic forces, possibly by lipid and protein partitioning into domains that pinch off to the cytoplasm as a result of line tension to their surround.
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Altered regulation of glutamate release and decreased functional activity and expression of GLT1 and GLAST glutamate transporters in the hippocampus of adolescent rats perinatally exposed to Delta(9)-THC
Anno: 2010
Rivista: PHARMACOLOGICAL RESEARCH
Autori/autrici: Castaldo, Pasqualina; Magi, Simona; Cataldi, M.; Arcangeli, Sara; Lariccia, Vincenzo; Nasti, ANNAMARIA ASSUNTA; Ferraro, L.; Tomasini, M. C.; Antonelli, T.; Cassano, T.; Cuomo, V.; Amoroso, Salvatore
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/51979
Citazioni:
Altered regulation of glutamate release and decreased functional activity and expression of GLT1 and GLAST glutamate transporters in the hippocampus of adolescent rats perinatally exposed to Delta(9)-THC / Castaldo, P., Magi, S., Cataldi, M., Arcangeli, S., Lariccia, V., Nasti, A.A., Ferraro, L., Tomasini, M.C., Antonelli, T., Cassano, T., Cuomo, V., Amoroso, S.. - In: PHARMACOLOGICAL RESEARCH. - ISSN 1043-6618. - 61:(2010), pp. 334-341. [10.1016/j.phrs.2009.11.008]
Abstract:
The long-term effects of perinatal Delta(9)-tetrahydrocannabinol (Delta(9)-THC) exposure - from gestational day (GD) 15 to postnatal day (PND) 9 - on hippocampal glutamatergic neurotransmission were studied in slices from the 40-day-old offspring of Delta(9)-THC exposed (Delta(9)-THC-rats) and vehic...le-exposed (control) dams. Basal and in K+-evoked endogenous hippocampal glutamate outflow were both significantly decreased in Delta(9)-THC-rats. The effect of short Delta(9)-THC exposure (0.1microM) on K(+)-evoked glutamate release disclosed a loss of the stimulatory effect of Delta(9)-THC on hippocampal glutamate release in Delta(9)-THC-rats, but not in controls. In addition, l-[(3)H]-glutamate uptake was significantly lower in hippocampal slices from Delta(9)-THC-rats, where a significant decrease in glutamate transporter 1 (GLT1) and glutamate/aspartate transporter (GLAST) protein was also detected. Collectively, these data demonstrate that perinatal exposure to cannabinoids induces long-term impairment in hippocampal glutamatergic neurotransmission that persist into adolescence
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Role of the mitochondrial sodium/calcium exchanger in neuronal physiology and in the pathogenesis of neurological diseases.
Anno: 2009
Rivista: PROGRESS IN NEUROBIOLOGY
Autori/autrici: Castaldo, Pasqualina; Cataldi, M.; Magi, Simona; Lariccia, Vincenzo; Arcangeli, Sara; Amoroso, Salvatore
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/52351
Citazioni:
Role of the mitochondrial sodium/calcium exchanger in neuronal physiology and in the pathogenesis of neurological diseases / Castaldo, P., Cataldi, M., Magi, S., Lariccia, V., Arcangeli, S., Amoroso, S.. - In: PROGRESS IN NEUROBIOLOGY. - ISSN 0301-0082. - 87:(2009), pp. 58-79. [10.1016/j.pneurobio.2008.09.017]
Abstract:
Abstract. In neurons, as in other excitable cells, mitochondria extrude Ca(2+) ions from their matrix in exchange with cytosolic Na(+) ions. This exchange is mediated by a specific transporter located in the inner mitochondrial membrane, the mitochondrial Na(+)/Ca(2+) exchanger (NCX(mito)). The s...toichiometry of NCX(mito)-operated Na(+)/Ca(2+) exchange has been the subject of a long controversy, but evidence of an electrogenic 3 Na(+)/1 Ca(2+) exchange is increasing. Although the molecular identity of NCX(mito) is still undetermined, data obtained in our laboratory suggest that besides the long-sought and as yet unfound mitochondrial-specific NCX, the three isoforms of plasmamembrane NCX can contribute to NCX(mito) in neurons and astrocytes. NCX(mito) has a role in controlling neuronal Ca(2+) homeostasis and neuronal bioenergetics. Indeed, by cycling the Ca(2+) ions captured by mitochondria back to the cytosol, NCX(mito) determines a shoulder in neuronal [Ca(2+)](c) responses to neurotransmitters and depolarizing stimuli which may then outlast stimulus duration. This persistent NCX(mito)-dependent Ca(2+) release has a role in post-tetanic potentiation, a form of short-term synaptic plasticity. By controlling [Ca(2+)](m) NCX(mito) regulates the activity of the Ca(2+)-sensitive enzymes pyruvate-, alpha-ketoglutarate- and isocitrate-dehydrogenases and affects the activity of the respiratory chain. Convincing experimental evidence suggests that supraphysiological activation of NCX(mito) contributes to neuronal cell death in the ischemic brain and, in epileptic neurons coping with seizure-induced ion overload, reduces the ability to reestablish normal ionic homeostasis. These data suggest that NCX(mito) could represent an important target for the development of new neurological drugs.
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Ruolo dello scambiatore sodio-calcio nel danno neuronale indotto da policlorurati bifenili
Anno: 2007
Autori/autrici: Magi, Simona
Lingua: IT
Classificazione IRIS: 8.2 Tesi di dottorato (EX-A3)
Scheda completa IRIS: https://iris.univpm.it/handle/11566/242475
Citazioni:
Ruolo dello scambiatore sodio-calcio nel danno neuronale indotto da policlorurati bifenili / Magi, Simona. - (2007 Jan 29).

Mitochondrial Localization of Na+/Ca2+ exchangers NCX1, 2 and 3 in neurons and astrocytes of adult rat brain in situ
Anno: 2007
Rivista: PHARMACOLOGICAL RESEARCH
Autori/autrici: Gobbi, P.; Castaldo, Pasqualina; Minelli, A.; Salucci, S.; Magi, Simona; Corcione, E.; Amoroso, Salvatore
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/53438
Citazioni:
Mitochondrial Localization of Na+/Ca2+ exchangers NCX1, 2 and 3 in neurons and astrocytes of adult rat brain in situ / Gobbi, P., Castaldo, P., Minelli, A., Salucci, S., Magi, S., Corcione, E., Amoroso, S.. - In: PHARMACOLOGICAL RESEARCH. - ISSN 1043-6618. - 56:(2007), pp. 556-565. [10.1016/j.phrs.2007.10.005]
Abstract:
Abstract. In neural cells, Na+/Ca2+ exchanger (NCX) participates in Ca2+ recycling across mitochondrial membranes, thus contributing to shape Ca2+ responses. NCX exchanger isoform proteins, NCX1-3, are widely distributed in mammalian brain, where they localize to neuronal, glial and endothelial c...ells, but anatomical data on their mitochondrial expression are scanty. In the present work, mitochondrial localization of NCX1-3 was investigated in rat neocortex and hippocampus by means of western blotting analysis and in situ electron microscopy immunocytochemistry. Results showed that a conspicuous population of neuronal and astrocytic mitochondria express NCX1-3, with distinct isoforms exhibiting differential patterns of mitochondrial expression. In neurons, percentages of NCXs-labelled mitochondria varied significantly between diverse subcellular regions: the majority of NCXs-expressing mitochondria were found in dendrites, often located beneath the plasmalemma and near postsynaptic sites. In astrocytes, most NCXs-labelled mitochondria were situated close to the cellular surface. Present quantitative and qualitative immunocytochemical data suggest that all NCX isoforms contribute to mitochondrial Ca2+ homeostasis in neurons and glial cells in vivo, and that NCXs may be particularly involved in handling Ca2+ in dendritic, subplasmalemmal mitochondria, thus emphasizing the role of mitochondrial NCX1-3 in shaping postsynaptic calcium transients.
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Cellular and subcellular localization of Na(+)-Ca(2+) exchanger protein isoforms, NCX1, NCX2, and NCX3 in cerebral cortex and hippocampus of adult rat
Anno: 2007
Rivista: CELL CALCIUM
Autori/autrici: Minelli, A.; Castaldo, Pasqualina; Gobbi, P.; Salucci, S.; Magi, Simona; Amoroso, Salvatore
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/51945
Citazioni:
Cellular and subcellular localization of Na(+)-Ca(2+) exchanger protein isoforms, NCX1, NCX2, and NCX3 in cerebral cortex and hippocampus of adult rat / Minelli, A., Castaldo, P., Gobbi, P., Salucci, S., Magi, S., Amoroso, S.. - In: CELL CALCIUM. - ISSN 0142-8020. - 41:(2007), pp. 221-234. [10.1016/j.ceca.2006.06.004]
Abstract:
Abstract. Na(+)-Ca(2+) exchanger (NCX) controls cytosolic Ca(2+) and Na(+) concentrations ([Ca(2+)](i) and [Na(+)](i)) in eukaryotic cells. Here we investigated by immunocytochemistry the cellular and subcellular localization of the three known NCX isoforms, NCX1, NCX2 and NCX3, in adult rat neoc...ortex and hippocampus. NCX1-3 were widely expressed in both brain areas: NCX1 immunoreactivity (ir) was exclusively associated to neuropilar puncta, while NCX2-3 were also detected in neuronal somata and dendrites. NCX1-3 ir was often identified around blood vessels. In both neocortex and hippocampus, all NCX isoforms were prominently expressed in dendrites and dendritic spines contacted by asymmetric axon terminals, whereas they were poorly expressed in presynaptic boutons. In addition, NCX1-3 ir was detected in astrocytes, notably in distal processes ensheathing excitatory synapses. All NCXs were expressed in perivascular astrocytic endfeet and endothelial cells. The robust expression of NCX1-3 in heterogeneous cell types in the brain in situ emphasizes their role in handling Ca(2+) and Na(+) in both excitable and non-excitable cells. Perisynaptic localization of NCX1-3 in dendrites and spines indicates that all isoforms are favourably located for buffering [Ca(2+)](i) in excitatory postsynaptic sites. NCX1-3 expressed in perisynaptic glial processes may participate in shaping astrocytic [Ca(2+)](i) transients evoked by ongoing synaptic activity.
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Prenatal exposure to the cannabinoid receptor agonist WIN 55,212-2 increases glutamate uptake through overexpression of GLT1 and EAAC1 glutamate transporter subtypes in rat frontal cerebral cortex
Anno: 2007
Rivista: NEUROPHARMACOLOGY
Autori/autrici: Castaldo, Pasqualina; Magi, Simona; Gaetani, S.; Cassano, T.; Ferraro, L.; Antonelli, T.; Amoroso, Salvatore; Cuomo, V.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/40891
Citazioni:
Prenatal exposure to the cannabinoid receptor agonist WIN 55,212-2 increases glutamate uptake through overexpression of GLT1 and EAAC1 glutamate transporter subtypes in rat frontal cerebral cortex / Castaldo, P., Magi, S., Gaetani, S., Cassano, T., Ferraro, L., Antonelli, T., Amoroso, S., Cuomo, V.. - In: NEUROPHARMACOLOGY. - ISSN 0028-3908. - 53:(2007), pp. 369-378. [10.1016/j.neuropharm.2007.05.019]
Abstract:
Prenatal exposure to the CB1 receptor agonist (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)-pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone) mesylate (WIN) at a daily dose of 0.5 mg/kg, and Delta9-tetrahydrocannabinol (Delta9-THC) at a daily dose of 5 mg/kg, reduced dialysate g...lutamate levels in frontal cerebral cortex of adolescent offspring (40-day-old) with respect to those born from vehicle-treated mothers. WIN treatment induced a statistically significant enhancement of Vmaxl-[3H]glutamate uptake, whereas it did not modify glutamate Km, in frontal cerebral cortex synaptosomes of adolescent rats. Western blotting analysis, performed either in membrane proteins derived from homogenates and in proteins extracted from synaptosomes of frontal cerebral cortex, revealed that prenatal WIN exposure enhanced the expression of glutamate transporter 1 (GLT1) and excitatory amino acid carrier 1 (EAAC1). Moreover, immunocytochemical analyses of frontal cortex area revealed a more intense GLT1 and EAAC1 immunoreactivity (ir) distribution in the WIN-treated group. Collectively these results show that prenatal exposure to the cannabinoid CB1 receptor agonist WIN increases expression and functional activity of GLT1 and EAAC1 glutamate transporters (GluTs) associated to a decrease of cortical glutamate outflow, in adolescent rats. These findings may contribute to explain the mechanism underlying the cognitive impairment observed in the offspring of mothers who used marijuana during pregnancy
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Antiproliferative effects of tocopherols (vitamin E) on murine glioma C6 cells: homologue-specific control of PKC/ERK and cyclin signaling
Anno: 2006
Rivista: FREE RADICAL BIOLOGY & MEDICINE
Autori/autrici: Betti, M.; Minelli, A.; Canonico, B.; Castaldo, Pasqualina; Magi, Simona; Aisa, M. C.; Piroddi, M.; Di Tomaso, V.; Galli, F.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/66092
Citazioni:
Antiproliferative effects of tocopherols (vitamin E) on murine glioma C6 cells: homologue-specific control of PKC/ERK and cyclin signaling / Betti, M., Minelli, A., Canonico, B., Castaldo, P., Magi, S., Aisa, M.C., Piroddi, M., Di Tomaso, V., Galli, F.. - In: FREE RADICAL BIOLOGY & MEDICINE. - ISSN 0891-5849. - 41:(2006), pp. 464-472. [10.1016/j.freeradbiomed.2006.04.012]
Abstract:
Chemoprevention strategies for brain tumors (specifically gliomas) are few and surprisingly poorly investigated. We have studied the effects of tocopherols (TOCs; vitamin E) on proliferation and death processes of murine glioma C6 cells. These vitamers showed different cell uptake and concentration-... and time-dependent inhibitory effects on cell growth that were significant at the lowest concentrations tested (1-10 microM). However, the inhibitory potency of TOCs seemed to reflect at least in part their actual cell concentrations at steady state, with the order of magnitude gamma-TOC >or= alpha-TOC > delta-TOC approximately or = beta-TOC. Moreover, for extracellular concentrations >or=10 microM, TOCs also showed a significant cytotoxic effects due mainly to necrosis, while apoptosis was negligible. Gamma-TOC (the form showing preferential cell uptake and lowest unspecific cytotoxicity) was the most effective inhibitor of cell cycle progression (arrest in G0/G1 phase) leading to lowered expression of cyclin E and cyclin-dependent kinases 2 and 4 and overexpression of p27 (specific inhibitor of S-phase entering). According to these signals, activated ERK1/2 and PKC upstream and Rb phosphorylation downstream were decreased. In conclusion, within TOCs the gamma form exerts the most potent and specific control of cell cycle progression in C6 cells (cytostatic effect). This suggests a chemopreventive role of this form of vitamin E in gliomas
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Involvement of the nitric oxide/protein kinase G pathway in polychlorinated biphenyl-induced cell death in SH-SY 5Y neuroblastoma cells.
Anno: 2006
Rivista: JOURNAL OF NEUROSCIENCE RESEARCH
Autori/autrici: Canzoniero, L. M.; Adornetto, A; Secondo, A; Magi, Simona; Dell'Aversano, C; Scorziello, A; Amoroso, Salvatore; DI RENZO, G.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/25979
Citazioni:
Involvement of the nitric oxide/protein kinase G pathway in polychlorinated biphenyl-induced cell death in SH-SY 5Y neuroblastoma cells / Canzoniero, L.M., Adornetto, A., Secondo, A., Magi, S., Dell'Aversano, C., Scorziello, A., Amoroso, S., DI RENZO, G.. - In: JOURNAL OF NEUROSCIENCE RESEARCH. - ISSN 0360-4012. - STAMPA. - 84:(2006), pp. 692-697. [10.1002/jnr.20971]
Abstract:
Abstract. Polychlorinated biphenyls (PCB) are persistent environmental contaminants whose chronic exposure can affect nervous system development and function. The cellular and molecular mechanisms underlying neuronal damage are not yet clear. In the present study, we investigated whether nitric o...xide (NO) could be involved in aroclor 1254 (A1254; a PCB mixture)-induced cytotoxicity in SH-SY5Y human neuroblastoma cells. Prolonged exposure (24 hr) to A1254 (10-100 microg/ml) caused a dose-dependent reduction of cell viability that was attenuated in the presence of a calcium entry blocker, gadolinum (Gd(3+)) at 10 microM, a concentration able to block voltage-sensitive calcium channels. In addition, A1254 caused an increase of cytosolic calcium that was dependent on extracellular calcium, as measured by fura-2 videomicroscopy. A1254-induced calcium rise may stimulate NO production through an activation of neuronal NOS (nNOS). Indeed, the concomitant addition of the selective nNOS inhibitor N(omega)-propyl-L-arginine (NPLA) and A1254 prevented cell injury, suggesting that NO production plays a major role in A1254-evoked cell injury. Furthermore, the exposure (14 hr) to A1254 (30 microg/ml) produced an up-regulation of the expression of beta isoform of nNOS. This up-regulation was calcium dependent and was accompanied by an enhancement of NO production as demonstrated by an increase of nitrite formation. Moreover, A1254-induced cell injury was prevented when KT 5823, a selective cGMP/PKG inhibitor, was added concomitantly to 30 microg/ml A1254. These results suggest that PCB-induced cell death in neuroblastoma cells is mediated by an activation of the cGMP/PKG pathway triggered by NO production.
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Involvement of Na+-Ca2+ exchanger in intracellular Ca2+ increase and neuronal injury induced by polychlorinated biphenyls in human neuroblastoma SH-SY5Y cells
Anno: 2005
Rivista: JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Autori/autrici: Magi, Simona; Castaldo, Pasqualina; Carrieri, G.; Scorziello, A.; Di Renzo, G.; Amoroso, Salvatore
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/50801
Citazioni:
Involvement of Na+-Ca2+ exchanger in intracellular Ca2+ increase and neuronal injury induced by polychlorinated biphenyls in human neuroblastoma SH-SY5Y cells / Magi, S., Castaldo, P., Carrieri, G., Scorziello, A., Di Renzo, G., Amoroso, S.. - In: THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS. - ISSN 0022-3565. - 315:(2005), pp. 291-296. [10.1124/jpet.105.088948]
Abstract:
In SH-SY5Y, a human neuroblastoma cell line, Aroclor 1254 (A1254), induced a dose-dependent (10-50 microg/ml) intracellular calcium concentration ([Ca2+]i) increase. Two rather specific sodium-calcium (Na+-Ca2+) exchanger (NCX) inhibitors, bepridil (10 microM) and KB-R7943 [2-[2-[4-(4-nitrobenzyloxy...) phenyl]ethyl]isothiourea methanesulfonate] (10 microM), reduced A1254-induced [Ca2+]i increase. A 24-h exposure to 30 microg/ml A1254 caused remarkable SH-SY5Y neuroblastoma cell damage. It is noteworthy that both bepridil and KB-R7943 counteracted A1254-induced neuronal injury. These results indicate that NCX contributes to [Ca2+]i increase and neuronal injury induced by A1254. RT-PCR experiments revealed in SH-SY5Y neuroblastoma cells the expression of NCX1 and NCX3 isoforms. To investigate which isoform was involved in [Ca2+]i increase and neuronal damage induced by A1254, we used specific antisense oligodeoxynucleotides (ODNs) to reduce NCX1 or NCX3 protein expression. The results showed that only NCX1 ODN reduced [Ca2+]i increase and neuronal injury induced by A1254. In conclusion, these results indicate that NCX1 may participate to [Ca2+]i increase and neurotoxicity evoked by A1254 in SH-SY5Y neuroblastoma cells
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Immunohistochemical evaluation of urokinase plasminogen activator receptor in noninvasive and early invasive urothelial papillary neoplasia.
Anno: 2004
Rivista: ANALYTICAL AND QUANTITATIVE CYTOLOGY AND HISTOLOGY
Autori/autrici: Vivani, C.; Magi, Simona; Mazzucchelli, Roberta; Bacchiocchi, R.; Santinelli, Alfredo; Muzzonigro, Giovanni; Blasi, F.; Montironi, Rodolfo; Fazioli, Francesca
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/57647
Citazioni:
Immunohistochemical evaluation of urokinase plasminogen activator receptor in noninvasive and early invasive urothelial papillary neoplasia / Vivani, C., Magi, S., Mazzucchelli, R., Bacchiocchi, R., Santinelli, A., Muzzonigro, G., Blasi, F., Montironi, R., Fazioli, F.. - In: ANALYTICAL AND QUANTITATIVE CYTOLOGY AND HISTOLOGY. - ISSN 0884-6812. - STAMPA. - 2004:(2004), pp. 15-21.

Expression studies of NMN adenylyltransferase in human cultured cell lines.
Anno: 2003
Rivista: EUROPEAN JOURNAL OF HISTOCHEMISTRY
Autori/autrici: Pucci, L.; Raffaelli, Nadia; Amoroso, Salvatore; Magi, Simona; Emanuelli, Monica; Amici, Adolfo; Magni, Giulio
Lingua: ENG
Classificazione IRIS: 1.5 Abstract in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/76620
Citazioni:
Expression studies of NMN adenylyltransferase in human cultured cell lines / Pucci, L., Raffaelli, N., Amoroso, S., Magi, S., Emanuelli, M., Amici, A., Magni, G.. - In: EUROPEAN JOURNAL OF HISTOCHEMISTRY. - ISSN 2038-8306. - 47:(2003), p. 4.