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.
Continua a leggere

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.
Continua a leggere

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.
Continua a leggere

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.
Continua a leggere

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.
Continua a leggere

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.
Continua a leggere

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.
Continua a leggere

Calcium Deregulation in Neurodegeneration and Neuroinflammation in Parkinson's Disease: Role of Calcium-Storing Organelles and Sodium-Calcium Exchanger
Anno: 2024
Rivista: CELLS
Autori/autrici: Bastioli, Guendalina; Piccirillo, Silvia; Graciotti, Laura; Carone, Marianna; Sprega, Giorgia; Taoussi, Omayema; Preziuso, Alessandra; Castaldo, Pasqualina
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/347855
Citazioni:
Calcium Deregulation in Neurodegeneration and Neuroinflammation in Parkinson's Disease: Role of Calcium-Storing Organelles and Sodium-Calcium Exchanger / Bastioli, G., Piccirillo, S., Graciotti, L., Carone, M., Sprega, G., Taoussi, O., Preziuso, A., Castaldo, P.. - In: CELLS. - ISSN 2073-4409. - 13:15(2024). [10.3390/cells13151301]
Abstract:
Parkinson’s disease (PD) is a progressive neurodegenerative disorder that lacks effective treatment strategies to halt or delay its progression. The homeostasis of Ca2+ ions is crucial for ensuring optimal cellular functions and survival, especially for neuronal cells. In the context of PD, th...e systems regulating cellular Ca2+ are compromised, leading to Ca2+-dependent synaptic dysfunction, impaired neuronal plasticity, and ultimately, neuronal loss. Recent research efforts directed toward understanding the pathology of PD have yielded significant insights, particularly highlighting the close relationship between Ca2+ dysregulation, neuroinflammation, and neurodegeneration. However, the precise mechanisms driving the selective loss of dopaminergic neurons in PD remain elusive. The disruption of Ca2+ homeostasis is a key factor, engaging various neurodegenerative and neuroinflammatory pathways and affecting intracellular organelles that store Ca2+. Specifically, impaired functioning of mitochondria, lysosomes, and the endoplasmic reticulum (ER) in Ca2+ metabolism is believed to contribute to the disease’s pathophysiology. The Na+-Ca2+ exchanger (NCX) is considered an important key regulator of Ca2+ homeostasis in various cell types, including neurons, astrocytes, and microglia. Alterations in NCX activity are associated with neurodegenerative processes in different models of PD. In this review, we will explore the role of Ca2+ dysregulation and neuroinflammation as primary drivers of PD-related neurodegeneration, with an emphasis on the pivotal role of NCX in the pathology of PD. Consequently, NCXs and their interplay with intracellular organelles may emerge as potentially pivotal players in the mechanisms underlying PD neurodegeneration, providing a promising avenue for therapeutic intervention aimed at halting neurodegeneration
Continua a leggere

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.
Continua a leggere

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.
Continua a leggere

miRNAs, Mesenchymal Stromal Cells and Major Neoplastic and Inflammatory Skin Diseases: A Page Being Written: A Systematic Review
Anno: 2023
Rivista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Autori/autrici: Di Vincenzo, Mariangela; Diotallevi, Federico; Piccirillo, Silvia; Carnevale, Gianluca; Offidani, Annamaria; Campanati, Anna; Orciani, Monia
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/322255
Citazioni:
miRNAs, Mesenchymal Stromal Cells and Major Neoplastic and Inflammatory Skin Diseases: A Page Being Written: A Systematic Review / Di Vincenzo, M., Diotallevi, F., Piccirillo, S., Carnevale, G., Offidani, A., Campanati, A., Orciani, M.. - In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - ISSN 1422-0067. - 24:10(2023). [10.3390/ijms24108502]
Abstract:
Micro RNAs (miRNAs) are a type of non-coding RNA (ncRNA) and typically interact with specific target mRNAs through complementary base pairing, affecting their translation and/or stability. MiRNAs regulate nearly all cellular functions, including the cell fate of mesenchymal stromal cells (MSCs). It ...is now accepted that various pathologies arise at the stem level, and, in this scenario, the role played by miRNAs in the fate of MSCs becomes of primary concern. Here we have considered the existing literature in the field of miRNAs, MSCs and skin diseases, classified as inflammatory (such as psoriasis and atopic dermatitis-AD) and neoplastic (melanoma and non-melanoma-skin-cancer including squamous cell and basal cell carcinoma) diseases. In this scoping review article, the evidence recovered indicates that this topic has attracted attention, but it is still a matter of opinion. A protocol for this review was registered in PROSPERO with the registration number "CRD42023420245". According to the different skin disorders and to the specific cellular mechanisms considered (cancer stem cells, extracellular vesicles, inflammation), miRNAs may play a pro- or anti-inflammatory, as well as a tumor suppressive, or supporting, role, indicating a complex regulation of their function. It is evident that the mode of action of miRNAs is more than a switch on-off, and all the observed effects of their dysregulated expression must be checked in a detailed analysis of the targeted proteins. The involvement of miRNAs has been studied mainly for squamous cell carcinoma and melanoma, and much less in psoriasis and AD; different mechanisms have been considered, such as miRNAs included in extracellular vesicles derived both from MSCs or tumor cells, miRNAs involved in cancer stem cells formation, up to miRNAs as candidates to be new therapeutic tools.
Continua a leggere

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.
Continua a leggere

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.
Continua a leggere

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.
Continua a leggere

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.
Continua a leggere

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.
Continua a leggere

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.
Continua a leggere

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.
Continua a leggere

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.
Continua a leggere

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.
Continua a leggere

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.
Continua a leggere

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.
Continua a leggere

Involvement of Na+/Ca2+ Exchanger (NCX) in Glutamate-Induced Neuroprotection in SH-SY5Y Differentiated Cells Subjected to Hypoxia/Reoxygenation (H/R) Injury
Anno: 2019
Autori/autrici: Piccirillo, Silvia
Lingua: ENG
Classificazione IRIS: 8.1 Tesi di dottorato
Scheda completa IRIS: https://iris.univpm.it/handle/11566/263512
Citazioni:
Involvement of Na+/Ca2+ Exchanger (NCX) in Glutamate-Induced Neuroprotection in SH-SY5Y Differentiated Cells Subjected to Hypoxia/Reoxygenation (H/R) Injury / Piccirillo, Silvia. - (2019 Mar 27).
Abstract:
L’ischemia cerebrale è una patologia caratterizzata dalla ridotta o totale assenza di ossigeno e di substrati metabolici che influiscono sulla respirazione aerobia determinando un danno mitocondriale in particolare nella sintesi di ATP e nello squilibrio ionico culminando nella morte ce...llulare. L’entità del danno non deriva solo dall’insulto ischemico ma anche dai successivi fenomeni deleteri stimolati dal ripristino del flusso sanguigno e dei livelli di ossigeno. Lo squilibrio metabolico cerebrale induce l’utilizzo di fonti energetiche alternative come il glutammato. Sebbene in passato il glutammato è sempre stato considerato neurotossico, recenti studi hanno evidenziato come il glutammato possa svolgere il ruolo di intermediario metabolico stimolando la sintesi di ATP e migliorando l’attività mitocondriale, grazie al ruolo essenziale svolto dallo scambiatore Na+ /Ca2+ (NCX) e dai trasportatori del glutammato Na+ dipendenti (EAATs). In particolare, il ruolo solto da NCX nella neuroprotezione indotta da glutammato è stato studiato utilizzando un modello in vitro di ischemia cerebrale, cellule di neuroblastoma umano SH-SY5Y differenziate sottoposte ad ipossia/reossigenazione (H/R). In questo modello il danno indotto da H/R determina un aumento della mortalità cellulare, una riduzione dei livelli intracellulari di ATP e un’alterazione dei livelli di Ca2+ intracellulare. L’aggiunta di glutammato all’inizio della fase di reossigenazione determina un parziale recupero del danno inducendo un significativo aumento dei livelli di ATP. Inoltre, l’aggiunta di glutammato recupera parzialmente la riduzione dell’attività reverse-mode di NCX indotto da H/R. La trasfezione con i siRNA diretti contro NCX1 ed EAAT3 bloccano gli effetti protettivi del glutammato, confermando il ruolo essenziale svolto da NCX ed EAAT3 in questo pathway. In conclusione, i risultati ottenuti mostrano un nuovo ruolo svolto dal glutammato come “fattore di sopravvivenza” nel miglioramento del danno indotto da ipossia/reossigenazione, e che l’interazione tra NCX1 ed EAAT3 è fondamentale per permettere al glutammato di esplicare la sua funzione neuroprotettiva.
Continua a leggere

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.
Continua a leggere

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.
Continua a leggere

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.
Continua a leggere

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.
Continua a leggere

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.
Continua a leggere