47 results on '"TEDESCHI, VALENTINA"'
Search Results
2. The 3-(3-oxoisoindolin-1-yl)pentane-2,4-dione (ISOAC1) as a new molecule able to inhibit Amyloid β aggregation and neurotoxicity
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Piccialli, Ilaria, Greco, Francesca, Roviello, Giovanni, Sisalli, Maria Josè, Tedeschi, Valentina, di Mola, Antonia, Borbone, Nicola, Oliviero, Giorgia, De Feo, Vincenzo, Secondo, Agnese, Massa, Antonio, and Pannaccione, Anna
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- 2023
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3. Pharmacological inhibition of lysosomal two-pore channel 2 (TPC2) confers neuroprotection in stroke via autophagy regulation
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Tedeschi, Valentina, Vinciguerra, Antonio, Sisalli, Maria Josè, Pignataro, Giuseppe, and Secondo, Agnese
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- 2023
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4. Na+/Ca2+ exchanger isoform 1 takes part to the Ca2+-related prosurvival pathway of SOD1 in primary motor neurons exposed to beta-methylamino-l-alanine
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Petrozziello, Tiziana, Boscia, Francesca, Tedeschi, Valentina, Pannaccione, Anna, de Rosa, Valeria, Corvino, Angela, Severino, Beatrice, Annunziato, Lucio, and Secondo, Agnese
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- 2022
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5. Involvement of K V 3.4 Channel in Parkinson's Disease: A Key Player in the Control of Midbrain and Striatum Differential Vulnerability during Disease Progression?
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Magliocca, Giorgia, Esposito, Emilia, Tufano, Michele, Piccialli, Ilaria, Rubino, Valentina, Tedeschi, Valentina, Sisalli, Maria Jose, Carriero, Flavia, Ruggiero, Giuseppina, Secondo, Agnese, Annunziato, Lucio, Scorziello, Antonella, and Pannaccione, Anna
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PARKINSON'S disease ,MESENCEPHALON ,NEURODEGENERATION ,DISEASE progression ,ASTROCYTES - Abstract
Parkinson's disease (PD), the second most common neurodegenerative disease in the elderly, is characterized by selective loss of dopaminergic neurons and accumulation of α-synuclein (α-syn), mitochondrial dysfunction, Ca
2+ dyshomeostasis, and neuroinflammation. Since current treatments for PD merely address symptoms, there is an urgent need to identify the PD pathophysiological mechanisms to develop better therapies. Increasing evidence has identified KV 3.4, a ROS-sensitive KV channel carrying fast-inactivating currents, as a potential therapeutic target against neurodegeneration. In fact, it has been hypothesized that KV 3.4 channels could play a role in PD etiopathogenesis, controlling astrocytic activation and detrimental pathways in A53T mice, a well-known model of familial PD. Here, we showed that the A53T midbrain, primarily involved in the initial phase of PD pathogenesis, displayed an early upregulation of the KV 3.4 channel at 4 months, followed by its reduction at 12 months, compared with age-matched WT. On the other hand, in the A53T striatum, the expression of KV 3.4 remained high at 12 months, decreasing thereafter, in 16-month-old mice. The proteomic profile highlighted a different detrimental phenotype in A53T brain areas. In fact, the A53T striatum and midbrain differently expressed neuroprotective/detrimental pathways, with the variation of astrocytic p27kip1 , XIAP, and Smac/DIABLO expression. Of note, a switch from protective to detrimental phenotype was characterized by the upregulation of Smac/DIABLO and downregulation of p27kip1 and XIAP. This occurred earlier in the A53T midbrain, at 12 months, compared with the striatum proteomic profile. In accordance, an upregulation of Smac/DIABLO and a downregulation of p27kip1 occurred in the A53T striatum only at 16 months, showing the slowest involvement of this brain area. Of interest, HIF-1α overexpression was associated with the detrimental profile in midbrain and its major vulnerability. At the cellular level, patch-clamp recordings revealed that primary A53T striatum astrocytes showed hyperpolarized resting membrane potentials and lower firing frequency associated with KV 3.4 ROS-dependent hyperactivity, whereas primary A53T midbrain astrocytes displayed a depolarized resting membrane potential accompanied by a slight increase of KV 3.4 currents. Accordingly, intracellular Ca2+ homeostasis was significantly altered in A53T midbrain astrocytes, in which the ER Ca2+ level was lower than in A53T striatum astrocytes and the respective littermate controls. Collectively, these results suggest that the early KV 3.4 overexpression and ROS-dependent hyperactivation in astrocytes could take part in the different vulnerabilities of midbrain and striatum, highlighting astrocytic KV 3.4 as a possible new therapeutic target in PD. [ABSTRACT FROM AUTHOR]- Published
- 2024
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6. Probing the Ca2+ mobilizing properties on primary cortical neurons of a new stable cADPR mimic
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D'Errico, Stefano, Greco, Francesca, Patrizia Falanga, Andrea, Tedeschi, Valentina, Piccialli, Ilaria, Marzano, Maria, Terracciano, Monica, Secondo, Agnese, Roviello, Giovanni Nicola, Oliviero, Giorgia, and Borbone, Nicola
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- 2021
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7. Rebound effects of NCX3 pharmacological inhibition: A novel strategy to accelerate myelin formation in oligodendrocytes
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Cammarota, Mariarosaria, de Rosa, Valeria, Pannaccione, Anna, Secondo, Agnese, Tedeschi, Valentina, Piccialli, Ilaria, Fiorino, Ferdinando, Severino, Beatrice, Annunziato, Lucio, and Boscia, Francesca
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- 2021
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8. Targeting staphylococcal enterotoxin B binding to CD28 as a new strategy for dampening superantigen-mediated intestinal epithelial barrier dysfunctions.
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Amormino, Carola, Russo, Emanuela, Tedeschi, Valentina, Fiorillo, Maria Teresa, Paiardini, Alessandro, Spallotta, Francesco, Rosanò, Laura, Tuosto, Loretta, and Kunkl, Martina
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CD28 antigen ,ENTEROTOXINS ,INTESTINES ,T cells ,PEPTIDES - Abstract
Staphylococcus aureus is a gram-positive bacterium that may cause intestinal inflammation by secreting enterotoxins, which commonly cause food-poisoning and gastrointestinal injuries. Staphylococcal enterotoxin B (SEB) acts as a superantigen (SAg) by binding in a bivalent manner the T-cell receptor (TCR) and the costimulatory receptor CD28, thus stimulating T cells to produce large amounts of inflammatory cytokines, which may affect intestinal epithelial barrier integrity and functions. However, the role of T cell-mediated SEB inflammatory activity remains unknown. Here we show that inflammatory cytokines produced by T cells following SEB stimulation induce dysfunctions in Caco-2 intestinal epithelial cells by promoting actin cytoskeleton remodelling and epithelial cellcell junction down-regulation. We also found that SEB-activated inflammatory T cells promote the up-regulation of epithelial-mesenchymal transition transcription factors (EMT-TFs) in a nuclear factor-kB (NF-kB)- and STAT3- dependent manner. Finally, by using a structure-based design approach, we identified a SEB mimetic peptide (pSEB116-132) that, by blocking the binding of SEB to CD28, dampens inflammatory-mediated dysregulation of intestinal epithelial barrier. [ABSTRACT FROM AUTHOR]
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- 2024
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9. The activation of Mucolipin TRP channel 1 (TRPML1) protects motor neurons from L-BMAA neurotoxicity by promoting autophagic clearance
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Tedeschi, Valentina, Petrozziello, Tiziana, Sisalli, Maria José, Boscia, Francesca, Canzoniero, Lorella Maria Teresa, and Secondo, Agnese
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- 2019
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10. ERAP1 and ERAP2 Haplotypes Influence Suboptimal HLA-B*27:05-Restricted Anti-Viral CD8+ T Cell Responses Cross-Reactive to Self-Epitopes.
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Tedeschi, Valentina, Paldino, Giorgia, Alba, Josephine, Molteni, Emanuele, Paladini, Fabiana, Scrivo, Rossana, Congia, Mattia, Cauli, Alberto, Caccavale, Rosalba, Paroli, Marino, Di Franco, Manuela, Tuosto, Loretta, Sorrentino, Rosa, D'Abramo, Marco, and Fiorillo, Maria Teresa
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T cells , *ALLELES , *CD8 antigen , *HLA histocompatibility antigens , *HAPLOTYPES , *PEPTIDES - Abstract
The human leukocyte antigen (HLA)-B*27 family of alleles is strongly associated with ankylosing spondylitis (AS), a chronic inflammatory disorder affecting the axial and peripheral joints, yet some HLA-B*27 variants not associated with AS have been shown. Since no major differences in the ligandome of associated compared to not-associated alleles have emerged, a plausible hypothesis is that the quantity rather than the quality of the presented epitopes makes the difference. In addition, the Endoplasmic Reticulum AminoPeptidases (ERAPs) 1 and 2, playing a crucial role in shaping the HLA class I epitopes, act as strong AS susceptibility factors, suggesting that an altered peptidome might be responsible for the activation of pathogenic CD8+ T cells. In this context, we have previously singled out a B*27:05-restricted CD8+ T cell response against pEBNA3A (RPPIFIRRL), an EBV peptide lacking the B*27 classic binding motif. Here, we show that a specific ERAP1/2 haplotype negatively correlates with such response in B*27:05 subjects. Moreover, we prove that the B*27:05 allele successfully presents peptides with the same suboptimal N-terminal RP motif, including the self-peptide, pDYNEIN (RPPIFGDFL). Overall, this study underscores the cooperation between the HLA-B*27 and ERAP1/2 allelic variants in defining CD8+ T cell reactivity to suboptimal viral and self-B*27 peptides and prompts further investigation of the B*27:05 peptidome composition. [ABSTRACT FROM AUTHOR]
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- 2023
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11. An allelic variant in the intergenic region between ERAP1 and ERAP2 correlates with an inverse expression of the two genes
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Paladini, Fabiana, Fiorillo, Maria Teresa, Vitulano, Carolina, Tedeschi, Valentina, Piga, Matteo, Cauli, Alberto, Mathieu, Alessandro, and Sorrentino, Rosa
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- 2018
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12. Na+/Ca2+ exchanger 1 on nuclear envelope controls PTEN/Akt pathway via nucleoplasmic Ca2+ regulation during neuronal differentiation
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Secondo, Agnese, Esposito, Alba, Petrozziello, Tiziana, Boscia, Francesca, Molinaro, Pasquale, Tedeschi, Valentina, Pannaccione, Anna, Ciccone, Roselia, Guida, Natascia, Di Renzo, Gianfranco, and Annunziato, Lucio
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- 2018
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13. The Ankylosing Spondylitis-Associated HLA-B*2705 Presents a B*0702-Restricted EBV Epitope and Sustains the Clonal Amplification of Cytotoxic T Cells in Patients
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Tedeschi, Valentina, Vitulano, Carolina, Cauli, Alberto, Paladini, Fabiana, Piga, Matteo, Mathieu, Alessandro, Sorrentino, Rosa, and Fiorillo, Maria Teresa
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- 2016
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14. SARS-CoV-2 Spike Protein Activates Human Lung Macrophages.
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Palestra, Francesco, Poto, Remo, Ciardi, Renato, Opromolla, Giorgia, Secondo, Agnese, Tedeschi, Valentina, Ferrara, Anne Lise, Di Crescenzo, Rosa Maria, Galdiero, Maria Rosaria, Cristinziano, Leonardo, Modestino, Luca, Marone, Gianni, Fiorelli, Alfonso, Varricchi, Gilda, and Loffredo, Stefania
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SARS-CoV-2 ,CARRIER proteins ,MACROPHAGES ,VIRUS diseases ,PROTEINS - Abstract
COVID-19 is a viral disease caused by SARS-CoV-2. This disease is characterized primarily, but not exclusively, by respiratory tract inflammation. SARS-CoV-2 infection relies on the binding of spike protein to ACE2 on the host cells. The virus uses the protease TMPRSS2 as an entry activator. Human lung macrophages (HLMs) are the most abundant immune cells in the lung and fulfill a variety of specialized functions mediated by the production of cytokines and chemokines. The aim of this project was to investigate the effects of spike protein on HLM activation and the expression of ACE2 and TMPRSS2 in HLMs. Spike protein induced CXCL8, IL-6, TNF-α, and IL-1β release from HLMs; promoted efficient phagocytosis; and induced dysfunction of intracellular Ca
2+ concentration by increasing lysosomal Ca2+ content in HLMs. Microscopy experiments revealed that HLM tracking was affected by spike protein activation. Finally, HLMs constitutively expressed mRNAs for ACE2 and TMPRSS2. In conclusion, during SARS-CoV-2 infection, macrophages seem to play a key role in lung injury, resulting in immunological dysfunction and respiratory disease. [ABSTRACT FROM AUTHOR]- Published
- 2023
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15. Cerium-Doped Self-Assembling Nanoparticles as a Novel Anti-Oxidant Delivery System Preserving Mitochondrial Function in Cortical Neurons Exposed to Ischemia-like Conditions.
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Nele, Valeria, Tedeschi, Valentina, Campani, Virginia, Ciancio, Raffaella, Angelillo, Alessia, Graziano, Sossio Fabio, De Rosa, Giuseppe, and Secondo, Agnese
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MITOCHONDRIA ,ANTIOXIDANTS ,REACTIVE oxygen species ,NANOPARTICLES ,NEURONS - Abstract
Neurodegenerative diseases are characterized by mitochondrial dysfunction leading to abnormal levels of reactive oxygen species (ROS), making the use of ROS-scavenging nanomaterials a promising therapeutic approach. Here, we combined the unique ROS-scavenging properties of cerium-based nanomaterials with the lipid self-assembling nanoparticles (SANP) technology. We optimized the preparation of cerium-doped SANP (Ce-SANP) and characterized the formulations in terms of both physiochemical and biological properties. Ce-SANP exhibited good colloidal properties and were able to mimic the activity of two ROS-scavenging enzymes, namely peroxidase and super oxide dismutase. Under ischemia-like conditions, Ce-SANP could rescue neuronal cells from mitochondrial suffering by reducing ROS production and preventing ATP level reduction. Furthermore, Ce-SANP prevented mitochondrial Ca
2+ homeostasis dysfunction, partially restoring mitochondrial Ca2+ handling. Taken together, these results highlight the potential of the anti-oxidant Ce-SANP platform technology to manage ROS levels and mitochondrial function for the treatment of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]- Published
- 2023
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16. Size-Based Effects of Anthropogenic Ultrafine Particles on Lysosomal TRPML1 Channel and Autophagy in Motoneuron-like Cells.
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Sapienza, Silvia, Tedeschi, Valentina, Apicella, Barbara, Palestra, Francesco, Russo, Carmela, Piccialli, Ilaria, Pannaccione, Anna, Loffredo, Stefania, and Secondo, Agnese
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AUTOPHAGY , *CARDIOPULMONARY system , *WESTERN immunoblotting , *MEMBRANE potential , *LYSOSOMES , *AMP-activated protein kinases - Abstract
Background: An emerging body of evidence indicates an association between anthropogenic particulate matter (PM) and neurodegeneration. Although the historical focus of PM toxicity has been on the cardiopulmonary system, ultrafine PM particles can also exert detrimental effects in the brain. However, only a few studies are available on the harmful interaction between PM and CNS and on the putative pathomechanisms. Methods: Ultrafine PM particles with a diameter < 0.1 μm (PM0.1) and nanoparticles < 20 nm (NP20) were sampled in a lab-scale combustion system. Their effect on cell tracking in the space was studied by time-lapse and high-content microscopy in NSC-34 motor neurons while pHrodo™ Green conjugates were used to detect PM endocytosis. Western blotting analysis was used to quantify protein expression of lysosomal channels (i.e., TRPML1 and TPC2) and autophagy markers. Current-clamp electrophysiology and Fura2-video imaging techniques were used to measure membrane potential, intracellular Ca2+ homeostasis and TRPML1 activity in NSC-34 cells exposed to PM0.1 and NP20. Results: NP20, but not PM0.1, reduced NSC-34 motor neuron movement in the space. Furthermore, NP20 was able to shift membrane potential of motor neurons toward more depolarizing values. PM0.1 and NP20 were able to enter into the cells by endocytosis and exerted mitochondrial toxicity with the consequent stimulation of ROS production. This latter event was sufficient to determine the hyperactivation of the lysosomal channel TRPML1. Consequently, both LC3-II and p62 protein expression increased after 48 h of exposure together with AMPK activation, suggesting an engulfment of autophagy. The antioxidant molecule Trolox restored TRPML1 function and autophagy. Conclusions: Restoring TRPML1 function by an antioxidant agent may be considered a protective mechanism able to reestablish autophagy flux in motor neurons exposed to nanoparticles. [ABSTRACT FROM AUTHOR]
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- 2022
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17. The emerging multifunctional roles of ERAP1, ERAP2 and IRAP between antigen processing and renin-angiotensin system modulation.
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Mattorre, Benedetta, Tedeschi, Valentina, Paldino, Giorgia, Fiorillo, Maria Teresa, Paladini, Fabiana, and Sorrentino, Rosa
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RENIN-angiotensin system ,ANTIGEN processing ,ECLAMPSIA ,ENDOPLASMIC reticulum ,ANGIOTENSIN II ,ANTIGEN presentation - Abstract
The Endoplasmic Reticulum Aminopeptidase 1 and 2 (ERAP1 and ERAP2) and Insulin Regulated Aminopeptidase (IRAP) are three M1 zinc metalloproteases whose role in antigen processing is the refining of peptidome either in the Endoplasmic reticulum (ERAP1 and ERAP2), or in the endosomes (IRAP). However, other novel and distinct functions are emerging. Here, we focus specifically on ERAP2. This gene has a peculiar evolutionary history, being absent in rodents and undergoing in humans to a balanced selection of two haplotypes, one of which not expressing the full length ERAP2. These observations suggest that its role in antigen presentation is not essential. An additional, less investigated role is in the regulation of the Renin Angiotensin System (RAS). ERAP1 and ERAP2 cleave Angiotensin II (Ang II) into Ang III and IV, which counteract the action of Ang II whereas IRAP is itself the receptor for Ang IV. We have recently reported that macrophages, independently from the haplotype, express and release a N-terminus ERAP2 "short" form which directly binds IRAP and the two molecules are co-expressed in the endosomes and on the cell membrane. This new evidence suggests that the maintenance of the ERAP2 gene in humans could be due to its activity in the regulation of the RAS system, possibly as an Ang IV agonist. Its role in the immune-mediated diseases as well as in disorders more specifically related to an imbalance of the RAS system, including hypertension, pre-eclampsia but also viral infections such as COVID-19, is discussed here. [ABSTRACT FROM AUTHOR]
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- 2022
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18. Increased K V 2.1 Channel Clustering Underlies the Reduction of Delayed Rectifier K + Currents in Hippocampal Neurons of the Tg2576 Alzheimer's Disease Mouse.
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Piccialli, Ilaria, Sisalli, Maria José, de Rosa, Valeria, Boscia, Francesca, Tedeschi, Valentina, Secondo, Agnese, and Pannaccione, Anna
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ALZHEIMER'S disease ,PYRAMIDAL neurons ,NEURONS ,HIPPOCAMPUS (Brain) ,POTASSIUM channels ,HOMEOSTASIS ,MICE ,WESTERN immunoblotting - Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the progressive deterioration of cognitive functions. Cortical and hippocampal hyperexcitability intervenes in the pathological derangement of brain activity leading to cognitive decline. As key regulators of neuronal excitability, the voltage-gated K
+ channels (KV ) might play a crucial role in the AD pathophysiology. Among them, the KV 2.1 channel, the main α subunit mediating the delayed rectifier K+ currents (IDR ) and controlling the intrinsic excitability of pyramidal neurons, has been poorly examined in AD. In the present study, we investigated the KV 2.1 protein expression and activity in hippocampal neurons from the Tg2576 mouse, a widely used transgenic model of AD. To this aim we performed whole-cell patch-clamp recordings, Western blotting, and immunofluorescence analyses. Our Western blotting results reveal that KV 2.1 was overexpressed in the hippocampus of 3-month-old Tg2576 mice and in primary hippocampal neurons from Tg2576 mouse embryos compared with the WT counterparts. Electrophysiological experiments unveiled that the whole IDR were reduced in the Tg2576 primary neurons compared with the WT neurons, and that this reduction was due to the loss of the KV 2.1 current component. Moreover, we found that the reduction of the KV 2.1-mediated currents was due to increased channel clustering, and that glutamate, a stimulus inducing KV 2.1 declustering, was able to restore the IDR to levels comparable to those of the WT neurons. These findings add new information about the dysregulation of ionic homeostasis in the Tg2576 AD mouse model and identify KV 2.1 as a possible player in the AD-related alterations of neuronal excitability. [ABSTRACT FROM AUTHOR]- Published
- 2022
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19. SARS-CoV-2 Spike Does Not Possess Intrinsic Superantigen-like Inflammatory Activity.
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Amormino, Carola, Tedeschi, Valentina, Paldino, Giorgia, Arcieri, Stefano, Fiorillo, Maria Teresa, Paiardini, Alessandro, Tuosto, Loretta, and Kunkl, Martina
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MULTISYSTEM inflammatory syndrome in children , *TOXIC shock syndrome , *SARS-CoV-2 , *T cells , *T cell receptors - Abstract
Multisystem inflammatory syndrome in children (MIS-C) is a rare hyperinflammatory disease occurring several weeks after SARS-CoV-2 infection. The clinical similarities between MIS-C and the toxic shock syndrome, together with the preferential expansion of T cells with a T-cell receptor variable β chain (TCRVβ) skewing, suggested a superantigen theory of MIS-C. For instance, recent in silico modelling evidenced the presence of a highly conserved motif within SARS-CoV-2 spike protein similar in structure to the superantigenic fragment of staphylococcal enterotoxin B (SEB). However, experimental data on the superantigenic activity of the SARS-CoV-2 spike have not yet been provided. Here, we assessed the superantigenic activity of the SARS-CoV-2 spike by analysing inflammatory cytokine production in both Jurkat cells and the peripheral blood CD4+ T cells stimulated with the SARS-CoV-2 spike or SEB as a control. We found that, unlike SEB, the SARS-CoV-2 spike does not exhibit an intrinsic superantigen-like activity. [ABSTRACT FROM AUTHOR]
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- 2022
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20. Exploring the Therapeutic Potential of Phytochemicals in Alzheimer's Disease: Focus on Polyphenols and Monoterpenes.
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Piccialli, Ilaria, Tedeschi, Valentina, Caputo, Lucia, D'Errico, Stefano, Ciccone, Roselia, De Feo, Vincenzo, Secondo, Agnese, and Pannaccione, Anna
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MONOTERPENES ,PHYTOCHEMICALS ,ALZHEIMER'S disease ,POLYPHENOLS ,SEARCH engines ,INSULIN resistance ,PEPTIDES ,MEMORY loss - Abstract
Alzheimer's disease (AD) is a chronic, complex neurodegenerative disorder mainly characterized by the irreversible loss of memory and cognitive functions. Different hypotheses have been proposed thus far to explain the etiology of this devastating disorder, including those centered on the Amyloid-β (Aβ) peptide aggregation, Tau hyperphosphorylation, neuroinflammation and oxidative stress. Nonetheless, the therapeutic strategies conceived thus far to treat AD neurodegeneration have proven unsuccessful, probably due to the use of single-target drugs unable to arrest the progressive deterioration of brain functions. For this reason, the theoretical description of the AD etiology has recently switched from over-emphasizing a single deleterious process to considering AD neurodegeneration as the result of different pathogenic mechanisms and their interplay. Moreover, much relevance has recently been conferred to several comorbidities inducing insulin resistance and brain energy hypometabolism, including diabetes and obesity. As consequence, much interest is currently accorded in AD treatment to a multi-target approach interfering with different pathways at the same time, and to life-style interventions aimed at preventing the modifiable risk-factors strictly associated with aging. In this context, phytochemical compounds are emerging as an enormous source to draw on in the search for multi-target agents completing or assisting the traditional pharmacological medicine. Intriguingly, many plant-derived compounds have proven their efficacy in counteracting several pathogenic processes such as the Aβ aggregation, neuroinflammation, oxidative stress and insulin resistance. Many strategies have also been conceived to overcome the limitations of some promising phytochemicals related to their poor pharmacokinetic profiles, including nanotechnology and synthetic routes. Considering the emerging therapeutic potential of natural medicine, the aim of the present review is therefore to highlight the most promising phytochemical compounds belonging to two major classes, polyphenols and monoterpenes, and to report the main findings about their mechanisms of action relating to the AD pathogenesis. [ABSTRACT FROM AUTHOR]
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- 2022
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21. CD8 + T Cell Senescence: Lights and Shadows in Viral Infections, Autoimmune Disorders and Cancer.
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Tedeschi, Valentina, Paldino, Giorgia, Kunkl, Martina, Paroli, Marino, Sorrentino, Rosa, Tuosto, Loretta, and Fiorillo, Maria Teresa
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T cells , *CELLULAR aging , *VIRUS diseases , *AUTOIMMUNE diseases , *YOUNG adults , *IMMUNOLOGIC memory - Abstract
CD8+ T lymphocytes are a heterogeneous class of cells that play a crucial role in the adaptive immune response against pathogens and cancer. During their lifetime, they acquire cytotoxic functions to ensure the clearance of infected or transformed cells and, in addition, they turn into memory lymphocytes, thus providing a long-term protection. During ageing, the thymic involution causes a reduction of circulating T cells and an enrichment of memory cells, partially explaining the lowering of the response towards novel antigens with implications in vaccine efficacy. Moreover, the persistent stimulation by several antigens throughout life favors the switching of CD8+ T cells towards a senescent phenotype contributing to a low-grade inflammation that is a major component of several ageing-related diseases. In genetically predisposed young people, an immunological stress caused by viral infections (e.g., HIV, CMV, SARS-CoV-2), autoimmune disorders or tumor microenvironment (TME) could mimic the ageing status with the consequent acceleration of T cell senescence. This, in turn, exacerbates the inflamed conditions with dramatic effects on the clinical progression of the disease. A better characterization of the phenotype as well as the functions of senescent CD8+ T cells can be pivotal to prevent age-related diseases, to improve vaccine strategies and, possibly, immunotherapies in autoimmune diseases and cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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22. Astrocytes and Inflammatory T Helper Cells: A Dangerous Liaison in Multiple Sclerosis.
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Kunkl, Martina, Amormino, Carola, Tedeschi, Valentina, Fiorillo, Maria Teresa, and Tuosto, Loretta
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T helper cells ,MULTIPLE sclerosis ,ASTROCYTES ,NEUROGLIA ,T cells ,NEUROMYELITIS optica ,MYELIN sheath diseases - Abstract
Multiple Sclerosis (MS) is a neurodegenerative autoimmune disorder of the central nervous system (CNS) characterized by the recruitment of self-reactive T lymphocytes, mainly inflammatory T helper (Th) cell subsets. Once recruited within the CNS, inflammatory Th cells produce several inflammatory cytokines and chemokines that activate resident glial cells, thus contributing to the breakdown of blood-brain barrier (BBB), demyelination and axonal loss. Astrocytes are recognized as key players of MS immunopathology, which respond to Th cell-defining cytokines by acquiring a reactive phenotype that amplify neuroinflammation into the CNS and contribute to MS progression. In this review, we summarize current knowledge of the astrocytic changes and behaviour in both MS and experimental autoimmune encephalomyelitis (EAE), and the contribution of pathogenic Th1, Th17 and Th1-like Th17 cell subsets, and CD8
+ T cells to the morphological and functional modifications occurring in astrocytes and their pathological outcomes. [ABSTRACT FROM AUTHOR]- Published
- 2022
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23. Na+/Ca2+ exchanger isoform 1 takes part to the Ca2+-related prosurvival pathway of SOD1 in primary motor neurons exposed to beta-methylamino-l-alanine.
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Petrozziello, Tiziana, Boscia, Francesca, Tedeschi, Valentina, Pannaccione, Anna, de Rosa, Valeria, Corvino, Angela, Severino, Beatrice, Annunziato, Lucio, and Secondo, Agnese
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MOTOR neurons ,PURINERGIC receptors ,CELL death ,MEMBRANE proteins ,BLOOD proteins ,CELL membranes ,CALCIUM ions - Abstract
Background: The cycad neurotoxin beta-methylamino-l-alanine (L-BMAA), one of the environmental trigger factor for amyotrophic lateral sclerosis/Parkinson-dementia complex (ALS/PDC), may cause neurodegeneration by disrupting organellar Ca
2+ homeostasis. Through the activation of Akt/ERK1/2 pathway, the Cu,Zn-superoxide dismutase (SOD1) and its non-metallated form, ApoSOD1, prevent endoplasmic reticulum (ER) stress-induced cell death in motor neurons exposed to L-BMAA. This occurs through the rapid increase of intracellular Ca2+ concentration ([Ca2+ ]i ) in part flowing from the extracellular compartment and in part released from ER. However, the molecular components of this mechanism remain uncharacterized. Methods: By an integrated approach consisting on the use of siRNA strategy, Western blotting, confocal double- labeling immunofluorescence, patch-clamp electrophysiology, and Fura 2-/SBFI-single-cell imaging, we explored in rat motor neuron-enriched cultures the involvement of the plasma membrane proteins Na+ /Ca2+ exchanger (NCX) and purinergic P2 X7 receptor as well as that of the intracellular cADP-ribose (cADPR) pathway, in the neuroprotective mechanism of SOD1. Results: We showed that SOD1-induced [Ca2+ ]i rise was prevented neither by A430879, a P2 X7 receptor specific antagonist or 8-bromo-cADPR, a cell permeant antagonist of cADP-ribose, but only by the pan inhibitor of NCX, CB-DMB. The same occurred for the ApoSOD1. Confocal double labeling immunofluorescence showed a huge expression of plasmalemmal NCX1 and intracellular NCX3 isoforms. Furthermore, we identified NCX1 reverse mode as the main mechanism responsible for the neuroprotective ER Ca2+ refilling elicited by SOD1 and ApoSOD1 through which they promoted translocation of active Akt in the nuclei of a subset of primary motor neurons. Finally, the activation of NCX1 by the specific agonist CN-PYB2 protected motor neurons from L-BMAA-induced cell death, mimicking the effect of SOD1. Conclusion: Collectively, our data indicate that SOD1 and ApoSOD1 exert their neuroprotective effect by modulating ER Ca2+ content through the activation of NCX1 reverse mode and Akt nuclear translocation in a subset of primary motor neurons. 7n_RSb6LJnzKN1GMcoyFaw Video Abstract [ABSTRACT FROM AUTHOR]- Published
- 2022
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24. New Insights into the Structure-Activity Relationship and Neuroprotective Profile of Benzodiazepinone Derivatives of Neurounina-1 as Modulators of the Na+/Ca2+ Exchanger Isoforms.
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Magli, Elisa, Fattorusso, Caterina, Persico, Marco, Corvino, Angela, Esposito, Gianluca, Fiorino, Ferdinando, Luciano, Paolo, Perissutti, Elisa, Santagada, Vincenzo, Severino, Beatrice, Tedeschi, Valentina, Pannaccione, Anna, Pignataro, Giuseppe, Caliendo, Giuseppe, Annunziato, Lucio, Secondo, Agnese, and Frecentese, Francesco
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- 2021
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25. The Na+/Ca2+ Exchanger 3 Is Functionally Coupled With the NaV1.6 Voltage-Gated Channel and Promotes an Endoplasmic Reticulum Ca2+ Refilling in a Transgenic Model of Alzheimer's Disease.
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Piccialli, Ilaria, Ciccone, Roselia, Secondo, Agnese, Boscia, Francesca, Tedeschi, Valentina, de Rosa, Valeria, Cepparulo, Pasquale, Annunziato, Lucio, and Pannaccione, Anna
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NEUROFIBRILLARY tangles ,ALZHEIMER'S disease ,DRUG target ,THETA rhythm ,ENDOPLASMIC reticulum ,HOMEOSTASIS - Abstract
The remodelling of neuronal ionic homeostasis by altered channels and transporters is a critical feature of the Alzheimer's disease (AD) pathogenesis. Different reports converge on the concept that the Na
+ /Ca2+ exchanger (NCX), as one of the main regulators of Na+ and Ca2+ concentrations and signalling, could exert a neuroprotective role in AD. The activity of NCX has been found to be increased in AD brains, where it seemed to correlate with an increased neuronal survival. Moreover, the enhancement of the NCX3 currents (INCX ) in primary neurons treated with the neurotoxic amyloid β 1–42 (Aβ1–42 ) oligomers prevented the endoplasmic reticulum (ER) stress and neuronal death. The present study has been designed to investigate any possible modulation of the INCX , the functional interaction between NCX and the NaV 1.6 channel, and their impact on the Ca2+ homeostasis in a transgenic in vitro model of AD, the primary hippocampal neurons from the Tg2576 mouse, which overproduce the Aβ1–42 peptide. Electrophysiological studies, carried in the presence of siRNA and the isoform-selective NCX inhibitor KB-R7943, showed that the activity of a specific NCX isoform, NCX3, was upregulated in its reverse, Ca2+ influx mode of operation in the Tg2576 neurons. The enhanced NCX activity contributed, in turn, to increase the ER Ca2+ content, without affecting the cytosolic Ca2+ concentrations of the Tg2576 neurons. Interestingly, our experiments have also uncovered a functional coupling between NCX3 and the voltage-gated NaV 1.6 channels. In particular, the increased NaV 1.6 currents appeared to be responsible for the upregulation of the reverse mode of NCX3, since both TTX and the Streptomyces griseolus antibiotic anisomycin, by reducing the NaV 1.6 currents, counteracted the increase of the INCX in the Tg2576 neurons. In agreement, our immunofluorescence analyses revealed that the NCX3/NaV 1.6 co-expression was increased in the Tg2576 hippocampal neurons in comparison with the WT neurons. Collectively, these findings indicate that NCX3 might intervene in the Ca2+ remodelling occurring in the Tg2576 primary neurons thus emerging as a molecular target with a neuroprotective potential, and provide a new outcome of the NaV 1.6 upregulation related to the modulation of the intracellular Ca2+ concentrations in AD neurons. [ABSTRACT FROM AUTHOR]- Published
- 2021
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26. Binding of Staphylococcal Enterotoxin B (SEB) to B7 Receptors Triggers TCR- and CD28-Mediated Inflammatory Signals in the Absence of MHC Class II Molecules.
- Author
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Kunkl, Martina, Amormino, Carola, Caristi, Silvana, Tedeschi, Valentina, Fiorillo, Maria Teresa, Levy, Revital, Popugailo, Andrey, Kaempfer, Raymond, and Tuosto, Loretta
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T cell receptors ,ENTEROTOXINS ,ANTIGEN presenting cells ,MOLECULES ,T cells - Abstract
The inflammatory activity of staphylococcal enterotoxin B (SEB) relies on its capacity to trigger polyclonal T-cell activation by binding both T-cell receptor (TCR) and costimulatory receptor CD28 on T cells and MHC class II and B7 molecules on antigen presenting cells (APC). Previous studies highlighted that SEB may bind TCR and CD28 molecules independently of MHC class II, yet the relative contribution of these interactions to the pro-inflammatory function of SEB remained unclear. Here, we show that binding to MHC class II is dispensable for the inflammatory activity of SEB, whereas binding to TCR, CD28 and B7 molecules is pivotal, in both human primary T cells and Jurkat T cell lines. In particular, our finding is that binding of SEB to B7 molecules suffices to trigger both TCR- and CD28-mediated inflammatory signalling. We also provide evidence that, by strengthening the interaction between CD28 and B7, SEB favours the recruitment of the TCR into the immunological synapse, thus inducing lethal inflammatory signalling. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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27. BIOLOGICAL ASPECTS OF NEW MOLECULAR THERAPIES FOR NEUROPATHOLOGIES.
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PICCIALLI, ILARIA, GRECO, FRANCESCA, ROVIELLO, GIOVANNI N., SISALLI, MARIA JOSÈ, TEDESCHI, VALENTINA, DI MOLA, ANTONIA, BORBONE, NICOLA, DE FEO, VINCENZO, SECONDO, AGNESE, MASSA, ANTONIO, PANNACCIONE, ANNA, NOLLI, MARIA GRAZIA, and OLIVIERO, GIORGIA
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ALZHEIMER'S disease ,BIOLOGICAL assay ,NEUROLOGICAL disorders ,THIOFLAVINS - Abstract
Introduction: Addressing the formidable therapeutic hurdles posed by Alzheimer's disease (AD), our study delves into the central role of amyloid β 1-42 (Aβ1-42) protein aggregation in its onset. Aim: Our investigation aims to assess the therapeutic potential of the isoindolinone derivative 3-(3-oxoisoindolin-1-yl)pentane-2,4-dione (ISOAC1) against the Aβ1-42-induced toxicity. Material and methods: Employing a combination of thioflavin T fluorescence assay and biological and cellular approaches, alongside other experimental methods, we explored ISOAC1's ability to mitigate Aβ1-42 aggregation and toxicity. Results and conclusions: Our study unveils ISOAC1's capacity to disrupt Aβ1-42 aggregation and impede its transition towards β-sheet structures. Furthermore, our findings shed light on ISOAC1's binding mechanisms with Aβ1-42, indicating its promise as a therapeutic agent. ISOAC1 emerges as a compelling neuroprotective compound, offering novel avenues for AD treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2024
28. Lysosomal calcium is modulated by STIM1/TRPML1 interaction which participates to neuronal survival during ischemic preconditioning.
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Tedeschi, Valentina, Sisalli, Maria José, Petrozziello, Tiziana, Canzoniero, Lorella Maria Teresa, and Secondo, Agnese
- Abstract
A robust activity of the lysosomal Ca2+ channel TRPML1 is sufficient to correct cellular defects in neurodegeneration. Importantly, lysosomes are refilled by the endoplasmic reticulum (ER). However, it is unclear how TRPML1 function could be modulated by the ER. Here, we deal with this issue in rat primary cortical neurons exposed to different oxygen conditions affecting neuronal survival. Under normoxic conditions, TRPML1: (1) showed a wide distribution within soma and along neuronal processes; (2) was stimulated by the synthetic agonist ML‐SA1 and the analog of its endogenous modulator, PI(3,5)P2 diC8; (3) its knockdown by siRNA strategy produced an ER Ca2+ accumulation; (4) co‐localized and co‐immunoprecipitated with the ER‐located Ca2+ sensor stromal interacting molecule 1 (STIM1). In cortical neurons lacking STIM1, ML‐SA1 and PI(3,5)P2 diC8 failed to induce Ca2+ release and, more deeply, they induced a negligible Ca2+ passage through the channel in neurons transfected with the genetically encoded Ca2+ indicator GCaMP3‐ML1. Moreover, TRPML1/STIM1 interplay changed at low‐oxygen conditions: both proteins were downregulated during the ischemic preconditioning (IPC) while during IPC followed by 1 hour of normoxia, at which STIM1 is upregulated, TRPML1 protein was reduced. However, during oxygen and glucose deprivation (OGD) followed by reoxygenation, TRPML1 and STIM1 proteins peaked at 8 hours of reoxygenation, when the proteins were co‐immunoprecipitated and reactive oxygen species (ROS) hyperproduction was measured in cortical neurons. This may lead to a persistent TRPML1 Ca2+ release and lysosomal Ca2+ loss. Collectively, we showed a new modulation exerted by STIM1 on TRPML1 activity that may differently intervene during hypoxia to regulate organellar Ca2+ homeostasis. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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29. The Multifaceted Nature of Aminopeptidases ERAP1, ERAP2, and LNPEP: From Evolution to Disease.
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Paladini, Fabiana, Fiorillo, Maria Teresa, Tedeschi, Valentina, Mattorre, Benedetta, and Sorrentino, Rosa
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AMINOPEPTIDASES ,CELL receptors ,ANGIOTENSIN receptors ,RENIN-angiotensin system ,CHROMOSOME duplication - Abstract
In the human genome, the aminopeptidases ERAP1, ERAP2 and LNPEP lie contiguously on chromosome 5. They share sequence homology, functions and associations with immune-mediated diseases. By analyzing their multifaceted activities as well as their expression in the zoological scale, we suggest here that the progenitor of the three aminopeptidases might be LNPEP from which the other two aminopeptidases could have derived by gene duplications. We also propose that their functions are partially redundant. More precisely, the evolutionary story of the three aminopeptidases might have been dictated by their role in regulating the renin–angiotensin system, which requires their controlled and coordinated expression. This hypothesis is supported by the many species that lack one or the other gene as well as by the lack of ERAP2 in rodents and a null expression in 25% of humans. Finally, we speculate that their role in antigen presentation has been acquired later on during evolution. They have therefore been diversified between those residing in the ER, ERAP1 and ERAP2, whose role is to refine the MHC-I peptidomes, and LNPEP, mostly present in the endosomal vesicles where it can contribute to antigen cross-presentation or move to the cell membrane as receptor for angiotensin IV. Their association with autoinflammatory/autoimmune diseases can therefore be two-fold: as "contributors" to the shaping of the immune-peptidomes as well as to the regulation of the vascular response. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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30. The rs75862629 minor allele in the endoplasmic reticulum aminopeptidases intergenic region affects human leucocyte antigen B27 expression and protects from ankylosing spondylitis in Sardinia.
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Paladini, Fabiana, Fiorillo, Maria Teresa, Tedeschi, Valentina, D'Otolo, Viviana, Piga, Matteo, Cauli, Alberto, Mathieu, Alessandro, and Sorrentino, Rosa
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ALLELES ,ANKYLOSING spondylitis ,DNA ,ENDOPLASMIC reticulum ,FLOW cytometry ,GENE expression ,GENETIC polymorphisms ,NUCLEOTIDES ,PROTEOLYTIC enzymes ,TRANSCRIPTION factors ,HLA-B27 antigen ,GENOTYPES - Abstract
Objectives HLA-B27 and the endoplasmic reticulum aminopeptidase 1 (ERAP1) and ERAP2 genes are predisposing factors for AS. A single nucleotide polymorphism (SNP) in the ERAP2 promoter (rs75862629) coordinates the transcription of both ERAP genes. We investigated whether this SNP associates with AS and whether it affects the expression of the two major HLA-B27 alleles present in Sardinia, the AS-associated B*2705 and the non-AS-associated B*2709. Methods Four SNPs in the ERAP region were genotyped in HLA-B*2705-positive patients with AS (n = 145), B27-positive healthy subjects (n = 126) and B27-negative controls (n = 250) and the allele and haplotype frequencies were derived. The expression of ERAP1 and ERAP2 mRNAs in 36 HLA-B27-positive B lymphoblastoid cell lines was measured by quantitative PCR. An electrophoretic mobility shift assay was performed to search for a nuclear factor binding the DNA sequence encompassing rs75862629. The expression of HLA-B27 molecules related to the SNP at rs75862629 was determined by flow cytometry. Results The minor allele G at rs75862629 was found significantly increased in B27 healthy individuals, both B*2705 and B*2709, compared with B*2705-positive patients with AS and B27-negative controls. The electrophoretic mobility shift assay indicated the lack of binding of a transcription factor as the cause of the observed reduction in the ERAP2 concomitant with a higher ERAP1 expression. Of note, this occurs with a different cell surface expression of the HLA-B*2705 and HLA-B*2709 molecules. Conclusion SNP rs75862629, by modulating simultaneously the expression of ERAP1 and ERAP2, provides protection from AS in HLA-B27-positive subjects in Sardinia. This has a functional impact on HLA-B27 expression and likely on disease onset. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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31. ORAI1/STIM1 Interaction Intervenes in Stroke and in Neuroprotection Induced by Ischemic Preconditioning Through Store-Operated Calcium Entry.
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Secondo, Agnese, Petrozziello, Tiziana, Tedeschi, Valentina, Boscia, Francesca, Vinciguerra, Antonio, Ciccone, Roselia, Pannaccione, Anna, Molinaro, Pasquale, Pignataro, Giuseppe, and Annunziato, Lucio
- Published
- 2019
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32. Expression analysis of HLA-E and NKG2A and NKG2C receptors points at a role for natural killer function in ankylosing spondylitis.
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Cauli, Alberto, Dessole, Grazia, Piga, Matteo, Angioni, Maria Maddalena, Pinna, Silvia, Floris, Alberto, Congia, Mattia, Mascia, Enrico, Paladini, Fabiana, Tedeschi, Valentina, Sorrentino, Rosa, Fiorillo, Maria Teresa, and Mathieu, Alessandro
- Published
- 2018
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33. The Peptide Repertoire of HLA‐B27 may include Ligands with Lysine at P2 Anchor Position.
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Yair‐Sabag, Shira, Tedeschi, Valentina, Vitulano, Carolina, Barnea, Eilon, Glaser, Fabian, Melamed Kadosh, Dganit, Taurog, Joel D., Fiorillo, Maria Teresa, Sorrentino, Rosa, and Admon, Arie
- Published
- 2018
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34. HLA Class I or Class II and Disease Association: Catch the Difference If You Can.
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Teresa Fiorillo, Maria, Paladini, Fabiana, Tedeschi, Valentina, and Sorrentino, Rosa
- Published
- 2017
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35. Identification and characterization of the promoter and transcription factors regulating the expression of cerebral sodium/calcium exchanger 2 (NCX2) gene.
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Calabrese, Lucrezia, Serani, Angelo, Natale, Silvia, Tedeschi, Valentina, Guida, Natascia, Valsecchi, Valeria, Secondo, Agnese, Formisano, Luigi, Annunziato, Lucio, and Molinaro, Pasquale
- Abstract
• NCX2 promoter is up-regulated by CREB1, Sp1 and Sp4 in PC12 cells. • NCX2 promoter has many putative binding sites for TFs involved in neuronal development and plasticity, regulation of processes related to metabolism, cell proliferation and oncogenesis. The isoform 2 of sodium-calcium exchanger family (NCX2) is selectively expressed in neuronal and glial cells where it participates in Ca
2+ -clearance following neuronal depolarization, synaptic plasticity, hippocampal-dependent learning and memory consolidation processes. On the other hand, NCX2 is also involved in a neuroprotective effect following stroke. Despite the relevance of this antiporter under physiological and pathophysiological conditions, no studies have been reported on its genetic/epigenetic regulation. Therefore, we identified, cloned, and characterized a transcriptional regulatory region (R3) of rat Slc8a2 gene encoding for NCX2. In particular, R3 sequence displayed a promoter activity in PC12, SH-SY5Y and U87MG cell lines consistent with their endogenous NCX2 expression levels. On the other hand, R3 failed to induce detectable luciferase activity in BHK cell line that does not express NCX2 under control conditions. These data support the hypothesis that R3 represents the promoter region of NCX2. Moreover, among several conserved binding sequences for transcription factors identified by in-silico analysis, we evaluated the transcriptional regulation and the binding sites of Sp1, Sp4, NFkB1, GATA2 and CREB1 on R3 sequence by using site-direct mutagenesis and ChIP assays. In particular, transfection of Sp1, Sp4, and CREB1 enhanced both R3 promoter activity and NCX2 transcription in PC12 cell line. More important, CREB1 transfection also enhanced NCX2 protein levels and NCX reverse mode activity in PC12 cells. Altogether, these data suggested that: (i) the identified region contained the regulatory promoter of the antiporter; (ii) NCX2 might represent a downstream effector of transcription factors involved in synaptic plasticity and neuronal survival. [Display omitted] [ABSTRACT FROM AUTHOR]- Published
- 2022
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36. Na+/Ca2+ exchanger isoform 1 (NCX1) and canonical transient receptor potential channel 6 (TRPC6) are recruited by STIM1 to mediate Store-Operated Calcium Entry in primary cortical neurons.
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Tedeschi, Valentina, Sisalli, Maria Josè, Pannaccione, Anna, Piccialli, Ilaria, Molinaro, Pasquale, Annunziato, Lucio, and Secondo, Agnese
- Abstract
• Na
+ /Ca2+ exchanger 1 (NCX1) activity is modulated by STIM1 in cortical neurons • NCX1 is recruited by STIM1 to take part in neuronal SOCE • TRPC6 is recruited by STIM1 in primary cortical neurons • Thapsigargin-mediated activation of TRPC6 produces a Na+ gradient useful for NCX1 reverse mode activation Excessive calcium (Ca2+ ) release from the endoplasmic reticulum (ER) represents an important hallmark of several neurodegenerative diseases. ER is recharged from Ca2+ through the so-called Store-Operated Calcium Entry (SOCE) thus providing Ca2+ signals to regulate critical cell functions. Single transmembrane-spanning domain protein stromal interacting molecule 1 (STIM1), mainly residing in the ER, and plasmalemmal channel Orai1 represent the SOCE key components at neuronal level. However, many other proteins participate to ER Ca2+ refilling including the Na+ /Ca2+ exchanger isoform 1 (NCX1), whose regulation by ER remains unknown. In this study, we tested the possibility that neuronal NCX1 may take part to SOCE through the interaction with STIM1. In rat primary cortical neurons and in nerve growth factor (NGF)-differentiated PC12 cells NCX1 knocking down by siRNA strategy significantly prevented SOCE as well as SOCE pharmacological inhibition by SKF-96365 and 2-APB. A significant reduction of SOCE was recorded also in synaptosomes from ncx1− /− mice brain compared with ncx1+ /+ mice. Double labeling confocal experiments showed a large co-localization between NCX1 and STIM1 in rat primary cortical neurons. Accordingly, NCX1 and STIM1 co-immunoprecipitated and functionally interacted each other during ischemic preconditioning, a phenomenon inducing ischemic tolerance. However, STIM1 knocking down reduced NCX1 activity recorded by either patch-clamp electrophysiology or Fura-2 single-cell microfluorimetry. Furthermore, canonical transient receptor potential channel 6 (TRPC6) was identified as the mechanism mediating local increase of sodium (Na+ ) useful to drive NCX1 reverse mode and, therefore, NCX1-mediated Ca2+ refilling. In fact, TRPC6 not only interacted with STIM1, as shown by the co-localization and co-immunoprecipitation with the ER Ca2+ sensor, but it also mediated 1,3-Benzenedicarboxylic acid, 4,4′-[1,4,10-trioxa-7,13-diazacyclopentadecane-7,13-diylbis(5-methoxy-6,12-benzofurandiyl)]bis-, tetrakis[(acetyloxy)methyl] ester (SBFI)-monitored Na+ increase elicited by thapsigargin in primary cortical neurons. Accordingly, efficient TRPC6 knockdown prevented thapsigargin-induced intracellular Na+ elevation and SOCE. Collectively, we identify NCX1 as a new partner of STIM1 in mediating SOCE, whose activation in the reverse mode may be facilitated by the local increase of Na+ concentration due to the interaction between STIM1 and TRPC6 in primary cortical neurons. [Display omitted] [ABSTRACT FROM AUTHOR]- Published
- 2022
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37. Interaction Pattern of Arg 62 in the A-Pocket of Differentially Disease-Associated HLA-B27 Subtypes Suggests Distinct TCR Binding Modes.
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Nurzia, Elisa, Narzi, Daniele, Cauli, Alberto, Mathieu, Alessandro, Tedeschi, Valentina, Caristi, Silvana, Sorrentino, Rosa, Böckmann, Rainer A., and Fiorillo, Maria Teresa
- Subjects
T cell receptors ,AUTOIMMUNE diseases ,INFLAMMATION ,PEPTIDES ,AMINO acids - Abstract
The single amino acid replacement Asp116His distinguishes the two subtypes HLA-B*2705 and HLA-B*2709 which are, respectively, associated and non-associated with Ankylosing Spondylitis, an autoimmune chronic inflammatory disease. The reason for this differential association is so far poorly understood and might be related to subtype-specific HLA:peptide conformations as well as to subtype/peptide-dependent dynamical properties on the nanoscale. Here, we combine functional experiments with extensive molecular dynamics simulations to investigate the molecular dynamics and function of the conserved Arg62 of the α1-helix for both B27 subtypes in complex with the self-peptides pVIPR (RRKWRRWHL) and TIS (RRLPIFSRL), and the viral peptides pLMP2 (RRRWRRLTV) and NPflu (SRYWAIRTR). Simulations of HLA:peptide systems suggest that peptide-stabilizing interactions of the Arg62 residue observed in crystal structures are metastable for both B27 subtypes under physiological conditions, rendering this arginine solvent-exposed and, probably, a key residue for TCR interaction more than peptide-binding. This view is supported by functional experiments with conservative (R62K) and nonconservative (R62A) B*2705 and B*2709 mutants that showed an overall reduction in their capability to present peptides to CD8+ T cells. Moreover, major subtype-dependent differences in the peptide recognition suggest distinct TCR binding modes for the B*2705 versus the B*2709 subtype. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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38. Plasma Membrane and Organellar Targets of STIM1 for Intracellular Calcium Handling in Health and Neurodegenerative Diseases.
- Author
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Tedeschi, Valentina, La Russa, Daniele, Franco, Cristina, Vinciguerra, Antonio, Amantea, Diana, and Secondo, Agnese
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CELL membranes , *INTRACELLULAR calcium , *TRP channels , *CELL physiology , *NEURODEGENERATION , *DRUG target - Abstract
Located at the level of the endoplasmic reticulum (ER) membrane, stromal interacting molecule 1 (STIM1) undergoes a complex conformational rearrangement after depletion of ER luminal Ca2+. Then, STIM1 translocates into discrete ER-plasma membrane (PM) junctions where it directly interacts with and activates plasma membrane Orai1 channels to refill ER with Ca2+. Furthermore, Ca2+ entry due to Orai1/STIM1 interaction may induce canonical transient receptor potential channel 1 (TRPC1) translocation to the plasma membrane, where it is activated by STIM1. All these events give rise to store-operated calcium entry (SOCE). Besides the main pathway underlying SOCE, which mainly involves Orai1 and TRPC1 activation, STIM1 modulates many other plasma membrane proteins in order to potentiate the influxof Ca2+. Furthermore, it is now clear that STIM1 may inhibit Ca2+ currents mediated by L-type Ca2+ channels. Interestingly, STIM1 also interacts with some intracellular channels and transporters, including nuclear and lysosomal ionic proteins, thus orchestrating organellar Ca2+ homeostasis. STIM1 and its partners/effectors are significantly modulated in diverse acute and chronic neurodegenerative conditions. This highlights the importance of further disclosing their cellular functions as they might represent promising molecular targets for neuroprotection. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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39. The Antioxidant Activity of Limonene Counteracts Neurotoxicity Triggered byAβ 1-42 Oligomers in Primary Cortical Neurons.
- Author
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Piccialli, Ilaria, Tedeschi, Valentina, Caputo, Lucia, Amato, Giuseppe, De Martino, Laura, De Feo, Vincenzo, Secondo, Agnese, and Pannaccione, Anna
- Subjects
LIMONENE ,OLIGOMERS ,ESSENTIAL oils ,ANTIOXIDANTS ,CELL death ,NEUROTOXICOLOGY ,POTASSIUM channels - Abstract
Many natural-derived compounds, including the essential oils from plants, are investigated to find new potential protective agents in several neurodegenerative disorders such as Alzheimer's disease (AD). In the present study, we tested the neuroprotective effect of limonene, one of the main components of the genus Citrus, against the neurotoxicity elicited by Aβ
1-42 oligomers, currently considered a triggering factor in AD. To this aim, we assessed the acetylcholinesterase activity by Ellman's colorimetric method, the mitochondrial dehydrogenase activity by MTT assay, the nuclear morphology by Hoechst 33258, the generation of reactive oxygen species (ROS) by DCFH-DA fluorescent dye, and the electrophysiological activity of KV 3.4 potassium channel subunits by patch-clamp electrophysiology. Interestingly, the monoterpene limonene showed a specific activity against acetylcholinesterase with an IC50 almost comparable to that of galantamine, used as positive control. Moreover, at the concentration of 10 µg/mL, limonene counteracted the increase of ROS production triggered by Aβ1-42 oligomers, thus preventing the upregulation of KV 3.4 activity. This, in turn, prevented cell death in primary cortical neurons, showing an interesting neuroprotective profile against Aβ1-42 -induced toxicity. Collectively, the present results showed that the antioxidant properties of the main component of the genus Citrus, limonene, may be useful to prevent neuronal suffering induced by Aβ1-42 oligomers preventing the hyperactivity of KV 3.4. [ABSTRACT FROM AUTHOR]- Published
- 2021
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40. The Anemonia sulcata Toxin BDS-I Protects Astrocytes Exposed to Aβ 1–42 Oligomers by Restoring [Ca 2+ ] i Transients and ER Ca 2+ Signaling.
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Piccialli, Ilaria, Tedeschi, Valentina, Boscia, Francesca, Ciccone, Roselia, Casamassa, Antonella, de Rosa, Valeria, Grieco, Paolo, Secondo, Agnese, and Pannaccione, Anna
- Subjects
- *
ASTROCYTES , *OLIGOMERS , *MARINE toxins , *NEUROGLIA , *POTASSIUM channels , *REACTIVE oxygen species , *INTRACELLULAR calcium - Abstract
Intracellular calcium concentration ([Ca2+]i) transients in astrocytes represent a highly plastic signaling pathway underlying the communication between neurons and glial cells. However, how this important phenomenon may be compromised in Alzheimer's disease (AD) remains unexplored. Moreover, the involvement of several K+ channels, including KV3.4 underlying the fast-inactivating currents, has been demonstrated in several AD models. Here, the effect of KV3.4 modulation by the marine toxin blood depressing substance-I (BDS-I) extracted from Anemonia sulcata has been studied on [Ca2+]i transients in rat primary cortical astrocytes exposed to Aβ1–42 oligomers. We showed that: (1) primary cortical astrocytes expressing KV3.4 channels displayed [Ca2+]i transients depending on the occurrence of membrane potential spikes, (2) BDS-I restored, in a dose-dependent way, [Ca2+]i transients in astrocytes exposed to Aβ1–42 oligomers (5 µM/48 h) by inhibiting hyperfunctional KV3.4 channels, (3) BDS-I counteracted Ca2+ overload into the endoplasmic reticulum (ER) induced by Aβ1–42 oligomers, (4) BDS-I prevented the expression of the ER stress markers including active caspase 12 and GRP78/BiP in astrocytes treated with Aβ1–42 oligomers, and (5) BDS-I prevented Aβ1–42-induced reactive oxygen species (ROS) production and cell suffering measured as mitochondrial activity and lactate dehydrogenase (LDH) release. Collectively, we proposed that the marine toxin BDS-I, by inhibiting the hyperfunctional KV3.4 channels and restoring [Ca2+]i oscillation frequency, prevented Aβ1–42-induced ER stress and cell suffering in astrocytes. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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41. The Impact of the 'Mis-Peptidome' on HLA Class I-Mediated Diseases: Contribution of ERAP1 and ERAP2 and Effects on the Immune Response.
- Author
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Tedeschi, Valentina, Paldino, Giorgia, Paladini, Fabiana, Mattorre, Benedetta, Tuosto, Loretta, Sorrentino, Rosa, and Fiorillo, Maria Teresa
- Subjects
- *
BEHCET'S disease , *IMMUNE response , *MASS analysis (Spectrometry) , *KILLER cells , *ANKYLOSING spondylitis - Abstract
The strong association with the Major Histocompatibility Complex (MHC) class I genes represents a shared trait for a group of autoimmune/autoinflammatory disorders having in common immunopathogenetic basis as well as clinical features. Accordingly, the main risk factors for Ankylosing Spondylitis (AS), prototype of the Spondyloarthropathies (SpA), the Behçet's disease (BD), the Psoriasis (Ps) and the Birdshot Chorioretinopathy (BSCR) are HLA-B*27, HLA-B*51, HLA-C*06:02 and HLA-A*29:02, respectively. Despite the strength of the association, the HLA pathogenetic role in these diseases is far from being thoroughly understood. Furthermore, Genome-Wide Association Studies (GWAS) have highlighted other important susceptibility factors such as Endoplasmic Reticulum Aminopeptidase (ERAP) 1 and, less frequently, ERAP2 that refine the peptidome presented by HLA class I molecules to CD8+ T cells. Mass spectrometry analysis provided considerable knowledge of HLA-B*27, HLA-B*51, HLA-C*06:02 and HLA-A*29:02 immunopeptidome. However, the combined effect of several ERAP1 and ERAP2 allelic variants could generate an altered pool of peptides accounting for the "mis-immunopeptidome" that ranges from suboptimal to pathogenetic/harmful peptides able to induce non-canonical or autoreactive CD8+ T responses, activation of NK cells and/or garbling the classical functions of the HLA class I molecules. This review will focus on this class of epitopes as possible elicitors of atypical/harmful immune responses which can contribute to the pathogenesis of chronic inflammatory diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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42. Nuclear localization of NCX: Role in Ca2+ handling and pathophysiological implications.
- Author
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Secondo, Agnese, Petrozziello, Tiziana, Tedeschi, Valentina, Boscia, Francesca, Pannaccione, Anna, Molinaro, Pasquale, and Annunziato, Lucio
- Abstract
Schematic representation of the most important channels, receptors, pumps and exchangers localized on plasma membrane, ER, mitochondria and nucleus that are responsible for the maintenance of intracellular Ca
2+ ions in a physiological range of concentration. • Nuclear calcium (Ca2+ ) concentration is controlled independently from cytosolic events by a local machinery. • Nuclear Na+ /Ca2+ exchanger (nuNCX) allows local Ca2+ flowing from nucleoplasm into nuclear envelope. • nuNCX shares some relevant regulatory features with the plasma membrane form of the exchanger. • nuNCX controls the activity of NFAT, CREB and DREAM through the modulation of nuclear Ca2+ level. • nuNCX controls neuronal differentiation through PTEN/Akt pathway and other cellular functions. Numerous lines of evidence indicate that nuclear calcium concentration ([Ca2+ ] n) may be controlled independently from cytosolic events by a local machinery. In particular, the perinuclear space between the inner nuclear membrane (INM) and the outer nuclear membrane (ONM) of the nuclear envelope (NE) likely serves as an intracellular store for Ca2+ ions. Since ONM is contiguous with the endoplasmic reticulum (ER), the perinuclear space is adjacent to the lumen of ER thus allowing a direct exchange of ions and factors between the two organelles. Moreover, INM and ONM are fused at the nuclear pore complex (NPC), which provides the only direct passageway between the nucleoplasm and cytoplasm. However, due to the presence of ion channels, exchangers and transporters, it has been generally accepted that nuclear ion fluxes may occur across ONM and INM. Within the INM, the Na+ /Ca2+ exchanger (NCX) isoform 1 seems to play an important role in handling Ca2+ through the different nuclear compartments. Particularly, nuclear NCX preferentially allows local Ca2+ flowing from nucleoplasm into NE lumen thanks to the Na+ gradient created by the juxtaposed Na+ /K+ -ATPase. Such transfer reduces abnormal elevation of [Ca2+ ] n within the nucleoplasm thus modulating specific transductional pathways and providing a protective mechanism against cell death. Despite very few studies on this issue, here we discuss those making major contribution to the field, also addressing the pathophysiological implication of nuclear NCX malfunction. [ABSTRACT FROM AUTHOR]- Published
- 2020
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43. Calcium Dyshomeostasis and Lysosomal Ca2+ Dysfunction in Amyotrophic Lateral Sclerosis.
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Tedeschi, Valentina, Petrozziello, Tiziana, and Secondo, Agnese
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AMYOTROPHIC lateral sclerosis , *MOTOR neurons , *LYSOSOMES , *ENDOPLASMIC reticulum , *CALCIUM , *NEURODEGENERATION , *ORGANELLES - Abstract
Recent findings in the understanding of amyotrophic lateral sclerosis (ALS) revealed that alteration in calcium (Ca2+) homeostasis may largely contribute to motor neuron demise. A large part of these alterations is due to dysfunctional Ca2+-storing organelles, including the endoplasmic reticulum (ER) and mitochondria. Very recently, lysosomal Ca2+ dysfunction has emerged as an important pathological change leading to neuronal loss in ALS. Remarkably, the Ca2+-storing organelles are interacting with each other at specialized domains controlling mitochondrial dynamics, ER/lysosomal function, and autophagy. This occurs as a result of interaction between specific ionic channels and Ca2+-dependent proteins located in each structure. Therefore, the dysregulation of these ionic mechanisms could be considered as a key element in the neurodegenerative process. This review will focus on the possible role of lysosomal Ca2+ dysfunction in the pathogenesis of several neurodegenerative diseases, including ALS and shed light on the possibility that specific lysosomal Ca2+ channels might represent new promising targets for preventing or at least delaying neurodegeneration in ALS. [ABSTRACT FROM AUTHOR]
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- 2019
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44. Unusual Placement of an EBV Epitope into the Groove of the Ankylosing Spondylitis-Associated HLA-B27 Allele Allows CD8+ T Cell Activation.
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Tedeschi, Valentina, Alba, Josephine, Paladini, Fabiana, Paroli, Marino, Cauli, Alberto, Mathieu, Alessandro, Sorrentino, Rosa, D'Abramo, Marco, and Fiorillo, Maria Teresa
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T cells , *HLA histocompatibility antigens , *HLA-B27 antigen , *SACROILIAC joint , *DRUG side effects - Abstract
The human leukocyte antigen HLA-B27 is a strong risk factor for Ankylosing Spondylitis (AS), an immune-mediated disorder affecting axial skeleton and sacroiliac joints. Additionally, evidence exists sustaining a strong protective role for HLA-B27 in viral infections. These two aspects could stem from common molecular mechanisms. Recently, we have found that the HLA-B*2705 presents an EBV epitope (pEBNA3A-RPPIFIRRL), lacking the canonical B27 binding motif but known as immunodominant in the HLA-B7 context of presentation. Notably, 69% of B*2705 carriers, mostly patients with AS, possess B*2705-restricted, pEBNA3A-specific CD8+ T cells. Contrarily, the non-AS-associated B*2709 allele, distinguished from the B*2705 by the single His116Asp polymorphism, is unable to display this peptide and, accordingly, B*2709 healthy subjects do not unleash specific T cell responses. Herein, we investigated whether the reactivity towards pEBNA3A could be a side effect of the recognition of the natural longer peptide (pKEBNA3A) having the classical B27 consensus (KRPPIFIRRL). The stimulation of PBMC from B*2705 positive patients with AS in parallel with both pEBNA3A and pKEBNA3A did not allow to reach an unambiguous conclusion since the differences in the magnitude of the response measured as percentage of IFNγ-producing CD8+ T cells were not statistically significant. Interestingly, computational analysis suggested a structural shift of pEBNA3A as well as of pKEBNA3A into the B27 grooves, leaving the A pocket partially unfilled. To our knowledge this is the first report of a viral peptide: HLA-B27 complex recognized by TCRs in spite of a partially empty groove. This implies a rethinking of the actual B27 immunopeptidome crucial for viral immune-surveillance and autoimmunity. [ABSTRACT FROM AUTHOR]
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- 2019
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45. Na+/Ca2+ exchanger 1 on nuclear envelope controls PTEN/Akt pathway via nucleoplasmic Ca2+ regulation during neuronal differentiation.
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Secondo, Agnese, Esposito, Alba, Petrozziello, Tiziana, Boscia, Francesca, Molinaro, Pasquale, Tedeschi, Valentina, Pannaccione, Anna, Ciccone, Roselia, Guida, Natascia, Di Renzo, Gianfranco, and Annunziato, Lucio
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- 2018
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46. Size-based effects of anthropogenic ultrafine particles on activation of human lung macrophages.
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Marcella, Simone, Apicella, Barbara, Secondo, Agnese, Palestra, Francesco, Opromolla, Giorgia, Ciardi, Renato, Tedeschi, Valentina, Ferrara, Anne Lise, Russo, Carmela, Rosaria Galdiero, Maria, Cristinziano, Leonardo, Modestino, Luca, Spadaro, Giuseppe, Fiorelli, Alfonso, and Loffredo, Stefania
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LUNGS , *MACROPHAGES , *CELL populations , *REACTIVE oxygen species , *PARTICULATE matter , *GENE expression - Abstract
The anthropogenic particulate matter (PM), suspended air dust that can be inhaled by humans and deposited in the lungs, is one of the main pollutants in the industrialized cities atmosphere. Recent studies have shown that PM has adverse effects on respiratory diseases. These effects are mainly due to the ultrafine particles (PM0.1, PM < 100 nm), which, thanks to their PM size, are efficiently deposited in nasal, tracheobronchial, and alveolar regions. Pulmonary macrophages are a heterogeneous cell population distributed in different lung compartments, whose role in inflammatory response to injury is of particular relevance. In this study, we investigated the effect of PM0.1 on Human Lung Macrophages (HLMs) activation evaluated as proinflammatory cytokines and chemokine release, Reactive Oxygen Species (ROS) production and intracellular Ca2+concentration ([Ca2+] i). Furthermore, PM0.1, after removal of organic fraction, was fractionated in nanoparticles both smaller (NP20) and bigger (NP100) than 20 nm by a properlydeveloped analytical protocol, allowed isolating their individual contribution. Interestingly, while PM0.1 and NP20 induced stimulatory effects on HLM cytokines release, NP100 had not effect. In particular, PM0.1 induced IL-6, IL-1β, TNF-α, but not CXCL8, release from HLMs. Moreover, PM0.1, NP20 and NP100 did not induce β-glucuronidase release, a preformed mediator contained in HLMs. The long time necessary for cytokines release (18 h) suggested that PM0.1 and NP20 could induce ex-novo production of the tested mediators. Accordingly, after 6 h of incubation, PM0.1 and NP20 induced mRNA expression of IL-6, TNF-α and IL-1β. Moreover, NP20 induced ROS production and [Ca2+] i increase in a time-dependent manner, without producing cytotoxicity. Collectively, the present data highlight the main proinflammatory role of NP20 among PM fractions. This is particularly of concern because this fraction is not currently covered by legal limits as it is not easily measured at the exhausts by the available technical methodologies, suggesting that it is mandatory to search for new monitoring techniques and strategies for limiting NP20 formation. [ABSTRACT FROM AUTHOR]
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- 2022
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47. Prolonged NCX activation prevents SOD1 accumulation, reduces neuroinflammation, ameliorates motor behavior and prolongs survival in a ALS mouse model.
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Anzilotti, Serenella, Valsecchi, Valeria, Brancaccio, Paola, Guida, Natascia, Laudati, Giusy, Tedeschi, Valentina, Petrozziello, Tiziana, Frecentese, Francesco, Magli, Elisa, Hassler, Brenda, Cuomo, Ornella, Formisano, Luigi, Secondo, Agnese, Annunziato, Lucio, and Pignataro, Giuseppe
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LABORATORY mice , *NEUROINFLAMMATION , *CALCIUM ions , *MOTOR neurons , *AMYOTROPHIC lateral sclerosis , *SPINAL cord - Abstract
Imbalance in cellular ionic homeostasis is a hallmark of several neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS). Sodium-calcium exchanger (NCX) is a membrane antiporter that, operating in a bidirectional way, couples the exchange of Ca2+ and Na + ions in neurons and glial cells, thus controlling the intracellular homeostasis of these ions. Among the three NCX genes, NCX1 and NCX2 are widely expressed within the CNS, while NCX3 is present only in skeletal muscles and at lower levels of expression in selected brain regions. ALS mice showed a reduction in the expression and activity of NCX1 and NCX2 consistent with disease progression, therefore we aimed to investigate their role in ALS pathophysiology. Notably, we demonstrated that the pharmacological activation of NCX1 and NCX2 by the prolonged treatment of SOD1G93A mice with the newly synthesized compound neurounina: (1) prevented the reduction in NCX activity observed in spinal cord; (2) preserved motor neurons survival in the ventral spinal horn of SOD1G93A mice; (3) prevented the spinal cord accumulation of misfolded SOD1; (4) reduced astroglia and microglia activation and spared the resident microglia cells in the spinal cord; (5) improved the lifespan and mitigated motor symptoms of ALS mice. The present study highlights the significant role of NCX1 and NCX2 in the pathophysiology of this neurodegenerative disorder and paves the way for the design of a new pharmacological approach for ALS. • The pharmacological activation of NCX1 and NCX2 prevented the reduction in NCX activity observed in spinal cord of ALS mice. • NCX activation preserved motor neurons survival in the ventral spinal horn of SOD1G93A mice. • NCX activation prevented the spinal cord accumulation of misfolded SOD1. • NCX activation reduced astroglia and microglia activation and spared the resident microglia cells in the spinal cord. • NCX activation improved the lifespan and mitigated motor symptoms of ALS mice. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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