96 research outputs found
La doppia discesa del filosofo. Una lettura politica della caverna platonica
No full textThe concept of a Platonic «political philosophy» is paradoxical. No other place reveals more clearly this paradox than the image of the cave in the Repub- lic. A true discourse about the polis should express the knowledge of the shades, once the philosopher becomes habituated to the darkness. However, it is possible to distinguish a double «descent» of the philosopher among the prisoners: in a first moment, he becomes the object of mockery and violence; in a second moment, he is equipped with political power. Political theory seems to be justified by the philo- sophical activity of government (the second descent), so it is necessary to ask about the meaning of a theory developed by someone who is just an observer of the polis, having no political power (the first descent). This is the position of Socrates, when describing the image of the cave. This is also the position of Plato as the author of The Republic
Endogenous neural precursor cells in health and disease
No full textNeurogenesis persists in the adult brain of mammals in the subventricular zone (SVZ) of the lateral ventricles and in the subgranular zone (SGZ) of the dentate gyms (DG). The complex interactions between intrinsic and extrinsic signals provided by cells in the niche but also from distant sources regulate the fate of neural stem/progenitor cells (NPCs) in these sites. This fine regulation is perturbed in aging and in pathological conditions leading to a different NPC behavior, tailored to the specific physio-pathological features. Indeed, NPCs exert in physiological and pathological conditions important neurogenic and non-neurogenic regulatory functions and participate in maintaining and protecting brain tissue homeostasis. In this review, we discuss intrinsic and extrinsic signals that regulate NPC activation and NPC functional role in various homeostatic and non-homeostatic conditions
sj-pdf-2-jcb-10.1177_0271678X231159958 - Supplemental material for Harmonization of sensorimotor deficit assessment in a registered multicentre pre-clinical randomized controlled trial using two models of ischemic stroke
No full textSupplemental material, sj-pdf-2-jcb-10.1177_0271678X231159958 for Harmonization of sensorimotor deficit assessment in a registered multicentre pre-clinical randomized controlled trial using two models of ischemic stroke by Alessia Valente, Jacopo Mariani, Serena Seminara, Mauro Tettamanti, Giuseppe Pignataro, Carlo Perego, Luigi Sironi, Felicita Pedata, Diana Amantea, Marco Bacigaluppi, Antonio Vinciguerra, Susanna Diamanti, Martina Viganò, Francesco Santangelo, Chiara Paola Zoia, Virginia Rodriguez-Menendez, Laura Castiglioni, Joanna Rzemieniec, Ilaria Dettori, Irene Bulli, Elisabetta Coppi, Chiara Di Santo, Ornella Cuomo, Giorgia Serena Gullotta, Erica Butti, Giacinto Bagetta, Gianvito Martino, Maria-Grazia De Simoni, Carlo Ferrarese, Stefano Fumagalli, Simone Beretta and for the TRICS study group in Journal of Cerebral Blood Flow & Metabolism</p
sj-pdf-1-jcb-10.1177_0271678X231159958 - Supplemental material for Harmonization of sensorimotor deficit assessment in a registered multicentre pre-clinical randomized controlled trial using two models of ischemic stroke
No full textSupplemental material, sj-pdf-1-jcb-10.1177_0271678X231159958 for Harmonization of sensorimotor deficit assessment in a registered multicentre pre-clinical randomized controlled trial using two models of ischemic stroke by Alessia Valente, Jacopo Mariani, Serena Seminara, Mauro Tettamanti, Giuseppe Pignataro, Carlo Perego, Luigi Sironi, Felicita Pedata, Diana Amantea, Marco Bacigaluppi, Antonio Vinciguerra, Susanna Diamanti, Martina Viganò, Francesco Santangelo, Chiara Paola Zoia, Virginia Rodriguez-Menendez, Laura Castiglioni, Joanna Rzemieniec, Ilaria Dettori, Irene Bulli, Elisabetta Coppi, Chiara Di Santo, Ornella Cuomo, Giorgia Serena Gullotta, Erica Butti, Giacinto Bagetta, Gianvito Martino, Maria-Grazia De Simoni, Carlo Ferrarese, Stefano Fumagalli, Simone Beretta and for the TRICS study group in Journal of Cerebral Blood Flow & Metabolism</p
To touch or to be touched? comparing appraisal of vicarious execution and reception of interpersonal touch
No full textPublisher Copyright: © 2024 Butti et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Unmyelinated C-Tactile (CT) fibres are activated by caress-like touch, eliciting a pleasant feeling that decreases for static and faster stroking. Previous studies documented this effect also for vicarious touch, hypothesising simulation mechanisms driving the perception and appreciation of observed interpersonal touch. Notably, less is known about appreciation of vicarious execution of touch, that is as referred to the one giving gentle touch. To address this issue, 53 healthy participants were asked to view and rate a series of videoclips displaying an individual being touched by another on hairy (i.e., hand dorsum) or glabrous (i.e., palm) skin sites, with touch being delivered at CT-optimal (5 cm/s) or non-CT optimal velocities (0 cm/s or 30 cm/s). Following the observation of each clip, participants were asked to rate self-referred desirability and model-referred pleasantness of vicarious touch for both executer (toucher-referred) and receiver (touchee-referred). Consistent with the CT fibres properties, for both self-referred desirability and model-referred pleasantness judgements of vicarious touch execution and reception, participants provided higher ratings for vicarious touch delivered at CT-optimal than other velocities, and when observed CT-optimal touch was delivered to the hand-dorsum compared to the palm. However, higher ratings were attributed to vicarious reception compared to execution of CT-optimal touch. Notably, individual differences in interoceptive trusting and attitude to interpersonal touch were positively correlated with, respectively, toucher- and touchee-related overall appraisal ratings of touch. These findings suggest that the appreciation of both toucher- and touchee-referred vicarious touch is specifically attuned to CT-optimal touch, even though they might rely on different neurocognitive mechanisms to understand affective information conveyed by interpersonal tactile interactions.Peer reviewe
Neural precursor cells rescue symptoms of Rett syndrome by activation of the Interferon γ pathway.
No full textThe beneficial effects of Neural Precursor Cell (NPC) transplantation in several neurological disorders are well established and they are generally mediated by the secretion of immunomodulatory and neurotrophic molecules. We therefore investigated whether Rett syndrome (RTT), that represents the first cause of severe intellectual disability in girls, might benefit from NPC-based therapy. Using in vitro co-cultures, we demonstrate that, by sensing the pathological context, NPC-secreted factors induce the recovery of morphological and synaptic defects typical of Mecp2 deficient neurons. In vivo, we prove that intracerebral transplantation of NPCs in RTT mice significantly ameliorates neurological functions. To uncover the molecular mechanisms underpinning the mediated benefic effects, we analyzed the transcriptional profile of the cerebellum of transplanted animals, disclosing the possible involvement of the Interferon γ (IFNγ) pathway. Accordingly, we report the capacity of IFNγ to rescue synaptic defects, as well as motor and cognitive alterations in Mecp2 deficient models, thereby suggesting this molecular pathway as a potential therapeutic target for RTT. [Abstract copyright: © 2024. The Author(s).
Subventricular zone neural progenitors reverse TNF-alpha effects in cortical neurons
No full textINTRODUCTION:
Tumor necrosis factor alpha (TNFα) plays a physiological role in controlling synaptic transmission and plasticity in the healthy central nervous system by modulating glutamate receptor trafficking to the plasma membrane. TNFα expression is also rapidly induced in response to tissue injury and infection. By promoting the insertion of Ca(2+) permeable-AMPA receptors into the neuronal plasma membrane, this cytokine may cause excessive Ca(2+) influx into neurons, thus enhancing neuronal death.
METHODS:
Primary cultures of cortical neurons were obtained from E18 foetal mice and incubated for 24 h with adult neural stem cells (aNPCs) either stimulated with lipopolysaccharide (LPS(+)aNPCs) or not (aNPCs). Cultures were treated with TNFα (100 ng/ml), and electrophysiological recordings were performed in different conditions to evaluate the effect of the cytokine on neuronal transmission.
RESULTS:
In this study, we demonstrate that aNPCs from the subventricular zone reverse the effects induced by the cytokine. Moreover, we show that the effect of aNPCs on cortical neurons is mediated by cannabinoid CB1 receptor activation.
CONCLUSION:
These data suggest that the role of aNPCs in preventing excitatory neurotransmission potentiation induced by TNFα on cortical neurons may have important implications for pathologies characterized by an inflammatory component affecting cortical neurons such as Alzheimer's disease
Neural Precursor Cells as a potential therapeutic approach for Rett Syndrome: identification of the involved molecular mechanisms
No full textRett syndrome (RTT) is a rare neurodevelopmental disorder, mostly caused by MECP2 mutations, representing the leading cause of severe intellectual disability in females. Unfortunately, no cure is available.
Considering the effectiveness of NPCs in the treatment of other neurological and neurodevelopmental diseases, we decided to investigate their therapeutic potential in RTT.
Our research demonstrated their efficacy in both RTT in vitro and in vivo mouse models.
Through a transwell-based co-culture system, we observed that NPCs promote morphological and synaptic rescues in Mecp2 null neurons. In vivo, we demonstrated a significant amelioration of the cognitive and motor defects of RTT mice, together with an increased lifespan, after NPCs transplantation.
The results highlighted that NPCs-mediated beneficial effects arise through “bystander” and paracrine mechanisms: by sensing the pathological environment, they secrete beneficial factors that promote immunomodulation, neuroprotection and brain plasticity.
To identify the molecular mechanisms set in motion by NPCs, we performed bulk RNA sequencing analyses on both models. Even if one candidate molecule has been identified and its efficacy validated, more studies are ongoing to further clarify other pathways modulated in KO neurons in presence of NPCs.
All data will be presented in the poster session to illustrate the value of this cellular approach in treating RTT and/or in identifying new defective pathways with putative therapeutic value
Neural Precursor Cells as a potential therapeutic approach for Rett Syndrome: identification of the involved molecular mechanisms
No full textRett syndrome (RTT) is a rare neurodevelopmental disorder, mostly caused by sporadic mutations in the X linked MECP2 gene. RTT, the primary cause of severe intellectual disability in females, currently lacks a cure; nonetheless, the FDA recently approved the first therapy utilizing a tripeptide of IGF1.
Neural Precursor Cells (NPCs) can sense the pathological environment when transplanted in it, they secrete beneficial factors that promote immunomodulation, neuroprotection, brain plasticity. These healing functions render NPCs an interesting cellular therapy for treating several neurodegenerative disorders. Since no study addressed their efficacy in neurodevelopmental diseases, we investigated their therapeutic potential in RTT, demonstrating their efficacy in vitro and in vivo. In vivo, we proved significant amelioration of the cognitive and motor defects of RTT mice, together with an increased lifespan, after NPCs transplantation. Through a transwell-based co-culture system, we observed that NPCs promote morphological and synaptic rescues in Mecp2 null neurons, demonstrating that NPCs-mediated beneficial effects arise through “bystander” and paracrine mechanisms.
RNA-seq studies of transplanted mice identified a candidate molecule involved in the benefic effects. Likely, the observed beneficial effects depend on the activation of different pathways. Therefore, my PhD studies are focused on exploiting a transwell-based co-culture system to identify the molecular mechanisms set in motion by NPCs in Mecp2-KO neurons.
Through a Bulk RNA-seq performed on immature neurons maintained, or not, in co-culture with NPCs we demonstrated positive effects on KO neurons when exposed to the NPCs secreted factors (e.g., enhancement in the synaptic compartment, typically defective in Rett neurons). Simultaneously, to understand which molecules are secreted by NPCs when exposed to the Mecp2-KO environment, their transcriptional profile is being investigated.
All data will be presented in the poster session to illustrate the value of this cellular approach in treating RTT and/or in identifying new defective pathways with putative therapeutic value
Neural precursor/stem cell-based therapy for Rett syndrome
No full textMECP2 mutations cause Rett syndrome (RTT), the first cause of severe intellectual disability in girls. Several studies proved that reduced levels of neurotrophic factors play a major role in RTT and their augmentation represents a valid therapeutic approach. Neural Precursor/Stem Cell (NPC) transplantation was proved safe and efficacious in many neurological disorders. Willing to respond to the unmet need of a cure for RTT, we are investigating the therapeutic potential of adult NPCs in Mecp2 null mice, modelling RTT.
Although the prime mechanism of NPC action is the replacement of damaged cells, it is now clear that transplanted cells often exert their benefits through a “bystander” mechanism. Indeed, by sensing the pathological environment, they promote immunomodulation, neuroprotection and brain plasticity through the secretion of a plethora of molecules, including neurotrophic factors and immunomodulatory substances. Therefore, transplanted NPCs adapt their fate and functions to the specific pathological context and can engage in a rich talk with resident cells, thus forming a close network that can persist after administration.
Our data demonstrate that NPC transplantation significantly prolong the lifespan of Mecp2 null mice, restoring memory and motor functions. We report that transplanted NPC localize along the meninges in the caudal zone of the brain by maintaining an immature phenotype, strongly suggesting the involvement of a paracrine effect. Therefore, using an in vitro transwell-based co-culture system, we confirmed the paracrine action of NPCs to promote morphological and synaptic rescues in Mecp2 null neurons. In addition, by exploring the beneficial effects of their secreted factors, we prove the NPC ability to adapt their phenotype depending on the pathological context, since their exposure on Mecp2 null neurons promotes the release of protective molecules.
In order to identify the molecular mechanisms behind NPC efficacy, we performed an RNA-seq study on transplanted brains and, supported by bioinformatics analysis, we prioritized and validated one molecular pathway. In particular, the selected recombinant molecule was effective in reverting motor and cognitive impairments, as well as breathing abnormalities, in Mecp2 null animals and in improving the synaptic alterations of null neurons.
Together, our data provide the "proof of concept" of a NPC-based therapeutic strategy for RTT and indicate the involvement of a putative molecule, which might be proposed as a novel therapeutic strategy
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