👤 Andrea Della Penna

The serotonin receptor 7 (5-HT7R) has been indicated as a key modulator of neuronal structure and function, playing critical roles in synaptic plasticity, dendritic spine formation, and cytoskeletal remodeling. 5-HT7R activation promotes neurite outgrowth, enhances long-term potentiation (LTP), stimulates local protein synthesis at synapses, and regulates mitochondrial functions, and the mTOR pathway. These properties make the 5-HT7R a compelling candidate for therapeutic intervention in neurodevelopmental disorders characterized by synaptic dysfunctions. Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by the loss of function of the maternal UBE3A gene, resulting in impairments of synaptic plasticity, dendritic spine density, protein synthesis, mitochondrial activity and mTOR signaling. Intriguingly, many of the processes altered in AS are the ones that are positively regulated by 5-HT7R activation. For instance, AS animal models exhibit reduced LTP and altered dendritic morphology and 5-HT7R stimulation enhances synaptic strength and spine formation in the brain of wild type rodents. Moreover, BDNF/TrkB function signaling is impaired and mitochondrial integrity is disrupted in AS and 5-HT7R agonists enhance the altered BDNF/TrkB signalling and restore mitochondrial dysfunctions in Rett syndrome (RTT) mice model. Interestingly, recent evidence demonstrates that pharmacological activation of 5-HT7Rs increases synaptic protein synthesis, restores LTP, enhances dendritic spine density, and improves cognitive function in an AS mouse model. These encouraging results open the way to future studies using neurons and brain organoids generated from iPSCs obtained from AS patients, which represent novel tools in preclinical research. Overall, 5-HT7R stimulation, by counteracting the molecular alterations associated with the loss of UBE3A, may represent a novel approach to restore neural function in the mature brain, leading to translational applications in AS patients, and possibly also in other synaptopathies. Clinical trial number: not applicable. Show less

Extracellular vesicles (EVs) are promising therapeutic tools in the treatment of cardiovascular disorders. We have recently shown that EVs from patients with Acute Coronary Syndrome (ACS) undergoing sham pre-conditioning, before percutaneous coronary intervention (PCI) were cardio-protective, while EVs from patients experiencing remote ischemic pre-conditioning (RIPC) failed to induce protection against ischemia/reperfusion Injury (IRI). No data on EVs from ACS patients recovered after PCI are currently available. Therefore, we herein investigated the cardio-protective properties of EVs, collected after PCI from the same patients. EVs recovered from 30 patients randomly assigned (1:1) to RIPC (EV-RIPC) or sham procedures (EV-naive) (NCT02195726) were characterized by TEM, FACS and Western blot analysis and evaluated for their mRNA content. The impact of EVs on hypoxia/reoxygenation damage and IRI, as well as the cardio-protective signaling pathways, were investigated in vitro (HMEC-1 + H9c2 co-culture) and ex vivo (isolated rat heart). Both EV-naive and EV-RIPC failed to drive cardio-protection both in vitro and ex vivo. Consistently, EV treatment failed to activate the canonical cardio-protective pathways. Specifically, PCI reduced the EV-naive Dusp6 mRNA content, found to be crucial for their cardio-protective action, and upregulated some stress- and cell-cycle-related genes in EV-RIPC. We provide the first evidence that in ACS patients, PCI reprograms the EV cargo, impairing EV-naive cardio-protective properties without improving EV-RIPC functional capability. Show less

The relevance of extracellular vesicles (EV) as mediators of cardiac damage or recovery upon Ischemia Reperfusion Injury (IRI) and Remote Ischemic PreConditioning (RIPC) is controversial. This study aimed to investigate whether serum-derived EV, recovered from patients with Acute Coronary Syndrome (ACS) and subjected to the RIPC or sham procedures, may be a suitable therapeutic approach to prevent IRI during Percutaneous-Coronary-Intervention (PCI). A double-blind, randomized, sham-controlled study (NCT02195726) has been extended, and EV were recovered from 30 patients who were randomly assigned (1:1) to undergo the RIPC- (EV-RIPC) or sham-procedures (EV-naive) before PCI. Patient-derived EV were analyzed by TEM, FACS and western blot. We found that troponin (TnT) was enriched in EV, compared to healthy subjects, regardless of diagnosis. EV-naive induced protection against IRI, both in-vitro and in the rat heart, unlike EV-RIPC. We noticed that EV-naive led to STAT-3 phosphorylation, while EV-RIPC to Erk-1/2 activation in the rat heart. Pre-treatment of the rat heart with specific STAT-3 and Erk-1/2 inhibitors led us to demonstrate that STAT-3 is crucial for EV-naive-mediated protection. In the same model, Erk-1/2 inhibition rescued STAT-3 activation and protection upon EV-RIPC treatment. 84 Human Cardiovascular Disease mRNAs were screened and DUSP6 mRNA was found enriched in patient-derived EV-naive. Indeed, DUSP6 silencing in EV-naive prevented STAT-3 phosphorylation and cardio-protection in the rat heart. This analysis of ACS-patients' EV proved: (i) EV-naive cardio-protective activity and mechanism of action; (ii) the lack of EV-RIPC-mediated cardio-protection; (iii) the properness of the in-vitro assay to predict EV effectiveness in-vivo. Show less