1,721,162 research outputs found
Lifestyles and ageing: targeting key mechanisms to shift the balance from unhealthy to healthy ageing
No full textThe increase in life expectancy has dramatically enhanced the prevalence of age-related chronic diseases resulting in growing costs for both society and individuals. Identification of strategies contributing to healthy ageing is thus one of the major challenges of the coming years. Lifestyle has a primary role among non-genetic factors affecting health and lifespan. In particular, nutrition, mental and physical activity impact the molecular and functional mechanisms whose alterations cause the major age-related diseases. A better understanding of mechanisms underlying the beneficial action of correct lifestyles is useful to develop interventions aimed at preventing and/or delaying the onset of chronic degenerative diseases, to identify high-risk populations who could be targeted in intervention trials as well as to identify novel biomarkers of healthy ageing. A multidisciplinary team of basic scientists and clinicians operating at the Catholic University Medical School in Rome is actively working on this topic to determine the ability of healthy lifestyles to promote active ageing and counteract the major age-related diseases affecting brain health, musculoskeletal function and gut microenvironment. This chapter summarizes our strategic approaches, the major results we obtained so far and the main experimental and translational perspectives
New perspectives in cyclic nucleotide-mediated functions in the CNS: the emerging role of cyclic nucleotide-gated (CNG) channels
Full text linkCyclic nucleotides play fundamental roles in the
central nervous system (CNS) under both physiological and
pathological conditions. The impact of cAMP and cGMP
signaling on neuronal and glial cell functions has been thoroughly
characterized. Most of their effects have been related
to cyclic nucleotide-dependent protein kinase activity. However,
cyclic nucleotide-gated (CNG) channels, first described
as key mediators of sensory transduction in retinal and olfactory
receptors, have been receiving increasing attention as
possible targets of cyclic nucleotides in the CNS. In the last
15 years, consistent evidence has emerged for their expression
in neurons and astrocytes of the rodent brain. Far less is
known, however, about the functional role of CNG channels
in these cells, although several of their features, such as Ca2+
permeability and prolonged activation in the presence of cyclic
nucleotides, make them ideal candidates for mediators of
physiological functions in the CNS. Here, we review literature
suggesting the involvement of CNG channels in a number of
CNS cellular functions (e.g., regulation of membrane potential,
neuronal excitability, and neurotransmitter release) as
well as in more complex phenomena, like brain plasticity,
adult neurogenesis, and pain sensitivity. The emerging picture
is that functional and dysfunctional cyclic nucleotide signaling
in the CNS has to be reconsidered including CNG channels
among possible targets. However, concerted efforts and multidisciplinary
approaches are still needed to get more in-depth
knowledge in this field
Epigenetic regulation of neural stem cells: The emerging role of nucleoporins
Full text linkNucleoporins (Nups) are components of the nuclear pore complex that, besides regulating nucleus-cytoplasmic transport, emerged as a hub for chromatin interaction and gene expression modulation. Specifically, Nups act in a dynamic manner both at specific gene level and in the topological organization of chromatin domains. As such, they play a fundamental role during development and determination of stemness/differentiation balance in stem cells. An increasing number of reports indicate the implication of Nups in many central nervous system functions with great impact on neurogenesis, neurophysiology, and neurological disorders. Nevertheless, the role of Nup-mediated epigenetic regulation in embryonic and adult neural stem cells (NSCs) is a field largely unexplored and the comprehension of their mechanisms of action is only beginning to be unveiled. After a brief overview of epigenetic mechanisms, we will present and discuss the emerging role of Nups as new effectors of neuroepigenetics and as dynamic platform for chromatin function with specific reference to the biology of NSCs
Dual role of brain-derived extracellular vesicles in dementia-related neurodegenerative disorders: cargo of disease spreading signals and diagnostic-therapeutic molecules
Full text linkNeurodegenerative disorders are one of the most common causes of disability and represent 6.3% of the global burden of disease. Among them, Alzheimer’s, Parkinson’s, and Huntington’s diseases cause cognitive decline, representing the most disabling symptom on both personal and social levels. The molecular mechanisms underlying the onset and progression of dementia are still poorly understood, and include secretory factors potentially affecting differentiated neurons, glial cells and neural stem cell niche. In the last decade, much attention has been devoted to exosomes as novel carriers of information exchanged among both neighbouring and distant cells. These vesicles can be generated and internalized by different brain cells including neurons, neural stem cells, astrocytes, and microglia, thereby affecting neural plasticity and cognitive functions in physiological and pathological conditions. Here, we review data on the roles of exosomes as carriers of bioactive molecules potentially involved in the pathogenesis of neurodegenerative disorders and detectable in biological fluids as biomarkers of dementia. We also discuss the experimental evidence of the therapeutic potential of stem cell-derived vesicles in experimental models of neurodegeneration-dependent cognitive decline
Therapeutic potential of stem cell-derived extracellular vesicles in neurodegenerative diseases associated with cognitive decline
No full text: In the central nervous system, cell-to-cell interaction is essential for brain plasticity and repair, and its alteration is critically involved in the development of neurodegenerative diseases. Neural stem cells are a plentiful source of biological signals promoting neuroplasticity and the maintenance of cognitive functions. Extracellular vesicles (EVs) represent an additional strategy for cells to release signals in the surrounding cellular environment or to exchange information among both neighboring and distant cells. In the last years, rising attention has been devoted to the ability of stem cell (SC)-derived EVs to counteract inflammatory and degenerative brain disorders taking advantage of their immunomodulatory capacities and regenerative potential. Here, we review the role of adult neurogenesis impairment in the cognitive decline associated with neurodegenerative diseases and describe the beneficial effects of SC-derived EVs on brain plasticity and repair also discussing the advantages of SC-derived EV administration versus SC transplantation in the treatment of neurodegenerative disorders
The Neuroscience Of Cocaine: Mechanisms And Treatment
No full textThe fundamental role of D-serine as co-agonist at the N-methyl-D-aspartate receptor (NMDAR), a major glutamate receptor subtype involved in synaptic plasticity, is well documented and experimental evidence indicates now that this D-amino acid is an influential player in the context of psychiatric diseases such as schizophrenia and depression. More recently, a direct link between cocaine addiction, another neuropsychiatric disorder, and D-serine signaling has been proposed by findings that D-serine levels are decreased in the nucleus accumbens of cocaine-treated rats. Such deficit in D-serine content leads to impairment of NMDAR-dependent synaptic plasticity and locomotor sensitization to cocaine, a behavioral hallmark of cocaine addiction. The D-serine hypothesis for cocaine addiction, here proposed, provides considerable insight in the understanding of the cocaine-induced neuroadaptations in reward-related neuronal circuits and opens new attractive perspectives for therapeutic approaches to treat this addictive state
Interleukin 1β receptor and synaptic dysfunction in recurrent brain infection with Herpes simplex virus type-1
Full text linkSeveral experimental evidence suggests a link between brain Herpes simplex virus type-1 infection and the occurrence of Alzheimer’s disease. However, the molecular mechanisms underlying this association are not completely understood. Among the molecular mediators of synaptic and cognitive dysfunction occurring after Herpes simplex virus type-1 infection and reactivation in the brain neuroinflammatory cytokines seem to occupy a central role. Here, we specifically reviewed literature reports dealing with the impact of neuroinflammation on synaptic dysfunction observed after recurrent Herpes simplex virus type-1 reactivation in the brain, highlighting the role of interleukins and, in particular, interleukin 1β as a possible target against Herpes simplex virus type-1-induced neuronal dysfunctions
RTAIAED: A Real-Time Ambulance in an Emergency Detector with a Pyramidal Part-Based Model Composed of MFCCs and YOLOv8
Full text linkIn emergency situations, every second counts for an ambulance navigating through traffic. Efficient use of traffic light systems can play a crucial role in minimizing response time. This paper introduces a novel automated Real-Time Ambulance in an Emergency Detector (RTAIAED). The proposed system uses special Lookout Stations (LSs) suitably positioned at a certain distance from each involved traffic light (TL), to obtain timely and safe transitions to green lights as the Ambulance in an Emergency (AIAE) approaches. The foundation of the proposed system is built on the simultaneous processing of video and audio data. The video analysis is inspired by the Part-Based Model theory integrating tailored video detectors that leverage a custom YOLOv8 model for enhanced precision. Concurrently the audio analysis component employs a neural network designed to analyze Mel Frequency Cepstral Coefficients (MFCCs) providing an accurate classification of auditory information. This dual-faceted approach facilitates a cohesive and synergistic analysis of sensory inputs. It incorporates a logic-based component to integrate and interpret the detections from each sensory channel, thereby ensuring the precise identification of an AIAE as it approaches a traffic light. Extensive experiments confirm the robustness of the approach and its reliable application in real-world scenarios thanks to its predictions in real time (reaching an fps of 11.8 on a Jetson Nano and a response time up to 0.25 s), showcasing the ability to detect AIAEs even in challenging conditions, such as noisy environments, nighttime, or adverse weather conditions, provided a suitable-quality camera is appropriately positioned. The RTAIAED is particularly effective on one-way roads, addressing the challenge of regulating the sequence of traffic light signals so as to ensure a green signal to the AIAE when arriving in front of the TL, despite the presence of the “double red” periods in which the one-way traffic is cleared of vehicles coming from one direction before allowing those coming from the other side. Also, it is suitable for managing temporary situations, like in the case of roadworks
Surprising toxicity and assembly behavior of amyloid beta-protein oxidized to sulfone.
No full textA beta (amyloid beta-peptide) is believed to cause AD (Alzheimer's disease). A beta 42 (A beta comprising 42 amino acids) is substantially more neurotoxic than A beta 40 (A beta comprising 40 amino acids), and this increased toxicity correlates with the existence of unique A beta 42 oligomers. Met(35) oxidation to sulfoxide or sulfone eliminates the differences in early oligomerization between A beta 40 and A beta 42. Met(35) oxidation to sulfoxide has been reported to decrease A beta assembly kinetics and neurotoxicity, whereas oxidation to sulfone has rarely been studied. Based on these data, we expected that oxidation of A beta to sulfone would also decrease its toxicity and assembly kinetics. To test this hypothesis, we compared systematically the effect of the wild-type, sulfoxide and sulfone forms of A beta 40 and A beta 42 on neuronal viability, dendritic spine morphology and macroscopic Ca2+ currents in primary neurons, and correlated the data with assembly kinetics. Surprisingly, we found that, in contrast with A beta-sulfoxide, A beta-sulfone was as toxic and aggregated as fast, as wild-type A beta. Thus, although A beta-sulfone is similar to A beta-sulfoxide in its dipole moment and oligomer size distribution, it behaves similarly to wild-type A beta in its aggregation kinetics and neurotoxicity. These surprising data decouple the toxicity of oxidized A beta from its initial oligomerization, and suggest that our current understanding of the effect of methionine oxidation in A beta is limited
Characterization of cancer stem cells (CSC) isolated from LI, a human glioblastoma (GBM) cell line
No full textIt is becoming increasingly clear that tumour development is due to a small fraction of mutated stem cells (CSC). Established cancer cell lines represent a good source of CSC with respect to tissue tumour samples because they do not contain any contaminating normal stem cells and it is easy to obtain large quantities of them. We isolated putative CSC via a non-adherent neurosphere (NS) assay from LI. Using a clonal assay, we selected from the primary NS two clones named F11 and D2. LI, F11 and D2 cells and these clones under differentiation were examined for expression of stem cell markers (CD133, Nestin, Musashi-1 and Sox-2), markers of differentiation (βIII-Tubulin and GFAP) and Ca2+-channels, by immunocytochemistry, western blot analysis and confocal Ca2+ imaging. Both F11 and D2 clones expressed higher levels of stem cell markers with respect to LI cells. Markers of differentiation were expressed at high levels in both LI cells and clones. The expression of Nestin, Sox-2, and βIII-Tubulin was down-regulated in clones under differentiation, whereas Musashi-1 was increased. LI, F11 and D2 cells did not exhibit Ca2+ signals following KCl-induced membrane depolarization, thus suggesting that they do not express functional voltage-dependent Ca2+-channels. Nevertheless, transient increases in intracellular Ca2+ levels were observed after cell exposure to ATP in both F11 and D2 during differentiation. The ATP treatment did not affect cell proliferation. The increased expression of stem cell markers and their decrease in cells under differentiation demonstrate the stem characteristics of clones we selected. The findings regarding expression of differentiation markers and of Ca2+-channels require further investigation. After a deeper characterization, both F11 and D2 could represent a good model to improve the knowledge on CSC and to identify new therapeutic approaches in GBM
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