1,721,189 research outputs found
Potential biomarkers and novel pharmacological targets in protein aggregation-related neurodegenerative diseases
Full text linkThe aggregation of specific proteins plays a pivotal role in the etiopathogenesis of several neurodegenerative diseases (NDs). β-Amyloid (Aβ) peptide-containing plaques and intraneuronal neurofibrillary tangles composed of hyperphosphorylated protein tau are the two main neuropathological lesions in Alzheimer's disease. Meanwhile, Parkinson's disease is defined by the presence of intraneuronal inclusions (Lewy bodies), in which α-synuclein (α-syn) has been identified as a major protein component. The current literature provides considerable insights into the mechanisms underlying oligomeric-related neurodegeneration, as well as the relationship between protein aggregation and ND, thus facilitating the development of novel putative biomarkers and/or pharmacological targets. Recently, α-syn, tau and Aβ have been shown to interact each other or with other "pathological proteins" to form toxic heteroaggregates. These latest findings are overcoming the concept that each neurodegenerative disease is related to the misfolding of a single specific protein. In this review, potential opportunities and pharmacological approaches targeting α-syn, tau and Aβ and their oligomeric forms are highlighted with examples from recent studies. Protein aggregation as a biomarker of NDs, in both the brain and peripheral fluids, is deeply explored. Finally, the relationship between biomarker establishment and assessment and their use as diagnostics or therapeutic targets are discussed
METODO PER LA DIAGNOSI DI MALATTIE NEURODEGENERATIVE
Full text linkSi descrive un metodo in vitro per la determinazione di malattie neurodegenerative, in particolare Parkinson e Alzheimer, basato sulla misurazione, in un campione di sangue periferico, dei complessi eteromerici di α-sinucleina con β-amiloide 1-42 e di α-sin con proteina Tau. Costituiscono ulteriori oggetti dell’invenzione un saggio immunochimico per la determinazione quantitativa di detti complessi eteromerici e un kit diagnostico per l’esecuzione del saggio
Adenosine receptors: what we know and what we are learning
No full textAdenosine, beside its role in the intermediate metabolism, mediates its physiological functions by interacting with four receptor subtypes named A(1), A(2A), A(2B) and A(3). All these receptors belong to the superfamily of G protein-coupled receptors that represent the most widely targeted pharmacological protein class. Since adenosine receptors are widespread throughout the body, they are involved in a variety of physiological processes and pathology including neurological, cardiovascular, inflammatory diseases and cancer. At now, it is ascertained that the biological responses evoked by the activation of a single receptor are the result of complex and integrated signalling pathways targeted by different receptor proteins, interacting each other. These pathways may in turn control receptor responsiveness over time through fine regulatory mechanisms including desensitization-internalization processes. The knowledge of adenosine receptor structure as well as the molecular mechanisms underlying the regulation of receptor functioning and of receptor-receptor interactions during physio and pathological conditions represent a pivotal starting point to the development of new drugs with high efficacy and selectivity for each adenosine receptor subtype. The goal of this review is to summarize what we now and what we are learning about adenosine receptor structure, signalling and regulatory mechanisms. In addition, to dissect the potential therapeutic application of adenosine receptor ligands, the pathophysiological role of the receptor subtypes in different tissues are discussed
Brain ageing and neurodegenerative disease: The role of cellular waste management
Full text linkAgeing is defined as a time-dependent functional decline that occurs in most of live organisms. Brain modification during the ageing process has been considered to predispose to neurodegenerative disorders. Despite intensive research, the exact mechanisms accounting for the switch from physiological brain ageing to neurodegeneration remain to be fully elucidated. At a cellular level, brain ageing is characterized by growing inflammation, oxidative stress, increased genomic instability, altered metabolism and the destruction of protein homeostasis, which causes the accumulation of cellular waste. In this respect, the ubiquitin proteasome system and autophagy represent the two main proteolytic systems accountable for misfolded proteins degradation in neurons. Not surprisingly, the impairment of these systems has been reported in ageing and neurodegenerative disorders characterized by inclusions of protein aggregates. Herein, we provide an overview of the molecular mechanisms that regulate ageing and neurodegenerative disorders, in particular those linked to an alteration of protein degradation. Moreover, the current therapeutic and nutritional interventions used to target protein degradation pathways are explored and discussed in the prospective of stalling or even reversing ageing and neurodegenerative processes
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Trazodone treatment protects neuronal-like cells from inflammatory insult by inhibiting NF-κB, p38 and JNK
Full text linkGrowing evidence suggests that alterations of the inflammatory/immune system contribute to the pathogenesis of major depression and that inflammatory processes may influence the antidepressant treatment response. Depressed patients exhibit increased levels of inflammatory markers in both the periphery and brain, and high co-morbidity exists between depression and diseases associated with inflammatory alterations. Trazodone (TDZ) is a triazolopyridine derivative that belongs to the class of serotonin receptor antagonists and reuptake inhibitors. Although the trophic and protective properties of classic antidepressants have extensively been exploited, the effects of TDZ remain to be fully elucidated. In this study, the pharmacological activities of TDZ on human neuronal-like cells were investigated under both physiological and inflammatory conditions. An in vitro inflammatory model was established using lipopolysaccharide (LPS) and tumour necrosis factor-α (TNF-α), which efficiently mimic the stress-related changes in neurotrophic and pro-inflammatory genes.Our results showed that TDZ significantly increased the mRNA expression of both brain-derived nerve factor (BDNF) and cAMP response element-binding protein (CREB) and decreased the cellular release of the pro-inflammatory cytokine interferon gamma (IFN-γ) in neuronal-like cells.In contrast, neuronal cell treatment with LPS and TNF-α decreased the expression of CREB and BDNF and increased the expression of nuclear factor kappa B (NF-κB), a primary transcription factor that functions in inflammatory response initiation. Moreover, the two agents induced the release of pro-inflammatory cytokines (. i.e., interleukin-6 and IFN-γ) and decreased the production of the anti-inflammatory cytokine interleukin-10. TDZ pre-treatment completely reversed the decrease in cell viability and counteracted the decrease in BDNF and CREB expression mediated by LPS-TNF-α. In addition, the production of inflammatory mediators was inhibited, and the release of interleukin-10 was restored to control levels.Furthermore, the intracellular signalling mechanism regulating TDZ-elicited effects was specifically investigated. TDZ induced extracellular signal-regulated kinase (ERK) phosphorylation and inhibited constitutive p38 activation. Moreover, TDZ counteracted the activation of p38 and c-Jun NH2-terminal kinase (JNK) elicited by LPS-TNF-α, suggesting that the neuro-protective role of TDZ could be mediated by p38 and JNK.Overall, our results demonstrated that the protective effects of TDZ under inflammation in neuronal-like cells function by decreasing pro-inflammatory signalling and by enhancing anti-inflammatory signalling
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