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Chronic and acute alcohol exposure prevents monocyte-derived dendritic cells from maturing in response to microbial stimuli
Full text linkGli alcolisti sono soggetti immunocompromessi per stile di vita caratterizzati da una disregolazione del sistema immunitario e quindi da una maggiore suscettibilità all’insorgenza di malattie infettive. L’alcol interferisce con le funzioni di cellule e molecole del sistema immunitario, compromettendo i meccanismi dell’immunità innata ed acquisita, umorale e cellulare, e determinando alterate risposte infiammatorie spesso associate a danni organo-specifici. Tuttavia i meccanismi che determinano la disfunzione immunitaria non sono ancora del tutto chiariti. Studi clinici e sperimentali hanno messo in evidenza che l’abuso cronico di alcol è associato ad una aumentata incidenza di infezioni polmonari da Streptococcus pneumoniae e Mycobacterium tuberculosis, di infezioni epatiche da HBV e HCV. L'associazione tra abuso d’alcol ed aumento dei decessi per infezioni è nota da più di 75 anni, ma solo negli ultimi 15 anni seri sforzi investigativi sono stati fatti per comprendere il ruolo dell’abuso alcolico nelle disfunzioni immunitarie. Gli alcolisti, la cui maggioranza ricade nella fascia socioeconomica povera, spesso soffrono condizioni di sovraffollamento e d’accesso limitato alle cure sanitarie, che possono aumentare la probabilità di contrarre e diffondere malattie infettive. Inoltre, molti alcolisti soffrono di malnutrizione e di malattie epatiche condizioni che possono compromettere il sistema immunitario e la sua capacità di resistere all’infezione. Le disfunzioni immunitarie indotte dall’alcol dipendono da vari fattori, tra cui la dose d’alcol e la durata d’esposizione (cronica vs acuta), dalla presenza e caratteristiche d’altri stimoli come le molecole microbiche. I difetti a carico delle cellule presentanti l'antigene (APC) sembrano giocare un ruolo fondamentale nell’alterazioni delle risposte dell’immunità cellulo-mediata e nella riduzione della proliferazione linfocitaria antigene specifica. Le cellule dendritiche (CD), cellule professionali presentanti l’antigene, sono tra le più potenti APCs, il loro grado di maturazione fenotipica e funzionale regola il grado e la tipologia della risposta immune che porta all’attivazione e la tolleranza.
Tra gli obbiettivi della ricerca sugli effetti dell’alcol sulla salute umana, c’è grande necessità di sviluppare approcci multimodali in grado di modulare e recuperare la funzionalità del sistema immune dai danni indotti dall’abuso di alcol.
Lo scopo principale della presente tesi è stato quello di approfondire lo studio dei meccanismi molecolari e cellulari indotti dall’alcol sulle cellule dell’immunità innata al fine di promuovere un’immunità protettiva specifica.
Per raggiungere questi obiettivi specifici è stato valutato i) il grado d’alterazione dell’immunità innata in soggetti immunocompromessi per abuso d’alcol (esposizione cronica) ed il grado d’alterazione di monociti e CD esposte in vitro all’etanolo (esposizione acuta); ii) l’efficacia del trattamento in vitro con cromoglicato sodico di monociti e CD come strategia adiuvante ad uso umano nel modello di differenziazione e maturazione delle CD.
In particolare, sono stati studiati gli effetti in vivo dell’esposizione cronica all’alcol sulla capacità dei monociti, ottenuti da soggetti alcolisti, di differenziare e maturare in vitro in CD funzionali. Per ampliare le attuali informazioni sui cambiamenti indotti dall’esposizione acuta all’alcol sulle cellule dendritiche è stato valutato il grado di alterazione delle CD esposte in vitro all’etanolo dopo induzione del processo di maturazione. In questo studio sono state allestite colture di CD generate da soggetti alcolisti cronici e da soggetti sani non bevitori. Mediante tecniche di immunochimica e di citometria a flusso è stata eseguita una caratterizzazione fenotipica e funzionale delle CD generate da monociti in presenza dei fattori di crescita IL-4 e GM-CSF. Le cellule dendritiche sono state caratterizzate a livello fenotipico e funzionale prima e dopo stimolazione con LPS (endocitosi, migrazione, produzione di citochine, capacità allostimolatoria), E’ stato inoltre valutata la capacità di cellule dendritiche esposte in vitro all’etanolo di polarizzare linfociti T naïve ed il tipo di polarizzazione indotto.
Come possibile approccio alla prevenzione degli effetti negativi dell’alcol sul sistema immunitario, è stata valutata la capacità del cromoglicato, farmaco utilizzato nella terapia anti-allergica e noto per la sua capacità di stabilizzare la polarità delle membrane cellulari, di esercitare in vitro un effetto adiuvante sulla funzionalità dei monociti e CD esposte all’etanolo. Per questo scopo abbiamo valutato in vitro l’attività del cromoglicato sul fenotipo e la funzione delle CD esposte all’etanolo, nel modello di differenziazione e di maturazione delle CD.
I risultati della presente tesi dimostrano come l'esposizione cronica e acuta all'alcol, anche a dosi moderate, influenza in vitro la maturazione fenotipica e funzionale delle cellule dendritiche in risposta ad uno stimolo maturativo microbico, quale LPS, suggerendo una ridotta capacità degli alcolisti cronici a controllare le infezioni.
Inoltre, i risultati della presente tesi mettono in evidenza il possibile ruolo di adiuvante del cromoglicato nel processo di differenziazione e maturazione delle CD, suggerendo come questo farmaco possa rappresentare uno strategia innovativa in grado di ripristinare la corretta funzionalità dell’immunità innata nei soggetti alcolisti e in tal modo migliorare la capacità del sistema immunitario a resistere all’infezioni.Research demonstrating alcohol's adverse effects on functions of the immune system supports clinical evidence of an increased incidence of infectious diseases, such as pneumoniae, tuberculosis and hepatitis C, as well as a greater susceptibility to cancer in humans chronically abusing alcohol. While the association of alcohol abuse with increased deaths from infections was made over 75 years ago, only in the past 15 years has serious investigative efforts been made to understand the role of alcoholic exposure on immune dysfunction. Among the many alcoholics whose socioeconomic status is poor, overcrowded living conditions and limited access to health care may increase the likelihood of contracting and spreading disease. In addition, many alcoholics suffer from malnutrition and liver disease, conditions that may themselves compromise the immune system's capacity to resist infection. Evidence from human and animal studies in vivo as well as from experiments in vitro suggests that alcohol abuse may exert adverse immunomodulatory effects on innate and adaptive immune responses. Alcohol-induced immune dysfunctions depend on various factors including the dose and duration of alcohol exposure (chronic vs acute) and on the presence and characteristics of additional stimuli such as microbial molecules.
Defects of antigen presenting cells (APC) appear to be pivotal in the alcohol-induced alterations of cell-mediated immunity and in decreased antigen (Ag)-specific T cell proliferation. Dendritic cells (DCs) are the most potent APCs. The functional state of DC maturation and their activation degree control immunity and tolerance.
The complex nature of the linkage between alcohol consumption, altered host immune responses, and infection remains controversial and incompletely understood. Most importantly, there is a need to develop a multimodal approach, including components of immune modulation and immune restoration, to repair possible damages in the host defence system induced by alcohol ingestion.
In this study we addressed this research need in: 1) to understand how alcohol exposure induces immune alterations that contribute to the occurrence of particular kinds of infectious diseases showing a higher incidence in alcohol abuser population than in the general population and 2) to develop strategies to reduce the occurrence of alcohol-induced immune alterations.
To clarify the immunological effects exerted by alcohol abuse on human monocyte-derived DCs we investigated whether in vivo chronic alcohol exposure alters the ability of monocytes from alcoholics to differentiate and mature in vitro into functional DCs. To extend current information on direct alcohol-induced changes in DCs, we evaluated whether in vitro acute ethanol (EtOH) treatment of differentiated immature DCs (iDCs) generated from chronic alcoholics and healthy control subjects impairs DC maturation. Using immunochemical and cytofluorimetric analysis we determined the phenotype and functions (endocytosis, migration, cytokine production and allostimulatory ability) of monocyte-derived DCs and analyzed the ability of iDCs to respond to the microbial product lipopolysaccharide (LPS). We also wanted to find out whether EtOH-treated antigen-stimulated DCs correctly primed naïve T lymphocytes, thus inducing T helper 1 (Th1) cell polarization.
As a possible approach in the prevention of alcohol's adverse effects on the immune system we investigated whether cromoglycate-like’ anti-allergic drugs -- by their well established property to stabilize membrane lipid polarity -- might exert in vitro an adjuvant effect on monocytes and DCs exposed to EtOH. For this purpose we evaluated in vitro activity of cromoglycate on DC phenotype and function exposed to EtOH in the well-established model of DC differentiation and maturation.
Our results showed that alcoholics’ monocytes differentiated into immature DCs with an altered phenotype and functions (alc-iDCs). Alc-iDCs showed fewer CD1a+ cells, weaker CD86 expression and higher HLA-DR expression associated with lower endocytosis and allostimulatory functions than did iDCs from healthy subjects (control-iDCs). Despite these impairments, alc-iDCs produced tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in large amounts. LPS stimulation failed to induce full phenotypical and functional alc-iDC maturation. In vitro acute EtOH exposure also prevented alc-iDCs and control-iDCs from maturing in response to LPS. T-cell priming experiments showed that EtOH treatment prevented LPS-stimulated control-DCs from priming and polarizing naïve allogeneic T cells into T helper 1 (Th1) cells, thus favouring a predominant T helper 2 (Th2) environment. Furthermore, this thesis establishes a new adjuvant effect of cromoglycate on the level of DC differentiation and maturation and suggests that cromoglycate may represent an innovative strategy to reverse the impaired immune response in alcoholics thus improving the immune system's capacity to resist infection
A Pivotal Role of Nrf2 in Neurodegenerative Disorders: A New Way for Therapeutic Strategies
Full text linkClinical and preclinical research indicates that neurodegenerative diseases are characterized by excess levels of oxidative stress (OS) biomarkers and by lower levels of antioxidant protection in the brain and peripheral tissues. Dysregulations in the oxidant/antioxidant balance are known to be a major factor in the pathogenesis of neurodegenerative diseases and involve mitochondrial dysfunction, protein misfolding, and neuroinflammation, all events that lead to the proteostatic collapse of neuronal cells and their loss. Nuclear factor-E2-related factor 2 (Nrf2) is a short-lived protein that works as a transcription factor and is related to the expression of many cytoprotective genes involved in xenobiotic metabolism and antioxidant responses. A major emerging function of Nrf2 from studies over the past decade is its role in resistance to OS. Nrf2 is a key regulator of OS defense and research supports a protective and defending role of Nrf2 against neurodegenerative conditions. This review describes the influence of Nrf2 on OS and in what way Nrf2 regulates antioxidant defense for neurodegenerative conditions. Furthermore, we evaluate recent research and evidence for a beneficial and potential role of specific Nrf2 activator compounds as therapeutic agents
Cytokine gene expression in peripheral blood mononuclear cells (PBMC) from patients with pharmacologically treated cystic echinococcosis
No full textA Perspective on Nrf2 Signaling Pathway for Neuroinflammation: A Potential Therapeutic Target in Alzheimer's and Parkinson's Diseases
Full text linkNeuroinflammation plays a pivotal role in Alzheimer's disease (AD) and Parkinson's disease (PD), the leading causes of dementia. These neurological disorders are characterized by the accumulation of misfolded proteins such as amyloid-ß (Aß), tau protein and α-synuclein, contributing to mitochondrial fragmentation, oxidative stress, and neuroinflammation. Misfolded proteins activate microglia, which induces neuroinflammation, expression of pro-inflammatory cytokines and subsequently facilitates synaptic damage and neuronal loss. So far, all the proposed drugs were based on the inhibition of protein aggregation and were failed in clinical trials. Therefore, the treatment options of dementia are still a challenging issue. Thus, it is worthwhile to study alternative therapeutic strategies. In this context, there is increasing data on the pivotal role of transcription factor NF- E2 p45-related factor 2 (Nrf2) on the redox homeostasis and anti-inflammatory functions in neurodegenerative disorders. Interestingly, Nrf2 signaling pathway has shown upregulation of antioxidant genes, inhibition of microglia-mediated inflammation, and improved mitochondrial function in neurodegenerative diseases, suggesting Nrf2 activation could be a novel therapeutic approach to target pathogenesis. The present review will examine the correlation between Nrf2 signaling with neuroinflammation in AD and PD
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
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Immunomodulazione delle cellule dendritiche come potenziale strategia terapeutica dell' aterosclerosi carotidea
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