1,720,976 research outputs found
Influence of hyperglycaemia and/or hyperinsulinemia on breast cancer and potential benefits from nutraceuticals obtained from eco-sustainable systems
No full textIl mondo occidentale e, sempre più, i paesi in via di sviluppo stanno affrontando un'epidemia di obesità guidata da cattive abitudini alimentari e da inattività fisica. In particolare, la dieta occidentale, caratterizzata dall'eccessivo consumo di alimenti altamente processati, ricchi di acidi grassi saturi a catena lunga e zuccheri, riveste un ruolo fondamentale nello sviluppo dell'obesità e delle sue comorbidità, incluso il Diabete Mellito di Tipo 2 (DMT2). È importante notare che il DMT2 non va considerato unicamente come un disturbo metabolico caratterizzato dalla presenza di iperglicemia cronica, poiché le alterazioni metaboliche ad esso associate incrementano il rischio di sviluppare altre patologie, fra cui il cancro al seno (CS). Allo stesso modo, alimenti ricchi di fibre, acidi grassi polinsaturi e antiossidanti, come le microalghe in quanto superfoods eco-sostenibile, possono migliorare la salute metabolica, contrastando così l'effetto del microambiente del DMT2 sulla patogenesi del CS. Alla luce di ciò, la presente tesi di dottorato si propone di valutare l'effetto dell'iperglicemia e dell'iperinsulinemia, entrambi tratti caratteristici del DMT2, sulla proliferazione cellulare e sull'epigenetica delle cellule di CS. Inoltre, il progetto di ricerca ha indagato se i nutraceutici derivati dalle microalghe possano contrastare l'effetto dell'iperglicemia e dell'iperinsulinemia sulla proliferazione delle cellule di CS.
Nel contesto di questo progetto, le indagini sono state condotte utilizzando due distinte linee cellulari di CS: MDA-MB-231 e MCF-7, che differiscono per l'espressione dei recettori ormonali.
Inizialmente, uno stimolo acuto con insulina ha confermato che sia le cellule MCF-7 che quelle MDA-MB-231 rispondono all'insulina mediante l'attivazione della via AKT, confermando così la loro idoneità sperimentale per gli obiettivi del progetto. L'iperinsulinemia cronica ha indotto un aumento significativo della proliferazione delle cellule MCF-7, alterando contestualmente il loro ciclo cellulare, mostrato attraverso l’incremento della fase S. Va segnalato che nelle cellule MCF-7 la proliferazione indotta dall'insulina si è rivelata dipendente dalla via AKT, poiché è stata annullata mediante trattamento un inibitore di AKT noto come MK-2206. Inoltre, nelle cellule MDA-MB-231, l'insulina ha potenziato la loro capacità di migrazione senza però provocare alcun effetto in termini di proliferazione. La capacità dell'insulina di aumentare il potenziale migratorio delle cellule MDA-MB-231 potrebbe dipendere da modificazioni epigenetiche innescate da questo ormone. Infatti, nelle cellule MDA-MB-231 l'iperinsulinemia ha modulato l'espressione di diversi microRNA (miRNA), inclusa la sovra-espressione del miR-1246, associato ai processi di metastasi, e la sotto-regolazione del miR-26b-3p, noto per la sua attività di soppressore tumorale. Sebbene l'iperglicemia non abbia indotto un incremento della proliferazione nelle cellule MDA-MB-231, ha modificato l'espressione dei miRNA, come evidenziato dalla sovra-espressione dei miR-105-5p e miR-301a-3p, indicando una complessa interazione tra fattori metabolici.
In aggiunta, i nutraceutici inducibili nelle microalghe analizzati, hanno dimostrato una notevole variabilità nei loro effetti citotossici. In particolare, il β-Carotene ha mostrato una marcata efficacia nel ridurre la vitalità in entrambe le linee cellulari di CS, sia quando non trattate sia quando trattate con insulina.
I risultati riportati suggeriscono che l'integrazione dei nutraceutici con le terapie farmacologiche tradizionali potrebbe migliorare gli esiti clinici, in particolare nei pazienti con una salute metabolica compromessa a causa del DMT2.
Future indagini dovrebbero essere atte ad esplorare le interazioni sinergiche tra nutraceutici selezionati e farmaci chemioterapici, su differenti sottotipi di CS, al fine di condurre alla traslazione dei risultai ottenuti ad applicazioni cliniche.The Western world and increasingly the developing countries are facing an obesity epidemic which is driven by poor dietary habits and physical inactivity. In particular, the Western diet, characterised by the overconsumption of highly processed foods rich in long-chain saturated fatty acids and sugar, is pivotal in driving obesity and its comorbidities, including Type 2 Diabetes Mellitus (T2DM). Of note, T2DM is not merely to be considered as a metabolic disorder marked by chronic hyperglycaemia, but the metabolic aberrations linked with T2DM increase the risk of the development of other diseases, including breast cancer (BC). To the same extent, foods rich in dietary fibre, polyunsaturated fatty acids and antioxidants, like the eco-sustainable superfoods microalgae, may improve metabolic health, thereby tackling the effect of the T2DM microenvironment on BC pathogenesis. In light of this, this doctoral thesis aims to evaluate the effect of hyperglycaemia and hyperinsulinemia, both key features of T2DM, on BC cell proliferation and epigenetics. Additionally, this research project investigated whether microalgae-derived nutraceuticals could counter the effect of hyperglycaemia and hyperinsulinemia on BC cell proliferation.
In the context of this doctoral thesis project, investigations were conducted utilizing two distinct BC cell lines: MDA-MB-231 and MCF-7, which differ in the expression of hormonal receptors. Initially, an acute insulin stimulus confirmed that both MCF-7 and MDA-MB-231 cells exhibit a response to insulin via the activation of the AKT pathway, validating their suitability to address the aims of the project. Chronic hyperinsulinemia induced a significant increase in MCF-7 cell proliferation while simultaneously altering cell cycle dynamics by increasing the S phase. Remarkably, insulin-induced proliferation was AKT-dependent as it was abrogated by the administration of the AKT inhibitor MK-2206 to MCF-7 cells. Furthermore, insulin enhanced the migratory potential of MDA-MB-231 cells without leading to any proliferative effect.
The ability of insulin to increase MDA-MB-231 cell migration potential may be dependent on epigenetic changes triggered by this hormone. Indeed, in MDA-MB-231 cells, hyperinsulinemia modulated the expression of several microRNAs (miRNAs), including the upregulation of miR-1246, which is associated with metastasis and the downregulation of miR-26b-3p, known for its tumour-suppressor activity. Although hyperglycaemia did not induce an increase in proliferation within MDA-MB-231 cells, it independently modified miRNA expression, as demonstrated by the overexpression of miR-105-5p and miR-301a-3p, indicating a complex interplay between metabolic factors.
Moreover, the nutraceuticals that are inducible in microalgae have demonstrated notable variability in their cytotoxic effects. Specifically, β-Carotene demonstrated a marked efficacy in diminishing viability in both the BC cell lines, under insulin-treated and untreated conditions. These results suggest that the integration of nutraceuticals with traditional therapies may improve clinical outcomes, particularly for patients with compromised metabolic health due to T2DM.
Future investigations should explore the synergistic interactions of selected nutraceuticals with chemotherapeutic drugs across different BC subtypes to pave the way for the translation of these findings into clinical applications
Breast Cancer Cell Line-Specific Responses to Insulin: Effects on Proliferation and Migration
No full textBreast cancer (BC) progression appears to be significantly influenced by the diabetic microenvironment, characterised by hyperglycaemia and hyperinsulinemia, though the exact cellular mechanisms remain partly unclear. This study investigated the effects of exposure to supra-physiological levels of glucose and insulin on two distinct BC cell models: hormone-responsive MCF-7 cells and triple-negative MDA-MB-231 cells. To evaluate the effects triggered by high insulin level in different BC cell subtypes, we analysed the activation status of PI3K/AKT and MAPK pathways, cell proliferation, cell distribution in cell cycle phases and cell migration. High insulin level significantly activates the insulin metabolic pathway via AKT phosphorylation in both cell lines while inducing pro-proliferative stimulus and modulation of cell distribution in cell cycle phases only in the hormone-responsive MCF-7 cell line. On the contrary, high-glucose containing medium alone did not modulate proliferation nor further increased it when combined with high insulin level in both the investigated cell lines. However, following insulin treatment, the MAPK pathway remained unaffected, suggesting that the proliferation effects in the MCF-7 cell line are mediated by AKT activation. This linkage was also demonstrated by AKT phosphorylation blockade, driven by the AKT inhibitor MK-2206, which negated the proliferative stimulus. Interestingly, while MDA-MB-231 cells, following chronic hyperinsulinemia exposure, did not exhibit enhanced proliferation, they displayed a marked increase in migratory behaviour. These findings suggest that chronic hyperinsulinemia, but not hyperglycaemia, exerts subtype-specific effects in BC, highlighting the potential of targeting insulin pathways for therapeutic intervention
Optical tissue clearing associated with 3D imaging: application in preclinical and clinical studies
No full textUnderstanding the inner morphology of intact tissues is one of the most competitive challenges in modern biology. Since the beginning of the twentieth century, optical tissue clearing (OTC) has provided solutions for volumetric imaging, allowing the microscopic visualization of thick sections of tissue, organoids, up to whole organs and organisms (for example, mouse or rat). Recently, tissue clearing has also been introduced in clinical settings to achieve a more accurate diagnosis with the support of 3D imaging. This review aims to give an overview of the most recent developments in OTC and 3D imaging and to illustrate their role in the field of medical diagnosis, with a specific focus on clinical applications. GRAPHICAL ABSTRACT: [Image: see text
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
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
Growth Inhibition of Retinoblastoma Cell Line by Exosome-Mediated Transfer of miR-142-3p
No full textINTRODUCTION: Retinoblastoma (Rb) is the most common ocular paediatric malignancy and is caused by a mutation of the two alleles of the tumor suppressor gene, RB1. The tumor microenvironment (TME) represents a complex system whose function is not yet well defined and where microvesicles, such as exosomes, play a key role in intercellular communication. Micro-RNAs (mRNAs) have emerged as important modifiers of biological mechanisms involved in cancer and been able to regulate tumor progression. METHODS: Co-culture of monocytes with retinoblastoma cell lines, showed a significant growth decrease. Given the interaction between Rb cells and monocytes, we investigated the role of the supernatant in the cross-talk between cell lines, by taking the product of the co-culture and then using it as a culture medium for Rb cells. RESULTS: miR-142-3p showed to be particularly over-expressed both in the Rb cell line and in the medium used for their culture, comparing to control cell line and the normal supernatant, respectively. Therefore, we provided evidence that miR-142-3p is released by monocytes in the co-culture medium’s exosomes and that it is subsequently up-taken by Rb cells, causing the inhibition of proliferation of Rb cell line by affecting cell cycle progression. CONCLUSION: This study highlights the role of exosomic miR-142-3p in the TME of Rb and identifies new molecular targets, which are able to control tumor growth aiming the development of a forward-looking miR-based strategy
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