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Investigation of glyoxalase 2 localization and its role as a survival factor in cancer cells
No full textQuesta tesi presenta un lavoro esteso sulla gliossalasi 2 e sui suoi ruoli aggiuntivi in linee cellulari di cancro al seno e non. La gliossalasi 2 (Glo2) è un enzima del sistema delle gliossalasi, critico per la detossificazione del metilgliossale (MGO) e attivo in parallelo alla glicolisi, utilizzando il glutatione come cofattore. Codificata dal gene HAGH, la Glo2 è presente sia nei mitocondri che nel citoplasma e svolge una funzione importante in numerose specie e tessuti, sia procarioti che eucarioti. Questo studio approfondisce nuovi aspetti della funzione di Glo2 nelle cellule di carcinoma mammario (MCF7) rispetto alle cellule normali (HDF), esplorando la sua localizzazione nucleare e il suo ruolo nella proliferazione cellulare e nella resistenza alla chemioterapia. I risultati indicano una sovraespressione di Glo2 nelle cellule tumorali, con livelli che aumentano durante le fasi proliferative (S e G2/M) del ciclo cellulare, suggerendo un coinvolgimento diretto nella crescita tumorale. Inoltre, è stato osservato che Glo2 partecipa alla S-glutationilazione, una modifica post-traslazionale potenziata nelle cellule tumorali sia nel citoplasma che nel nucleo. L'inibizione di Glo2 mediante l'inibitore P-nitrocarbobenzoxyglutathione (p-NCBG) ha aumentato la sensibilità delle cellule tumorali alla doxorubicina, suggerendo che Glo2 può contribuire alla resistenza tumorale modulando lo stress ossidativo. Questi risultati identificano Glo2 come un potenziale bersaglio terapeutico per migliorare l'efficacia dei trattamenti contro il cancro e suggeriscono un ruolo più ampio di Glo2 nei meccanismi di regolazione cellulare e nelle patologie associate. This thesis presents an extended work concerning the glyoxalase 2 and additional roles in breast cancer and non-cancer cell lines. Glyoxalase 2 (Glo2) is an enzyme of the glyoxalase system, critical for detoxification of methylglyoxal (MGO) and active in parallel with glycolysis, using glutathione as a cofactor. Encoded by the HAGH gene, Glo2 is present in both mitochondria and cytoplasm and plays an important function in numerous species and tissues, both prokaryotic and eukaryotic. This study delves into new aspects of Glo2 function in breast carcinoma cells (MCF7) compared with normal cells (HDF), exploring its nuclear localization and its role in cell proliferation and chemotherapy resistance. The results indicate overexpression of Glo2 in cancer cells, with levels increasing during the proliferative (S and G2/M) phases of the cell cycle, suggesting direct involvement in tumor growth. In addition, Glo2 has been observed to participate in S-glutathionylation, an enhanced post-translational modification in cancer cells in both the cytoplasm and nucleus. Inhibition of Glo2 by the inhibitor P-nitrocarbobenzoxyglutathione (p-NCBG) increased the sensitivity of cancer cells to doxorubicin, suggesting that Glo2 may contribute to tumor resistance by modulating oxidative stress. These findings identify Glo2 as a potential therapeutic target for improving the efficacy of cancer treatments, and suggest a broader role of Glo2 in cellular regulatory mechanisms and pathologies associated with oxidative stress.
Integration of Lipid-Functionalized Epigallocatechin-3-gallate into PLGA Matrix as a Novel Polyphenol-Based Nanoantioxidant
Get PDFThe search for polyphenol-based materials with antioxidant activity is a growing research area in the biomedical field. To obtain an efficient and stable nanoantioxidant, a novel biosystem was designed by integrating a lipophilic derivative of epigallocatechin-3-gallate (named EGCG-C18) on the surface of poly(lactic-co-glycolic acid) (PLGA). Poly(vinyl alcohol) (PVA) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol) (DSPE-PEG2000) were selected as polymeric and lipidic stabilizers, respectively, and their influence on both physical properties and the antioxidant activity of nanoantioxidant was investigated by a combined in silico and experimental approach. Full-atom molecular dynamics (MD) simulations were carried out to describe the different self-assembly processes of all components and the interactions that guided the EGCG-C18 insertion inside the PLGA matrix. Together with infrared spectroscopy results, the formation of an antioxidant lipid shell on the PLGA surface was clear. Dynamic light scattering and transmission electron microscopy showed that in the presence of DSPE-PEG2000, NPs were smaller than those treated with PVA. In addition, the different stabilizers used strongly influenced the ROS-scavenging ability of nanomaterials and this effect was strictly related to the molecular organization of EGCG-C18. MD showed that the apolar interaction between the alkyl chains of DSPE-PEG2000 and EGCG-C18 oriented the phenolic groups of the polyphenol toward the solvent, providing an ability of NP to scavenge hydroxyl radicals over to free EGCG-C18 and PLGA/PVA NPs. Finally, the ability of nanoantioxidants to protect human dermal fibroblasts from cell death induced by oxidative stress has been tested, revealing the high potential of these novel NPs as polyphenol-based materials
Epigenetic Properties of Compounds Contained in Functional Foods Against Cancer
Get PDFEpigenetics encompasses reversible and heritable genomic changes in histones, DNA expression, and non-coding RNAs that occur without modifying the nucleotide DNA sequence. These changes play a critical role in modulating cell function in both healthy and pathological conditions. Dysregulated epigenetic mechanisms are implicated in various diseases, including cardiovascular disorders, neurodegenerative diseases, obesity, and mainly cancer. Therefore, to develop innovative therapeutic strategies, research for compounds able to modulate the complex epigenetic landscape of cancer is rapidly surging. Dietary phytochemicals, mostly flavonoids but also tetraterpenoids, organosulfur compounds, and isothiocyanates, represent biologically active molecules found in vegetables, fruits, medicinal plants, and beverages. These natural organic compounds exhibit epigenetic modulatory properties by influencing the activity of epigenetics key enzymes, such as DNA methyltransferases, histone acetyltransferases and deacetylases, and histone methyltransferases and demethylases. Due to the reversibility of the modifications that they induce, their minimal adverse effects, and their potent epigenetic regulatory activity, dietary phytochemicals hold significant promise as antitumor agents and warrant further investigation. This review aims to consolidate current data on the diverse epigenetic effects of the six major flavonoid subclasses, as well as other natural compounds, in the context of cancer. The goal is to identify new therapeutic epigenetic targets for drug development, whether as stand-alone treatments or in combination with conventional antitumor approaches
Identification of Flavone Derivative Displaying a 4′-Aminophenoxy Moiety as Potential Selective Anticancer Agent in NSCLC Tumor Cells
No full textFive heterocyclic derivatives were synthesized by functionalization of a flavone nucleus with an aminophenoxy moiety. Their cytotoxicity was investigated in vitro in two models of human non-small cell lung cancer (NSCLC) cells (A549 and NCI-H1975) by using MTT assay and the results compared to those obtained in healthy fibroblasts as a non-malignant cell model. One of the aminophenoxy flavone derivatives (APF-1) was found to be effective at low micromolar concentrations in both lung cancer cell lines with a higher selective index (SI). Flow cytometric analyses showed that APF-1 induced apoptosis and cell cycle arrest in the G2/M phase through the up-regulation of p21 expression. Therefore, the aminophenoxy flavone-based compounds may be promising cancer-selective agents and could serve as a base for further research into the design of flavone-based anticancer drugs
Glyoxalase 2: Towards a Broader View of the Second Player of the Glyoxalase System
Get PDFGlyoxalase 2 is a mitochondrial and cytoplasmic protein belonging to the metallo-β-lactamase family encoded by the hydroxyacylglutathione hydrolase (HAGH) gene. This enzyme is the second enzyme of the glyoxalase system that is responsible for detoxification of the α-ketothaldehyde methylglyoxal in cells. The two enzymes glyoxalase 1 (Glo1) and glyoxalase 2 (Glo2) form the complete glyoxalase pathway, which utilizes glutathione as cofactor in eukaryotic cells. The importance of Glo2 is highlighted by its ubiquitous distribution in prokaryotic and eukaryotic organisms. Its function in the system has been well defined, but in recent years, additional roles are emerging, especially those related to oxidative stress. This review focuses on Glo2 by considering its genetics, molecular and structural properties, its involvement in post-translational modifications and its interaction with specific metabolic pathways. The purpose of this review is to focus attention on an enzyme that, from the most recent studies, appears to play a role in multiple regulatory pathways that may be important in certain diseases such as cancer or oxidative stress-related diseases
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
Get PDF“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
Get PDFWe 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
Get PDFWe 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
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