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CITED2 cooperates with ISL1 and promotes cardiac differentiation of mouse embryonic stem cells

Publication . Pacheco-Leyva, Ivette; Matias, Ana Catarina; Oliveira, Daniel V.; Santos, João; Nascimento, Rita; Guerreiro, Eduarda; Michell, Anna C.; van De Vrugt, Annebel M.; Machado-Oliveira, Gisela; Ferreira, Guilherme; Domian, Ibrahim; Bragança, José

The transcriptional regulator CITED2 is essential for heart development. Here, we investigated the role of CITED2 in the specification of cardiac cell fate from mouse embryonic stem cells (ESC). The overexpression of CITED2 in undifferentiated ESC was sufficient to promote cardiac cell emergence upon differentiation. Conversely, the depletion of Cited2 at the onset of differentiation resulted in a decline of ESC ability to generate cardiac cells. Moreover, loss of Cited2 expression impairs the expression of early mesoderm markers and cardiogenic transcription factors (Isl1, Gata4, Tbx5). The cardiogenic defects in Cited2-depleted cells were rescued by treatment with recombinant CITED2 protein. We showed that Cited2 expression is enriched in cardiac progenitors either derived from ESC or mouse embryonic hearts. Finally, we demonstrated that CITED2 and ISL1 proteins interact physically and cooperate to promote ESC differentiation toward cardiomyocytes. Collectively, our results show that Cited2 plays a pivotal role in cardiac commitment of ESC.

2016-12Journal article

Open Access

Context-dependent roles for lymphotoxin-beta receptor signaling in cancer development

Publication . Fernandes, Mónica T.; Dejardin, Emmanuel; Rodrigues Dos Santos, Nuno

The LT alpha(1)beta(2) and LIGHT TNF superfamily cytokines exert pleiotropic physiological functions through the activation of their cognate lymphotoxin-beta receptor (LT beta R). Interestingly, since the discovery of these proteins, accumulating evidence has pinpointed a role for LT beta R signaling in carcinogenesis. Early studies have shown a potential anti-tumoral role in a subset of solid cancers either by triggering apoptosis in malignant cells or by eliciting an anti-tumor immune response. However, more recent studies provided robust evidence that LT beta R signaling is also involved in diverse cell-intrinsic and microenvironment-dependent pro-oncogenic mechanisms, affecting several solid and hematological malignancies. Consequently, the usefulness of LT beta R signaling axis blockade has been investigated as a potential therapeutic approach for cancer. Considering the seemingly opposite roles of LT beta R signaling in diverse cancer types and their key implications for therapy, we here extensively review the different mechanisms by which LT beta R activation affects carcinogenesis, focusing on the diverse contexts and different models assessed. (C) 2016 Elsevier B.V. All rights reserved.

2016-04Journal article

Open Access

Behavior of pyrene as a polarity probe in palmitoylsphingomyelin and palmitoylsphingomyelin/cholesterol bilayers: A molecular dynamics simulation study

Publication . do Canto, António M. T. M.; Santos, Patrícia D.; Martins, Jorge; Loura, Luís M. S.

Pyrene is a polycyclic aromatic hydrocarbon noted for its remarkable optical spectroscopic properties. Among its uses as a fluorescent probe, measurement of lipid bilayer's equivalent polarity through the pyrene Ham effect stands out. To this effect, the ratio of the intensities of the first and third vibronic bands (I-1/I-3) in its emission spectrum of pyrene is measured. However, issues concerning the precise location of bilayer-inserted pyrene and the possibility of probe-induced perturbation of host bilayer properties are potential sources of concern in this regard. Atomistic molecular dynamics simulations constitute a useful method for the characterization of lipid membrane systems, and, in particular, to understand the behavior of fluorescence probes upon incorporation in lipid bilayers. In this report, we present a detailed characterization of the behavior of pyrene in fluid N-palmitoylsphingomyelin (PSM) and PSM/cholesterol membranes, with emphasis on the degree of proximity between the probe and water molecules inside bilayers, related to the use of pyrene to measure equivalent lipid bilayer polarity. It is concluded that pyrene exerts minor effects on bilayer properties, with slight local disordering being apparent for high cholesterol content. Whereas rotation and lateral diffusion of pyrene are greatly slowed in cholesterol rich systems, its relative transverse location is not significantly affected. While hydration of PSM bilayers, as sensed by pyrene, is already low compared to that of fluid phosphatidylcholine, it becomes even smaller for high cholesterol mole fraction at the studied temperature. (C) 2014 Elsevier B.V. All rights reserved.

2015-09Journal article

Open Access

Anti-acetylcholinesterase, antidiabetic, anti-inflammatory, antityrosinase and antixanthine oxidase activities of Moroccan propolis

Publication . EL-GEUNDOUZ, Soukaina; S, Azza; Lyoussi, Badiaa; Antunes, Maria Dulce; Faleiro, Maria Leonor; Miguel, Maria

Biological properties of Moroccan propolis have been scarcely studied. In the present work, the total phenols and flavonoids from 21 samples of propolis collected in different places of Morocco or 3 supplied in the market were determined, as well as the invitro capacity for inhibiting the activities of acetylcholinesterase, -glucosidase, -amylase, lipoxygenase, tyrosinase, xanthine oxidase and hyaluronidase. The results showed that samples 1 (region Fez-Boulemane, Sefrou city) (IC50=0.065, 0.006, 0.020, 0.050, 0.014mgmL(-1)) and 23 (marketed) (IC50=0.018, 0.002, 0.046, 0.037, 0.008mgmL(-1)) had the best invitro capacity for inhibiting the -amylase, -glucosidase, lipoxygenase, tyrosinase and xanthine oxidase activities, respectively. A negative correlation between IC50 values and concentration of phenols, flavones and flavanones was found. These activities corresponded to the generally higher amounts of phenols and flavonoids. In the same region, propolis samples have dissimilar phenol content and enzyme inhibitory activities.

2016-08Journal article

Open Access

The antibacterial, anti-biofilm, anti-inflammatory and virulence inhibition properties of Portuguese honeys

Publication . Silva, Carina Isabel da; S, Azza; Faleiro, Maria Leonor; Miguel, Maria; Neto, Luís

In Portugal, beekeeping activity has a significant weight among livestock production. The antimicrobial activities of Portuguese honeys have been reported, but the anti-biofilm formation and anti-virulence abilities have not been investigated. The main goal of this work was to study the impact of three monofloral honeys (citrus, lavender and strawberry tree) honeys on adherence of Staphylococcus aureus, methicillin-resistant S. aureus (MRSA) and Pseudomonas aeruginosa, as well as the influence of the same honeys on virulence using Galleria mellonella as a model. In addition, the general physico-chemical characterization of these honeys and the microbial quality were also performed. The anti-inflammatory activity was also estimated by analyzing the activity of the enzymes hyaluronidase and lipoxygenase. The tested honeys complied with European legislation and no microbial contamination was observed. Of all the honeys at 12.5 and 25%, w/v the citrus honey caused the highest inhibitory activity against P. aeruginosa. Strawberry tree honey at 25% w/v was able to significantly inhibit the MRSA strains. Anti-biofilm formation and anti-inflammatory activities were observed. The different honeys impaired the virulence of S. aureus and MRSA strains. The Portuguese honeys were capable of combating the tested bacterial pathogens not only by inhibiting their growth but also by affecting important pathogenicity properties, such as adherence and virulence.

2016Journal article

Open Access