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- Avaliação da Qualidade Nutricional de Alimentos Processados de Base VegetalPublication . Moreira, Tiago; Motta, Carla; Figueira, Maria EduardoNos últimos anos, o consumo de dietas de base vegetal tem aumentado significativamente devido sobretudo ao aumento de evidência científica acerca dos benefícios deste tipo de alimentação, nomeadamente no que diz respeito ao combate às doenças não transmissíveis. Para além disso, verifica-se que a comercialização de produtos alimentares à base de plantas tem vindo a aumentar, apresentando-se como alternativa aos produtos de origem animal. O principal objetivo deste trabalho, foi a análise da qualidade nutricional, incluindo a qualidade proteica, de hambúrgueres veganos, prontos a comer, disponíveis na área da grande Lisboa. Para isso, procedeu-se à recolha da informação nutricional de hambúrgueres ultraprocessados (HUP) e à determinação dos macronutrientes, bem como de minerais, oligoelementos e aminoácidos, de forma a calcular a qualidade nutricional e proteica, em hambúrgueres prontos a comer (HPC) em restaurantes. Em relação, ao perfil nutricional dos HPC apresentam teores proteicos entre 13 gramas e 31 g/porção de alimento, enquanto nos HUP varia entre os 2,9 gramas e 30 gramas. Do ponto de vista da qualidade proteica os HPC apresentaram em todas as amostras os aminoácidos sulfurados como limitantes. Os teores de gordura encontram-se entre os 3,2 g/100g e 35 g/100g . No que diz respeito ao perfil em ácidos gordos, os saturados contribuem entre 2% e 28 % do aporte diário por 2000 Kcal. O teor de fibra contribui com 5% a 69% da dose diária recomendada de 25 g/dia. No que diz respeito ao sal, verificou-se um contributo para a dose recomendada de 5g diárias entre 23% a 75% para os HPC e 16% a 30% nos HUP. Existem no mercado muitos HUP e HPC cuja qualidade nutricional pode ser questionável. Com este trabalho esperamos contribuir para alertar para uma escolha informada e saudável, destes produtos, bem como na ajuda para a reformulação deste tipo de produto.
- Internal ribosome entry site-mediated translation of UPF1 contributes to its oncogenic role in colorectal cancerPublication . Lacerda, Rafaela; Menezes, Juliane; Elias, Adriana; Romão, LuísaColorectal cancer (CRC) is the third cause of death worldwide and projections point towards an increase for the next two decades. Many genes are misregulated in CRC, contributing to the development of the disease. Up-frameshift 1 (UPF1) is involved in many cellular mechanisms such as nonsense-mediated mRNA decay, cell cycle progression, or telomere maintenance and homeostasis. It also works as a tumour suppressor protein in most cancers but not in CRC, in which UPF1 plays an oncogenic role. We used the Xena platform to perform in silico analyses that revealed UPF1 is overexpressed in CRC contrary to several other analysed cancers. Besides, UPF1 expression levels are increased in CRC compared to the counterpart normal tissues. Experimentally, we confirmed these data and observed that endogenous UPF1 expression is maintained in different CRC cell lines under endoplasmic reticulum (ER) stress. To understand the mechanism underlying such maintenance, we used a bicistronic reporter construct to test whether UPF1 5’UTR can mediate alternative translation initiation and we concluded that such sequence contains an internal ribosome entry site (IRES) that maintains UPF1 expression in both normal and stress conditions in a 5’ cap-independent way. Deletional and mutational analysis of UPF1 5’UTR showed that nucleotides 1–100 (stem loop (SL) I) and 151–275 (SL III) — out of 275 nucleotides — are the minimal required sequences for the IRES to work properly. Using RNA antisense oligonucleotides (ASOs) targeting UPF1 IRES SL I and III, we observed a reduced UPF1 expression in HCT116 (CRC) cells. Altogether, these results suggest that UPF1 expression levels are maintained by the IRES-mediated translation mechanisms under conditions impairing canonical translation, such as those that mimic the tumour microenvironment. Thus, ASOs may be an upcoming therapy to target such alternative mechanism of translation initiation and prevent CRC development.
- Translational Regulation of the Human PERK by Upstream Open Reading FramesPublication . Fernandes, Rafael; Rodrigues, Rosário; Lopes, Pedro; Romão, LuísaUpstream open reading frames (uORFs) are cis-acting elements located within the 5’ leader sequence (5’UTR) of transcripts, which can regulate translation of the correspondent main open reading frame (mORF). During endoplasmic reticulum (ER) stress, the accumulation of unfolded proteins activates the ER-resident PKR-like ER kinase (PERK), which results in phosphorylation of eIF2α to inhibit global mRNA translation, while allowing the selective uORF-mediated translation of downstream effectors responsible for stress resolution or, ultimately, cell death. The dual role of PERK in regulating cell fate was implicated in human diseases, like diabetes, neurodegenerative disorders and cancer. Moreover, mutations in the EIF2AK3 gene (encoding PERK) were associated with the rare genetic disease, Wolcott-Rallison Syndrome (WRS). In this work, we aimed to study the translational regulatory role of 5 AUG- and 3 non-AUG-uORFs identified in the PERK 5’UTR and assess its biological relevance. While uORF2 and the non-AUG-uORFs 5, 6 and 7 (numbered according to their distance to the 5’ end of the mRNA) do not seem to have a regulatory role, uORF1, uORF3, uORF4 and uORF8 together present a strong repressive effect over mORF translation in basal conditions. Also, we observe that uORF1 is frequently translated allowing low levels of translation re-initiation at the main ORF. Curiously, we found that when PERK is overexpressed, it leads to the spontaneous activation of a portion of PERK in the absence of any stress stimulus, possibly highlighting the biological relevance of its uORF-mediated translational regulation. Conversely, during ER stress, increased bypass of uORF1 results in a modest degree of translational de-repression, which may help to counterbalance the increased rate of PERK protein turnover observed in these conditions. We also observed that alteration of the PERK uORFs by mutations found in WRS patients modify mORF expression, providing a possible link to the disease. Altogether, we highlight the importance of including 5’UTRs in the screening of disease-related mutations and the necessity of functional studies to assess their role in pathogenesis.
- Gene-environment interactions in Autism Spectrum Disorder (ASD)Publication . Santos, João Xavier; Vicente, Astrid Moura; Nunes, AnaAutism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental disorder characterized by deficits in social communication and interaction and repetitive and restricted behaviors. While heritability estimates support a role for gene-environment interactions in ASD etiology, there is a paucity of strategies that integrate both components. The objective of this work was to identify gene-environment interactions involved in ASD risk. Through a systematic literature review we identified neurotoxic xenobiotics previously implicated in ASD, including air pollutants and endocrine disruptors. Using a school-based screening strategy we provide an updated prevalence estimate for 7-9 years old children from Centro Region of Portugal, of 0.5% (95% CI: 0.3-0.7). Leveraging public air quality monitoring data we estimated early-life exposure to criteria air pollutants in 217 ASD-subjects, and show that exposure to particulate matter during critical neurodevelopmental windows is associated with a higher clinical severity of ASD. In silico inspection of large genetic datasets (N=6224) showed that ASD-subjects carry predicted-damaging variants in a panel of 77 genes involved in the regulation of detoxification and physiological barriers (blood-brain barrier and placenta) permeability (XenoReg genes). Database query indicates that these genes interact with ASD implicated xenobiotics. Through biochemical analyses of neonatal dried blood spots and the piloting of an early-life exposures assessment questionnaire we retrospectively collected environmental data for 70 ASD-children. The integration of environmental and sequencing data revealed a group of 13 patients for whom gene-environment interactions likely contributed to disease etiology. We present evidence that genetically-susceptible subjects might be at higher risk of ASD due to an increased vulnerability to early-life exposures. Possible underlying neuropathological mechanisms, including neuroinflammation, oxidative stress, endocrine disruption and epigenetics, warrant experimental validation. This work reinforces the need for clinical stratification and for monitoring early-life exposures, providing knowledge that, prospectively, may be translated to personalized medicine strategies applied in clinical practice.