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(Poly)phenol-digested metabolites modulate alpha-synuclein toxicity by regulating proteostasis

Publication . Macedo, Diana; Jardim, Carolina; Figueira, Inês; Almeida, A. Filipa; McDougall, Gordon J.; Stewart, Derek; Yuste, Jose E.; Tomás-Barberán, Francisco A.; Tenreiro, Sandra; Outeiro, Tiago; Santos, Cláudia N.

Parkinson's disease (PD) is an age-related neurodegenerative disease associated with the misfolding and aggregation of alpha-synuclein (aSyn). The molecular underpinnings of PD are still obscure, but nutrition may play an important role in the prevention, onset, and disease progression. Dietary (poly)phenols revert and prevent age-related cognitive decline and neurodegeneration in model systems. However, only limited attempts were made to evaluate the impact of digestion on the bioactivities of (poly)phenols and determine their mechanisms of action. This constitutes a challenge for the development of (poly)phenol-based nutritional therapies. Here, we subjected (poly)phenols from Arbutus unedo to in vitro digestion and tested the products in cell models of PD based on the cytotoxicity of aSyn. The (poly)phenol-digested metabolites from A. unedo leaves (LPDMs) effectively counteracted aSyn and H2O2 toxicity in yeast and human cells, improving viability by reducing aSyn aggregation and inducing its clearance. In addition, LPDMs modulated pathways associated with aSyn toxicity, such as oxidative stress, endoplasmic reticulum (ER) stress, mitochondrial impairment, and SIR2 expression. Overall, LPDMs reduced aSyn toxicity, enhanced the efficiency of ER-associated protein degradation by the proteasome and autophagy, and reduced oxidative stress. In total, our study opens novel avenues for the exploitation of (poly)phenols in nutrition and health.

2018Journal article

Open access

Serum levels of placental growth factor reflect the severity of retinopathy of prematurity

Publication . Almeida, Ana C.; Bitoque, Diogo B.; Martins, Catarina; Coelho, Constança; Borrego, Luís Miguel; Silva, Gabriela A.

Retinopathy of prematurity (ROP) is a neovascular disorder of the immature retina and a leading cause of preventable blindness worldwide.1 A two-phase hypothesis for ROP pathogenesis has been suggested.1 Phase one is vaso-obliteration, where physiological vascularity is compromised and retinal vascular development is delayed by a hyperoxic environment. This induces vasoconstriction, with decreased levels of vascular endothelial growth factor (VEGF) and insulin growth factor-1. Phase two is vasoproliferation, where the avascular retina becomes hypoxic and releases angiogenic factors. This can lead to increased angiogenesis, with abnormal proliferation of the retinal vessels into the vitreous culminating in a retinal detachment.1 Placental growth factor (PGF) is a member of the VEGF family. Its precise contribution to ocular angiogenesis is not understood,2 but it may be important in ROP.

2021Journal article

Restricted access

The prevalence of dementia in a Portuguese community sample : a 10/66 Dementia Research Group study

Publication . Pereira, Manuel Gonçalves; Cardoso, Ana; Verdelho, Ana; Silva, Joaquim Alves da; Almeida, Manuel Caldas de; Fernandes, Alexandra; Raminhos, Cátia; Ferri, Cleusa P.; Prina, A. Matthew; Prince, Martin; Xavier, Miguel

Background: Dementia imposes a high burden of disease worldwide. Recent epidemiological studies in European community samples are scarce. In Portugal, community prevalence data is very limited. The 10/66 Dementia Research Group (DRG) population-based research programmes are focused in low and middle income countries, where the assessments proved to be culture and education fair. We applied the 10/66 DRG prevalence survey methodology in Portugal, where levels of illiteracy in older populations are still high. Methods: A cross-sectional comprehensive one-phase survey was conducted of all residents aged 65 and over of two geographically defined catchment areas in Southern Portugal (one urban and one rural site). Nursing home residents were not included in the present study. Standardized 10/66 DRG assessments include a cognitive module, an informant interview and the Geriatric Mental State-AGECAT, providing data on dementia diagnosis and subtypes, mental disorders including depression, physical health, anthropometry, demographics, disability/functioning, health service utilization, care arrangements and caregiver strain. Results: We interviewed 1405 old age participants (mean age 74.9, SD = 6.7 years; 55.5% women) after 313 (18.2%) refusals to participate. The prevalence rate for dementia in community-dwellers was 9.23% (95% CI 7.80–10.90) using the 10/66 DRG algorithm and 3.65% (95% CI 2.97–4.97) using DSM-IV criteria. Pure Alzheimer’s disease was the most prevalent dementia subtype (41.9%). The prevalence of dementia was strongly age-dependent for both criteria, but there was no association with sex. Conclusions: Dementia prevalence was higher than previously reported in Portugal. The discrepancy between prevalence according to the 10/66 DRG algorithm and the DSM-IV criteria is consistent with that observed in less developed countries; this suggests potential underestimation using the latter approach, although relative validity of these two approaches remains to be confirmed in the European context. We improved the evidence base to raise awareness and empower advocacy about dementia in Portugal, so that the complex needs of frail older people may be met in better ways.

2017Journal article

Open access

Structural and biophysical insights into the mode of covalent binding of rationally designed potent BMX inhibitors

Publication . Seixas, João D.; Sousa, Bárbara B.; Marques, Marta C.; Guerreiro, Ana; Traquete, Rui; Rodrigues, Tiago; Albuquerque, Inês S.; Sousa, Marcos F. Q.; Lemos, Ana R.; Sousa, Pedro M. F.; Bandeiras, Tiago M.; Wu, Di; Doyle, Shelby K.; Robinson, Carol V.; Koehler, Angela N.; Corzana, Francisco; Matias, Pedro M.; Bernardes, Gonçalo J. L.

The bone marrow tyrosine kinase in chromosome X (BMX) is pursued as a drug target because of its role in various pathophysiological processes. We designed BMX covalent inhibitors with single-digit nanomolar potency with unexploited topological pharmacophore patterns. Importantly, we reveal the first X-ray crystal structure of covalently inhibited BMX at Cys496, which displays key interactions with Lys445, responsible for hampering ATP catalysis and the DFG-out-like motif, typical of an inactive conformation. Molecular dynamic simulations also showed this interaction for two ligand/BMX complexes. Kinome selectivity profiling showed that the most potent compound is the strongest binder, displays intracellular target engagement in BMX-transfected cells with two-digit nanomolar inhibitory potency, and leads to BMX degradation PC3 in cells. The new inhibitors displayed anti-proliferative effects in androgen-receptor positive prostate cancer cells that where further increased when combined with known inhibitors of related signaling pathways, such as PI3K, AKT and Androgen Receptor. We expect these findings to guide development of new selective BMX therapeutic approaches.

2020Journal article

Open access

Is the proteome of bronchoalveolar lavage extracellular vesicles a marker of advanced lung cancer?

Publication . Carvalho, Ana Sofia; Moraes, Maria Carolina Strano; Hyun Na, Chan; Fierro-Monti, Ivo; Henriques, Andreia; Zahedi, Sara; Bodo, Cristian; Tranfield, Erin M; Sousa, Ana Laura; Farinho, Ana; Rodrigues, Luís Vaz; Pinto, Paula; Bárbara, Cristina; Mota, Leonor; Abreu, Tiago Tavares de; Semedo, Júlio; Seixas, Susana; Kumar, Prashant; Costa-Silva, Bruno; Pandey, Akhilesh; Matthiesen, Rune

Acellular bronchoalveolar lavage (BAL) proteomics can partially separate lung cancer from non-lung cancer patients based on principal component analysis and multivariate analysis. Furthermore, the variance in the proteomics data sets is correlated mainly with lung cancer status and, to a lesser extent, smoking status and gender. Despite these advances BAL small and large extracellular vehicles (EVs) proteomes reveal aberrant protein expression in paracrine signaling mechanisms in cancer initiation and progression. We consequently present a case-control study of 24 bronchoalveolar lavage extracellular vesicle samples which were analyzed by state-of-the-art liquid chromatography-mass spectrometry (LC-MS). We obtained evidence that BAL EVs proteome complexity correlated with lung cancer stage 4 and mortality within two years´ follow-up (p value = 0.006). The potential therapeutic target DNMT3B complex is significantly up-regulated in tumor tissue and BAL EVs. The computational analysis of the immune and fibroblast cell markers in EVs suggests that patients who deceased within the follow-up period display higher marker expression indicative of innate immune and fibroblast cells (four out of five cases). This study provides insights into the proteome content of BAL EVs and their correlation to clinical outcomes.

2020Journal article

Open access