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Projeto de investigação
iNOVA4Health - Programme in Translational Medicine (iBET, CEDOC/FCM, IPOLFG e ITQB)
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Publicações
Glycation modulates glutamatergic signaling and exacerbates Parkinson’s disease-like phenotypes
Publication . Chegão, Ana; Guarda, Mariana; Alexandre, Bruno M.; Shvachiy, Liana; Temido Ferreira, Mariana; Marques-Morgado, Inês; Fernandes Gomes, Bárbara; Matthiesen, Rune; Lopes, Luisa V.; Florindo, Pedro R.; Gomes, Ricardo A.; Gomes-Alves, Patrícia; Coelho, Joana E; Outeiro, Tiago; Vicente Miranda, Hugo
Alpha-synuclein (aSyn) is a central player in the pathogenesis of synucleinopathies due to its accumulation in typical protein aggregates in the brain. However, it is still unclear how it contributes to neurodegeneration. Type-2 diabetes mellitus is a risk factor for Parkinson's disease (PD). Interestingly, a common molecular alteration among these disorders is the age-associated increase in protein glycation. We hypothesized that glycation-induced neuronal dysfunction is a contributing factor in synucleinopathies. Here, we dissected the impact of methylglyoxal (MGO, a glycating agent) in mice overexpressing aSyn in the brain. We found that MGO-glycation potentiates motor, cognitive, olfactory, and colonic dysfunction in aSyn transgenic (Thy1-aSyn) mice that received a single dose of MGO via intracerebroventricular injection. aSyn accumulates in the midbrain, striatum, and prefrontal cortex, and protein glycation is increased in the cerebellum and midbrain. SWATH mass spectrometry analysis, used to quantify changes in the brain proteome, revealed that MGO mainly increase glutamatergic-associated proteins in the midbrain (NMDA, AMPA, glutaminase, VGLUT and EAAT1), but not in the prefrontal cortex, where it mainly affects the electron transport chain. The glycated proteins in the midbrain of MGO-injected Thy1-aSyn mice strongly correlate with PD and dopaminergic pathways. Overall, we demonstrated that MGO-induced glycation accelerates PD-like sensorimotor and cognitive alterations and suggest that the increase of glutamatergic signaling may underly these events. Our study sheds new light into the enhanced vulnerability of the midbrain in PD-related synaptic dysfunction and suggests that glycation suppressors and anti-glutamatergic drugs may hold promise as disease-modifying therapies for synucleinopathies.
Nanofertilizer use for adaptation and mitigation of the agriculture/climate change dichotomy effects
Publication . Saraiva, Raquel; Ferreira, Quirina; Rodrigues, Gonçalo C.; Oliveira, Margarida
Agriculture is considered a significant climate change (CC) driver due to greenhouse gas
(GHG) emissions and the loss of fertilizers that contribute to water eutrophication. On the other
hand, climate change effects are already impacting agriculture, endangering food security. This paper
explores the dichotomies of the effects of agriculture on CC as well as of CC on agriculture, focusing
on the contribution that nanofertilizers can bring to this complex system in both directions. The
strategies to reduce CC while adapting and mitigating its effects must be a global effort. It is not
possible to focus only on the reduction in GHG emissions to stop the effects that are already being
felt worldwide. Nanofertilizers, especially slow- and controlled-release nanofertilizers, can reduce
the nutrient input and also boost productivity while mitigating some CC effects, such as soil nutrient
imbalance and agricultural emissions. As so, this review highlights the benefits of nanofertilizers and
their role as a part of the strategy to reduce the reach of CC and mitigate its ever-growing effects, and
presents some guidelines for the increased use of these materials in order to enhance their efficacy in
this strategy.
Therapeutic targeting of PD-1/PD-L1 blockade by novel small-molecule inhibitors recruits cytotoxic T cells into solid tumor microenvironment
Publication . Acúrcio, Rita C; Pozzi, Sabina; Carreira, Barbara; Pojo, Marta; Gómez-Cebrián, Nuria; Casimiro, Sandra; Fernandes, Adelaide; Barateiro, Andreia; Farricha, Vitor; Soares Do Brito, Joaquim; Leandro, P; Salvador, Jorge A. R.; Graca, Luis; Puchades-Carrasco, Leonor; Costa, Luis; Satchi-Fainaro, Ronit; Guedes, R. C.; Florindo, Helena F
Background: Inhibiting programmed cell death protein 1 (PD-1) or PD-ligand 1 (PD-L1) has shown exciting clinical outcomes in diverse human cancers. So far, only monoclonal antibodies are approved as PD-1/PD-L1 inhibitors. While significant clinical outcomes are observed on patients who respond to these therapeutics, a large proportion of the patients do not benefit from the currently available immune checkpoint inhibitors, which strongly emphasize the importance of developing new immunotherapeutic agents.
Methods: In this study, we followed a transdisciplinary approach to discover novel small molecules that can modulate PD-1/PD-L1 interaction. To that end, we employed in silico analyses combined with in vitro, ex vivo, and in vivo experimental studies to assess the ability of novel compounds to modulate PD-1/PD-L1 interaction and enhance T-cell function.
Results: Accordingly, in this study we report the identification of novel small molecules, which like anti-PD-L1/PD-1 antibodies, can stimulate human adaptive immune responses. Unlike these biological compounds, our newly-identified small molecules enabled an extensive infiltration of T lymphocytes into three-dimensional solid tumor models, and the recruitment of cytotoxic T lymphocytes to the tumor microenvironment in vivo, unveiling a unique potential to transform cancer immunotherapy.
Conclusions: We identified a new promising family of small-molecule candidates that regulate the PD-L1/PD-1 signaling pathway, promoting an extensive infiltration of effector CD8 T cells to the tumor microenvironment.
Dietary (poly)phenols in traumatic brain injury
Publication . Carecho, Rafael; Carregosa, Diogo; Ratilal, Bernardo; Figueira, Inês; Ávila-Gálvez, Maria Angeles; dos Santos, Cláudia Nunes; Loncarevic-Vasiljkovic, Natasa
Traumatic brain injury (TBI) remains one of the leading causes of death and disability in young adults worldwide. Despite growing evidence and advances in our knowledge regarding the multifaceted pathophysiology of TBI, the underlying mechanisms, though, are still to be fully elucidated. Whereas initial brain insult involves acute and irreversible primary damage to the brain, the processes of subsequent secondary brain injury progress gradually over months to years, providing a window of opportunity for therapeutic interventions. To date, extensive research has been focused on the identification of druggable targets involved in these processes. Despite several decades of successful pre-clinical studies and very promising results, when transferred to clinics, these drugs showed, at best, modest beneficial effects, but more often, an absence of effects or even very harsh side effects in TBI patients. This reality has highlighted the need for novel approaches that will be able to respond to the complexity of the TBI and tackle TBI pathological processes on multiple levels. Recent evidence strongly indicates that nutritional interventions may provide a unique opportunity to enhance the repair processes after TBI. Dietary (poly)phenols, a big class of compounds abundantly found in fruits and vegetables, have emerged in the past few years as promising agents to be used in TBI settings due to their proven pleiotropic effects. Here, we give an overview of the pathophysiology of TBI and the underlying molecular mechanisms, followed by a state-of-the-art summary of the studies that have evaluated the efficacy of (poly)phenols administration to decrease TBI-associated damage in various animal TBI models and in a limited number of clinical trials. The current limitations on our knowledge concerning (poly)phenol effects in TBI in the pre-clinical studies are also discussed.
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Entidade financiadora
Fundação para a Ciência e a Tecnologia
Programa de financiamento
6817 - DCRRNI ID
Número da atribuição
UIDB/04462/2020