Percorrer por autor "Portugal, Camila C."
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- Altered environmental perception by parental stress and depression vulnerability: impact on mothers and offspringPublication . Alves, Renata L.; Portugal, Camila C.; Lopes, Igor M.; Oliveira, Pedro; Alves, Cecília J.; Barbosa, Fernando; Summavielle, Teresa; Magalhães, Ana; Summavielle, TeresaDepressive mothers often find the mother-child interaction to be challenging. Parental stress may further impair mother-child attachment, which may increase the risk of negative developmental consequences. We used rats with different vulnerability to depression (Wistar and Kyoto) to investigate the impact of stress (maternal separationMS) on maternal behaviour and adolescent offspring cognition. MS in Kyoto dams increased pup-contact, resulting in higher oxytocin levels and lower anxiety-like behaviour after weaning, while worsening their adolescent offspring cognitive behaviour. Whereas MS in Wistar dams elicited higher quality of pup-directed behaviour, increasing Brain-Derived Neurotrophic Factor (BDNF) in the offspring, which seems to have prevented a negative impact on cognition. Hypothalamic oxytocin seems to impact the salience of the social environment cues (as negative for Kyoto) leading to different coping strategies. Our findings highlight the importance of contextual and individual factors in the understanding of the oxytocin role in modulating maternal behaviour and stress regulatory processes.
- Early-life stress affects drug abuse susceptibility in adolescent rat model independently of depression vulnerabilityPublication . Alves, Renata L.; Oliveira, Pedro; Lopes, Igor M.; Portugal, Camila C.; Alves, Cecília J.; Barbosa, Fernando; Summavielle, Teresa; Magalhães, AnaThe development of substance abuse problems occurs due to a diverse combination of risk factors. Among these risks, studies have reported depression and early-life stress as of importance. These two factors often occur simultaneously, however, there is a lack of understanding of how their combined effect may impact vulnerability to drug abuse in adolescence. The present study used rats with different vulnerability to depression (Wistar and Wistar-Kyoto) to investigate the impact of maternal separation (MS) on emotional state and drug addiction vulnerability during the adolescence period. Mothers and their litters were subjected to MS (180 min/day) from postnatal day 2 to 14. The offspring emotional state was assessed by observing their exploratory behavior. Drug abuse vulnerability was assessed through conditioning to cocaine. MS impacted the emotional state in both strains. Wistar responded with increased exploration, while Wistar-Kyoto increased anxiety-like behaviours. Despite the different coping strategies displayed by the two strains when challenged with the behavioural tests, drug conditioning was equally impacted by MS in both strains. Early-life stress appears to affect drug abuse vulnerability in adolescence independently of a depression background, suggesting emotional state as the main driving risk factor.
- Identification of Eschweilenol C in derivative of Terminalia fagifolia Mart. and green synthesis of bioactive and biocompatible silver nanoparticlesPublication . Araujo, Alyne Rodrigues de; Ramos-Jesus, Joilson; Oliveira, Taiane Maria de; Carvalho, Andressa Maria A. de; Nunes, Paulo Humberto M.; Daboit, Tatiane Caroline; Carvalho, Ana P.; Barroso, M. Fátima; Almeida, Miguel Peixoto de; Plácido, Alexandra; Rodrigues, Artur; Portugal, Camila C.; Socodato, Renato; Relvas, João B.; Delerue-Matos, Cristina; Silva, Durcilene Alves da; Eaton, Peter; Leite, José Roberto de Souza de A.A green synthetic route was developed to prepare silver nanoparticles (AgNPs) in aqueous solution for biological applications. Eschweilenol C, a compound derivative ellagic acid was identified as the main constituent of the aqueous fraction of the ethanolic extract of Terminalia fagifolia Mart. by NMR analysis. In the green synthesis, the ethanolic extract of T. fagifolia and its aqueous fraction were used to promote silver reduction and nanoparticle stabilization. The synthesized AgNPs presented a spherical or polygonal morphology shape by TEM analysis and AgNPs showed high levels of antioxidant and considerable antibacterial and antifungal activities. Synthesized nanoparticles presented significant antioxidant activity by sequestration of DPPH and ABTS radicals, in addition to iron reduction (FRAP assay) and measurement of antioxidant capacity in ORAC units, in addition, AgNP synthesized with the aqueous fraction also demonstrated antioxidant potential in microglial cells. Gram-positive and Gram-negative bacteria were susceptible to growth inhibition by the nanoparticles, among which the AgNPs formed by the ethanolic extract was the most effective. The data obtained by AFM images suggested that AgNPs could lead to the lysis of bacteria and subsequent death. The antifungal assays showed high efficiency against yeasts and dermatophytes. This work represents the first description of antifungal activity by AgNPs against Fonsecaea pedrosoi, the etiologic agent of chromoblastomycosis. In relation to biocompatibility, the AgNPs induced lower haemolysis than AgNO3.
- Maternal stress and vulnerability to depression: coping and maternal care strategies and its consequences on adolescent offspringPublication . Alves, Renata L.; Portugal, Camila C.; Lopes, Igor M.; Oliveira, Pedro; Alves, Cecília J.; Barbosa, Fernando; Summavielle, Teresa; Magalhães, AnaDepressive mothers often find mother-child interaction to be challenging. Maternal stress may further impair mother-child attachment, which may increase the risk of negative developmental consequences. We used rats with different vulnerability to depressive-like behavior (Wistar and Kyoto) to investigate the impact of stress (maternal separation-MS) on maternal behavior and adolescent offspring cognition. MS in Kyoto dams increased pup-contact, resulting in higher oxytocin levels and lower anxiety-like behavior after weaning, while worsening their adolescent offspring cognitive behavior. Whereas MS in Wistar dams elicited higher quality of pup-directed behavior, increasing brain-derived neurotrophic factor (BDNF) in the offspring, which seems to have prevented a negative impact on cognition. Hypothalamic oxytocin seems to affect the salience of the social environment cues (negatively for Kyoto) leading to different coping strategies. Our findings highlight the importance of contextual and individual factors in the understanding of the oxytocin role in modulating maternal behavior and stress regulatory processes.
- Microglia dysfunction caused by the loss of rhoa disrupts neuronal physiology and leads to neurodegenerationPublication . Socodato, Renato; Portugal, Camila C.; Canedo, Teresa; Rodrigues, Artur; Almeida, Tiago O.; Henriques, Joana F.; Vaz, Sandra H.; Magalhães, João; Silva, Cátia M.; Baptista, Filipa I.; Alves, Renata L.; Coelho-Santos, Vanessa; Silva, Ana Paula; Paes-de-Carvalho, Roberto; Magalhães, Ana; Brakebusch, Cord; Sebastião, Ana M.; Summavielle, Teresa; Ambrósio, António F.; Relvas, João B.Nervous tissue homeostasis requires the regulation of microglia activity. Using conditional gene targeting in mice, we demonstrate that genetic ablation of the small GTPase Rhoa in adult microglia is sufficient to trigger spontaneous microglia activation, producing a neurological phenotype (including synapse and neuron loss, impairment of long-term potentiation [LTP], formation of β-amyloid plaques, and memory deficits). Mechanistically, loss of Rhoa in microglia triggers Src activation and Src-mediated tumor necrosis factor (TNF) production, leading to excitotoxic glutamate secretion. Inhibiting Src in microglia Rhoa-deficient mice attenuates microglia dysregulation and the ensuing neurological phenotype. We also find that the Rhoa/Src signaling pathway is disrupted in microglia of the APP/PS1 mouse model of Alzheimer disease and that low doses of Aβ oligomers trigger microglia neurotoxic polarization through the disruption of Rhoa-to-Src signaling. Overall, our results indicate that disturbing Rho GTPase signaling in microglia can directly cause neurodegeneration.
- Microglial RAC1 drives experience-dependent brain plasticityPublication . Almeida, Tiago O.; Portugal, Camila C.; Santos, Evelyn C. S.; Moreira, Joana Tedim; Ferreira, João Galvão; Canedo, Teresa; Magalhães, Ana; Summavielle, Teresa; Summavielle, TeresaMicroglia, the immune defenders of the brain, continuously extend and retract their processes to sense and decipher their local environment. This includes interactions with synapses to maintain brain homeostasis. To do this, microglia rely on the actin cytoskeleton and subsequent intracellular signaling, which is adapted in response to external signals released by cells undergoing intense synaptic activity. Thus, proteins that regulate actin cytoskeleton dynamics, intracellular trafficking, and integration of extracellular signaling, such as RhoA, Rac1 and Cdc42 from the Rho GTPase family, are good candidates to govern microglial sensing capacity and homeostasis. In this study, using conditional cellspecific gene targeting in mice combined with multi-omics approaches, immunofluorescence, and behavioral tests we aimed to identify the roles of Rho GTPase Rac1 in microglia homeostasis. We demonstrate that the Rho GTPase Rac1 is essential for microglia to sense and interpret their local microenvironment. This impacts the microglia-synapse crosstalk that is required for experiencedependent plasticity, a fundamental brain property impaired in several neuropsychiatric disorders. Furthermore, phosphoproteomics profiling of microglia isolated from mice exposed to an environmental enrichment protocol (known to induce experience-dependent synaptic plasticity and cognitive performance) detects a large modulation of Rho GTPase signaling, predominantly of Rac1. Additionally, our results show that environmental enrichment likely requires tight regulation of Rho GTPase-dependent pathways. Ablation of microglial Rac1 affected pathways involved in microglia-synapse communication, disrupted experience-dependent synaptic remodeling and blocked the gains in learning, memory, and sociability induced by environmental enrichment. Overall, our results place microglial Rac1 as a central regulator of pathways involved in the microglia-synapse crosstalk required for experience-dependent synaptic plasticity and cognitive performance, suggesting that modulation of Rho GTPase signaling in microglia might be a useful strategy to boost neuroplasticity in health and disease.
- Microglial Rac1 is essential for experience-dependent brain plasticity and cognitive performancePublication . Socodato, Renato; Almeida, Tiago O.; Portugal, Camila C.; Santos, Evelyn C.S.; Tedim-Moreira, Joana; Ferreira, João Galvão; Canedo, Teresa; Baptista, Filipa I.; Magalhães, Ana; Ambrósio, António F.; Brakebusch, Cord; Rubinstein, Boris; Moreira, Irina S.; Summavielle, Teresa; Pinto, Inês Mendes; Relvas, João B.Microglia, the largest population of brain immune cells, continuously interact with synapses to maintain brain homeostasis. In this study, we use conditional cell-specific gene targeting in mice with multi-omics approaches and demonstrate that the RhoGTPase Rac1 is an essential requirement for microglia to sense and interpret the brain microenvironment. This is crucial for microglia-synapse crosstalk that drives experience-dependent plasticity, a fundamental brain property impaired in several neuropsychiatric disorders. Phosphoproteomics profiling detects a large modulation of RhoGTPase signaling, predominantly of Rac1, in microglia of mice exposed to an environmental enrichment protocol known to induce experience-dependent brain plasticity and cognitive performance. Ablation of microglial Rac1 affects pathways involved in microglia-synapse communication, disrupts experience-dependent synaptic remodeling, and blocks the gains in learning, memory, and sociability induced by environmental enrichment. Our results reveal microglial Rac1 as a central regulator of pathways involved in the microglia-synapse crosstalk required for experience-dependent synaptic plasticity and cognitive performance.
- Microglial Rac1 is essential for microglia-synapse crosstalk and cognitive performancePublication . Almeida, Tiago O.; Socodato, Renato; Portugal, Camila C.; Santos, Evelyn C. S.; Moreira, Joana Tedim; Ferreira, João Galvão; Canedo, Teresa; Magalhães, Ana; Summavielle, Teresa; Relvas, João B.; Summavielle, TeresaMicroglia, the main immune defenders of the brain, rapidly detect and react to stimuli due to constant extension andretraction of their processes. When engaged by external cues, that can be either inflammatory or products resulting from synaptic activity, microglia dramatically change their morphology and initiate a response to reestablish brain homeostasis. Additionally, microglia can also regulate and sustain synaptic activity by secreting a plethora of factors. While some of these factors are already described, there is still much to understand on how exactly microglia-secreted factors modulate synaptic function. Rac1, a well-known member of the Rho GTPase family, is a critical regulator of actin cytoskeleton dynamics and reorganization. Furthermore, Rac1 is a component of NADPH oxidase complex, a key element for phagocytic cup formation and it also regulates NF-κB pathway activation. In the central nervous system (CNS), Rac1 is involved in axon guidance and growth, but it is also linked with Alzheimer´s disease,since it regulates the expression of amyloid precursor protein in hippocampal neurons. Although extensively studied in other cell types in and outside of the CNS, there is a profound knowledge gap on how Rac1 regulates microglia function in homeostasis and in response to external stimuli. Combining cell-specific conditional gene ablation, RNAseq, flow cytometry, immunofluorescence, proteomics and phosphoproteomics, FRET live cell imaging and mouse behavior, we aimed at describing for the first time Rac1 roles in microglial function. We observed that microglia specific Rac1 ablation impaired the capacity of microglia to sense and respond to changes in their local environment. To promote changes on the brain environment, we performed a protocol of environmental enrichment (EE), mimicking currently used therapeutic approaches for enhancing brain plasticity in patients with brain disorders. EE had a profound impact on the microglial phosphoproteomic landscape, showing a strong effect on Rho GTPase signaling. Interestingly, we showed that Rac1 signaling was the most significantly altered pathway, followed by Cdc42 and RhoA signaling, allowing us to define a hierarchy between them. Besides, EE led to an overall improvement of cognitive performance. Strikingly, ablating Rac1 from microglia completely prevented this EE-dependent cognitive enhancement and disrupted microglia-synapse crosstalk, ultimately impacting the synaptic proteomic and phosphoproteomic profiles of these mice. Overall, this is a first step into understanding how Rac1 mediates microglial responses to their local environment. This places Rac1 as anessential target for further studies and reinforces the importance of Rho GTPases signaling for adult microglial function.
- Structure and function of a novel antioxidant peptide from the skin of tropical frogsPublication . Barbosa, Eder Alves; Oliveira, Ana; Plácido, Alexandra; Socodato, Renato; Portugal, Camila C.; Mafud, Ana Carolina; Ombredane, Alicia S.; Moreira, Daniel C.; Vale, Nuno; Bessa, Lucinda J.; Joanitti, Graziella A.; Alves, Cláudia; Gomes, Paula; Delerue-Matos, Cristina; Mascarenhas, Yvonne Primerano; Marani, Mariela M.; Relvas, João B.; Pintado, Manuela; Leite, José Roberto S.A.The amphibian skin plays an important role protecting the organism from external harmful factors such as microorganisms or UV radiation. Based on biorational strategies, many studies have investigated the cutaneous secretion of anurans as a source of bioactive molecules. By a peptidomic approach, a novel antioxidant peptide (AOP) with in vitro free radical scavenging ability was isolated from Physalaemus nattereri. The AOP, named antioxidin-I, has a molecular weight [M+H]+ = 1543.69Da and a TWYFITPYIPDK primary amino acid sequence. The gene encoding the antioxidin-I precursor was expressed in the skin tissue of three other Tropical frog species: Phyllomedusa tarsius, P. distincta and Pithecopus rohdei. cDNA sequencing revealed highly homologous regions (signal peptide and acidic region). Mature antioxidin-I has a novel primary sequence with low similarity compared with previously described amphibian's AOPs. Antioxidin-I adopts a random structure even at high concentrations of hydrophobic solvent, it has poor antimicrobial activity and poor performance in free radical scavenging assays in vitro, with the exception of the ORAC assay. However, antioxidin-I presented a low cytotoxicity and suppressed menadione-induced redox imbalance when tested with fibroblast in culture. In addition, it had the capacity to substantially attenuate the hypoxia-induced production of reactive oxygen species when tested in hypoxia exposed living microglial cells, suggesting a potential neuroprotective role for this peptide.