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- N-Acetylcysteine treatment may compensate motor impairments through dopaminergic transmission modulation in a striatal 6-Hydroxydopamine Parkinson’s disease rat modelPublication . Caridade-Silva, Rita; Araújo, Bruna; Martins-Macedo, Joana; Teixeira, Fábio G.Preventing degeneration and the loss of dopaminergic neurons (DAn) in the brain while mitigating motor symptoms remains a challenge in Parkinson’s Disease (PD) treatment development. In light of this, developing or repositioning potential disease-modifying approaches is imperative to achieve meaningful translational gains in PD research. Under this concept, N-acetylcysteine (NAC) has revealed promising perspectives in preserving the dopaminergic system capability and modulating PD mechanisms. Although NAC has been shown to act as an antioxidant and (neuro)protector of the brain, it has yet to be acknowledged how this repurposed drug can improve motor symptomatology and provide disease-modifying properties in PD. Therefore, in the present work, we assessed the impact of NAC on motor and histological deficits in a striatal 6-hydroxydopamine (6-OHDA) rat model of PD. The results revealed that NAC enhanced DAn viability, as we found that it could restore dopamine transporter (DAT) levels compared to the untreated 6-OHDA group. Such findings were positively correlated with a significant amelioration in the motor outcomes of the 6-OHDA-treated animals, demonstrating that NAC may, somehow, be a modulator of PD degenerative mechanisms. Overall, we postulated a proof-of-concept milestone concerning the therapeutic application of NAC. Nevertheless, it is extremely important to understand the complexity of this drug and how its therapeutical properties interact with the cellular and molecular PD mechanisms.
- Glial-restricted precursors stimulate endogenous cytogenesis and effectively recover emotional deficits in a model of cytogenesis ablationPublication . Martins-Macedo, Joana; Araújo, Bruna; Anjo, Sandra I.; Silveira-Rosa, Tiago; Patrício, Patrícia; Alves, Nuno Dinis; Silva, Joana M.; Teixeira, Fábio G.; Manadas, Bruno; Rodrigues, Ana J.; Lepore, Angelo C.; Salgado, António J.; Gomes, Eduardo D.; Pinto, Luísa; Gomes, EduardoAdult cytogenesis, the continuous generation of newly-born neurons (neurogenesis) and glial cells (gliogenesis) throughout life, is highly impaired in several neuropsychiatric disorders, such as Major Depressive Disorder (MDD), impacting negatively on cognitive and emotional domains. Despite playing a critical role in brain homeostasis, the importance of gliogenesis has been overlooked, both in healthy and diseased states. To examine the role of newly formed glia, we transplanted Glial Restricted Precursors (GRPs) into the adult hippocampal dentate gyrus (DG), or injected their secreted factors (secretome), into a previously validated transgenic GFAP-tk rat line, in which cytogenesis is transiently compromised. We explored the long-term effects of both treatments on physiological and behavioral outcomes. Grafted GRPs reversed anxiety-like deficits and demonstrated an antidepressant-like effect, while the secretome promoted recovery of only anxiety-like behavior. Furthermore, GRPs elicited a recovery of neurogenic and gliogenic levels in the ventral DG, highlighting the unique involvement of these cells in the regulation of brain cytogenesis. Both GRPs and their secretome induced significant alterations in the DG proteome, directly influencing proteins and pathways related to cytogenesis, regulation of neural plasticity and neuronal development. With this work, we demonstrate a valuable and specific contribution of glial progenitors to normalizing gliogenic levels, rescuing neurogenesis and, importantly, promoting recovery of emotional deficits characteristic of disorders such as MDD.
- From peripheral to central (Neuro)degeneration: Is heart-kidney a new axial paradigm for Parkinson’s disease?Publication . Teixeira, Catarina; Caridade-Silva, Rita; Martins-Macedo, Joana; Araújo, Bruna; Gomes, Eduardo; Vilela, Cristiana; Soares-Guedes, Carla; Pires, Inês Falcão; Alencastre, Inês; G. Teixeira, Fábio; Gomes, EduardoParkinson’s Disease (PD) is primarily characterized by the accumulation of alpha-synuclein (αSyn) and the loss of dopaminergic neurons (DAn). The most evident repercussions of the disease include sympathetic and parasympathetic dysfunction, decreased dopamine (DA) levels, and impaired voluntary movements. Given the multifactorial nature of PD, it is now recognized that several systemic diseases may predispose individuals to the onset and progression of PD as well as influence its therapeutic outcomes. Recent studies have highlighted that patients with cardiovascular disease (CVD) and chronic kidney disease (CKD) face an increased risk of developing PD, independent of the shared risk factors. Indeed, substantial evidence supports the connections between the brain, heart, and kidneys. Elements such as the dopaminergic system, blood pressure regulation, inflammation, autophagy, oxidative stress, and calcium (Ca2+) signaling are recognized as crucial for the functioning of each organ individually. However, these factors may also significantly impact the overall health of the triad. Understanding the interconnection between the brain, heart, and kidneys would be groundbreaking in enhancing our knowledge about their interactions, enabling prompt interventions in the early stages of the disease. With this perspective, this review analyzes the current understanding of the brain-heart-kidney axis as a potential new paradigm for diagnosing and managing PD.
- Estrogen receptor beta agonist influences presynaptic NMDA receptor distribution in the paraventricular hypothalamic nucleus following hypertension in a mouse model of perimenopausePublication . Sommer, Garrett; López, Claudia Rodríguez; Hirschkorn, Adi; Calimano, Gianna; Marques-Lopes, Jose; Milner, Teresa A.; Glass, Michael J.As women transition to menopause (i.e., perimenopause), they become more susceptible to hypertension. Animal studies using a mouse model of peri-menopause (peri-AOF) have revealed that hypertension susceptibility is associated with increased postsynaptic glutamatergic NMDA receptor plasticity in the paraventricular hypothalamic nucleus (PVN), a brain area critical for blood pressure regulation. The aim of this study was to determine if presynaptic NMDA receptors also play a role in neural plasticity in peri-AOF hypertension susceptibility. For comparison, males were also studied. Following slow pressor Angiotensin II (AngII), both peri-AOF and male mice became hypertensive; however, peri-AOF females showed higher cytoplasmic NMDA receptor levels. To determine the involvement of estrogen signaling in AngII-induced hypertension, an estrogen receptor beta (ERß) agonist was co-administered. In peri-AOF females, but not males, activation of ERß blocked hypertension and increased NMDA receptors on the membrane of axon terminals where it would be more available for binding of glutamate. These results indicate that sex-dependent recruitment of presynaptic NMDA receptors in the PVN is influenced by ERß signaling in a mouse model of perimenopause.
- Vascular dysfunction in adipose tissue: Its impact on type 2 diabetes and cancerPublication . Silva, Daniela Rosendo; Aguiar, Gonçalo; Luís, Carla; Soares, Raquel; Coelho, Pedro; Coelho, PedroThe overgrowth of adipose tissue is a major trigger for the development of other metabolic disorders, like insulin resistance, hypertension, type 2 diabetes, cardiovascular disease, and cancer. Among the causes of this association lies the fact that increased adiposity is accompanied by a nonfunctioning vascular component. Accordingly, vascular dysfunction within the adipose tissue is common in obesity and associated with deregulated metabolic cues such as decreased nitric oxide (NO), increased oxidative stress and hypoxia. These will result in metabolic comorbidities, which ultimately may end up in type 2 diabetes and cancer. The current study addresses the state-of-the-art regarding the mechanisms involved, focusing on two diseases with huge prevalence worldwide: type 2 diabetes and cancer. Understanding how adipose tissue vascular dysfunction impacts on metabolic disease is of paramount importance and may lead to innovative therapeutic approaches.
- Eco‑friendly cleaning agent applied for ex situ remediation of beach sand contaminated with crude oilPublication . Santos, Adriana Vieira dos; Santos, Verena Filgueiras Borges dos; Fernandes, Virgínia Cruz; Figueiredo, Sónia Adriana; Grosso, Clara; Delerue‑Matos, Cristina; Simonelli, George; Santos, Luiz Carlos Lobato dos; Fernandes, VirgíniaCoastal oil spills cause significant adverse effects, and removing weathered crude oil mixed with sand remains a considerable challenge. To address this, an environmentally friendly cleaning agent was formulated using a vegetable oil-based microemulsion for sediment cleaning. The relationship between microemulsion composition and its efficiency in cleaning oil-contaminated sediments in coastal environments was investigated. Component selection followed criteria of low toxicity and high biodegradability, including pine oil as the oily phase, distilled water as the aqueous phase, saponified coconut oil as the surfactant, and isopropyl alcohol as the cosurfactant. Pseudoternary phase diagrams were constructed using a cosurfactant/surfactant ratio of 10. The microemulsified cleaning agents were characterized and optimized using Scheffé's simplex lattice design, with refractive index, viscosity, conductivity, and specific gravity as response variables. Biodegradable microemulsion systems were successfully applied to remediate oil-contaminated beach sand, where higher proportions of the oily phase, specifically 30% and 60%, demonstrated excellent oil removal performance. The remediation process effectively incorporated the crude oil contaminant into the oily phase of the microemulsion, achieving a maximum removal efficiency of 90%. Additionally, the microemulsion exhibited stability for 30 days and maintained efficiency for up to five reuse cycles. This study highlights the potential of environmentally friendly microemulsions derived from vegetable oils for effective remediation of beach sand contaminated with crude oil, particularly through in situ soil washing or soil flushing, reinforcing the viability and sustainability of these cleaning agents.
- Sustainable carotenoid extraction from macroalgae: Optimizing microwave-assisted extraction using response surface methodologyPublication . Lopes, Andreia; Correia-Sá, Luísa; Vieira, Mónica; Delerue-Matos, Cristina; Soares, Cristina; Grosso, Clara; Vieira, MónicaThis study aimed at optimizing carotenoid extraction using the macroalga Himanthalia elongata (L.) S.F.Gray as a model. Firstly, traditional extraction procedures were employed, using various solvents and temperatures to enhance the extraction conditions. Once the most effective extraction conditions were identified, the study transitioned to a more efficient and environmentally friendly approach, microwave-assisted extraction (MAE). By applying a three-parameter (solid-tosolvent ratio, temperature, and time) Box–Behnken design, the optimal extraction conditions were found to be a solid-to-solvent ratio of 1/13.6 g/mL at 60 ◦C for 15 min. Under these conditions, the predicted and experimental carotenoid contents were 2.94 and 2.12 µg/mL, respectively. Furthermore, an HPLC-DAD method was developed and validated for the characterization of carotenoids. βCarotene was the predominant carotenoid in H. elongata, alongside fucoxanthin. The optimized MAE method was applied to other seaweeds, including Fucus vesiculosus L., Codium tomentosum Stackhouse, Gracilaria gracilis (Stackhouse) Steentoft, L.M.Irvine & Farnham, and Eiseinia bicyclis (Kjellman) Setchell. Among all, F. vesiculosus exhibited the highest carotenoid content compared to the others. This study concludes that MAE under optimized conditions is an effective and sustainable approach for carotenoid extraction, providing significant yields of bioactive compounds such as β-carotene and fucoxanthin, which have promising applications in enhancing human health and nutrition.
- High efficacy of chloroquine-derived bile salts in Pluronic F127 micelles against blood-stage Plasmodium falciparumPublication . Silva, Ana Teresa; Prudêncio, Miguel; Oliveira, Isabel S.; Nogueira, Fátima; Morais, Inês; Santana, Sofia; Ferraz, Ricardo; Workneh, Eyob A.; Gomes, Paula; Marques, Eduardo F.; Ferraz, RicardoColloidal nanocarriers can play a key role in the efficacious delivery of drugs, including antimalarials. Here, we investigated the ability of polymeric micelles of the block copolymer F127 to act as nanovehicles for two organic salts derived from chloroquine and human bile acids, namely, chloroquinium cholate (iCQP1) and chloroquinium glycocholate (iCQP1g). We have previously reported the strong in vitro antiplasmodial activity of these salts, which displayed IC50 values of 13 and 15 nM against blood forms of Plasmodium falciparum, respectively. By deriving from amphiphilic lipids, iCQP1 and iCQP1g also enclose the ability to act as surface-active ionic liquids (SAILs). The micellization properties of neat F127 and of the F127/SAIL mixtures were initially investigated to gain physicochemical insight into the interaction between polymer and bioactive SAILs, resorting to differential scanning calorimetry, surface tension measurements and dynamic light scattering. Micelle formation by F127 is an endothermic process strongly temperature and concentration dependent. Interestingly, this process is significantly changed when the molar fraction of SAIL (xSAIL) in the F127/SAIL mixture is varied between 0.33 and 0.90. Both SAILs favor the formation of mixed micelles by decreasing the micellization temperature, and (observed only when for xSAIL = 0.33) by synergistically decreasing the cmc. Concomitantly, the micellar size is reduced from 18 to 13 nm as xSAIL is increased from 0.33 to 0.90. Crucially, in vitro assays show that when the SAILs are loaded into F127 polymeric micelles, their antiplasmodial efficacy is substantially enhanced, with a significant drop in IC50, especially for the iCQP1/F127 system. This opens new possibilities for the nanoformulations of antimalarial compounds.
- Effect of competitive exclusion in rabbits using an autochthonous probioticPublication . Cunha, Sara; Mendes, Ângelo; Rego, Dinis; Meireles, Diana; Fernandes, Ruben; Carvalho, André; Costa, Paulo Martins da; Fernandes, RúbenAnimal nutrition has been severely challenged by the ban on antimicrobials as growth promoters. This has fostered the study of alternative methods to avoid colonisation by pathogenic bacteria as well as to improve the growth of animals and feed conversion efficiency. These new options should not alter the normal intestinal microbiota, or affect it as little as possible. The use of probiotics, which are live microorganisms that beneficially affect the host by improving its intestinal microbial balance, can be seen as a promising way to achieve that goal. In this study, New Zealand White rabbits were fed diets containing an autochthonous probiotic of Enterococcus spp., with the strains EaI, EfaI and EfaD, and Escherichia coli, with the strains ECI 1, ECI 2 and ECD, during a 25-d trial, to evaluate the impact of the probiotic on the faecal microbiota, including population dynamics and antimicrobial resistance profiles. A control group of rabbits, which was fed a diet containing a commonly used mixture of antimicrobials (colistin, oxytetracycline, and valnemulin), was also studied. To assess the colonisation ability of the mentioned probiotic, the faecal microbiota of the rabbits was characterised up to 10 d after the administration had ended. Isolates of enterococci and E. coli were studied for phylogenetic relationships using enterobacterial repetitive intergenic consensus (ERIC-PCR) and pulse-field gel electrophoresis (PFGE), respectively. Although partially affected by an unexpected clinical impairment suffered by the rabbits in the experimental group, our results showed the following. The difference between the growth rate of the animals treated with antimicrobials and those fed the probiotic was not statistically significant (P> 0.05). The competitive exclusion product was present in the faecal samples in a large proportion, but stopped being recovered by culture as soon as the administration ended and the housing conditions were changed. Multidrug-resistant strains of enterococci and E. coli were more commonly recovered from faecal samples of animals fed diets containing antimicrobials, than from rabbits fed diets with our probiotic formula. The use of E. coli probiotics to prevent infection by enteropathogenic strains must be carefully considered due to the possible occurrence of gastrointestinal signs. On the other hand, enterococci strains may be more effective, but lack the long-term colonisation ability.
- Molecular characterization of quinolone resistance mechanisms and extended-spectrum ß-lactamase production in Escherichia coli isolated from dogsPublication . Meireles, D.; Leite-Martins, L.; Bessa, J.; Cunha, S.; Fernandes, Ruben; Matos, A. de; Manaia, C.M.; Costa, P. Martins da; Fernandes, RúbenThe increasing prevalence of antimicrobial resistances is now a worldwide problem. Investigating the mechanisms by which pets harboring resistant strains may receive and/or transfer resistance determinants is essential to better understanding how owners and pets can interact safely. Here, we characterized the genetic determinants conferring resistance to β-lactams and quinolones in 38 multidrug-resistant Escherichia coli isolated from fecal samples of dogs, through PCR and sequencing. The most frequent genotype included the β-lactamase groups TEM (n = 5), and both TEM + CTX-M-1 (n = 5). Within the CTX-M group, we identified the genes CTX-M-32, CTX-M-1, CTX-M-15, CTX-M-55/79, CTX-M-14 and CTX-M-2/44. Thirty isolates resistant to ciprofloxacin presented two mutations in the gyrA gene and one or two mutations in the parC gene. A mutation in gyrA (reported here for the first time), due to a transversion and transition (TCG → GTG) originating a substitution of a serine by a valine in position 83 was also detected. The plasmid-encoded quinolone resistance gene, qnrs1, was detected in three isolates. Dogs can be a reservoir of genetic determinants conferring antimicrobial resistance and thus may play an important role in the spread of antimicrobial resistance to humans and other co-habitant animals.