ABC2-Artigos (em revistas ou actas indexadas)
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- Activity induced genes expression is impaired in polyglutamine spinocerebellar ataxiasPublication . Torquato Afonso, Inês; Vilhena Catarino Brito, David; Bading, Hilmar; Nóbrega, ClévioPolyglutamine Spinocerebellar ataxias (SCAs) are a group of 6 incurable genetic disorders, caused by an expansion of the trinucleotide cytosine-adenine-guanine in their causative genes, which produces a protein with an expanded glutamine region. This project focuses on the study of Spinocerebellar ataxia type 2 (SCA2) and type 3 (SCA3) (1), which are rare dominantly inherited disorders that primarily impair the cerebellum therefore leading to motor ataxia. Activity-induced inhibitor of death (AID), are a group of pro-survival 9 genes which were found to be neuroprotector in several neurological disorders, including stroke, glaucoma, AD, HD, and ALS (2). In this project, we aim to investigate about the relevance of the expression of AID genes for cerebellum function and whether their expression levels are impaired in SCA2 and SCA3
- Optimization of stroke management workflow in the emergency department of Maputo central hospital: implementation proposalPublication . Buque, H.; Bauaze, E. Namburete; Lorenzo, E.; Nzwalo, HipólitoStroke is a leading cause of morbidity and mortality in Mozambique, with a high incidence among young adults. Maputo Central Hospital (HCM) receives a substantial number of stroke patients daily, but lacks a dedicated Stoke Unit, facing challenges that delay timely and effective care.
- Unraveling the potential of gasotransmitters as neurogenic and neuroprotective molecules: focus on Alzheimer's and Parkinson's diseases.Publication . Simao, Sonia; Filipa Santos, Daniela; Teixeira, Mariana; Ribeiro Agostinho, Rafaela; Rodrigues, Joana; Vitorino, Marta; Pombinho de Araújo, Inês MariaAlzheimer's disease and Parkinson's disease are the two most prevalent neurodegenerative disorders worldwide, both characterized by progressive neuronal loss. Despite distinct pathophysiological features, they share cellular dysfunctions such as abnormal protein aggregation, oxidative stress, and neuroinflammation, research into which might be beneficial for developing novel therapeutic strategies that could tackle both conditions. This review highlights the emerging role of the gasotransmitters nitric oxide, carbon monoxide and hydrogen sulfide as modulators of adult neurogenesis and neuroprotection in Alzheimer's disease and Parkinson's disease. We have gathered recent evidence demonstrating that these endogenous gases exert anti-inflammatory, antioxidant, and anti-apoptotic effects, and, critically, promote neurogenesis - suggesting a dual neuroprotective and neuroregenerative therapeutic potential. The unique physicochemical features of these gasotransmitters, including their ability to cross the blood-brain barrier and diffuse rapidly throughout the neural tissue, further support their suitability as candidates for innovative neuroregenerative treatments. While clinical translation remains challenging, harnessing the neurogenic and neuroprotective actions of these gasotransmitters may offer transformative avenues for addressing the increasing burden of Alzheimer's disease and Parkinson's disease.
- Drug-related glomerular phenotypes: a global pharmacovigilance perspectivePublication . Baptista, Alexandre; Macedo, Ana; Marreiros, Ana; Coelho, André; Perazella, Mark A.Abstract: Introduction: Adverse drug reactions are a significant problem in modern society, stemming from the increase in prescribed medications, over-the-counter drugs, and overall polypharmacy. Glomerular disorders are one of the frequently reported renal conditions associated with medication use. VigiBase is a significant tool for evaluating events associated with drug use, and, to the authors’ knowledge, no study has yet assessed this database to identify the primary medications associated with glomerular disorders. Materials and Methods: We collected data from VigiBase for 54 years and evaluated data based on global frequencies, disproportionality (IC025 values), nephrotoxic potential, and physiopathological mechanisms. Results: Over the evaluation period, 33.932.051 spontaneous notifications of adverse drug reactions reported in VigiBase were assessed, from which 106.775 notifications of drug-associated glomerular disorders were extracted. The isolated medications were classified as ‘potential nephrotoxins’ (47.0%), with 40% of the medications lacking scientific references to report any association with the development of glomerular disorders. Among the evaluated medications, Inotersen (IC025 of 8.3), Penicillamine (IC025 6.8), Bevacizumab (IC025 5.9) and Lenvatinib (IC025 5.4) were identified as having the strongest association with these glomerular disorders. For medications classified as ‘non-nephrotoxic’, a high disproportionality index was observed, suggesting drugs that might be considered as new potential nephrotoxins. Conclusions: Drug-induced glomerular disorders were significantly associated with medications that had no established nephrotoxic role but demonstrated a high disproportionality index in VigiBase. These newly alleged nephrotoxic drugs warrant further evaluation in dedicated studies to assess their true nephrotoxic potential.
- Transcriptomic profiling of zebrafish mutant for cdkl5 reveals dysregulated gene expression associated with neuronal, muscle, visual and skeletal developmentPublication . Varela, Tatiana da Conceição Domingos ; Domingos Varela, Débora Cristina; Conceição, Natércia; Cancela, M. LeonorZebrafish is a well-recognized model for studying human genetic disorders. Recently, we proposed the homozygous cdkl5sa21938 mutant zebrafish as a model of CDKL5 deficiency disorder (CDD), a developmental epileptic encephalopathy with diverse symptoms. This study aimed to explore Cdkl5-associated molecular mechanisms in zebrafish and assess their similarity to those in mammals. We conducted RNA sequencing on whole cdkl5−/− zebrafish and wild-type siblings at 5- and 35-days post-fertilization (dpf) to compare their gene expression profiles. Most significant differentially expressed genes (DEGs) were related to muscle, neuronal, and visual systems which are affected in CDD. Gene Ontology analysis revealed downregulated DEGs enriched in muscle development, extracellular matrix, and actin cytoskeleton functions at both stages, while upregulated DEGs were enriched in eye development functions at 35 dpf. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed enrichment of downregulated DEGs in focal adhesion and extracellular matrix (ECM)-receptor interaction pathways at both stages. Neuronal development DEGs were mainly downregulated at both stages, while synaptic signaling DEGs were upregulated at 35 dpf. Crossing cdkl5−/− mutants with the Hb9:GFP transgenic line showed fewer motor neuron cells with shorter axons compared to the wild type, which may explain the impaired motor phenotype observed in zebrafish and CDD patients. Moreover, we identified key downregulated DEGs related to cartilage development at both stages and bone development at 35 dpf, potentially explaining the skeletal defects seen in zebrafish and CDD individuals. In conclusion, Cdkl5 loss in zebrafish leads to dysregulation of genes involved in CDKL5-associated functions in mammals, providing new insights into its less studied functions and phenotypes.
- Methylation status of the telomerase reverse transcriptase promoter in parotid tumours and adjacent parotid gland tissue: a pilot study on the implications for recurrence and development of malignancyPublication . Paiva Correia, Antonio; Apolónio, Joana; Nadal, Alfons; Brandão, José Ricardo; Silva, Nádia; Machado, Bianca; Archilla, Ivan; Castelo-Branco, Pedro; Hellquist, HenrikBackground/Objectives: The methylation of the hypermethylated oncological region (THOR) of human telomerase reverse transcriptase (hTERT) may forecast tumour aggressiveness. This pilot study aimed to evaluate THOR methylation as a potential biomarker for recurrence/malignant transformation in salivary gland pleomorphic adenomas (PA). Methods: THOR methylation was assessed by quantitative pyrosequencing in 96 parotid tissue samples (benign and malignant), including non-neoplastic parotid tissue, PA, recurrent PA (rPA), and carcinomas, along with their adjacent tissues. TERT promoter mutations (TPMs) were analysed by Sanger sequencing. Results: THOR methylation significantly differed across the seven groups. Malignant tissues showed higher THOR methylation than non-neoplastic tissues, whereas benign tumours showed no significant difference from non-neoplastic tissue. THOR methylation in rPA was closer to carcinoma than to normal tissue, similar in rPA and tissues adjacent to rPA, and higher in tissues adjacent to carcinomas than in non-neoplastic tissues. A subset of PA-adjacent tissues showed epigenetic alterations, suggesting an increased risk of recurrence or malignant transformation (5–15%). No TPMs were detected. Conclusions: THOR methylation may add information to differentiate normal from carcinogenic tissues and, as such, may be included in a biomarkers panel. Epigenetic alterations in PA-adjacent tissues with normal histology highlight the need for improved diagnostic markers.
- Delays in the stroke care pathway in a low-income setting: an audit study from MozambiquePublication . Buque, Helena Agostinho; Smith, Lee; Lopes, Dino; Pizzol, Damiano; Lorenzo, Elder; Arroz, Nachan; Bacallau, Lazara; Sidat, Mohsin; Bauaze, Evangelina Namburete; Nzwalo, HipólitoBackground: The burden of stroke is on the rise in low-income countries (LICs). Organized stroke care (OSC) is crucial for improving outcomes in LICs and is the very first step to reducing delays in diagnosis and treatment. We aim to evaluate delay times (DT) in accessing OSC at the national reference hospital of Mozambique, a LIC from southern Africa. Methods: An observational study based on consecutive case series of 59 stroke patients confirmed by computed tomography (CT) scans over a period of 3 months (May–July 2023). The total DT (from stroke onset to inward hospitalization) was the main outcome. Other specific DTs were analyzed including initial symptoms to arrival and admission (DT0), arrival to CT scans (DT1), arrival of laboratory results (DT2), and arrival to inward hospitalization (DT3). Results: The mean age was 61.9 (min 30–max 90) and 45.8% were female. The median total DT was 20 h. The median time DT0 was 10.6 h (interquartile range (IQR): 16.48). The median DT1 and DT2 were 4 h (IQR: 3.5) and 5 h (IQR: 2.6), respectively. The median DT3 was 10 h (IQR: 4). None of the patients were treated under a stroke code. Conclusions: This study reveals an unacceptable prehospital and in-hospital DT. Waiting for the CT scan contributed to a large proportion of the total DT, which among other factors can be explained by the absence of a stroke code and limited imaging capacity. These findings mirror disparities in stroke care seen in other LICs, where late presentation, scarce imaging, and limited specialized protocols are common. The urgent implementation of organized prehospital and in-hospital stroke pathways is needed in Maputo to improve outcomes.
- A new variant in the NALCN channel is responsible for cerebellar ataxia and cognitive impairmentPublication . Cabrita Pinto, Rute Luísa; Fancellu, Roberto; Markushi, Tiziana Benzi; Viaggi, Silvia; Testa, Barbara; Conteduca, Giuseppina; Fitzsimmons, Lane; Coviello, Domenico; Covone, Angela ElviraCLIFAHDD syndrome (OMIM # 616266) is a rare neurodevelopmental disorder caused by mutations in the NALCN gene. It is characterized by hypotonia, developmental delay, and congenital contractures of the limbs and face. We report a 33-year-old Italian woman with a mild form of CLIFAHDD who exhibited early-onset language difficulties and mild intellectual disability and later developed gait and balance impairments in adulthood. Whole Exome Sequencing (WES) identified a novel missense variant c.1514A>T; p.(Lys505Met) in the NALCN gene. The allele frequency of this variant is not detected (MAF = 0.0), the variant is classified as likely pathogenic according to ACMG criteria, and predicted to be probably damaging by PolyPhen-2. It affects a critical residue within the second pore-forming domain of the NALCN channel, potentially altering lipid interactions and channel regulation. Sanger sequencing and segregation analysis confirmed the variant to be heterozygous and de novo. The patient's milder symptoms and later onset, compared to severe pediatric cases, suggest that the clinical spectrum of CLIFAHDD syndrome may be broader than previously recognized. These findings underscore the potential influence of mutation location on disease presentation and severity.
- Drug repurposing for targeting cancer stem-like cells in glioblastomaPublication . De Sousa-Coelho, Ana Luísa; Solaković, Brigita; Bento, Alexandra Diogo; Teotónio Fernandes, Mónica AlexandraGlioblastoma (GBM) is one of the deadliest types of cancer, characterized by a short life expectancy after diagnosis, mostly related to therapy resistance and recurrence. GBM stem-like cells (GSCs) reside within the tumor and contribute to these features; therefore, finding drugs that specifically target such cells holds promise to halt GBM progression. The primary objective of this work is to comprehensively review and discuss the potential of hard drug repurposing to target GSCs. Several studies evaluating drugs showing anti-GSC activity, originally approved for non-cancer indications, were identified. These mainly included antidiabetics (e.g., Metformin, Phenformin, and Sitagliptin), antihypertensives (e.g., Nicardipine, Doxazosin, and Prazosin), antimicrobials (e.g., Pyrvinium pamoate, Flubendazole, and Clofazimine), and central nervous system-acting drugs (e.g., Chlorpromazine, Fluvoxamine, and Disulfiram). Relevant candidates include those that disrupt GSC metabolism, namely impairing mitochondrial function, such as Metformin, Chlorpromazine, and Pyrvinium pamoate. Multiple signaling pathways may be involved, namely the Wnt, PI3K/AKT, and STAT3 pathways, among others. Also significant were those drugs tested in combination, resulting in increased sensitivity to Temozolomide (TMZ), the standard pharmacological treatment available for GBM. Some repurposed agents, such as Disulfiram and Metformin, have already reached clinical testing, although none have yet been incorporated into clinical practice. Importantly, major translational barriers remain, like limited blood–brain barrier penetration and the lack of robust clinical trials. In conclusion, drug repurposing is an affordable and suitable strategy to target GSCs, impairing cell viability, reducing stemness, and enhancing their sensitivity to TMZ, which has potential that should be further explored to improve patients’ clinical outcomes.
- CITED Proteins in cardiac development and lifelong heart functionPublication . Bragança, José; Cabrita Pinto, Rute Luísa; Vairinho Ventura, Igor; Ferreira, Silvana; Marreiros, AntónioThe CITED proteins function as transcriptional modulators that are essential for vertebrate development. These proteins interact with numerous partners, notably transcription factors and co-activators. The hallmark of the CITED family is their conserved carboxy-terminal domain, which interacts strongly with the CBP/p300 co-activators. The expression of CITED genes is detected early during embryogenesis within embryonic and foetal regions critical for cardiac morphogenesis, among other developmental processes. Notably, CITED2 loss of function is strongly associated with congenital heart malformations in mice and zebrafish embryos, as well as congenital heart disease (CHD) in humans, whereas other CITED family members are not critical for cardiogenesis. Emerging evidence implicates CITED2 and CITED4 in regulating heart physiological adaptations and protective responses to pathological stress. This review provides a detailed analysis of CITED proteins and their interactors, focusing on CITED-target genes relevant for cardiogenesis and heart disease. We also highlight recent findings indicating that CITED2 and CITED4 may be instrumental for the development of novel therapeutic strategies to mitigate CHD and preserve adult cardiac function.