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- Drug resistance and epigenetic modulatory potential of epigallocatechin-3-gallate against Staphylococcus aureusPublication . Zeferino, Ana Sofia; Mira, Ana Rita; Delgadinho, Mariana; Brito, Miguel; Ponte, Tomás; Ribeiro, EdnaAntimicrobial resistance of human pathogens, such as methicillin-resistant Staphylococcus aureus, is described by the World Health Organization as a health global challenge and efforts must be made for the discovery of new effective and safe compounds. This work aims to evaluate epigallocatechin-3-gallate (EGCG) epigenetic and modulatory drug potential against S. aureus in vitro and in vivo. S. aureus strains were isolated from the commensal flora of healthy volunteers. Antibiotic susceptibility and synergistic assay were assessed through disk diffusion accordingly to EUCAST guidelines with and without co-exposure to EGCG at final concentrations of 250 µg/ml, 100 µg/ml, 50 µg/ml, and 25 µg/ml. Transcriptional expression of orfx, spdC, and WalKR was performed through qRT-PCR. A 90-day interventional study was performed with daily consumption of 225 mg of EGCG. Obtained data revealed a high prevalence of S. aureus colonization in healthcare workers and clearly demonstrated the antimicrobial and synergistic potential of EGCG as well as divergent resistant phenotypes associated with altered transcriptional expression of epigenetic and drug response modulators genes. Here, we demonstrate the potential of EGCG for antimicrobial treatment and/or therapeutic adjuvant against antibiotic-resistant microorganisms and report divergent patterns of epigenetic modulators expression associated with phenotypic resistance profiles.
- Are genetic modifiers the answer to different responses to hydroxyurea treatment? A pharmacogenetic study in sickle cell anemia Angolan childrenPublication . Ginete, Catarina; Delgadinho, Mariana; Santos, Brígida; Pinto, Vera; Silva, Carina; Miranda, Armandina; Brito, MiguelSickle cell anemia (SCA) is an inherited disease affecting the hemoglobin that is particularly common in sub-Saharan Africa. Although monogenic, phenotypes are markedly heterogeneous in terms of severity and life span. Hydroxyurea is still the most common treatment for these patients, and the response to treatment is highly variable and seems to be an inherited trait. Therefore, identifying the variants that might predict hydroxyurea response is important for identifying patients who will have a poorer or non-response to treatment, and the ones that are more prone to suffer from severe side effects. In the present pharmacogenetic study, we analyzed the exons of 77 genes described in the literature as potentially associated with hydroxyurea metabolism in Angolan children treated with hydroxyurea and evaluated the drug response considering fetal hemoglobin levels, other hematological and biochemical parameters, hemolysis, number of vaso-occlusive crises and hospitalizations. Thirty variants were identified in 18 of those genes as possibly associated with drug response, five of them in gene DCHS2. Other polymorphisms in this gene were also associated with hematological, biochemical, and clinical parameters. Further research examining the maximum tolerated dose and fixed-dose with a larger sample size is necessary to corroborate these findings.
- Genotypic diversity among Angolan children with sickle cell anemiaPublication . Delgadinho, Mariana; Ginete, Catarina; Santos, Brígida; Miranda, Armandina; Brito, MiguelBackground. Sickle cell anemia (SCA) is an inherited blood disorder that affects over 300,000 newborns worldwide every year, being particularly prevalent in Sub-Saharan Africa. Despite being a monogenic disease, SCA shows a remarkably high clinical heterogeneity. Several studies have already demonstrated the existence of some polymorphisms that can provide major clinical benefits, producing a mild phenotype. Moreover, the existence of distinct haplotypes can also influence the phenotype patterns of certain populations, leading to different clinical manifestations. Our aim was to assess the association between polymorphisms in genes previously related to SCA disease severity in an Angolan pediatric population. Methods. This study analyzed clinical and biological data collected from 192 Angolan children. Using NGS data, we classified the HBB haplotypes based on four previously described SNPs (rs3834466, rs28440105, rs10128556, and rs968857) and the genotype for the SNPs in HBG2 (rs7482144), BCL11A (rs4671393, rs11886868, rs1427407, rs7557939), HBS1L-MYB (rs66650371) and BGLT3 (rs7924684) genes. Results. The CAR haplotype was undoubtedly the most common HBB haplotype in our population. The HbF values and the ratio of gamma chains were statistically significant for almost all of the variants studied. We reported for the first time an association between rs7924684 in the BGLT3 gene and gamma chains ratio. Conclusions. The current findings emphasize the importance personalized medicine would have if applied to SCA patient care since some of the variants studied might predict the phenotype and the overall response to treatment
- Genetic modifiers of stroke in patients with sickle cell disease: a scoping reviewPublication . Oni, Morohuntodun O.; Brito, Miguel; Rotman, Chloe; Archer, Natasha M.Sickle cell disease (SCD) clinically manifests itself with a myriad of complications. Stroke, both ischemic and hemorrhagic, as well as silent white matter changes, occurs at a relatively high prevalence. Understanding why and in whom stroke is most likely to occur is critical to the effective prevention and treatment of individuals with SCD. Genetic studies, including genome- and exome-wide association studies (GWAS and EWAS), have found several key modifiers associated with increased stroke/stroke risk in SCD via mechanisms including Hemoglobin F (HbF) modulation, inflammation, cellular adhesion, endothelial disruption, and hemolysis. We present a review of the modifiers that have most clearly demonstrated an association to date. More studies are needed to validate other potential polymorphisms and identify new ones. Incorporating gene-focused screenings in clinical care could provide avenues for more targeted, more effective, and less toxic prevention of stroke in this population. The data from this review will be used to inform the initial GWAS performed by the International Hemoglobinopathy Research Network (INHERENT) consortium.
- The nuclear levels of thioredoxin reductase 1, gamma-H2AX, and yap are modulated by primary cilia in response to high glucose levelsPublication . Marques, Rita; Paiva, Mariana; Ginete, Catarina; Nolasco, Sofia; Marinho, Susana H.; Veiga, Luisa; Brito, Miguel; Soares, Helena; Carmona, BrunoDiabetes is a condition characterized by impaired regulation of blood glucose levels, leading to various complications such as hypertension, cardiovascular disease, and retinopathy. Diabetic retinopathy (DR), caused by a disrupted retinal blood barrier, is associated with oxidative stress resulting from dysregulated glucose levels in the retina. The primary cilium, an organelle involved in energy balance and glucose homeostasis, has been implicated in the development of various diseases known as ciliopathies, which include overlapping phenotypes such as obesity, diabetes, and retinopathy. This study aims to investigate the impact of high glucose levels on primary cilia assembly in retinal pigment epithelium (RPE-1) cell cultures and explore the role of cilia in the cellular response to high glucose levels. RPE-1 cells were grown in media supplemented with different glucose concentrations (5 mM, 25 mM, and 5 mM glucose + 20 mM mannitol), and cilia assembly was induced before or after glucose supplementation. The results revealed that glucose supplementation did not affect the number of ciliated cells, but cells supplemented with 25 mM glucose exhibited shorter cilia. To understand the role of cilia in response to high glucose levels, the nuclear levels of thioredoxin reductase 1 (TRXR1), a key enzyme involved in combating oxidative stress triggered by hyperglycemia, were evaluated. Additionally, γH2AX, a marker of DNA breaks and cellular senescence, and YAP, a Hippo pathway effector, were examined. It was observed that glucose supplementation, particularly at high levels (25 mM), influenced the nuclear levels of TRXR1, γH2AX, and YAP. Notably, the presence of cilia modulated the cellular response to high glucose levels, modulating the levels of these proteins. These preliminary findings indicate that primary cilia significantly influence the cellular response to high glucose concentrations, which are known to induce oxidative stress and potentially contribute to the development of DR.
- Effects of Quercetin in transcriptional and post-transcriptional regulation of fetal hemoglobinPublication . Canteiro, Beatriz; Mendes, Maria; Jacques, Filipa; Delgadinho, Mariana; Oliveira, Ketlyn; Ginete, Catarina; Gomes, Mário; Ribeiro, Edna; Brito, Miguel; Gomes, Anita Q.Hemoglobinopathies are a group of inherited blood disorders that primarily affect red blood cells. The most common type is known as sickle cell anemia (SCA). It is characterized by mutations in the HBB gene, which encodes the β-subunit of human hemoglobin, giving rise to hemoglobin S (HbS). When deoxygenated, HbS polymerizes in the red blood cell, giving it a sickle shape and making it rigid and fragile. Fetal hemoglobin (HbF) is the major genetic modulator of the hematologic and clinical features of sickle cell disease, an effect mediated by its exclusion from the sickle hemoglobin polymer. Fetal hemoglobin genes are genetically regulated, and the level of HbF and its distribution among sickle erythrocytes is highly variable. Currently, therapies that induce HbF are promising, such as hydroxyurea (HU). However, due to high costs for underdeveloped countries and the adverse side effects, it is important to test alternative products and develop new compounds, such as Quercetin, a natural flavonoid present in plants that has antioxidant and anti-inflammatory properties.
- Effects of Carica papaya leaf extracts in transcriptional regulation of fetal hemoglobinPublication . Mendes, M.; Canteiro, Beatriz; Delgadinho, Mariana; Oliveira, Ketlyn; Ginete, Catarina; Gomes, Mário; Ribeiro, Edna; Brito, Miguel; Gomes, Anita Q.Purpose: Sickle cell disease (SCD) is one of the most common human genetic disorders, which is caused by a single point mutation (Glu6Val) on the HBB gene. Currently, one of the treatments for this global health problem involves the induction of fetal hemoglobin (HbF). There are some drugs on the market that pharmacologically induce HbF, namely Hydroxyurea (HU), however, their safety concerns and the expensive cost in low- and middle-income countries limit their use. In this context, it is essential to study novel fetal hemoglobin-inducing compounds that have fewer adverse effects and are widely available, such as natural compounds. Therefore, the main aim of this work was to evaluate the effects of Carica Papaya methanolic leaf extracts (CPMLE) in HbF reactivation.
- Microbiological contamination assessment in higher education institutesPublication . Viegas, Carla; Pimenta, Raquel; Dias, Marta; Gomes, Bianca; Brito, Miguel; Caetano, Liliana Aranha; Carolino, Elisabete; Gomes, Anita Q.The higher education sector represents a unique environment and it acts as a work environment, a learning environment for students, and frequently, also a home environment. The aim of this study was to determine the microbial contamination (SARS-CoV-2, fungi, and bacteria) in Higher Education Facilities (HEI) by using active and passive sampling methods and combining culture-based methods with molecular tools targeting Aspergillus section Fumigati. In addition, the resistance to azole profile was also assessed. Surface samples showed a range of total bacterial contamination between 1 × 103 to 3.1 × 106 CFU·m−2, while Gram-negative bacteria ranged from 0 to 1.9 × 104 CFU·m−2. Fungal contamination ranged from 2 × 103 to 1.8 × 105 CFU·m−2 on MEA and from 5 × 103 to 1.7 × 105 CFU·m−2 on DG18. The most prevalent species found on both media was Cladosporium sp. (47.36% MEA; 32.33% DG18). Aspergillus genera were observed on MEA (3.21%) and DG18 (14.66%), but not in the supplemented media used for the azole screening. Aspergillus section Fumigati was detected in 2 air samples (2.22%, 2 out of 90 samples) by qPCR. When testing for SARS-CoV-2 all results were negative. The present study showed that although cleaning and disinfection procedures are done regularly due to the COVID-19 pandemic, being effective in eliminating SARS-CoV-2, surfaces were often contaminated with microorganisms other than SARS-CoV-2. This can be a result of increasing resistance to biocides, and to the wide range of environmental factors that can contribute to the dissemination of microbial contamination indoors.
- Effects of quercetin in transcriptional regulation of fetal hemoglobinPublication . Canteiro, B.; Mendes, M.; Delgadinho, Mariana; Oliveira, K.; Ginete, Catarina; Gomes, M.; Brito, Miguel; Gomes, Anita Q.; Ribeiro, EdnaPurpose: Sickle cell disease (SCD) is a genetic blood disorder that affects the shape and transport of red blood cells (RBCs) in blood vessels, leading to various clinical complications. The pharmacological reactivation of Fetal Hemoglobin (HbF) is considered to be a viable therapeutic method in SCD. In this regard, hydroxyurea (HU), a powerful ribonucleotide reductase inhibitor, is being employed as a HbF-inducing pharmaceutical. However, its cytotoxicity, carcinogenic potential, and variable effects limit its use. Thus, a major challenge today is to identify new agents, with high HbF-inducing activity, low cytotoxicity, and available in low- and middle-income countries, such as natural compounds. Quercetin, a natural flavonoid, has been identified as a potential HbF inducer. The main aim of this work was to evaluate Quercetin's role in the reactivation of fetal hemoglobin (HbF) by analyzing the expression of globin and HbF regulatory/silencing genes.
- Gut microbiota impact on Angolan children with sickle cell diseasePublication . Brito, Miguel; Delgadinho, Mariana; Ginete, Catarina; Mendes, Joana; Vasconcelos, J.; Santos, BrígidaIntroduction: Clinical manifestations of Sickle cell disease (SCD) are very heterogeneous, and the intestinal microbiome appears to be crucial in the modulation of inflammation, cell adhesion, and induction of aged neutrophils, which are the main interveners of recurrent vaso-occlusive crisis. Enterocyte injury, increased permeability, altered microbial composition, and bacterial overgrowth have all been documented as microbial and pathophysiologic changes in the gut microbiome of SCD patients in recent research studies. Microbiota analysis in SCD populations will be essential to demonstrate the importance of specific bacteria and their function in this disease and provide new insights for attenuating symptoms and new drug targets. Purpose: Given this, our aim is to sequence by NGS bacterial 16S RNA gene in order to characterize the gut microbiome of SCD children and healthy siblings, as a control.
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