Browsing by Author "Medeiros, Rui"
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- ABCB1 C1236T, G2677TA and C3435T genetic polymorphisms and antidepressant response phenotypes: results from a portuguese major depressive disorder cohortPublication . Santos, Marlene; Lima, Luís; Carvalho, Serafim; Brandão, Andreia; Barroso, Fátima; Cruz, Agostinho; Medeiros, RuiP-glycoprotein (P-GP) is a transporter molecule expressed on the apical surface of capillary endothelial cells of the Blood–Brain Barrier (BBB), whose activity heavily influences drug distribution, including antidepressants. This transporter is encoded by ABCB1 gene, and genetic variations within ABCB1 gene have been proposed to affect drug efflux and have been previously associated with depression. In this context, we aimed to evaluate the role of C1236T, G2677TA and C3435T ABCB1 genetic polymorphisms in antidepressant treatment phenotypes from a cohort of patients harboring Major Depressive Disorder. Patients enrolled in the study consisted of 80 individuals with Major Depressive Disorder, who took part in a 27-month follow-up study at HML, Portugal. To investigate the correlation between ABCB1 polymorphisms and antidepressant response phenotypes, DNA was extracted from peripheral blood, and C1236T, C3435T and G2677TA polymorphisms were genotyped with TaqMan® SNP Genotyping Assays. Despite the fact that the evaluated polymorphisms (C1236T, C3435T and G2677TA) were not associated with treatment resistant depression, or relapse, we observed that patients carrying TT genotype of the C3435T polymorphism remit earlier than the ones carrying CC or CT genotypes (10.2 weeks vs. 14.9 and 21.3, respectively, p = 0.028, Log-rank test). Since we found an association with C3435T and time to remission, and not to the absence of remission, we suggest that this polymorphism could have an impact on antidepressant drug distribution, and thus influence on the time to remission will occur, without influencing the risk of remission itself.
- An overview of the therapeutic potential of dimeric flavonoids for targeting cancer hallmarksPublication . Lopes, Inês; Meireles, Isabel; Rocha, Rafaela; Medeiros, Rui; Cerqueira, FátimaEvidence found in the literature indicates that dimeric flavonoids constitute important therapeutic options against cancer. Using these molecules to prevent cancer progression might be a novel and promising therapeutic approach with advantages like fewer side effects, easy access in nature, overall health benefits and overcoming drug resistance. Cancer is a complex disease and still not understood, but there are some common mechanisms and biological characteristics underlying tumor progression that have been scrutinized over the years. This information was summarized in a conceptual framework designated as hallmarks of cancer. Dimeric flavonoids exert biological effects in several pathways involved in cancer hallmarks including cell growth, cell cycle, apoptosis, metastasis and metabolism.
- Antimicrobial activity of dimeric flavonoidsPublication . Lopes, Inês; Campos, Carla; Medeiros, Rui; Cerqueira, FátimaDistributed throughout the environment are various microorganisms such as bacteria, fungi, parasites, and viruses. Although many are part of the human microbiome, many are pathogenic and cause infections ranging from mild to severe. In recent years, the identification of multidrug-resistant microorganisms has become a serious public health problem. The resulting infections call into question the therapeutic capacity of health systems and lead to approximately 70,000 deaths annually worldwide. The progressive resistance to antibiotics and antifungals has been a major challenge for the medical and pharmaceutical community, requiring the search for new compounds with antimicrobial properties. Several studies have demonstrated the potential of natural and synthesized flavonoids, especially the dimers of these molecules. In this review are presented many examples of dimeric flavonoids that have demonstrated antimicrobial activity against viruses, like influenza and Human Immunodeficiency Virus (HIV), protozoal infections, such as Leishmaniasis and Malaria, fungal infections by Candida albicans and Cryptococcus neoformans, and bacterial infections caused, for example, by Staphylococcus aureus and Escherichia coli. In the pursuit to find potential safe agents for therapy in microbial infections, natural dimeric flavonoids are an option not only for the antimicrobial activity, but also for the low toxicity usually associated with these compounds when compared to classic antimicrobials.
- Bdnf-NRF2 crosstalk in depression disorderPublication . Santos, Marlene; Caldevilla, Renato; Morais, Stephanie; Carvalho, Serafim; Medeiros, Rui; Barroso, Maria FátimaThe World Health Organization estimates that major depressive disorder (MDD) affects over 264 million individuals globally, posing a significant public health challenge. Treatment-resistant depression (TRD) represents a severe form of MDD with poor treatment outcomes. Genetic variations are known to impact MDD treatment responses, yet genome-wide association studies have struggled to identify consistent marker alleles. Previous research has linked the Brain Derived Neurotrophic Factor (BDNF) genetic polymorphism with TRD. BDNF is essential for neuronal survival and neuroplasticity, processes influenced by antidepressant treatment, and regulated by transcription factors like Nuclear factor erythroid 2-related factor 2 (NRF2). NRF2 regulates antioxidant and anti-inflammatory responses and plays a crucial role in depression pathogenesis. NRF2 knockout mice exhibit reduced BDNF levels and depression-like behaviors, indicating that NRF2activation enhances BDNF expression and antidepressant efficacy. The BDNF rs6265 (Val66Met) polymorphism is associated with variations in antidepressant response rates. Research suggests that the interaction between BDNF and NRF2 pathways could enhance antidepressant effectiveness. NRF2 activation, such as through the compound sulforaphane, has demonstrated rapid antidepressant effects by increasing BDNF expression. Lower levels of NRF2 and BDNF are observed in stress-induced depression models, and ketamine treatment influences NRF2-related genes. Simultaneously, there is a growing need for efficient genotyping methods, and genosensors offer a promising solution. This presentation will address the interplay between BDNF and NRF2 in depression, explore its relationship in antidepressant response, and present a putative genosensor for BDNF rs6265 (Val66Met) polymorphism identification, improving antidepressant treatment outcome.
- Characterization of genetic polymorphisms CYP2R1 rs2060793 and CYP2R1 rs12794714: potential biomarkers in endometriosis predispositionPublication . Varandas, Tatiana; Dias, Francisca; Sousa, Ana; Amorim, Manuela; Medeiros, RuiEndometriosis is an estrogen-dependent gynecologic disorder defined by the presence of endometrium outside the uterine cavity. Vitamin D is a steroid hormone known for its importance in various biological processes. Vitamin D may play a direct role in the changes that the endometrium undergoes during the menstrual cycle, as endometrial tissue also expresses enzymes involved in metabolism. The study of genetic polymorphisms in the genes of vitamin D metabolism, namely CYP2R1 rs2060793 and CYP2R1 rs12794714, may contribute to a better understanding to the development of endometriosis and become potential biomarkers of the disease. To evaluate the applicability of CYP2R1 rs2060793 and CYP2R1 rs12794714 polymorphisms as potential biomarkers of genetic predisposition to the development of endometriosis. A case-control study was carried out that included the analysis of 482 women recruited between 2011 and 2018 in two public hospitals in Rio de Janeiro, Brazil, as part of the "Cooperation Protocol" between UEZO and CI-IPOP. Genetic polymorphisms were analysed by allelic discrimination with the StepOnePlusTMreal-time PCR system using TaqManTMprobes. There was an association between women carrying the A allele of CYP2R1 rs12794714 polymorphism and early development of endometriosis in about 10 years (p=0.026). We also found that women carrying the A allele of the CYP2R1 rs12794714 polymorphism along with a BMI<30, caucasian women, and without ovarian disease developed endometriosis 10 years (p=0.031), 14 years (p=0.013), and 15 years (p=0.004) earlier, respectively, than women with the GG genotype. Although endometriosis appears at older age, there are factors that may be associated with the development of this pathology at an earlier age. The influence of genetic background, present from birth, seems to be of fundamental importance in the development of the disease at an early age. The allele A of CYP2R1 rs12794714 polymorphism could become a potential biomarker for disease prognosis.
- Common genetic polymorphisms in the ABCB1 gene are associated with risk of major depressive disorder in male Portuguese individualsPublication . Santos, Marlene; Carvalho, Serafim; Lima, Luís; Nogueira, Augusto; Assis, Joana; Mota-Pereira, Jorge; Pimentel, Paulo; Maia, Dulce; Correia, Diana; Gomes, Sofia; Cruz, Agostinho; Medeiros, RuiMajor depressive disorder (MDD) is a highly prevalent disorder, which has been associated with an abnormal response of the hypothalamus–pituitary–adrenal (HPA) axis. Reports have argued that an abnormal HPA axis response can be due to an altered P-Glycoprotein (P-GP) function. This argument suggests that genetic polymorphisms in ABCB1 may have an effect on the HPA axis activity; however, it is still not clear if this influences the risk of MDD. Our study aims to evaluate the effect of ABCB1 C1236T, G2677TA and C3435T genetic polymorphisms on MDD risk in a subset of Portuguese patients. DNA samples from 80 MDD patients and 160 control subjects were genotyped using TaqMan SNP Genotyping assays. A significant protection for MDD males carrying the T allele was observed (C1236T: odds ratio (OR) = 0.360, 95% confidence interval [CI]: [0.140– 0.950], p = 0.022; C3435T: OR= 0.306, 95% CI: [0.096–0.980], p = 0.042; and G2677TA: OR= 0.300, 95% CI: [0.100– 0.870], p = 0.013). Male Portuguese individuals carrying the 1236T/2677T/3435T haplotype had nearly 70% less risk of developing MDD (OR = 0.313, 95% CI: [0.118–0.832], p = 0.016, FDR p = 0.032). No significant differences were observed regarding the overall subjects. Our results suggest that genetic variability of the ABCB1 is associated with MDD development in male Portuguese patients. To the best of our knowledge, this is the first report in Caucasian samples to analyze the effect of these ABCB1 genetic polymorphisms on MDD risk.
- A cyclam salt as an antifungal agent: Interference with Candida spp. and Cryptococcus neoformans mechanisms of virulencePublication . Cerqueira, Fátima; Medeiros, Rui; Lopes, Inês; Campos, Carla; Ferraz, Maria Pia; Silva, Fernando; Alves, Luís G.; Pinto, EugéniaThe importance of fungal infections, particularly those caused by yeasts, is increasing among the medical community. Candida albicans and Cryptococcus neoformans are amongst the high-priority fungal species identified by the World Health Organization (WHO) and are considered in the critical group, while Candida krusei is included in the medium-priority group. The cyclam salt H4[H2(4-CF3PhCH2)2Cyclam]Cl4 proved to be active against the growth of these three yeasts, and the aim of this work was to verify its interference with their virulence mechanisms, whether shared or unique. H4[H2(4-CF3PhCH2)2Cyclam]Cl4 significantly inhibited biofilm production and catalase activity, being able to interfere with C. albicans dimorphic transition and C. neoformans melanin production. At the minimal inhibitory concentration (MIC) values, H4[H2(4-CF3PhCH2)2Cyclam]Cl4 had no antioxidant effect, as determined by the DPPH method. When using the RAW264.7 macrophage cell line, H4[H2(4-CF3PhCH2)2Cyclam]Cl4 reduced nitric oxide (NO) detection (the Griess reaction), but this effect was associated with a significant toxic effect on the cells.
- Design of an electrochemical genosensor for the BDNF gene polymorphism sequence detection using an enzymatic labelled DNA probePublication . Caldevilla, Renato; Morais, Stephanie; Carvalho, Serafim; Medeiros, Rui; Delerue-Matos, Cristina; Cruz, Agostinho; Santos, Marlene; Barroso, M. FátimaThe BDNF gene is associated with high degrees of variability in antidepressant treatments. The Val66Met polymorphism is widely known as a source of this variability, warranting growing interest in genotyping patients that undergo antidepressant treatment to better suit their needs. This paper reports on an electrochemical genosensing platform, based on gold electrodes, capable of detecting this polymorphism, through the use of synthetic enzymatic labelled DNA-probes for 2 different BDNF alleles. The sensor showed promising results, and its applicability to real samples is currently being tested.
- Disclosing the antifungal mechanisms of the Cyclam Salt H4[H2(4-CF3PhCH2)2Cyclam]Cl4 against Candida albicans and Candida kruseiPublication . Costa, Inês; Lopes, Inês; Morais, Mariana; Silva, Renata; Remião, Fernando; Medeiros, Rui; Alves, Luís G.; Pinto, Eugénia; Cerqueira, FátimaMycoses are one of the major causes of morbidity/mortality among immunocompromised individuals. Considering the importance of these infections, the World Health Organization (WHO) defined a priority list of fungi for health in 2022 that include Candida albicans as belonging to the critical priority group and Pichia kudriavzevii (Candida krusei) to the medium priority group. The existence of few available antifungal drugs, their high toxicity, the acquired fungal resistance, and the appearance of new species with a broader spectrum of resistance, points out the need for searching for new antifungals, preferably with new and multiple mechanisms of action. The cyclam salt H4[H2(4-CF3PhCH2)2Cyclam]Cl4 was previously tested against several fungi and revealed an interesting activity, with minimal inhibitory concentration (MIC) values of 8 µg/mL for C. krusei and of 128 µg/mL for C. albicans. The main objective of the present work was to deeply understand the mechanisms involved in its antifungal activity. The effects of the cyclam salt on yeast metabolic viability (resazurin reduction assay), yeast mitochondrial function (JC-1 probe), production of reactive oxygen species (DCFH-DA probe) and on intracellular ATP levels (luciferin/luciferase assay) were evaluated. H4[H2(4-CF3PhCH2)2Cyclam]Cl4 induced a significant decrease in the metabolic activity of both C. albicans and C. krusei, an increase in Reactive Oxygen Species (ROS) production, and an impaired mitochondrial function. The latter was observed by the depolarization of the mitochondrial membrane and decrease in ATP intracellular levels, mechanisms that seems to be involved in the antifungal activity of H4[H2(4-CF3PhCH2)2Cyclam]Cl4. The interference of the cyclam salt with human cells revealed a CC50 value against HEK-293 embryonic kidney cells of 1.1 μg/mL and a HC10 value against human red blood cells of 0.8 μg/mL.
- FAS -670A>G genetic polymorphism Is associated with treatment resistant depressionPublication . Santos, Marlene; Carvalho, Serafim; Lima, Luís; Mota-Pereira, Jorge; Pimentel, Paulo; Maia, Dulce; Correia, Diana; Gomes, Sofia; Cruz, Agostinho; Medeiros, RuiHippocampal neurogenesis has been suggested as a downstream event of antidepressants (AD) mechanism of action and might explain the lag time between AD administration and the therapeutic effect. Despite the widespread use of AD in the context of Major Depressive Disorder (MDD) there are no reliable biomarkers of treatment response phenotypes, and a significant proportion of patients display Treatment Resistant Depression (TRD). Fas/FasL system is one of the best-known death-receptor mediated cell signaling systems and is recognized to regulate cell proliferation and tumor cell growth. Recently this pathway has been described to be involved in neurogenesis and neuroplasticity. Since FAS -670A>G and FASL -844T>C functional polymorphisms never been evaluated in the context of depression and antidepressant therapy, we genotyped FAS -670A>G and FASL -844T>C in a subset of 80 MDD patients to evaluate their role in antidepressant treatment response phenotypes. We found that the presence of FAS -670G allele was associated with antidepressant bad prognosis (relapse or TRD: OR=6.200; 95% CI: [1.875–20.499]; p=0.001), and we observed that patients carrying this allele have a higher risk to develop TRD (OR=10.895; 95% CI: [1.362–87.135]; p=0.008). Moreover, multivariate analysis adjusted to potentials confounders showed that patients carrying G allele have higher risk of early relapse (HR=3.827; 95% CI: [1.072–13.659]; p=0.039). FAS mRNA levels were down-regulated among G carriers, whose genotypes were more common in TRD patients. No association was found between FASL-844T>C genetic polymorphism and any treatment phenotypes. Small sample size. Patients used antidepressants with different mechanisms of action. To the best of our knowledge this is the first study to evaluate the role of FAS functional polymorphism in the outcome of antidepressant therapy. This preliminary report associates FAS -670A>G genetic polymorphism with Treatment Resistant Depression and with time to relapse. The current results may possibly be given to the recent recognized role of Fas in neurogenesis and/or neuroplasticity.