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- Detecting BDNF gene polymorphisms using genosensors and molecular biology toolsPublication . Caldevilla, Renato; Morais, Stephanie L.; Cruz, Agostinho; Barroso, M. Fátima; Santos, MarleneMajor depressive disorder (MDD) is a complex and highly prevalent psychiatric disorder with a high impact on quality of life and negative effects on mood, behaviour, and cognition. Currently, the main medical treatment for MDD is antidepressant medication. The selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, sertraline, fluvoxamine, paroxetine and citalopram, are the most commonly prescribed drugs. However, as with all antidepressant treatments, about 30–40% of MDD patients do not respond sufficiently to SSRIs. Several factors, including genetic factors, play important roles in antidepressant responses. BDNF is one of the most investigated genes regarding depression and antidepressant response. In fact, the rs6265 (Val66Met) non-synonymous polymorphism, has been demonstrated to decrease pro-BDNF processing, and consequently affect the dependent secretion of BDNF. Curiously, carriers of Met-allele have been described to have smaller hippocampal volume, either in healthy or depressed patients. So, it is likely they can contribute to the interindividual differences in patient´s responses to antidepressants. Therefore, it is crucial to develop methodologies to predict the individual antidepressant response. In this work, two analytical approaches based in molecular biology and electrochemical genosensor techniques are under development to create a low-cost genotyping platform able to genotype BDNF SNPs related with antidepressants therapeutic response.
- 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.
- Construction and optimization of an electrochemical genosensor for the detection of BDNF gene Val66Met polymorphismPublication . Caldevilla, Renato; Santos, Marlene; Barroso, M. FátimaMajor depression disorder (MDD) is the most prevalent psychiatric condition worldwide. Currently, antidepressants constitute the main pharmacological treatment for this condition. Despite the growing arsenal of antidepressant medications, almost half of MDD patients have insufficient remission rates during their treatments. A growing body of scientific evidence points to genetic factors as having a crucial role in patients’ response to antidepressant treatments. One of these genetic components is the BDNF gene, that codes for the BDNF neurotrophin, an important player in neuroplasticity and neurogenesis.
- Electrochemical chemically based sensors and emerging enzymatic biosensors for antidepressant drug detection: a reviewPublication . Caldevilla, Renato; Morais, Stephanie L.; Cruz, Agostinho; Delerue-Matos, Cristina; Moreira, Fernando; Pacheco, João G.; Santos, Marlene; Barroso, Maria FátimaMajor depressive disorder is a widespread condition with antidepressants as the main pharmacological treatment. However, some patients experience concerning adverse reactions or have an inadequate response to treatment. Analytical chromatographic techniques, among other techniques, are valuable tools for investigating medication complications, including those associated with antidepressants. Nevertheless, there is a growing need to address the limitations associated with these techniques. In recent years, electrochemical (bio)sensors have garnered significant attention due to their lower cost, portability, and precision. Electrochemical (bio)sensors can be used for various applications related to depression, such as monitoring the levels of antidepressants in biological and in environmental samples. They can provide accurate and rapid results, which could facilitate personalized treatment and improve patient outcomes. This state-of-the-art literature review aims to explore the latest advancements in the electrochemical detection of antidepressants. The review focuses on two types of electrochemical sensors: Chemically modified sensors and enzyme-based biosensors. The referred papers are carefully categorized according to their respective sensor type. The review examines the differences between the two sensing methods, highlights their unique features and limitations, and provides an in-depth analysis of each sensor.
- Is there a link between NRF2 and depression?Publication . Santos, Marlene; Fonseca, Débora; Caldevilla, Renato; Barroso, M. Fátima; Cruz, AgostinhoDepression is a common mental health disorder that affects millions of people worldwide. Recent studies have highlighted the role of oxidative stress and inflammation in the pathogenesis of depression. NRF2 is a transcription factor that plays a crucial role in cellular defense against oxidative stress by binding to antioxidant response elements (AREs) located in the promoter region of various phase II antioxidant enzymes and stress-responsive enzymes. Decreased Keap1-Nrf2 signaling has been implicated in the development of mood disorders, such as Major Depressive Disorder. Therefore, this review aims to evaluate the in vitro and in vivo evidence of the involvement of Nrf2 in depression. A review was conducted on the PubMed database for articles published until March 8, 2022 Papers that evaluated NRF2 in animals and/or cell lines with depression and were published in English were included in the review. Studies that addressed other diseases/topics, systematic reviews, and those that did not address NRF2 were excluded. Quality assessment was performed according to Koch et al., 2022. Out of the 203 possibly relevant abstracts found through the PubMed search, 45 papers were included in the review. The results suggest that Nrf2 levels tend to decrease in animals exposed to oxidative stress or depressive behavior. When animals were treated with antidepressants or anti-inflammatory drugs, Nrf2 levels increased. Additionally, the study found that IL-10 and BDNF were key elements that were positively influenced by Nrf2 levels, protecting against oxidative stress through Keap1/Nrf2. The findings suggest that Nrf2 activation may play a crucial role in controlling oxidative stress and inflammation during depression. Furthermore, it provides evidence of the involvement of Nrf2 in depression and highlights its potential as a therapeutic target. However, further studies on clinical samples are necessary to evaluate NRF2’s putative effect in depression and antidepressant response.
- Avaliação da atividade antioxidante do extrato etanólico da Adansonia digitataPublication . Santos, Daniela; Carvalho, Daniel; Rente, Ana; Silva, Jorge; Caldevilla, Renato; Cardoso, Andreia; Oliveira, Ana Isabel; Pinho, CláudiaO Baobá (Adansonia digitata) é uma planta africana usada na medicina tradicional devido às suas propriedades antioxidantes, resultante da sua composição em compostos fenólicos, que desempenham um papel importante na prevenção de doenças associadas ao stress oxidativo. O principal objetivo deste trabalho é avaliar a atividade antioxidante do extrato etanólico de A. digitata. Estudo experimental com análise do extrato etanólico 70 % (V/V) de A. digitataproveniente do fruto seco, obtido comercialmente. A aferição da atividade antioxidante foi feita através de diferentes ensaios: radical (2,2-diphenyl-1-picrylhydrazyl (DPPH), poder redutor do ferro (FRAP) e quelação da ferrozina. No ensaio FRAP a maior percentagem de redução do ferro foi 2,75 %, obtida com a maior concentração testada (1000 μg/ml). Em relação ao ensaio da ferrozina, as percentagens de quelação do ferro variaram entre 19,88 ± 2,50 % e 27,08 ± 8,64 %, onde a percentagem mais elevada foi obtida com a concentração de 30 μg/ml. Os resultados foram inferiores aos do controlo positivo (EDTA), cujas percentagens de inibição rondaram os 100 %. No ensaio do DPPH, o extrato do baobá obteve um IC50 de 656,97 ± 12,45 μg/ml, valor muito acima do controlo positivo usado, a quercetina (IC50 = 1,8 μg/ml). Os estudos de avaliação da atividade antioxidante existentes na literatura com a planta têm sido realizados com diferentes solventes (ex: água, metanol, acetona) e partes da planta (ex: folhas, polpa do fruto). Num estudo de Irondi et al., (2016) o extrato metanólico, proveniente de folhas de baobá, demonstrou um valor de IC50 para o ensaio de DPPH de 230 ± 0,01 μg/ml. Por sua vez, num estudo de Ismail et al., (2019) os melhores valores de FRAP foram obtidos com 80% acetona (5141,19 ± 45,37 mg Trolox/100 g peso seco); os melhores valores de DPPH obtiveram-se com acetona acídica (acetona + água + HCl) (80:19:1; V/V/V) (2501,46 ± 50,61 mg Trolox/100 g peso seco) e com 80% acetona (2390,07 ± 49,15 mg Trolox/100 g peso seco). Alguns autores consideram que os extratos vegetais têm uma atividade antioxidante elevada ou significativa quando os ensaios apresentam valores de IC50 < 50 μg/ml; uma atividade moderada com valores de IC50 entre 50 e 100 μg/ml; e uma atividade antioxidante baixa com valores de IC50 > 100 μg/ml. Os resultados obtidos neste estudo demonstram que o extrato de baobá analisado parece ter uma baixa atividade antioxidante. Contudo, são necessários mais estudos com a planta, utilizando ensaios complementares e diferentes técnicas extrativas,no sentido de confirmar o potencial antioxidante do extrato etanólico de baobá.
- Avaliação in vitro da segurança do extrato etanólico da Adansonia digitata em células cutâneasPublication . Santos, Daniela; Carvalho, Daniel; Rente, Ana; Silva, Jorge; Caldevilla, Renato; Cardoso, Andreia; Oliveira, Ana Isabel; Pinho, CláudiaO baobá (Adonsonia digatata) é uma árvore nativa de África, pertencente à família Bombacaceae e ao género Adansonia. É utilizada na medicina tradicional africana para o tratamento de diversas doenças devido às suas atividades anti-inflamatórias, antioxidantes e antimicrobianas, tendo atraído o interesse da indústria farmacêutica. Com base na eficácia de diversos extratos de A. digitata, tem sido colocada a hipótese de que a planta poderá exibir também outras atividades biológicas, no entanto os dados relativos à sua toxicidade são ainda escassos. Desta forma, o trabalho tem como principal objetivo avaliar a segurança, in vitro, do extrato etanólico de A. digitata, numa linhagem de células da pele (HaCaT). Trata-se de um estudo experimental com análise do extrato etanólico a 70 %(V/V) de frutos de A. digitata. Para a determinação da segurança do extrato numa linhagem celular de queratinócitos humanos (HaCaT), recorreu-se ao ensaio do brometo de 3-(4,5-dimetiltiazol-2-il)-2,5-difeniltetrazólio (MTT). No ensaio MTT, o extrato de baobá testado em concentrações que variaram de 5 μg/ml a 1000 μg/ml, apresentou percentagens de viabilidade celular entre os 77,81 ± 0,5 % e 131,22 ± 9,6 %, sendo que nas concentrações inferiores a 500μg/ml, os valores de viabilidade obtidos foram superiores a 100 %. O valor mais alto encontrado foi na concentração de 5 μg/ml. Desta forma, o extrato parece ter um efeito não citotóxico nas células HaCaT, após 48 horas de incubação. De acordo com o National Cancer Institute, um extrato bruto é geralmente considerado como tendo atividade citotóxica in vitro se o IC50é < 20 μg/mL Partindo deste pressuposto, os resultados do extrato etanólico de baobá podem providenciar um suporte quanto à segurança do seu uso tradicional. Os estudos de citotoxicidade de extratos de baobá são escassos, no entanto, no seu estudo, Dzoyemet al., (2014) demonstraram que o extrato do fruto de baobá, preparado com acetona, apresentou um IC50de 204 ± 0,01 μg/ml contra células Vero, após 48 horas de incubação. O baobá em concentrações inferiores a 500 μg/ml parece ser seguro para a linhagem celular estudada. Contudo, mais estudos são necessários para se concluir sobre a sua atividade protetora em concentrações mais altas nesta e noutras linhagens celulares, assim como em extratos preparados com outros solventes e diferentes partes da planta.
- CYTED Network: GEnoPsySEn - Development of genosensors for pharmacogenomic targets in the central nervous systemPublication . Santos, Marlene; Caldevilla, Renato; Grosso, Clara; Simal-Gandara, J.; Molina, Patricia G.; Pinto, Giovanny R.; Villa, Cristian C.; Serra, Gloria; Feria-Romero, Iris A.; Solano, Ovidio; Sanabria, Diana P. Dresseler; Souto, Pilar Villaverde; Comba, Fausto N.; Barroso, M. FátimaThe GenoPsySEN thematic network is a newly CYTED approved collaborative project between institutions and investigators from Argentina, Brazil, Colombia, El Salvador, Mexico, Spain, Paraguay, Portugal, and Uruguay, aimed at incorporating their expertise in various scientific disciplines into the successful development of genosensors for the detection of genetic variations affecting drug response in neuropsychiatric diseases. This project seeks to transfer scientific and technological results that can be applied to improve the Ibero-American Public Health Systems and contribute to reducing the number of patients without adequate treatment.