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- Evaluation of Specific Anthraquinones as New catechol-O-methyltransferase Inhibitors: Virtual Docking, Molecular Dynamics, Inhibition and Cytotoxicity In Vitro StudiesPublication . Proença, Fábio Alexandre Esteves; Passarinha, Luís António Paulino; Silvestre, Samuel MartinsParkinson´s disease (PD) is the second most prevalent age-related neurodegenerative disorder around the world, with no cure currently in sight. This condition is caused by the gradual loss of the brain's dopaminergic neurons, in the substantia nigra pars compacta of the brain. This progressive neuronal loss leads to the typical symptoms of the disease characterized by rigidity, resting tremor, bradykinesia, and postural imbalance. Actually, the conventional therapy for this pathology consists in the administration of oral levodopa (L-DOPA), a natural dopamine precursor, and two enzymatic inhibitors: one for Catechol-O-Methyltransferase (COMT) and the other for the peripheral aromatic L-amino acid decarboxylase (AADC). In terms of central nervous system, AADC can transform the administered L-DOPA in dopamine, and both substances, at central and peripheral level, can be metabolized by COMT. In humans, the COMT enzyme is present in two isoforms, a soluble isoform (S-COMT) and the membrane-bounded isoform (MB-COMT). Despite their similarities in the primary amino acid sequences, there is a accentuated difference in the kinetic behavior of both isoforms. MB-COMT tends to have a higher affinity for the substrate (lower Km) than SCOMT. On the other hand, S-COMT has a much higher catalytic reaction capacity (Vmax) than MB-COMT. Those differences in the kinetic behavior of the isoforms determined the role of the isoenzymes, with MB-COMT being physiologically more relevant due to its role in catecholamine methylation at physiological concentrations. Typically, COMT inhibitors enhance L-DOPA and dopamine bioavailability and effectiveness. However, they are often associated with toxicity and/or limited ability to cross the blood-brain barrier (BBB). This underscored the need to discover/ develop novel molecules with greater potency, reduced toxicity, and better pharmacokinetic properties than the existing inhibitors in clinical use. This dissertation investigates the potential of anthraquinones as potential COMT inhibitors, based on their molecular skeleton similarity with tolcapone. Anthraquinones are a subclass of quinones derived from anthracene with anti-tumor, anti-inflammatory, and neuroprotective properties, among others. They are characterized by having three planar rings with two ketones groups on the second ring. The inhibition of MB-COMT by nine anthraquinone family compounds was evaluated in vitro, using an analytical method previously described by the research group. From the obtained results, four of the nine compounds in study exhibited an enzymatic inhibition capacity close to 60%, at 100 µM. After, a cytotoxicity evaluation was performed for these 4 compounds by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays using two different cell lines, normal human dermal fibroblasts (NHDF) and a rat dopaminergic neural cell line (N27). From that cytotoxic evaluation it was observed that the compounds in study displayed a cytotoxicity profile similar to the described inhibitor, tolcapone. In silico trials were performed using Autodock Vina complementing the in vitro findings by analyzing interactions and the positioning of the compounds in relation to the protein´s active center. The results were ranked based on the binding energy and key interactions with critical residues for MB-COMT´s catalytic capacity. Promising molecules were further analyzed using molecular dynamics simulations, using the commercial inhibitor tolcapone as a positive control. The principal Adsorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties were also predicted intending to complement the pharmacokinetic analysis and toxicity of the molecules. The in vitro and in silico obtained results suggest that purpurin, alizarin, 3-nitroalizarin and lucidin are promising candidates as COMT inhibitors, however, half maximal inhibitory concentration (IC50) assays for the enzymatic inhibition and for cytotoxicity, need to be performed to properly evaluate the potential of this molecules.
- Impacto do Projeto Intergeracional Aldeias Educadoras na qualidade do sono, estado cognitivo, ansiedade e sintomatologia depressivaPublication . Barbosa, Luísa Maria Rodrigues Silva Correia; Afonso, Rosa Marina Lopes Brás Martins; Patto, Maria da Assunção Morais e Cunha VazIntrodução: O envelhecimento é um processo natural e dinâmico marcado por uma sequência de perdas funcionais experienciadas de forma diferente por cada adulto mais velho, tornando-os vulneráveis ao isolamento social e ao declínio do bem-estar emocional. Os programas intergeracionais, como o projeto “Aldeias Educadoras”, surgem como uma estratégia para promover o envelhecimento ativo, com potencial de melhorar o bem-estar biopsicossocial dos adultos idosos. Esta investigação visa avaliar o impacto deste projeto a nível da qualidade do sono, estado cognitivo, depressão e ansiedade dos sujeitos intervencionados, focando-se na participação social de idosos em atividades comunitárias e escolares. Materiais e Métodos: Trata-se de um estudo quasi-experimental com comparação pré e pós intervenção desenvolvido com 19 participantes, 5 do sexo masculino e 14 do sexo feminino, com idades entre os 67-83 anos, residentes em meio rural. O programa consistiu na implementação de sessões na comunidade e na escola, durante 9 meses, onde os adultos mais velhos partilhavam e exploravam temas sobre a identidade local. Foram analisados parâmetros médicos e psicológicos, com ênfase na qualidade do sono (avaliada por uma adaptação do Índice de Qualidade do Sono de Pittsburgh), estado cognitivo (Mini-Mental State Examination), depressão (Escala de Depressão Geriátrica) e ansiedade (Inventário Geriátrico de Ansiedade). Resultados: Os resultados indicaram uma redução significativa nos níveis de depressão (p<0,001) e ansiedade (p=0,003) após a intervenção, sugerindo um impacto positivo das atividades intergeracionais e suporte emocional proporcionado aos idosos. No entanto, as variáveis relacionadas à qualidade do sono (p=0,404) e ao estado cognitivo (p= 0,165) não apresentaram mudanças estatisticamente significativas. Conclusão: Os resultados sugerem benefícios decorrentes da participação na intervenção intergeracional "Aldeias Educadoras" no envelhecimento ativo dos participantes mais velhos. No entanto, estudos mais aprofundados e metodologicamente mais robustos são recomendados para fornecer uma visão mais abrangente e compreensiva dos efeitos de programas intergeracionais, especialmente a nível do estado cognitivo e da qualidade do sono.