Synthesis and Evaluation of Phenolic Metabolites and Analogues

• Autor(a) principal: Mendes, Diogo Cardoso
• Data de Publicação: 2022
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
• Texto Completo: http://hdl.handle.net/10362/133840
• topic: (Poly)phenol metabolites; Microbiota; Microglia; Neuro-inflammation; Halogenated analogues; Domínio/Área Científica::Engenharia e Tecnologia::Outras Engenharias e Tecnologias

Flavonoids are one of the most dominant family of (poly)phenol compounds found in fruits and vegetables from human dietary habits. Flavonoids, however, have been shown to be metabolized by gut microbiota into several phenolic metabolites. Such phenolic metabolites have been identified in human circulation and demonstrated to possess several therapeutic applications, such as modulating microglial inflammatory response, meanwhile being capable of crossing the blood brain barrier (BBB) [1]. Nevertheless, the study of these phenolic metabolites remain lacking since many are not commercially available and have never been synthesized. In our work novel phenolic metabolites, including sulfate, glucuronide, glycine and glutathione conjugates, have been synthetized and their ability to attenuate microglia mediated neuroinflammation, a central hallmark of neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease, tested. To address neuroinflammation the capability of the phenolic metabolites to decrease the release of inflammatory cytokines i.e. TNF-α in a model of N9 microglia cell line stimulated with lipopolysaccharides (LPS) was evaluated. The results revelated that many phenolic metabolites could reduce the release of this cytokine, while showing no cytotoxic effects. To add to this effort, we also synthesized halogenated analogues of these phenolic metabolites to ascertain if this structural change could provide a better suppression of microglia mediated neuroinflammation. Overall, our results exemplify the potential anti-inflammatory effects of dietary and gut microbiota-derived phenolic metabolites and analogues in alleviating microglia mediated neuroinflammation and further clarify their role in the prevention of neurodegenerative diseases.