Faculdade de Ciências e Tecnologia
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Browsing Faculdade de Ciências e Tecnologia by Field of Science and Technology (FOS) "Ciências Médicas"
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- Antibiotherapy of infections caused by multidrug-resistant Gram-positive cocciPublication . Matos, Carlos Adriano Albuquerque Andrade de; Conceição, Jaime Manuel Guedes Morais daSince the discovery of penicillin almost 100 years ago, antibiotics have revolutionized the treatment of many bacterial infections that were previously incurable and often lethal. Nonetheless, success of antibiotherapy is currently challenged by the emergence and dissemination of antimicrobial resistance, which occurs when changes in microorganisms render drugs ineffective. Misuse of antibiotics in humans, animals and the environment is often presented as one of the main causes for the selection of microorganisms that are increasingly resistant to currently available antimicrobial agents. Infections by resistant pathogens constitute one of the most important threats to global public health in the 21st century, being associated with high levels of morbidity and mortality, as well as a significant economic burden. Recent estimates suggest that, in 2019, approximately 1.27 million deaths worldwide were attributable to antibiotic-resistant bacterial infections. Among these, more than 141.000 deaths were attributable to three multidrug-resistant Gram-positive cocci, namely: methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Staphylococcus aureus (VRSA) and vancomycin-resistant Enterococcus (VRE). These bacteria are responsible for a large percentage of nosocomial infections and constitute a priority for new antimicrobial drug development. This Dissertation aims to explore and analyze the current pharmacological approaches to the treatment of infections caused by the above bacteria. A description of these pathogens will be performed, addressing, among other relevant characteristics, their principal resistance mechanisms and the main clinical syndromes they can cause. Then, current antibiotherapeutic approaches used to manage each syndrome will be presented. The main pharmacological characteristics of each of the principal drugs mentioned in this context will be described, including its mechanism of action, posology and administration route, pharmacokinetic features, undesirable effects and main pharmacological interactions. Comprehension of existing antibiotherapy practices will contribute to the optimization of the use of available medicines and will help delineate the future of multi-drug resistant Gram-positive cocci anti-infective chemotherapy.
- Characterization of the contribution of S-nitrosylated proteins to the aggregation of alpha-synuclein in Parkinson´s DiseasePublication . Teixeira, Mariana Filipa Fernandes; Araújo, Inês; Outeiro, TiagoAlpha-synuclein (-Syn) is present in Lewy Bodies and its aggregation has been associated with Parkinson's disease (PD). However, the cause of -Syn aggregation is unknown. An increase in reactive nitrogen species (RNS) in PD has been described, which can lead to oxidative posttranslational modifications such as S-nitrosylation. This chemical process involves the covalent attachment of a nitric oxide group (NO) to a cysteine thiol within a protein to generate an S-nitrosothiol (SNO). Because it does not have cysteine residues in its structure, -Syn is not a direct target of S-nitrosylation. When S-nitrosylated, enzymes such as protein disulfide isomerase (PDI) and serine racemase (SR) can cause misfolded proteins to aggregate. Nonetheless, no research has been conducted to determine how S-nitrosylation of these proteins is involved in -Syn aggregation. The current study aimed to determine how S-nitrosylation in the proteome, induced by CysNO treatment, affects -Syn aggregation and cell viability by examining the presence of -Syn aggregates and cleaved caspase-3 in SH-SY5Y cells expressing WT, A53T, or A30P -Syn. The western blot results indicate that PDI is indeed S-nitrosylated. However, SR was not proven to be S-nitrosylated. These results indicate that only one protein (PDI) may contribute to the aggregation process of - Syn. Using the immunocytochemistry technique, the percentage of transfected cells, the number of transfected cells with aggregates, the presence of cleaved caspase-3 (an indicator of cell death) and the presence of condensed/fragmented nuclei were quantified. These results showed that S-nitrosylation increases aggregation of -Syn, depending on its form. And that the amount of cytotoxicity present in cells exposed to CysNO is not significant. These studies suggest that S-nitrosylation may increase the aggregation process of -Syn. Future studies could elucidate a cause-effect between the nitrosylation of proteins such as PDI and the aggregation of -Syn.