Publications

Abstract Propargylamine is a chemical moiety whose properties have made it a widely distributed group within the fields of medicinal chemistry and chemical biology. Its particular reactivity has traditionally popularized the preparation of propargylamine derivatives using a large variety of synthetic strategies, which have facilitated the access to these compounds for the study of their biomedical potential. This review comprehensively covers and analyzes the applications that propargylamine-based derivatives have achieved in the drug discovery field, both from a medicinal chemistry perspective and from a chemical biology-oriented approach. The principal therapeutic fields where propargylamine-based compounds have made an impact are identified, and a discussion of their influence and growing potential is included. Tweetable abstractPropargylamine derivatives are commonly present in various areas of #drugdiscovery. In this new @fsgfmc review article, scientists @aitorcarneiro and @mariacmatos from @UPorto and @UniversidadeUSC discuss the reasons underlying recent uses and applications of these compounds.

Abstract Like the well-known sulfa drugs, Sulfonamides are ascribed to a myriad of biological activities, including antioxidant activity. In fact, several tertiary sulfonamides, particularly N, N-disubstituted analogues, are recognized as antioxidants that can prevent or minimize oxidative damage associated with several oxidative-stress-related diseases. The structural diversity of this class of compounds paved the way for drug discovery programs aimed at finding therapeutic agents. Attributes such as low-cost synthetic procedures, easy accessibility of reagents, and a broad spectrum of biological activities made sulfonamides and derivatives excellent candidates for synthesizing chemical libraries with structural diversity. Sulfonamide-based drugs are most of the sulfur-containing drugs approved by the United States Food and Drug Administration (FDA). Although sulfonamide derivatives have been extensively exploited as antibacterial agents, their therapeutic potential as antioxidants is relatively underexplored despite the prevalence of oxidative stress-mediated diseases and the urgent need for new and more effective antioxidant drugs. Some sulfonamide derivatives were shown to activate the nuclear factor erythroid 2-related factor 2 (Nrf2), the main regulator of the endogenous antioxidant response, a critical process used by cells in response to oxidative stress. The antioxidant role of sulfonamides and derivatives as Nrf2 activators is also reviewed. The antioxidant mechanism of action of sulfonamides has not been fully clarified, but as they have antioxidant properties, it is a subject worthy of in-depth study. The present review is focused on sulfonamides and derivatives as potential antioxidants along the period 2013-2021 and intends to stimulate research in the area.

Abstract Ferroptosis is a type of regulated cell death characterized by intracellular accumulation of iron and reactive oxy-gen species, inhibition of system Xc-, glutathione depletion, nicotinamide adenine dinucleotide phosphate oxida-tion and lipid peroxidation. Since its discovery and characterization in 2012, many efforts have been made to reveal the underlying mechanisms, modulating compounds, and its involvement in disease pathways.Ferroptosis inducers include erastin, sorafenib, sulfasalazine and glutamate, which, by inhibiting system Xc-, pre-vent the import of cysteine into the cells. RSL3, statins, Ml162 and Ml210 induce ferroptosis by inhibiting gluta-thione peroxidase 4 (GPX4), which is responsible for preventing the formation of lipid peroxides, and FIN56 and withaferin trigger GPX4 degradation. On the other side, ferroptosis inhibitors include ferrostatin-1, liproxstatin-1, alpha-tocopherol, zileuton, FSP1, CoQ10 and BH4, which interrupt the lipid peroxidation cascade. Additionally, deferoxamine, deferiprone and N-acetylcysteine, by targeting other cellular pathways, have also been classified as ferroptosis inhibitors.Increased evidence has established the involvement of ferroptosis in distinct brain diseases, including Alzheimer's, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis, multiple sclerosis, and Friedreich's ataxia. Thus, a deep understanding of how ferroptosis contributes to these diseases, and how it can be modulated, can open a new window of opportunities for novel therapeutic strategies and targets. Other stud-ies have shown a sensitivity of cancer cells with mutated RAS to ferroptosis induction and that chemotherapeutic agents and ferroptosis inducers synergize in tumor treatment. Thus, it is tempting to consider that ferroptosis may arise as a target mechanistic pathway for the treatment of brain tumors.Therefore, this work provides an up-to-date review on the molecular and cellular mechanisms of ferroptosis and their involvement in brain diseases. In addition, information on the main ferroptosis inducers and inhibitors and their molecular targets is also provided.(c) 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

Abstract The Portuguese Decree-Law No. 102-D/2020, of December 10 (PCM, 2020b), dictates the implementation of biowaste selective collection networks or the separation and recycling of biowaste at the source until December 31, 2023. This chapter aims to analyze the financial support provided to municipalities (local authorities) for implementing biowaste collection solutions, such as on public roads or through door-to-door collection, and to citizens for adopting biowaste separation and recycling practices through domestic or community composting. The authors also explore the application of the polluter-pays principle, which requires citizens to pay environmental taxes and fees to support sustainable development. Regarding this focus, the chapter highlights the legal, financial, and fiscal measures used to support biowaste collection and recycling efforts in Portugal, providing insight into the steps needed to achieve a sustainable environment while addressing the economic and social needs of the population. © 2023, IGI Global.

Abstract Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of upper and lower motor neurons (MNs) leading to paralysis and, ultimately, death by respiratory failure 3-5 years after diagnosis. Edaravone and Riluzole, the only drugs currently approved for ALS treatment, only provide mild symptomatic relief to patients. Extraordinary progress in understanding the biology of ALS provided new grounds for drug discovery. Over the last two decades, mitochondria and oxidative stress (OS), iron metabolism and ferroptosis, and the major reg-ulators of hypoxia and inflammation - HIF and NF-kappa B - emerged as promising targets for ALS therapeutic intervention. In this review, we focused our attention on these targets to outline and discuss current advances in ALS drug development. Based on the challenges and the roadblocks, we believe that the rational design of multi -target ligands able to modulate the complex network of events behind the disease can provide effective therapies in a foreseeable future.

Abstract Psychiatric and neurological disorders affect millions of people worldwide. Currently available treatments may help to improve symptoms, but they cannot cure the diseases. Therefore, there is an urgent need for potent and safe therapeutic solutions. 8-Amide and 8-carbamatecoumarins were synthetized and evaluated as human monoamine oxidase A and B (hMAO-A and hMAO-B) inhibitors. Comparison between both scaffolds has been established, and we hypothesized that the introduction of different substituents can modulate hMAO activity and selectivity. N-(7-Hydroxy-4-methylcoumarin-8-yl)-4-methylbenzamide (9) and ethyl N-(7-hydroxy-4-methylcoumarin-8-yl)carbamate (20) proved to be the most active and selective hMAO-A inhibitors (IC50 = 15.0 nM and IC50 = 22.0 nM, respectively), being compound 9 an irreversible hMAO-A inhibitor twenty-four times more active in vitro than moclobemide, a drug used in the treatment of depression and anxiety. Based on PAMPA assay results, both compounds proved to be good candidates to cross the blood-brain barrier. In addition, these compounds showed non-significant cytotoxicity on neuronal viability assays. Also, the best compound proved to have a t1/2 of 6.84 min, an intrinsic clearance of 195.63 mu L min-1 mg-1 protein, and to be chemically stable at pH 3.0, 7.4 and 10.0. Docking studies were performed to better understand the binding affinities and selectivity profiles for both hMAO isoforms. Finally, theoretical drug-like properties calculations corroborate the potential of both scaffolds on the search for new therapeutic solutions for psychiatric disorders as depression.

Abstract The European Union (EU) prioritises sustainable development and aims to achieve climate neutrality by 2050 through investments in green technologies and a legislative climate framework. Waste collection and treatment systems, including biowaste like food waste, protect natural capital and citizens' well-being. Directive 2008/98/EC defines biowaste and sets the stage for exploring alternative solutions. This study focuses on the city of Guarda (Portugal) and analyses the use of disposers for food waste treatment. By comparing storage/collection systems with disposers regarding environmental and economic costs and benefits, the study aims to determine the most effective solution for collecting food waste. The analysis utilises a simulator provided by the Portuguese Fundo Ambiental (R). The results show that while operating costs are higher for food waste collection systems, disposers require a more significant initial investment. Nevertheless, the cost-benefit ratio favours disposers, while the net present value analysis suggests that the food waste collection system is more favourable. Additionally, food waste collection systems contribute to higher greenhouse gas (GHG) emissions per tonne of food waste compared to using disposers.

Abstract Simple Summary Non-alcoholic fatty liver disease (NAFLD) is a global pandemic that affects 25% of the world's population and represents a serious health and economic concern worldwide resulting from unhealthy dietary habits combined with a sedentary lifestyle, although genetic contributions have been documented. Although the molecular mechanisms that cause the progression are not fully understood, metabolic-dysfunction-associated fatty liver disease is strong evidence that mitochondrial dysfunction plays a significant role in NAFLD. This review postulates that the regulation of hepatocytes' mitochondrial physiology to maintain hepatic mitochondrial mass, integrity, and function are differently altered during NAFLD progression. This review summarizes evidence linking mitochondrial (dys)function with NAFLD pathophysiology, discriminating it in different disease stages (simple steatosis, steatohepatitis, liver fibrosis, cirrhosis, and hepatocellular carcinoma). As mitochondrial dysfunction is considered a driving force in NAFLD progression, targeting hepatocytes' mitochondrial physiology could contribute to establishing an effective therapy for NAFLD. However, additional studies on distinct mitochondrial sub-populations roles in NAFLD, the impact of mitochondrial (mis)communication with other subcellular organelles (peroxisomes and lipid droplets), the impact of negligible pathways, such as fatty acid oxidation, de novo lipogenesis, and the pentose phosphate pathway in the hepatocytes' mitochondrial physiology in different stages of NAFLD are topics to explore. Non-alcoholic fatty liver disease (NAFLD) is a global pandemic affecting 25% of the world's population and is a serious health and economic concern worldwide. NAFLD is mainly the result of unhealthy dietary habits combined with sedentary lifestyle, although some genetic contributions to NAFLD have been documented. NAFLD is characterized by the excessive accumulation of triglycerides (TGs) in hepatocytes and encompasses a spectrum of chronic liver abnormalities, ranging from simple steatosis (NAFL) to steatohepatitis (NASH), significant liver fibrosis, cirrhosis, and hepatocellular carcinoma. Although the molecular mechanisms that cause the progression of steatosis to severe liver damage are not fully understood, metabolic-dysfunction-associated fatty liver disease is strong evidence that mitochondrial dysfunction plays a significant role in the development and progression of NAFLD. Mitochondria are highly dynamic organelles that undergo functional and structural adaptations to meet the metabolic requirements of the cell. Alterations in nutrient availability or cellular energy needs can modify mitochondria formation through biogenesis or the opposite processes of fission and fusion and fragmentation. In NAFL, simple steatosis can be seen as an adaptive response to storing lipotoxic free fatty acids (FFAs) as inert TGs due to chronic perturbation in lipid metabolism and lipotoxic insults. However, when liver hepatocytes' adaptive mechanisms are overburdened, lipotoxicity occurs, contributing to reactive oxygen species (ROS) formation, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress. Impaired mitochondrial fatty acid oxidation, reduction in mitochondrial quality, and disrupted mitochondrial function are associated with a decrease in the energy levels and impaired redox balance and negatively affect mitochondria hepatocyte tolerance towards damaging hits. However, the sequence of events underlying mitochondrial failure from steatosis to hepatocarcinoma is still yet to be fully clarified. This review provides an overview of our understanding of mitochondrial adaptation in initial NAFLD stages and highlights how hepatic mitochondrial dysfunction and heterogeneity contribute to disease pathophysiology progression, from steatosis to hepatocellular carcinoma. Improving our understanding of different aspects of hepatocytes' mitochondrial physiology in the context of disease development and progression is crucial to improving diagnosis, management, and therapy of NAFLD/NASH.

Abstract Ferroptosis is a type of regulated cell death promoted by the appearance of oxidative perturbations in the intracellular microenvironment constitutively controlled by glutathione peroxidase 4 (GPX4). It is characterized by increased production of reactive oxygen species, intracellular iron accumulation, lipid peroxidation, inhibition of system Xc-, glutathione depletion, and decreased GPX4 activity. Several pieces of evidence support the involvement of ferroptosis in distinct neurodegenerative diseases. In vitro and in vivo models allow a reliable transition to clinical studies. Several in vitro models, including differentiated SH-SY5Y and PC12 cells, among others, have been used to investigate the pathophysiological mechanisms of distinct neurodegenerative diseases, including ferroptosis. In addition, they can be useful in the development of potential ferroptosis inhibitors that can be used as disease-modifying drugs for the treatment of such diseases. On the other hand, in vivo models based on the manipulation of rodents and invertebrate animals, such as Drosophila melanogaster, Caenorhabditis elegans, and zebrafish, have been increasingly used for research in neurodegeneration. This work provides an up-to-date review of the main in vitro and in vivo models that can be used to evaluate ferroptosis in the most prevalent neurodegenerative diseases, and to explore potential new drug targets and novel drug candidates for effective disease-modifying therapies.

Abstract <jats:title>Abstract</jats:title> <jats:p>In recent decades, the increasing demand for energy and raw materials in modern societies has led to a significant increase in mining exploration. However, this has also sparked the emergence of movements against mining exploration all over the world, particularly in Europe. During the operation of open pit mines, materials are deposited on the surface and subjected to weathering processes. These processes can create an environmental impact by causing the migration of chemical elements from soils to waters. Given the importance of the theme of water and soil contamination nowadays, it is important to verify the potential environmental impact resulting from open pit mine exploration. Laboratory tests were used to simulate weather conditions due to leaching of soils in a lithiniferous feldspar mine located in the centre of Portugal. Soil samples, resulting from the activity of the C57 mine (Guarda, Portugal) were collected and determined its granulometry. Water samples (surface and underground) were also collected in the area to allow a characterization of the existing waters upstream and downstream of the mining operation. To simulate the soil leaching process, the Soxhlet extractor method was utilized, and spectroscopic methods were used to determine the alkali and alkaline earth metals, as well as the transition and post-transition metals. Upon comparison with the results obtained for surface and groundwater, the findings suggest that there are notable concentrations of certain elements in the weathering solution, throughout the 3,000-hour duration of the laboratory test. This indicates that, for certain chemical elements, particularly aluminium and chromium, there may be some adverse effects on water quality.</jats:p>