Degree: Doctor



Showing 5 latest publications. Total publications: 320
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1. From Non-Alcoholic Fatty Liver to Hepatocellular Carcinoma: A Story of (Mal)Adapted Mitochondria, Amorim, R; Magalhaes, CC; Borges, F Oliveira, PJ; Teixeira, J in BIOLOGY-BASEL, 2023, Volume: 12, 
Review,  Indexed in: crossref, scopus, wos  DOI: 10.3390/biology12040595 P-00Y-BMD
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.

2. Propargylamine: an important moiety in drug discovery, Carneiro, A; Uriarte, E; Borges, F Matos, MJ in FUTURE MEDICINAL CHEMISTRY, 2023, ISSN: 1756-8919,  Volume: 15, 
Review,  Indexed in: crossref, scopus, wos  DOI: 10.4155/fmc-2022-0243 P-00Y-43C
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.

3. Drug discovery and amyotrophic lateral sclerosis: Emerging challenges and therapeutic opportunities, Soares, P; Silva, C; Chavarria, D; Silva, FSG; Oliveira, PJ; Borges, F in AGEING RESEARCH REVIEWS, 2023, ISSN: 1568-1637,  Volume: 83, 
Review,  Indexed in: crossref, wos  DOI: 10.1016/j.arr.2022.101790 P-00X-G0Q
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.

4. Modulating Cytotoxicity with Lego-like Chemistry: Upgrading Mitochondriotropic Antioxidants with Prototypical Cationic Carrier Bricks, Benfeito, S; Fernandes, C; Chavarria, D; Barreiro, S; Cagide, F; Sequeira, L; Teixeira, J; Silva, R; Remiao, F; Oliveira, PJ; Uriarte, E; Borges, F in JOURNAL OF MEDICINAL CHEMISTRY, 2023, ISSN: 0022-2623,  Volume: 66, 
Article,  Indexed in: wos  DOI: 10.1021/acs.jmedchem.2c01630 P-00Z-WFT
Abstract Although the lipophilic triphenylphosphonium (TPP+) cation is widely used to target antioxidants to mitochondria, TPP+- based derivatives have shown cytotoxicity in several biological in vitro models. We confirmed that Mito.TPP is cytotoxic to both human neuronal (SH-SY5Y) and hepatic (HepG2) cells, decreasing intra-cellular adenosine triphosphate (ATP) levels, leading to mitochondrial membrane depolarization and reduced mitochondrial mass after 24 h. We surpassed this concern using nitrogen-derived cationic carriers (Mito.PICO, Mito.ISOQ, and Mito.IMIDZ). As opposed to Mito.TPP, these novel compounds were not cytotoxic to SH-SY5Y and HepG2 cells up to 50 mu M and after 24 h of incubation. All of the cationic derivatives accumulated inside the mitochondrial matrix and acted as neuroprotective agents against iron(III), hydrogen peroxide, and tert-butyl hydroperoxide insults. The overall data showed that nitrogen-based cationic carriers can modulate the biological performance of mitochondria-directed antioxidants and are an alternative to the TPP cation.

5. Sulfonamide a Valid Scaffold for Antioxidant Drug Development, Egbujor, MC; Garrido, J; Borges, F Saso, L in MINI-REVIEWS IN ORGANIC CHEMISTRY, 2023, ISSN: 1570-193X,  Volume: 20, 
Review,  Indexed in: crossref, wos  DOI: 10.2174/1570193x19666220411134006 P-00X-4T1
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.