Showing: 10 from total: 2087 publications
21. 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 
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.

22. Research Models to Study Ferroptosis's Impact in Neurodegenerative Diseases
Costa, I ; Barbosa, DJ ; Silva, V ; Benfeito, S ; Borges, F ; Remiao, F ; Silva, R
in PHARMACEUTICS, 2023, Volume: 15, 
Review,  Indexed in: crossref, scopus, wos 
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.

23. Unraveling the In Vitro Toxicity Profile of Psychedelic 2C Phenethylamines and Their N-Benzylphenethylamine (NBOMe) Analogues
Martins, D ; Gil-Martins, E ; Cagide, F ; da Fonseca, C ; Benfeito, S ; Fernandes, C ; Chavarria, D ; Remiao, F ; Silva, R ; Borges, F
in PHARMACEUTICALS, 2023, ISSN: 1424-8247,  Volume: 16, 
Article,  Indexed in: crossref, scopus, wos 
Abstract Mescaline derivative (2C phenethylamines) drugs have been modified by the introduction of a N-2-methoxybenzyl group to originate a new series of compounds with recognized and potent psychedelic effects, the NBOMe-drugs. Although they are prevalent in unregulated drug markets, their toxicity profile is still poorly understood, despite several reports highlighting cases of acute intoxication, with brain and liver toxicity. Thus, in this study, mescaline, 2C-N (insertion of a nitro in the para position of the 2C phenethylamines aromatic ring) and 2C-B (insertion of a bromide in the para position of the 2C phenethylamines aromatic ring) and their corresponding NBOMe counterparts, mescaline-NBOMe, 25N-NBOMe and 25B-NBOMe, were synthetized and the in vitro neuro- and hepatocytotoxicity evaluated in differentiated SH-SY5Y and HepG2 cell lines, respectively. Cytotoxicity, oxidative stress, metabolic and energetic studies were performed to evaluate the main pathways involved in their toxicity. Our results demonstrated that the presence of the N-2-methoxybenzyl group significantly increased the in vitro cytotoxicity of 2C phenethylamines drugs in both cell lines, with the NBOMe drugs presenting lower EC50 values when compared to their counterparts. Consistently, our data showed a correlation between the drug's lipophilicity and the EC50 values, except for 2C-B. The 2C-B presented higher cytotoxic effects in both cell lines than mescaline-NBOMe, a result that can be explained by its higher passive permeability. All the NBOMe derivatives were able to cross the blood-brain barrier. Considering metabolic studies, the cytotoxicity of these drugs was shown to be influenced by inhibition of cytochrome P450 (CYP), which suggests a potential role of this enzyme complex, especially CYP3A4 and CYP2D6 isoenzymes in SH-SY5Y cells, in their detoxification or bioactivation. Furthermore, in differentiated SH-SY5Y cells, the drugs were able to induce mitochondrial membrane depolarization, and to disrupt GSH and ATP intracellular levels, these effects being concentration dependent and more pronounced for the NBOMe derivatives. No ROS overproduction was detected for any of the drugs in the tested experimental conditions. A correlation between a drug's lipophilicity and the EC50 values in both cell lines, except for 2C-B, was also obtained. In summary, the introduction of a NBOMe moiety to the parent drugs significantly increases their lipophilicity, brain permeability and cytotoxic effects, with GSH and ATP homeostasis disruption. The inhibition of CYP3A4 and CYP2D6 emphasized that CYP-mediated metabolism impacts the toxicity of these drugs.

24. Rivastigmine–Benzimidazole Hybrids as Promising Multitarget Metal-Modulating Compounds for Potential Treatment of Neurodegenerative Diseases
Vicente-Zurdo, D ; Brunetti, L ; Piemontese, L ; Guedes, B ; Cardoso, SM ; Chavarria, D ; Borges, F ; Madrid, Y ; Chaves, S ; Santos, MA
in International Journal of Molecular Sciences, 2023, Volume: 24, 
Article,  Indexed in: crossref 
Abstract <jats:p>With the goal of combating the multi-faceted Alzheimer’s disease (AD), a series of Rivastigmine-Benzimidazole (RIV–BIM) hybrids was recently reported by us as multitarget-directed ligands, thanks to their capacity to tackle important hallmarks of AD. In particular, they exhibited antioxidant activity, acted as cholinesterase inhibitors, and inhibited amyloid-β (Aβ) aggregation. Herein, we moved forward in this project, studying their ability to chelate redox-active biometal ions, Cu(II) and Fe(III), with widely recognized roles in the generation of oxidative reactive species and in protein misfolding and aggregation in both AD and Parkinson’s disease (PD). Although Cu(II) chelation showed higher efficiency for the positional isomers of series 5 than those of series 4 of the hybrids, the Aβ-aggregation inhibition appears more dependent on their capacity for fibril intercalation than on copper chelation. Since monoamine oxidases (MAOs) are also important targets for the treatment of AD and PD, the capacity of these hybrids to inhibit MAO-A and MAO-B was evaluated, and they showed higher activity and selectivity for MAO-A. The rationalization of the experimental evaluations (metal chelation and MAO inhibition) was supported by computational molecular modeling studies. Finally, some compounds showed also neuroprotective effects in human neuroblastoma (SH-SY5Y cells) upon treatment with 1-methyl-4-phenylpyridinium (MPP+), a neurotoxic metabolite of a Parkinsonian-inducing agent.</jats:p>

25. 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: crossref, scopus, wos 
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.

26. Phytochemicals and quaternary phosphonium ionic liquids: Connecting the dots to develop a new class of antimicrobial agents
Chavarria, D ; Borges, A ; Benfeito, S ; Sequeira, L ; Ribeiro, M ; Oliveira, C ; Borges, F ; Simoes, M ; Cagide, F
in JOURNAL OF ADVANCED RESEARCH, 2023, ISSN: 2090-1232,  Volume: 54, 
Article,  Indexed in: crossref, scopus, unpaywall, wos 
Abstract Introduction: The infections by multidrug-resistant bacteria are a growing threat to human health, and the efficacy of the available antibiotics is gradually decreasing. As such, new antibiotic classes are urgently needed. Objectives: This study aims to evaluate the antimicrobial activity, safety and mechanism of action of phytochemical-based triphenylphosphonium (TPP') conjugates. Methods: A library of phytochemical-based TPP' conjugates was repositioned and extended, and its antimicrobial activity was evaluated against a panel of Gram-positive (methicillin-resistant Staphylococcus aureus - MRSA) and Gram-negative bacteria (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii) and fungi (Candida albicans, Cryptococcus neoformans var. grubii). The compounds' cytotoxicity and haemolytic profile were also evaluated. To unravel the mechanism of action of the best compounds, the alterations in the surface charge, bacterial membrane integrity, and cytoplasmic leakage were assessed. Results: Structure-activity-toxicity data revealed the contributions of the different structural components (phenolic ring, carbon-based spacers, carboxamide group, alkyl linker) to the compounds' bioactivity and safety. Dihydrocinnamic derivatives 5 m and 5n stood out as safe, potent and selective antibacterial agents against S. aureus (MIC < 0.25 lg/mL; CC50 > 32 lg/mL; HC10 > 32 lg/mL). Mechanistic studies sug- gest that the antibacterial activity of compounds 5 m and 5n may result from interactions with the bac- terial cell wall and membrane. Conclusions: Collectively, these studies demonstrate the potential of phytochemical-based TPP+ conju- gates as a new class of antibiotics. (c) 2023 The Authors. Published by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

27. An Update on Recent Studies Focusing on the Antioxidant Properties of <i>Salvia</i> Species
Iacopetta, D ; Ceramella, J ; Scumaci, D ; Catalano, A ; Sinicropi, MS ; Tundis, R ; Alcaro, S ; Borges, F
in ANTIOXIDANTS, 2023, Volume: 12, 
Review,  Indexed in: scopus, wos 
Abstract Nutrition has crucial effects and a significant role in disease prevention. Recently, nutraceuticals have attracted much attention in scientific research due to their pleiotropic effects and relatively non-toxic behavior. Among the biological effects displayed by plants belonging to the Lamiaceae family, such as antibacterial, anticancer, anti-inflammatory, and anticholinesterase, sage is well known for its antioxidant properties and is a rich source of numerous compounds that are biologically active, amongst them polyphenols, with more than 160 types identified. In this review we summarized some of the significant studies published in the last decade reporting the most employed extraction methods and the different assays that are useful for establishing the antioxidant properties of some sage species. Even though the scientific literature contains plenty of data regarding the antioxidant properties of many sage species, further studies are needed in order to gain a deeper understanding of the mechanism of action and the compounds responsible for their antioxidant activity. Finally, it should be taken into account that the data on the antioxidant properties of sage extracts are often difficult to compare with each other, since a series of variables in the extraction procedures, the type of assay used, and standardization may affect the final result.

28. 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 
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.

29. A combined experimental and computational thermodynamic study of fluoronitrophenol isomers
Ferreira, AIMCL ; Amaral, LMPF ; da Silva, MAVR
in JOURNAL OF CHEMICAL THERMODYNAMICS, 2023, ISSN: 0021-9614,  Volume: 178, 
Article,  Indexed in: scopus, wos 
Abstract Combustion energies of the 5-fluoro-2-nitrophenol, 4-fluoro-2-nitrophenol, 3-fluoro-4-nitrophenol and 2-fluoro-4-nitrophenol isomers were obtained by means of a rotating-bomb combustion calorimeter. From these de-terminations, standard molar combustion enthalpies and standard molar formation enthalpies, at T = 298.15 K, in the crystalline state, were derived. The Knudsen mass-loss effusion technique was used to determine the standard molar enthalpies, entropies and Gibbs energies of sublimation, at T = 298.15 K, of the studied com-pounds. The standard molar enthalpies of sublimation of the four isomers were also measured by Calvet microcalorimetry. The gas-phase standard molar enthalpies of formation were derived from the experimental measurements, at T = 298.15 K, for the fluoronitrophenols studied.Additionally, the standard molar enthalpies of formation were estimated by means of computational meth-odology at the G3(MP2)//B3LYP level. The estimated values are in very good agreement with experimental data, giving us support to estimate the gas-phase enthalpies of formation of the remaining isomers whose values have not been determined experimentally.A simple group additivity scheme was successfully applied for prediction of molar enthalpies of formation. The computational study was also extended to the determination of O-H bond dissociation enthalpies for all the isomers.

30. Citizen Science in Promoting Chemical-Environmental Awareness of Students in the Context of Marine Pollution by (Micro)Plastics
Araújo, JL ; Morais, C ; Paiva, JC
in REVISTA ELECTRONICA EDUCARE, 2023, ISSN: 1409-4258,  Volume: 27, 
Article,  Indexed in: authenticus, crossref, scopus, unpaywall, wos 
Abstract Objective. To evaluate how the tasks carried out by the students in the scope of the PVC educational citizen science project for monitoring the quality of coastal waters contributed to raising their awareness of the problems of marine litter, in particular, the pollution of the ocean by plastics and microplastics, and the importance of chemistry in society. Methods. The project stage here presented consisted of six asynchronous tasks, conducted with digital mediation through the Moodle platform. The project took place in the 2018/2019 school year and involved 442 students and nine chemistry teachers from a middle school in the northern coastal region of Portugal. Data on the impact on students' awareness of the contexts considered were collected from the outputs the students produced in each task. The data were analyzed using the content analysis technique. Discussion. From this analysis emerged indicators of the PVC project's positive contribution to raising students' awareness of the pollution of marine environments by (micro)plastics, as well as raising awareness of the role of chemistry in society. The students expressed positive opinions toward this science and recognized its links with other areas of science and technology. Conclusion. Thus, it was found that citizen science projects significantly promote students' awareness of chemical-environmental subjects by exploring current and relevant contexts.