Browsing by Author "Fernandes, Eduarda"
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- 3,4-Methylenedioxymethamphetamine hepatotoxicity under the heat stress condition: novel insights from in vitro metabolomic studiesPublication . Araújo, Ana Margarida; Enea, Maria; Fernandes, Eduarda; Carvalho, Félix; de Lourdes Bastos, Maria; Carvalho, Márcia; Guedes de Pinho, PaulaHyperthermia has been extensively reported as a life-threatening consequence of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) abuse. In this work, we used a sensitive untargeted metabolomic approach based on gas chromatography-mass spectrometry to evaluate the impact of hyperthermia on the hepatic metabolic changes caused by MDMA. For this purpose, primary mouse hepatocytes were exposed to subtoxic (LC01 and LC10) and toxic (LC30) concentrations of MDMA for 24 h, at 37 or 40.5 °C (simulating body temperature increase after MDMA consumption), and alterations on both intracellular metabolome and extracellular volatilome were evaluated. Multivariate analysis showed that metabolic patterns clearly discriminate MDMA treated cells from control cells, both in normothermic and hyperthermic conditions. The metabolic signature was found to be largely common to MDMA subtoxic and toxic concentrations, although with evident differences in the magnitude of response, with metabolic changes significantly more pronounced at 40.5 °C. Discriminant metabolites associated with MDMA-induced hepatotoxicity are mostly involved in the amino acid metabolism, aminoacyl tRNA biosynthesis, glutathione metabolism, tricarboxylic acid cycle, and pyruvate metabolism. Moreover, our metabolomic findings were corroborated by classical toxicity parameters, demonstrating the high sensitivity of this omic approach to assess molecular-level effects. Overall, this study indicates that MDMA triggers significant metabolic alterations on hepatic cells, even at low concentrations, that are clearly exacerbated at high temperatures. These findings provide new metabolic pieces to solve the puzzle of MDMA's hepatotoxicity mechanism and emphasize the increased risks of MDMA abuse due to the thermogenic action of the drug.
- Bioactive compounds and scavenging capacity of Adansonia digitata L. (Baobab fruit) pulp extracts against ROS and RNS of physiological relevancePublication . Ferreira da Vinha, Ana; Costa, Anabela S.G.; Pimentel, Filipa B.; Santo, Liliana Espírito; Silva, Carla Sousa e; Freitas, Marisa; Fernandes, Eduarda; Oliveira, M. Beatriz P.P.Background: Baobab fruit is valued for its nutritional and medicinal benefits. Although it is acknowledged that baobab pulp is beneficial for health, studies that link its nutraceutical properties to the ability to eliminate reactive species (ROS and RNS) are scarce. Methods: The nutritional profile and the antioxidant properties of baobab pulp extracts from Angola were evaluated. Thus, for the first time, the evaluation of in vitro scavenging capacity against the most physiologically relevant reactive oxygen species (ROS) and reactive nitrogen species (RNS) were the focus of inves tigation. Results: Angolan fruit pulp presented high contents of ash (8.0%) and total dietary fiber (52%). Vitamin E content was reported for the first time in fruit pulp. Green solvents were used to quantify bioactive compounds and antioxidant activity. Hydroalcoholic extracts exhibited the high est contents of phenolics (1573.0 mg/100 g) and flavonoids (768.7 mg/100 g). Thus, hydroalcoholic extracts showed higher antioxidant activity, and higher scavenging capacity for ROS (O2•−, H2O2, HOCl, ROO•) and RNS (•NO, ONOO−), being most active for •NO and ONOO−. Conclusion: For the first time, Angolan baobab fruit was described in respect to its nutritional contribution as well as its positive antioxidant effects, both as a functional food and as a nutraceutical ingredient.
- Bioactive lipids: pharmaceutical, nutraceutical, and cosmeceutical applicationsPublication . Fernandes, Eduarda; Lopes, Carla Martins; Lúcio, Marlene
- A biophysical approach to formulation development: drug-plasma protein interactionPublication . Fernandes, Eduarda; Soares, Telma; Oliveira, M.E.C.D. Real; Lopes, Carla Martins; Lúcio, MarleneIn this work, the binding constant of ACV to human serum albumin was determined by binding isotherms. Nonlinear leastsquares best fit to intrinsic fluorescence quenching effect of the drug was used to determine the association constants between drug and the serum protein at one affinity binding site (Kb=1.79x103 M-1). A red shift of the fluorescent spectra confirms association. Thermodynamic parameters for the binding indicated that electrostatic interactions are predominantly involved in the binding of this drug to human serum albumin. This was further confirmed by electrophoretic and dynamic light scattering, where a progressive charge neutralization of the protein was followed by an increase of the size of albumin-drug complex.
- Chapter 4 - Organic nanocarriers for brain drug deliveryPublication . Lúcio, Marlene; Lopes, Carla Martins; Fernandes, Eduarda; Gonçalves, Hugo; Real Oliveira, Maria ElisabeteAlthough the blood–brain barrier remains a major barrier to drug delivery, organic nanocarriers (ONCs) have been demonstrated to be effective in targeting and delivering therapeutic agents to the brain and have provided promising preclinical outcomes. Because of their favourable physicochemical properties, such as biocompatible composition, nanometric dimensions, large surface area compared to volume and easily tuneable surfaces, ONCs have proven to be excellent transport vehicles capable of prolonging drug (or other therapeutic agents) circulation time and of addressing the challenges posed by numerous diseases affecting the brain.This chapter presents an overview of the different types of ONCs for brain delivery, including a description of their advantages and disadvantages, and a set of preclinical studies illustrating the most effective strategies for effective brain distribution. Biodegradation and bioelimination issues and future challenges for effective clinical translation are also addressed.
- Chapter 5 - Lipid-based nanocarriers for co-delivery of anticancer drugs and natural compoundsPublication . Fernandes, Eduarda; Soares, Telma; Lopes, Carla Martins; Real Oliveira, Maria Elisabete; Lúcio, Marlene
- Diclofenac’s toxicity revisited with biomimetic models and biophysical studiesPublication . Lúcio, Marlene; Lopes, Carla Martins; Fernandes, Eduarda; Soares, Telma; Real Oliveira, Maria Elisabete
- Diclofenac: topical gastrointestinal damage revisited with biomimetic models and biophysical studiesPublication . Lúcio, Marlene; Lopes, Carla Martins; Fernandes, Eduarda; Soares, Telma; Real Oliveira, Maria Elisabete
- Editor’s highlight: characterization of hepatotoxicity mechanisms triggered by designer cathinone drugs (β-Keto amphetamines)Publication . Valente, Maria João; Araújo, Ana Margarida; Bastos, Maria de Lourdes; Fernandes, Eduarda; Carvalho, Félix; Guedes de Pinho, Paula; Carvalho, MárciaThe use of cathinone designer drugs in recreational settings has been associated with severe toxic effects, including liver damage. The precise mechanisms by which cathinones induce hepatotoxicity and whether they act by common pathways remain to be elucidated. Herein, we assessed the toxicity of the cathinones methylone, pentedrone, 3,4-methylenedioxypyrovalerone (MDPV) and 4-methylethcathinone (4-MEC) in primary rat hepatocytes (PRH) and HepaRG cells, and compared with that of 3,4-methylenedioxymethamphetamine (MDMA). MDPV and pentedrone were significantly more toxic than MDMA, while methylone was the least cytotoxic compound. Importantly, PRH revealed to be the most sensitive experimental model and was thus used to explore the mechanisms underlying the observed toxicity. All drugs elicited the formation of reactive oxygen and nitrogen species (ROS and RNS), but more markedly for methylone, pentedrone and 4-MEC. GSH depletion was also a common effect at the highest concentration tested, whereas only MDPV and pentedrone caused a significant decrease in ATP levels. The antioxidants ascorbic acid or N-acetyl-L-cysteine partially attenuated the observed cell death. All cathinones triggered significant caspase activation and apoptosis, which was partially reversed by the caspase inhibitor Ac-LETD-CHO. In conclusion, the present data shows that (1) cathinones induce in vitro hepatotoxic effects that vary in magnitude among the different analogues, (2) oxidative stress and mitochondrial dysfunction play a role in cathinones-induced hepatic injury, and (3) apoptosis appears to be an important pathway of cell death elicited by these novel drugs.
- GC–MS metabolomics reveals disturbed metabolic pathways in primary mouse hepatocytes exposed to subtoxic levels of 3,4-methylenedioxymethamphetamine (MDMA)Publication . Araújo, Ana Margarida; Bastos, Maria de Lourdes; Fernandes, Eduarda; Carvalho, Félix; Carvalho, Márcia; Guedes de Pinho, Paula3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is a well-known hepatotoxic drug. Although its toxicity has been thoroughly studied at high concentrations, there is still insufficient knowledge on possible alterations of cell function at subtoxic concentrations, which are in fact more representative concentrations of intoxication scenarios. In this study, a gas chromatography-mass spectrometry (GC-MS) metabolomics approach was used to investigate the metabolic changes in primary mouse hepatocytes (PMH) exposed to two subtoxic concentrations of MDMA (LC01 and LC10) for 24 h. Metabolomic profiling of both intracellular metabolites and volatile metabolites in the extracellular medium of PMH was performed. Multivariate analysis showed that the metabolic pattern of cells exposed to MDMA discriminates from the controls in a concentration-dependent manner. Exposure to LC10 MDMA induces a significant increase in some intracellular metabolites, including oleic acid and palmitic acid, and a decrease in glutamate, aspartate, 5-oxoproline, fumarate, malate, phosphoric acid, α-ketoglutarate and citrate. Extracellular metabolites such as acetophenone, formaldehyde, pivalic acid, glyoxal and 2-butanone were found significantly increased after exposure to MDMA, compared to controls, whereas 4-methylheptane, 2,4-dimethyl-1-heptene, nonanal, among others, were found significantly decreased. The panel of discriminatory metabolites is mainly involved in tricarboxylic acid (TCA) cycle, fatty acid metabolism, glutamate metabolism, antioxidant defenses and possibly changes in the liver enzyme machinery. Overall, these results highlight the potential of the intra- and extracellular metabolome to study alterations triggered by subtoxic concentrations of MDMA in hepatic cell functions, which represents a more realistic appraisal of early toxicity events posed by exposure to this drug. In addition, these results also revealed some metabolites that may be used as potential biomarkers indicative of early events in the hepatotoxicity induced by MDMA.
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