13 results on '"Duarte, José Alberto"'
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2. Voluntary Exercise has Long-Term In Vivo Protective Effects on Osteocyte Viability and Bone Strength Following Ovariectomy
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Fonseca, Hélder, Moreira-Gonçalves, Daniel, Esteves, José Luís Soares, Viriato, Nuno, Vaz, Mário, Mota, Maria Paula, and Duarte, José Alberto
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- 2011
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3. Proteolysis activation and proteome alterations in murine skeletal muscle submitted to 1 week of hindlimb suspension
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Ferreira, Rita, Vitorino, Rui, Neuparth, Maria João, Appell, Hans-Joachim, Duarte, José Alberto, and Amado, Francisco
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- 2009
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4. IL6 (-174) and TNFA (-308) promoter polymorphisms are associated with systemic creatine kinase response to eccentric exercise
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Yamin, Chen, Duarte, José Alberto Ramos, Oliveira, José Manuel Fernandes, Amir, Offer, Sagiv, Moran, Eynon, Nir, Sagiv, Michael, and Amir, Ruthie E.
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- 2008
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5. Cellular patterns of the atrophic response in murine soleus and gastrocnemius muscles submitted to simulated weightlessness
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Ferreira, Rita, Vitorino, Rui, Neuparth, Maria João, Appell, Hans-Joachim, Amado, Francisco, and Duarte, José Alberto
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- 2007
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6. Skeletal muscle atrophy increases cell proliferation in mice gastrocnemius during the first week of hindlimb suspension
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Ferreira, Rita, Neuparth, Maria João, Ascensão, António, Magalhães, José, Vitorino, Rui, Duarte, José Alberto, and Amado, Francisco
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- 2006
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7. The role of inflammation and antioxidant defenses in the cardiotoxicity of doxorubicin in elderly CD-1 male mice.
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Reis-Mendes A, Ferreira M, Duarte JA, Duarte-Araújo M, Remião F, Carvalho F, Sousa E, Bastos ML, and Costa VM
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- Animals, Male, Mice, Apoptosis, bcl-2-Associated X Protein metabolism, Cardiotoxicity etiology, Doxorubicin pharmacology, Fibrosis, Inflammation metabolism, NF-kappa B metabolism, Oxidative Stress, Signal Transduction, Antioxidants metabolism, Neoplasms
- Abstract
Doxorubicin (DOX) is a potent chemotherapeutic agent used against several cancer types. However, due to its cardiotoxic adverse effects, the use of this drug may be also life-threatening. Although most cancer patients are elderly, they are poorly represented and evaluated in pre-clinical and clinical studies. Considering this, the present work aims to evaluate inflammation and oxidative stress as the main mechanisms of DOX-induced cardiotoxicity, in an innovative approach using an experimental model constituted of elderly animals treated with a clinically relevant human cumulative dose of DOX. Elderly (18-20 months) CD-1 male mice received biweekly DOX administrations, for 3 weeks, to reach a cumulative dose of 9.0 mg/kg. One week (1W) or two months (2 M) after the last DOX administration, the heart was collected to determine both drug's short and longer cardiac adverse effects. The obtained results showed that DOX causes cardiac histological damage and fibrosis at both time points. In the 1W-DOX group, the number of nuclear factor kappa B (NF-κB) p65 immunopositive cells increased and a trend toward increased NF-κB p65 expression was seen. An increase of inducible nitric oxide synthase (iNOS) and interleukin (IL)-33 and a trend toward increased IL-6 and B-cell lymphoma-2-associated X (Bax) expression were seen after DOX. In the same group, a decrease in IL-1β, p62, and microtubule-associated protein 1A/1B-light chain 3 (LC3)-I, p38 mitogen-activated protein kinase (MAPK) expression was observed. Contrariwise, the animals sacrificed 2 M after DOX showed a significant increase in glutathione peroxidase 1 and Bax expression with persistent cardiac damage and fibrosis, while carbonylated proteins, erythroid-2-related factor 2 (Nrf2), NF-κB p65, myeloperoxidase, LC3-I, and LC3-II expression decreased. In conclusion, our study demonstrated that in an elderly mouse population, DOX induces cardiac inflammation, autophagy, and apoptosis in the heart in the short term. When kept for a longer period, oxidative-stress-linked pathways remained altered, as well as autophagy markers and tissue damage after DOX treatment, emphasizing the need for continuous post-treatment cardiac monitoring., (© 2023. The Author(s).)
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- 2023
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8. In vivo toxicometabolomics reveals multi-organ and urine metabolic changes in mice upon acute exposure to human-relevant doses of 3,4-methylenedioxypyrovalerone (MDPV).
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Araújo AM, Carvalho M, Costa VM, Duarte JA, Dinis-Oliveira RJ, Bastos ML, Guedes de Pinho P, and Carvalho F
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- 3-Hydroxybutyric Acid biosynthesis, Animals, Biomarkers, Blood Chemical Analysis, Dose-Response Relationship, Drug, Fatty Acids biosynthesis, Gas Chromatography-Mass Spectrometry, Homeostasis drug effects, Humans, Kidney pathology, Liver pathology, Male, Metabolome, Mice, Urine chemistry, Synthetic Cathinone, Benzodioxoles metabolism, Benzodioxoles toxicity, Brain metabolism, Kidney metabolism, Liver metabolism, Myocardium metabolism, Pyrrolidines metabolism, Pyrrolidines toxicity
- Abstract
3,4-Methylenedioxypyrovalerone (MDPV) is consumed worldwide, despite its potential to cause toxicity in several organs and even death. There is a recognized need to clarify the biological pathways through which MDPV elicits general and target-organ toxicity. In this work, a comprehensive untargeted GC-MS-based metabolomics analysis was performed, aiming to detect metabolic changes in putative target organs (brain, heart, kidneys and liver) but also in urine of mice after acute exposure to human-relevant doses of MDPV. Male CD-1 mice received binge intraperitoneal administrations of saline or MDPV (2.5 mg/kg or 5 mg/kg) every 2 h, for a total of three injections. Twenty-four hours after the first administration, target organs, urine and blood samples were collected for metabolomics, biochemical and histological analysis. Hepatic and renal tissues of MDPV-treated mice showed moderate histopathological changes but no significant differences were found in plasma and tissue biochemical markers of organ injury. In contrast, the multivariate analysis significantly discriminated the organs and urine of MDPV-treated mice from the control (except for the lowest dose in the brain), allowing the identification of a panoply of metabolites. Those levels were significantly deviated in relation to physiological conditions and showed an organ specific response towards the drug. Kidneys and liver showed the greatest metabolic changes. Metabolites related with energetic metabolism, antioxidant defenses and inflammatory response were significantly changed in the liver of MDPV-dosed animals, while the kidneys seem to have developed an adaptive response against oxidative stress caused by MDPV. On the other hand, the dysregulation of metabolites that contribute to metabolic acidosis was also observed in this organ. The heart showed an increase of fatty acid biosynthesis, possibly as an adaptation to maintain the cardiac energy homeostasis. In the brain, changes in 3-hydroxybutyric acid levels may reflect the activation of a neurotoxic pathway. However, the increase in metabolites with neuroprotective properties seems to counteract this change. Metabolic profiling of urine from MDPV-treated mice suggested that glutathione-dependent antioxidant pathways may be particularly involved in the compensatory mechanism to counteract oxidative stress induced by MDPV. Overall, this study reports, for the first time, the metabolic profile of liver, kidneys, heart, brain, and urine of MDPV-dosed mice, providing unique insights into the biological pathways of toxicity. Our findings also underline the value of toxicometabolomics as a robust and sensitive tool for detecting adaptive/toxic cellular responses upon exposure to a physiologically relevant dose of a toxic agent, earlier than conventional toxicity tests.
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- 2021
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9. Mitoxantrone impairs proteasome activity and prompts early energetic and proteomic changes in HL-1 cardiomyocytes at clinically relevant concentrations.
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Costa VM, Capela JP, Sousa JR, Eleutério RP, Rodrigues PRS, Dores-Sousa JL, Carvalho RA, Lourdes Bastos M, Duarte JA, Remião F, Almeida MG, Varner KJ, and Carvalho F
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- Animals, Apoptosis Regulatory Proteins metabolism, Cardiotoxicity, Cell Line, Dose-Response Relationship, Drug, Heart Diseases metabolism, Mice, Myocytes, Cardiac metabolism, Oxidative Stress drug effects, Protein Carbonylation, Time Factors, Energy Metabolism drug effects, Heart Diseases chemically induced, Mitoxantrone toxicity, Myocytes, Cardiac drug effects, Proteasome Endopeptidase Complex metabolism, Proteome, Proteomics
- Abstract
Mitoxantrone (MTX) is used to treat several types of cancers and to improve neurological disability in multiple sclerosis. Unfortunately, cardiotoxicity is a severe and common adverse effect in MTX-treated patients. Herein, we aimed to study early and late mechanisms of MTX-induced cardiotoxicity using murine HL-1 cardiomyocytes. Cells were exposed to MTX (0.1, 1 or 10 µM) during short (2, 4, 6, or 12 h) or longer incubation periods (24 or 48 h). At earlier time points, (6 and 12 h) cytotoxicity was already observed for 1 and 10 µM MTX. Proteomic analysis of total protein extracts found 14 proteins with higher expression and 26 with lower expression in the cells exposed for 12 h to MTX (pH gradients 4-7 and 6-11). Of note, the expression of the regulatory protein 14-3-3 protein epsilon was increased by a factor of two and three, after exposure to 1 and 10 µM MTX, respectively. At earlier time-points, 10 µM MTX increased intracellular ATP levels, while decreasing media lactate levels. At later stages (24 and 48 h), MTX-induced cytotoxicity was concentration and time-dependent, according to the MTT reduction and lactate dehydrogenase leakage assays, while caspase-9, -8 and -3 activities increased at 24 h. Regarding cellular redox status, total glutathione increased in 1 µM MTX (24 h), and that increase was dependent on gamma-glutamylcysteine synthetase activity. Meanwhile, for both 1 and 10 µM MTX, oxidized glutathione was significantly higher than control at 48 h. Moreover, MTX was able to significantly decrease proteasomal chymotrypsin-like activity in a concentration and time-independent manner. In summary, MTX significantly altered proteomic, energetic and oxidative stress homeostasis in cardiomyocytes at clinically relevant concentrations and our data clearly demonstrate that MTX causes early cardiotoxicity that needs further study.
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- 2020
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10. An effective antidotal combination of polymyxin B and methylprednisolone for α-amanitin intoxication.
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Garcia J, Costa VM, Bovolini A, Duarte JA, Rodrigues DF, de Lourdes Bastos M, and Carvalho F
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- Amanita chemistry, Animals, Anti-Inflammatory Agents administration & dosage, Anti-Inflammatory Agents pharmacology, Antidotes administration & dosage, Drug Therapy, Combination, Male, Methylprednisolone administration & dosage, Mice, Mushroom Poisoning drug therapy, Polymyxin B administration & dosage, Treatment Outcome, Alpha-Amanitin poisoning, Antidotes pharmacology, Methylprednisolone pharmacology, Polymyxin B pharmacology
- Abstract
Amanita phalloides is one of the most toxic mushrooms worldwide, and it is involved in the majority of human fatal cases of mushroom poisoning. α-Amanitin, the most deleterious toxin of A. phalloides to humans, inhibits RNA polymerase II (RNAPII), causing hepatic and renal failure. Previously, we have shown that polymyxin B (polB) reverts α-amanitin inhibition of RNAPII, although it was not able to guarantee the full survival of α-amanitin-intoxicated mice or prevent α-amanitin pro-inflammatory effects. α-Amanitin is also a substrate of the organic-anion-transporting polypeptide 1B3 (OATP1B3) and Na(+)-taurocholate cotransporter polypeptide (NTCP) transporters. Therefore, in the present work, we used a combination of polB [(2.5 mg/kg intraperitoneal (i.p.)] with the anti-inflammatory and NTCP inhibitor drug, methylprednisolone (MP) (10 mg/kg i.p.), as an attempt to fully revert α-amanitin-induced toxicity (0.33 mg/kg i.p.) in CD-1 mice. Results showed that the administration of the polB + MP combination, 4 h after α-amanitin, led to the full survival of the intoxicated animals, with a significant attenuation of α-amanitin-induced renal and hepatic necrosis. Also, the combination polB + MP led to a decrease of aminotransferase plasma levels, of the renal myeloperoxidase activity and of renal inflammatory cell infiltrate promoted by α-amanitin, although not preventing any of the hepatic pro-inflammatory effect of the toxin. The obtained results indicate that this combination may represent an important and valuable therapeutic approach to be used against α-amanitin intoxication.
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- 2019
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11. Regular voluntary running has favorable histological effects on doxorubicin-induced kidney toxicity in Wistar rats.
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Cardoso DF, Coriolano HA, and Duarte JA
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- Animals, Antibiotics, Antineoplastic toxicity, Collagen metabolism, Male, Physical Conditioning, Animal physiology, Random Allocation, Rats, Rats, Wistar, Renal Insufficiency metabolism, Renal Insufficiency therapy, Doxorubicin toxicity, Renal Insufficiency chemically induced, Renal Insufficiency pathology, Running physiology
- Abstract
Knowing the therapeutic effects of regular physical exercise on kidney toxicity induced by a single dose of doxorubicin (DOX) in animal models, the aim of this study is to verify the effectiveness of regular voluntary running on kidney histology after a prolonged DOX administration, mimicking a chemotherapy protocol. Thirty-four male Wistar rats were randomly divided into two clusters: DOX (n = 17) and SSS (sterile saline solution, n = 17), receiving a weekly intraperitoneal injection of DOX (2 mg/kg) or vehicle for 7 weeks, respectively. Two weeks after the last injection, five animals from each cluster (SSSG, n = 5; DOXG, n = 5) were euthanized, while the remaining ones were divided into sedentary (DOXsed, n = 6; SSSsed, n = 6) and active subgroups (DOXact, n = 6; SSSact, n = 6). Active animals were placed individually in cages with a running wheel for regular voluntary activity. After 2 months, the animals were euthanized and kidneys were histologically examined. Compared to SSSG, kidneys from DOXG revealed higher levels of damage, more collagen content and thickening of Bowman's capsule (p < .05). The levels of damage and thickness of Bowman's capsule increased in DOXsed as compared to DOXG (p < .05). Compared to DOXsed, the DOXact presented an overall improvement in kidney structure (p < .05), with a decrease in collagen content and of the thickness of Bowman's capsule. The results allow concluding that regular voluntary running attenuate the long-term harmful effects on kidney structure induced by a prolonged DOX treatment. These results, supporting the potential benefit of physical activity in patients under DOX treatment, need to be tested in humans.
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- 2018
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12. Methylone and MDPV activate autophagy in human dopaminergic SH-SY5Y cells: a new insight into the context of β-keto amphetamines-related neurotoxicity.
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Valente MJ, Amaral C, Correia-da-Silva G, Duarte JA, Bastos ML, Carvalho F, Guedes de Pinho P, and Carvalho M
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- Acetylcysteine pharmacology, Amphetamines toxicity, Apoptosis drug effects, Benzodioxoles administration & dosage, Cell Line, Central Nervous System Stimulants toxicity, Dopamine Uptake Inhibitors toxicity, Dopaminergic Neurons metabolism, Dopaminergic Neurons pathology, Dose-Response Relationship, Drug, Humans, Methamphetamine administration & dosage, Methamphetamine toxicity, Microtubule-Associated Proteins metabolism, Neurotoxicity Syndromes etiology, Oxidative Stress drug effects, Pyrrolidines administration & dosage, Synthetic Cathinone, Autophagy drug effects, Benzodioxoles toxicity, Dopaminergic Neurons drug effects, Methamphetamine analogs & derivatives, Pyrrolidines toxicity
- Abstract
Autophagy has an essential role in neuronal homeostasis and its dysregulation has been recently linked to neurotoxic effects of a growing list of psychoactive drugs, including amphetamines. However, the role of autophagy in β-keto amphetamine (β-KA) designer drugs-induced neurotoxicity has hitherto not been investigated. In the present study, we show that two commonly abused cathinone derivatives, 3,4-methylenedioxymethcathinone (methylone) and 3,4-methylenedioxypyrovalerone (MDPV), elicit morphological changes consistent with autophagy and neurodegeneration, including formation of autophagic vacuoles and neurite retraction in dopaminergic SH-SY5Y cells. Methylone and MDPV prompted the formation of acidic vesicular organelles (AVOs) and lead to increased expression of the autophagy-associated protein LC3-II in a concentration- and time-dependent manner. Electron microscopy confirmed the presence of autophagosomes with typical double membranes and autolysosomes in cells exposed to both β-KA. The autophagic flux was further confirmed using bafilomycin A1, a known inhibitor of the late phase of autophagy. Moreover, we showed that autophagy markers were activated before the triggering of cell death and caspase 3 activation, suggesting that β-KA-induced autophagy precedes apoptotic cell death. To address the role of oxidative stress in autophagy induction, we also investigated the effects of antioxidant treatment with N-acetyl-L-cysteine (NAC) on autophagy and apoptotic markers altered by these drugs. NAC significantly attenuated methylone- and MDPV-induced cell death by completely inhibiting the generation of reactive oxygen and nitrogen species, and hampering both apoptotic and autophagic activity, suggesting that oxidative stress plays an important role in mediating autophagy and apoptosis elicited by these drugs.
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- 2017
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13. A breakthrough on Amanita phalloides poisoning: an effective antidotal effect by polymyxin B.
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Garcia J, Costa VM, Carvalho AT, Silvestre R, Duarte JA, Dourado DF, Arbo MD, Baltazar T, Dinis-Oliveira RJ, Baptista P, de Lourdes Bastos M, and Carvalho F
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- Alpha-Amanitin poisoning, Animals, Antidotes administration & dosage, Computer Simulation, Humans, Liver Failure etiology, Liver Failure prevention & control, Male, Mice, Molecular Docking Simulation, Molecular Dynamics Simulation, Polymyxin B administration & dosage, RNA Polymerase II antagonists & inhibitors, Renal Insufficiency etiology, Renal Insufficiency prevention & control, Survival Rate, Time Factors, Amanita, Antidotes pharmacology, Mushroom Poisoning drug therapy, Polymyxin B pharmacology
- Abstract
Amanita phalloides is responsible for more than 90 % of mushroom-related fatalities, and no effective antidote is available. α-Amanitin, the main toxin of A. phalloides, inhibits RNA polymerase II (RNAP II), causing hepatic and kidney failure. In silico studies included docking and molecular dynamics simulation coupled to molecular mechanics with generalized Born and surface area method energy decomposition on RNAP II. They were performed with a clinical drug that shares chemical similarities to α-amanitin, polymyxin B. The results show that polymyxin B potentially binds to RNAP II in the same interface of α-amanitin, preventing the toxin from binding to RNAP II. In vivo, the inhibition of the mRNA transcripts elicited by α-amanitin was efficiently reverted by polymyxin B in the kidneys. Moreover, polymyxin B significantly decreased the hepatic and renal α-amanitin-induced injury as seen by the histology and hepatic aminotransferases plasma data. In the survival assay, all animals exposed to α-amanitin died within 5 days, whereas 50 % survived up to 30 days when polymyxin B was administered 4, 8, and 12 h post-α-amanitin. Moreover, a single dose of polymyxin B administered concomitantly with α-amanitin was able to guarantee 100 % survival. Polymyxin B protects RNAP II from inactivation leading to an effective prevention of organ damage and increasing survival in α-amanitin-treated animals. The present use of clinically relevant concentrations of an already human-use-approved drug prompts the use of polymyxin B as an antidote for A. phalloides poisoning in humans.
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- 2015
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