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Article ; Online: FoxO3 and oxidative stress: a multifaceted role in cellular adaptation.

Bernardo, Victoria Simões / Torres, Flaviene Felix / da Silva, Danilo Grünig Humberto

Journal of molecular medicine (Berlin, Germany)

2023 Volume 101, Issue 1-2, Page(s) 83–99

Abstract: Oxidative stress is a major cause of morbidity and mortality in human health and disease. In this review, we focus on the Forkhead Box (Fox) subclass O3 (FoxO3), an extensively studied transcription factor that plays a pleiotropic role in a wide range of ...

Abstract	Oxidative stress is a major cause of morbidity and mortality in human health and disease. In this review, we focus on the Forkhead Box (Fox) subclass O3 (FoxO3), an extensively studied transcription factor that plays a pleiotropic role in a wide range of physiological and pathological processes by regulating multiple gene regulatory networks involved in the modulation of numerous aspects of cellular metabolism, including fuel metabolism, cell death, and stress resistance. This review will also focus on regulatory mechanisms of FoxO3 expression and activity, such as crucial post-translational modifications and non-coding RNAs. Moreover, this work discusses and evidences some pathways to how this transcription factor and reactive oxygen species regulate each other, which may lead to the pathogenesis of various types of diseases. Therefore, in addition to being a promising therapeutic target, the FoxO3-regulated signaling pathways can also be used as reliable diagnostic and prognostic biomarkers and indicators for drug responsiveness.
MeSH term(s)	Humans ; Forkhead Box Protein O3/metabolism ; Forkhead Transcription Factors/metabolism ; Gene Expression Regulation ; Oxidative Stress/genetics ; Signal Transduction
Chemical Substances	Forkhead Box Protein O3 ; Forkhead Transcription Factors ; FOXO3 protein, human
Language	English
Publishing date	2023-01-04
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1223802-8
ISSN	1432-1440 ; 0946-2716
ISSN (online)	1432-1440
ISSN	0946-2716
DOI	10.1007/s00109-022-02281-5
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Article: Decreased malondialdehyde levels in fish (Astyanax altiparanae) exposed to diesel: Evidence of metabolism by aldehyde dehydrogenase in the liver and excretion in water

Garcia, Danielly / da Silva, Danilo Grünig Humberto / de Almeida, Eduardo Alves / Lima, Daína

Ecotoxicology and environmental safety. 2020 Mar. 01, v. 190

2020

Abstract: Increased malondialdehyde (MDA) levels are commonly considered an indicator of lipid peroxidation derived from oxidative stress insults promoted by exposure of fish to pollutants. However, a decrease in MDA levels after xenobiotic exposure has been also ... ...

Abstract	Increased malondialdehyde (MDA) levels are commonly considered an indicator of lipid peroxidation derived from oxidative stress insults promoted by exposure of fish to pollutants. However, a decrease in MDA levels after xenobiotic exposure has been also reported, an effect that is mostly attributed to enhanced antioxidant defenses. In this study, we assessed whether pollutant-mediated MDA decrease would be associated with antioxidant enhancement or with its metabolism by aldehyde dehydrogenase (ALDH) in the liver and gills of lambari (Astyanax altiparanae) exposed to diesel oil (0.001, 0.01, and 0.1 mL/L). MDA levels were decreased in the liver of lambari exposed to diesel. The activities of the antioxidant enzymes, catalase (CAT) and glutathione peroxidase (GPx), were unchanged in the liver, while that of glucose-6-phosphate dehydrogenase (G6PDH) was decreased. In contrast, levels of total glutathione (tGSH) and the activity of glutathione S-transferase (GST) were increased in the liver, which partly support antioxidant protection against lipid peroxidation. More importantly, ALDH activity increased in a concentration-dependent manner, being negatively correlated with MDA levels, indicating MDA metabolism by ALDH. In the gills, diesel exposure increased MDA and lipid hydroperoxide levels, and promoted increases in antioxidant defenses, indicating oxidative stress. Curiously, ALDH activity was undetectable in the gills, supporting the possibility of direct MDA excretion in the water by the gills. Analyses of MDA in the water revealed increased levels of MDA in the aquaria in which the fish were exposed to diesel, compared to control aquaria. A second experiment was carried out in which the fish were intraperitoneally injected with MDA (10 mg/kg) and analyzed after 1, 6, and 12 h. MDA injection caused a time-dependent decrease in hepatic MDA levels, did not alter ALDH, CAT, GPx, and GST activities, and decreased G6PDH activity and tGSH levels. In the gills, MDA injection caused a slight increase in MDA levels after 1 h, but did not alter GPx, G6PDH, and GST activities. MDA injection also enhanced CAT activity and tGSH levels in the gills. MDA concentration in water increased progressively after 1, 6, and 12 h, supporting the hypothesis of direct MDA excretion as an alternative route for MDA elimination in fish. Our results suggest that the decreased MDA levels after exposure of lambari to diesel oil pollutant probably reflects an association between enhanced antioxidant protection, MDA metabolism, and MDA excretion in water.
Keywords	alcohol oxidoreductases ; aldehyde dehydrogenase ; antioxidant activity ; antioxidant enzymes ; aquariums ; Astyanax altiparanae ; catalase ; diesel fuel ; enzyme activity ; excretion ; fish ; gills ; glutathione ; glutathione peroxidase ; glutathione transferase ; lipid peroxidation ; lipid peroxides ; liver ; malondialdehyde ; metabolism ; oxidative stress ; pollutants ; xenobiotics
Language	English
Dates of publication	2020-0301
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	436536-7
ISSN	1090-2414 ; 0147-6513
ISSN (online)	1090-2414
ISSN	0147-6513
DOI	10.1016/j.ecoenv.2019.110107
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Article ; Online: Decreased malondialdehyde levels in fish (Astyanax altiparanae) exposed to diesel: Evidence of metabolism by aldehyde dehydrogenase in the liver and excretion in water.

Garcia, Danielly / Lima, Daína / da Silva, Danilo Grünig Humberto / de Almeida, Eduardo Alves

Ecotoxicology and environmental safety

2020 Volume 190, Page(s) 110107

Abstract	Increased malondialdehyde (MDA) levels are commonly considered an indicator of lipid peroxidation derived from oxidative stress insults promoted by exposure of fish to pollutants. However, a decrease in MDA levels after xenobiotic exposure has been also reported, an effect that is mostly attributed to enhanced antioxidant defenses. In this study, we assessed whether pollutant-mediated MDA decrease would be associated with antioxidant enhancement or with its metabolism by aldehyde dehydrogenase (ALDH) in the liver and gills of lambari (Astyanax altiparanae) exposed to diesel oil (0.001, 0.01, and 0.1 mL/L). MDA levels were decreased in the liver of lambari exposed to diesel. The activities of the antioxidant enzymes, catalase (CAT) and glutathione peroxidase (GPx), were unchanged in the liver, while that of glucose-6-phosphate dehydrogenase (G6PDH) was decreased. In contrast, levels of total glutathione (tGSH) and the activity of glutathione S-transferase (GST) were increased in the liver, which partly support antioxidant protection against lipid peroxidation. More importantly, ALDH activity increased in a concentration-dependent manner, being negatively correlated with MDA levels, indicating MDA metabolism by ALDH. In the gills, diesel exposure increased MDA and lipid hydroperoxide levels, and promoted increases in antioxidant defenses, indicating oxidative stress. Curiously, ALDH activity was undetectable in the gills, supporting the possibility of direct MDA excretion in the water by the gills. Analyses of MDA in the water revealed increased levels of MDA in the aquaria in which the fish were exposed to diesel, compared to control aquaria. A second experiment was carried out in which the fish were intraperitoneally injected with MDA (10 mg/kg) and analyzed after 1, 6, and 12 h. MDA injection caused a time-dependent decrease in hepatic MDA levels, did not alter ALDH, CAT, GPx, and GST activities, and decreased G6PDH activity and tGSH levels. In the gills, MDA injection caused a slight increase in MDA levels after 1 h, but did not alter GPx, G6PDH, and GST activities. MDA injection also enhanced CAT activity and tGSH levels in the gills. MDA concentration in water increased progressively after 1, 6, and 12 h, supporting the hypothesis of direct MDA excretion as an alternative route for MDA elimination in fish. Our results suggest that the decreased MDA levels after exposure of lambari to diesel oil pollutant probably reflects an association between enhanced antioxidant protection, MDA metabolism, and MDA excretion in water.
MeSH term(s)	Aldehyde Dehydrogenase/metabolism ; Animals ; Antioxidants/metabolism ; Catalase/metabolism ; Characidae/metabolism ; Fishes/metabolism ; Gasoline/toxicity ; Gills/metabolism ; Glutathione/metabolism ; Glutathione Peroxidase/metabolism ; Glutathione Transferase/metabolism ; Lipid Peroxidation ; Liver/metabolism ; Malondialdehyde/metabolism ; Oxidative Stress ; Seafood ; Water Pollutants, Chemical/metabolism ; Water Pollutants, Chemical/toxicity
Chemical Substances	Antioxidants ; Gasoline ; Water Pollutants, Chemical ; Malondialdehyde (4Y8F71G49Q) ; Catalase (EC 1.11.1.6) ; Glutathione Peroxidase (EC 1.11.1.9) ; Aldehyde Dehydrogenase (EC 1.2.1.3) ; Glutathione Transferase (EC 2.5.1.18) ; Glutathione (GAN16C9B8O)
Language	English
Publishing date	2020-01-02
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	436536-7
ISSN	1090-2414 ; 0147-6513
ISSN (online)	1090-2414
ISSN	0147-6513
DOI	10.1016/j.ecoenv.2019.110107
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Article ; Online: Peroxiredoxins in erythrocytes: far beyond the antioxidant role.

de Paula, Carla Peres / de Oliveira da Silva, João Pedro Maia / Romanello, Karen Simone / Bernardo, Victoria Simões / Torres, Flaviene Felix / da Silva, Danilo Grünig Humberto / da Cunha, Anderson Ferreira

Journal of molecular medicine (Berlin, Germany)

2023 Volume 101, Issue 11, Page(s) 1335–1353

Abstract: The red blood cells (RBCs) are essential to transport oxygen ( ... ...

Abstract	The red blood cells (RBCs) are essential to transport oxygen (O
MeSH term(s)	Humans ; Antioxidants/metabolism ; Peroxiredoxins/chemistry ; Peroxiredoxins/metabolism ; Oxidative Stress ; Erythrocytes/metabolism ; Oxidation-Reduction ; Hydrogen Peroxide ; Oxygen ; Hemolysis
Chemical Substances	Antioxidants ; Peroxiredoxins (EC 1.11.1.15) ; Hydrogen Peroxide (BBX060AN9V) ; Oxygen (S88TT14065)
Language	English
Publishing date	2023-09-20
Publishing country	Germany
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	1223802-8
ISSN	1432-1440 ; 0946-2716
ISSN (online)	1432-1440
ISSN	0946-2716
DOI	10.1007/s00109-023-02368-7
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Article ; Online: Prolonged erythrocyte auto-incubation as an alternative model for oxidant generation system.

da Silva, Danilo Grünig Humberto / Chaves, Nayara Alves / Miyamoto, Sayuri / de Almeida, Eduardo Alves

Toxicology in vitro : an international journal published in association with BIBRA

2019 Volume 56, Page(s) 62–74

Abstract: This study investigated the effects of incubation period and melatonin treatment on red blood cell (RBC) metabolism in an auto-incubation model of ... ...

Abstract	This study investigated the effects of incubation period and melatonin treatment on red blood cell (RBC) metabolism in an auto-incubation model of H
MeSH term(s)	Adult ; Antioxidants/pharmacology ; Cell Culture Techniques ; Cells, Cultured ; Erythrocytes/drug effects ; Erythrocytes/metabolism ; Female ; Hemolysis/drug effects ; Humans ; Hydrogen Peroxide/pharmacology ; Male ; Melatonin/pharmacology ; Oxidants/pharmacology ; Oxidative Stress/drug effects ; Uric Acid/pharmacology
Chemical Substances	Antioxidants ; Oxidants ; Uric Acid (268B43MJ25) ; Hydrogen Peroxide (BBX060AN9V) ; Melatonin (JL5DK93RCL)
Language	English
Publishing date	2019-01-14
Publishing country	England
Document type	Journal Article
ZDB-ID	639064-x
ISSN	1879-3177 ; 0887-2333
ISSN (online)	1879-3177
ISSN	0887-2333
DOI	10.1016/j.tiv.2019.01.006
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Article ; Online: Potential Cytoprotective and Regulatory Effects of Ergothioneine on Gene Expression of Proteins Involved in Erythroid Adaptation Mechanisms and Redox Pathways in K562 Cells

Bernardo, Victoria Simões / Torres, Flaviene Felix / de Paula, Carla Peres / da Silva, João Pedro Maia de Oliveira / Almeida, Eduardo Alves de / da Cunha, Anderson Ferreira / da Silva, Danilo Grünig Humberto

Genes (Basel). 2022 Dec. 15, v. 13, no. 12

2022

Abstract: This study aimed to establish the importance of ergothioneine (ERT) in the erythroid adaptation mechanisms by appraising the expression levels of redox-related genes associated with the PI3K/AKT/FoxO3 and Nrf2-ARE pathways using K562 cells induced to ... ...

Abstract	This study aimed to establish the importance of ergothioneine (ERT) in the erythroid adaptation mechanisms by appraising the expression levels of redox-related genes associated with the PI3K/AKT/FoxO3 and Nrf2-ARE pathways using K562 cells induced to erythroid differentiation and H₂O₂-oxidative stress. Cell viability and gene expression were evaluated. Two concentrations of ERT were assessed, 1 nM (C1) and 100 µM (C2), with and without stress induction (100 µM H₂O₂). Assessments were made in three periods of the cellular differentiation process (D0, D2, and D4). The C1 treatment promoted the induction of FOXO3 (D0 and 2), PSMB5, and 6 expressions (D4); C1 + H₂O₂ treatment showed the highest levels of NRF2 transcripts, KEAP1 (D0), YWHAQ (D2 and 4), PSMB5 (D2) and PSMB6 (D4); and C2 + H₂O₂ (D2) an increase in FOXO3 and MST1 expression, with a decrease of YWHAQ and NRF2 was observed. in C2 + H₂O₂ (D2) an increase in FOXO3 and MST1, with a decrease in YWHAQ and NRF2 was observed All ERT treatments increased gamma-globin expression. Statistical multivariate analyzes highlighted that the Nrf2-ARE pathway presented a greater contribution in the production of PRDX1, SOD1, CAT, and PSBM5 mRNAs, whereas the PI3K/AKT/FoxO3 pathway was associated with the PRDX2 and TRX transcripts. In conclusion, ERT presented a cytoprotective action through Nrf2 and FoxO3, with the latter seeming to contribute to erythroid proliferation/differentiation.
Keywords	cell differentiation ; cell viability ; gene expression
Language	English
Dates of publication	2022-1215
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article ; Online
ZDB-ID	2527218-4
ISSN	2073-4425
ISSN	2073-4425
DOI	10.3390/genes13122368
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Article ; Online: Influence of Melatonin Treatment on Cellular Mechanisms of Redox Adaptation in K562 Erythroleukemic Cells

Torres, Flaviene Felix / Bernardo, Victoria Simões / de Paula, Carla Peres / da Silva, João Pedro Maia de Oliveira / Almeida, Eduardo Alves de / da Cunha, Anderson Ferreira / da Silva, Danilo Grünig Humberto

Genes (Basel). 2022 Dec. 11, v. 13, no. 12

2022

Abstract: Melatonin (MEL) presents well-documented pleiotropic actions against oxidative stress (OS), acting indirectly through activation of transcription factors, e.g., FoxO3 and Nrf2. Thus, this study aimed to investigate the possible modulating effects of MEL ... ...

Abstract	Melatonin (MEL) presents well-documented pleiotropic actions against oxidative stress (OS), acting indirectly through activation of transcription factors, e.g., FoxO3 and Nrf2. Thus, this study aimed to investigate the possible modulating effects of MEL on the redox signaling pathways PI3K/AKT/FoxO3 and Keap1/Nrf2/ARE in K562 erythroleukemic cells subjected to OS induction. For this, the viability, and transcript levels of genes involved in redox adaptation were evaluated in K562 cells in different periods of erythroid differentiation: under OS induction by hydrogen peroxide (100 µM H₂O₂); treated with 1 nM (C1) and 1 mM (C2) MEL; and associated or not with stress induction. We observed a restoration of physiological levels of Nrf2 in both MEL concentrations under OS. The C1 was related to enhanced expression of antioxidant and proteasome genes through the Nrf2-ARE pathway, while C2 to the induction of FOXO3 expression, suggesting an involvement with apoptotic pathway, according to BIM transcript levels. The effects of MEL administration in these cells showed a period and dose-dependent pattern against induced-OS, with direct and indirect actions through different pathways of cellular adaptation, reinforcing the importance of this indolamine in the regulation of cellular homeostasis, being a promising therapeutic alternative for diseases that present an exacerbated OS.
Keywords	apoptosis ; dose response ; homeostasis ; hydrogen peroxide ; melatonin ; oxidative stress ; proteasome endopeptidase complex ; therapeutics ; viability
Language	English
Dates of publication	2022-1211
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article ; Online
ZDB-ID	2527218-4
ISSN	2073-4425
ISSN	2073-4425
DOI	10.3390/genes13122337
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Article ; Online: Influence of Melatonin Treatment on Cellular Mechanisms of Redox Adaptation in K562 Erythroleukemic Cells.

Torres, Flaviene Felix / Bernardo, Victoria Simões / de Paula, Carla Peres / da Silva, João Pedro Maia de Oliveira / de Almeida, Eduardo Alves / da Cunha, Anderson Ferreira / da Silva, Danilo Grünig Humberto

Genes

2022 Volume 13, Issue 12

Abstract	Melatonin (MEL) presents well-documented pleiotropic actions against oxidative stress (OS), acting indirectly through activation of transcription factors, e.g., FoxO3 and Nrf2. Thus, this study aimed to investigate the possible modulating effects of MEL on the redox signaling pathways PI3K/AKT/FoxO3 and Keap1/Nrf2/ARE in K562 erythroleukemic cells subjected to OS induction. For this, the viability, and transcript levels of genes involved in redox adaptation were evaluated in K562 cells in different periods of erythroid differentiation: under OS induction by hydrogen peroxide (100 µM H
Language	English
Publishing date	2022-12-11
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527218-4
ISSN	2073-4425 ; 2073-4425
ISSN (online)	2073-4425
ISSN	2073-4425
DOI	10.3390/genes13122337
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Article ; Online: Potential Cytoprotective and Regulatory Effects of Ergothioneine on Gene Expression of Proteins Involved in Erythroid Adaptation Mechanisms and Redox Pathways in K562 Cells.

Bernardo, Victoria Simões / Torres, Flaviene Felix / de Paula, Carla Peres / da Silva, João Pedro Maia de Oliveira / de Almeida, Eduardo Alves / da Cunha, Anderson Ferreira / da Silva, Danilo Grünig Humberto

Genes

2022 Volume 13, Issue 12

Abstract	This study aimed to establish the importance of ergothioneine (ERT) in the erythroid adaptation mechanisms by appraising the expression levels of redox-related genes associated with the PI3K/AKT/FoxO3 and Nrf2-ARE pathways using K562 cells induced to erythroid differentiation and H
Language	English
Publishing date	2022-12-15
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527218-4
ISSN	2073-4425 ; 2073-4425
ISSN (online)	2073-4425
ISSN	2073-4425
DOI	10.3390/genes13122368
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Article ; Online: Oxidative stress biomarkers in treatment-responsive and treatment-resistant schizophrenia patients.

Buosi, Patrick / Borghi, Fábio Aparecido / Lopes, Angélica Marta / Facincani, Isabela da Silva / Fernandes-Ferreira, Rafael / Oliveira-Brancati, Camila Ive Ferreira / do Carmo, Tayanne Silva / Souza, Dorotéia Rossi Silva / da Silva, Danilo Grünig Humberto / de Almeida, Eduardo Alves / de Araújo Filho, Gerardo Maria

Trends in psychiatry and psychotherapy

2021 Volume 43, Issue 4, Page(s) 278–285

Abstract: Introduction: Schizophrenia is a complex psychiatric disorder that affects approximately twenty million people worldwide. Various factors have been associated with the physiopathology of this disease such as oxidative stress, which is an imbalance ... ...

Abstract	Introduction: Schizophrenia is a complex psychiatric disorder that affects approximately twenty million people worldwide. Various factors have been associated with the physiopathology of this disease such as oxidative stress, which is an imbalance between pro-oxidant and antioxidant molecules. Objective: This study evaluated the association between biomarkers of oxidative stress and response to pharmacological treatment among patients with schizophrenia in the context of their clinical information, demographic data, and lifestyle. Methods: A total of 89 subjects were included, 26 of whom were treatment-responsive schizophrenia patients (Group 1), 27 treatment-resistant schizophrenia patients (Group 2), and 36 healthy controls (Group 3). All of the subjects completed a questionnaire to provide clinical and demographic data, and all provided peripheral blood samples. The oxidative stress markers analyzed using spectrophotometry were catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), total glutathione (GSH-t), malondialdehyde (MDA), and Trolox-equivalent antioxidant capacity (TEAC; p < 0.05). Results: When all schizophrenia patients (G1 + G2) were compared to the control group, SOD levels were found to be lower among schizophrenia patients (p < 0.0001), while MDA and CAT levels were higher (p < 0.0001 and p = 0.0191, respectively). GPx, GSH-t, and TEAC levels were similar in all three groups (p > 0.05). Conclusion: Lower SOD levels and higher MDA and CAT levels indicate oxidative damage in schizophrenia patients, regardless of their response to pharmacological treatment. Smoking is associated with oxidative stress, in addition, a family history of the disease was also found to be correlated with cases of schizophrenia, which reflects the relevance of genetics in disease development.
MeSH term(s)	Biomarkers ; Glutathione Peroxidase/metabolism ; Humans ; Oxidative Stress ; Schizophrenia/drug therapy ; Schizophrenia, Treatment-Resistant
Chemical Substances	Biomarkers ; Glutathione Peroxidase (EC 1.11.1.9)
Language	English
Publishing date	2021-01-01
Publishing country	Brazil
Document type	Journal Article
ZDB-ID	2708374-3
ISSN	2238-0019 ; 2238-0019
ISSN (online)	2238-0019
ISSN	2238-0019
DOI	10.47626/2237-6089-2020-0078
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