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Special Issue "The Importance of Thioredoxin System for Redox Regulation and Health"

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A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Antioxidant Enzyme Systems".

Deadline for manuscript submissions: closed (15 March 2023) | Viewed by 2318

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Dr. Cristina M. L. Carvalho

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Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal
Interests: molecular mechanisms of toxicity; thioredoxin and glutaredoxin systems; cancer; mercury and methylmercury toxicity; environmental and human risk assessment; biomarkers & food safety
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Dr. Vasco Branco

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1. Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal
2. Centro de Investigação Interdisciplinar Egas Moniz (CiiEM), Instituto Universitário Egas Moniz (IUEM), Quinta da Granja, Monte de Caparica, 2829-511 Caparica, Portugal
Interests: mercury toxicity; selenium and selenoproteins; redox active systems; mechanisms of toxicity
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Thioredoxin system encompasses thioredoxin reductase (TrxR), thioredoxin (Trx) and NADPH and is central to the regulation of cell redox homeostasis. Trx was discovered 60 years ago as a hydrogen donor for the reduction of ribonucleotides by ribonucleotide reductase (RNR) and is fundamental for repairing oxidized proteins.

TrxR isoforms, TrxR1; TrxR2; TrxR3 also known as TGR, besides their importance to regenerate oxidized thioredoxin in cytoplasm and in mitochondria, have been decisive to understand the importance of selenium as a micronutrient and its risk–benefit relationship as an antioxidant. Toxification processes have been linked to TrxR inhibition at the active site Sec by xenobiotics such as heavy metals.

The importance of the thioredoxin system extends far beyond the direct action of Trx, TrxR and NADPH as antioxidants. There are crucial interactions of these elements that become determinant for Redox Biology. Examples of those are the complexes between Trx and Apoptosis Signaling Kinase 1 (ASK-1) or Thioredoxin interacting protein (TxniP); oxidation of Trx, as a result of oxidative stress, releases ASK-1 and triggers an apoptotic cascade.

The thioredoxin system is of outmost importance for protein repair and folding, oxidative stress defense, redox signaling, DNA replication and repair, transcription; glucose metabolism, cell cycle arrest and apoptosis regulation. Dysregulation and disrepair of the thioredoxin system has been related to pathological processes such as inflammation, cancer, neurodegenerative and cardiovascular diseases, and diabetes, among others.

Review papers, research papers and short communications are very welcome in the following topics:

Transcription factors regulating the thioredoxin system expression;
Homeostasis and Redox systems cooperation;
Crosstalk between the thioredoxin and the glutathione/glutaredoxin systems;
Nutrition and the activity of the thioredoxin system;
Thioredoxin system in health promotion;
Molecular mechanisms of toxicity involving the thioredoxin system;
Thioredoxin system and neurodegenerative diseases;
Thioredoxin system in cancer and cancer therapy;
Thioredoxin system and fertility outcome;
Thioredoxin system and disease evolution;
Thioredoxin system failure and cell death.
Other related to the subject of the Special Issue can also be proposed by authors to editors.

*Dedicated to our mentor Arne Holmgren, a full-life enthusiastic researcher that always embraced new ideas and will be forever a pioneer on the importance of the thioredoxin system in health and disease, and also to his mentor Peter Reichard who significantly contributed for the discovery thioredoxin and ribonucleotide reductase 60 years ago.

Dr. Cristina M. L. Carvalho
Dr. Vasco Branco
Guest Editors

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Keywords

thioredoxin system
thioredoxin
thioredoxin reductase
redox regulation
redox biology

Published Papers (3 papers)

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Research

Open AccessArticle

Loss of Peroxiredoxin IV Protects Mice from Azoxymethane/Dextran Sulfate Sodium-Induced Colorectal Cancer Development

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Antioxidants 2023, 12(3), 677; https://doi.org/10.3390/antiox12030677 - 09 Mar 2023

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Abstract

Peroxiredoxin IV (Prx4), a typical two-cysteine-containing member of the peroxidase family, functions as an antioxidant to maintain cellular redox homeostasis through the reduction of reactive oxygen species (ROS) via cycles of oxidation–reduction reactions. Under oxidative stress, all Prxs including Prx4 are inactivated as their catalytic cysteines undergo hyperoxidation, and hyperoxidized two-cysteine Prxs can be exclusively repaired and revitalized through the reduction cycle catalyzed by sulfiredoxin (Srx). Previously, we showed that Prx4 is a preferred substrate of Srx, and knockout of Srx in mice leads to resistance to azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colon carcinogenesis. To further understand the significance of the Srx/Prx4 axis in colorectal cancer development, Prx4^−/− mice were established and subjected to standard AOM/DSS protocol. Compared with wildtype littermates, mice with Prx4^−/− genotype had significantly fewer and smaller tumors. Histopathological analysis revealed that loss of Prx4 leads to increased cell death through lipid peroxidation and lower infiltration of inflammatory cells in the knockout tumors compared to wildtype. Treatment with DSS alone also showed decreased infiltration of macrophages and lymphocytes in the colon of knockout mice, suggesting a role for Prx4 in inflammatory response. In addition, loss of Prx4 caused alterations in plasma cytokines and chemokines after DSS and AOM/DSS treatments. These findings suggest that loss of Prx4 protects mice from AOM/DSS-induced colon tumorigenesis. Thus, targeting Prx4 may provide novel strategies for colon cancer prevention and treatment. Full article

(This article belongs to the Special Issue The Importance of Thioredoxin System for Redox Regulation and Health)

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Open AccessArticle

A Buried Water Network Modulates the Activity of the Escherichia coli Disulphide Catalyst DsbA

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Antioxidants 2023, 12(2), 380; https://doi.org/10.3390/antiox12020380 - 04 Feb 2023

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Abstract

The formation of disulphide bonds is an essential step in the folding of many proteins that enter the secretory pathway; therefore, it is not surprising that eukaryotic and prokaryotic organisms have dedicated enzymatic systems to catalyse this process. In bacteria, one such enzyme is disulphide bond-forming protein A (DsbA), a thioredoxin-like thiol oxidase that catalyses the oxidative folding of proteins required for virulence and fitness. A large body of work on DsbA proteins, particularly Escherichia coli DsbA (EcDsbA), has demonstrated the key role that the Cys³⁰-XX-Cys³³ catalytic motif and its unique redox properties play in the thiol oxidase activity of this enzyme. Using mutational and functional analyses, here we identify that a set of charged residues, which form an acidic groove on the non-catalytic face of the enzyme, further modulate the activity of EcDsbA. Our high-resolution structures indicate that these residues form a water-mediated proton wire that can transfer protons from the bulk solvent to the active site. Our results support the view that proton shuffling may facilitate the stabilisation of the buried Cys³³ thiolate formed during the redox reaction and promote the correct direction of the EcDsbA–substrate thiol–disulphide exchange. Comparison with other proteins of the same class and proteins of the thioredoxin-superfamily in general suggest that a proton relay system appears to be a conserved catalytic feature among this widespread superfamily of proteins. Furthermore, this study also indicates that the acidic groove of DsbA could be a promising allosteric site to develop novel DsbA inhibitors as antibacterial therapeutics. Full article

(This article belongs to the Special Issue The Importance of Thioredoxin System for Redox Regulation and Health)

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Open AccessArticle

Selenium and Redox Enzyme Activity in Pregnant Women Exposed to Methylmercury

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Antioxidants 2022, 11(11), 2291; https://doi.org/10.3390/antiox11112291 - 19 Nov 2022

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Abstract

Selenium (Se) is a micronutrient with essential physiological functions achieved through the production of selenoproteins. Adequate Se intake has health benefits and reduces mercury (Hg) toxicity, which is important due to its neurotoxicity. This study determined the Se status and redox enzyme, including selenoproteins’, activity in pregnant women highly exposed to Hg (between 1 to 54 µg Hg/L blood) via fish consumption. A cross-sectional study enrolling 513 women between the first and third trimester of pregnancy from Madeira, Portugal was conducted, encompassing collection of blood and plasma samples. Samples were analyzed for total Se and Hg levels in whole blood and plasma, and plasma activity of redox-active proteins, such as glutathione peroxidase (GPx), thioredoxin reductase (TrxR) and thioredoxin (Trx). Enzyme activities were related to Se and Hg levels in blood. Se levels in whole blood (65.0 ± 13.1 µg/L) indicated this population had a sub-optimal Se status, which translated to low plasma GPx activity (69.7 ± 28.4 U/L). The activity of TrxR (12.3 ± 5.60 ng/mL) was not affected by the low Se levels. On the other hand, the decrease in Trx activity with an increase in Hg might be a good indicator to prevent fetal susceptibility. Full article

(This article belongs to the Special Issue The Importance of Thioredoxin System for Redox Regulation and Health)

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