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Antioxidants
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The Importance of Thioredoxin System for Redox Regulation and Health
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The Importance of Thioredoxin System for Redox Regulation and Health

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 16571

Special Issue Editors

Dr. Cristina Carvalho

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Guest Editor
Department of Pharmaceutical Sciences and Medicines, Faculty of Pharmacy, Research Institute for Medicines (iMed.ULisboa), University of Lisbon, 1600-049 Lisbon, Portugal
Interests: risk assessment and exposure assessment of risky populations; molecular mechanisms of toxicity; thioredoxin and glutaredoxin systems; mercury, methylmercury and thimerosal; drug repurposing; cancer
Special Issues, Collections and Topics in MDPI journals
Dr. Vasco Branco

E-Mail Website
Guest Editor
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

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antioxidants is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • thioredoxin system
  • thioredoxin
  • thioredoxin reductase
  • redox regulation
  • redox biology

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Published Papers (6 papers)

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12 pages, 898 KiB  
Article
Hemodialysis Serum Stimulates the TXNIP-eNOS-STAT3 Inflammatory Pathway In Vitro
by Keren Cohen-Hagai, Hadil Kashua, Sydney Benchetrit and Tali Zitman-Gal
Antioxidants 2023, 12(5), 1109; https://doi.org/10.3390/antiox12051109 - 17 May 2023
Viewed by 2327
Abstract
Background: Endothelial dysfunction, vascular inflammation and accelerated atherosclerosis have been investigated extensively in patients with chronic kidney disease (CKD). These conditions, as well as protein–energy malnutrition and oxidative stress, impair kidney function and contribute to increased morbidity and mortality among patients with end-stage [...] Read more.
Background: Endothelial dysfunction, vascular inflammation and accelerated atherosclerosis have been investigated extensively in patients with chronic kidney disease (CKD). These conditions, as well as protein–energy malnutrition and oxidative stress, impair kidney function and contribute to increased morbidity and mortality among patients with end-stage kidney disease undergoing hemodialysis (HD). TXNIP, a key regulator of oxidative stress, has been linked to inflammation and suppresses eNOS activity. STAT3 activation adds to endothelial cell dysfunction, macrophage polarization, immunity and inflammation. Therefore, it is critically involved in atherosclerosis. This study evaluated the effect of sera from HD patients on the TXNIP-eNOS-STAT3 pathway using an in vitro model of human umbilical vein endothelial cells (HUVECs). Methods: Thirty HD patients with end-stage kidney disease and ten healthy volunteers were recruited. Serum samples were taken at dialysis initiation. HUVECs were treated with HD or healthy serum (10% v/v) for 24 h. Then, cells were collected for mRNA and protein analysis. Results: TXNIP mRNA and protein expression were significantly increased in HUVECs treated with HD serum compared to healthy controls (fold changes: 2.41 ± 1.84 vs. 1.41 ± 0.5 and 2.04 ± 1.16 vs. 0.92 ± 0.29, respectively), as were IL-8 mRNA (fold changes: 2.22 ± 1.09 vs. 0.98 ± 0.64) and STAT3 protein expression (fold changes: 1.31 ± 0.75 vs. 0.57 ± 0.43). The expression of eNOS mRNA and protein (fold changes: 0.64 ± 0.11 vs. 0.95 ± 0.24; 0.56 ± 0.28 vs. 4.35 ± 1.77, respectively) and that of SOCS3 and SIRT1 proteins were decreased. Patients’ nutritional status, reflected by their malnutrition–inflammation scores, did not affect these inflammatory markers. Conclusions: This study showed that sera from HD patients stimulated a novel inflammatory pathway, regardless of their nutritional status. Full article
(This article belongs to the Special Issue The Importance of Thioredoxin System for Redox Regulation and Health)
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19 pages, 3796 KiB  
Article
Bacillus subtilis YtpP and Thioredoxin A Are New Players in the Coenzyme-A-Mediated Defense Mechanism against Cellular Stress
by Maria-Armineh Tossounian, Maria Baczynska, William Dalton, Sew Yeu Peak-Chew, Kipras Undzenas, George Korza, Valeriy Filonenko, Mark Skehel, Peter Setlow and Ivan Gout
Antioxidants 2023, 12(4), 938; https://doi.org/10.3390/antiox12040938 - 15 Apr 2023
Cited by 5 | Viewed by 3606
Abstract
Coenzyme A (CoA) is an important cellular metabolite that is critical for metabolic processes and the regulation of gene expression. Recent discovery of the antioxidant function of CoA has highlighted its protective role that leads to the formation of a mixed disulfide bond [...] Read more.
Coenzyme A (CoA) is an important cellular metabolite that is critical for metabolic processes and the regulation of gene expression. Recent discovery of the antioxidant function of CoA has highlighted its protective role that leads to the formation of a mixed disulfide bond with protein cysteines, which is termed protein CoAlation. To date, more than 2000 CoAlated bacterial and mammalian proteins have been identified in cellular responses to oxidative stress, with the majority being involved in metabolic pathways (60%). Studies have shown that protein CoAlation is a widespread post-translational modification which modulates the activity and conformation of the modified proteins. The induction of protein CoAlation by oxidative stress was found to be rapidly reversed after the removal of oxidizing agents from the medium of cultured cells. In this study, we developed an enzyme-linked immunosorbent assay (ELISA)-based deCoAlation assay to detect deCoAlation activity from Bacillus subtilis and Bacillus megaterium lysates. We then used a combination of ELISA-based assay and purification strategies to show that deCoAlation is an enzyme-driven mechanism. Using mass-spectrometry and deCoAlation assays, we identified B. subtilis YtpP (thioredoxin-like protein) and thioredoxin A (TrxA) as enzymes that can remove CoA from different substrates. With mutagenesis studies, we identified YtpP and TrxA catalytic cysteine residues and proposed a possible deCoAlation mechanism for CoAlated methionine sulfoxide reducatse A (MsrA) and peroxiredoxin 5 (PRDX5) proteins, which results in the release of both CoA and the reduced form of MsrA or PRDX5. Overall, this paper reveals the deCoAlation activity of YtpP and TrxA and opens doors to future studies on the CoA-mediated redox regulation of CoAlated proteins under various cellular stress conditions. Full article
(This article belongs to the Special Issue The Importance of Thioredoxin System for Redox Regulation and Health)
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15 pages, 2014 KiB  
Article
Inhibitory Peptide of Soluble Guanylyl Cyclase/Trx1 Interface Blunts the Dual Redox Signaling Functions of the Complex
by Chuanlong Cui, Ping Shu, Tanaz Sadeghian, Waqas Younis, Hong Li and Annie Beuve
Antioxidants 2023, 12(4), 906; https://doi.org/10.3390/antiox12040906 - 10 Apr 2023
Cited by 1 | Viewed by 1905
Abstract
Soluble guanylyl cyclase (GC1) and oxido-reductase thioredoxin (Trx1) form a complex that mediates two NO signaling pathways as a function of the redox state of cells. Under physiological conditions, reduced Trx1 (rTrx1) supports the canonical NO-GC1-cGMP pathway by protecting GC1 activity from thiol [...] Read more.
Soluble guanylyl cyclase (GC1) and oxido-reductase thioredoxin (Trx1) form a complex that mediates two NO signaling pathways as a function of the redox state of cells. Under physiological conditions, reduced Trx1 (rTrx1) supports the canonical NO-GC1-cGMP pathway by protecting GC1 activity from thiol oxidation. Under oxidative stress, the NO-cGMP pathway is disrupted by the S-nitrosation of GC1 (addition of a NO group to a cysteine). In turn, SNO-GC1 initiates transnitrosation cascades, using oxidized thioredoxin (oTrx1) as a nitrosothiol relay. We designed an inhibitory peptide that blocked the interaction between GC1 and Trx1. This inhibition resulted in the loss of a) the rTrx1 enhancing effect of GC1 cGMP-forming activity in vitro and in cells and its ability to reduce the multimeric oxidized GC1 and b) GC1’s ability to fully reduce oTrx1, thus identifying GC1 novel reductase activity. Moreover, an inhibitory peptide blocked the transfer of S-nitrosothiols from SNO-GC1 to oTrx1. In Jurkat T cells, oTrx1 transnitrosates procaspase-3, thereby inhibiting caspase-3 activity. Using the inhibitory peptide, we demonstrated that S-nitrosation of caspase-3 is the result of a transnitrosation cascade initiated by SNO-GC1 and mediated by oTrx1. Consequently, the peptide significantly increased caspase-3 activity in Jurkat cells, providing a promising therapy for some cancers. Full article
(This article belongs to the Special Issue The Importance of Thioredoxin System for Redox Regulation and Health)
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20 pages, 62676 KiB  
Article
Loss of Peroxiredoxin IV Protects Mice from Azoxymethane/Dextran Sulfate Sodium-Induced Colorectal Cancer Development
by Pratik Thapa, Hong Jiang, Na Ding, Yanning Hao, Aziza Alshahrani, Eun Y. Lee, Junichi Fujii and Qiou Wei
Antioxidants 2023, 12(3), 677; https://doi.org/10.3390/antiox12030677 - 9 Mar 2023
Cited by 6 | Viewed by 2519
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 [...] Read more.
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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21 pages, 2326 KiB  
Article
A Buried Water Network Modulates the Activity of the Escherichia coli Disulphide Catalyst DsbA
by Geqing Wang, Jilong Qin, Anthony D. Verderosa, Lilian Hor, Carlos Santos-Martin, Jason J. Paxman, Jennifer L. Martin, Makrina Totsika and Begoña Heras
Antioxidants 2023, 12(2), 380; https://doi.org/10.3390/antiox12020380 - 4 Feb 2023
Cited by 4 | Viewed by 2881
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 [...] Read more.
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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17 pages, 2724 KiB  
Article
Selenium and Redox Enzyme Activity in Pregnant Women Exposed to Methylmercury
by Vasco Branco, Luís Carvalho, Cássia Barboza, Eduarda Mendes, Afonso Cavaco and Cristina Carvalho
Antioxidants 2022, 11(11), 2291; https://doi.org/10.3390/antiox11112291 - 19 Nov 2022
Cited by 3 | Viewed by 2134
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 [...] Read more.
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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