Regulation of the thioredoxin-dependent system as an element of pharmacotherapy in redox-impaired diseases

The action of many exogenous factors as well as disturbed metabolic processes of cells contribute to the increased production of oxidants, which leads to redox imbalance and, as a consequence, metabolic changes, including death or tumor transformation of cells. However, each cell is equipped with antioxidants to prevent this type of situation.One of the antioxidant systems functioning in cells is the thioredoxin dependent system, which includes thioredoxin (Trx), thioredoxin reductase (TrxR) and thioredoxin peroxidase (TPx), which have the ability to reduce oxidized forms of cell components at the expense of nicotinamidoadenine dinucleotide phosphate (NADPH). This effect results from the spatial structure of Trx and TrxR, which allows the formation of an intramolecular disulfide bridge within the thioredoxin molecule and two intermolecular selenesulfide bridges within the thioredoxin reductase dimer. Another, equally important function of the thioredoxin-dependent system is to regulate the expression of many proteins through factors such as NFκB transcription factor and apoptosis regulating kinase (ASK-1), which trigger cascades of metabolic transformations ultimately leading to cell proliferation or apoptosis. The increase in expression /activity of Trx-dependent system components is observed in the development of many cancers. Therefore, the search for selective thioredoxin or thioredoxin reductase inhibitors is currently one of the main research directions in cancer pharmacotherapy. It has been shown that many naturally occurring polyphenolic compounds of natural origin with antioxidant activity (e.g. quercetin or curcumin) inactivate the Trx-dependent system. At the same time, a number of synthetic compounds, including complex compounds, that are used in cancer therapy (e.g. cisplatin, auranofin, gadolinium motexafin) also inhibit the action of the thioredoxin system.

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Antioxidant Activities and Selenogene Transcription in the European Sea Bass (Dicentrarchus labrax) Liver Depend, in a Non-linear Manner, on the Se/Hg Molar Ratio of the Feeds

Biological Trace Element Research ◽

10.1007/s12011-021-02835-7 ◽

2021 ◽

Author(s):

Marinelle Espino ◽

Harkaitz Eguiraun ◽

Oihane Diaz de Cerio ◽

José Antonio Carrero ◽

Nestor Etxebarria ◽

...

Keyword(s):

Antioxidant Activities ◽

Dicentrarchus Labrax ◽

Thioredoxin Reductase ◽

Sea Bass ◽

Molar Ratio ◽

Antioxidant Systems ◽

European Sea Bass ◽

Thioredoxin System ◽

Non Linear ◽

Linear Manner

AbstractFeeding 3.9 and 6.7 mg Hg/kg (Se/Hg molar ratios of 0.8 and 0.4, respectively) for 14 days negatively affected Dicentrarchus labrax growth and total DNTB- and thioredoxin-reductase (TrxR) activities and the transcription of four redox genes (txn1, gpx1, txnrd3, and txnrd2) in the liver, but a diet with 0.5 mg Hg/kg (Se/Hg molar ratio 6.6) slightly increased both reductase activities and the transcription of txn1, gpx1, and txnrd2. Feeding 6.7 mg Hg/kg for 53 days downregulated the genes of the thioredoxin system (txn1, txnrd3, and txnrd2) but upregulated gpx1, confirming the previously proposed complementarity among the antioxidant systems. Substitution of 20% of the feed by thawed white fish (hake) slightly counteracted the negative effects of Hg. The effects were not statistically significant and were dependent, in a non-linear manner, on the Se/Hg molar ratio of the feed but not on its Hg concentration. These results stress the need to consider the Se/Hg molar ratio of the feed/food when evaluating the toxicity of Hg.

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Antioxidant Activity of the Yeast Mitochondrial One-Cys Peroxiredoxin Is Dependent on Thioredoxin Reductase and Glutathione In Vivo

Molecular and Cellular Biology ◽

10.1128/mcb.01918-08 ◽

2009 ◽

Vol 29 (11) ◽

pp. 3229-3240 ◽

Cited By ~ 50

Author(s):

Darren Greetham ◽

Chris M. Grant

Keyword(s):

Oxidative Stress ◽

Antioxidant Activity ◽

Thioredoxin Reductase ◽

Disulfide Bridge ◽

Cysteine Residue ◽

In Vitro Assays ◽

Redox Partner ◽

Thioredoxin System

ABSTRACT Peroxiredoxins are ubiquitous enzymes which protect cells against oxidative stress. The first step of catalysis is common to all peroxiredoxins and results in oxidation of a conserved peroxidatic cysteine residue to sulfenic acid. This forms an intermolecular disulfide bridge in the case of 2-Cys peroxiredoxins, which is a substrate for the thioredoxin system. 1-Cys Prx's contain a peroxidatic cysteine but do not contain a second conserved cysteine residue, and hence the identity of the in vivo reduction system has been unclear. Here, we show that the yeast mitochondrial 1-Cys Prx1 is reactivated by glutathionylation of the catalytic cysteine residue and subsequent reduction by thioredoxin reductase (Trr2) coupled with glutathione (GSH). This novel mechanism does not require the usual thioredoxin (Trx3) redox partner of Trr2 for antioxidant activity, although in vitro assays show that the Trr2/Trx3 and Trr2/GSH systems exhibit similar capacities for supporting Prx1 catalysis. Our data also indicate that mitochondria are a main target of cadmium-induced oxidative stress and that Prx1 is particularly required to protect against mitochondrial oxidation. This study demonstrates a physiological reaction mechanism for 1-Cys peroxiredoxins and reveals a new role in protection against mitochondrial heavy metal toxicity.

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Targeting Bacterial Antioxidant Systems for Antibiotics Development

Current Medicinal Chemistry ◽

10.2174/0929867326666191007163654 ◽

2020 ◽

Vol 27 (12) ◽

pp. 1922-1939 ◽

Cited By ~ 3

Author(s):

Xiaoyuan Ren ◽

Lili Zou ◽

Arne Holmgren

Keyword(s):

Defense Mechanism ◽

Thioredoxin Reductase ◽

Drug Repurposing ◽

Multidrug Resistant ◽

Modern Medicine ◽

Resistant Bacteria ◽

Antioxidant Systems ◽

Gram Negative Bacteria ◽

Reductase Inhibitors ◽

Bacterial Cell Death

: The emergence of multidrug-resistant bacteria has become an urgent issue in modern medicine which requires novel strategies to develop antibiotics. Recent studies have supported the hypothesis that antibiotic-induced bacterial cell death is mediated by Reactive Oxygen Species (ROS). The hypothesis also highlighted the importance of antioxidant systems, the defense mechanism which contributes to antibiotic resistance. Thioredoxin and glutathione systems are the two major thiol-dependent systems which not only provide antioxidant capacity but also participate in various biological events in bacteria, such as DNA synthesis and protein folding. The biological importance makes them promising targets for novel antibiotics development. Based on the idea, ebselen and auranofin, two bacterial thioredoxin reductase inhibitors, have been found to inhibit the growth of bacteria lacking the GSH efficiently. A recent study combining ebselen and silver exhibited a strong synergistic effect against Multidrug-Resistant (MDR) Gram-negative bacteria which possess both thioredoxin and glutathione systems. These drug-repurposing studies are promising for quick clinical usage due to their well-known profile.

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Natural thioredoxin reductase inhibitors from Jatropha integerrima

RSC Advances ◽

10.1039/c5ra07274c ◽

2015 ◽

Vol 5 (58) ◽

pp. 47235-47243 ◽

Cited By ~ 22

Author(s):

Jian-Yong Zhu ◽

Lan-Lan Lou ◽

Yan-Qiong Guo ◽

Wei Li ◽

Yan-Hong Guo ◽

...

Keyword(s):

Thioredoxin Reductase ◽

Reductase Inhibitors

Nine new diterpenoids were isolated from Jatropha integerrima. The active diterpenoids represent the rare examples of non-aromatic TrxR inhibitors from nature.

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Recent Advances in the Development of Thioredoxin Reductase Inhibitors as Anticancer Agents

Current Drug Targets ◽

10.2174/138945012803530224 ◽

2012 ◽

Vol 13 (11) ◽

pp. 1432-1444 ◽

Cited By ~ 30

Author(s):

Yang Liu ◽

Yijing Li ◽

Shenghui Yu ◽

Guisen Zhao

Keyword(s):

Anticancer Agents ◽

Thioredoxin Reductase ◽

Reductase Inhibitors ◽

Recent Advances

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New Insights into the Potential of Endogenous Redox Systems in Wheat Bread Dough

Antioxidants ◽

10.3390/antiox7120190 ◽

2018 ◽

Vol 7 (12) ◽

pp. 190 ◽

Cited By ~ 2

Author(s):

Nicolas Navrot ◽

Rikke Buhl Holstborg ◽

Per Hägglund ◽

Inge Povlsen ◽

Birte Svensson

Keyword(s):

Nicotinamide Adenine Dinucleotide Phosphate ◽

Thioredoxin Reductase ◽

Heat Stability ◽

Wheat Bread ◽

Enzymatic System ◽

Redox Systems ◽

Bread Dough ◽

Seed Formation ◽

Protein Substrates ◽

Thioredoxin System

Various redox compounds are known to influence the structure of the gluten network in bread dough, and hence its strength. The cereal thioredoxin system (NTS), composed of nicotinamide adenine dinucleotide phosphate (NADPH)-dependent thioredoxin reductase (NTR) and thioredoxin (Trx), is a major reducing enzymatic system that is involved in seed formation and germination. NTS is a particularly interesting tool for food processing due to its heat stability and its broad range of protein substrates. We show here that barley NTS is capable of remodeling the gluten network and weakening bread dough. Furthermore, functional wheat Trx that is present in the dough can be recruited by the addition of recombinant barley NTR, resulting in dough weakening. These results confirm the potential of NTS, especially NTR, as a useful tool in baking for weakening strong doughs, or in flat product baking.

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Mapping the phenotypic repertoire of the cytoplasmic 2-Cys peroxiredoxin – thioredoxin system. 1. Understanding commonalities and differences among cell types

10.1101/224428 ◽

2017 ◽

Author(s):

Gianluca Selvaggio ◽

Pedro M. B. M. Coelho ◽

Armindo Salvador

Keyword(s):

Cell Lines ◽

Thioredoxin Reductase ◽

Cell Types ◽

Cell Physiology ◽

Related Factor ◽

Similar Response ◽

Redox Biology ◽

Analytical Approximations ◽

Thioredoxin System ◽

Reduction Capacity

AbstractThe system (PTTRS) formed by typical 2-Cys peroxiredoxins (Prx), thioredoxin (Trx), Trx reductase (TrxR), and sulfiredoxin (Srx) is central in antioxidant protection and redox signaling in the cytoplasm of eukaryotic cells. Understanding how the PTTRS integrates these functions requires tracing phenotypes to molecular properties, which is non-trivial. Here we analyze this problem based on a model that captures the PTTRS’ conserved features. We have mapped the conditions that generate each distinct response to H2O2 supply rates (νsup), and estimated the parameters for thirteen human cell types and for Saccharomyces cerevisiae. The resulting composition-to-phenotype map yielded the following experimentally testable predictions. The PTTRS permits many distinct responses including ultra-sensitivity and hysteresis. However, nearly all tumor cell lines showed a similar response characterized by limited Trx-S- depletion and a substantial but self-limited gradual accumulation of hyperoxidized Prx at high νsup. This similarity ensues from strong correlations between the TrxR, Srx and Prx activities over cell lines, which contribute to maintain the Prx-SS reduction capacity in slight excess over the maximal steady state Prx-SS production. In turn, in erythrocytes, hepatocytes and HepG2 cells high νsup depletes Trx-S- and oxidizes Prx mainly to Prx-SS. In all nucleated human cells the Prx-SS reduction capacity defined a threshold separating two different regimes. At sub-threshold νsup cytoplasmic H2O2 is determined by Prx, nM-range and spatially localized, whereas at supra-threshold νsup it is determined by much less active alternative sinks and μM-range throughout the cytoplasm. The yeast shows a distinct response where the Prx Tsa1 accumulates in sulfenate form at high νsup. This is mainly due to an exceptional stability of Tsa1’s sulfenate.The implications of these findings for thiol redox regulation and cell physiology are discussed. All estimates were thoroughly documented and provided, together with analytical approximations for system properties, as a resource for quantitative redox biology.AbbreviationsASK1, apoptosis signal-regulating kinase 1; Cat, catalase; GSH, glutathione; GPx1, glutathione peroxidase 1; Grx, glutaredoxin; KEAP1, Kelch-like ECH-associated protein 1; NRF2, nuclear factor erythroid 2-related factor 2; Prx, typical 2-Cys peroxiredoxin; PTTRS, peroxiredoxin / thioredoxin / thioredoxin reductase system; Srx, sulfiredoxin; Trx, thioredoxin; TrxR, thioredoxin reductase.

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