Novel electrophilic amides amenable by the Ugi reaction perturb thioredoxin system via thioredoxin reductase 1 (TrxR1) inhibition: Identification of DVD-445 as a new lead compound for anticancer therapy

Selenium is an essential trace element in mammals, but is toxic at high levels. It is best known for its cancer prevention activity, but cancer cells are more sensitive to selenite toxicity than normal cells. Since selenite treatment leads to oxidative stress, and the Trx (thioredoxin) system is a major antioxidative system, we examined the interplay between TR1 (Trx reductase 1) and Trx1 deficiencies and selenite toxicity in DT cells, a malignant mouse cell line, and the corresponding parental NIH 3T3 cells. TR1-deficient cells were far more sensitive to selenite toxicity than Trx1-deficient or control cells. In contrast, this effect was not seen in cells treated with hydrogen peroxide, suggesting that the increased sensitivity of TR1 deficiency to selenite was not due to oxidative stress caused by this compound. Further analyses revealed that only TR1-deficient cells manifested strongly enhanced production and secretion of glutathione, which was associated with increased sensitivity of the cells to selenite. The results suggest a new role for TR1 in cancer that is independent of Trx reduction and compensated for by the glutathione system. The results also suggest that the enhanced selenite toxicity of cancer cells and simultaneous inhibition of TR1 can provide a new avenue for cancer therapy.

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Targeting the Selenoprotein Thioredoxin Reductase 1 for Anticancer Therapy

Advances in Cancer Research - Selenium and Selenoproteins in Cancer ◽

10.1016/bs.acr.2017.07.005 ◽

2017 ◽

pp. 139-151 ◽

Cited By ~ 25

Author(s):

Elias S.J. Arnér

Keyword(s):

Thioredoxin Reductase ◽

Anticancer Therapy ◽

Thioredoxin Reductase 1

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System-wide identification and prioritization of enzyme substrates by thermal analysis

Nature Communications ◽

10.1038/s41467-021-21540-6 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Amir Ata Saei ◽

Christian M. Beusch ◽

Pierre Sabatier ◽

Juan Astorga Wells ◽

Hassan Gharibi ◽

...

Keyword(s):

Thermal Analysis ◽

Thioredoxin Reductase ◽

Structural Level ◽

Post Translational Modification ◽

Post Translational Modifications ◽

Enzyme Substrate ◽

Thioredoxin Reductase 1 ◽

Enzyme Substrates ◽

Substrate Proteins

AbstractDespite the immense importance of enzyme–substrate reactions, there is a lack of general and unbiased tools for identifying and prioritizing substrate proteins that are modified by the enzyme on the structural level. Here we describe a high-throughput unbiased proteomics method called System-wide Identification and prioritization of Enzyme Substrates by Thermal Analysis (SIESTA). The approach assumes that the enzymatic post-translational modification of substrate proteins is likely to change their thermal stability. In our proof-of-concept studies, SIESTA successfully identifies several known and novel substrate candidates for selenoprotein thioredoxin reductase 1, protein kinase B (AKT1) and poly-(ADP-ribose) polymerase-10 systems. Wider application of SIESTA can enhance our understanding of the role of enzymes in homeostasis and disease, opening opportunities to investigate the effect of post-translational modifications on signal transduction and facilitate drug discovery.

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Oxidative stress response in regulatory and conventional T cells: a comparison between patients with chronic coronary syndrome and healthy subjects

Journal of Translational Medicine ◽

10.1186/s12967-021-02906-2 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Anna K. Lundberg ◽

Rosanna W. S. Chung ◽

Louise Zeijlon ◽

Gustav Fernström ◽

Lena Jonasson

Keyword(s):

Oxidative Stress ◽

T Cells ◽

Mononuclear Cells ◽

Ex Vivo ◽

Thioredoxin Reductase ◽

Healthy Controls ◽

Antioxidant Genes ◽

Consistent Finding ◽

Coronary Syndrome ◽

Thioredoxin Reductase 1

Abstract Background Inflammation and oxidative stress form a vicious circle in atherosclerosis. Oxidative stress can have detrimental effects on T cells. A unique subset of CD4+ T cells, known as regulatory T (Treg) cells, has been associated with atheroprotective effects. Reduced numbers of Treg cells is a consistent finding in patients with chronic coronary syndrome (CCS). However, it is unclear to what extent these cells are sensitive to oxidative stress. In this pilot study, we tested the hypothesis that oxidative stress might be a potential contributor to the Treg cell deficit in CCS patients. Methods Thirty patients with CCS and 24 healthy controls were included. Treg (CD4+CD25+CD127−) and conventional T (CD4+CD25−, Tconv) cells were isolated and treated with increasing doses of H2O2. Intracellular ROS levels and cell death were measured after 2 and 18 h, respectively. The expression of antioxidant genes was measured in freshly isolated Treg and Tconv cells. Also, total antioxidant capacity (TAC) was measured in fresh peripheral blood mononuclear cells, and oxidized (ox) LDL/LDL ratios were determined in plasma. Results At all doses of H2O2, Treg cells accumulated more ROS and exhibited higher rates of death than their Tconv counterparts, p < 0.0001. Treg cells also expressed higher levels of antioxidant genes, including thioredoxin and thioredoxin reductase-1 (p < 0.0001), though without any differences between CCS patients and controls. Tconv cells from CCS patients were, on the other hand, more sensitive to oxidative stress ex vivo and expressed more thioredoxin reductase-1 than Tconv cells from controls, p < 0.05. Also, TAC levels were lower in patients, 0.97 vs 1.53 UAE/100 µg, p = 0.001, while oxLDL/LDL ratios were higher, 29 vs 22, p = 0.006. Conclusion Treg cells isolated from either CCS patients or healthy controls were all highly sensitive to oxidative stress ex vivo. There were signs of oxidant-antioxidant imbalance in CCS patients and we thus assume that oxidative stress may play a role in the reduction of Treg cells in vivo.

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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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