An Integrative Genomics Approach Identifies Activation of Thioredoxin/Thioredoxin Reductase-1-Mediated Oxidative Stress Defense Pathway and Inhibition of Angiogenesis in Obese Nondiabetic Human Subjects

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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Fur controls iron homeostasis and oxidative stress defense in the oligotrophic alpha-proteobacterium Caulobacter crescentus

Nucleic Acids Research ◽

10.1093/nar/gkp509 ◽

2009 ◽

Vol 37 (14) ◽

pp. 4812-4825 ◽

Cited By ~ 40

Author(s):

José F. da Silva Neto ◽

Vânia S. Braz ◽

Valéria C. S. Italiani ◽

Marilis V. Marques

Keyword(s):

Oxidative Stress ◽

Iron Homeostasis ◽

Caulobacter Crescentus ◽

Oxidative Stress Defense ◽

And Oxidative Stress ◽

Stress Defense

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LncRNA ENST00000453774.1 contributes to oxidative stress defense dependent on autophagy mediation to reduce extracellular matrix and alleviate renal fibrosis

Journal of Cellular Physiology ◽

10.1002/jcp.27590 ◽

2018 ◽

Vol 234 (6) ◽

pp. 9130-9143 ◽

Cited By ~ 10

Author(s):

Xiangcheng Xiao ◽

Qiongjing Yuan ◽

Yusa Chen ◽

Zhihua Huang ◽

Xi Fang ◽

...

Keyword(s):

Oxidative Stress ◽

Extracellular Matrix ◽

Renal Fibrosis ◽

Oxidative Stress Defense ◽

Stress Defense

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Role of thioredoxin reductase 1 in dysplastic transformation of human breast epithelial cells triggered by chronic oxidative stress

Scientific Reports ◽

10.1038/srep36860 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 19

Author(s):

Chaoran Dong ◽

Lei Zhang ◽

Ruoxuan Sun ◽

Jianying Liu ◽

Hanwei Yin ◽

...

Keyword(s):

Oxidative Stress ◽

Epithelial Cells ◽

Thioredoxin Reductase ◽

Human Breast ◽

Breast Epithelial Cells ◽

Chronic Oxidative Stress ◽

Thioredoxin Reductase 1 ◽

Breast Epithelial ◽

Human Breast Epithelial Cells

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Mycothiol, a Low-Molecular-Weight Thiol Drafted for Oxidative Stress Defense Duty

Glutathione ◽

10.1201/9781351261760-19 ◽

2018 ◽

pp. 331-356

Author(s):

Leonardo Astolfi Rosado ◽

Brandán Pedre ◽

Joris Messens

Keyword(s):

Oxidative Stress ◽

Molecular Weight ◽

Low Molecular Weight ◽

Oxidative Stress Defense ◽

Stress Defense

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Oxidative Stress Response in Regulatory and Conventional T Cells: A Comparison Between Patients with Chronic Coronary Syndrome and Healthy Subjects

10.21203/rs.3.rs-110580/v1 ◽

2020 ◽

Author(s):

Anna K Lundberg ◽

Rosanna WS 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 BackgroundInflammation 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 the present study, we tested the hypothesis that oxidative stress might be a potential contributor to the Treg cell deficit in CCS patients. MethodsThirty 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. Alxo, total antioxidant capacity (TAC) was measured in fresh peripheral blood mononuclear cells. ResultsAt 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. ConclusionTreg cells isolated from either CCS patients or healthy controls were all highly sensitive to oxidative stress ex vivo. There were however signs of oxidant-antioxidant imbalance in CCS patients and we thus assume that oxidative stress plays a role in the reduction of Treg cells in vivo.

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Acetylated Thioredoxin Reductase 1 Resists Oxidative Inactivation

Frontiers in Chemistry ◽

10.3389/fchem.2021.747236 ◽

2021 ◽

Vol 9 ◽

Author(s):

David. E. Wright ◽

Nikolaus Panaseiko ◽

Patrick O’Donoghue

Keyword(s):

Oxidative Stress ◽

Thioredoxin Reductase ◽

Oxygen Species ◽

Site Specific ◽

Oxidative Inactivation ◽

Thioredoxin Reductase 1 ◽

Lysine Residues ◽

Canonical Amino Acid ◽

Genetic Code Expansion ◽

Low Activity

Thioredoxin Reductase 1 (TrxR1) is an enzyme that protects human cells against reactive oxygen species generated during oxidative stress or in response to chemotherapies. Acetylation of TrxR1 is associated with oxidative stress, but the function of TrxR1 acetylation in oxidizing conditions is unknown. Using genetic code expansion, we produced recombinant and site-specifically acetylated variants of TrxR1 that also contain the non-canonical amino acid, selenocysteine, which is essential for TrxR1 activity. We previously showed site-specific acetylation at three different lysine residues increases TrxR1 activity by reducing the levels of linked dimers and low activity TrxR1 tetramers. Here we use enzymological studies to show that acetylated TrxR1 is resistant to both oxidative inactivation and peroxide-induced multimer formation. To compare the effect of programmed acetylation at specific lysine residues to non-specific acetylation, we produced acetylated TrxR1 using aspirin as a model non-enzymatic acetyl donor. Mass spectrometry confirmed aspirin-induced acetylation at multiple lysine residues in TrxR1. In contrast to unmodified TrxR1, the non-specifically acetylated enzyme showed no loss of activity under increasing and strongly oxidating conditions. Our data suggest that both site-specific and general acetylation of TrxR1 regulate the enzyme’s ability to resist oxidative damage.

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Interplay between cytosolic disulfide reductase systems and the Nrf2/Keap1 pathway

Biochemical Society Transactions ◽

10.1042/bst20150021 ◽

2015 ◽

Vol 43 (4) ◽

pp. 632-638 ◽

Cited By ~ 21

Author(s):

Edward E. Schmidt

Keyword(s):

Oxidative Stress ◽

Thioredoxin Reductase ◽

Reducing Power ◽

Nuclear Factor ◽

Independent Source ◽

Nrf2 Pathway ◽

Thioredoxin Reductase 1 ◽

Disulfide Reductase ◽

The Status ◽

Thioredoxin 1

NADPH transfers reducing power from bioenergetic pathways to thioredoxin reductase-1 (TrxR1) and glutathione reductase (GR) to support essential reductive systems. Surprisingly, it was recently shown that mouse livers lacking both TrxR1 and GR (‘TR/GR-null’) can sustain redox (reduction-oxidation) homoeostasis using a previously unrecognized NADPH-independent source of reducing power fuelled by dietary methionine. The NADPH-dependent systems are robustly redundant in liver, such that disruption of either TrxR1 or GR alone does not cause oxidative stress. However, disruption of TrxR1 induces transcription factor Nrf2 (nuclear factor erythroid-derived 2-like-2) whereas disruption of GR does not. This suggests the Nrf2 pathway responds directly to the status of the thioredoxin-1 (Trx1) system. The proximal regulator of Nrf2 is Keap1 (Kelch-like ECH-associated protein-1), a cysteine (Cys)-rich protein that normally interacts transiently with Nrf2, targeting it for degradation. During oxidative stress, this interaction is stabilized, preventing degradation of newly synthesized Nrf2, thereby allowing Nrf2 accumulation. Within the Trx1 system, TrxR1 and peroxiredoxins (Prxs) contain some of the most reactive nucleophilic residues in the cell, making them likely targets for oxidants or electrophiles. We propose that Keap1 activity and therefore Nrf2 is regulated by interactions of Trx1 system enzymes with oxidants. In TR/GR-null livers, Nrf2 activity is further induced, revealing that TrxR-independent systems also repress Nrf2 and these might be induced by more extreme challenges.

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