Inhibition of Thioredoxin and Thioredoxin Reductase by 4-Hydroxy-2-nonenal in Vitro and in Vivo

2006 ◽  
Vol 128 (6) ◽  
pp. 1879-1885 ◽  
Author(s):  
Jianguo Fang ◽  
Arne Holmgren
Keyword(s):  
Thioredoxin Reductase

In vivo and in vitro inhibition of mice thioredoxin reductase by methylmercury

BioMetals ◽  
2010 ◽  
Vol 23 (6) ◽  
pp. 1171-1177 ◽  
Author(s):  
Caroline Wagner ◽  
Jéssie H. Sudati ◽  
Cristina W. Nogueira ◽  
João B. T. Rocha
Keyword(s):  
Thioredoxin Reductase ◽  
In Vitro Inhibition

scholarly journals Control of Thioredoxin Reductase Gene (trxB) Transcription by SarA in Staphylococcus aureus

2009 ◽  
Vol 192 (1) ◽  
pp. 336-345 ◽  
Author(s):  
Anand Ballal ◽  
Adhar C. Manna
Keyword(s):  
Oxidative Stress ◽  
Staphylococcus Aureus ◽  
Dna Binding ◽  
Target Genes ◽  
Thioredoxin Reductase ◽  
Negative Regulator ◽  
Binding Studies ◽  
Oxidizing Agents

ABSTRACT Thioredoxin reductase (encoded by trxB) protects Staphylococcus aureus against oxygen or disulfide stress and is indispensable for growth. Among the different sarA family mutants analyzed, transcription of trxB was markedly elevated in the sarA mutant under conditions of aerobic as well as microaerophilic growth, indicating that SarA acts as a negative regulator of trxB expression. Gel shift analysis showed that purified SarA protein binds directly to the trxB promoter region DNA in vitro. DNA binding of SarA was essential for repression of trxB transcription in vivo in S. aureus. Northern blot analysis and DNA binding studies of the purified wild-type SarA and the mutant SarAC9G with oxidizing agents indicated that oxidation of Cys-9 reduced the binding of SarA to the trxB promoter DNA. Oxidizing agents, in particular diamide, could further enhance transcription of the trxB gene in the sarA mutant, suggesting the presence of a SarA-independent mode of trxB induction. Analysis of two oxidative stress-responsive sarA regulatory target genes, trxB and sodM, with various mutant sarA constructs showed a differential ability of the SarA to regulate expression of the two above-mentioned genes in vivo. The overall data demonstrate the important role played by SarA in modulating expression of genes involved in oxidative stress resistance in S. aureus.

Distinct electron transfer from ferredoxin–thioredoxin reductase to multiple thioredoxin isoforms in chloroplasts

2017 ◽  
Vol 474 (8) ◽  
pp. 1347-1360 ◽  
Author(s):  
Keisuke Yoshida ◽  
Toru Hisabori
Keyword(s):  
Electron Transfer ◽  
Redox Regulation ◽  
Thioredoxin Reductase ◽  
Reducing Power ◽  
Redox Potentials ◽  
Regulation Network ◽  
Electron Transfers ◽  
Kinetics Of

Thiol-based redox regulation is considered to support light-responsive control of various chloroplast functions. The redox cascade via ferredoxin–thioredoxin reductase (FTR)/thioredoxin (Trx) has been recognized as a key to transmitting reducing power; however, Arabidopsis thaliana genome sequencing has revealed that as many as five Trx subtypes encoded by a total of 10 nuclear genes are targeted to chloroplasts. Because each Trx isoform seems to have a distinct target selectivity, the electron distribution from FTR to multiple Trxs is thought to be the critical branch point for determining the consequence of chloroplast redox regulation. In the present study, we aimed to comprehensively characterize the kinetics of electron transfer from FTR to 10 Trx isoforms. We prepared the recombinant FTR protein from Arabidopsis in the heterodimeric form containing the Fe–S cluster. By reconstituting the FTR/Trx system in vitro, we showed that FTR prepared here was enzymatically active and suitable for uncovering biochemical features of chloroplast redox regulation. A series of redox state determinations using the thiol-modifying reagent, 4-acetamido-4′-maleimidylstilbene-2,2′-disulfonate, indicated that all chloroplast Trx isoforms are commonly reduced by FTR; however, significantly different efficiencies were evident. These differences were apparently correlated with the distinct midpoint redox potentials among Trxs. Even when the experiments were performed under conditions of hypothetical in vivo stoichiometry of FTR and Trxs, a similar trend in distinguishable electron transfers was observed. These data highlight an aspect of highly organized circuits in the chloroplast redox regulation network.

scholarly journals ROS-mediated inactivation of the PI3K/AKT pathway is involved in the antigastric cancer effects of thioredoxin reductase-1 inhibitor chaetocin

2019 ◽  
Vol 10 (11) ◽  
Author(s):  
Chuangyu Wen ◽  
Huihui Wang ◽  
Xiaobin Wu ◽  
Lu He ◽  
Qian Zhou ◽  
...  
Keyword(s):  
Critical Role ◽  
Thioredoxin Reductase ◽  
Akt Pathway ◽  
Ros Generation ◽  
In Vivo Models ◽  
M Phase ◽  
Tumorigenesis And Progression ◽  
Induced Apoptosis

Abstract Novel drugs are urgently needed for gastric cancer (GC) treatment. The thioredoxin-thioredoxin reductase (TRX-TRXR) system has been found to play a critical role in GC tumorigenesis and progression. Thus, agents that target the TRX-TRXR system may be highly efficacious as GC treatments. In this study, we showed that chaetocin, a natural product isolated from the Chaetomium species of fungi, inhibited proliferation, induced G2/M phase arrest and caspase-dependent apoptosis in both in vitro and in vivo models (cell xenografts and patient-derived xenografts) of GC. Chaetocin inactivated TRXR-1, resulting in the accumulation of reactive oxygen species (ROS) in GC cells; overexpression of TRX-1 as well as cotreatment of GC cells with the ROS scavenger N-acetyl-L-cysteine attenuated chaetocin-induced apoptosis; chaetocin-induced apoptosis was significantly increased when GC cells were cotreated with auranofin. Moreover, chaetocin was shown to inactivate the PI3K/AKT pathway by inducing ROS generation; AKT-1 overexpression also attenuated chaetocin-induced apoptosis. Taken together, these results reveal that chaetocin induces the excessive accumulation of ROS via inhibition of TRXR-1. This is followed by PI3K/AKT pathway inactivation, which ultimately inhibits proliferation and induces caspase-dependent apoptosis in GC cells. Chaetocin therefore may be a potential agent for GC treatment.

scholarly journals Thioredoxin Reductase-1 Inhibition Augments Endogenous Glutathione-Dependent Antioxidant Responses in Experimental Bronchopulmonary Dysplasia

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Stephanie B. Wall ◽  
Rachael Wood ◽  
Katelyn Dunigan ◽  
Qian Li ◽  
Rui Li ◽  
...  
Keyword(s):  
Lung Injury ◽  
Thioredoxin Reductase ◽  
Antioxidant Defenses ◽  
Mrna Levels ◽  
Newborn Mice ◽  
Antioxidant Responses ◽  
Thioredoxin Reductase 1 ◽  
Gpx Activity

Background. Aurothioglucose- (ATG-) mediated inhibition of thioredoxin reductase-1 (TXNRD1) improves alveolarization in experimental murine bronchopulmonary dysplasia (BPD). Glutathione (GSH) mediates susceptibility to neonatal and adult oxidative lung injury. We have previously shown that ATG attenuates hyperoxic lung injury and enhances glutathione- (GSH-) dependent antioxidant defenses in adult mice. Hypothesis. The present studies evaluated the effects of TXNRD1 inhibition on GSH-dependent antioxidant defenses in newborn mice in vivo and lung epithelia in vitro. Methods. Newborn mice received intraperitoneal ATG or saline prior to room air or 85% hyperoxia exposure. Glutamate-cysteine ligase (GCL) catalytic (Gclc) and modifier (Gclm) mRNA levels, total GSH levels, total GSH peroxidase (GPx) activity, and Gpx2 expression were determined in lung homogenates. In vitro, murine transformed club cells (mtCCs) were treated with the TXNRD1 inhibitor auranofin (AFN) or vehicle in the presence or absence of the GCL inhibitor buthionine sulfoximine (BSO). Results. In vivo, ATG enhanced hyperoxia-induced increases in Gclc mRNA levels, total GSH contents, and GPx activity. In vitro, AFN increased Gclm mRNA levels, intracellular and extracellular GSH levels, and GPx activity. BSO prevented AFN-induced increases in GSH levels. Conclusions. Our data are consistent with a model in which TXNRD1 inhibition augments hyperoxia-induced GSH-dependent antioxidant responses in neonatal mice. Discrepancies between in vivo and in vitro results highlight the need for methodologies that permit accurate assessments of the GSH system at the single-cell level.

scholarly journals Cytoplasmic Thioredoxin Reductase Is Essential for Embryogenesis but Dispensable for Cardiac Development

2005 ◽  
Vol 25 (5) ◽  
pp. 1980-1988 ◽  
Author(s):  
Cemile Jakupoglu ◽  
Gerhard K. H. Przemeck ◽  
Manuela Schneider ◽  
Stéphanie G. Moreno ◽  
Nadja Mayr ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Cardiac Development ◽  
Ex Vivo ◽  
Cell Communication ◽  
Thioredoxin Reductase ◽  
Early Embryonic Lethality ◽  
The Individual ◽  
Thioredoxin Reductases

ABSTRACT Two distinct thioredoxin/thioredoxin reductase systems are present in the cytosol and the mitochondria of mammalian cells. Thioredoxins (Txn), the main substrates of thioredoxin reductases (Txnrd), are involved in numerous physiological processes, including cell-cell communication, redox metabolism, proliferation, and apoptosis. To investigate the individual contribution of mitochondrial (Txnrd2) and cytoplasmic (Txnrd1) thioredoxin reductases in vivo, we generated a mouse strain with a conditionally targeted deletion of Txnrd1. We show here that the ubiquitous Cre-mediated inactivation of Txnrd1 leads to early embryonic lethality. Homozygous mutant embryos display severe growth retardation and fail to turn. In accordance with the observed growth impairment in vivo, Txnrd1-deficient embryonic fibroblasts do not proliferate in vitro. In contrast, ex vivo-cultured embryonic Txnrd1-deficient cardiomyocytes are not affected, and mice with a heart-specific inactivation of Txnrd1 develop normally and appear healthy. Our results indicate that Txnrd1 plays an essential role during embryogenesis in most developing tissues except the heart.

scholarly journals Biomarkers of Adverse Response to Mercury: Histopathology versus Thioredoxin Reductase Activity

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Vasco Branco ◽  
Paula Ramos ◽  
João Canário ◽  
Jun Lu ◽  
Arne Holmgren ◽  
...  
Keyword(s):  
Reductase Activity ◽  
Thioredoxin Reductase ◽  
Mercury Toxicity ◽  
Histopathological Changes ◽  
Mercury Compounds ◽  
Stress Markers ◽  
Liver And Kidney ◽  
Potential Use

Exposure to mercury is normally assessed by measuring its accumulation in hair, blood or urine. Currently, the biomarkers of effect that have been proposed for mercurials, such as coproporphyrines or oxidative stress markers, are not sensitive enough and lack specificity. Selenium and selenoproteins are important targets for mercury and thioredoxin reductase (TrxR) in particular was shown to be very sensitive to mercury compounds bothin vitroandin vivo. In this study we looked into the relation between the inhibition of thioredoxin reductase (TrxR) activity and histopathological changes caused by exposure to mercurials. Juvenile zeabra-seabreams were exposed to Hg2+or MeHg for 28 days and histopathological changes were analyzed in the liver and kidney as well as TrxR activity. Both mercurials caused histopathological changes in liver and kidney, albeit Hg2+caused more extensive and severe lesions. Likewise, both mercurials decreased TrxR activity, being Hg2+a stronger inhibitor. Co-exposure to Hg2+and Se fully prevented TrxR inhibition in the liver and reduced the severity of lesions in the organ. These results show that upon exposure to mercurials, histopathological alterations correlate with the level of TrxR activity and point to the potential use of this enzyme as a biomarker of mercury toxicity.

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

2009 ◽  
Vol 29 (11) ◽  
pp. 3229-3240 ◽  
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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