Journal articles: 'Thioredoxin; oxidative stress'

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Berndt, Carsten, Christopher Horst Lillig, and Arne Holmgren. "Thiol-based mechanisms of the thioredoxin and glutaredoxin systems: implications for diseases in the cardiovascular system." American Journal of Physiology-Heart and Circulatory Physiology 292, no. 3 (March 2007): H1227—H1236. http://dx.doi.org/10.1152/ajpheart.01162.2006.

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Reactive oxygen species (ROS) and the cellular thiol redox state are crucial mediators of multiple cell processes like growth, differentiation, and apoptosis. Excessive ROS production or oxidative stress is associated with several diseases, including cardiovascular disorders like ischemia-reperfusion. To prevent ROS-induced disorders, the heart is equipped with effective antioxidant systems. Key players in defense against oxidative stress are members of the thioredoxin-fold family of proteins. Of these, thioredoxins and glutaredoxins maintain a reduced intracellular redox state in mammalian cells by the reduction of protein thiols. The reversible oxidation of Cys-Gly-Pro-Cys or Cys-Pro(Ser)-Tyr-Cys active site cysteine residues is used in reversible electron transport. Thioredoxins and glutaredoxins belong to corresponding systems consisting of NADPH, thioredoxin reductase, and thioredoxin or NADPH, glutathione reductase, glutathione, and glutaredoxin, respectively. Thioredoxin as well as glutaredoxin activities appear to be very important for the progression and severity of several cardiovascular disorders. These proteins function not only as antioxidants, they inhibit or activate apoptotic signaling molecules like apoptosis signal-regulating kinase 1 and Ras or transcription factors like NF-κB. Thioredoxin activity is regulated by the endogenous inhibitor thioredoxin-binding protein 2 (TBP-2), indicating an important role of the balance between thioredoxin and TBP-2 levels in cardiovascular diseases. In this review, we will summarize cardioprotective effects of endogenous thioredoxin and glutaredoxin systems as well as the high potential in clinical applications of exogenously applied thioredoxin or glutaredoxin or the induction of endogenous thioredoxin and glutaredoxin systems.

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Trotter, Eleanor W., and Chris M. Grant. "Overlapping Roles of the Cytoplasmic and Mitochondrial Redox Regulatory Systems in the Yeast Saccharomyces cerevisiae." Eukaryotic Cell 4, no. 2 (February 2005): 392–400. http://dx.doi.org/10.1128/ec.4.2.392-400.2005.

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ABSTRACT Thioredoxins are small, highly conserved oxidoreductases which are required to maintain the redox homeostasis of the cell. Saccharomyces cerevisiae contains a cytoplasmic thioredoxin system (TRX1, TRX2, and TRR1) as well as a complete mitochondrial thioredoxin system, comprising a thioredoxin (TRX3) and a thioredoxin reductase (TRR2). In the present study we have analyzed the functional overlap between the two systems. By constructing mutant strains with deletions of both the mitochondrial and cytoplasmic systems (trr1 trr2 and trx1 trx2 trx3), we show that cells can survive in the absence of both systems. Analysis of the redox state of the cytoplasmic thioredoxins reveals that they are maintained independently of the mitochondrial system. Similarly, analysis of the redox state of Trx3 reveals that it is maintained in the reduced form in wild-type cells and in mutants lacking components of the cytoplasmic thioredoxin system (trx1 trx2 or trr1). Surprisingly, the redox state of Trx3 is also unaffected by the loss of the mitochondrial thioredoxin reductase (trr2) and is largely maintained in the reduced form unless cells are exposed to an oxidative stress. Since glutathione reductase (Glr1) has been shown to colocalize to the cytoplasm and mitochondria, we examined whether loss of GLR1 influences the redox state of Trx3. During normal growth conditions, deletion of TRR2 and GLR1 was found to result in partial oxidation of Trx3, indicating that both Trr2 and Glr1 are required to maintain the redox state of Trx3. The oxidation of Trx3 in this double mutant is even more pronounced during oxidative stress or respiratory growth conditions. Taken together, these data indicate that Glr1 and Trr2 have an overlapping function in the mitochondria.

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Smits, Wiep Klaas, Jean-Yves F. Dubois, Sierd Bron, Jan Maarten van Dijl, and Oscar P. Kuipers. "Tricksy Business: Transcriptome Analysis Reveals the Involvement of Thioredoxin A in Redox Homeostasis, Oxidative Stress, Sulfur Metabolism, and Cellular Differentiation in Bacillus subtilis." Journal of Bacteriology 187, no. 12 (June 15, 2005): 3921–30. http://dx.doi.org/10.1128/jb.187.12.3921-3930.2005.

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ABSTRACT Thioredoxins are important thiol-reactive proteins. Most knowledge about this class of proteins is derived from proteome studies, and little is known about the global transcriptional response of cells to various thioredoxin levels. In Bacillus subtilis, thioredoxin A is encoded by trxA and is essential for viability. In this study, we report the effects of minimal induction of a strain carrying an IPTG (isopropyl-β-d-thiogalactopyranoside)-inducible trxA gene (ItrxA) on transcription levels, as determined by DNA macroarrays. The effective depletion of thioredoxin A leads to the induction of genes involved in the oxidative stress response (but not those dependent on PerR), phage-related functions, and sulfur utilization. Also, several stationary-phase processes, such as sporulation and competence, are affected. The majority of these phenotypes are rescued by a higher induction level of ItrxA, leading to an approximately wild-type level of thioredoxin A protein. A comparison with other studies shows that the effects of thioredoxin depletion are distinct from, but show some similarity to, oxidative stress and disulfide stress. Some of the transcriptional effects may be linked to thioredoxin-interacting proteins. Finally, thioredoxin-linked processes appear to be conserved between prokaryotes and eukaryotes.

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Rohrbach, Susanne, Stefanie Gruenler, Mirja Teschner, and Juergen Holtz. "The thioredoxin system in aging muscle: key role of mitochondrial thioredoxin reductase in the protective effects of caloric restriction?" American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 291, no. 4 (October 2006): R927—R935. http://dx.doi.org/10.1152/ajpregu.00890.2005.

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Cellular redox balance is maintained by various antioxidative systems. Among those is the thioredoxin system, consisting of thioredoxin, thioredoxin reductase, and NADPH. In the present study, we examined the effects of caloric restriction (2 mo) on the expression of the cytosolic and mitochondrial thioredoxin system in skeletal muscle and heart of senescent and young rats. Mitochondrial thioredoxin reductase (TrxR2) is significantly reduced in aging skeletal and cardiac muscle and renormalized after caloric restriction, while the cytosolic isoform remains unchanged. Thioredoxins (mitochondrial Trx2, cytosolic Trx1) are not influenced by caloric restriction. In skeletal and cardiac muscle of young rats, caloric restriction has no effect on the expression of thioredoxins or thioredoxin reductases. Enforced reduction of TrxR2 (small interfering RNA) in myoblasts under exposure to ceramide or TNF-α causes a dramatic enhancement of nucleosomal DNA cleavage, caspase 9 activation, and mitochondrial reactive oxygen species release, together with reduced cell viability, while this TrxR2 reduction is without effect in unstimulated myoblasts under basal conditions. Oxidative stress in vitro (H2O2in C2C12myoblasts and myotubes) results in different changes: TrxR2, Trx2, and Trx1 are induced without alterations in the cytosolic thioredoxin reductase isoforms. Thus aging is associated with a TrxR2 reduction in skeletal muscle and heart, which enhances susceptibility to apoptotic stimuli but is renormalized after short-term caloric restriction. Exogenous oxidative stress does not result in these age-related changes of TrxR2.

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Watson, Walter H., and Dean P. Jones. "Oxidation of nuclear thioredoxin during oxidative stress." FEBS Letters 543, no. 1-3 (April 29, 2003): 144–47. http://dx.doi.org/10.1016/s0014-5793(03)00430-7.

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Masutani, Hiroshi, Yoshimi Yamaguchi, Ryoko Otsuki, Nobue Kanoh, Yuji Kunimoto, Kazuo Murata, and Junji Yodoi. "Important Role of Antioxidants in Oxidative Stress Thioredoxin and Thioredoxin Inducers against Oxidative Stress." Journal of Clinical Biochemistry and Nutrition 37, no. 2 (2005): 45–53. http://dx.doi.org/10.3164/jcbn.37.45.

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Achard, Maud E. S., Amanda J. Hamilton, Tarek Dankowski, Begoña Heras, Mark S. Schembri, Jennifer L. Edwards, Michael P. Jennings, and Alastair G. McEwan. "A Periplasmic Thioredoxin-Like Protein Plays a Role in Defense against Oxidative Stress in Neisseria gonorrhoeae." Infection and Immunity 77, no. 11 (August 17, 2009): 4934–39. http://dx.doi.org/10.1128/iai.00714-09.

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ABSTRACT Thioredoxin-like proteins of the TlpA/ResE/CcmG subfamily are known to face the periplasm in gram-negative bacteria. Using the tlpA gene of Bradyrhizobium japonicum as a query, we identified a locus (NGO1923) in Neisseria gonorrhoeae that encodes a thioredoxin-like protein (NG_TlpA). Bioinformatics analysis indicated that the predicted NG_TlpA protein contained a cleavable signal peptide at the N terminus, and secondary structure analysis identified a thioredoxin fold with a helical insertion (∼25 residues), similar to that found in B. japonicum TlpA but absent in cytoplasmic thioredoxins. Biochemical characterization of a recombinant form of NG_TlpA revealed a standard redox potential (E0′) of −206 mV. This property and the observation that the oxidized form of the protein exhibited greater thermal stability than the reduced species indicated that NG_TlpA is a reducing thioredoxin and not an oxidizing thiol-disulfide oxidoreductase like DsbA. The thioredoxin activity of NG_TlpA was confirmed in an insulin disulfide reduction assay. A tlpA mutant of N. gonorrhoeae strain 1291 was found to be highly sensitive to oxidative killing by paraquat and hydrogen peroxide, indicating an antioxidant role for the NG_TlpA in this bacterium. The tlpA mutant also exhibited reduced intracellular survival in human primary cervical epithelial cells.

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Flores, Lisa C., Melanie Ortiz, Sara Dube, Gene B. Hubbard, Shuko Lee, Adam Salmon, Yiqiang Zhang, and Yuji Ikeno. "Thioredoxin, oxidative stress, cancer and aging." Longevity & Healthspan 1, no. 1 (2012): 4. http://dx.doi.org/10.1186/2046-2395-1-4.

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Silva-Adaya, Daniela, María E. Gonsebatt, and Jorge Guevara. "Thioredoxin System Regulation in the Central Nervous System: Experimental Models and Clinical Evidence." Oxidative Medicine and Cellular Longevity 2014 (2014): 1–13. http://dx.doi.org/10.1155/2014/590808.

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The reactive oxygen species produced continuously during oxidative metabolism are generated at very high rates in the brain. Therefore, defending against oxidative stress is an essential task within the brain. An important cellular system against oxidative stress is the thioredoxin system (TS). TS is composed of thioredoxin, thioredoxin reductase, and NADPH. This review focuses on the evidence gathered in recent investigations into the central nervous system, specifically the different brain regions in which the TS is expressed. Furthermore, we address the conditions that modulate the thioredoxin system in both, animal models and the postmortem brains of human patients associated with the most common neurodegenerative disorders, in which the thioredoxin system could play an important part.

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Bjur, Eva, Sofia Eriksson-Ygberg, Fredrik Åslund, and Mikael Rhen. "Thioredoxin 1 Promotes Intracellular Replication and Virulence of Salmonella enterica Serovar Typhimurium." Infection and Immunity 74, no. 9 (September 2006): 5140–51. http://dx.doi.org/10.1128/iai.00449-06.

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ABSTRACT The effect of the cytoplasmic reductase and protein chaperone thioredoxin 1 on the virulence of Salmonella enterica serovar Typhimurium was evaluated by deleting the trxA, trxB, or trxC gene of the cellular thioredoxin system, the grxA or gshA gene of the glutathione/glutaredoxin system, or the dsbC gene coding for a thioredoxin-dependent periplasmic disulfide bond isomerase. Mutants were tested for tolerance to oxidative and nitric oxide donor substances in vitro, for invasion and intracellular replication in cultured epithelial and macrophage-like cells, and for virulence in BALB/c mice. In these experiments only the gshA mutant, which was defective in glutathione synthesis, exhibited sensitization to oxidative stress in vitro and a small decrease in virulence. In contrast, the trxA mutant did not exhibit any growth defects or decreased tolerance to oxidative or nitric oxide stress in vitro, yet there were pronounced decreases in intracellular replication and mouse virulence. Complementation analyses using defined catalytic variants of thioredoxin 1 showed that there is a direct correlation between the redox potential of thioredoxin 1 and restoration of intracellular replication of the trxA mutant. Attenuation of mouse virulence that was caused by a deficiency in thioredoxin 1 was restored by expression of wild-type thioredoxin 1 in trans but not by expression of a catalytically inactive variant. These results clearly imply that in S. enterica serovar Typhimurium, the redox-active protein thioredoxin 1 promotes virulence, whereas in vitro tolerance to oxidative stress depends on production of glutathione.

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Zhao, Ming. "THIOREDOXIN STABILIZES LYSOSOMAL MEMBRANE AGAINST OXIDATIVE STRESS." Shock 21, Supplement (March 2004): 29. http://dx.doi.org/10.1097/00024382-200403001-00114.

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Joshi, Manjunath B., Danila Ivanov, Maria Philippova, Emmanouil Kyriakakis, Paul Erne, and Thérèse J. Resink. "A requirement for thioredoxin in redox-sensitive modulation of T-cadherin expression in endothelial cells." Biochemical Journal 416, no. 2 (November 12, 2008): 271–80. http://dx.doi.org/10.1042/bj20080765.

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T-cad (T-cadherin), a glycosylphosphatidylinositol-anchored cadherin superfamily member, is expressed widely in the brain and cardiovascular system, and absent, decreased, or even increased, in cancers. Mechanisms controlling T-cad expression are poorly understood. The present study investigated transcriptional regulation of T-cad in ECs (endothelial cells). Conditions of oxidative stress (serum-deprivation or presence of H2O2) elevate T-cad mRNA and protein levels in ECs. Reporter gene analysis, using serially deleted T-cad promoter stretches ranging from −99 to −2304 bp, located the minimal promoter region of T-cad within −285 bp from the translation start site. Reporter activity in ECs transfected with the −285 bp construct increased under conditions of oxidative stress, and this was normalized by antioxidant N-acetylcysteine. An electrophoretic-mobility-shift assay revealed a specific nucleoprotein complex unique to −156 to −203 bp, which increased when nuclear extracts from oxidatively stressed ECs were used, suggesting the presence of redox-sensitive binding element(s). MS analysis of the nucleoprotein complex unique to −156 to −203 bp after streptavidin–agarose pull-down detected the presence of the redox-active protein thioredoxin. The presence of thioredoxin-1 in a nuclear extract from oxidatively stressed ECs was demonstrated after immunoprecipitation and immunoblotting. Transfection of ECs with thioredoxin-1 small interfering RNA abrogated oxidative-stress-induced up-regulation of T-cad transcripts and protein. We conclude that thioredoxin-1 is an important determinant of redox-sensitive transcriptional up-regulation of T-cad in ECs.

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Missall, Tricia A., and Jennifer K. Lodge. "Thioredoxin Reductase Is Essential for Viability in the Fungal Pathogen Cryptococcus neoformans." Eukaryotic Cell 4, no. 2 (February 2005): 487–89. http://dx.doi.org/10.1128/ec.4.2.487-489.2005.

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ABSTRACT Thioredoxin reductase (TRR1) is an important component of the thioredoxin oxidative stress resistance pathway. Here we show that it is induced during oxidative and nitrosative stress and is preferentially localized to the mitochondria in Cryptococcus neoformans. The C. neoformans TRR1 gene encodes the low-molecular-weight isoform of the thioredoxin reductase enzyme, which shares little homology with that of its mammalian host. By replacing the endogenous TRR1 promoter with an inducible copper transporter promoter, we showed that Trr1 appears to be essential for viability of this pathogenic fungus, making it a potential antifungal target.

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Ross, Sarah J., Victoria J. Findlay, Panagiota Malakasi, and Brian A. Morgan. "Thioredoxin Peroxidase Is Required for the Transcriptional Response to Oxidative Stress in Budding Yeast." Molecular Biology of the Cell 11, no. 8 (August 2000): 2631–42. http://dx.doi.org/10.1091/mbc.11.8.2631.

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A genetic screen was performed in Saccharomyces cerevisiae to identify mechanisms important for the transcriptional activation of genes encoding antioxidant proteins. Thioredoxin peroxidase, Tsa1p, of the thioredoxin system, was found to be essential for the transcriptional induction of other components of the thioredoxin system, TRX2 (thioredoxin) andTRR1 (thioredoxin reductase), in response to H2O2. The expression of TRX2 andTRR1 is known to be regulated by the transcription factors Yap1p and Skn7p in response to H2O2, and the Tsa1p-dependent regulation of TRX2 requires the Yap1p/Skn7p pathway. The data suggest that expression of components of the thioredoxin system is dependent on the activity of Tsa1p in response to H2O2in a Yap1p/Skn7p-dependent pathway.

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Seco-Cervera, Marta, Pilar González-Cabo, Federico Pallardó, Carlos Romá-Mateo, and José García-Giménez. "Thioredoxin and Glutaredoxin Systems as Potential Targets for the Development of New Treatments in Friedreich’s Ataxia." Antioxidants 9, no. 12 (December 10, 2020): 1257. http://dx.doi.org/10.3390/antiox9121257.

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The thioredoxin family consists of a small group of redox proteins present in all organisms and composed of thioredoxins (TRXs), glutaredoxins (GLRXs) and peroxiredoxins (PRDXs) which are found in the extracellular fluid, the cytoplasm, the mitochondria and in the nucleus with functions that include antioxidation, signaling and transcriptional control, among others. The importance of thioredoxin family proteins in neurodegenerative diseases is gaining relevance because some of these proteins have demonstrated an important role in the central nervous system by mediating neuroprotection against oxidative stress, contributing to mitochondrial function and regulating gene expression. Specifically, in the context of Friedreich’s ataxia (FRDA), thioredoxin family proteins may have a special role in the regulation of Nrf2 expression and function, in Fe-S cluster metabolism, controlling the expression of genes located at the iron-response element (IRE) and probably regulating ferroptosis. Therefore, comprehension of the mechanisms that closely link thioredoxin family proteins with cellular processes affected in FRDA will serve as a cornerstone to design improved therapeutic strategies.

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Ansari, Shabbir, Usha R. Pendurthi, and L. Vijaya Mohan Rao. "Tissue Factor Decryption By Oxidative Stress-Induced Lipid Peroxidation: Potential Mechanisms." Blood 126, no. 23 (December 3, 2015): 125. http://dx.doi.org/10.1182/blood.v126.23.125.125.

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Abstract Cellular lipid peroxidation is known to contribute to the initiation and propagation of atherothrombosis. Recently, we showed that 4-hydroxynonenal (HNE), one of the most abundant reactive aldehydes generated from the oxidation of ω-6 fatty acids, enhanced tissue factor (TF) activity on monocytic cells by externalizing phosphatidylserine (PS) in p38 MAPK activation-dependent manner. However, at present, the link between HNE-induced oxidative stress and p38 MAPK activation and the relation of p38 MAPK activation to PS externalization is not fully known. In the present study, we investigated the role of mitochondrial electron transport chain and reactive oxygen species (ROS) generation in HNE-mediated TF decryption. In addition, we also investigated the thioredoxin reductase-thioredoxin-ASK-1 axis in regulating p38 MAPK activation and PS externalization in decrypting TF. To elucidate potential mechanisms of HNE-induced TF decryption, we first determined the role of specific mitochondrial electron transport chain complexes in regulating TF activity. Since THP-1 cells used in the study had a measurable basal TF activity, they were not further treated with LPS or other agonists to induce TF synthesis. The electron transport chain in these cells was disrupted by specific inhibitors and cell surface TF activity was measured by factor X activation assay. Inhibition of complex I and complex IV by rotenone and sodium azide, respectively, enhanced the procoagulant activity of basal level TF. However, the inhibition of complex I and IV had no significant effect on the HNE-mediated increase in TF activity. Interestingly, inhibition of ATP synthase/complex V by oligomycin significantly inhibited the HNE-mediated enhanced TF activity, indicating that HNE-mediated TF decryption may involve the generation of ATP. In agreement with earlier published studies in monocytes/macrophages, stimulation of THP-1 cells with ATP increased cell surface TF activity. However, at present, it is yet to be shown that HNE treatment actually increased the production of ATP and that this ATP is responsible for the HNE-mediated TF decryption. It is also possible that HNE, either through a generation of ROS in mitochondria or directly, can affect the activity of thioredoxin either by intracellular signaling or by directly forming an adduct with it. Therefore, we next investigated the effect of HNE on the activity of thioredoxin reductase, the enzyme known to regulate thioredoxin activity in the cell. Our data showed that HNE treatment inhibited the activity of thioredoxin reductase in a concentration-dependent manner, 40 µM of HNE inhibiting 50% of the activity and a complete inhibition at 80µM of HNE. To further determine the downstream signaling cascade involved in the PS externalization and TF decryption on exposure to HNE, we analyzed the effect of HNE on the activation of MKK3 and MKK6, the protein kinases known to activate p38 MAPK and the downstream signaling activator of thioredoxin/thioredoxin reductase pathway. HNE treatment increased the phosphorylation of MKK3 and MKK6 in a time-dependent manner. In summary, our data suggest that HNE may mediate TF decryption via modulation of thioredoxin/thioredoxin reductase system, which results in activation of MKK3/MKK6, which in turn activates p38 MAPK that is responsible for PS externalization. The study highlights the potential role of oxidative stress in regulating TF activity in thrombotic disorders and provides a mechanistic link between disorders associated with cellular oxidative stress and thrombosis. Disclosures No relevant conflicts of interest to declare.

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Zeller, Tanja, and Gabriele Klug. "Thioredoxins in bacteria: functions in oxidative stress response and regulation of thioredoxin genes." Naturwissenschaften 93, no. 6 (March 23, 2006): 259–66. http://dx.doi.org/10.1007/s00114-006-0106-1.

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Shakhristova, Evgeniya V., Elena A. Stepovaya, Evgeniy V. Rudikov, Olga S. Sushitskaya, Daria O. Rodionova, and Vaycheslav V. Novitsky. "The Role of Redox Proteins in Arresting Proliferation of Breast Epithelial Cells Under Oxidative Stress." Annals of the Russian academy of medical sciences 73, no. 5 (October 25, 2018): 289–93. http://dx.doi.org/10.15690/vramn1030.

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Background: Redox status imbalance against the backdrop of oxidative stress development underlies the pathogenesis of a whole range of diseases. Many intracellular proteins contain free thiol groups and undergo redox regulation which is one of the key processes in controlling cell proliferation. Thioredoxin and glutaredoxin are involved in maintaining intracellular redox homeostasis and act as candidates in regulating proliferation. This provides prospects for future development of methods for diagnosis and targeted therapy of socially sensitive diseases accompanied by oxidative stress. The aim of the study is to reveal the role of redox proteins in molecular mechanisms of regulating HBL-100 breast epithelial cell proliferation under the effect of roscovitine, a cell cycle inhibitor. Materials and methods: Two research groups were formed. They included HBL-100 human breast epithelial cells incubated in the presence and absence of 20 mcM roscovitine for 18 hours. The intracellular thioredoxin levels were determined using Western blot analysis with specific monoclonal antibodies. Distribution of the cells among cell cycle phases were evaluated by flow cytometry. The activity of glutathione reductase, glutathione peroxidase, and thioredoxin reductase were measured by spectrophotometry. Results: Under the effect of roscovitine in the HBL-100 cells, cell cycle arrest in the G2/М phases occurred and oxidative stress developed. In the meantime, the decrease in the thioredoxin and glutaredoxin concentrations was registered along with the change in the functional activity of glutathione-dependent enzymes. Conclusions: Application of roscovitine, a cell cycle inhibitor, allowed creating a model of oxidative stress in the breast epithelial cells against the backdrop of inhibited cell proliferation. We identified that thioredoxin and glutaredoxin contributed to impairment of cell cycle progression. It points at a possibility to regulate cell proliferation by modulating the functional features of cellular redox-dependent proteins in different pathologies accompanied by oxidative stress.

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May, Holly, Jieh-Juen Yu, Rishein Gupta, M. Neal Guentzel, and Bernard Arulanandam. "Role of Acinetobacter baumannii thioredoxin in bacterial dissemination by modulation of mucosal oxidative homeostasis." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 216.9. http://dx.doi.org/10.4049/jimmunol.198.supp.216.9.

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Abstract Acinetobacter baumannii is an increasing cause of hospital-acquired infections and a prominent cause of combat-related infections in the Middle East. Infections with this bacterium lead to a TLR4 response that initiates a potent innate immune response. Bacterial coinfection may occur in hospitalized patients, and endotoxin (LPS) released from one Gram-negative bacterium may have profound effects on pathogenesis of other co-infecting bacteria. Specifically, LPS induced oxidative stress has a significant impact on mucosal barrier function, leading to enhanced permeability and bacterial translocation. To delineate the importance of LPS in E. coli and Ab coinfection, we utilized a murine model of pulmonary Ab infection with oxidative stress induced via LPS injection. While the bacterial factors involved in translocation under oxidative stress are largely unknown, one plausible factor, based on previous research in our lab, is thioredoxin. Thioredoxin-1 (Trx1/TrxA) is a member of the thioredoxin protein superfamily that can be reversibly oxidized and reduced to facilitate reduction of disulfide bonds, as well as for protecting against free-radical damage. Our lab has created a mutant of Ab Clinical isolate 79 (Ci79) that lacks thioredoxin-1 (ΔTrxA). Using this mutant, the effects of thioredoxin on bacterial translocation during oxidative stress can be determined. Mice given E. coli LPS showed significantly increased translocation of Ci79 via organ burden. Mice infected with ΔTrxA showed significantly less translocation than the WT strains. Additionally, when Ci79 was treated with a TrxA blocker before infection, survival was increased and organ burden decreased.

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Bjørklund, Geir, Lili Zou, Massimiliano Peana, Christos T. Chasapis, Tony Hangan, Jun Lu, and Michael Maes. "The Role of the Thioredoxin System in Brain Diseases." Antioxidants 11, no. 11 (October 31, 2022): 2161. http://dx.doi.org/10.3390/antiox11112161.

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The thioredoxin system, consisting of thioredoxin (Trx), thioredoxin reductase (TrxR), and NADPH, plays a fundamental role in the control of antioxidant defenses, cell proliferation, redox states, and apoptosis. Aberrations in the Trx system may lead to increased oxidative stress toxicity and neurodegenerative processes. This study reviews the role of the Trx system in the pathophysiology and treatment of Alzheimer’s, Parkinson’s and Huntington’s diseases, brain stroke, and multiple sclerosis. Trx system plays an important role in the pathophysiology of those disorders via multiple interactions through oxidative stress, apoptotic, neuro-immune, and pro-survival pathways. Multiple aberrations in Trx and TrxR systems related to other redox systems and their multiple reciprocal relationships with the neurodegenerative, neuro-inflammatory, and neuro-oxidative pathways are here analyzed. Genetic and environmental factors (nutrition, metals, and toxins) may impact the function of the Trx system, thereby contributing to neuropsychiatric disease. Aberrations in the Trx and TrxR systems could be a promising drug target to prevent and treat neurodegenerative, neuro-inflammatory, neuro-oxidative stress processes, and related brain disorders.

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Scharf, Christian, Sabine Riethdorf, Henrik Ernst, Susanne Engelmann, Uwe Völker, and Michael Hecker. "Thioredoxin Is an Essential Protein Induced by Multiple Stresses in Bacillus subtilis." Journal of Bacteriology 180, no. 7 (April 1, 1998): 1869–77. http://dx.doi.org/10.1128/jb.180.7.1869-1877.1998.

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ABSTRACT Thioredoxin, a small, ubiquitous protein which participates in redox reactions through the reversible oxidation of its active center dithiol to a disulfide, is an essential protein in Bacillus subtilis. A variety of stresses, including heat or salt stress or ethanol treatment, strongly enhanced the synthesis of thioredoxin inB. subtilis. The stress induction of the monocistronictrxA gene encoding thioredoxin occurs at two promoters. The general stress sigma factor, ςB, was required for the initiation of transcription at the upstream site, SB, and the promoter preceding the downstream start site, SA, was presumably recognized by the vegetative sigma factor, ςA. In contrast to the heat-inducible, ςA-dependent promoters preceding the chaperone-encoding operons groESL anddnaK, no CIRCE (for controlling inverted repeat of chaperone expression) was present in the vicinity of the start site, SA. The induction patterns of the promoters differed, with the upstream promoter displaying the typical stress induction of ςB-dependent promoters. Transcription initiating at SA, but not at SB, was also induced after treatment with hydrogen peroxide or puromycin. Such a double control of stress induction at two different promoters seems to be typical of a subgroup of class III heat shock genes of B. subtilis, likeclpC, and it either allows the cells to raise the level of the antioxidant thioredoxin after oxidative stress or allows stressed cells to accumulate thioredoxin. These increased levels of thioredoxin might help stressed B. subtilis cells to maintain the native and reduced state of cellular proteins.

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Viefhues, Anne, Jens Heller, Nora Temme, and Paul Tudzynski. "Redox Systems in Botrytis cinerea: Impact on Development and Virulence." Molecular Plant-Microbe Interactions® 27, no. 8 (August 2014): 858–74. http://dx.doi.org/10.1094/mpmi-01-14-0012-r.

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The thioredoxin system is of great importance for maintenance of cellular redox homeostasis. Here, we show that it has a severe influence on virulence of Botrytis cinerea, demonstrating that redox processes are important for host-pathogen interactions in this necrotrophic plant pathogen. The thioredoxin system is composed of two enzymes, the thioredoxin and the thioredoxin reductase. We identified two genes encoding for thioredoxins (bctrx1, bctrx2) and one gene encoding for a thioredoxin reductase (bctrr1) in the genome of B. cinerea. Knockout mutants of bctrx1 and bctrr1 were severely impaired in virulence and more sensitive to oxidative stress. Additionally, Δbctrr1 showed enhanced H2O2 production and retarded growth. To investigate the impact of the second major cellular redox system, glutathione, we generated deletion mutants for two glutathione reductase genes. The effects were only marginal; deletion of bcglr1 resulted in reduced germination and, correspondingly, to retarded infection as well as reduced growth on minimal medium, whereas bcglr2 deletion had no distinctive phenotype. In summary, we showed that the balanced redox status maintained by the thioredoxin system is essential for development and pathogenesis of B. cinerea, whereas the second major cellular redox system, the glutathione system, seems to have only minor impact on these processes.

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Uziel, Orit, Ilya Borovok, Rachel Schreiber, Gerald Cohen, and Yair Aharonowitz. "Transcriptional Regulation of the Staphylococcus aureus Thioredoxin and Thioredoxin Reductase Genes in Response to Oxygen and Disulfide Stress." Journal of Bacteriology 186, no. 2 (January 15, 2004): 326–34. http://dx.doi.org/10.1128/jb.186.2.326-334.2004.

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ABSTRACT In this report we describe the cloning, organization, and promoter analysis of the Staphylococcus aureus thioredoxin (trxA) and thioredoxin reductase (trxB) genes and their transcription in response to changes in oxygen concentration and to oxidative stress compounds. Northern analysis showed that the S. aureus trxA and trxB genes were transcribed equally well in aerobic and anaerobic conditions. Several oxidative stress compounds were found to rapidly induce transcription of the trxA and trxB genes. The most pronounced effects were seen with diamide, a thiol-specific oxidant that promotes disulfide bond formation; menadione, a redox cycling agent; and τ-butyl hydroperoxide, an organic peroxide. In each case the induction was independent of the general stress sigma factor σB. These studies show that the S. aureus trxA and trxB genes are upregulated following exposure to these oxidative stress agents, resulting in increased disulfide bond formation. In contrast, no effect of hydrogen peroxide on induction of the trxA and trxB genes was seen. We also show that the S. aureus thioredoxin reductase appears to be essential for growth. This observation, coupled with structural differences between the bacterial and mammalian thioredoxin reductases, suggests that it may serve as a target for the development of new antimicrobials.

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Rand, Jonathan D., and Chris M. Grant. "The Thioredoxin System Protects Ribosomes against Stress-induced Aggregation." Molecular Biology of the Cell 17, no. 1 (January 2006): 387–401. http://dx.doi.org/10.1091/mbc.e05-06-0520.

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We previously showed that thioredoxins are required for dithiothreitol (DTT) tolerance, suggesting they maintain redox homeostasis in response to both oxidative and reductive stress conditions. In this present study, we screened the complete set of viable deletion strains in Saccharomyces cerevisiae for sensitivity to DTT to identify cell functions involved in resistance to reductive stress. We identified 195 mutants, whose gene products are localized throughout the cell. DTT-sensitive mutants were distributed among most major biological processes, but they particularly affected gene expression, metabolism, and the secretory pathway. Strikingly, a mutant lacking TSA1, encoding a peroxiredoxin, showed a similar sensitivity to DTT as a thioredoxin mutant. Epistasis analysis indicated that thioredoxins function upstream of Tsa1 in providing tolerance to DTT. Our data show that the chaperone function of Tsa1, rather than its peroxidase function, is required for this activity. Cells lacking TSA1 were found to accumulate aggregated proteins, and this was exacerbated by exposure to DTT. Analysis of the protein aggregates revealed that they are predominantly composed of ribosomal proteins. Furthermore, aggregation was found to correlate with an inhibition of translation initiation. We propose that Tsa1 normally functions to chaperone misassembled ribosomal proteins, preventing the toxicity that arises from their aggregation.

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Schulze, P. Christian, Jun Yoshioka, Tomosaburo Takahashi, Zhiheng He, George L. King, and Richard T. Lee. "Hyperglycemia Promotes Oxidative Stress through Inhibition of Thioredoxin Function by Thioredoxin-interacting Protein." Journal of Biological Chemistry 279, no. 29 (May 5, 2004): 30369–74. http://dx.doi.org/10.1074/jbc.m400549200.

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Tyagi, Neetu, Kara C. Sedoris, Mesia Steed, Alexander V. Ovechkin, Karni S. Moshal, and Suresh C. Tyagi. "Mechanisms of homocysteine-induced oxidative stress." American Journal of Physiology-Heart and Circulatory Physiology 289, no. 6 (December 2005): H2649—H2656. http://dx.doi.org/10.1152/ajpheart.00548.2005.

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Hyperhomocysteinemia decreases vascular reactivity and is associated with cardiovascular morbidity and mortality. However, pathogenic mechanisms that increase oxidative stress by homocysteine (Hcy) are unsubstantiated. The aim of this study was to examine the molecular mechanism by which Hcy triggers oxidative stress and reduces bioavailability of nitric oxide (NO) in cardiac microvascular endothelial cells (MVEC). MVEC were cultured for 0–24 h with 0–100 μM Hcy. Differential expression of protease-activated receptors (PARs), thioredoxin, NADPH oxidase, endothelial NO synthase, inducible NO synthase, neuronal NO synthase, and dimethylarginine-dimethylaminohydrolase (DDAH) were measured by real-time quantitative RT-PCR. Reactive oxygen species were measured by using a fluorescent probe, 2′,7′-dichlorofluorescein diacetate. Levels of asymmetric dimethylarginine (ADMA) were measured by ELISA and NO levels by the Griess method in the cultured MVEC. There were no alterations in the basal NO levels with 0–100 μM Hcy and 0–24 h of treatment. However, Hcy significantly induced inducible NO synthase and decreased endothelial NO synthase without altering neuronal NO synthase levels. There was significant accumulation of ADMA, in part because of reduced DDAH expression by Hcy in MVEC. Nitrotyrosine expression was increased significantly by Hcy. The results suggest that Hcy activates PAR-4, which induces production of reactive oxygen species by increasing NADPH oxidase and decreasing thioredoxin expression and reduces NO bioavailability in cultured MVEC by 1) increasing NO2-tyrosine formation and 2) accumulating ADMA by decreasing DDAH expression.

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Greetham, Darren, and Chris M. Grant. "Antioxidant Activity of the Yeast Mitochondrial One-Cys Peroxiredoxin Is Dependent on Thioredoxin Reductase and Glutathione In Vivo." Molecular and Cellular Biology 29, no. 11 (March 30, 2009): 3229–40. http://dx.doi.org/10.1128/mcb.01918-08.

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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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Köhsler, Martina, David Leitsch, Alvie Loufouma Mbouaka, Maximilian Wekerle, and Julia Walochnik. "Transcriptional changes of proteins of the thioredoxin and glutathione systems in Acanthamoeba spp. under oxidative stress – an RNA approach." Parasite 29 (2022): 24. http://dx.doi.org/10.1051/parasite/2022025.

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The thioredoxin (Trx) and the glutathione (GSH) systems represent important antioxidant systems in cells and in particular thioredoxin reductase (TrxR) has been shown to constitute a promising drug target in parasites. For the facultative protozoal pathogen Acanthamoeba, it was demonstrated that a bacterial TrxR as well as a TrxR, characteristic of higher eukaryotes, mammals and humans is expressed on the protein level. However, only bacterial TrxR is strongly induced by oxidative stress in Acanthamoeba castellanii. In this study, the impact of oxidative stress on key enzymes involved in the thioredoxin and the glutathione system of A. castellanii under different culture conditions and of clinical Acanthamoeba isolates was evaluated on the RNA level employing RT-qPCR. Additionally, the effect of auranofin, a thioredoxin reductase inhibitor, already established as a potential drug in other parasites, on target enzymes in A. castellanii was investigated. Oxidative stress induced by hydrogen peroxide led to significant stimulation of bacterial TrxR and thioredoxin, while diamide had a strong impact on all investigated enzymes. Different strains displayed distinct transcriptional responses, rather correlating to sensitivity against the respective stressor than to respective pathogenic potential. Culture conditions appear to have a major effect on transcriptional changes in A. castellanii. Treatment with auranofin led to transcriptional activation of the GSH system, indicating its role as a potential backup for the Trx system. Altogether, our data provide more profound insights into the complex redox system of Acanthamoeba, preparing the ground for further investigations on this topic.

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Garrigós, Víctor, Cecilia Picazo, Emilia Matallana, and Agustín Aranda. "Wine Yeast Peroxiredoxin TSA1 Plays a Role in Growth, Stress Response and Trehalose Metabolism in Biomass Propagation." Microorganisms 8, no. 10 (October 6, 2020): 1537. http://dx.doi.org/10.3390/microorganisms8101537.

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Peroxiredoxins are a family of peroxide-degrading enzymes for challenging oxidative stress. They receive their reducing power from redox-controlling proteins called thioredoxins, and these, in turn, from thioredoxin reductase. The main cytosolic peroxiredoxin is Tsa1, a moonlighting protein that also acts as protein chaperone a redox switch controlling some metabolic events. Gene deletion of peroxiredoxins in wine yeasts indicate that TSA1, thioredoxins and thioredoxin reductase TRR1 are required for normal growth in medium with glucose and sucrose as carbon sources. TSA1 gene deletion also diminishes growth in molasses, both in flasks and bioreactors. The TSA1 mutation brings about an expected change in redox parameters but, interestingly, it also triggers a variety of metabolic changes. It influences trehalose accumulation, lowering it in first molasses growth stages, but increasing it at the end of batch growth, when respiratory metabolism is set up. Glycogen accumulation at the entry of the stationary phase also increases in the tsa1Δ mutant. The mutation reduces fermentative capacity in grape juice, but the vinification profile does not significantly change. However, acetic acid and acetaldehyde production decrease when TSA1 is absent. Hence, TSA1 plays a role in the regulation of metabolic reactions leading to the production of such relevant enological molecules.

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Park, Ah-Mee, and Yuichiro J. Suzuki. "Effects of intermittent hypoxia on oxidative stress-induced myocardial damage in mice." Journal of Applied Physiology 102, no. 5 (May 2007): 1806–14. http://dx.doi.org/10.1152/japplphysiol.01291.2006.

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Obstructive sleep apnea is associated with increased risk for cardiovascular diseases. As obstructive sleep apnea is characterized by episodic cycles of hypoxia and normoxia during sleep, we investigated effects of intermittent hypoxia (IH) on ischemia-reperfusion-induced myocardial injury. C57BL/6 mice were subjected to IH (2 min 6% O2 and 2 min 21% O2) for 8 h/day for 1, 2, or 4 wk; isolated hearts were then subjected to ischemia-reperfusion. IH for 1 or 2 wk significantly enhanced ischemia-reperfusion-induced myocardial injury. However, enhanced cardiac damage was not seen in mice treated with 4 wk of IH, suggesting that the heart has adapted to chronic IH. Ischemia-reperfusion-induced lipid peroxidation and protein carbonylation were enhanced with 2 wk of IH, while, with 4 wk, oxidative stress was normalized to levels in animals without IH. H2O2 scavenging activity in adapted hearts was higher after ischemia-reperfusion, suggesting the increased antioxidant capacity. This might be due to the involvement of thioredoxin, as the expression level of this protein was increased, while levels of other antioxidant enzymes were unchanged. In the heart from mice treated with 2 wk of IH, ischemia-reperfusion was found to decrease thioredoxin. Ischemia-reperfusion injury can also be enhanced when thioredoxin reductase was inhibited in control hearts. These results demonstrate that IH changes the susceptibility of the heart to oxidative stress in part via alteration of thioredoxin.

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Zhou, Rongbin, Aubry Tardivel, Bernard Thorens, Inpyo Choi, and Jürg Tschopp. "Thioredoxin-interacting protein links oxidative stress to inflammasome activation." Nature Immunology 11, no. 2 (December 20, 2009): 136–40. http://dx.doi.org/10.1038/ni.1831.

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Sordillo, Lorraine M., Chris Corl, and Jeffery Gandy. "Thioredoxin reductase attenuates vascular inflammatory responses during oxidative stress." FASEB Journal 22, S2 (April 2008): 454. http://dx.doi.org/10.1096/fasebj.22.2_supplement.454.

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J. Svensson, Malin, and Jan Larsson. "Thioredoxin-2 affects lifespan and oxidative stress in Drosophila." Hereditas 144, no. 1 (February 22, 2007): 25–32. http://dx.doi.org/10.1111/j.2007.0018-0661.01990.x.

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Zhou, Jiaojie, Ke Yao, Yidong Zhang, Guangdi Chen, Kairan Lai, Houfa Yin, and Yibo Yu. "Thioredoxin Binding Protein-2 Regulates Autophagy of Human Lens Epithelial Cells under Oxidative Stress via Inhibition of Akt Phosphorylation." Oxidative Medicine and Cellular Longevity 2016 (2016): 1–17. http://dx.doi.org/10.1155/2016/4856431.

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Oxidative stress plays an essential role in the development of age-related cataract. Thioredoxin binding protein-2 (TBP-2) is a negative regulator of thioredoxin (Trx), which deteriorates cellular antioxidant system. Our study focused on the autophagy-regulating effect of TBP-2 under oxidative stress in human lens epithelial cells (LECs). Human lens epithelial cells were used for cell culture and treatment. Lentiviral-based transfection system was used for overexpression of TBP-2. Cytotoxicity assay, western blot analysis, GFP/mCherry-fused LC3 plasmid, immunofluorescence, and transmission electronic microscopy were performed. The results showed that autophagic response of LECs with increased LC3-II, p62, and GFP/mCherry-LC3 puncta (P<0.01) was induced by oxidative stress. Overexpression of TBP-2 further strengthens this response and worsens the cell viability (P<0.01). Knockdown of TBP-2 attenuates the autophagic response and cell viability loss induced by oxidative stress. TBP-2 mainly regulates autophagy in the initiation stage, which is mTOR-independent and probably caused by the dephosphorylation of Akt under oxidative stress. These findings suggest a novel role of TBP-2 in human LECs under oxidative stress. Oxidative stress can cause cell injury and autophagy in LECs, and TBP-2 regulates this response. Hence, this study provides evidence regarding the role of TBP-2 in lens and the possible mechanism of cataract development.

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Mallén-Ponce, Manuel J., María José Huertas, and Francisco J. Florencio. "Exploring the Diversity of the Thioredoxin Systems in Cyanobacteria." Antioxidants 11, no. 4 (March 28, 2022): 654. http://dx.doi.org/10.3390/antiox11040654.

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Cyanobacteria evolved the ability to perform oxygenic photosynthesis using light energy to reduce CO2 from electrons extracted from water and form nutrients. These organisms also developed light-dependent redox regulation through the Trx system, formed by thioredoxins (Trxs) and thioredoxin reductases (TRs). Trxs are thiol-disulfide oxidoreductases that serve as reducing substrates for target enzymes involved in numerous processes such as photosynthetic CO2 fixation and stress responses. We focus on the evolutionary diversity of Trx systems in cyanobacteria and discuss their phylogenetic relationships. The study shows that most cyanobacteria contain at least one copy of each identified Trx, and TrxA is the only one present in all genomes analyzed. Ferredoxin thioredoxin reductase (FTR) is present in all groups except Gloeobacter and Prochlorococcus, where there is a ferredoxin flavin-thioredoxin reductase (FFTR). Our data suggest that both TRs may have coexisted in ancestral cyanobacteria together with other evolutionarily related proteins such as NTRC or DDOR, probably used against oxidative stress. Phylogenetic studies indicate that they have different evolutionary histories. As cyanobacteria diversified to occupy new habitats, some of these proteins were gradually lost in some groups. Finally, we also review the physiological relevance of redox regulation in cyanobacteria through the study of target enzymes.

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Lee, Jang Hoon, Hyung Jung Kim, Chul Min Ahn, Sung Kyu Kim, and Won Young Lee. "Induction of Thioredoxin by Oxidative Stress and Overexpression of Thioredoxin in Lung Cancer Tissue." Tuberculosis and Respiratory Diseases 46, no. 3 (1999): 327. http://dx.doi.org/10.4046/trd.1999.46.3.327.

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Guevara-Flores, Alberto, Irene P. del Arenal, Guillermo Mendoza-Hernández, Juan Pablo Pardo, Oscar Flores-Herrera, and Juan L. Rendón. "Mitochondrial Thioredoxin-Glutathione Reductase from LarvalTaenia crassiceps(Cysticerci)." Journal of Parasitology Research 2010 (2010): 1–11. http://dx.doi.org/10.1155/2010/719856.

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Mitochondrial thioredoxin-glutathione reductase was purified from larvalTaenia crassiceps(cysticerci). The preparation showed NADPH-dependent reductase activity with either thioredoxin or GSSG, and was able to perform thiol/disulfide exchange reactions. At25∘Cspecific activities were437 ± 27mU mg-1and840 ± 49mU mg-1with thioredoxin and GSSG, respectively. ApparentKmvalues were0.87 ± 0.04 μM,41 ± 6 μM and19 ± 10 μM for thioredoxin, GSSG and NADPH, respectively. Thioredoxin from eukaryotic sources was accepted as substrate. The enzyme reduced H2O2in a NADPH-dependent manner, although with low catalytic efficiency. In the presence of thioredoxin, mitochondrial TGR showed a thioredoxin peroxidase-like activity. All disulfide reductase activities were inhibited by auranofin, suggesting mTGR is dependent on selenocysteine. The reductase activity with GSSG showed a higher dependence on temperature as compared with the DTNB reductase activity. The variation of the GSSG- and DTNB reductase activities on pH was dependent on the disulfide substrate. Like the cytosolic isoform, mTGR showed a hysteretic kinetic behavior at moderate or high GSSG concentrations, but it was less sensitive to calcium. The enzyme was able to protect glutamine synthetase from oxidative inactivation, suggesting that mTGR is competent to contend with oxidative stress.

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Ji Cho, Min, Sung-Jin Yoon, Wooil Kim, Jongjin Park, Jangwook Lee, Jong-Gil Park, Young-Lai Cho, et al. "Oxidative stress-mediated TXNIP loss causes RPE dysfunction." Experimental & Molecular Medicine 51, no. 10 (October 2019): 1–13. http://dx.doi.org/10.1038/s12276-019-0327-y.

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Abstract The disruption of the retinal pigment epithelium (RPE), for example, through oxidative damage, is a common factor underlying age-related macular degeneration (AMD). Aberrant autophagy also contributes to AMD pathology, as autophagy maintains RPE homeostasis to ensure blood–retinal barrier (BRB) integrity and protect photoreceptors. Thioredoxin-interacting protein (TXNIP) promotes cellular oxidative stress by inhibiting thioredoxin reducing capacity and is in turn inversely regulated by reactive oxygen species levels; however, its role in oxidative stress-induced RPE cell dysfunction and the mechanistic link between TXNIP and autophagy are largely unknown. Here, we observed that TXNIP expression was rapidly downregulated in RPE cells under oxidative stress and that RPE cell proliferation was decreased. TXNIP knockdown demonstrated that the suppression of proliferation resulted from TXNIP depletion-induced autophagic flux, causing increased p53 activation via nuclear localization, which in turn enhanced AMPK phosphorylation and activation. Moreover, TXNIP downregulation further negatively impacted BRB integrity by disrupting RPE cell tight junctions and enhancing cell motility by phosphorylating, and thereby activating, Src kinase. Finally, we also revealed that TXNIP knockdown upregulated HIF-1α, leading to the enhanced secretion of VEGF from RPE cells and the stimulation of angiogenesis in cocultured human retinal microvascular endothelial cells. This suggests that the exposure of RPE cells to sustained oxidative stress may promote choroidal neovascularization, another AMD pathology. Together, these findings reveal three distinct mechanisms by which TXNIP downregulation disrupts RPE cell function and thereby exacerbates AMD pathogenesis. Accordingly, reinforcing or restoring BRB integrity by targeting TXNIP may serve as an effective therapeutic strategy for preventing or attenuating photoreceptor damage in AMD.

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Serata, Masaki, Tohru Iino, Emi Yasuda, and Tomoyuki Sako. "Roles of thioredoxin and thioredoxin reductase in the resistance to oxidative stress in Lactobacillus casei." Microbiology 158, no. 4 (April 1, 2012): 953–62. http://dx.doi.org/10.1099/mic.0.053942-0.

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Moon, Sungchur, M. Rohan Fernando, and Marjorie F. Lou. "Induction of Thioltransferase and Thioredoxin/Thioredoxin Reductase Systems in Cultured Porcine Lenses under Oxidative Stress." Investigative Opthalmology & Visual Science 46, no. 10 (October 1, 2005): 3783. http://dx.doi.org/10.1167/iovs.05-0237.

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Si, Mei-Ru, Lei Zhang, Zhi-Fang Yang, Yi-Xiang Xu, Ying-Bao Liu, Cheng-Ying Jiang, Yao Wang, Xi-Hui Shen, and Shuang-Jiang Liu. "NrdH Redoxin Enhances Resistance to Multiple Oxidative Stresses by Acting as a Peroxidase Cofactor in Corynebacterium glutamicum." Applied and Environmental Microbiology 80, no. 5 (December 27, 2013): 1750–62. http://dx.doi.org/10.1128/aem.03654-13.

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ABSTRACTNrdH redoxins are small protein disulfide oxidoreductases behaving like thioredoxins but sharing a high amino acid sequence similarity to glutaredoxins. Although NrdH redoxins are supposed to be another candidate in the antioxidant system, their physiological roles in oxidative stress remain unclear. In this study, we confirmed that theCorynebacterium glutamicumNrdH redoxin catalytically reduces the disulfides in the class Ib ribonucleotide reductases (RNR), insulin and 5,5′-dithiobis-(2-nitrobenzoic acid) (DTNB), by exclusively receiving electrons from thioredoxin reductase. Overexpression of NrdH increased the resistance ofC. glutamicumto multiple oxidative stresses by reducing ROS accumulation. Accordingly, elevated expression of thenrdHgene was observed when theC. glutamicumwild-type strain was exposed to oxidative stress conditions. It was discovered that the NrdH-mediated resistance to oxidative stresses was largely dependent on the presence of the thiol peroxidase Prx, as the increased resistance to oxidative stresses mediated by overexpression of NrdH was largely abrogated in theprxmutant. Furthermore, we showed that NrdH facilitated the hydroperoxide reduction activity of Prx by directly targeting and serving as its electron donor. Thus, we present evidence that the NrdH redoxin can protect against the damaging effects of reactive oxygen species (ROS) induced by various exogenous oxidative stresses by acting as a peroxidase cofactor.

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Whayne, Thomas F., Narasimham Parinandi, and Nilanjana Maulik. "Thioredoxins in cardiovascular disease." Canadian Journal of Physiology and Pharmacology 93, no. 11 (November 2015): 903–11. http://dx.doi.org/10.1139/cjpp-2015-0105.

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Key thioredoxin (Trx) system components are nicotinamide adenine dinucleotide phosphate (NADPH), Trx reductase (TrxR), and Trx. TrxR catalyzes disulfide reduction in Trx with NADPH as cofactor. Because Trx is an antioxidant, oxidative stress results in an increase in Trx, which has a reduced disulfide component. If Trx is suppressed, oxidative stress in higher. In contrast a decrease in oxidative stress is associated with low Trx levels. Trx is involved in inflammation, apoptosis, embryogenesis, and cardiovascular disease (CVD). This review focuses on the Trx system in CVD. Abnormal Trx binding occurs in mouse familial combined hyperlipidemia; however, this has not been confirmed in humans. Congestive heart failure is a manifestation of many CVDs, which may be improved by attenuating oxidative stress through the suppression of Trx and decreased reactive oxygen species. Angiotensin II is associated with hypertension and other CVDs, and its receptor blockade results in decreased oxidative stress with reduced Trx levels. Inflammation is a major causative factor of CVDs, and myocarditis as an example, is associated with increased Trx levels. Vascular endothelial dysfunction has an association with CVD. This dysfunction is alleviated by hormone replacement therapy, which involves decreased oxidative stress and Trx levels. Diabetes mellitus has a major association with CVDs; increase in Trx levels may reflect insulin resistance. Identification of Trx system abnormalities may lead to innovative approaches to treat multiple CVDs and other pathologies.

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Nishinaka, Y., H. Masutani, H. Nakamura, and J. Yodoi. "Regulatory roles of thioredoxin in oxidative stress-induced cellular responses." Redox Report 6, no. 5 (October 2001): 289–95. http://dx.doi.org/10.1179/135100001101536427.

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Cunniff, Brian, Gregg W. Snider, Nicholas Fredette, Jason Stumpff, Robert J. Hondal, and Nicholas H. Heintz. "Resolution of oxidative stress by thioredoxin reductase: Cysteine versus selenocysteine." Redox Biology 2 (2014): 475–84. http://dx.doi.org/10.1016/j.redox.2014.01.021.

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FERNANDO, M. Rohan, Hiroki NANRI, Shinichirou YOSHITAKE, Kazue NAGATA-KUNO, and Shigeki MINAKAMI. "Thioredoxin regenerates proteins inactivated by oxidative stress in endothelial cells." European Journal of Biochemistry 209, no. 3 (November 1992): 917–22. http://dx.doi.org/10.1111/j.1432-1033.1992.tb17363.x.

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Cunningham, Geneva M., Madeline G. Roman, Lisa C. Flores, Gene B. Hubbard, Adam B. Salmon, Yiqiang Zhang, Jonathan Gelfond, and Yuji Ikeno. "The paradoxical role of thioredoxin on oxidative stress and aging." Archives of Biochemistry and Biophysics 576 (June 2015): 32–38. http://dx.doi.org/10.1016/j.abb.2015.02.025.

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Zhang, Lu, James R. Alfano, and Donald F. Becker. "Proline Metabolism IncreaseskatGExpression and Oxidative Stress Resistance in Escherichia coli." Journal of Bacteriology 197, no. 3 (November 10, 2014): 431–40. http://dx.doi.org/10.1128/jb.02282-14.

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The oxidation ofl-proline to glutamate in Gram-negative bacteria is catalyzed by the proline utilization A (PutA) flavoenzyme, which contains proline dehydrogenase (PRODH) and Δ1-pyrroline-5-carboxylate (P5C) dehydrogenase domains in a single polypeptide. Previous studies have suggested that aside from providing energy, proline metabolism influences oxidative stress resistance in different organisms. To explore this potential role and the mechanism, we characterized the oxidative stress resistance of wild-type andputAmutant strains ofEscherichia coli. Initial stress assays revealed that theputAmutant strain was significantly more sensitive to oxidative stress than the parental wild-type strain. Expression of PutA in theputAmutant strain restored oxidative stress resistance, confirming that depletion of PutA was responsible for the oxidative stress phenotype. Treatment of wild-type cells with proline significantly increased hydroperoxidase I (encoded bykatG) expression and activity. Furthermore, the ΔkatGstrain failed to respond to proline, indicating a critical role for hydroperoxidase I in the mechanism of proline protection. The global regulator OxyR activates the expression ofkatGalong with several other genes involved in oxidative stress defense. In addition tokatG, proline increased the expression ofgrxA(glutaredoxin 1) andtrxC(thioredoxin 2) of the OxyR regulon, implicating OxyR in proline protection. Proline oxidative metabolism was shown to generate hydrogen peroxide, indicating that proline increases oxidative stress tolerance inE. colivia a preadaptive effect involving endogenous hydrogen peroxide production and enhanced catalase-peroxidase activity.

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Lehtonen, Siri T., Steffen Ohlmeier, Riitta Kaarteenaho-Wiik, Terttu Harju, Paavo Pääkkö, Ylermi Soini, and Vuokko L. Kinnula. "Does the Oxidative Stress in Chronic Obstructive Pulmonary Disease Cause Thioredoxin/Peroxiredoxin Oxidation?" Antioxidants & Redox Signaling 10, no. 4 (April 2008): 813–20. http://dx.doi.org/10.1089/ars.2007.1952.

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Li, Kuanyu, Silke Hein, Wenxin Zou, and Gabriele Klug. "The Glutathione-Glutaredoxin System in Rhodobacter capsulatus: Part of a Complex Regulatory Network Controlling Defense against Oxidative Stress." Journal of Bacteriology 186, no. 20 (October 15, 2004): 6800–6808. http://dx.doi.org/10.1128/jb.186.20.6800-6808.2004.

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ABSTRACT Mutants with defects in components of the glutathione-glutaredoxin (GSH/Grx) system of Rhodobacter capsulatus were constructed to study its role in defense against oxidative stress and the redox-dependent formation of photosynthetic complexes. The lack of the glutaredoxin 3 gene (grxC) or the glutathione synthetase B gene (gshB) resulted in lower growth rates under aerobic conditions and higher sensitivity to oxidative stress, confirming the role of the GSH/Grx system in oxidative stress defense. Both mutants are highly sensitive to disulfide stress, indicating a major contribution of the GSH/Grx system to the thiol-disulfide redox buffer in the cytoplasm. Like mutations in the thioredoxin system, mutations in the GSH/Grx system affected the formation of photosynthetic complexes, which is redox dependent in R. capsulatus. Expression of the genes grxC, gshB, grxA for glutaredoxin 1, and gorA for glutathione reductase, all encoding components of the GSH/Grx system, was not induced by oxidative stress. Other genes, for which a role in oxidative stress was established in Escherichia coli, acnA, fpr, fur, and katG, were strongly induced by oxidative stress in R. capsulatus. Mutations in the grxC, and/or gshB, and/or trxC (thioredoxin 2) genes affected expression of these genes, indicating an interplay of the different defense systems against oxidative stress. The OxyR and the SoxRS regulons control the expression of many genes involved in oxidative stress defense in E. coli in response to H2O2 and superoxide, respectively. Our data and the available genome sequence of R. capsulatus suggest that a SoxRS system is lacking but an alternative superoxide specific regulator exists in R. capsulatus. While the expression of gorA and grxA is regulated by H2O2 in E. coli this is not the case in R. capsulatus, indicating that the OxyR regulons of these two species are significantly different.

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Kuge, Shusuke, Minetaro Arita, Asako Murayama, Kazuhiro Maeta, Shingo Izawa, Yoshiharu Inoue, and Akio Nomoto. "Regulation of the Yeast Yap1p Nuclear Export Signal Is Mediated by Redox Signal-Induced Reversible Disulfide Bond Formation." Molecular and Cellular Biology 21, no. 18 (September 15, 2001): 6139–50. http://dx.doi.org/10.1128/mcb.21.18.6139-6150.2001.

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Abstract:

ABSTRACT Yap1p, a crucial transcription factor in the oxidative stress response of Saccharomyces cerevisiae, is transported in and out of the nucleus under nonstress conditions. The nuclear export step is specifically inhibited by H2O2 or the thiol oxidant diamide, resulting in Yap1p nuclear accumulation and induction of transcription of its target genes. Here we provide evidence for sensing of H2O2 and diamide mediated by disulfide bond formation in the C-terminal cysteine-rich region (c-CRD), which contains 3 conserved cysteines and the nuclear export signal (NES). The H2O2 or diamide-induced oxidation of the c-CRD in vivo correlates with induced Yap1p nuclear localization. Both were initiated within 1 min of application of oxidative stress, before the intracellular redox status of thioredoxin and glutathione was affected. The cysteine residues in the middle region of Yap1p (n-CRD) are required for prolonged nuclear localization of Yap1p in response to H2O2 and are thus also required for maximum transcriptional activity. Using mass spectrometry analysis, the H2O2-induced oxidation of the c-CRD in vitro was detected as an intramolecular disulfide linkage between the first (Cys598) and second (Cys620) cysteine residues; this linkage could be reduced by thioredoxin. In contrast, diamide induced each pair of disulfide linkage in the c-CRD, but in this case the cysteine residues in the n-CRD appeared to be dispensable for the response. Our data provide evidence for molecular mechanisms of redox signal sensing through the thiol-disulfide redox cycle coupled with the thioredoxin system in the Yap1p NES.

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Journal articles on the topic 'Thioredoxin; oxidative stress'

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