Special Issue "Peroxiredoxin"

A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Antioxidant Enzyme Systems".

Deadline for manuscript submissions: 30 November 2022.

Special Issue Editor

Prof. Ho Hee Jang
E-Mail Website
Guest Editor
Department of Biochemistry, College of Medicine, Gachon University, Incheon 21999, Korea
Interests: 2-Cys peroxiredoxin; prx-interacting partners; stress signaling; chaperone activity; post-translational modifications; redox regulation

Special Issue Information

Dear Colleagues,

In 1987, Kim and colleagues identified the first peroxiredoxin (Prx) protein, a thiol-specific antioxidant, in yeast [1,2]. Since then, researchers have identified six isoforms of Prx in mammalian cells alone. Prxs are key molecules in intracellular ROS homeostasis that play important biological roles in various cellular processes including cell growth, differentiation, apoptosis, the immune response, and metabolism. In addition, Prxs have been found to play roles in a variety of post-translational modifications such as phosphorylation, ubiquitination, and glutathionylation.

The goal of this Special Issue is to bring together current views, new insights, and cutting-edge research on the biological roles of Prxs. These include Prxs sourced from all species, from prokaryotes to eukaryotes, including those found in E. coli, plants, yeasts, and animals.

I look forward to your contribution.

References

  1. Kim, K., Kim, I.H., Lee, K.Y., Rhee, S.G., and Stadtman, E.R (1988). The isolation and purification of a specific “protector” protein which inhibits enzyme inactivation by a thiol/Fe(III)/O2 mixed-function oxidation system. J. Biol. Chem. 263, 4704-4711.
  2. Kim, I.H., Kim, K., and Rhee, S.G (1989). Induction of an antioxidant protein of Saccharomyces cerevisiae by O2, Fe3+, or 2-mercaptoethanol. Proc. Natl. Acad. Sci. USA. 86, 6018-6022.

Prof. Ho Hee Jang
Guest Editor

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Keywords

  • peroxiredoxin
  • reactive oxygen species
  • stress response
  • redox signaling
  • peroxidase activity
  • chaperone activity
  • protein–protein interaction
  • post-translational modifications

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Published Papers (19 papers)

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Research

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Article
Hyperoxidation of Peroxiredoxins and Effects on Physiology of Drosophila
Antioxidants 2021, 10(4), 606; https://doi.org/10.3390/antiox10040606 - 15 Apr 2021
Viewed by 747
Abstract
The catalytic activity of peroxiredoxins (Prx) is determined by the conserved peroxidatic cysteine (CysP), which reacts with peroxides to form sulfenic acid (Cys-SOH). Under conditions of oxidative stress, CysP is oxidized to catalytically inactive sulfinic (Cys-SO2) and sulfonic [...] Read more.
The catalytic activity of peroxiredoxins (Prx) is determined by the conserved peroxidatic cysteine (CysP), which reacts with peroxides to form sulfenic acid (Cys-SOH). Under conditions of oxidative stress, CysP is oxidized to catalytically inactive sulfinic (Cys-SO2) and sulfonic (Cys-SO3) forms. The Cys-SO2 form can be reduced in a reaction catalyzed by sulfiredoxin (Srx). To explore the physiological significance of peroxiredoxin overoxidation, we investigated daily variations in the oxidation state of 2-Cys peroxiredoxins in flies of different ages, or under conditions when the pro-oxidative load is high. We found no statistically significant changes in the 2-Cys Prxs monomer:dimer ratio, which indirectly reflects changes in the Prx catalytic activity. However, we found daily variations in Prx-SO2/3 that were more pronounced in older flies as well as in flies lacking Srx. Unexpectedly, the srx mutant flies did not exhibit a diminished survivorship under normal or oxidative stress conditions. Moreover, the srx mutant was characterized by a higher physiological activity. In conclusion, catalytically inactive forms of Prx-SO2/3 serve not only as a marker of cellular oxidative burden, but may also play a role in an adaptive response, leading to a positive effect on the physiology of Drosophila melanogaster. Full article
(This article belongs to the Special Issue Peroxiredoxin)
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Article
Maturation of Mitochondrially Targeted Prx V Involves a Second Cleavage by Mitochondrial Intermediate Peptidase That Is Sensitive to Inhibition by H2O2
Antioxidants 2021, 10(3), 346; https://doi.org/10.3390/antiox10030346 - 25 Feb 2021
Cited by 2 | Viewed by 630
Abstract
Prx V mRNA contains two in-frame AUG codons, producing a long (L-Prx V) and short form of Prx V (S-Prx V), and mouse L-Prx V is expressed as a precursor protein containing a 49-amino acid N-terminal mitochondria targeting sequence. Here, we show that [...] Read more.
Prx V mRNA contains two in-frame AUG codons, producing a long (L-Prx V) and short form of Prx V (S-Prx V), and mouse L-Prx V is expressed as a precursor protein containing a 49-amino acid N-terminal mitochondria targeting sequence. Here, we show that the N-terminal 41-residue sequence of L-Prx V is cleaved by mitochondrial processing peptidase (MPP) in the mitochondrial matrix to produce an intermediate Prx V (I-Prx V) with a destabilizing phenylalanine at its N-terminus, and further, that the next 8-residue sequence is cleaved by mitochondrial intermediate peptidase (MIP) to convert I-Prx V to a stabilized mature form that is identical to S-Prx V. Further, we show that when mitochondrial H2O2 levels are increased in HeLa cells using rotenone, in several mouse tissues by deleting Prx III, and in the adrenal gland by deleting Srx or by exposing mice to immobilized stress, I-Prx V accumulates transiently and mature S-Prx V levels decrease in mitochondria over time. These findings support the view that MIP is inhibited by H2O2, resulting in the accumulation and subsequent degradation of I-Prx V, identifying a role for redox mediated regulation of Prx V proteolytic maturation and expression in mitochondria. Full article
(This article belongs to the Special Issue Peroxiredoxin)
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Article
Tyrosine Phosphorylation Modulates Peroxiredoxin-2 Activity in Normal and Diseased Red Cells
Antioxidants 2021, 10(2), 206; https://doi.org/10.3390/antiox10020206 - 01 Feb 2021
Viewed by 692
Abstract
Peroxiredoxin-2 (Prx2) is the third most abundant cytoplasmic protein in red blood cells. Prx2 belongs to a well-known family of antioxidants, the peroxiredoxins (Prxs), that are widely expressed in mammalian cells. Prx2 is a typical, homodimeric, 2-Cys Prx that uses two cysteine residues [...] Read more.
Peroxiredoxin-2 (Prx2) is the third most abundant cytoplasmic protein in red blood cells. Prx2 belongs to a well-known family of antioxidants, the peroxiredoxins (Prxs), that are widely expressed in mammalian cells. Prx2 is a typical, homodimeric, 2-Cys Prx that uses two cysteine residues to accomplish the task of detoxifying a vast range of organic peroxides, H2O2, and peroxynitrite. Although progress has been made on functional characterization of Prx2, much still remains to be investigated on Prx2 post-translational changes. Here, we first show that Prx2 is Tyrosine (Tyr) phosphorylated by Syk in red cells exposed to oxidation induced by diamide. We identified Tyr-193 in both recombinant Prx2 and native Prx2 from red cells as a specific target of Syk. Bioinformatic analysis suggests that phosphorylation of Tyr-193 allows Prx2 conformational change that is more favorable for its peroxidase activity. Indeed, Syk-induced Tyr phosphorylation of Prx2 enhances in vitro Prx2 activity, but also contributes to Prx2 translocation to the membrane of red cells exposed to diamide. The biologic importance of Tyr-193 phospho-Prx2 is further supported by data on red cells from a mouse model of humanized sickle cell disease (SCD). SCD is globally distributed, hereditary red cell disorder, characterized by severe red cell oxidation due to the pathologic sickle hemoglobin. SCD red cells show Tyr-phosphorylated Prx2 bound to the membrane and increased Prx2 activity when compared to healthy erythrocytes. Collectively, our data highlight the novel link between redox related signaling and Prx2 function in normal and diseased red cells. Full article
(This article belongs to the Special Issue Peroxiredoxin)
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Article
Function and Regulation of Chloroplast Peroxiredoxin IIE
Antioxidants 2021, 10(2), 152; https://doi.org/10.3390/antiox10020152 - 21 Jan 2021
Cited by 1 | Viewed by 775
Abstract
Peroxiredoxins (PRX) are thiol peroxidases that are highly conserved throughout all biological kingdoms. Increasing evidence suggests that their high reactivity toward peroxides has a function not only in antioxidant defense but in particular in redox regulation of the cell. Peroxiredoxin IIE (PRX-IIE) is [...] Read more.
Peroxiredoxins (PRX) are thiol peroxidases that are highly conserved throughout all biological kingdoms. Increasing evidence suggests that their high reactivity toward peroxides has a function not only in antioxidant defense but in particular in redox regulation of the cell. Peroxiredoxin IIE (PRX-IIE) is one of three PRX types found in plastids and has previously been linked to pathogen defense and protection from protein nitration. However, its posttranslational regulation and its function in the chloroplast protein network remained to be explored. Using recombinant protein, it was shown that the peroxidatic Cys121 is subjected to multiple posttranslational modifications, namely disulfide formation, S-nitrosation, S-glutathionylation, and hyperoxidation. Slightly oxidized glutathione fostered S-glutathionylation and inhibited activity in vitro. Immobilized recombinant PRX-IIE allowed trapping and subsequent identification of interaction partners by mass spectrometry. Interaction with the 14-3-3 υ protein was confirmed in vitro and was shown to be stimulated under oxidizing conditions. Interactions did not depend on phosphorylation as revealed by testing phospho-mimicry variants of PRX-IIE. Based on these data it is proposed that 14-3-3υ guides PRX‑IIE to certain target proteins, possibly for redox regulation. These findings together with the other identified potential interaction partners of type II PRXs localized to plastids, mitochondria, and cytosol provide a new perspective on the redox regulatory network of the cell. Full article
(This article belongs to the Special Issue Peroxiredoxin)
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Article
Discovery of Spilanthol Endoperoxide as a Redox Natural Compound Active against Mammalian Prx3 and Chlamydia trachomatis Infection
Antioxidants 2020, 9(12), 1220; https://doi.org/10.3390/antiox9121220 - 03 Dec 2020
Viewed by 882
Abstract
Chlamydia trachomatis (Ct) is a bacterial intracellular pathogen responsible for a plethora of diseases ranging from blindness to pelvic inflammatory diseases and cervical cancer. Although this disease is effectively treated with antibiotics, concerns for development of resistance prompt the need for new low-cost [...] Read more.
Chlamydia trachomatis (Ct) is a bacterial intracellular pathogen responsible for a plethora of diseases ranging from blindness to pelvic inflammatory diseases and cervical cancer. Although this disease is effectively treated with antibiotics, concerns for development of resistance prompt the need for new low-cost treatments. Here we report the activity of spilanthol (SPL), a natural compound with demonstrated anti-inflammatory properties, against Ct infections. Using chemical probes selective for imaging mitochondrial protein sulfenylation and complementary assays, we identify an increase in mitochondrial oxidative state by SPL as the underlying mechanism leading to disruption of host cell F-actin cytoskeletal organization and inhibition of chlamydial infection. The peroxidation product of SPL (SPL endoperoxide, SPLE), envisioned to be the active compound in the cellular milieu, was chemically synthesized and showed more potent anti-chlamydial activity. Comparison of SPL and SPLE reactivity with mammalian peroxiredoxins, demonstrated preferred reactivity of SPLE with Prx3, and virtual lack of SPL reaction with any of the reduced Prx isoforms investigated. Cumulatively, these findings support the function of SPL as a pro-drug, which is converted to SPLE in the cellular milieu leading to inhibition of Prx3, increased mitochondrial oxidation and disruption of F-actin network, and inhibition of Ct infection. Full article
(This article belongs to the Special Issue Peroxiredoxin)
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Article
Redox–Oligomeric State of Peroxiredoxin-2 and Glyceraldehyde-3-Phosphate Dehydrogenase in Obstructive Sleep Apnea Red Blood Cells under Positive Airway Pressure Therapy
Antioxidants 2020, 9(12), 1184; https://doi.org/10.3390/antiox9121184 - 26 Nov 2020
Viewed by 859
Abstract
In this study, we examined the effect of six months of positive airway pressure (PAP) therapy on Obstructive Sleep Apnea (OSA) red blood cell (RBC) proteome by two dimensional difference gel electrophoresis (2D-DIGE) - based proteomics followed by Western blotting (WB) validation. The [...] Read more.
In this study, we examined the effect of six months of positive airway pressure (PAP) therapy on Obstructive Sleep Apnea (OSA) red blood cell (RBC) proteome by two dimensional difference gel electrophoresis (2D-DIGE) - based proteomics followed by Western blotting (WB) validation. The discovered dysregulated proteins/proteoforms are associated with cell death, H2O2 catabolic/metabolic process, stress response, and protein oligomerization. Validation by nonreducing WB was performed for peroxiredoxin-2 (PRDX2) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) by using antibodies against the sulfinylated/sulfonylated cysteine of these proteins to better evaluate their redox–oligomeric states under OSA and/or in response to PAP therapy. The results indicated that the redox–oligomeric state of GAPDH and PRDX2 involving overoxidation by sulfinic/sulfonic acids were differentially modulated in OSA RBC, which might be compromising RBC homeostasis. PAP therapy by restoring this modulation induced a higher oligomerization of overoxidized GAPDH and PRDX2 in some patients that could be associated with eryptosis and the chaperone “gain” of function, respectively. This varied response following PAP may result from the complex interplay between OSA and OSA metabolic comorbidity. Hence, information on the redox status of PRDX2 and GAPDH in RBC will help to better recognize OSA subtypes and predict the therapeutic response in these patients. GAPDH monomer combined with body mass index (BMI) and PRDX2 S-S dimer combined with homeostatic model assessment for insulin resistance (HOMA-IR) showed to be very promising biomarkers to predict OSA and OSA severity, respectively. Full article
(This article belongs to the Special Issue Peroxiredoxin)
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Article
Upregulation of Peroxiredoxin-2 in Well-Differentiated Pancreatic Neuroendocrine Tumors and Its Utility as a Biomarker for Predicting the Response to Everolimus
Antioxidants 2020, 9(11), 1104; https://doi.org/10.3390/antiox9111104 - 09 Nov 2020
Cited by 1 | Viewed by 763
Abstract
Pancreatic neuroendocrine neoplasms (pNENs) account for 2–3% of pancreatic malignancies. Peroxiredoxins (Prdxs), which are major cellular antioxidants, are involved in multiple oncogenic signaling pathways. We investigated the role of peroxiredoxin-2 in QGP-1 human pNEN cell line and patient-derived pNEN tissue. To validate the [...] Read more.
Pancreatic neuroendocrine neoplasms (pNENs) account for 2–3% of pancreatic malignancies. Peroxiredoxins (Prdxs), which are major cellular antioxidants, are involved in multiple oncogenic signaling pathways. We investigated the role of peroxiredoxin-2 in QGP-1 human pNEN cell line and patient-derived pNEN tissue. To validate the cancer stem cell-like cell characteristics of QGP-1 cells in spheroid culture, in vitro analyses and xenografting were performed. Furthermore, immunohistochemical staining was conducted to verify the overexpression of Prdx2 in pNEN tissue. Prdx2 expression was high at the mRNA and protein levels in QGP-1 cells. Prdx2 was also overexpressed in patient-derived pNEN tissue. Silencing of Prdx2 using siRNA induced overexpression and phosphorylation of ERK and AKT in QGP-1. Cell proliferation was increased by treating QGP-1 cells with siPrdx2, and the IC50 of everolimus increased suggesting resistance to everolimus. Interestingly, QGP-1 spheroid cells, which exhibited cancer stem cell-like features, exhibited lower expression of Prdx2 and mTOR. The results suggest that Prdx2 expression level and its activity may be a potential predictive biomarker for therapeutic response or resistance to everolimus in pNEN. Full article
(This article belongs to the Special Issue Peroxiredoxin)
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Article
Sigma-1 Receptor Engages an Anti-Inflammatory and Antioxidant Feedback Loop Mediated by Peroxiredoxin in Experimental Colitis
Antioxidants 2020, 9(11), 1081; https://doi.org/10.3390/antiox9111081 - 04 Nov 2020
Cited by 4 | Viewed by 713
Abstract
Inflammatory bowel disease (IBD), comprising Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic inflammatory condition of the gastrointestinal tract. Since the treatment of IBD is still an unresolved issue, we designed our study to investigate the effect of a novel therapeutic [...] Read more.
Inflammatory bowel disease (IBD), comprising Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic inflammatory condition of the gastrointestinal tract. Since the treatment of IBD is still an unresolved issue, we designed our study to investigate the effect of a novel therapeutic target, sigma-1 receptor (σ1R), considering its ability to activate antioxidant molecules. As a model, 2,4,6-trinitrobenzenesulfonic acid (TNBS) was used to induce colitis in Wistar–Harlan male rats. To test the beneficial effects of σ1R, animals were treated intracolonically (i.c.): (1) separately with an agonist (fluvoxamine (FLV)), (2) with an antagonist of the receptor (BD1063), or (3) as a co-treatment. Our results showed that FLV significantly decreased the severity of inflammation and increased the body weight of the animals. On the contrary, simultaneous treatment of FLV with BD1063 diminished the beneficial effects of FLV. Furthermore, FLV significantly enhanced the levels of glutathione (GSH) and peroxiredoxin 1 (PRDX1) and caused a significant reduction in 3-nitrotyrosine (3-NT) levels, the effects of which were abolished by co-treatment with BD1063. Taken together, our results suggest that the activation of σ1R in TNBS-induced colitis through FLV may be a promising therapeutic strategy, and its protective effect seems to involve the antioxidant pathway system. Full article
(This article belongs to the Special Issue Peroxiredoxin)
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Article
Exploring the Functional Relationship between y-Type Thioredoxins and 2-Cys Peroxiredoxins in Arabidopsis Chloroplasts
Antioxidants 2020, 9(11), 1072; https://doi.org/10.3390/antiox9111072 - 31 Oct 2020
Cited by 2 | Viewed by 990
Abstract
Thioredoxins (Trxs) are small, ubiquitous enzymes that catalyze disulphide–dithiol interchange in target enzymes. The large set of chloroplast Trxs, including f, m, x and y subtypes, use reducing equivalents fueled by photoreduced ferredoxin (Fdx) for fine-tuning photosynthetic performance and metabolism through [...] Read more.
Thioredoxins (Trxs) are small, ubiquitous enzymes that catalyze disulphide–dithiol interchange in target enzymes. The large set of chloroplast Trxs, including f, m, x and y subtypes, use reducing equivalents fueled by photoreduced ferredoxin (Fdx) for fine-tuning photosynthetic performance and metabolism through the control of the activity of redox-sensitive proteins. Although biochemical analyses suggested functional diversity of chloroplast Trxs, genetic studies have established that deficiency in a particular Trx subtype has subtle phenotypic effects, leading to the proposal that the Trx isoforms are functionally redundant. In addition, chloroplasts contain an NADPH-dependent Trx reductase with a joint Trx domain, termed NTRC. Interestingly, Arabidopsis mutants combining the deficiencies of x- or f-type Trxs and NTRC display very severe growth inhibition phenotypes, which are partially rescued by decreased levels of 2-Cys peroxiredoxins (Prxs). These findings indicate that the reducing capacity of Trxs f and x is modulated by the redox balance of 2-Cys Prxs, which is controlled by NTRC. In this study, we explored whether NTRC acts as a master regulator of the pool of chloroplast Trxs by analyzing its functional relationship with Trxs y. While Trx y interacts with 2-Cys Prxs in vitro and in planta, the analysis of Arabidopsis mutants devoid of NTRC and Trxs y suggests that Trxs y have only a minor effect, if any, on the redox state of 2-Cys Prxs. Full article
(This article belongs to the Special Issue Peroxiredoxin)
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Article
Ablation of Peroxiredoxin V Exacerbates Ischemia/Reperfusion-Induced Kidney Injury in Mice
Antioxidants 2020, 9(8), 769; https://doi.org/10.3390/antiox9080769 - 18 Aug 2020
Cited by 5 | Viewed by 1183
Abstract
Ischemia/reperfusion (I/R) is one of the major causes of acute kidney injury (AKI) and associated with increased mortality and progression to chronic kidney injury (CKI). Molecular mechanisms underlying I/R injury involve the production and excessive accumulation of reactive oxygen species (ROS). Peroxiredoxin (Prx) [...] Read more.
Ischemia/reperfusion (I/R) is one of the major causes of acute kidney injury (AKI) and associated with increased mortality and progression to chronic kidney injury (CKI). Molecular mechanisms underlying I/R injury involve the production and excessive accumulation of reactive oxygen species (ROS). Peroxiredoxin (Prx) V, a cysteine-dependent peroxidase, is located in the cytosol, mitochondria, and peroxisome and has an intensive ROS scavenging activity. Therefore, we focused on the role of Prx V during I/R-induced AKI using Prx V knockout (KO) mice. Ablation of Prx V augmented tubular damage, apoptosis, and declined renal function. Prx V deletion also showed higher susceptibility to I/R injury with increased markers for oxidative stress, ER stress, and inflammation in the kidney. Overall, these results demonstrate that Prx V protects the kidneys against I/R-induced injury. Full article
(This article belongs to the Special Issue Peroxiredoxin)
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Article
Comparative Study of Protective Action of Exogenous 2-Cys Peroxiredoxins (Prx1 and Prx2) Under Renal Ischemia-Reperfusion Injury
Antioxidants 2020, 9(8), 680; https://doi.org/10.3390/antiox9080680 - 29 Jul 2020
Cited by 2 | Viewed by 936
Abstract
The pathogenesis of ischemia-reperfusion (I/R) injuries is based on oxidative stress caused by a sharp increase in the concentration of free radicals, reactive oxygen species (ROS) and secondary products of free radical oxidation of biological macromolecules during reperfusion. Application of exogenous antioxidants lowers [...] Read more.
The pathogenesis of ischemia-reperfusion (I/R) injuries is based on oxidative stress caused by a sharp increase in the concentration of free radicals, reactive oxygen species (ROS) and secondary products of free radical oxidation of biological macromolecules during reperfusion. Application of exogenous antioxidants lowers the level of ROS in the affected tissues, suppresses or adjusts the course of oxidative stress, thereby substantially reducing the severity of I/R injury. We believe that the use of antioxidant enzymes may be the most promising line of effort since they possess higher efficiency than low molecular weight antioxidants. Among antioxidant enzymes, of great interest are peroxiredoxins (Prx1–6) which reduce a wide range of organic and inorganic peroxide substrates. In an animal model of bilateral I/R injury of kidneys (using histological, biochemical, and molecular biological methods) it was shown that intravenous administration of recombinant typical 2-Cys peroxiredoxins (Prx1 and Prx2) effectively reduces the severity of I/R damage, contributing to the normalization of the structural and functional state of the kidneys and an almost 2-fold increase in the survival of experimental animals. The use of recombinant Prx1 or Prx2 can be an efficient approach for the prevention and treatment of renal I/R injury. Full article
(This article belongs to the Special Issue Peroxiredoxin)
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Article
Triple Combination of Ascorbate, Menadione and the Inhibition of Peroxiredoxin-1 Produces Synergistic Cytotoxic Effects in Triple-Negative Breast Cancer Cells
Antioxidants 2020, 9(4), 320; https://doi.org/10.3390/antiox9040320 - 16 Apr 2020
Cited by 7 | Viewed by 1403
Abstract
Triple-negative breast cancer (TNBC) is an aggressive form of mammary malignancy currently without satisfactory systemic treatment options. Agents generating reactive oxygen species (ROS), such as ascorbate (Asc) and menadione (Men), especially applied in combination, have been proposed as an alternative anticancer modality. However, [...] Read more.
Triple-negative breast cancer (TNBC) is an aggressive form of mammary malignancy currently without satisfactory systemic treatment options. Agents generating reactive oxygen species (ROS), such as ascorbate (Asc) and menadione (Men), especially applied in combination, have been proposed as an alternative anticancer modality. However, their effectiveness can be hampered by the cytoprotective effects of elevated antioxidant enzymes (e.g., peroxiredoxins, PRDX) in cancer. In this study, PRDX1 mRNA and protein expression were assessed in TNBC tissues by analysis of the online RNA-seq datasets and immunohistochemical staining of tissue microarray, respectively. We demonstrated that PRDX1 mRNA expression was markedly elevated in primary TNBC tumors as compared to non-malignant controls, with PRDX1 protein staining intensity correlating with favorable survival parameters. Subsequently, PRDX1 functionality in TNBC cell lines or non-malignant mammary cells was targeted by genetic silencing or chemically by auranofin (AUR). The PRDX1-knockdown or AUR treatment resulted in inhibition of the growth of TNBC cells in vitro. These cytotoxic effects were further synergistically potentiated by the incubation with a combination of the prooxidant agents, Asc and Men. In conclusion, we report that the PRDX1-related antioxidant system is essential for maintaining redox homeostasis in TNBC cells and can be an attractive therapeutic target in combination with ROS-generating agents. Full article
(This article belongs to the Special Issue Peroxiredoxin)
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Article
The Peroxidatic Thiol of Peroxiredoxin 1 is Nitrosated by Nitrosoglutathione but Coordinates to the Dinitrosyl Iron Complex of Glutathione
Antioxidants 2020, 9(4), 276; https://doi.org/10.3390/antiox9040276 - 25 Mar 2020
Cited by 5 | Viewed by 1283
Abstract
Protein S-nitrosation is an important consequence of NO·metabolism with implications in physiology and pathology. The mechanisms responsible for S-nitrosation in vivo remain debatable and kinetic data on protein S-nitrosation by different agents are limited. 2-Cys peroxiredoxins, in particular Prx1 and Prx2, [...] Read more.
Protein S-nitrosation is an important consequence of NO·metabolism with implications in physiology and pathology. The mechanisms responsible for S-nitrosation in vivo remain debatable and kinetic data on protein S-nitrosation by different agents are limited. 2-Cys peroxiredoxins, in particular Prx1 and Prx2, were detected as being S-nitrosated in multiple mammalian cells under a variety of conditions. Here, we investigated the kinetics of Prx1 S-nitrosation by nitrosoglutathione (GSNO), a recognized biological nitrosating agent, and by the dinitrosyl-iron complex of glutathione (DNIC-GS; [Fe(NO)2(GS)2]), a hypothetical nitrosating agent. Kinetics studies following the intrinsic fluorescence of Prx1 and its mutants (C83SC173S and C52S) were complemented by product analysis; all experiments were performed at pH 7.4 and 25 ℃. The results show GSNO-mediated nitrosation of Prx1 peroxidatic residue ( k + N O C y s 52 = 15.4 ± 0.4 M−1. s−1) and of Prx1 Cys83 residue ( k + N O C y s 83 = 1.7 ± 0.4 M−1. s−1). The reaction of nitrosated Prx1 with GSH was also monitored and provided a second-order rate constant for Prx1Cys52NO denitrosation of k N O C y s 52 = 14.4 ± 0.3 M−1. s−1. In contrast, the reaction of DNIC-GS with Prx1 did not nitrosate the enzyme but formed DNIC-Prx1 complexes. The peroxidatic Prx1 Cys was identified as the residue that more rapidly replaces the GS ligand from DNIC-GS ( k D N I C C y s 52 = 7.0 ± 0.4 M−1. s−1) to produce DNIC-Prx1 ([Fe(NO)2(GS)(Cys52-Prx1)]). Altogether, the data showed that in addition to S-nitrosation, the Prx1 peroxidatic residue can replace the GS ligand from DNIC-GS, forming stable DNIC-Prx1, and both modifications disrupt important redox switches. Full article
(This article belongs to the Special Issue Peroxiredoxin)
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Article
Peroxiredoxin 6 Down-Regulation Induces Metabolic Remodeling and Cell Cycle Arrest in HepG2 Cells
Antioxidants 2019, 8(11), 505; https://doi.org/10.3390/antiox8110505 - 23 Oct 2019
Cited by 3 | Viewed by 1681
Abstract
Peroxiredoxin 6 (Prdx6) is the only member of 1-Cys subfamily of peroxiredoxins in human cells. It is the only Prdx acting on phospholipid hydroperoxides possessing two additional sites with phospholipase A2 (PLA2) and lysophosphatidylcholine-acyl transferase (LPCAT) activities. There are contrasting reports on the [...] Read more.
Peroxiredoxin 6 (Prdx6) is the only member of 1-Cys subfamily of peroxiredoxins in human cells. It is the only Prdx acting on phospholipid hydroperoxides possessing two additional sites with phospholipase A2 (PLA2) and lysophosphatidylcholine-acyl transferase (LPCAT) activities. There are contrasting reports on the roles and mechanisms of multifunctional Prdx6 in several pathologies and on its sensitivity to, and influence on, the redox environment. We have down-regulated Prdx6 with specific siRNA in hepatoblastoma HepG2 cells to study its role in cell proliferation, redox homeostasis, and metabolic programming. Cell proliferation and cell number decreased while cell volume increased; import of glucose and nucleotide biosynthesis also diminished while polyamines, phospholipids, and most glycolipids increased. A proteomic quantitative analysis suggested changes in membrane arrangement and vesicle trafficking as well as redox changes in enzymes of carbon and glutathione metabolism, pentose-phosphate pathway, citrate cycle, fatty acid metabolism, biosynthesis of aminoacids, and Glycolysis/Gluconeogenesis. Specific redox changes in Hexokinase-2 (HK2), Prdx6, intracellular chloride ion channel-1 (CLIC1), PEP-carboxykinase-2 (PCK2), and 3-phosphoglycerate dehydrogenase (PHGDH) are compatible with the metabolic remodeling toward a predominant gluconeogenic flow from aminoacids with diversion at 3-phospohglycerate toward serine and other biosynthetic pathways thereon and with cell cycle arrest at G1/S transition. Full article
(This article belongs to the Special Issue Peroxiredoxin)
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Review
Redox Regulation of PTEN by Peroxiredoxins
Antioxidants 2021, 10(2), 302; https://doi.org/10.3390/antiox10020302 - 16 Feb 2021
Cited by 4 | Viewed by 862
Abstract
Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is known as a tumor suppressor gene that is frequently mutated in numerous human cancers and inherited syndromes. PTEN functions as a negative regulator of PI3K/Akt signaling pathway by dephosphorylating phosphatidylinositol (3, [...] Read more.
Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is known as a tumor suppressor gene that is frequently mutated in numerous human cancers and inherited syndromes. PTEN functions as a negative regulator of PI3K/Akt signaling pathway by dephosphorylating phosphatidylinositol (3, 4, 5)-trisphosphate (PIP3) to phosphatidylinositol (4, 5)-bisphosphate (PIP2), which leads to the inhibition of cell growth, proliferation, cell survival, and protein synthesis. PTEN contains a cysteine residue in the active site that can be oxidized by peroxides, forming an intramolecular disulfide bond between Cys124 and Cys71. Redox regulation of PTEN by reactive oxygen species (ROS) plays a crucial role in cellular signaling. Peroxiredoxins (Prxs) are a superfamily of peroxidase that catalyzes reduction of peroxides and maintains redox homeostasis. Mammalian Prxs have 6 isoforms (I-VI) and can scavenge cellular peroxides. It has been demonstrated that Prx I can preserve and promote the tumor-suppressive function of PTEN by preventing oxidation of PTEN under benign oxidative stress via direct interaction. Also, Prx II-deficient cells increased PTEN oxidation and insulin sensitivity. Furthermore, Prx III has been shown to protect PTEN from oxidation induced by 15s-HpETE and 12s-HpETE, these are potent inflammatory and pro-oxidant mediators. Understanding the tight connection between PTEN and Prxs is important for providing novel therapies. Herein, we summarized recent studies focusing on the relationship of Prxs and the redox regulation of PTEN. Full article
(This article belongs to the Special Issue Peroxiredoxin)
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Review
Recent Progress in the Study of Peroxiredoxin in the Harmful Algal Bloom Species Chattonella marina
Antioxidants 2021, 10(2), 162; https://doi.org/10.3390/antiox10020162 - 22 Jan 2021
Cited by 1 | Viewed by 881
Abstract
Peroxiredoxin (Prx) is a relatively recently discovered antioxidant enzyme family that scavenges peroxides and is known to be present in organisms from biological taxa ranging from bacteria to multicellular eukaryotes, including photosynthetic organisms. Although there have been many studies of the Prx family [...] Read more.
Peroxiredoxin (Prx) is a relatively recently discovered antioxidant enzyme family that scavenges peroxides and is known to be present in organisms from biological taxa ranging from bacteria to multicellular eukaryotes, including photosynthetic organisms. Although there have been many studies of the Prx family in higher plants, green algae, and cyanobacteria, few studies have concerned raphidophytes and dinoflagellates, which are among the eukaryotic algae that cause harmful algal blooms (HABs). In our proteomic study using 2-D electrophoresis, we found a highly expressed 2-Cys peroxiredoxin (2-CysPrx) in the raphidophyte Chattonella marina var. antiqua, a species that induces mass mortality of aquacultured fish. The abundance of the C. marina 2-CysPrx enzyme was highest in the exponential growth phase, during which photosynthetic activity was high, and it then decreased by about a factor of two during the late stationary growth phase. This pattern suggested that 2-CysPrx is a key enzyme involved in the maintenance of high photosynthesis activity. In addition, the fact that the depression of photosynthesis by excessively high irradiance was more severe in the 2-CysPrx low-expression strain (wild type) than in the normal-expression strain (wild type) of C. marina suggested that 2-CysPrx played a critical role in protecting the cell from oxidative stress caused by exposure to excessively high irradiance. In the field of HAB research, estimates of growth potential have been desired to predict the population dynamics of HABs for mitigating damage to fisheries. Therefore, omics approaches have recently begun to be applied to elucidate the physiology of the growth of HAB species. In this review, we describe the progress we have made using a molecular physiological approach to identify the roles of 2-CysPrx and other antioxidant enzymes in mitigating environmental stress associated with strong light and high temperatures and resultant oxidative stress. We also describe results of a survey of expressed Prx genes and their growth-phase-dependent behavior in C. marina using RNA-seq analysis. Finally, we speculate about the function of these genes and the ecological significance of 2-CysPrx, such as its involvement in circadian rhythms and the toxicity of C. marina to fish. Full article
(This article belongs to the Special Issue Peroxiredoxin)
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Review
Peroxiredoxins in Neurodegenerative Diseases
Antioxidants 2020, 9(12), 1203; https://doi.org/10.3390/antiox9121203 - 30 Nov 2020
Cited by 7 | Viewed by 925
Abstract
Substantial evidence indicates that oxidative/nitrosative stress contributes to the neurodegenerative diseases. Peroxiredoxins (PRDXs) are one of the enzymatic antioxidant mechanisms neutralizing reactive oxygen/nitrogen species. Since mammalian PRDXs were identified 30 years ago, their significance was long overshadowed by the other well-studied ROS/RNS defense [...] Read more.
Substantial evidence indicates that oxidative/nitrosative stress contributes to the neurodegenerative diseases. Peroxiredoxins (PRDXs) are one of the enzymatic antioxidant mechanisms neutralizing reactive oxygen/nitrogen species. Since mammalian PRDXs were identified 30 years ago, their significance was long overshadowed by the other well-studied ROS/RNS defense systems. An increasing number of studies suggests that these enzymes may be involved in the neurodegenerative process. This article reviews the current knowledge on the expression and putative roles of PRDXs in neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and dementia with Lewy bodies, multiple sclerosis, amyotrophic lateral sclerosis and Huntington’s disease. Full article
(This article belongs to the Special Issue Peroxiredoxin)
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Review
The Role of Hydrogen Peroxide and Peroxiredoxins throughout the Cell Cycle
Antioxidants 2020, 9(4), 280; https://doi.org/10.3390/antiox9040280 - 26 Mar 2020
Cited by 5 | Viewed by 2091
Abstract
Hydrogen peroxide (H2O2) is an oxidizing agent that induces cellular damage at inappropriate concentrations and gives rise to an arrest during cell cycle progression, causing cell death. Recent evidence indicates that H2O2 also acts as a [...] Read more.
Hydrogen peroxide (H2O2) is an oxidizing agent that induces cellular damage at inappropriate concentrations and gives rise to an arrest during cell cycle progression, causing cell death. Recent evidence indicates that H2O2 also acts as a promoter for cell cycle progression by oxidizing specific thiol proteins. The intracellular concentration of H2O2 is regulated tightly, enabling its use as a cellular signaling molecule while minimizing its potential to cause cellular damage. Peroxiredoxins (Prxs) have peroxidase activity toward H2O2, organic hydroperoxides, and peroxynitrite for protecting cells from oxidative stress. They are suggested to work as signaling mediators, allowing the local accumulation of H2O2 by inactivating their peroxidase activity uniquely compared with other antioxidant proteins such as catalase and glutathione peroxidase. Given that Prxs are highly sensitive to oxidation by H2O2, they act as sensors and transducers of H2O2 signaling via transferring their oxidation state to effector proteins. The concentrations of intracellular H2O2 increase as the cell cycle progresses from G1 to mitosis. Here, we summarize the roles of Prxs with regard to the regulation of cell cycle-dependent kinase activity and anaphase-promoting complex/cyclosome in terms of changes in H2O2 levels. Protection of the cell from unwanted progression of the cell cycle is suggested to be a role of Prx. We discuss the possible roles of Prxs to control H2O2 levels. Full article
(This article belongs to the Special Issue Peroxiredoxin)
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Review
Knockout Mouse Models for Peroxiredoxins
Antioxidants 2020, 9(2), 182; https://doi.org/10.3390/antiox9020182 - 22 Feb 2020
Cited by 10 | Viewed by 1616
Abstract
Peroxiredoxins (PRDXs) are members of a highly conserved peroxidase family and maintain intracellular reactive oxygen species (ROS) homeostasis. The family members are expressed in most organisms and involved in various biological processes, such as cellular protection against ROS, inflammation, carcinogenesis, atherosclerosis, heart diseases, [...] Read more.
Peroxiredoxins (PRDXs) are members of a highly conserved peroxidase family and maintain intracellular reactive oxygen species (ROS) homeostasis. The family members are expressed in most organisms and involved in various biological processes, such as cellular protection against ROS, inflammation, carcinogenesis, atherosclerosis, heart diseases, and metabolism. In mammals, six PRDX members have been identified and are subdivided into three subfamilies: typical 2-Cys (PRDX1, PRDX2, PRDX3, and PRDX4), atypical 2-Cys (PRDX5), and 1-Cys (PRDX6) subfamilies. Knockout mouse models of PRDXs have been developed to investigate their in vivo roles. This review presents an overview of the knockout mouse models of PRDXs with emphases on the biological and physiological changes of these model mice. Full article
(This article belongs to the Special Issue Peroxiredoxin)
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