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17 pages, 8915 KiB

Open AccessArticle

Mitochondrial Peroxiredoxin III Protects against Non-Alcoholic Fatty Liver Disease Caused by a Methionine-Choline Deficient Diet

by Jiyoung Park, Nam Hee Kim, Ho Jin Yi, Sue Goo Rhee and Hyun Ae Woo

Antioxidants 2023, 12(1), 9; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox12010009 - 21 Dec 2022

Viewed by 2032

Abstract

Non-alcoholic fatty liver disease (NAFLD) is emerging as the most common chronic liver disease worldwide. In addition, NAFLD may increase the risk of cardiovascular and liver-related diseases, and displays features of metabolic syndrome. In NAFLD, oxidative stress is primarily caused by excessive free [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is emerging as the most common chronic liver disease worldwide. In addition, NAFLD may increase the risk of cardiovascular and liver-related diseases, and displays features of metabolic syndrome. In NAFLD, oxidative stress is primarily caused by excessive free fatty acids. The oxidation of fatty acids is usually caused by β-oxidation of mitochondria under normal conditions, resulting in the production of energy. However, when the inflow of fatty acids in NAFLD becomes excessive, the β-oxidation of mitochondria becomes saturated and the oxidation process increases at sites including peroxisomes and microsomes, thereby increasing production of reactive oxygen species (ROS). Thus, hepatic mitochondrial ROS play an important role in the pathogenesis of NAFLD. Eliminating mitochondrial ROS may improve NAFLD, but the underlying mechanism remains unclear. We examined the effect of mitochondrial ROS on NAFLD by focusing on peroxiredoxin (Prx), an antioxidant protein that can remove hydrogen peroxide. The protective effect and pathological phenomenon of mitochondrial peroxiredoxin in methionine-choline deficient diet (MCD)-induced liver injury was assessed in a mouse model of NAFLD. In these mice, mitochondrial peroxiredoxin deficiency significantly increased hepatic steatosis and fibrosis. In addition, ablation of Prx III enhances susceptibility to MCD diet-induced oxidative stress and exacerbates NAFLD progression by promoting inflammation. The binding assay results also showed that Prx III-deficient mice had more severe liver damage than Prx III-abundant mice in MCD diet liver injury models. The present data suggest that mitochondrial peroxiredoxin III could be a therapeutic target for preventing and suppressing diet-induced NAFLD. Full article

(This article belongs to the Special Issue Physiological and Pathological Significance of Peroxiredoxins)

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15 pages, 2455 KiB

Open AccessArticle

Behavioral and Synaptic Phenotypes of Female Prdx6^−/− Mice

by Tanita Pairojana, Sarayut Phasuk, Pavithra Suresh and Ingrid Y. Liu

Antioxidants 2022, 11(6), 1201; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11061201 - 19 Jun 2022

Cited by 2 | Viewed by 2235

Abstract

Peroxiredoxin 6 (PRDX6) is expressed throughout the brain, including the hippocampus, where it plays a potential role in synaptic regulation and forming emotional and spatial memories. PRDX6 is predominantly detected in the female mouse’s hippocampus; thus, we investigate the effect of the Prdx6 [...] Read more.

Peroxiredoxin 6 (PRDX6) is expressed throughout the brain, including the hippocampus, where it plays a potential role in synaptic regulation and forming emotional and spatial memories. PRDX6 is predominantly detected in the female mouse’s hippocampus; thus, we investigate the effect of the Prdx6 gene on behavioral phenotypes and synaptic functions using female Prdx6 knockout (Prdx6^−/−) mice. Our results demonstrate that female Prdx6^−/− mice exhibited anxiety-like behavior, enhanced contextual fear memory, and impaired spatial memory. We also found increased, paired–pulse facilitation ratios, and decreased long-term potentiation (LTP) in the hippocampal region of these female Prdx6^−/− mice. The present study helps to understand better the PRDX6’s role in emotional response and spatial memory formation in female mice. Full article

(This article belongs to the Special Issue Physiological and Pathological Significance of Peroxiredoxins)

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19 pages, 2481 KiB

Open AccessArticle

Role of the Redox State of Human Peroxiredoxin-5 on Its TLR4-Activating DAMP Function

by Mégane A. Poncin, Pierre Van Meerbeeck, Joshua D. Simpson, André Clippe, François Tyckaert, Fabrice Bouillenne, Hervé Degand, André Matagne, Pierre Morsomme, Bernard Knoops and David Alsteens

Antioxidants 2021, 10(12), 1902; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10121902 - 27 Nov 2021

Cited by 5 | Viewed by 2671

Abstract

Human peroxiredoxin-5 (PRDX5) is a unique redox-sensitive protein that plays a dual role in brain ischemia-reperfusion injury. While intracellular PRDX5 has been reported to act as a neuroprotective antioxidative enzyme by scavenging peroxides, once released extracellularly from necrotic brain cells, the protein aggravates [...] Read more.

Human peroxiredoxin-5 (PRDX5) is a unique redox-sensitive protein that plays a dual role in brain ischemia-reperfusion injury. While intracellular PRDX5 has been reported to act as a neuroprotective antioxidative enzyme by scavenging peroxides, once released extracellularly from necrotic brain cells, the protein aggravates neural cell death by inducing expression of proinflammatory cytokines in macrophages through activation of Toll-like receptor (TLR) 2 (TLR2) and 4 (TLR4). Although recent evidence showed that PRDX5 was able to interact directly with TLR4, little is known regarding the role of the cysteine redox state of PRDX5 on its DAMP function. To gain insights into the role of PRDX5 redox-active cysteine residues in the TLR4-dependent proinflammatory activity of the protein, we used a recombinant human PRDX5 in the disulfide (oxidized) form and a mutant version lacking the peroxidatic cysteine, as well as chemically reduced and hyperoxidized PRDX5 proteins. We first analyzed the oxidation state and oligomerization profile by Western blot, mass spectrometry, and SEC-MALS. Using ELISA, we demonstrate that the disulfide bridge between the enzymatic cysteines is required to allow improved TLR4-dependent IL-8 secretion. Moreover, single-molecule force spectroscopy experiments revealed that TLR4 alone is not sufficient to discriminate the different PRDX5 redox forms. Finally, flow cytometry binding assays show that disulfide PRDX5 has a higher propensity to bind to the surface of living TLR4-expressing cells than the mutant protein. Taken together, these results demonstrate the importance of the redox state of PRDX5 cysteine residues on TLR4-induced inflammation. Full article

(This article belongs to the Special Issue Physiological and Pathological Significance of Peroxiredoxins)

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14 pages, 2541 KiB

Open AccessArticle

Physiological Functions of Thiol Peroxidases (Gpx1 and Prdx2) during Xenopus laevis Embryonic Development

by Hongchan Lee, Na Young Lee, Youni Kim, Hong-Seok Choi, Tayaba Ismail, Hong-Yeoul Ryu, Dong-Hyung Cho, Zae Young Ryoo, Dong-Seok Lee, Taeg Kyu Kwon, Tae Joo Park, Taejoon Kwon and Hyun-Shik Lee

Antioxidants 2021, 10(10), 1636; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10101636 - 17 Oct 2021

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Abstract

Glutathione peroxidase 1 (Gpx1) and peroxiredoxin 2 (Prdx2) belong to the thiol peroxidase family of antioxidants, and have been studied for their antioxidant functions and roles in cancers. However, the physiological significance of Gpx1 and Prdx2 during vertebrate embryogenesis are lacking. Currently, we [...] Read more.

Glutathione peroxidase 1 (Gpx1) and peroxiredoxin 2 (Prdx2) belong to the thiol peroxidase family of antioxidants, and have been studied for their antioxidant functions and roles in cancers. However, the physiological significance of Gpx1 and Prdx2 during vertebrate embryogenesis are lacking. Currently, we investigated the functional roles of Gpx1 and Prdx2 during vertebrate embryogenesis using Xenopus laevis as a vertebrate model. Our investigations revealed the zygotic nature of gpx1 having its localization in the eye region of developing embryos, whereas prdx2 exhibited a maternal nature and were localized in embryonic ventral blood islands. Furthermore, the gpx1-morphants exhibited malformed eyes with incompletely detached lenses. However, the depletion of prdx2 has not established its involvement with embryogenesis. A molecular analysis of gpx1-depleted embryos revealed the perturbed expression of a cryba1-lens-specific marker and also exhibited reactive oxygen species (ROS) accumulation in the eye regions of gpx1-morphants. Additionally, transcriptomics analysis of gpx1-knockout embryos demonstrated the involvement of Wnt, cadherin, and integrin signaling pathways in the development of malformed eyes. Conclusively, our findings indicate the association of gpx1 with a complex network of embryonic developmental pathways and ROS responses, but detailed investigation is a prerequisite in order to pinpoint the mechanistic details of these interactions. Full article

(This article belongs to the Special Issue Physiological and Pathological Significance of Peroxiredoxins)

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15 pages, 3308 KiB

Open AccessArticle

Peroxiredoxin 6 Knockout Mice Demonstrate Anxiety Behavior and Attenuated Contextual Fear Memory after Receiving Acute Immobilization Stress

by Sarayut Phasuk, Peeraporn Varinthra, Andaman Nitjapol, Korakod Bandasak and Ingrid Y. Liu

Antioxidants 2021, 10(9), 1416; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10091416 - 04 Sep 2021

Cited by 1 | Viewed by 2963

Abstract

Stress can elicit glucocorticoid release to promote coping mechanisms and influence learning and memory performance. Individual memory performance varies in response to stress, and the underlying mechanism is not clear yet. Peroxiredoxin 6 (PRDX6) is a multifunctional enzyme participating in both physiological and [...] Read more.

Stress can elicit glucocorticoid release to promote coping mechanisms and influence learning and memory performance. Individual memory performance varies in response to stress, and the underlying mechanism is not clear yet. Peroxiredoxin 6 (PRDX6) is a multifunctional enzyme participating in both physiological and pathological conditions. Several studies have demonstrated the correlation between PRDX6 expression level and stress-related disorders. Our recent finding indicates that lack of the Prdx6 gene leads to enhanced fear memory. However, it is unknown whether PRDX6 is involved in changes in anxiety response and memory performance upon stress. The present study reveals that hippocampal PRDX6 level is downregulated 30 min after acute immobilization stress (AIS) and trace fear conditioning (TFC). In human retinal pigment epithelium (ARPE-19) cells, the PRDX6 expression level decreases after being treated with stress hormone corticosterone. Lack of PRDX6 caused elevated basal H₂O₂ levels in the hippocampus, basolateral amygdala, and medial prefrontal cortex, brain regions involved in anxiety response and fear memory formation. Additionally, this H₂O₂ level was still high in the medial prefrontal cortex of the knockout mice under AIS. Anxiety behavior of Prdx6^−/− mice was enhanced after immobilization for 30 min. After exposure to AIS before a contextual test, Prdx6^−/− mice displayed a contextual fear memory deficit. Our results showed that the memory performance of Prdx6^−/− mice was impaired when responding to AIS, accompanied by dysregulated H₂O₂ levels. The present study helps better understand the function of PRDX6 in memory performance after acute stress. Full article

(This article belongs to the Special Issue Physiological and Pathological Significance of Peroxiredoxins)

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16 pages, 3731 KiB

Open AccessArticle

Genetic Inactivation of Peroxiredoxin-I Impairs the Growth of Human Pancreatic Cancer Cells

by Hajar Dahou, Marie-Albane Minati, Patrick Jacquemin and Mohamad Assi

Antioxidants 2021, 10(4), 570; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10040570 - 08 Apr 2021

Cited by 9 | Viewed by 2736

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with few therapeutic options. The identification of new promising targets is, therefore, an urgent need. Using available transcriptomic datasets, we first found that Peroxiredoxin-1 gene (PRDX1) expression was significantly increased in human pancreatic [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with few therapeutic options. The identification of new promising targets is, therefore, an urgent need. Using available transcriptomic datasets, we first found that Peroxiredoxin-1 gene (PRDX1) expression was significantly increased in human pancreatic tumors, but not in the other gastrointestinal cancers; its high expression correlated with shortened patient survival. We confirmed by immunostaining on mouse pancreata the increased Peroxiredoxin-I protein (PRX-I) expression in pancreatic neoplastic lesions and PDAC. To question the role of PRX-I in pancreatic cancer, we genetically inactivated its expression in multiple human PDAC cell lines, using siRNA and CRISPR/Cas9. In both strategies, PRX-I ablation led to reduced survival of PDAC cells. This was mainly due to an increase in the production of reactive oxygen species (ROS), accumulation of oxidative DNA damage (i.e., 8-oxoguanine), and cell cycle blockade at G2/M. Finally, we found that PRX-I ablation disrupts the autophagic flux in PDAC cells, which is essential for their survival. This proof-of-concept study supports a pro-oncogenic role for PRX-I in PDAC. Full article

(This article belongs to the Special Issue Physiological and Pathological Significance of Peroxiredoxins)

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Review

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30 pages, 1667 KiB

Open AccessReview

Peroxiredoxin 2: An Important Element of the Antioxidant Defense of the Erythrocyte

by Izabela Sadowska-Bartosz and Grzegorz Bartosz

Antioxidants 2023, 12(5), 1012; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox12051012 - 27 Apr 2023

Cited by 1 | Viewed by 1817

Abstract

Peroxiredoxin 2 (Prdx2) is the third most abundant erythrocyte protein. It was known previously as calpromotin since its binding to the membrane stimulates the calcium-dependent potassium channel. Prdx2 is present mostly in cytosol in the form of non-covalent dimers but may associate into [...] Read more.

Peroxiredoxin 2 (Prdx2) is the third most abundant erythrocyte protein. It was known previously as calpromotin since its binding to the membrane stimulates the calcium-dependent potassium channel. Prdx2 is present mostly in cytosol in the form of non-covalent dimers but may associate into doughnut-like decamers and other oligomers. Prdx2 reacts rapidly with hydrogen peroxide (k > 10⁷ M⁻¹ s⁻¹). It is the main erythrocyte antioxidant that removes hydrogen peroxide formed endogenously by hemoglobin autoxidation. Prdx2 also reduces other peroxides including lipid, urate, amino acid, and protein hydroperoxides and peroxynitrite. Oxidized Prdx2 can be reduced at the expense of thioredoxin but also of other thiols, especially glutathione. Further reactions of Prdx2 with oxidants lead to hyperoxidation (formation of sulfinyl or sulfonyl derivatives of the peroxidative cysteine). The sulfinyl derivative can be reduced by sulfiredoxin. Circadian oscillations in the level of hyperoxidation of erythrocyte Prdx2 were reported. The protein can be subject to post-translational modifications; some of them, such as phosphorylation, nitration, and acetylation, increase its activity. Prdx2 can also act as a chaperone for hemoglobin and erythrocyte membrane proteins, especially during the maturation of erythrocyte precursors. The extent of Prdx2 oxidation is increased in various diseases and can be an index of oxidative stress. Full article

(This article belongs to the Special Issue Physiological and Pathological Significance of Peroxiredoxins)

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15 pages, 2146 KiB

Open AccessReview

The Role of Peroxiredoxins in the Regulation of Sepsis

by Toshihiko Aki, Kana Unuma and Koichi Uemura

Antioxidants 2022, 11(1), 126; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11010126 - 06 Jan 2022

Cited by 4 | Viewed by 2375

Abstract

Oxidative stress, a result of a disturbance in redox homeostasis, is considered to be one of the main aggravating events in the pathogenesis of immune disorders. Peroxiredoxins (Prdxs) are an enzyme family that catalyzes the reduction of peroxides, including hydrogen peroxide, lipid peroxides, [...] Read more.

Oxidative stress, a result of a disturbance in redox homeostasis, is considered to be one of the main aggravating events in the pathogenesis of immune disorders. Peroxiredoxins (Prdxs) are an enzyme family that catalyzes the reduction of peroxides, including hydrogen peroxide, lipid peroxides, and nitrogen peroxides. Although the maintenance of cellular redox homeostasis through Prdxs is essential for surviving in adverse environments, Prdxs also participate in the regulation of cellular signal transduction by modulating the activities of a panel of molecules involved in the signal transduction process. Although Prdxs were discovered as intracellular anti-oxidative enzymes, recent research has revealed that Prdxs also play important roles in the extracellular milieu. Indeed, Prdxs have been shown to have the capacity to activate immune cells through ligation with innate immune receptors such as toll-like receptors (TLRs). In this review, we will summarize the intracellular as well as extracellular roles of Prdxs for and against the pathogenesis of inflammatory disorders including sepsis, hemorrhagic shock, and drug-induced liver injury. Full article

(This article belongs to the Special Issue Physiological and Pathological Significance of Peroxiredoxins)

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15 pages, 2749 KiB

Open AccessReview

Peroxiredoxins as Potential Targets for Cardiovascular Disease

by Se-Jin Jeong, Jong-Gil Park and Goo Taeg Oh

Antioxidants 2021, 10(8), 1244; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10081244 - 03 Aug 2021

Cited by 24 | Viewed by 3143

Abstract

Increased oxidative stress (OS) is considered a common etiology in the pathogenesis of cardiovascular disease (CVD). Therefore, the precise regulation of reactive oxygen species (ROS) in cardiovascular cells is essential to maintain normal physiological functions. Numerous regulators of cellular homeostasis are reportedly influenced [...] Read more.

Increased oxidative stress (OS) is considered a common etiology in the pathogenesis of cardiovascular disease (CVD). Therefore, the precise regulation of reactive oxygen species (ROS) in cardiovascular cells is essential to maintain normal physiological functions. Numerous regulators of cellular homeostasis are reportedly influenced by ROS. Hydrogen peroxide (H₂O₂), as an endogenous ROS in aerobic cells, is a toxic substance that can induce OS. However, many studies conducted over the past two decades have provided substantial evidence that H₂O₂ acts as a diffusible intracellular signaling messenger. Antioxidant enzymes, including superoxide dismutases, catalase, glutathione peroxidases, and peroxiredoxins (Prdxs), maintain the balance of ROS levels against augmentation of ROS production during the pathogenesis of CVD. Especially, Prdxs are regulatory sensors of transduced intracellular signals. The intracellular abundance of Prdxs that specifically react with H₂O₂ act as regulatory proteins. In this review, we focus on the role of Prdxs in the regulation of ROS-induced pathological changes in the development of CVD. Full article

(This article belongs to the Special Issue Physiological and Pathological Significance of Peroxiredoxins)

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