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1
Kim, Yosup, and Ho Hee Jang. "Role of Cytosolic 2-Cys Prx1 and Prx2 in Redox Signaling." Antioxidants 8, no. 6 (June 10, 2019): 169. http://dx.doi.org/10.3390/antiox8060169.
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Peroxiredoxins (Prxs), a family of peroxidases, are reactive oxygen species scavengers that hydrolyze H2O2 through catalytic cysteine. Mammalian Prxs comprise six isoforms (typical 2-Cys Prxs; Prx1–4, atypical 2-Cys Prx; Prx5, and 1-Cys Prx; Prx6) that are distributed over various cellular compartments as they are classified according to the position and number of conserved cysteine. 2-Cys Prx1 and Prx2 are abundant proteins that are ubiquitously expressed mainly in the cytosol, and over 90% of their amino acid sequences are homologous. Prx1 and Prx2 protect cells from ROS-mediated oxidative stress through the elimination of H2O2 and regulate cellular signaling through redox-dependent mechanism. In addition, Prx1 and Prx2 are able to bind to a diversity of interaction partners to regulate other various cellular processes in cancer (i.e., regulation of the protein redox status, cell growth, apoptosis, and tumorigenesis). Thus, Prx1 and Prx2 can be potential therapeutic targets and it is particularly important to control their level or activity. This review focuses on cytosolic 2-Cys Prx1 and Prx2 and their role in the regulation of redox signaling based on protein-protein interaction.
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Lankin, V. Z., M. G. Sharapov, R. G. Goncharov, A. K. Tikhaze, and V. I. Novoselov. "Natural dicarbonyls inhibit peroxidase activity of peroxiredoxins." Доклады Академии наук 485, no. 3 (May 21, 2019): 377–80. http://dx.doi.org/10.31857/s0869-56524853377-380.
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It has been established that the activity of recombinant human peroxiredoxins (Prx1, Prx2, Prx4 and Prx6) inhibits by natural dicarbonyls formed during free radical peroxidation of unsaturated lipids (malonic dialdehyde) and oxidative transformations of glucose (glyoxal, methylglyoxal). The possible role of peroxiredoxins activity decreasing under oxidative and carbonyl stress is discussed as an important factor that includes molecular mechanisms of vascular wall damage in atherosclerosis and diabetes mellitus.
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Chen, Jun, Dong-Nan Cui, Hidayat Ullah, Shuang Li, Fan Pan, Chao-Min Xu, Xiong-Bing Tu, and Ze-Hua Zhang. "The Function of LmPrx6 in Diapause Regulation in Locusta migratoria Through the Insulin Signaling Pathway." Insects 11, no. 11 (November 5, 2020): 763. http://dx.doi.org/10.3390/insects11110763.
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Peroxiredoxins (Prxs), which scavenge reactive oxygen species (ROS), are cysteine-dependent peroxide reductases that group into six structurally discernable classes: AhpC-Prx1, BCP-PrxQ, Prx5, Prx6, Tpx, and AhpE. A previous study showed that forkhead box protein O (FOXO) in the insulin signaling pathway (ISP) plays a vital role in regulating locust diapause by phosphorylation, which can be promoted by the high level of ROS. Furthermore, the analysis of transcriptome between diapause and non-diapause phenotypes showed that one of the Prxs, LmPrx6, which belongs to the Prx6 class, was involved. We presumed that LmPrx6 might play a critical role in diapause induction of Locusta migratoria and LmPrx6 may therefore provide a useful target of control methods based on RNA interference (RNAi). To verify our hypothesis, LmPrx6 was initially cloned from L. migratoria to make dsLmPrx6 and four important targets were tested, including protein-tyrosine phosphorylase 1B (LmPTP1B), insulin receptor (LmIR), RAC serine/threonine-protein kinase (LmAKT), and LmFOXO in ISP. When LmPrx6 was knocked down, the diapause rate was significantly reduced. The phosphorylation level of LmPTP1B significantly decreased while the phosphorylation levels of LmIR, LmAKT, and LmFOXO were significantly increased. Moreover, we identified the effect on two categories of genes downstream of LmFOXO, including stress tolerance and storage of energy reserves. Results showed that the mRNA levels of catalase and Mn superoxide dismutase (Mn-SOD), which enhanced stress tolerance, were significantly downregulated after silencing of LmPrx6. The mRNA levels of glycogen synthase and phosphoenolpyruvate carboxy kinase (PEPCK) that influence energy storage were also downregulated after knocking down of LmPrx6. The silencing of LmPrx6 indicates that this regulatory protein may probably be an ideal target for RNAi-based diapause control of L. migratoria.
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Otero-Losada, Matilde, Canepa L, Lucas Udovin, Tamara Kobiec, Nicolás Toro-Urrego, Kölliker-Frers Rodolfo A., and Francisco Capani. "Long-Term Effects of Hypoxia-Reoxygenation on Thioredoxins in Rat Central Nervous System." Current Pharmaceutical Design 25, no. 45 (January 10, 2020): 4791–98. http://dx.doi.org/10.2174/1381612825666191211111926.
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Background: Oxidative stress induced by the oxidative pathway dysregulation following ischemia/ reperfusion has been proposed as an important cause of neuronal death and brain damage. The proteins of the thioredoxin (Trx) family are crucial mediators of protein function regulating the intracellular hydrogen peroxide levels and redox-sensitive post-translational protein changes. Aim: To analyze the expression and distribution of fourteen members of the Trx family, potentially essential for the regeneration upon long-term brain damage, in a perinatal hypoxia-ischemia rat model induced by common carotid artery ligation. Methods: The right common carotid artery (CCA) was exposed by an incision on the right side of the neck, isolated from nerve and vein, and permanently ligated. Sham-surgery rats underwent right CCA surgical exposure but no ligation. Euthanasia was administered to all rats at 30, 60, and 90 days of age. Protein expression and distribution of fourteen members of the Trx family and related proteins (Grx1, Grx2, Grx3, Grx5, Prx1, Prx2, Prx3, Prx4, Prx5, Prx6, Trx1, Trx2, TrxR1, TrxR2) was examined in the most hypoxia susceptible rat brain areas, namely, cerebellum, corpus striatum, and the hippocampus. Results: The thioredoxin proteins displayed a complex, cell-type, and tissue-specific expression pattern following ischemia/reperfusion. Even 60 days after ischemia/reperfusion, Western blot analysis showed a persistent expression of Trx1 and Grx2 in several brain areas. Conclusion: The Trx family of proteins might contribute to long-term survival and recovery supporting their therapeutic use to curtail ischemic brain oxidative damage following an ischemia/reperfusion insult. Characterization of ischemia/reperfusion oxidative brain damage and analysis of the involved mechanisms are required to understand the underneath processes triggered by ischemia/reperfusion and to what extent and in what way thioredoxins contribute to recovery from brain hypoxic stress.
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Nelson, Kimberly J., Terri Messier, Stephanie Milczarek, Alexis Saaman, Stacie Beuschel, Uma Gandhi, Nicholas Heintz, Terrence L. Smalley, W. Todd Lowther, and Brian Cunniff. "Unique Cellular and Biochemical Features of Human Mitochondrial Peroxiredoxin 3 Establish the Molecular Basis for Its Specific Reaction with Thiostrepton." Antioxidants 10, no. 2 (January 20, 2021): 150. http://dx.doi.org/10.3390/antiox10020150.
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A central hallmark of tumorigenesis is metabolic alterations that increase mitochondrial reactive oxygen species (mROS). In response, cancer cells upregulate their antioxidant capacity and redox-responsive signaling pathways. A promising chemotherapeutic approach is to increase ROS to levels incompatible with tumor cell survival. Mitochondrial peroxiredoxin 3 (PRX3) plays a significant role in detoxifying hydrogen peroxide (H2O2). PRX3 is a molecular target of thiostrepton (TS), a natural product and FDA-approved antibiotic. TS inactivates PRX3 by covalently adducting its two catalytic cysteine residues and crosslinking the homodimer. Using cellular models of malignant mesothelioma, we show here that PRX3 expression and mROS levels in cells correlate with sensitivity to TS and that TS reacts selectively with PRX3 relative to other PRX isoforms. Using recombinant PRXs 1–5, we demonstrate that TS preferentially reacts with a reduced thiolate in the PRX3 dimer at mitochondrial pH. We also show that partially oxidized PRX3 fully dissociates to dimers, while partially oxidized PRX1 and PRX2 remain largely decameric. The ability of TS to react with engineered dimers of PRX1 and PRX2 at mitochondrial pH, but inefficiently with wild-type decameric protein at cytoplasmic pH, supports a novel mechanism of action and explains the specificity of TS for PRX3. Thus, the unique structure and propensity of PRX3 to form dimers contribute to its increased sensitivity to TS-mediated inactivation, making PRX3 a promising target for prooxidant cancer therapy.
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Forshaw, Tom E., Julie A. Reisz, Kimberly J. Nelson, Rajesh Gumpena, J. Reed Lawson, Thomas J. Jönsson, Hanzhi Wu, et al. "Specificity of Human Sulfiredoxin for Reductant and Peroxiredoxin Oligomeric State." Antioxidants 10, no. 6 (June 11, 2021): 946. http://dx.doi.org/10.3390/antiox10060946.
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Human peroxiredoxins (Prx) are a family of antioxidant enzymes involved in a myriad of cellular functions and diseases. During the reaction with peroxides (e.g., H2O2), the typical 2-Cys Prxs change oligomeric structure between higher order (do)decamers and disulfide-linked dimers, with the hyperoxidized inactive state (-SO2H) favoring the multimeric structure of the reduced enzyme. Here, we present a study on the structural requirements for the repair of hyperoxidized 2-Cys Prxs by human sulfiredoxin (Srx) and the relative efficacy of physiological reductants hydrogen sulfide (H2S) and glutathione (GSH) in this reaction. The crystal structure of the toroidal Prx1-Srx complex shows an extended active site interface. The loss of this interface within engineered Prx2 and Prx3 dimers yielded variants more resistant to hyperoxidation and repair by Srx. Finally, we reveal for the first time Prx isoform-dependent use of and potential cooperation between GSH and H2S in supporting Srx activity.
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Carvalho, Larissa A. C., Rodrigo G. Queijo, Alexandre L. B. Baccaro, Ádamo D. D. Siena, Wilson A. Silva, Tiago Rodrigues, and Silvya Stuchi Maria-Engler. "Redox-Related Proteins in Melanoma Progression." Antioxidants 11, no. 3 (February 22, 2022): 438. http://dx.doi.org/10.3390/antiox11030438.
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Melanoma is the most aggressive type of skin cancer. Despite the available therapies, the minimum residual disease is still refractory. Reactive oxygen and nitrogen species (ROS and RNS) play a dual role in melanoma, where redox imbalance is involved from initiation to metastasis and resistance. Redox proteins modulate the disease by controlling ROS/RNS levels in immune response, proliferation, invasion, and relapse. Chemotherapeutics such as BRAF and MEK inhibitors promote oxidative stress, but high ROS/RNS amounts with a robust antioxidant system allow cells to be adaptive and cooperate to non-toxic levels. These proteins could act as biomarkers and possible targets. By understanding the complex mechanisms involved in adaptation and searching for new targets to make cells more susceptible to treatment, the disease might be overcome. Therefore, exploring the role of redox-sensitive proteins and the modulation of redox homeostasis may provide clues to new therapies. This study analyzes information obtained from a public cohort of melanoma patients about the expression of redox-generating and detoxifying proteins in melanoma during the disease stages, genetic alterations, and overall patient survival status. According to our analysis, 66% of the isoforms presented differential expression on melanoma progression: NOS2, SOD1, NOX4, PRX3, PXDN and GPX1 are increased during melanoma progression, while CAT, GPX3, TXNIP, and PRX2 are decreased. Besides, the stage of the disease could influence the result as well. The levels of PRX1, PRX5 and PRX6 can be increased or decreased depending on the stage. We showed that all analyzed isoforms presented some genetic alteration on the gene, most of them (78%) for increased mRNA expression. Interestingly, 34% of all melanoma patients showed genetic alterations on TRX1, most for decreased mRNA expression. Additionally, 15% of the isoforms showed a significant reduction in overall patient survival status for an altered group (PRX3, PRX5, TR2, and GR) and the unaltered group (NOX4). Although no such specific antioxidant therapy is approved for melanoma yet, inhibitors or mimetics of these redox-sensitive proteins have achieved very promising results. We foresee that forthcoming investigations on the modulation of these proteins will bring significant advances for cancer therapy.
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Peskin, Alexander V., Nina Dickerhof, Rebecca A. Poynton, Louise N. Paton, Paul E. Pace, Mark B. Hampton, and Christine C. Winterbourn. "Hyperoxidation of Peroxiredoxins 2 and 3." Journal of Biological Chemistry 288, no. 20 (March 29, 2013): 14170–77. http://dx.doi.org/10.1074/jbc.m113.460881.
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Typical 2-Cys peroxiredoxins (Prxs) react rapidly with H2O2 to form a sulfenic acid, which then condenses with the resolving cysteine of the adjacent Prx in the homodimer or reacts with another H2O2 to become hyperoxidized. Hyperoxidation inactivates the Prx and is implicated in cell signaling. Prxs vary in susceptibility to hyperoxidation. We determined rate constants for disulfide formation and hyperoxidation for human recombinant Prx2 and Prx3 by analyzing the relative proportions of hyperoxidized and dimeric products using mass spectrometry as a function of H2O2 concentration (in the absence of reductive cycling) and in competition with catalase at a fixed concentration of H2O2. This gave a second order rate constant for hyperoxidation of 12,000 m−1 s−1 and a rate constant for disulfide formation of 2 s−1 for Prx2. A similar hyperoxidation rate constant for Prx3 was measured, but its rate of disulfide formation was ∼10-fold higher, making it is more resistant than Prx2 to hyperoxidation. There are two active sites within the homodimer, and at low H2O2 concentrations one site was hyperoxidized and the other present as a disulfide. Prx with two hyperoxidized sites formed progressively at higher H2O2 concentrations. Although the sulfenic acid forms of Prx2 and Prx3 are ∼1000-fold less reactive with H2O2 than their active site thiols, they react several orders of magnitude faster than most reduced thiol proteins. This observation has important implications for understanding the mechanism of peroxide sensing in cells.
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Suzuki, Yuichiro J., Lucia Marcocci, Takashi Shimomura, Yuki Tatenaka, Yuya Ohuchi, and Tinatin I. Brelidze. "Protein Redox State Monitoring Studies of Thiol Reactivity." Antioxidants 8, no. 5 (May 22, 2019): 143. http://dx.doi.org/10.3390/antiox8050143.
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Protein cysteine thiol status is a major determinant of oxidative stress and oxidant signaling. The -SulfoBiotics- Protein Redox State Monitoring Kit provides a unique opportunity to investigate protein thiol states. This system adds a 15-kDa Protein-SHifter to reduced cysteine residues, and this molecular mass shift can be detected by gel electrophoresis. Even in biological samples, Protein-SHifter Plus allows the thiol states of specific proteins to be studied using Western blotting. Peroxiredoxin 6 (Prx6) is a unique one-cysteine peroxiredoxin that scavenges peroxides by utilizing conserved Cysteine-47. Human Prx6 also contains an additional non-conserved cysteine residue, while rat Prx6 only has the catalytic cysteine. In cultured cells, cysteine residues of Prx6 were found to be predominantly fully reduced. The treatment of human cells with hydrogen peroxide (H2O2) formed Prx6 with one cysteine reduced. Since catalytic cysteine becomes oxidized in rat cells by the same H2O2 treatment and treating denatured human Prx6 with H2O2 results in the oxidation of both cysteines, non-conserved cysteine may not be accessible to H2O2 in human cells. We also found that untreated cells contained Prx6 multimers bound through disulfide bonds. Surprisingly, treating cells with H2O2 eliminated these Prx6 multimers. In contrast, treating cell lysates with H2O2 promoted the formation of Prx6 multimers. Similarly, treating purified preparations of the recombinant cyclic nucleotide-binding domain of the human hyperpolarization-activated cyclic nucleotide-modulated channels with H2O2 promoted the formation of multimers. These studies revealed that the cellular environment defines the susceptibility of protein cysteines to H2O2 and determines whether H2O2 acts as a facilitator or a disrupter of disulfide bonds.
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Aón Bertolino, Ma Laura, Christopher Horst Lillig, and Capani Francisco. "The Thioredoxin Family Proteins: Histopathological Time Course Study in the Asphyctic Male Rat Brain." Microscopy and Microanalysis 26, S1 (March 2020): 183–84. http://dx.doi.org/10.1017/s1431927620001130.
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Summary:Thioredoxin Family of proteins as Thioredoxin (Trxs), Glutaredoxins (Grxs) and Peroxiredoxins (Prxs) are one of the most important agents in the defense of oxidative stress and redox regulation. Perinatal asphyxia (AP) a disorder generated at the expense of the deficit of oxygen associated or not to ischemia, affects 5 to 10 of every 1,000 live births in developing country and is a serious health problem worldwide. Alterations in antioxidant protection systems are involved in the pathogenesis of hypoxic-ischemic insult and neuronal death. For these reasons it is proposed that the AP can cause changes in the distribution and expression of antioxidant proteins and enhance their deleterious or neuroprotective effects on the CNS. Methods: to determine the implication of the proteins role induced in the hypoxic brain injury, an animal model in vivo of PA was used in this work. In the first instance, the identification of the distribution of Trxs family proteins Trx1, Trx2, TrxR1, TrxR2, Txnip, Grx1, Grx2, Grx3, Grx5, γ-GCS, Prx1, Prx2, Prx3, Prx4, Prx5 and Prx6 was performed by immunohistochemistry on areas most sensitive to a hypoxia-ischemia insult: cerebellum, striatum, hippocampus, spinal cord, sustantia nigra, cortex and retina. Previous studies suggest that these proteins have an extensive and characteristic distribution in various cell types and regions of the CNS, although we observed significant differences in labeling intensity and distribution with conventional and fluorescence optical microscopy. After determining the cellular localization of Trxs, their behavior was studied by during a hypoxic- ischemic event by setting a time course at different times (2, 4, 6, 12, 24 and 72 hours post AP). Results: Trx1, Trx2, Grx1 and Grx2 proteins constitutes the main oxidoreductases in the cytosol and mitochondria, both in physiological and pathological conditions. Thus, for the short asphyxia times in which they were studied, Trx1 was detected with increased expression at 2 hours and up to 4 hours post-AP, arguing a probable neuroprotective effect, although not enough, if taken into account tissue liability and high levels of free radicals detected at initial hours and the presence of structural damage at 7 days post-AP. Trx2 shows its increase at 6 and 12 hours and Grx1 at 24 hours. For Grx2, values elicited with the ELISA technique in the initial time curve were not representative in their expression in the hippocampus, contrary to the findings in the distribution in the striatum, where Grx2 was observed to be increased. Although at 7 hours post-AP levels begin to decline, these redoxins appears to be essential in the initial response to injury. Conclusions: by demonstrating of the presence of these enzymes in different cell types and specific regions of the brain in rats subjected to AP provided us with important morphological evidence base to study later some of the molecular mechanisms involved in the pathogenesis of cerebral ischemia that will help to generate new therapeutic tools to mitigate a disease whose neurological complications have no definitive solution.
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Suzuki, Yuichiro J., Faisal Almansour, Camilla Cucinotta, Vladyslava Rybka, and Lucia Marcocci. "Cell signaling promoting protein carbonylation does not cause sulfhydryl oxidation: Implications to the mechanism of redox signaling." F1000Research 6 (April 10, 2017): 455. http://dx.doi.org/10.12688/f1000research.11296.1.
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Reactive oxygen species (ROS) have been recognized as second messengers, however, targeting mechanisms for ROS in cell signaling have not been defined. While ROS oxidizing protein cysteine thiols has been the most popular proposed mechanism, our laboratory proposed that ligand/receptor-mediated cell signaling involves protein carbonylation. Peroxiredoxin-6 (Prx6) is one protein that is carbonylated at 10 min after the platelet-derived growth factor (PDGF) stimulation of human pulmonary artery smooth muscle cells. In the present study, the SulfoBiotics Protein Redox State Monitoring Kit Plus (Dojindo Molecular Technologies) was used to test if cysteine residues of Prx6 are oxidized in response to the PDGF stimulation. Human Prx6 has a molecular weight of 25 kDa and contains two cysteine residues. The Dojindo system adds the 15 kDa Protein-SHifter if these cysteine residues are reduced in the cells. Results showed that, in untreated cells, the Prx6 molecule predominantly exhibited the 55 kDa band, indicating that both cysteine residues are reduced in the cells. Treatment of cells with 1 mM H2O2 caused the disappearance of the 55 kDa band and the appearance of a 40 kDa band, suggesting that the high concentration of H2O2 oxidized one of the two cysteine residues in the Prx6 molecule. By contrast, PDGF stimulation had no effects on the thiol status of the Prx6 molecule. We concluded that protein carbonylation is a more sensitive target of ROS during ligand/receptor-mediated cell signaling than sulfhydryl oxidation.
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VERMEIRE, J. J., and T. P. YOSHINO. "Antioxidant gene expression and function in in vitro-developing Schistosoma mansoni mother sporocysts: possible role in self-protection." Parasitology 134, no. 10 (April 20, 2007): 1369–78. http://dx.doi.org/10.1017/s0031182007002697.
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SUMMARYThe ability of the larval forms of Schistosoma mansoni to invade and parasitize their molluscan host, Biomphalaria glabrata, is determined by a multitude of factors. In this study we sought to elucidate the possible mechanisms by which the invading larvae are able to counteract the potentially harmful oxidative environment presented by the host upon initial miracidial infection. This was attempted by examining the gene expression profile of parasite antioxidant enzymes of the linked glutathione-(GSH) thioredoxin (Trx) redox pathway during early intramolluscan larval development. Three such enzymes, the peroxiredoxins (Prx1, Prx2 and Prx3) were examined as to their activity and sites of expression within S. mansoni miracidia and in vitro-cultured mother sporocysts. Results of these studies demonstrated that the H2O2-reducing enzymes Prx1 and 2 are upregulated during early mother sporocyst development compared to miracidia. Immunolocalization studies further indicated that Prx1 and Prx2 proteins are expressed within the apical papillae of miracidia and tegumental syncytium of sporocysts, and are released with parasite excretory-secretory proteins (ESP) during in vitro larval transformation. Removal of Prx1 and Prx2 from larval ESP by immunoabsorption significantly reduced the ability of ESP to breakdown exogenous H2O2, thereby directly linking ESP Prx proteins with H2O2-scavenging activity. Moreover, exposure of live sporocysts to exogenous H2O2 stimulated an upregulation of Prx1 and 2 gene expression suggesting the involvement of H2O2–responsive elements in regulating larval Prx gene expression. These data provide evidence that Prx1 and Prx2 may function in the protection of S. mansoni sporocysts during the early stages of infection.
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Suzuki, Yuichiro Justin. "Post-Translationally Regulated Protein Arginine-to-Proline Conversion in Alzheimer’s Brains." Life 12, no. 7 (June 28, 2022): 967. http://dx.doi.org/10.3390/life12070967.
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The current belief is that amino acid sequences in protein structures are defined by DNA sequences. I challenge this concept by hypothesizing that an arginine (Arg) residue in the protein structure can post-translationally be converted to a proline (Pro) residue through a redox mechanism. Reactive oxygen species promote the formation of protein carbonylation, particularly on Arg and Pro residues, which both produce glutamyl semialdehyde. Our previous studies suggested that the Pro-to-glutamyl semialdehyde reaction could be reversible in the biological system, thereby opening up a pathway for the conversion of Arg to glutamyl semialdehyde by oxidation, and subsequently, to Pro by reduction in the protein structure. Our mass spectrometry and immunoblotting experiments provided evidence of the occurrence of the Arg-to-Pro conversion at position 108 (R108P) of the peroxiredoxin 6 (Prx6) protein in biological tissues and cells. In the human brain, Prx6 (R108P) occurs, and some Alzheimer’s brains exhibit increased Prx6 (R108P) levels, while others show decreased levels, indicating the complexity of redox processes in the disease state. I propose that Prx6 (R108P), as well as other post-translationally regulated protein Arg-to-Pro conversions, occur in the human body and play physiological and pathological roles.
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Gordeeva, A. E., M. G. Sharapov, and V. I. Novoselov. "The effect of exogenous peroxiredoxin 6 on morphofunctional state of isolated rat kidney." Russian Journal of Transplantology and Artificial Organs 23, no. 3 (September 16, 2021): 122–33. http://dx.doi.org/10.15825/1995-1191-2021-3-122-133.
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Objective: to investigate the role of peroxiredoxin 6 (PRX6) in preserving the morphofunctional state of ischemic isolated kidney during perfusion.Materials and methods. The model of an isolated perfused rat kidney was used. Ischemia time was 5 and 20 minutes, perfusion was 50 minutes. To evaluate the effectiveness of PRX6 at different ischemia times, we used the conventional criteria of kidney function and histological methods.Results. During short warm ischemia times, exogenous PRX6 improves the morphofunctional state of an isolated kidney during perfusion. During this period, the main criteria for functioning of the isolated ischemic kidney reach acceptable values, renal parenchyma is without severe damage. By the end of perfusion, there was an increase in urine flow rate, glomerular filtration rate, fractional glucose reabsorption, urine urea concentration and proportion of primary urine from 1.5 to 2 times compared with the control lesion. At 20-minute ischemia, the isolated kidney can be recognized as non-viable according to the functioning criteria; the positive effect of PRX6 is leveled.Conclusion. The use of recombinant peroxiredoxin 6 for preserving the morphofunctional state of isolated kidneys can be an effective approach in preventing ischemia–reperfusion injury.
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Peskin, Alexander V., Andrew G. Cox, Péter Nagy, Philip E. Morgan, Mark B. Hampton, Michael J. Davies, and Christine C. Winterbourn. "Removal of amino acid, peptide and protein hydroperoxides by reaction with peroxiredoxins 2 and 3." Biochemical Journal 432, no. 2 (November 12, 2010): 313–21. http://dx.doi.org/10.1042/bj20101156.
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Prxs (peroxiredoxins) are a ubiquitous family of cysteine-dependent peroxidases that react rapidly with H2O2 and alkyl hydroperoxides and provide defence against these reactive oxidants. Hydroperoxides are also formed on amino acids and proteins during oxidative stress, and they too are a potential cause of biological damage. We have investigated whether Prxs react with amino acid, peptide and protein hydroperoxides, and whether the reactions are sufficiently rapid for these enzymes to provide antioxidant protection against these oxidants. Isolated Prx2, which is a cytosolic protein, and Prx3, which resides within mitochondria, were reacted with a selection of hydroperoxides generated by γ-radiolysis or singlet oxygen, on free amino acids, peptides and proteins. Reactions were followed by measuring the accumulation of disulfide-linked Prx dimers, via non-reducing SDS/PAGE, or the loss of the corresponding hydroperoxide, using quench-flow and LC (liquid chromatography)/MS. All the hydroperoxides induced rapid oxidation, with little difference in reactivity between Prx2 and Prx3. N-acetyl leucine hydroperoxides reacted with Prx2 with a rate constant of 4×104 M−1·s−1. Hydroperoxides present on leucine, isoleucine or tyrosine reacted at a comparable rate, whereas histidine hydroperoxides were ~10-fold less reactive. Hydroperoxides present on lysozyme and BSA reacted with rate constants of ~100 M−1·s−1. Addition of an uncharged derivative of leucine hydroperoxide to intact erythrocytes caused Prx2 oxidation with no concomitant loss in GSH, as did BSA hydroperoxide when added to concentrated erythrocyte lysate. Prxs are therefore favoured intracellular targets for peptide/protein hydroperoxides and have the potential to detoxify these species in vivo.
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Mitchell, J. M., D. M. Hicklin, P. M. Doughty, J. H. Hicklin, J. W. Dickert, S. M. Tolbert, R. Peterkova, and M. J. Kern. "The Prx1 Homeobox Gene is Critical for Molar Tooth Morphogenesis." Journal of Dental Research 85, no. 10 (October 2006): 888–93. http://dx.doi.org/10.1177/154405910608501003.
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The paired-related homeobox genes, Prx1 and Prx2, encode transcription factors critical for orofacial development. Prx1−/−/ Prx2−/− neonates have mandibular hypoplasia and malformed mandibular incisors. Although the mandibular incisor phenotype has been briefly described (ten Berge et al., 1998 , 2001 ; Lu et al., 1999 ), very little is known about the role of Prx proteins during tooth morphogenesis. Since the posterior mandibular region was relatively normal, we examined molar tooth development in Prx1−/−/ Prx2−/− embryos to determine whether the tooth malformation is primary to the loss of Prx protein or secondary to defects in surrounding tissues. Three-dimensional (3D) morphological reconstructions demonstrated that Prx1−/−/ Prx2−/− embryos had molar malformations, including cuspal changes and ectopic epithelial projections. Although we demonstrate that Prx1 protein is expressed only mesenchymally, 3D reconstructions showed important morphological defects in epithelial tissues at the cap and bell stages. Analysis of these data suggests that the Prx homeoproteins are critical for mesenchymal-epithelial signaling during tooth morphogenesis.
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Jeong, Yu Jeong, Young-Cheon Kim, June Seung Lee, Dong-Gwan Kim, and Jeong Hwan Lee. "Reduced Expression of PRX2/ATPRX1, PRX8, PRX35, and PRX73 Affects Cell Elongation, Vegetative Growth, and Vasculature Structures in Arabidopsis thaliana." Plants 11, no. 23 (December 2, 2022): 3353. http://dx.doi.org/10.3390/plants11233353.
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Class III peroxidases (PRXs) are involved in a broad spectrum of physiological and developmental processes throughout the life cycle of plants. However, the specific function of each PRX member in the family remains largely unknown. In this study, we selected four class III peroxidase genes (PRX2/ATPRX1, PRX8, PRX35, and PRX73) from a previous genome-wide transcriptome analysis, and performed phenotypic and morphological analyses, including histochemical staining, in PRX2RNAi, PRX8RNAi, PRX35RNAi, and PRX73RNAi plants. The reduced mRNA levels of corresponding PRX genes in PRX2RNAi, PRX8RNAi, PRX35RNAi, and PRX73RNAi seedlings resulted in elongated hypocotyls and roots, and slightly faster vegetative growth. To investigate internal structural changes in the vasculature, we performed histochemical staining, which revealed alterations in cell wall structures in the main vasculature of hypocotyls, stems, and roots of each PRXRNAi plant compared to wild-type (Col-0) plants. Furthermore, we found that PRX35RNAi plants displayed the decrease in the cell wall in vascular regions, which are involved in downregulation of lignin biosynthesis and biosynthesis-regulated genes’ expression. Taken together, these results indicated that the reduced expression levels of PRX2/ATPRX1, PRX8, PRX35, and PRX73 affected hypocotyl and root elongation, vegetative growth, and the vasculature structures in hypocotyl, stem, and root tissues, suggesting that the four class III PRX genes play roles in plant developmental processes.
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Gordeeva, Alina E., Ezhena A. Kurganova, and Vladimir I. Novoselov. "Effect of Peroxiredoxin 6 on Nephrons in the Early Reperfusion Period After Renal Ischemia in Rats." Journal of Medical and Biological Research, no. 1 (February 10, 2023): 75–85. http://dx.doi.org/10.37482/2687-1491-z130.
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Renal reperfusion injury develops rapidly after ischemia relief. It is with the onset of reperfusion that a cascade of pathological processes is launched, which means that measures to protect the kidney have to be taken as early as in this period. The aim of the paper was to study the effect of exogenous peroxiredoxin 6 (Prx6) on the morphofunctional state of nephrons in the initial reperfusion period following ischemia. Materials and methods. The right kidney of rats was subjected to 45-minute ischemia with prior left-sided nephrectomy and examined after 2, 5 and 24 hours of reperfusion. Exogenous Prx6 was administered intravenously 15 minutes before ischemia. Results. The research showed that nephrectomy has no effect on the morphology of a single kidney, but leads to an increase in urea and creatinine in the blood within 24 hours. We noted signs of morphological and functional damage to nephrons after 2 hours of reperfusion, which tend to increase in the course of 24 hours. In addition, we observed a rise in blood creatinine and urea concentrations, an increase in the areas of renal corpuscles, glomeruli, and Bowman’s capsule, as well as dystrophic changes in nephrocytes and an increase in the immunosignal area of the kidney injury molecule-1 (KIM-1). When exogenous Prx6 was used, we observed normalization of the size of nephron components, a decrease in KIM-1 immunosignal and an improvement in the kidney’s excretory function both in the early reperfusion period and after 24 hours. Thus, exogenous Prx6 reduces damage to nephrons during the early reperfusion period, which improves their compensatory and adaptive properties in ischemia-reperfusion injury.
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ten Berge, Derk, Antje Brouwer, Jeroen Korving, Mark J. Reijnen, Estia J. van Raaij, Fons Verbeek, William Gaffield, and Frits Meijlink. "Prx1andPrx2are upstream regulators of sonic hedgehog and control cell proliferation during mandibular arch morphogenesis." Development 128, no. 15 (August 1, 2001): 2929–38. http://dx.doi.org/10.1242/dev.128.15.2929.
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The aristaless-related homeobox genes Prx1 and Prx2 are required for correct skeletogenesis in many structures. Mice that lack both Prx1 and Prx2 functions display reduction or absence of skeletal elements in the skull, face, limbs and vertebral column. A striking phenotype is found in the lower jaw, which shows loss of midline structures, and the presence of a single, medially located incisor. We investigated development of the mandibular arch of Prx1−/−Prx2−/− mutants to obtain insight into the molecular basis of the lower jaw abnormalities. We observed in mutant embryos a local decrease in proliferation of mandibular arch mesenchyme in a medial area. Interestingly, in the oral epithelium adjacent to this mesenchyme, sonic hedgehog (Shh) expression was strongly reduced, indicative of a function for Prx genes in indirect regulation of Shh. Wild-type embryos that were exposed to the hedgehog-pathway inhibitor, jervine, partially phenocopied the lower jaw defects of Prx1−/−Prx2−/− mutants. In addition, this treatment led to loss of the mandibular incisors. We present a model that describes how loss of Shh expression in Prx1−/−Prx2−/− mutants leads to abnormal morphogenesis of the mandibular arch.
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Federti, Enrica, Alessandro Matte, Veronica Riccardi, Kevin Peikert, Seth L. Alper, Adrian Danek, Ruth H. Walker, et al. "Adaptative Up-Regulation of PRX2 and PRX5 Expression Characterizes Brain from a Mouse Model of Chorea-Acanthocytosis." Antioxidants 11, no. 1 (December 29, 2021): 76. http://dx.doi.org/10.3390/antiox11010076.
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The peroxiredoxins (PRXs) constitute a ubiquitous antioxidant. Growing evidence in neurodegenerative disorders such as Parkinson’s disease (PD) or Alzheimer’s disease (AD) has highlighted a crucial role for PRXs against neuro-oxidation. Chorea-acanthocytosis/Vps13A disease (ChAc) is a devastating, life-shortening disorder characterized by acanthocytosis, neurodegeneration and abnormal proteostasis. We recently developed a Vps13a−/− ChAc-mouse model, showing acanthocytosis, neurodegeneration and neuroinflammation which could be restored by LYN inactivation. Here, we show in our Vps13a−/− mice protein oxidation, NRF2 activation and upregulation of downstream cytoprotective systems NQO1, SRXN1 and TRXR in basal ganglia. This was associated with upregulation of PRX2/5 expression compared to wild-type mice. PRX2 expression was age-dependent in both mouse strains, whereas only Vps13a−/− PRX5 expression was increased independent of age. LYN deficiency or nilotinib-mediated LYN inhibition improved autophagy in Vps13a−/− mice. In Vps13a−/−; Lyn−/− basal ganglia, absence of LYN resulted in reduced NRF2 activation and down-regulated expression of PRX2/5, SRXN1 and TRXR. Nilotinib treatment of Vps13a−/− mice reduced basal ganglia oxidation, and plasma PRX5 levels, suggesting plasma PRX5 as a possible ChAc biomarker. Our data support initiation of therapeutic Lyn inhibition as promptly as possible after ChAc diagnosis to minimize development of irreversible neuronal damage during otherwise inevitable ChAc progression.
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Sauer, Uwe H., Yogesh Mishra, Michael Hall, Kwangho Nam, Stefan Jansson, and Wolfgang P. Schröder. "Dimeric cyanobacterial 1-Cys Prx6 is a moonlighting protein." Acta Crystallographica Section A Foundations and Advances 72, a1 (August 28, 2016): s247—s248. http://dx.doi.org/10.1107/s205327331609625x.
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ten Berge, D., A. Brouwer, J. Korving, J. F. Martin, and F. Meijlink. "Prx1 and Prx2 in skeletogenesis: roles in the craniofacial region, inner ear and limbs." Development 125, no. 19 (October 1, 1998): 3831–42. http://dx.doi.org/10.1242/dev.125.19.3831.
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Prx1 and Prx2 are closely related paired-class homeobox genes that are expressed in very similar patterns predominantly in mesenchyme. Prx1 loss-of-function mutants show skeletal defects in skull, limbs and vertebral column (Martin, J. F., Bradley, A. and Olson, E. N. (1995) Genes Dev. 9, 1237–1249). We report here that mice in which Prx2 is inactivated by a lacZ insertion had no skeletal defects, whereas Prx1/Prx2 double mutants showed many novel abnormalities in addition to an aggravation of the Prx1 single mutant phenotype. We found defects in external, middle and inner ear, reduction or loss of skull bones, a reduced and sometimes cleft mandible, and limb abnormalities including postaxial polydactyly and bent zeugopods. A single, or no incisor was present in the lower jaw, and ectopic expression of Fgf8 and Pax9 was found medially in the mandibular arch. A novel method to detect β-galactosidase activity in hydroxyethylmethacrylate sections allowed detailed analysis of Prx2 expression in affected structures. Our results suggest a role for Prx genes in mediating epitheliomesenchymal interactions in inner ear and lower jaw. In addition, Prx1 and Prx2 are involved in interactions between perichondrium and chondrocytes that regulate their proliferation or differentiation in the bones of the zeugopods.
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Wang, Mei-Jen, Hsin-Yi Huang, Tsung-Lang Chiu, Hui-Fen Chang, and Hsin-Rong Wu. "Peroxiredoxin 5 Silencing Sensitizes Dopaminergic Neuronal Cells to Rotenone via DNA Damage-Triggered ATM/p53/PUMA Signaling-Mediated Apoptosis." Cells 9, no. 1 (December 19, 2019): 22. http://dx.doi.org/10.3390/cells9010022.
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Peroxiredoxins (Prxs) are a family of thioredoxin peroxidases. Accumulating evidence suggests that changes in the expression of Prxs may be involved in neurodegenerative diseases pathology. However, the expression and function of Prxs in Parkinson’s disease (PD) remains unclear. Here, we showed that Prx5 was the most downregulated of the six Prx subtypes in dopaminergic (DA) neurons in rotenone-induced cellular and rat models of PD, suggesting possible roles in regulating their survival. Depletion of Prx5 sensitized SH-SY5Y DA neuronal cells to rotenone-induced apoptosis. The extent of mitochondrial membrane potential collapse, cytochrome c release, and caspase activation was increased by Prx5 loss. Furthermore, Prx5 knockdown enhanced the induction of PUMA by rotenone through a p53-dependent mechanism. Using RNA interference approaches, we demonstrated that the p53/PUMA signaling was essential for Prx5 silencing-exacerbated mitochondria-driven apoptosis. Additionally, downregulation of Prx5 augmented rotenone-induced DNA damage manifested as induction of phosphorylated histone H2AX (γ-H2AX) and activation of ataxia telangiectasia mutated (ATM) kinase. The pharmacological inactivation of ATM revealed that ATM was integral to p53 activation by DNA damage. These findings provided a novel link between Prx5 and DNA damage-triggered ATM/p53/PUMA signaling in a rotenone-induced PD model. Thus, Prx5 might play an important role in protection against rotenone-induced DA neurodegeneration.
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Stroobants, Sander, Inge Van Molle, Queen Saidi, Karl Jonckheere, Dominique Maes, and Eveline Peeters. "Structure of the Prx6-subfamily 1-Cys peroxiredoxin from Sulfolobus islandicus." Acta Crystallographica Section F Structural Biology Communications 75, no. 6 (May 13, 2019): 428–34. http://dx.doi.org/10.1107/s2053230x19006472.
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Aerobic thermoacidophilic archaea belonging to the genus Sulfolobus harbor peroxiredoxins, thiol-dependent peroxidases that assist in protecting the cells from oxidative damage. Here, the crystal structure of the 1-Cys peroxiredoxin from Sulfolobus islandicus, named 1-Cys SiPrx, is presented. A 2.75 Å resolution data set was collected from a crystal belonging to space group P212121, with unit-cell parameters a = 86.8, b = 159.1, c = 189.3 Å, α = β = γ = 90°. The structure was solved by molecular replacement using the homologous Aeropyrum pernix peroxiredoxin (ApPrx) structure as a search model. In the crystal structure, 1-Cys SiPrx assembles into a ring-shaped decamer composed of five homodimers. This quaternary structure corresponds to the oligomeric state of the protein in solution, as observed by size-exclusion chromatography. 1-Cys SiPrx harbors only a single cysteine, which is the peroxidatic cysteine, and lacks both of the cysteines that are highly conserved in the C-terminal arm domain in other archaeal Prx6-subfamily proteins such as ApPrx and that are involved in the association of dimers into higher-molecular-weight decamers and dodecamers. It is thus concluded that the Sulfolobus Prx6-subfamily protein undergoes decamerization independently of arm-domain cysteines.
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Wang, Xumei, Shaoxia Wang, Jinxin Wang, Hong Guo, Zhaopeng Dong, Lijuan Chai, Limin Hu, Yue Zhang, Hong Wang, and Lu Chen. "Neuroprotective Effect of Xueshuantong for Injection (Lyophilized) in Transient and Permanent Rat Cerebral Ischemia Model." Evidence-Based Complementary and Alternative Medicine 2015 (2015): 1–13. http://dx.doi.org/10.1155/2015/134685.
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Xueshuantong for Injection (Lyophilized) (XST), a Chinese Materia Medica standardized product extracted fromPanax notoginseng(Burk.), is used extensively for the treatment of cerebrovascular diseases such as acutely cerebral infarction clinically in China. In the present study, we evaluated the acute and extended protective effects of XST in different rat cerebral ischemic model and explored its effect on peroxiredoxin (Prx) 6-toll-like receptor (TLR) 4 signaling pathway. We found that XST treatment for 3 days could significantly inhibit transient middle cerebral artery occlusion (MCAO) induced infarct volume and swelling percent and regulate the mRNA expression of interleukin-1β(IL-1β), IL-17, IL-23p19, tumor necrosis factor-α(TNFα), and inducible nitric oxide synthase (iNOS) in brain. Further study demonstrated that treatment with XST suppressed the protein expression of peroxiredoxin (Prx) 6-toll-like receptor (TLR) 4 and phosphorylation level of p38 and upregulated the phosphorylation level of STAT3. In permanent MCAO rats, XST could reduce the infarct volume and swelling percent. Moreover, our results revealed that XST treatment could increase the rats’ weight and improve a batch of functional outcomes. In conclusion, the present data suggested that XST could protect against ischemia injury in transient and permanent MCAO rats, which might be related to Prx6-TLR4 pathway.
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Yang, Ye, Wenguang Cai, Junchao Wang, Weimin Pan, Lin Liu, Mingzhu Wang, and Min Zhang. "Crystal structure of Arabidopsis thaliana peroxiredoxin A C119S mutant." Acta Crystallographica Section F Structural Biology Communications 74, no. 10 (September 19, 2018): 625–31. http://dx.doi.org/10.1107/s2053230x18010920.
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Peroxiredoxins (Prxs), a large family of antioxidant enzymes, are abundant in all living organisms. Peroxiredoxin A (PrxA) from Arabidopsis thaliana belongs to the typical 2-Cys Prx family and is localized in the chloroplast. This article reports the crystal structure of a PrxA C119S mutant refined to 2.6 Å resolution. The protein exists as a decamer both in the crystal structure and in solution. The structure is in the reduced state suitable for the approach of peroxide, though conformational changes are needed for the resolving process.
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Phalen, Timothy J., Kelly Weirather, Paula B. Deming, Vikas Anathy, Alan K. Howe, Albert van der Vliet, Thomas J. Jönsson, Leslie B. Poole, and Nicholas H. Heintz. "Oxidation state governs structural transitions in peroxiredoxin II that correlate with cell cycle arrest and recovery." Journal of Cell Biology 175, no. 5 (December 4, 2006): 779–89. http://dx.doi.org/10.1083/jcb.200606005.
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Inactivation of eukaryotic 2-Cys peroxiredoxins (Prxs) by hyperoxidation has been proposed to promote accumulation of hydrogen peroxide (H2O2) for redox-dependent signaling events. We examined the oxidation and oligomeric states of PrxI and -II in epithelial cells during mitogenic signaling and in response to fluxes of H2O2. During normal mitogenic signaling, hyperoxidation of PrxI and -II was not detected. In contrast, H2O2-dependent cell cycle arrest was correlated with hyperoxidation of PrxII, which resulted in quantitative recruitment of ∼66- and ∼140-kD PrxII complexes into large filamentous oligomers. Expression of cyclin D1 and cell proliferation did not resume until PrxII-SO2H was reduced and native PrxII complexes were regenerated. Ectopic expression of PrxI or -II increased Prx-SO2H levels in response to oxidant exposure and failed to protect cells from arrest. We propose a model in which Prxs function as peroxide dosimeters in subcellular processes that involve redox cycling, with hyperoxidation controlling structural transitions that alert cells of perturbations in peroxide homeostasis.
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Ahn, Jinsook, Kyung Ku Jang, Inseong Jo, Hasan Nurhasni, Jong Gyu Lim, Jin-Wook Yoo, Sang Ho Choi, and Nam-Chul Ha. "Crystal structure of peroxiredoxin 3 from Vibrio vulnificus and its implications for scavenging peroxides and nitric oxide." IUCrJ 5, no. 1 (January 1, 2018): 82–92. http://dx.doi.org/10.1107/s205225251701750x.
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Peroxiredoxins (Prxs) are ubiquitous cysteine-based peroxidase enzymes. Recently, a new type of Prx, VvPrx3, was identified in the pathogenic bacterium Vibrio vulnificus as being important for survival in macrophages. It employs only one catalytic cysteine residue to decompose peroxides. Here, crystal structures of VvPrx3 representing its reduced and oxidized states have been determined, together with an H2O2-bound structure, at high resolution. The crystal structure representing the reduced Prx3 showed a typical dimeric interface, called the A-type interface. However, VvPrx3 forms an oligomeric interface mediated by a disulfide bond between two catalytic cysteine residues from two adjacent dimers, which differs from the doughnut-like oligomers that appear in most Prxs. Subsequent biochemical studies showed that this disulfide bond was induced by treatment with nitric oxide (NO) as well as with peroxides. Consistently, NO treatment induced expression of the prx3 gene in V. vulnificus, and VvPrx3 was crucial for the survival of bacteria in the presence of NO. Taken together, the function and mechanism of VvPrx3 in scavenging peroxides and NO stress via oligomerization are proposed. These findings contribute to the understanding of the diverse functions of Prxs during pathogenic processes at the molecular level.
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Turovsky, Egor A., Elena G. Varlamova, and Egor Y. Plotnikov. "Mechanisms Underlying the Protective Effect of the Peroxiredoxin-6 Are Mediated via the Protection of Astrocytes during Ischemia/Reoxygenation." International Journal of Molecular Sciences 22, no. 16 (August 16, 2021): 8805. http://dx.doi.org/10.3390/ijms22168805.
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Ischemia-like conditions reflect almost the entire spectrum of events that occur during cerebral ischemia, including the induction of oxidative stress, Ca2+ overload, glutamate excitotoxicity, and activation of necrosis and apoptosis in brain cells. Mechanisms for the protective effects of the antioxidant enzyme peroxiredoxin-6 (Prx-6) on hippocampal cells during oxygen-glucose deprivation/reoxygenation (OGD/R) were investigated. Using the methods of fluorescence microscopy, inhibitory analysis, vitality tests and PCR, it was shown that 24-h incubation of mixed hippocampal cell cultures with Prx-6 does not affect the generation of a reversible phase of a OGD-induced rise in Ca2+ ions in cytosol ([Ca2+]i), but inhibits a global increase in [Ca2+]i in astrocytes completely and in neurons by 70%. In addition, after 40 min of OGD, cell necrosis is suppressed, especially in the astrocyte population. This effect is associated with the complex action of Prx-6 on neuroglial networks. As an antioxidant, Prx-6 has a more pronounced and astrocyte-directed effect, compared to the exogenous antioxidant vitamin E (Vit E). Prx-6 inhibits ROS production in mitochondria by increasing the antioxidant capacity of cells and altering the expression of genes encoding redox status proteins. Due to the close bond between [Ca2+]i and intracellular ROS, this effect of Prx-6 is one of its protective mechanisms. Moreover, Prx-6 effectively suppresses not only necrosis, but also apoptosis during OGD and reoxygenation. Incubation with Prx-6 leads to activation of the basic expression of genes encoding protective kinases—PI3K, CaMKII, PKC, anti-apoptotic proteins—Stat3 and Bcl-2, while inhibiting the expression of signaling kinases and factors involved in apoptosis activation—Ikk, Src, NF-κb, Caspase-3, p53, Fas, etc. This effect on the basic expression of the genome leads to the cell preconditions, which is expressed in the inhibition of caspase-3 during OGD/reoxygenation. A significant effect of Prx-6 is directed on suppression of the level of pro-inflammatory cytokine IL-1β and factor TNFα, as well as genes encoding NMDA- and kainate receptor subunits, which was established for the first time for this antioxidant enzyme. The protective effect of Prx-6 is due to its antioxidant properties, since mutant Prx-6 (mutPrx-6, Prx6-C47S) leads to polar opposite effects, contributing to oxidative stress, activation of apoptosis and cell death through receptor action on TLR4.
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Park, Hee Jung, Ji Hye Jun, Jae Yeon Kim, Hye Jung Jang, Ja-Yun Lim, Si Hyun Bae, and Gi Jin Kim. "Phosphatase of Regenerating Liver-1 (PRL-1)-Overexpressing Placenta-Derived Mesenchymal Stem Cells Enhance Antioxidant Effects via Peroxiredoxin 3 in TAA-Injured Rat Livers." Antioxidants 12, no. 1 (December 26, 2022): 46. http://dx.doi.org/10.3390/antiox12010046.
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DNA damage repair is induced by several factors and is critical for cell survival, and many cellular DNA damage repair mechanisms are closely linked. Antioxidant enzymes that control cytokine-induced peroxide levels, such as peroxiredoxins (Prxs) and catalase (CAT), are involved in DNA repair systems. We previously demonstrated that placenta-derived mesenchymal stem cells (PD-MSCs) that overexpress PRL-1 (PRL-1(+)) promote liver regeneration via antioxidant effects in TAA-injured livers. However, the efficacy of these cells in regeneration and the role of Prxs in their DNA repair system have not been reported. Therefore, our objective was to analyze the Prx-based DNA repair mechanism in naïve or PRL-1(+)-transplanted TAA-injured rat livers. Apoptotic cell numbers were significantly decreased in the PRL-1(+) transplantation group versus the nontransplantation (NTx) group (p < 0.05). The expression of antioxidant markers was significantly increased in PRL-1(+) cells compared to NTx cells (p < 0.05). MitoSOX and Prx3 demonstrated a significant negative correlation coefficient (R2 = −0.8123). Furthermore, DNA damage marker levels were significantly decreased in PRL-1(+) cells compared to NTx cells (p < 0.05). In conclusion, increased Prx3 levels in PRL-1(+) cells result in an effective antioxidant effect in TAA-injured liver disease, and Prx3 is also involved in repairing damaged DNA.
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Mattè, Alessandro, Enrica Federti, Elena Tibaldi, Maria Luisa Di Paolo, Giovanni Bisello, Mariarita Bertoldi, Andrea Carpentieri, et al. "Tyrosine Phosphorylation Modulates Peroxiredoxin-2 Activity in Normal and Diseased Red Cells." Antioxidants 10, no. 2 (February 1, 2021): 206. http://dx.doi.org/10.3390/antiox10020206.
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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.
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Chuchue, Tatsanee, Weerachai Tanboon, Benjaphorn Prapagdee, James M. Dubbs, Paiboon Vattanaviboon, and Skorn Mongkolsuk. "ohrR and ohr Are the Primary Sensor/Regulator and Protective Genes against Organic Hydroperoxide Stress in Agrobacterium tumefaciens." Journal of Bacteriology 188, no. 3 (February 1, 2006): 842–51. http://dx.doi.org/10.1128/jb.188.3.842-851.2006.
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ABSTRACT The genes involved in organic hydroperoxide protection in Agrobacterium tumefaciens were functionally evaluated. Gene inactivation studies and functional analyses have identified ohr, encoding a thiol peroxidase, as the gene primarily responsible for organic hydroperoxide protection in A. tumefaciens. An ohr mutant was sensitive to organic hydroperoxide killing and had a reduced capacity to metabolize organic hydroperoxides. ohr is located next to, and is divergently transcribed from, ohrR, encoding a sensor and transcription regulator of organic hydroperoxide stress. Transcription of both ohr and ohrR was induced by exposure to organic hydroperoxides but not by exposure to other oxidants. This induction required functional ohrR. The results of gel mobility shift and DNase I footprinting assays with purified OhrR, combined with in vivo promoter deletion analyses, confirmed that OhrR regulated both ohrR and ohr by binding to a single OhrR binding box that overlapped the ohrR and ohr promoters. ohrR and ohr are both required for the establishment of a novel cumene hydroperoxide-induced adaptive response. Inactivation or overexpression of other Prx family genes (prx1, prx2, prx3, bcp1, and bcp2) did not affect either the resistance to, or the ability to degrade, organic hydroperoxide. Taken together, the results of biochemical, gene regulation and physiological studies support the role of ohrR and ohr as the primary system in sensing and protecting A. tumefaciens from organic hydroperoxide stress.
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Poynton, Rebecca A., Alexander V. Peskin, Alexina C. Haynes, W. Todd Lowther, Mark B. Hampton, and Christine C. Winterbourn. "Kinetic analysis of structural influences on the susceptibility of peroxiredoxins 2 and 3 to hyperoxidation." Biochemical Journal 473, no. 4 (February 9, 2016): 411–21. http://dx.doi.org/10.1042/bj20150572.
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The greater resistance of Prx3 than Prx2 to hyperoxidation is partly explained by differences in four C-terminal amino acids. In addition, only one active-site cysteine in the Prx3 homodimer is susceptible to hyperoxidation whereas both become hyperoxidized in Prx2.
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Lehtonen, Siri T., Piia M. H. Markkanen, Mirva Peltoniemi, Sang Won Kang, and Vuokko L. Kinnula. "Variable overoxidation of peroxiredoxins in human lung cells in severe oxidative stress." American Journal of Physiology-Lung Cellular and Molecular Physiology 288, no. 5 (May 2005): L997—L1001. http://dx.doi.org/10.1152/ajplung.00432.2004.
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Peroxiredoxins (Prxs) are a group of thiol containing proteins that participate both in signal transduction and in the breakdown of hydrogen peroxide (H2O2) during oxidative stress. Six distinct Prxs have been characterized in human cells (Prxs I–VI). Prxs I–IV form dimers held together by disulfide bonds, Prx V forms intramolecular bond, but the mechanism of Prx VI, so-called 1-Cys Prx, is still unclear. Here we describe the regulation of all six Prxs in cultured human lung A549 and BEAS-2B cells. The cells were exposed to variable concentrations of H2O2, menadione, tumor necrosis factor-α or transforming growth factor-β. To evoke glutathione depletion, the cells were furthermore treated with buthionine sulfoximine. Only high concentrations (300 μM) of H2O2 caused a minor increase (<28%, 4 h) in the expression of Prxs I, IV, and VI. Severe oxidant stress (250–500 μM H2O2) caused a significant increase in the proportion of the monomeric forms of Prxs I–IV; this was reversible at lower H2O2 concentrations (≤250 μM). This recovery of Prx overoxidation differed among the various Prxs; Prx I was recovered within 24 h, but recovery required 48 h for Prx III. Overall, Prxs are not significantly modulated by mild oxidant stress or cytokines, but there is variable, though reversible, overoxidation in these proteins during severe oxidant exposure.
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De Zoysa, Mahanama, Jae-Ho Ryu, Hee-Chung Chung, Cheol-Hee Kim, Chamilani Nikapitiya, Chulhong Oh, Hyowon Kim, K. Saranya Revathy, Ilson Whang, and Jehee Lee. "Molecular characterization, immune responses and DNA protection activity of rock bream (Oplegnathus fasciatus), peroxiredoxin 6 (Prx6)." Fish & Shellfish Immunology 33, no. 1 (July 2012): 28–35. http://dx.doi.org/10.1016/j.fsi.2012.03.029.
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Oliva, Karen, Gillian Barker, Gregory E. Rice, Mark J. Bailey, and Martha Lappas. "2D-DIGE to identify proteins associated with gestational diabetes in omental adipose tissue." Journal of Endocrinology 218, no. 2 (May 24, 2013): 165–78. http://dx.doi.org/10.1530/joe-13-0010.
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Gestational diabetes mellitus (GDM) is a significant risk factor for the type 2 diabetes epidemic in many populations. Maternal adipose tissue plays a central role in the pathophysiology of GDM. Thus, the aim of this study was to determine the effect of GDM on the proteome of adipose tissue. Omental adipose tissue was obtained at the time of term Caesarean section from women with normal glucose tolerance (NGT) or GDM. 2D-difference gel electrophoresis (DIGE), followed by mass spectrometry, was used to identify protein spots (n=6 patients per group). Western blotting was used for confirmation of six of the spot differences (n=6 patients per group). We found 14 proteins that were differentially expressed between NGT and GDM adipose tissue (≥1.4-fold,P<0.05). GDM was associated with an up-regulation of four proteins: collagen alpha-2(VI) chain (CO6A2 (COL6A2)), fibrinogen beta chain (FIBB (FGB)), lumican (LUM) and S100A9. On the other hand, a total of ten proteins were found to be down-regulated in adipose tissue from GDM women. These were alpha-1-antitrypsin (AIAT (SERPINA1)), annexin A5 (ANXA5), fatty acid-binding protein, adipocyte (FABP4), glutathione S-transferase P (GSTP (GSTP1)), heat-shock protein beta-1 (HSP27 (HSPB1)), lactate dehydrogenase B chain (LDHB), perilipin-1 (PLIN1), peroxiredoxin-6 (PRX6 (PRDX6)), selenium-binding protein 1 (SBP1) and vinculin (VINC (VCL)). In conclusion, proteomic analysis of omental fat reveals differential expression of several proteins in GDM patients and NGT pregnant women. This study revealed differences in expression of proteins that are involved in inflammation, lipid and glucose metabolism and oxidative stress and added further evidence to support the role of visceral adiposity in the pathogenesis of GDM.
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Cox, Andrew G., Andree G. Pearson, Juliet M. Pullar, Thomas J. Jönsson, W. Todd Lowther, Christine C. Winterbourn, and Mark B. Hampton. "Mitochondrial peroxiredoxin 3 is more resilient to hyperoxidation than cytoplasmic peroxiredoxins." Biochemical Journal 421, no. 1 (June 12, 2009): 51–58. http://dx.doi.org/10.1042/bj20090242.
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The Prxs (peroxiredoxins) are a family of cysteine-dependent peroxidases that decompose hydrogen peroxide. Prxs become hyperoxidized when a sulfenic acid formed during the catalytic cycle reacts with hydrogen peroxide. In the present study, Western blot methodology was developed to quantify hyperoxidation of individual 2-Cys Prxs in cells. It revealed that Prx 1 and 2 were hyperoxidized at lower doses of hydrogen peroxide than would be predicted from in vitro data, suggesting intracellular factors that promote hyperoxidation. In contrast, mitochondrial Prx 3 was considerably more resistant to hyperoxidation. The concentration of Prx 3 was estimated at 125 μM in the mitochondrial matrix of Jurkat T-lymphoma cells. Although the local cellular environment could influence susceptibility, purified Prx 3 was also more resistant to hyperoxidation, suggesting that despite having C-terminal motifs similar to sensitive eukaryote Prxs, other structural features must contribute to the innate resilience of Prx 3 to hyperoxidation.
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Feng, Yulong, Renhui Wei, Aiying Liu, Senmiao Fan, JinCan Che, Zhen Zhang, Baoming Tian, Youlu Yuan, Gongyao Shi, and Haihong Shang. "Genome-wide identification, evolution, expression, and alternative splicing profiles of peroxiredoxin genes in cotton." PeerJ 9 (January 18, 2021): e10685. http://dx.doi.org/10.7717/peerj.10685.
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Peroxiredoxin (PRX) is a ubiquitous thioredoxin-dependent peroxidase that can eliminate excessive free radicals produced by stress and protect cells from oxidative damage. PRXs are also involved in reactive oxygen species (ROS)- and redox-dependent signaling by performing redox interactions with other proteins and modify their redox status. At present, PRX family identification, evolution and regulation research has been conducted in some plants; however, systematic research about this family is lacking in cotton. In this study, a total of 44 PRXs were identified in the cotton genome. Phylogenetic and conserved active site analyses showed that the PRXs were divided into six subfamilies according to the conserved site (PxxxTxxC…S…W/F) and conserved cysteinyl residues positions. Segmental duplication and polyploid events were the main methods for PRX family expansion, and the PRXs of diploid G. arboreum were the donors of PRXs in the D subgenomes of allotetraploid G. hirsutum and G. barbadense during the evolution of the PRX family. qRT-PCR analysis confirmed that cis-acting elements play important roles in regulating the expression of PRXs. Alternative splicing events occurred in GhPRX14-D that can increased the complexity of transcripts in G. hirsutum. Subcellular localization showed that most PRX members were located in chloroplasts, the cytoplasmic membrane and the nucleus. Our results provide systematic support for a better understanding of PRXs in cotton and a starting point for further studies of the specific functions of PRXs in cotton.
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Haapasalo, Toomas, Kristiina Nordfors, Sally Järvelä, Eloise Kok, Pauli Sallinen, Vuokko L. Kinnula, Hannu Kalervo Haapasalo, and Ylermi Soini. "Peroxiredoxins and their expression in ependymomas." Journal of Clinical Pathology 66, no. 1 (October 16, 2012): 12–17. http://dx.doi.org/10.1136/jclinpath-2012-201048.
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AimsPeroxiredoxins I–VI (Prxs) have recently been shown to have a role in the tumorigenesis of astrocytic brain tumours. In some tumour types they are associated with Nrf2 (transcription factor NF-E2-related factor), a sensor of oxidative stress, and DJ-1 (also known as PARK7), a protein known to stabilise Nrf2.MethodsWe investigated the immunohistochemical expression of Prxs I–VI, Nrf2 and DJ-1 in a total of 76 ependymomas and their relationship with clinicopathological features of these tumours.ResultsThere was a significant expression of all Prxs except Prx IV in the ependymomas. Strong nuclear and cytoplasmic expression of Nrf2 could be detected in these tumours. Prx I expression was significantly associated with cytoplasmic and nuclear Nrf2 expression. Prx I expression was also associated with tumour site, with cerebellar ependymomas having a lower expression of Prx I than other tumours. DJ-1 did not associate with Prxs but nuclear DJ-1 had an inverse association with nuclear Nrf2. Cytoplasmic DJ-1 associated with worse survival in ependymoma patients.ConclusionsThis study indicates that oxidative mechanisms as reflected by Nrf2 expression are highly activated in ependymomas. Prxs, especially Prx I, were associated with Nrf2 expression, suggesting a role for Nrf2 in Prx I synthesis in ependymomas. While DJ-1 did not associate with any of the Prxs, its expression was associated with worsened patient survival and could have a role as a prognostic marker in ependymomas.
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Tamura, Atsushi, Asato Tonegawa, Yoshinori Arisaka, and Nobuhiko Yui. "Versatile synthesis of end-reactive polyrotaxanes applicable to fabrication of supramolecular biomaterials." Beilstein Journal of Organic Chemistry 12 (December 28, 2016): 2883–92. http://dx.doi.org/10.3762/bjoc.12.287.
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Cyclodextrin (CD)-threaded polyrotaxanes (PRXs) with reactive functional groups at the terminals of the axle polymers are attractive candidates for the design of supramolecular materials. Herein, we describe a novel and simple synthetic method for end-reactive PRXs using bis(2-amino-3-phenylpropyl) poly(ethylene glycol) (PEG-Ph-NH2) as an axle polymer and commercially available 4-substituted benzoic acids as capping reagents. The terminal 2-amino-3-phenylpropyl groups of PEG-Ph-NH2 block the dethreading of the α-CDs after capping with 4-substituted benzoic acids. By this method, two series of azide group-terminated polyrotaxanes (benzylazide: PRX-Bn-N3, phenylazide: PRX-Ph-N3,) were synthesized for functionalization via click reactions. The PRX-Bn-N3 and PRX-Ph-N3 reacted quickly and efficiently with p-(tert-butyl)phenylacetylene via copper-catalyzed click reactions. Additionally, the terminal azide groups of the PRX-Bn-N3 could be modified with dibenzylcyclooctyne (DBCO)-conjugated fluorescent molecules via a copper-free click reaction; this fluorescently labeled PRX was utilized for intracellular fluorescence imaging. The method of synthesizing end-reactive PRXs described herein is simple and versatile for the design of diverse functional PRXs and can be applied to the fabrication of PRX-based supramolecular biomaterials.
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Trstenjak Prebanda, Mojca, Petra Matjan-Štefin, Boris Turk, and Nataša Kopitar-Jerala. "Altered Expression of Peroxiredoxins in Mouse Model of Progressive Myoclonus Epilepsy upon LPS-Induced Neuroinflammation." Antioxidants 10, no. 3 (February 27, 2021): 357. http://dx.doi.org/10.3390/antiox10030357.
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Stefin B (cystatin B) is an inhibitor of endo-lysosomal cysteine cathepsin, and the loss-of-function mutations in the stefin B gene were reported in patients with Unverricht–Lundborg disease (EPM1), a form of progressive myoclonus epilepsy. Stefin B-deficient mice, a mouse model of the disease, display key features of EPM1, including myoclonic seizures. Although the underlying mechanism is not yet completely clear, it was reported that the impaired redox homeostasis and inflammation in the brain contribute to the progression of the disease. In the present study, we investigated if lipopolysaccharide (LPS)-triggered neuroinflammation affected the protein levels of redox-sensitive proteins: thioredoxin (Trx1), thioredoxin reductase (TrxR), peroxiredoxins (Prxs) in brain and cerebella of stefin B-deficient mice. LPS challenge was found to result in a marked elevation of Trx1 and TrxR in the brain and cerebella of stefin B deficient mice, while Prx1 was upregulated only in cerebella after LPS challenge. Mitochondrial peroxiredoxin 3 (Prx3), was upregulated also in the cerebellar tissue lysates prepared from unchallenged stefin B deficient mice, while after LPS challenge Prx3 was upregulated in stefin B deficient brain and cerebella. Our results imply the role of oxidative stress in the progression of the disease.
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Yoo, Eun-Sun, Yeung-Chul Mun, Jee-Young Ahn, Jung-Won Huh, and Chu-Myong Seong. "Prx II(Peroxiredoxin II) Activity Has Important Roles As a New Mechanism to Control ABL Tyrosine Kinase Activity in STIs(Signal Transduction Inhibitor) Treated CML Patients." Blood 128, no. 22 (December 2, 2016): 5431. http://dx.doi.org/10.1182/blood.v128.22.5431.5431.
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Abstract Purpose: In this study, we investigated the roles of PRX II, one of 3 critical peroxidases besides catalase and GPXs, in CML primary cells at diagnosis and remission while patients were treated with STI(Signal Transduction Inhibitor) and tested the same roles in Imatinib(IM) sensitive Ph+ cell lines and resistant cell lines as well. Methods: Newly diagnosed CML cells, IM resistant K562 cells and parental K562 cells were treated STIs and analyzed western blot assay to detect BCR-ABL, phosphorylated BCR-ABL and PRX2 protein expression level. We added N-Acetylcysteine (0-5mM, 6hr) to K562 cells to show antioxidant effect of imatinib and analyzed DCF-DA detection for intracellular ROS level and western blot for PRX2 protein level. MTT assay was performed to detect cell death by NAC time-dependent treatment of 5mM NAC(0, 24, 40, 48hr). Imatinib resistant K562 cells were established by treatment of gradual increment of imatinib. We also repeatedly investigated the effects of IM therapy using PRXII overexpressed K562 cells by transfection. Results: At diagnosis of CML, ROS level was elevated and PRX II was either absent or significantly suppressed. As Ph chromosomes were decreased with STIs, suppressed or absent PRXs levels were restored to the level of normal individuals. These findings were also inversely correlated with the level of Ph chromosomes in the cases of disease progression and re-remission with further treatment. When STI were treated in Ph positive cell line, we found deceased cell survival and ROS level by MTT assay and DCF-DA methods respectively, but elevated PRX II by western blot. By the treatment of NAC into Ph+ cell lines, the level of DCF-DA was decreased and MTT level was down, but PRX II level was elevated. Interestingly, the level of BCR-ABL oncogene were decreased in PRX II tranfected cells. Meanwhile, we observed that PRX II restoration was mild or weak in Imatinib resistant K-562, which we established in our lab. Conclusions: The importance of the roles of ROS and its PRX II, antioxydant enzymes in CML is further extablished by our work. Our finding may contribute to find a new pathway on which TKIs are working besides the mechanisms of ATP binding competitively, blocking the binding of ABL-BCR kinase and substract resulting apoptosis of Ph+ cells. Furthermore, our finding may be useful to overcome the STIs resistant CML in the clinics. Disclosures No relevant conflicts of interest to declare.
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Huang, Suhua, Mingxia Lin, Xiaowei Pan, Qiwen Tan, and Kai-Leng Tan. "The potential of MLC901 (NeuroAiD II™), a traditional Chinese medicine." Neuroscience Research Notes 2, no. 2 (May 22, 2019): 18–24. http://dx.doi.org/10.31117/neuroscirn.v2i2.32.
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Stroke, also known as cerebral ischemia, is a common neurological disease. The therapeutic potential of MLC901 (NeuroAiD II™) has been reported in clinical trials on traumatic brain injury as well as in animal and cell models. MLC901 reduced the infarction size, ischemia-induced neurological deficits and pro-inflammatory infiltration of phagocyte. It also inhibited the ischemia-induced expression of pro-inflammatory mediators and Prx6, TLR4 signalling, and phosphorylation of NFκB. We found that the beneficial effects of MLC901 are in coherent with studies performed on the individual active ingredient. MLC901 may develop its efficacy through a synergistic effect via nine herbal extracts. MLC901 is a multifaceted traditional Chinese medicine. A cocktail of herbs provides a broader spectrum of targets. This may surpass single-target drug treatment in terms of side effect and therapeutic efficacy. MLC901 leads to various potential research directions on the development or improvement of a feasible, effective and promising herbal formulation for treating stroke patients.
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Huang, Hongwen, Fenny Dane, and Joseph D. Norton. "232 LINKAGE RELATIONSHIPS OF ISOZYME AND MORPHOLOGICAL MARKERS IN INTERSPECIFIC CROSSES OF CHESTNUT." HortScience 29, no. 5 (May 1994): 462f—462. http://dx.doi.org/10.21273/hortsci.29.5.462f.
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Linkage relations among eight isozyme genes, Acp-3, Est-1, Est-5, Prx-1, Prx-2, Prx-3, Me and Adh, and two morphological markers, Inh, and Twh, were investigated in one F2 and two BC1 families of interspecific crosses between the American chestnut (Castanea dentata) and the Chinese chestnut (C. mollissima). Inh was found to be consistently linked with Prx-1 and Est-5 in all families. The order of these three genes was determined to be-Ihn--Prx1--Est5. In addition, four other gene pairs, Acp3--Inh, Acp3--Prx1, Me--Inh and Twh--Inh were found to be linked in one of the three families investigated. The four isozyme genes and two morphological marker genes were tentatively integrated into one linkage group with the following gene order Acp3--Me--Twh--Inh--Prx1-Est5. This study demonstrated that isozyme genes can be integrated with morphological marker genes into a single linkage map without the need for additional crosses.
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Cox, Andrew G., Christine C. Winterbourn, and Mark B. Hampton. "Mitochondrial peroxiredoxin involvement in antioxidant defence and redox signalling." Biochemical Journal 425, no. 2 (December 23, 2009): 313–25. http://dx.doi.org/10.1042/bj20091541.
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Prxs (peroxiredoxins) are a family of proteins that are extremely effective at scavenging peroxides. The Prxs exhibit a number of intriguing properties that distinguish them from conventional antioxidants, including a susceptibility to inactivation by hyperoxidation in the presence of excess peroxide and the ability to form complex oligomeric structures. These properties, combined with a high cellular abundance and reactivity with hydrogen peroxide, have led to speculation that the Prxs function as redox sensors that transmit signals as part of the cellular response to oxidative stress. Multicellular organisms express several different Prxs that can be categorized by their subcellular distribution. In mammals, Prx 3 and Prx 5 are targeted to the mitochondrial matrix. Mitochondria are a major source of hydrogen peroxide, and this oxidant is implicated in the damage associated with aging and a number of pathologies. Hydrogen peroxide can also act as a second messenger, and is linked with signalling events in mitochondria, including the induction of apoptosis. A simple kinetic competition analysis estimates that Prx 3 will be the target for up to 90% of hydrogen peroxide generated in the matrix. Therefore, mitochondrial Prxs have the potential to play a major role in mitochondrial redox signalling, but the extent of this role and the mechanisms involved are currently unclear.
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Godoy, José R., Sarah Pittrich, Svetlana Slavic, Christopher Horst Lillig, Eva-Maria Hanschmann, and Reinhold G. Erben. "Thioredoxin 1 is upregulated in the bone and bone marrow following experimental myocardial infarction: evidence for a remote organ response." Histochemistry and Cell Biology 155, no. 1 (November 8, 2020): 89–99. http://dx.doi.org/10.1007/s00418-020-01939-w.
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AbstractIschemia and reperfusion events, such as myocardial infarction (MI), are reported to induce remote organ damage severely compromising patient outcomes. Tissue survival and functional restoration relies on the activation of endogenous redox regulatory systems such as the oxidoreductases of the thioredoxin (Trx) family. Trxs and peroxiredoxins (Prxs) are essential for the redox regulation of protein thiol groups and for the reduction of hydrogen peroxide, respectively. Here, we determined whether experimental MI induces changes in Trxs and Prxs in the heart as well as in secondary organs. Levels and localization of Trx1, TrxR1, Trx2, Prx1, and Prx2 were analyzed in the femur, vertebrae, and kidneys of rats following MI or sham surgery. Trx1 levels were significantly increased in the heart (P = 0.0017) and femur (P < 0.0001) of MI animals. In the femur and lumbar vertebrae, Trx1 upregulation was detected in bone-lining cells, osteoblasts, megakaryocytes, and other hematopoietic cells. Serum levels of Trx1 increased significantly 2 days after MI compared to sham animals (P = 0.0085). Differential regulation of Trx1 in the bone was also detected by immunohistochemistry 1 month after MI. N-Acetyl-cysteine treatment over a period of 1 month induced a significant reduction of Trx1 levels in the bone of MI rats compared to sham and to MI vehicle. This study provides first evidence that MI induces remote organ upregulation of the redox protein Trx1 in the bone, as a response to ischemia–reperfusion injury in the heart.
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Hu, Chengyun, Feibiao Dai, Jiawu Wang, Lai Jiang, Di Wang, Jie Gao, Jun Huang, et al. "Peroxiredoxin-5 Knockdown Accelerates Pressure Overload-Induced Cardiac Hypertrophy in Mice." Oxidative Medicine and Cellular Longevity 2022 (January 29, 2022): 1–12. http://dx.doi.org/10.1155/2022/5067544.
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A recent study showed that peroxiredoxins (Prxs) play an important role in the development of pathological cardiac hypertrophy. However, the involvement of Prx5 in cardiac hypertrophy remains unclear. Therefore, this study is aimed at investigating the role and mechanisms of Prx5 in pathological cardiac hypertrophy and dysfunction. Transverse aortic constriction (TAC) surgery was performed to establish a pressure overload-induced cardiac hypertrophy model. In this study, we found that Prx5 expression was upregulated in hypertrophic hearts and cardiomyocytes. In addition, Prx5 knockdown accelerated pressure overload-induced cardiac hypertrophy and dysfunction in mice by activating oxidative stress and cardiomyocyte apoptosis. Importantly, heart deterioration caused by Prx5 knockdown was related to mitogen-activated protein kinase (MAPK) pathway activation. These findings suggest that Prx5 could be a novel target for treating cardiac hypertrophy and heart failure.
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Ow, Suet-Hui, Pei-Jou Chua, and Boon-Huat Bay. "Epigenetic regulation of peroxiredoxins: Implications in the pathogenesis of cancer." Experimental Biology and Medicine 242, no. 2 (October 4, 2016): 140–47. http://dx.doi.org/10.1177/1535370216669834.
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Peroxiredoxin I to VI (PRX I–VI), a family of highly conserved antioxidants, has been implicated in numerous diseases. There have been reports that PRXs are expressed aberrantly in a variety of tumors, implying that they could play an important role in carcinogenesis. Epigenetic mechanisms such as DNA methylation, histone modifications, and microRNAs have been reported to modulate expression of PRXs. In addition, the use of epigenetic regulators, such as histone deacetylases, has been demonstrated to restore PRX to normal levels, indicating that the reversible nature of epigenetics can be exploited for future treatments.
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Nguyen Huu, Thang, Jiyoung Park, Ying Zhang, Iha Park, Hyun Joong Yoon, Hyun Ae Woo, and Seung-Rock Lee. "Redox Regulation of PTEN by Peroxiredoxins." Antioxidants 10, no. 2 (February 16, 2021): 302. http://dx.doi.org/10.3390/antiox10020302.
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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.
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Pace, Paul E., Alexander V. Peskin, Min-Hi Han, Mark B. Hampton, and Christine C. Winterbourn. "Hyperoxidized peroxiredoxin 2 interacts with the protein disulfide- isomerase ERp46." Biochemical Journal 453, no. 3 (July 12, 2013): 475–85. http://dx.doi.org/10.1042/bj20130030.
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Prx (peroxiredoxin) 2 protects cells from deleterious oxidative damage. It catalyses the breakdown of hydroperoxides through a highly reactive cysteine residue and has been linked to chaperone activity that promotes cell survival under conditions of oxidative stress. It may also be involved in redox signalling by binding to other proteins. In the present study we have searched for binding partners of Prx2 in H2O2-treated Jurkat and human umbilical vein endothelial cells and discovered that the hyperoxidized form selectively co-precipitated with the protein disulfide-isomerase ERp46. Mutant analyses revealed that loss of the peroxidative cysteine residue of Prx2 also facilitated complex formation with ERp46, even without H2O2 treatment, whereas the resolving cysteine residue of Prx2 was indispensible for the interaction to occur. The complex involved a stable non-covalent interaction that was disassociated by the reduction of intramolecular disulfides in ERp46, or by disruption of the decameric structure of hyperoxidized Prx2. This is the first example of a protein interaction dependent on the hyperoxidized status of a Prx.