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Glutathione peroxidases (GPxs) are a family of enzymes that play a critical role in cellular redox homeostasis through the reduction of lipid hydroperoxides to alcohols, using glutathione as a substrate. Among them, GPx4 is particularly of interest in the regulation of ferroptosis, a form of iron-dependent programmed cell death driven by the accumulation of lipid peroxides in the endoplasmic reticulum, mitochondria, and plasma membrane. Ferroptosis has emerged as a crucial pathway in the context of cancer, particularly pancreatic cancer, which is notoriously resistant to conventional therapies. GPx4 acts as a key inhibitor of ferroptosis by detoxifying lipid peroxides, thereby preventing cell death. However, this protective mechanism also enables cancer cells to survive under oxidative stress, which makes GPx4 a potential druggable target in cancer therapy. The inhibition of GPx4 can trigger ferroptosis selectively in cancer cells, especially in those that rely heavily on this pathway for survival, such as pancreatic cancer cells. Consequently, targeting GPx4 and other GPX family members offers a promising therapeutic strategy to sensitize pancreatic cancer cells to ferroptosis, potentially overcoming resistance to current treatments and improving patient outcomes. Current research is focusing on the development of small-molecule inhibitors of GPx4 as potential candidates for pancreatic cancer treatment. [ABSTRACT FROM AUTHOR]

Impaired intestinal homeostasis is a major pathological feature of inflammatory bowel diseases (IBD). Mannose and selenium (Se) both demonstrate potential anti-inflammatory and anti-oxidative properties. However, most lectin receptors bind free monosaccharide ligands with relatively low affinity and most Se species induce side effects beyond a very narrow range of dosage. This has contributed to a poorly explored therapies for IBD that combine mannose and Se to target intestinal epithelial cells (IECs) for normalization gut homeostasis. Herein, a facile and safe strategy for ulcerative colitis (UC) treatment was developed using optimized, mannose-functionalized Se nanoparticles (M-SeNPs) encapsulated within a colon-targeted hydrogel delivery system containing alginate (SA) and chitosan (CS). This biocompatible nanosystem was efficiently taken up by IECs and led to increased expression of Se-dependent glutathione peroxidases (GPXs), thereby modulating IECs' immune response. Using a mouse model of DSS-induced colitis, (CS/SA)-embedding M-SeNPs (C/S-MSe) were found to mitigate oxidative stress and inflammation through the inhibition of the NF-kB pathway in the colon. This stabilized mucosal homeostasis of IECs and ameliorated colitis-related symptoms, thereby providing a potential new approach for treatment of IBD. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes mellitus (T2DM) is characterized by postprandial dysmetabolism, which has been linked to post-meal redox disturbances. Oleocanthal (OO), one of the most potent bioactive phenols of extra virgin olive oil, has shown redox modulating properties in vitro. However, its acute, in vivo antioxidant properties have never been studied before. Objective: The aim of this study was to investigate the kinetics of five redox markers (Thiobarbituric acid-reactive substances [TBARS] and glutathione peroxidase activity in serum-GPx3 and erythrocytes (GPx1), protein carbonyls in serum) after the consumption different meals. Design: Five different isocaloric meals comprised of white bread and butter (BU) or butter plus ibuprofen (BU-IBU) or olive oil poor in OO or olive oils containing 250 and 500 mg/Kg of oleocanthal (OO250 and OO500, respectively). We hypothesized that OO-rich olive oil will reduce postprandial oxidative stress in T2DM patients compared to other lipid sources. This study involved 10 patients with T2DM and had a cross-over design. Results: The comparison of incremental Area Under Curves (iAUCs) has shown that OO-rich olive oils were able to alleviate the increments of thiobarbituric acid-reactive substances (TBARS) and GPx3 and induce a higher red blood cells (RBCs) GPx1 activity compared to OO (P < 0.05). The effect was dose and redox marker depended. Correlation analysis in the pooled sample demonstrated a positive association between postprandial ex vivo platelet sensitivity to ADP and iAUC TBARS. In conclusion, our study has shown that OO-rich olive oils can favorably modulate lipid peroxidation and RBC GPx activity in T2DM patients when consumed as part of a carbohydrate meal. Discussion: This study demonstrates for the first time that, apart from its anti-inflammatory and antiplatelet properties, OO can also exert acute antioxidant effects. Conclusion: This finding emphasizes the health benefits of extra virgin olive oil, particularly those with a high OO content, for T2DM patients.

Abstract Impaired intestinal homeostasis is a major pathological feature of inflammatory bowel diseases (IBD). Mannose and selenium (Se) both demonstrate potential anti-inflammatory and anti-oxidative properties. However, most lectin receptors bind free monosaccharide ligands with relatively low affinity and most Se species induce side effects beyond a very narrow range of dosage. This has contributed to a poorly explored therapies for IBD that combine mannose and Se to target intestinal epithelial cells (IECs) for normalization gut homeostasis. Herein, a facile and safe strategy for ulcerative colitis (UC) treatment was developed using optimized, mannose-functionalized Se nanoparticles (M-SeNPs) encapsulated within a colon-targeted hydrogel delivery system containing alginate (SA) and chitosan (CS). This biocompatible nanosystem was efficiently taken up by IECs and led to increased expression of Se-dependent glutathione peroxidases (GPXs), thereby modulating IECs’ immune response. Using a mouse model of DSS-induced colitis, (CS/SA)-embedding M-SeNPs (C/S-MSe) were found to mitigate oxidative stress and inflammation through the inhibition of the NF-kB pathway in the colon. This stabilized mucosal homeostasis of IECs and ameliorated colitis-related symptoms, thereby providing a potential new approach for treatment of IBD.

Glutathione peroxidases (GPxs) are a family of enzymes that play a critical role in cellular redox homeostasis through the reduction of lipid hydroperoxides to alcohols, using glutathione as a substrate. Among them, GPx4 is particularly of interest in the regulation of ferroptosis, a form of iron-dependent programmed cell death driven by the accumulation of lipid peroxides in the endoplasmic reticulum, mitochondria, and plasma membrane. Ferroptosis has emerged as a crucial pathway in the context of cancer, particularly pancreatic cancer, which is notoriously resistant to conventional therapies. GPx4 acts as a key inhibitor of ferroptosis by detoxifying lipid peroxides, thereby preventing cell death. However, this protective mechanism also enables cancer cells to survive under oxidative stress, which makes GPx4 a potential druggable target in cancer therapy. The inhibition of GPx4 can trigger ferroptosis selectively in cancer cells, especially in those that rely heavily on this pathway for survival, such as pancreatic cancer cells. Consequently, targeting GPx4 and other GPX family members offers a promising therapeutic strategy to sensitize pancreatic cancer cells to ferroptosis, potentially overcoming resistance to current treatments and improving patient outcomes. Current research is focusing on the development of small-molecule inhibitors of GPx4 as potential candidates for pancreatic cancer treatment.

Living organisms use selenium mainly in the form of selenocysteine in the active site of oxidoreductases. Here, selenium's unique chemistry is believed to modulate the reaction mechanism and enhance the catalytic efficiency of specific enzymes in ways not achievable with a sulfur-containing cysteine. However, despite the fact that selenium/sulfur have different physicochemical properties, several selenoproteins have fully functional cysteine-containing homologues and some organisms do not use selenocysteine at all. In this review, selected selenocysteine-containing proteins will be discussed to showcase both situations: (i) selenium as an obligatory element for the protein's physiological function, and (ii) selenium presenting no clear advantage over sulfur (functional proteins with either selenium or sulfur). Selenium's physiological roles in antioxidant defence (to maintain cellular redox status/hinder oxidative stress), hormone metabolism, DNA synthesis, and repair (maintain genetic stability) will be also highlighted, as well as selenium's role in human health. Formate dehydrogenases, hydrogenases, glutathione peroxidases, thioredoxin reductases, and iodothyronine deiodinases will be herein featured. [ABSTRACT FROM AUTHOR]

The glutathione (GSH) system is one of the most powerful intracellular antioxidant systems for the elimination of reactive oxygen species (ROS) and maintaining cellular redox homeostasis. However, the rapid kinetics information (at the millisecond to the second level) during the dynamic antioxidation process of the GSH system remains unclear. As such, we specifically developed a novel dual‐wire nanosensor (DWNS) that can selectively and synchronously measure the levels of GSH and ROS with high temporal resolution, and applied it to monitor the transient ROS generation as well as the rapid antioxidation process of the GSH system in individual cancer cells. These measurements revealed that the glutathione peroxidase (GPx) in the GSH system is rapidly initiated against ROS burst in a sub‐second time scale, but the elimination process is short‐lived, ending after a few seconds, while some ROS are still present in the cells. This study is expected to open new perspectives for understanding the GSH antioxidant system and studying some redox imbalance‐related physiological. [ABSTRACT FROM AUTHOR]

Selenocysteine (Sec)‐derived cyclic selenenyl amides, formed by the intramolecular cyclization of Sec selenenic acids (Sec–SeOHs), have been postulated to function as protective forms in the bypass mechanism of glutathione peroxidase (GPx). However, their chemical properties have not been experimentally elucidated in proteins or small‐molecule systems. Recently, we reported the first nuclear magnetic resonance observation of Sec–SeOHs and their cyclization to the corresponding cyclic selenenyl amides by using selenopeptide model systems incorporated in a molecular cradle. Herein, we elucidate the structures and reactivities of Sec‐derived cyclic selenenyl amides. The crystal structures and reactions toward a cysteine thiol or a 1,3‐diketone‐type chemical probe indicated the highly electrophilic character of cyclic selenenyl amides. This suggests that they can serve not only as protective forms to suppress the inactivation of Sec–SeOHs in GPx but also as highly electrophilic intermediates in the reactions of selenoproteins. [ABSTRACT FROM AUTHOR]

Glutathione peroxidases (GPxs) are important antioxidant enzymes that act at distinct levels of the antioxidant defense. In vertebrates, there are several glutathione peroxidase (GPx) isoforms with different cellular and tissue distribution, but little is known about their interrelationships. The shrimp Litopenaeus vannamei is the main crustacean cultivated worldwide. It is affected by environmental stressors, including hypoxia and reoxygenation that cause reactive oxygen species accumulation. Thus, the antioxidant response modulation is key for shrimp resilience. Recently, several GPx isoforms genes were identified in the L. vannamei genome sequence, but their functions are just beginning to be studied. As in vertebrates, shrimp GPx isoforms can present differences in their antioxidant responses. Also, there could be interrelationships among the isoforms that may influence their responses. We evaluated shrimp GPx2 and GPx4 expressions during hypoxia, reoxygenation, and GPx4 knock-down using RNAi for silencing, as well as the enzymatic activity of total GPx and GPx4. Also, glutathione content in hepatopancreas was evaluated. GPx2 and GPx4 presented similar expression patterns during hypoxia and reoxygenation. Their expressions decreased during hypoxia and were reestablished in reoxygenation at 6 h in non-silenced shrimp. GPx2 expression was down-regulated by GPx4 knock-down, suggesting that GPx4 affects GPx2 expression. Total GPx activity changed in hypoxia and reoxygenation at 6 h but not at 12 h, while GPx4 activity was not affected by any stressor. The GSH/GSSG ratio in hepatopancreas indicated that at early hours, the redox status remains well-modulated but at 12 h it is impaired by hypoxia and reoxygenation. [Display omitted] • Shrimp GPx2 and GPx4 expression patterns in hepatopancreas are similar during oxygen stress. • GPx2 gene expression is down-regulated during GPx4 silencing. • Total GPx and GPx4 enzymatic activity are not affected by GPx4 knock-down. • Total GPx activity decrease during hypoxia and is reestablished in reoxygenation. • Hepatopancreas redox status is impaired at prologued hypoxia and reoxygenation stress. [ABSTRACT FROM AUTHOR]

Extensive research efforts in the field of brain tumor studies have led to the reclassification of tumors by the World Health Organization (WHO) and the identification of various molecular subtypes, aimed at enhancing diagnosis and treatment strategies. However, the quest for biomarkers that can provide a deeper understanding of tumor development mechanisms, particularly in the case of gliomas, remains imperative due to their persistently incurable nature. Oxidative stress has been widely recognized as a key mechanism contributing to the formation and progression of malignant tumors, with imbalances in antioxidant defense systems being one of the underlying causes for the excess production of reactive oxygen species (ROS) implicated in tumor initiation. In this study, we investigated the gene expression patterns of the eight known isoforms of glutathione peroxidase (GPx) in brain tissue obtained from male and female control rats, as well as rats with transplacental ethyl nitrosourea (ENU)-induced brain tumors. Employing the delta-delta Ct method for RT-PCR, we observed minimal expression levels of gpx2, gpx5, gpx6, and gpx7 in the brain tissue from the healthy control animals, while gpx3 and gpx8 exhibited moderate expression levels. Notably, gpx1 and gpx4 displayed the highest expression levels. Gender differences were not observed in the expression profiles of these isoforms in the control animals. Conversely, the tumor tissue exhibited elevated relative expression levels in all isoforms, except for gpx4, which remained unchanged, and gpx5, which exhibited alterations solely in female animals. Moreover, except for gpx1, which displayed no gender differences, the relative expression values of gpx2, gpx3, gpx6, gpx7, and gpx8 were significantly higher in the male animals compared to their female counterparts. Hence, the analysis of glutathione peroxidase isoforms may serve as a valuable approach for discerning the behavior of brain tumors in clinical settings. [ABSTRACT FROM AUTHOR]

Several studies revealed that expression levels of glutathione peroxidase 1 (Gpx-1) can be associated with cancer development, mainly through its role in hydroperoxide scavenging by regulating intracellular reactive oxygen species (ROS) levels. Therefore, our aim was to investigate the expression of Gpx-1 protein in a population of Polish patients with colon adenocarcinoma in the absence of any therapy prior to radical surgery. The study was carried out using colon tissue from patients with adenocarcinoma of the colon confirmed by histopathological examination. Gpx-1 antibody was used to determine the immunohistochemical expression of Gpx-1. The Chi2test or Chi2Yatesa test were used to analyse the associations between the immunohistochemical expression of Gpx-1 and clinical parameters. The relationship between Gpx-1 expression, and 5-year patient survival was examined using Kaplan–Meier analysis and the log-rank test. Intracellular localisation of Gpx-1 was detected by the use of transmission electron microscopy (TEM). Western blot analysis was used for the evaluation of Gpx-1 protein expression levels in cancer cell lines in vitro. Immunohistochemical study revealed that the high expression of Gpx-1 was associated with the tumour's histological grade, proliferating cell nuclear antigen (PCNA) immunohistochemical expression, depth of invasion, and angioinvasion (all p < 0.001) (4). The high immunohistochemical expression of Gpx-1 is correlated with poor prognosis of colon adenocarcinoma patients. [ABSTRACT FROM AUTHOR]

Glutathione peroxidases (GPXs) are key reactive oxygen species (ROS) scavenging enzyme that catalyses the reduction of H2O2 to prevent the cellular machinery from H2O2 damage. Plant GPXs are similar to animal GPXs, but their active region contains cysteine instead of selenocysteine. Plant GPXs are monomeric proteins that are linked to thioredoxin (Trx) and glutathione (GSH) detoxification pathways. They employ Trx more effectively than GSH to decrease H2O2 and organic peroxides. GPX keeps the thiol-disulfide balance in check and also collaborates with peroxiredoxins and glutathione-S-transferases (GSTs) to maintain redox homeostasis. GPX plays an important role in response to abiotic and biotic stresses and during plant growth and development processes. Depending on their subcellular localization and the existence of unique cis-acting regulatory elements in the upstream promoter region, various GPX genes respond differently to environmental stresses. The significance of GPXs in response to various abiotic stresses, for instance, cold, drought, heat, oxidative, salt and metal stresses has been discussed in this review. Moreover, we have also explored the involvement of GPXs in plant growth and developmental processes. Hence, this review provides valuable information about the GPX genes which could be utilized in genetic engineering to boost agricultural plant yields under unfavourable conditions. [ABSTRACT FROM AUTHOR]

Living organisms use selenium mainly in the form of selenocysteine in the active site of oxidoreductases. Here, selenium’s unique chemistry is believed to modulate the reaction mechanism and enhance the catalytic efficiency of specific enzymes in ways not achievable with a sulfur-containing cysteine. However, despite the fact that selenium/sulfur have different physicochemical properties, several selenoproteins have fully functional cysteine-containing homologues and some organisms do not use selenocysteine at all. In this review, selected selenocysteine-containing proteins will be discussed to showcase both situations: (i) selenium as an obligatory element for the protein’s physiological function, and (ii) selenium presenting no clear advantage over sulfur (functional proteins with either selenium or sulfur). Selenium’s physiological roles in antioxidant defence (to maintain cellular redox status/hinder oxidative stress), hormone metabolism, DNA synthesis, and repair (maintain genetic stability) will be also highlighted, as well as selenium’s role in human health. Formate dehydrogenases, hydrogenases, glutathione peroxidases, thioredoxin reductases, and iodothyronine deiodinases will be herein featured.

Background: Type 2 diabetes mellitus (T2DM) is characterized by postprandial dysmetabolism, which has been linked to post-meal redox disturbances. Oleocanthal (OO), one of the most potent bioactive phenols of extra virgin olive oil, has shown redox modulating properties in vitro. However, its acute, in vivo antioxidant properties have never been studied before., Objective: The aim of this study was to investigate the kinetics of five redox markers (Thiobarbituric acid-reactive substances [TBARS] and glutathione peroxidase activity in serum-GPx3 and erythrocytes (GPx1), protein carbonyls in serum) after the consumption different meals., Design: Five different isocaloric meals comprised of white bread and butter (BU) or butter plus ibuprofen (BU-IBU) or olive oil poor in OO or olive oils containing 250 and 500 mg/Kg of oleocanthal (OO250 and OO500, respectively). We hypothesized that OO-rich olive oil will reduce postprandial oxidative stress in T2DM patients compared to other lipid sources. This study involved 10 patients with T2DM and had a cross-over design., Results: The comparison of incremental Area Under Curves (iAUCs) has shown that OO-rich olive oils were able to alleviate the increments of thiobarbituric acid-reactive substances (TBARS) and GPx3 and induce a higher red blood cells (RBCs) GPx1 activity compared to OO ( P < 0.05). The effect was dose and redox marker depended. Correlation analysis in the pooled sample demonstrated a positive association between postprandial ex vivo platelet sensitivity to ADP and iAUC TBARS. In conclusion, our study has shown that OO-rich olive oils can favorably modulate lipid peroxidation and RBC GPx activity in T2DM patients when consumed as part of a carbohydrate meal., Discussion: This study demonstrates for the first time that, apart from its anti-inflammatory and antiplatelet properties, OO can also exert acute antioxidant effects., Conclusion: This finding emphasizes the health benefits of extra virgin olive oil, particularly those with a high OO content, for T2DM patients., Competing Interests: The authors declare no conflicts of interest and funding., (© 2024 Maria Efthymia Katsa et al.)

Selenium was recognized as a non-toxic element in the second half of the 20th century. Since then, the positive impact of selenium on the functioning of the human body has been noticed. It has been shown that low levels of selenium in the body are significantly associated with a higher risk of developing cancer. Selenium acts as an antioxidant and inhibits the proliferation of cancer cells. It has been shown that selenium supplementation may contribute to reducing the risk of DNA mutations and carcinogenesis. Nanomedicine has become very helpful in both the diagnosis and treatment of cancer. Due to its anticancer properties, selenium is used in nanotechnology as selenium nanoparticles.

Several studies revealed that expression levels of glutathione peroxidase 1 (Gpx-1) can be associated with cancer development, mainly through its role in hydroperoxide scavenging by regulating intracellular reactive oxygen species (ROS) levels. Therefore, our aim was to investigate the expression of Gpx-1 protein in a population of Polish patients with colon adenocarcinoma in the absence of any therapy prior to radical surgery. The study was carried out using colon tissue from patients with adenocarcinoma of the colon confirmed by histopathological examination. Gpx-1 antibody was used to determine the immunohistochemical expression of Gpx-1. The Chi2test or Chi2Yatesa test were used to analyse the associations between the immunohistochemical expression of Gpx-1 and clinical parameters. The relationship between Gpx-1 expression, and 5-year patient survival was examined using Kaplan–Meier analysis and the log-rank test. Intracellular localisation of Gpx-1 was detected by the use of transmission electron microscopy (TEM). Western blot analysis was used for the evaluation of Gpx-1 protein expression levels in cancer cell lines in vitro. Immunohistochemical study revealed that the high expression of Gpx-1 was associated with the tumour’s histological grade, proliferating cell nuclear antigen (PCNA) immunohistochemical expression, depth of invasion, and angioinvasion (all p < 0.001) (4). The high immunohistochemical expression of Gpx-1 is correlated with poor prognosis of colon adenocarcinoma patients.

Maize (Zea mays L) is an important cereal with extensive adaptability and multifaceted usages. However, various abiotic and biotic stresses limit the productivity of maize across the globe. Exposure of plant to stresses disturb the balance between reactive oxygen species (ROS) production and scavenging, which subsequently increases cellular damage and death of plants. Tolerant genotypes have evolved higher output of scavenging antioxidative defence compounds (ADCs) during stresses as one of the protective mechanisms. The glutathione peroxidases (GPXs) are the broad class of ADCs family. The plant GPXs catalyse the reduction of hydrogen peroxide (H 2 O 2), lipid hydroperoxides and organic hydroperoxides to the corresponding alcohol, and facilitate the regulation of stress tolerance mechanisms. The present investigation was framed to study the maize GPXs using evolutionary and functional analyses. Seven GPX genes with thirteen splice-variants and sixty-three types of cis -acting elements were identified through whole-genome scanning in maize. Evolutionary analysis of GPXs in monocots and dicots revealed mixed and lineage-specific grouping patterns in phylogeny. The expression of ZmGPX splice variants was studied in drought and waterlogging tolerant (L1621701) and sensitive (PML10) genotypes in root and shoot tissues. Further, the differential expression of splice variants of ZmGPX1 , ZmGPX3 , ZmGPX6 and ZmGPX7 and regulatory network analysis suggested the splicing and regulatory elements mediated stress responses. The present investigation suggests targeting the splicing machinery of GPXs as an approach to enhance the stress tolerance in maize. • The GPX gene family consisting of seven genes was identified in maize by a genome-wide analysis. • GPXs are evolved prior to monocots and dicots divergence and intron losses resulted subsequent divergence within lineage. • Genetic background, regulatory elements and splicing events contributes to functional diversification of ZmGPXs. • Regulatory network analysis shown the putative miRNAs and TFs controlling ZmGPXs expression for growth and stress adaptation. [ABSTRACT FROM AUTHOR]

The functional activity of selenoproteins has a wide range of effects on complex pathogenetic processes, including teratogenesis, immuno-inflammatory, neurodegenerative. Being active participants and promoters of many signaling pathways, selenoproteins support the lively interest of a wide scientific community. This review is devoted to the analysis of recent data describing the participation of selenoproteins in various molecular interactions mediating important signaling pathways. Data processing was carried out by the method of complex analysis. For convenience, all selenoproteins were divided into groups depending on their location and function. Among the group of selenoproteins of the ER membrane, selenoprotein N affects the absorption of Ca2+ by the endoplasmic reticulum mediated by oxidoreductin (ERO1), a key player in the CHOP/ERO1 branch, a pathogenic mechanism that causes myopathy. Another selenoprotein of the ER membrane selenoprotein K binding to the DHHC6 protein affects the IP3R receptor that regulates Ca2+ flux. Selenoprotein K is able to affect another protein of the endoplasmic reticulum CHERP, also appearing in Ca2+ transport. Selenoprotein S, associated with the lumen of ER, is able to influence the VCP protein, which ensures the incorporation of selenoprotein K into the ER membrane. Selenoprotein M, as an ER lumen protein, affects the phosphorylation of STAT3 by leptin, which confirms that Sel M is a positive regulator of leptin signaling. Selenoprotein S also related to luminal selenoproteins ER is a modulator of the IRE1α-sXBP1 signaling pathway. Nuclear selenoprotein H will directly affect the suppressor of malignant tumours, p53 protein, the activation of which increases with Sel H deficiency. The same selenoprotein is involved in redox regulation. Among the cytoplasmic selenoproteins, abundant investigations are devoted to SelP, which affects the PI3K/Akt/Erk signaling pathway during ischemia/reperfusion, is transported into the myoblasts through the plasmalemma after binding to the apoER2 receptor, and into the neurons to the megaline receptor and in general, selenoprotein P plays the role of a pool that stores the necessary trace element and releases it, if necessary, for vital selenoproteins. The thioredoxin reductase family plays a key role in the invasion and metastasis of salivary adenoid cystic carcinoma through the influence on the TGF-β-Akt/GSK-3β pathway during epithelial-mesenchymal transition. The deletion of thioredoxin reductase 1 affects the levels of messengers of the Wnt/β-catenin signaling pathway. No less studied is the glutathione peroxidase group, of which GPX3 is able to inhibit signaling in the Wnt/β-catenin pathway and thereby inhibit thyroid metastasis, as well as suppress protein levels in the PI3K/Akt/c-fos pathway. A key observation is that in cases of carcinogenesis, a decrease in GPX3 and its hypermethylation are almost always found. Among deiodinases, deiodinase 3 acts as a promoter of the oncogenes BRAF, MEK or p38, while stimulating a decrease in the expression of cyclin D1. The dependence of the level of deiodinase 3 on the Hedgehog (SHH) signaling pathway is also noted. Methionine sulfoxide reductase A can compete for the uptake of ubiquitin, reduce p38, JNK and ERK promoters of the MAPK signaling pathway; methionine sulfoxide reductase B1 suppresses MAPK signaling messengers, and also increases PARP and caspase 3.

Reactive oxygen species (ROS) play essential roles in plant development and environmental stress responses. In this study, ROS dynamics, the glutathione redox status, the expression and subcellular localization of glutathione peroxidases (GPXs), and the effects of inhibitors of ROS-mediated metabolism were investigated along with fertilization and early zygotic embryogenesis in rice (Oryza sativa). Zygotes and early embryos exhibited developmental arrest upon inhibition of ROS production. Egg cells accumulated high ROS levels, and, after fertilization, intracellular ROS levels progressively declined in zygotes in which de novo expression of GPX1 and 3 was observed through upregulation of the genes. In addition to inhibition of GPX activity, depletion of glutathione impeded early embryonic development and led to failure of the zygote to appropriately decrease H2O2 levels. Moreover, through monitoring of the glutathione redox status, the developing zygotes exhibited a progressive glutathione oxidation, which became extremely delayed under inhibited GPX activity. Our results provide insights into the importance of ROS dynamics, GPX antioxidant activity, and glutathione redox metabolism during zygotic/embryonic development. [ABSTRACT FROM AUTHOR]

In this review, we discuss the pathogenesis of some socially significant diseases associated with the development of oxidative stress, such as atherosclerosis, diabetes, and radiation sickness, as well as the possibilities of the therapeutic application of low-molecular-weight natural and synthetic antioxidants for the correction of free radical-induced pathologies. The main focus of this review is the role of two phylogenetically close families of hydroperoxide-reducing antioxidant enzymes peroxiredoxins and glutathione peroxidases – in counteracting oxidative stress. We also present examples of the application of exogenous recombinant antioxidant enzymes as therapeutic agents in the treatment of pathologies associated with free-radical processes and discuss the prospects of the therapeutic use of exogenous antioxidant enzymes, as well as the ways to improve their therapeutic properties. [ABSTRACT FROM AUTHOR]

The review presents current concepts of the molecular mechanisms of oxidative stress development and describes main stages of the free-radical reactions in oxidative stress. Endogenous and exogenous factors of the oxidative stress development, including dysfunction of cell oxidoreductase systems, as well as the effects of various external physicochemical factors, are discussed. The review also describes the main components of the antioxidant defense system and stages of its evolution, with a special focus on peroxiredoxins, glutathione peroxidases, and glutathione S-transferases, which share some phylogenetic, structural, and catalytic properties. The substrate specificity, as well as the similarities and differences in the catalytic mechanisms of these enzymes, are discussed in detail. The role of peroxiredoxins, glutathione peroxidases, and glutathione S-transferases in the regulation of hydroperoxide-mediated intracellular and intercellular signaling and interactions of these enzymes with receptors and non-receptor proteins are described. An important contribution of hydroperoxide-reducing enzymes to the antioxidant protection and regulation of such cell processes as growth, differentiation, and apoptosis is demonstrated. [ABSTRACT FROM AUTHOR]

Glutathione peroxidases (GPXs) are non-heme peroxidases catalyzing the reduction of H2O2 or organic hydroperoxides to water or corresponding alcohols using glutathione (GSH) or thioredoxin (TRX) as a reducing agent. In contrast to animal GPXs, the plant enzymes are non-seleno monomeric proteins that generally utilize TRX more effectively than GSH but can be a putative link between the two main redox systems. Because of the substantial differences compared to non-plant GPXs, use of the GPX-like (GPXL) name was suggested for Arabidopsis enzymes. GPX(L)s not only can protect cells from stress-induced oxidative damages but are crucial components of plant development and growth. Due to fine-tuning the H2O2 metabolism and redox homeostasis, they are involved in the whole life cycle even under normal growth conditions. Significantly new mechanisms were discovered related to their transcriptional, post-transcriptional and post-translational modifications by describing gene regulatory networks, interacting microRNA families, or identifying Lys decrotonylation in enzyme activation. Their involvement in epigenetic mechanisms was evidenced. Detailed genetic, evolutionary, and bio-chemical characterization, and comparison of the main functions of GPXs, demonstrated their species-specific roles. The multisided involvement of GPX(L)s in the regulation of the entire plant life ensure that their significance will be more widely recognized and applied in the future.

Significance: The selenium-containing Glutathione peroxidases (GPxs)1–4 protect against oxidative challenge, inhibit inflammation and oxidant-induced regulated cell death. Recent Advances: GPx1 and GPx4 dampen phosphorylation cascades predominantly via prevention of inactivation of phosphatases by H2O2 or lipid hydroperoxides. GPx2 regulates the balance between regeneration and apoptotic cell shedding in the intestine. It inhibits inflammation-induced carcinogenesis in the gut but promotes growth of established cancers. GPx3 deficiency facilitates platelet aggregation likely via disinhibition of thromboxane biosynthesis. It is also considered a tumor suppressor. GPx4 is expressed in three different forms. The cytosolic form proved to inhibit interleukin-1-driven nuclear factor κB activation and leukotriene biosynthesis. Moreover, it is a key regulator of ferroptosis, because it reduces hydroperoxy groups of complex lipids and silences lipoxygenases. By alternate substrate use, the nuclear form contributes to chromatin compaction. Mitochondrial GPx4 forms the mitochondrial sheath of spermatozoa and, thus, guarantees male fertility. Out of the less characterized GPxs, the cysteine-containing GPx7 and GPx8 are unique in contributing to oxidative protein folding in the endoplasmic reticulum by reacting with protein isomerase as an alternate substrate. A yeast 2-Cysteine glutathione peroxidase equipped with CP and CR was reported to sense H2O2 for inducing an adaptive response. Critical Issues: Most of the findings compiled are derived from tissue culture and/or animal studies only. Their impact on human physiology is sometimes questionable. Future Directions: The expression of individual GPxs and GPx-dependent regulatory phenomena are to be further investigated, in particular in respect to human health. [ABSTRACT FROM AUTHOR]

Among the chalcogens, selenium is the key element for catalyzed H2O2 reduction. In organic synthesis, catalytic amounts of organo mono- and di-selenides are largely used in different classes of oxidations, in which H2O2 alone is poorly efficient. Biological hydroperoxide metabolism is dominated by peroxidases and thioredoxin reductases, which balance hydroperoxide challenge and contribute to redox regulation. When their selenocysteine is replaced by cysteine, the cellular antioxidant defense system is impaired. Finally, classes of organoselenides have been synthesized with the aim of mimicking the biological strategy of glutathione peroxidases, but their therapeutic application has so far been limited. Moreover, their therapeutic use may be doubted, because H2O2 is not only toxic but also serves as an important messenger. Therefore, over-optimization of H2O2 reduction may lead to unexpected disturbances of metabolic regulation. Common to all these systems is the nucleophilic attack of selenium to one oxygen of the peroxide bond promoting its disruption. In this contribution, we revisit selected examples from chemistry and biology, and, by using results from accurate quantum mechanical modelling, we provide an accurate unified picture of selenium’s capacity of reducing hydroperoxides. There is clear evidence that the selenoenzymes remain superior in terms of catalytic efficiency.

In the present work, generation of hydrogen peroxide in Chlamydomonas reinhardtii Dang. cells under hypothermia was demonstrated. Analysis in these cells of genes' transcription encoding the enzymes involved in detoxification of H2O2 in them, such as ascorbate peroxidases (APX1, APX2 and APX3), catalases (CAT1 and CAT2), and glutathione peroxidases (GPX1, GPX3, GPX4 and GPX5), showed that action of low temperature (7°C) leads to lowering transcription of genes encoding catalases and ascorbate peroxidases. At the same time, induction of three GPX genes, GPX1, GPX3, and GPX5, was found under these conditions. Maximal (50 times) elevation in transcription levels was determined for the GPX3 gene. As a result, the gene encoding glutathione peroxidase 3 is suggested as a potential marker for C. reinhardtii's response to cold treatment. In addition, it was shown that hydrogen peroxide is involved in the regulation of the induction of the GPX3 gene under the action of low temperature. [ABSTRACT FROM AUTHOR]

This article, titled "Cover Feature: Highly Electrophilic Intermediates in the Bypass Mechanism of Glutathione Peroxidase: Synthesis, Reactivity, and Structures of Selenocysteine-Derived Cyclic Selenenyl Amides," explores the role of selenocysteine cyclic selenenyl amides in the catalytic cycle of the antioxidant enzyme glutathione peroxidase (GPx). The study reveals that these intermediates, previously overlooked, have dual functionality. They not only prevent the inactivation of GPx but also act as highly electrophilic intermediates in selenoprotein reactions. The researchers compare the roles of these intermediates to a chess king, dynamically adapting to their application. [Extracted from the article]

The beginnings of redox biology are recalled with special emphasis on formation, metabolism and function of reactive oxygen and nitrogen species in mammalian systems. The review covers the early history of heme peroxidases and the metabolism of hydrogen peroxide, the discovery of selenium as integral part of glutathione peroxidases, which expanded the scope of the field to other hydroperoxides including lipid hydroperoxides, the discovery of superoxide dismutases and superoxide radicals in biological systems and their role in host defense, tissue damage, metabolic regulation and signaling, the identification of the endothelial-derived relaxing factor as the nitrogen monoxide radical (more commonly named nitric oxide) and its physiological and pathological implications. The article highlights the perception of hydrogen peroxide and other hydroperoxides as signaling molecules, which marks the beginning of the flourishing fields of redox regulation and redox signaling. Final comments describe the development of the redox language. In the 18th and 19th century, it was highly individualized and hard to translate into modern terminology. In the 20th century, the redox language co-developed with the chemical terminology and became clearer. More recently, the introduction and inflationary use of poorly defined terms has unfortunately impaired the understanding of redox events in biological systems.

In the present work, an extensive analysis of the putative glutathione peroxidases (GPx) of the eukaryotic microorganism model Tetrahymena thermophila is carried out. A comparative analysis with GPx present in other Tetrahymena species and other very taxonomically diverse ciliates is also performed. A majority of ciliate GPx have replaced the selenocysteine (Sec) by Cys in its catalytic center, so they can be considered as phospholipid hydroperoxide glutathione peroxidases (PHGPx). Selenocysteine insertion sequence (SECIS) elements have been detected in several ciliate GPx that do not incorporate Sec in their amino acid sequences, and conversely, in other ciliate GPx with Sec, no SECIS elements are detected. These anomalies are analyzed and discussed. From the phylogenetic analysis using the ciliate GPx amino acid sequences, the existence of extensive intra- and interspecific gene duplications that produced multiple GPx isoforms in each species is inferred. The ancestral character of the selenoproteins is also corroborated. The analysis by qRT-PCR of six selected T. thermophila GPx genes has shown a quantitative differential expression between them, depending on the stressor (oxidizing agents, apoptotic inducer or metals) and the time of exposure.

Selenium (Se) is an essential trace nutrient required for optimal human health. It has long been suggested that selenium has anti-cancer properties. However, clinical trials have shown inconclusive results on the potential of Se to prevent cancer. The suggested role of Se in the prevention of cancer is centered around its role as an antioxidant. Recently, the potential of selenium as a drug rather than a supplement has been uncovered. Selenium compounds can generate reactive oxygen species that could enhance the treatment of cancer. Transformed cells have high oxidative distress. As normal cells have a greater capacity to meet oxidative challenges than tumor cells, increasing the flux of oxidants with high dose selenium treatment could result in cancer-specific cell killing. If the availability of Se is limited, supplementation of Se can increase the expression and activities of Se-dependent proteins and enzymes. In cell culture, selenium deficiency is often overlooked. We review the importance of achieving normal selenium biology and how Se deficiency can lead to adverse effects. We examine the vital role of selenium in the prevention and treatment of cancer. Finally, we examine the properties of Se-compounds to better understand how each can be used to address different research questions.

Background Exhaustive exercise causes muscle damage accompanied by oxidative stress and inflammation leading to muscle fatigue and muscle soreness. Lemon verbena leaves, commonly used as tea and refreshing beverage, demonstrated antioxidant and anti-inflammatory properties. The aim of this study was to investigate the effects of a proprietary lemon verbena extract (Recoverben®) on muscle strength and recovery after exhaustive exercise in comparison to a placebo product. Methods The study was performed as a randomized, placebo-controlled, double-blind study with parallel design. Forty-four healthy males and females, which were 22–50 years old and active in sports, were randomized to 400 mg lemon verbena extract once daily or placebo. The 15 days intervention was divided into 10 days supplementation prior to the exhaustive exercise day (intensive jump-protocol), one day during the test and four days after. Muscle strength (MVC), muscle damage (CK), oxidative stress (GPx), inflammation (IL6) and volunteer-reported muscle soreness intensity were assessed pre and post exercise. Results Participants in the lemon verbena group benefited from less muscle damage as well as faster and full recovery. Compared to placebo, lemon verbena extract receiving participants had significantly less exercise-related loss of muscle strength (p = 0.0311) over all timepoints, improved glutathione peroxidase activity by trend (p = 0.0681) and less movement induced pain (p = 0.0788) by trend. Creatine kinase and IL-6 didn’t show significant discrimmination between groups. Conclusion Lemon verbena extract (Recoverben®) has been shown to be a safe and well-tolerated natural sports ingredient, by reducing muscle damage after exhaustive exercise. Trial registration The trial was registered in the clinical trials registry (clinical trial.gov NCT02923102). Registered 28 September 2016

Living organisms use selenium mainly in the form of selenocysteine in the active site of oxidoreductases. Here, selenium's unique chemistry is believed to modulate the reaction mechanism and enhance the catalytic efficiency of specific enzymes in ways not achievable with a sulfur-containing cysteine. However, despite the fact that selenium/sulfur have different physicochemical properties, several selenoproteins have fully functional cysteine-containing homologues and some organisms do not use selenocysteine at all. In this review, selected selenocysteine-containing proteins will be discussed to showcase both situations: (i) selenium as an obligatory element for the protein's physiological function, and (ii) selenium presenting no clear advantage over sulfur (functional proteins with either selenium or sulfur). Selenium's physiological roles in antioxidant defence (to maintain cellular redox status/hinder oxidative stress), hormone metabolism, DNA synthesis, and repair (maintain genetic stability) will be also highlighted, as well as selenium's role in human health. Formate dehydrogenases, hydrogenases, glutathione peroxidases, thioredoxin reductases, and iodothyronine deiodinases will be herein featured.

Background: Exhaustive exercise causes muscle damage accompanied by oxidative stress and inflammation leading to muscle fatigue and muscle soreness. Lemon verbena leaves, commonly used as tea and refreshing beverage, demonstrated antioxidant and anti-inflammatory properties. The aim of this study was to investigate the effects of a proprietary lemon verbena extract (Recoverben®) on muscle strength and recovery after exhaustive exercise in comparison to a placebo product. Methods: The study was performed as a randomized, placebo-controlled, double-blind study with parallel design. Forty-four healthy males and females, which were 22–50 years old and active in sports, were randomized to 400 mg lemon verbena extract once daily or placebo. The 15 days intervention was divided into 10 days supplementation prior to the exhaustive exercise day (intensive jump-protocol), one day during the test and four days after. Muscle strength (MVC), muscle damage (CK), oxidative stress (GPx), inflammation (IL6) and volunteer-reported muscle soreness intensity were assessed pre and post exercise. Results: Participants in the lemon verbena group benefited from less muscle damage as well as faster and full recovery. Compared to placebo, lemon verbena extract receiving participants had significantly less exercise-related loss of muscle strength (p = 0.0311) over all timepoints, improved glutathione peroxidase activity by trend (p = 0.0681) and less movement induced pain (p = 0.0788) by trend. Creatine kinase and IL-6 didn't show significant discrimmination between groups. Conclusion: Lemon verbena extract (Recoverben®) has been shown to be a safe and well-tolerated natural sports ingredient, by reducing muscle damage after exhaustive exercise. Trial registration: The trial was registered in the clinical trials registry (clinical trial.gov NCT02923102). Registered 28 September 2016 [ABSTRACT FROM AUTHOR]

Abstract Selenocysteine-containing proteins (selenoproteins) have been implicated in the regulation of various cell signaling pathways, many of which are linked to colorectal malignancies. In this in-depth excurse into the selenoprotein literature, we review possible roles for human selenoproteins in colorectal cancer, focusing on the typical hallmarks of cancer cells and their tumor-enabling characteristics. Human genome studies of single nucleotide polymorphisms in various genes coding for selenoproteins have revealed potential involvement of glutathione peroxidases, thioredoxin reductases, and other proteins. Cell culture studies with targeted down-regulation of selenoproteins and studies utilizing knockout/transgenic animal models have helped elucidate the potential roles of individual selenoproteins in this malignancy. Those selenoproteins, for which strong links to development or progression of colorectal cancer have been described, may be potential future targets for clinical interventions. Graphical abstract fx1 Highlights • Many selenoproteins have been implicated to play a direct or indirect role in CRC. • Highly likely role in CRC: DIO3, GPX1-2, TXNRD1, DIO3, SELENOF,P,S. • Potential role in CRC: GPX3-4, MSRB1, TXNRD2-3, SELENOM,N,W. • Selenoproteins are potential targets for CRC treatment or prevention strategies. [ABSTRACT FROM AUTHOR]

Malignant astrocytoma is the most commonly occurring brain tumour in humans. Oxidative stress is implicated in the development of cancers. Superoxide dismutase 2 (SOD2) was found to exert tumour suppressive effect in basic research, but increased SOD2 protein level was associated with higher aggressiveness of human astrocytomas. However, studies reporting alterations of antioxidant enzymes in human astrocytomas often employed less accurate methods or included different types of tumours. Here we analysed the mRNA levels, activities, and protein levels of primary antioxidant enzymes in control brain tissues and various grades of astrocytomas obtained from 40 patients. SOD1 expression, SOD1 activity, and SOD1 protein level were lower in Grade IV astrocytomas. SOD2 expression was lower in low-grade (Grades I and II) and Grade III astrocytomas than in controls, but SOD2 expression and SOD2 protein level were higher in Grade IV astrocytomas than in Grade III astrocytomas. Although there was no change in SOD2 activity and a lower activity of citrate synthase (CS), the MnSOD:CS ratio increased in Grade IV astrocytomas compared with controls and low-grade astrocytomas. Furthermore, SOD1 activity, CS activity, SOD1 expression, GPX4 expression, and GPX4 protein level were inversely correlated with the malignancy, whereas catalase activity, catalase protein, SOD2 protein level, and the SOD2:CS ratio were positively correlated with the degree of malignancy. Lower SOD2:CS ratio was associated with poor outcomes for Grade IV astrocytomas. This is the first study to quantify changes of various primary antioxidant enzymes in different grades of astrocytomas at different levels concurrently in human astrocytomas. [ABSTRACT FROM AUTHOR]

Abstract: The objectives of the present study were to investigate the effects of selenium (Se) supplementation during in vitro maturation (IVM) on the developmental capacity of yak (Bos grunniens) oocytes. Nuclear maturation, DNA integrity, glutathione peroxidase (GSH‐Px) activity, subsequent embryonic development, and gene expression after in vitro fertilization (IVF) were evaluated. The Se concentrations in yak plasma and follicular fluid were 0.142 and 0.069 μg/mL, respectively. The DNA damage in cumulus cells decreased significantly with 2 and 4 μg/mL supplementation of sodium selenite to IVM medium (P < 0.05). Total GSH‐Px activity in oocytes increased in all Se supplementation groups, and the 2 and 4 μg/mL groups were significantly higher than the control group (0 μg/mL). However, the cleavage rate was not significantly different after Se supplementation (P > 0.05). The IVF blastocyst formation rates of 0, 1 and 4 μg/mL sodium selenite groups were 47.7%, 51.2% and 58.9%, respectively. The 2 μg/mL sodium selenite group had the highest blastocyst formation rate (60.5%). Gene expression analysis revealed that the quantity of transcripts associated with selenoprotein and protein synthesis were high in the 2 and 4 μg/mL groups. In conclusion, both GSH‐Px activity of oocytes and DNA integrity of cumulus cells significantly increased with supplemental Se during oocyte IVM. Considering that embryonic development is responsive to Se supplementation, we inferred that appropriate Se concentrations during IVM were beneficial for yak oocyte maturation and subsequent development. [ABSTRACT FROM AUTHOR]

Oxidative stress (OS) associated with direct contact with the environment and light exposure is a very potent and continuous stressor of the ocular surface and internal structures of the eye that are required to manage its effects. Constant replenishment of tears together with the superficial lipid layer produced by the meibomian glands (MG) is one protective mechanism. The lipid-rich fraction of the tears coats the deeper aqueous fraction, preventing its evaporation. However, lipids are particularly sensitive to oxidative damage that could alter tear film quality. To counteract oxidative damage, MG along with other structures of the ocular surface use primary antioxidant (AO) systems to limit OS damage such as lipid peroxidation. Limited information concerning the primary enzymatic AO system of the human MG prompted this investigation. Using different approaches (RT-PCR, enzymatic activity assays and immuno-fluorescent microscopy), we determined the presence, distribution and subcellular locations of the major AO enzymes belonging to the classical catalytic triad (superoxide dismutase, catalase and glutathione peroxidases) in adult human MG and conjunctiva (Conj). We showed that both tissues exhibit glutathione peroxidase expression. In addition to the ubiquitous cytosolic GPx1 protein, there was significant expression of GPx2, GPx4 and GPx7. These isoforms are known to preferentially scavenge phospholipid-hydroperoxide compounds. This characterization of the primary AO system of human MG and Conj may help pave the way for the development of diagnostic procedures and have implications for treatment of common MG dysfunction (MGD) and dry eye syndrome (DES). [ABSTRACT FROM AUTHOR]

Glutathione peroxidases (GPXs) are enzymes that are present in almost all organisms with the primary function of limiting peroxide accumulation. In mammals, two of the eight members (GPX7 and GPX8) reside in the endoplasmic reticulum (ER). A peculiar feature of GPX8 is the concomitant presence of a conserved N-terminal transmembrane domain (TMD) and a C-terminal KDEL-like motif for ER localization. Aims: Investigating whether and how GPX8 impacts Ca2+ homeostasis and signaling. Results: We show that GPX8 is enriched in mitochondria-associated membranes and regulates Ca2+ storage and fluxes. Its levels correlate with [Ca2+]ER, and cytosolic and mitochondrial Ca2+ fluxes. GPX7, which lacks a TMD, does not share these properties. Deleting or replacing the GPX8 TMD with an unrelated N-terminal membrane integration sequence abolishes all effects on Ca2+ fluxes, whereas appending the GPX8 TMD to GPX7 transfers the Ca2+-regulating properties. Innovation and Conclusion: The notion that the TMD of GPX8, in addition to its enzymatic activity, is essential for regulating Ca2+ dynamics reveals a novel level of integration between redox-related proteins and Ca2+ signaling/homeostasis. Antioxid. Redox Signal. 27, 583-595. [ABSTRACT FROM AUTHOR]

Insulin resistance (IR) is the hallmark of type 2 diabetes mellitus (T2DM), which is one of the most important chronic noncommunicable diseases. Effective and feasible strategies to treat IR are still urgently needed. Previous research studies reported that whole body vibration (WBV) was beneficial for IR in clinical; however, its underlying mechanisms remains unknown. In the present study, db/db mice were treated with WBV administration 60 min/day for 12 weeks and the impaired insulin sensitivity was improved. Besides, liver steatosis was also ameliorated. Further explorations revealed that WBV could reduce the expression of SREBP1c and increase the expression of GSH-Px and consequently suppress oxidative stress. In conclusion, WBV attenuates oxidative stress to ameliorate liver steatosis and thus improves insulin resistance in db/db mice. Therefore, WBV administration is a promising treatment for individuals who suffered from central obesity and IR. [ABSTRACT FROM AUTHOR]

The early work of Helmut Sies on mammalian hydroperoxide metabolism is reviewed with particular emphasis on the in situ function of catalase and glutathione peroxidase1. Starting out from a catalase-dominated thinking in the middle of the last century, Sies first demonstrated, by whole organ spectroscopy, that H 2 O 2 is generated in rat liver and metabolized by catalase. In a joined effort with the author's group, he then worked out that glutathione peroxidase can kinetically compete with catalase in hydroperoxide metabolism in situ . In compartmentalized cells, however, the “competition” of the two enzymes turned out to be a mutual complementation because of their different subcellular location. The studies for the first time documented that the metabolism of freely diffusible hydroperoxides is compartmentalized and, thus, paved the way to a better understanding of oxidant challenges and redox regulation. The article, garnished with personal memories, is meant as a nostalgic journey though ancient times of biochemistry with their changing fashions and paradigms, revealing the roots of topical perspectives and controversies in redox biology. [ABSTRACT FROM AUTHOR]

The biology of glutathione peroxidases and peroxiredoxins is reviewed with emphasis on their role in metabolic regulation. Apart from their obvious function in balancing oxidative challenge, these thiol peroxidases are not only implicated in orchestrating the adaptive response to oxidative stress, but also in regulating signaling triggered by hormones, growth factors and cytokines. The mechanisms presently discussed comprise dampening of redox-sensitive regulatory processes by elimination of hydroperoxides, suppression of lipoxygenase activity, committing suicide to save H2O2for signaling, direct binding to receptors or regulatory proteins in a peroxidase activity-independent manner, or acting as sensors for hydroperoxides and as transducers of oxidant signals. The various mechanistic proposals are discussed in the light of kinetic data, which unfortunately are scarce. Taking into account pivotal criteria of a meaningful regulatory circuit, kinetic plausibility and specificity, the mechanistic concepts implying a direct sensor/transducer function of the thiol peroxidases appear most appealing. With rate constants for the reaction with hydroperoxide of 105–108M− 1s− 1, thiol peroxidases are qualified as kinetically preferred hydroperoxide sensors, and the ability of the oxidized enzymes to react with defined protein thiols lends specificity to the transduction process. The versatility of thiol peroxidases, however, allows multiple ways of interaction with regulatory pathways. [ABSTRACT FROM AUTHOR]