Essential trace element selenium and redox regulation: its metabolism, physiological function, and related diseases

in Redox Experimental Medicine
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  • 1 Laboratory of Molecular Biology and Metabolism, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan

Correspondence should be addressed to Y Saito; Email: yoshiro.saito.a8@tohoku.ac.jp

Graphical abstract

Abstract

The essential trace element selenium plays a significant role in redox homeostasis in the human body. Selenium is very reactive and has a potent toxicity; however, the living body cleverly utilizes its reactivity for redox reactions. The biological function of selenium is mainly mediated by selenoproteins, which contain selenocysteine, a cysteine analogue that possesses selenium instead of sulphur. Twenty-five types of human selenoproteins have been identified, including glutathione peroxidase (GPX; for the reduction of hydrogen peroxide and lipid hydroperoxide) and thioredoxin reductase (for redox regulation). Selenoprotein P (SELENOP), which is a major selenoprotein in the plasma, is mainly synthesized in the liver and secreted into the plasma. As a multifunctional protein with selenium-transporting activity, GPX-like activity, and metal-binding properties, SELENOP plays a vital role in selenium metabolism and redox regulation. This review focuses on the relationship between selenium metabolism and redox regulation, particularly on the physiological role of selenoproteins and the pathophysiological implications of its disorder. Furthermore, the significant roles of selenium in infectious diseases and its utility for phylaxis are discussed.

Abstract

Graphical abstract

Abstract

The essential trace element selenium plays a significant role in redox homeostasis in the human body. Selenium is very reactive and has a potent toxicity; however, the living body cleverly utilizes its reactivity for redox reactions. The biological function of selenium is mainly mediated by selenoproteins, which contain selenocysteine, a cysteine analogue that possesses selenium instead of sulphur. Twenty-five types of human selenoproteins have been identified, including glutathione peroxidase (GPX; for the reduction of hydrogen peroxide and lipid hydroperoxide) and thioredoxin reductase (for redox regulation). Selenoprotein P (SELENOP), which is a major selenoprotein in the plasma, is mainly synthesized in the liver and secreted into the plasma. As a multifunctional protein with selenium-transporting activity, GPX-like activity, and metal-binding properties, SELENOP plays a vital role in selenium metabolism and redox regulation. This review focuses on the relationship between selenium metabolism and redox regulation, particularly on the physiological role of selenoproteins and the pathophysiological implications of its disorder. Furthermore, the significant roles of selenium in infectious diseases and its utility for phylaxis are discussed.

Introduction

More than 200 years have passed since the discovery of the essential trace element selenium. Selenium is a type of chalcogen in group 16 of the periodic table with a large electron orbital, which facilitates the emission and reception of electrons. The toxicity of selenium and its properties as an essential trace element have been clarified (Rayman 2012, Labunskyy et al. 2014, Saito 2021b). Selenium-containing proteins are called selenoproteins, which play a significant role in the removal of reactive oxygen species (ROS) and redox regulation. Selenoproteins are also a key factor in the antioxidant system (Conrad et al. 2018, Dagnell et al. 2018). Although selenium is an essential element, it is highly toxic and has a particularly narrow appropriate range between deficiency and excess. This mini review focused on the role of selenoproteins in redox regulation, particularly on the regulation of selenium metabolism by selenoprotein P (SELENOP). Furthermore, the relationship between the physiological functions of selenoproteins and diseases, especially their involvement in the redox regulation, has been described. Finally, the importance of selenium in the protection against infection is described and the potential of selenium-containing compounds as pharmaceuticals is discussed.

Properties of the essential trace element selenium

Selenium was discovered in 1817 by the Swedish chemist Jöns Jacob Berzelius. It is an element that was named after the moon goddess ‘Selene’ because of its similarity to tellurium, which means the Earth. Selenium has a larger electron orbit and is more reactive than oxygen and sulphur, which belong to group 16 of the periodic table. Toxicity was first identified as the action of selenium on the living body (Barceloux 1999, Anan et al. 2015, Hadrup & Ravn-Haren 2020). Nausea, diarrhoea, headache, and neuropathy are symptoms of excessive selenium. A pathology associated with selenium deficiency was later identified as Keshan disease, which is associated with severe cardiomyopathy caused by selenium deficiency (Fairweather-Tait et al. 2011, Zhou et al. 2018). Keshan disease is an endemic disease in the Keshan region of China, where the selenium concentration in soil is low. In addition, the increased pathogenicity of coxsackievirus associated with selenium deficiency is deeply involved in the development of cardiomyopathy (Levander & Beck 1997, Cermelli et al. 2002). Associations with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been reported recently (see chapter 6), suggesting the importance of selenium in the protection against viral infection. In addition, the incidence of arteriosclerosis and cancer (e.g. prostate cancer) increases with the decrease in blood selenium concentration in areas where the concentration of selenium in soil is low (Burk 2002, Avery & Hoffmann 2018). These disorders caused by selenium deficiency have been improved by selenium supplementation, and the necessity of selenium has become widely recognized. Selenium is known as an element with a particularly narrow appropriate range between deficiency and excess compared with other elements and nutrients. In contrast, recent epidemiological studies have shown that the risk of lifestyle-related diseases, such as type 2 diabetes, increases with the elevation in the blood levels of selenium (Rayman & Stranges 2013, Rees et al. 2013, Vinceti et al. 2022). As a selenium-containing protein in the plasma, SELENOP is significantly involved in the onset and progression of type 2 diabetes (Misu et al. 2010, Saito 2020, Takamura 2020). The risk of disability and disease associated with selenium excess as well as deficiency clearly reflects the characteristics of this element.

Role of selenoproteins in the antioxidative system and redox regulation

Selenoproteins contain selenium in the form of selenocysteine (Sec), which is an amino acid in which the sulphur in cysteine is replaced by selenium and plays an essential physiological role (Lee et al. 1989, Berry et al. 1991, Flohe 2009). Twenty-five types of selenoproteins have been identified in humans, which are related to several biological processes, including the antioxidant system and redox regulation (Table 1) (Kryukov et al. 2003, Hatfield et al. 2014). The functions of representative selenoproteins are given below.

Table 1

Function of selenoproteins.

SelenoproteinAbbreviationCharacter and function
Glutathione peroxidase 1GPxl, GPXlKO mouse shows highly sensitive to oxidative stress
Glutathione peroxidase 2GPx2, GPX2Protein levels are maintained under selenium deficiency
Glutathione peroxidase 3GPx3, GPX3Synthesized in the kidney and secreted into plasma
Glutathione peroxidase 4GPx4, GPX4Cytoplasm/mitochondria/nucleolus-specific isoforms are present KO mouse is embryonic lethal
Glutathione peroxidase 6GPx6, GPX6Exists in olfactory
lodothyronine deodinase 1D11, D1, D101Activates thyroid hormone
lodothyronine deodinase 2D12, D2, D102Tissue-specific activation of thyroid hormone
lodothyronine deodinase 3D13, D3, D103Tissue-specific inactivation of thyroid hormone
Thioredoxin reductase 1TrxRl, TRl, TXNRDlKO mouse is embryonic lethal
Thioredoxin reductase 2TrxR2, TR3, TXNRD2Mitochondria-specific Txnrd2 KO is embryonic lethal
Thioredoxin reductase 3TrxR3, TR2, TXNRD3Testis-specific Glutaredoxin activity
Selenophosphate synthetase 2SPS2, SEPHS2Selenophosphate synthesis
Selenoprotein PSeP, SELENOP, SelP, SEPPlSelenium transport and GPx4-like activity

KO mice have neuropathy and spermatogenesis failure
Methionine-R-sulphide reductaseMsrBl, SelR, SelX, MSRBlReduction of oxidized methionine
Selenoprotein FSep15, SEP15, SELENOF, SelFInvolved in protein folding in the endoplasmic reticulum Interaction with UGTR
Selenoprotein HSELENOH, SelHAntioxidative function
Selenoprotein ISELENOI, Sell, SEPI, EPTlSynthesis of phospholipid (PE)
Selenoprotein KSELENOK, SelKInvolved in Ca2 regulation via the endoplasmic reticulum
Selenoprotein MSELENOM, SelM, SEPMInvolved in protein folding in the endoplasmic reticulum
Selenoprotein NSELENON, SelN, SepN, SEPNlExists in the endoplasmic reticulum; necessary for muscle formation
Selenoprotein 0SELENOO, SelOExists in the mitochondria
Selenoprotein SSELENOS, SelS, SEPSl, VIMPExists in the endoplasmic reticulum
Selenoprotein TSELENOT, SellExists in the endoplasmic reticulum
Selenoprotein VSELENOV, SelVExists in testis
Selenoprotein WSELENOW, SelW, SEPWlAntioxidative function

Glutathione peroxidase (GPX), the first selenoprotein to be identified, is an enzyme that reduces and detoxifies hydroperoxides in the presence of glutathione (GSH) (Fig. 1A) (Flohe 2009, Brigelius-Flohe & Maiorino 2013). Sec forms the active site of GPX where the selenol (SeH) residue of Sec directly reacts with peroxides, such as hydrogen peroxide, and is then oxidized to SeOH while hydrogen peroxide is reduced to water. The SeOH is then reduced by GSH, returns to the SeH form, and reacts with the next peroxide in a ping-pong mechanism. Although six GPXs have been identified, GPX5 does not contain selenium and its antioxidative activity is unclear. GPX1 to GPX4 have been investigated extensively (Takahashi et al. 1990, Maiorino 2018, Saito 2021a). GPX1, GPX2, and GPX3 mainly reduce hydrogen peroxide as a substrate, whereas GPX4 has a unique substrate specificity and directly reduces phospholipid hydroperoxide (PL-OOH) (Thomas et al. 1990, Takebe et al. 2002, Ursini et al. 2022). GPX4 was identified as a regulator of ferroptosis, a type of nonapoptotic cell death that depends on lipid peroxidation and iron metabolism (Dixon et al. 2012, Stockwell et al. 2017, Ursini & Maiorino 2020). Radical-scavenging lipophilic antioxidants, such as vitamin E and coenzyme Q10, and iron chelators, such as deferoxamine, inhibit ferroptosis (Conrad et al. 2018, Saito 2021c). In turn, ferroptosis inducers, such as RSL3 and erastin, have inhibitory effects on GPX4 and the cystine transporter xCT, to maintain cellular GSH, underscoring the significance of the GSH-GPX4 axis in this form of cell death (Dixon et al. 2012, Friedmann Angeli et al. 2014). GPx4 KO mice exhibit embryonic lethality, and the reducing activity of PL-OOH has been shown to be essential for survival and cell proliferation (Imai et al. 2009, Ingold et al. 2018).

Figure 1
Figure 1

Function of representative selenoproteins. (A) Glutathione peroxidase (GPX) reduces several hydroperoxides (hydrogen peroxide, H2O2; phospholipid hydroperoxide, PL-OOH) by using glutathione (GSH). (B) Thioredoxin (TRN) reductase (TRNRD) reduces oxidized TRN by using NADPH. (C) Domain structure and function of selenoprotein P.

Citation: Redox Experimental Medicine 2022, 1; 10.1530/REM-22-0010

Thioredoxin reductase (TRNRD) is a selenoprotein that is responsible for redox control (Fig. 1B). TRNRD is an NADPH-dependent flavin enzyme that consumes NADPH and reduces TRN, and its active site is formed by Sec (Lu & Holmgren 2014, Dagnell et al. 2018). TRNRD1 is present in the cytoplasm and nucleus, whereas TRNRD2 is expressed in mitochondria. TRNRD3 is highly expressed in the testis. TRN has a CxxC motif (C: Cys; x: others), reduces protein disulphides and forms disulphide bonds with itself, to become oxidized TRN (Arner & Holmgren 2000, Lu & Holmgren 2014). TRN interacts with various molecules, such as peroxidase, ribonucleotide reductase, and the signalling molecule ASK1, and regulates their activity through redox reactions (Fujino et al. 2007). KO mice for either TRN or TRNRD exhibit embryonic lethality, thus demonstrating the importance of the TRN–TRNRD system.

Iodothyronine deiodinase (DI), which activates or inactivates the thyroid hormone, is also a selenoprotein that is represented by three types, that is, DI1, DI2, and DI3, which have different substrate characteristics and intracellular localizations (Kohrle 2000, 2013, Labunskyy et al. 2014). The physiological function of DI indicates that selenoproteins are involved not only in the antioxidant system but also in growth/development and energy metabolism.

As the major selenium-containing protein, SELENOP accounts for 50% of human plasma selenium, with the ‘P’ standing for ‘plasma’ (Fig. 1C). SELENOP is synthesized mainly in the liver and secreted into plasma (Saito & Takahashi 2002, Burk & Hill 2015). SELENOP has ten Sec residues in the polypeptide chain, which makes SELENOP multifunctional (Fig. 1C); SELENOP has GPX4-like reducing activity for PL-OOH and a Sec residue on the N-terminal side is the active site of this enzyme, while SELENOP has a selenium-transporting activity that efficiently delivers selenium to the cells, in which abundant nine Sec residues on the C-terminal side play their role (Saito et al. 1999, 2004). The function of SELENOP to transport selenium from the liver to each organ is mediated by SELENOP receptors, such as lipoprotein receptor-related protein 1 (LRP1), LRP2 (megalin), and LRP8 (ApoER2) (Burk & Hill 2015, Saito 2021b). LRP8 mediates preferential selenium transport to the brain, testis, thyroid gland, and bone. In SELENOP KO mice, selenium content in the brain and testis is decreased, and male infertility with failure of spermatogenesis is observed, in which LRP8 KO mice show a similar phenotype (Hill et al. 2003, Schomburg et al. 2003). SELENOP and LRP8 interact at the blood–brain barrier and also within the brain to maintain selenium (Burk et al. 2014). The significance of SELENOP expression in the brain for maintaining selenium levels was demonstrated in liver-specific SELENOP KO mice (Schomburg et al. 2004, Renko et al. 2008). A His-rich region that contains consecutive His residues is located in the middle of SELENOP, and a typical heparin-binding motif XBBXB (B: a basic amino acid) in this region is responsible for the heparin-binding properties of SELENOP (Saito 2020b). In addition, SELENOP binds heavy metals such as copper and cadmium, and its consecutive His residues function as a natural, high-affinity His-tag binding site for nickel-nitrilotriacetic acid (Ni-NTA) agarose (Suzuki et al. 1998, Du et al. 2014). SELENOP is also identified as a major methylmercury-binding protein in plasma, suggesting that it plays a role in the detoxication of heavy metals (Liu et al. 2018).

Selenium metabolism and selenoprotein P synthesis

Selenium metabolism is strictly regulated in our body, and Sec contained in selenoprotein is uniquely synthesized on tRNA using inorganic selenium (Fig. 2). Sec is encoded by one of the stop codons UGA and is also called the 21st amino acid that is translated (Berry et al. 1991, Hatfield et al. 2014). Serine binds to tRNASec, which has the anticodon of UGA, and the hydroxyl group (-OH) of Ser undergoes phosphorylation (Fig. 2, lower scheme). Selenophosphate synthetase 2 (SPS2) produces selenophosphate (H2SePO3) from inorganic selenium and ATP. SPS2 is a selenoprotein and is thought to be involved in the self-regulation of the Sec synthesis system. By the action of Sec synthase, selenol group (-SeH) is generated from H2SePO3 and phosphorylated Ser-tRNASec, and the synthesis of Sec on tRNA is completed (Mihara et al. 2000). The translation mechanism by which Sec-tRNASec is inserted into the polypeptide chain is shown in Fig. 3. For the translation of Sec, Sec-insertion sequence (SECIS), a stable loop structure in the 3’-UTR (3’UTR) of mRNA, is indispensable (Fig. 3A). SECIS-binding protein 2 (SBP2), eucaryote elongation factor for Sec translation (eEFSec), and Sec-tRNASec form a complex in SECIS (Fig. 3B). When the translation reaches UGA, Sec-tRNASec is supplied from the SECIS complex (Copeland et al. 2000). Then, translation continues, and translation stops at a stop codon other than UGA. SECIS structure is found in 3’UTR of all selenoprotein mRNAs and is important for the stability of mRNA (Seyedali & Berry 2014). Selenoprotein mRNA without SBP2 and Sec-tRNASec is degraded by nonsense-mediated mRNA decay (NMD) because of the presence of the stop codon UGA in the open reading frame (ORF). Under selenium-deficient condition with the decrease of Sec-tRNASec, UPF1, which is essential for NMD, binds to selenoprotein mRNA and promotes its degradation (Seyedali & Berry 2014). The affinity between SECIS and SBP2 is not uniform and is different between selenoproteins (Low et al. 2000). SECIS of TRNRD and GPX4 have a strong affinity for SBP2, while that of GPX1 has a low affinity. Under selenium-deficient condition with low Sec-tRNASec, the biosynthesis of GPX1 is suppressed and instead selenium is preferentially used for the biosynthesis of TRNRD and GPX4. It is interesting to note that SELENOP is the only selenoprotein that has two SECISs in 3’UTR of its mRNA. This machinery is understood as a system that efficiently utilizes limited selenium for important selenoprotein synthesis.

Figure 2
Figure 2

Synthetic pathway of selenocysteine (Sec) from selenium-containing amino acids. SeMet is converted to Sec by Met metabolizing enzymes (#1–#5) indistinguishable from sulphur. CBS (#4) and CSE (#5) are also known as cysteine persulphide-producing enzymes. Inorganic selenium is generated from Sec by Sec lyase and is converted to selenophosphate by SPS2. By the action of SecS, Sec is produced on tRNA from selenophosphate and phosphorylated Ser-tRNASec.

Citation: Redox Experimental Medicine 2022, 1; 10.1530/REM-22-0010

Figure 3
Figure 3

Translation mechanism of selenoprotein. (A) Structure of selenoprotein mRNA. (B) Mechanism of selenocysteine insertion. eEFsec, eukaryotic elongation factor for Sec translation; eIF4a3, eukaryotic initiation factor, SBP2, SECIS-binding protein 2; RPL30, ribosomal protein L30.

Citation: Redox Experimental Medicine 2022, 1; 10.1530/REM-22-0010

Selenium for the Sec synthesis is from foods. After being digested, selenium is absorbed from the digestive tract and enters the synthetic pathway of selenoprotein, but the metabolic pathway depends on the chemical form of selenium. In the case of Sec in the food, the inorganic selenium produced by Sec lyase enters the Sec synthesis system (Fig. 2, upper scheme) (Mihara et al. 2000). On the other hand, selenomethionine (SeMet), a methionine homolog containing selenium instead of sulphur, is one of the main selenium sources absorbed in the body (Schrauzer 2000). Absorbed SeMet is metabolized indistinguishable from methionine, and a part of it is directly incorporated into proteins. SeMet is occasionally converted to Sec by the methionine metabolic enzyme and then enters the Sec synthesis system through the action of Sec lyase (Fig. 2, upper scheme).

The liver plays a central role in selenium metabolism (Fig. 4). Of the selenium absorbed in the liver, the selenium used for the biosynthesis of SELENOP is secreted into the blood and used for the synthesis of selenoprotein in each organ (Hill et al. 2012, Saito 2021b). Absorbed SeMet is randomly distributed to blood and tissues. In addition, there are other routes that enter the systemic circulation as small molecules and routes that are excreted into urine as selenosugar and trimethylselenonium (Kobayashi et al. 2002).

Figure 4
Figure 4

Expression regulatory mechanism of selenoprotein in the liver. The liver plays a central role in selenium metabolism. Dietary selenium can be divided into selenocysteine synthesis or excretion as selenosugar and trimethylselenonium ion, (CH3)3Se+. In the Sec synthesis system, selenium synthesized as SELENOP enters the systemic circulation. Small selenium-containing compounds bound to albumin also enter the systemic circulation.

Citation: Redox Experimental Medicine 2022, 1; 10.1530/REM-22-0010

SELENOP expression is regulated by several factors (Fig. 4) (Saito 2020a). Selenium deficiency reduces SELENOP expression through a decrease in Sec-tRNASec. The expression of SELENOP is also regulated by transcription; the levels of SELENOP mRNA are lowered by cytokines such as interleukin 6, tumour necrosis factor alpha, interferon gamma, and transforming growth factor beta, as well as by insulin. On the other hand, SELENOP mRNA levels are increased under hyperglycaemia and high fat (Takamura 2020). The nuclear translocation of the transcription factor FoxO3a and the expression of SELENOP increase by the decrease of AMP-activated protein kinase (AMPK) activity that is associated with hyperglycaemia (Misu et al. 2010). Transcriptional regulation of SELENOP via FoxO1, PGC1α, and HNF4α has also been known, and selenoprotein expression is closely related to glucose and energy metabolism (Saito 2020a). Recently, long ncRNA (lncRNA) that inhibits selenoprotein P translation, L-IST, has been identified (Mita et al. 2021). This lncRNA interacted with the SELENOP mRNA and inhibited its binding to the SBP2, resulting in the decrease of ribosome binding.

Selenoproteins related diseases and redox regulation

Disorders due to selenium deficiency or excess have been recognized for a long time, but in recent years, a relationship between changes in selenoprotein expression and lifestyle-related diseases has been found (Rayman & Stranges 2013, Rees et al. 2013, Vinceti et al. 2022). In type 2 diabetes patients, levels of SELENOP mRNA in the liver and blood SELENOP protein were increased (Misu et al. 2010). A positive correlation was observed between the blood SELENOP levels and the blood glucose levels after glucose loading and the fasting blood glucose, indicating the relationship between the increase in SELNOP and the deterioration of glucose metabolism. Since insulin resistance increases in mice administered with SELENOP corresponding to the increased amount in diabetic patients, excess SELENOP is considered to act as a ‘bad guy’ involved in the onset and progression of diabetes (Misu et al. 2010). It was also clarified that excess SELENOP impairs the function of pancreatic β-cells and reduces insulin secretory capacity (Mita et al. 2017). Further, excess SELENOP increases exercise resistance and impairs cold-induced thermogenesis in brown fat, indicating systematic deteriorating effects on glucose and energy metabolism (Misu et al. 2017, Oo et al. 2022). Insulin resistance and insulin secretion are improved by the administration of a neutralizing antibody that suppresses the intracellular uptake of SELENOP in diabetes model mice, suggesting that excess SELENOP is a good target of lifestyle-related diseases (Mita et al. 2017). Furthermore, the increased expression of SELENOP is involved in the formation of lesions in pulmonary hypertension, suggesting that the abnormal expression control of SELENOP is involved in various diseases (Kikuchi et al. 2018).

Various relationships have been shown between cancer and selenoproteins (Rayman 2012, Hatfield et al. 2014). In ‘initiation,’ irreversible changes of genomic information during the carcinogenesis, antioxidant systems, and selenoproteins act to protect against ROS-induced DNA damage. On the other hand, in ‘promotion,’ in which cells with DNA damage start to proliferate, and in ‘progression,’ in which new properties as cancer cells are acquired and malignancy increases, the enhancement of selenoprotein expression promotes the growth of cancer cells. GPX4 and TRNRD1 have been identified as a target for anti-cancer agents (Dagnell et al. 2018, Stockwell et al. 2017). GPX4 inhibitors try to use for the induction of ferroptosis for cancer cells. TRNRD1 is involved in DNA repair, has the effect of activating the tumor suppressor p53, and is thought to act on the suppression of carcinogenesis. On the other hand, TRNRD1 is highly expressed in cancer cells, and inactivation of TRNRD1 is effective in suppressing the growth of cancer cells. TRNRD1 is considered to be involved in the onset and progression of cancer in terms of both merits and demerits.

Selenium and infectious disease

The significance of selenium levels in the defence against infection is strongly recognized, and the fact that Keshan disease, which was first reported as selenium deficiency, is associated with the virulence of the Coxsackie virus reflects its consequence (Levander et al. 1997, Cermelli et al. 2002). In human immunodeficiency virus patients, the decreases in survival rate with the decline in selenium level have been known, and the significance of the selenium levels against several infectious diseases, such as influenza virus, hepatitis virus, and West Nile virus, has been shown (Verma et al. 2008, Himoto et al. 2011, Yu et al. 2011, Rayman 2012). Furthermore, the relevance of the coronavirus disease 2019 (COVID-19) has been actively investigated, and the correlation between selenium levels and the risk of aggravation or the cure rate in the infection of SARS-CoV-2 has been reported (Zhang et al. 2020). Particularly, it has recently been reported that SELENOP levels are more associated with severity than selenium and that SELENOP, Zn, and age can be the predicted biomarkers for the risk of severity (Heller et al. 2021). The relevance of COVID-19 disease risk with the SELENOP function is very attractive. Cytokine storms are thought to be a cause to trigger aggravation, while the antioxidant system functions as an important regulator of cytokine production and inflammatory response. The SELENOP function in macrophages, especially the relationship with the M1 and M2 ratio, needs to be elucidated to understand the defence system for the pathogen.

Selenium might be useful as a therapeutic agent for infectious diseases. SARS-CoV-2 has two cysteine proteases called papain-like protease (PLpro) and chymotrypsin-like protease (CLpro) on its genome, and the activity of these proteases plays an essential role in the growth of this virus. Particularly, CLpro is an attractive drug discovery target because it is involved in the maturation of multiple viral proteins, including spike protein. Approximately 10,000 compounds have been screened to identify the inhibitors of CLpro, and ‘ebselen’ has been identified as a compound that inhibits CLpro and suppresses virus growth (Jin et al. 2020). Ebselen is a selenium-containing compound developed as a GPX mimic that removes ROS by using a GSH as a reductant (Sies & Parnham 2020). It was investigated up to Phase III as a brain metabolism improving drug, but its development was abandoned due to hepatotoxicity of long-term administration and insufficient efficacy compared to existing drugs. Since the inhibitory effect of ebselen on cysteine proteases, such as papain, has been known, it is not strange that ebselen inhibits CLpro activity (Sies & Parnham 2020). The inhibitory effect of ebselen on the Mycobacterium tuberculosis-derived transpeptidase with reactive cysteine and the formation of selenosulphide (Se-S) bonds with active cysteine have also been reported (de Munnik et al. 2019). In addition, the inhibitory effect of ebselen derivatives on CLpro and the formation of a covalent bond with reactive cysteine were reported (Menendez et al. 2020). Furthermore, ebselen is expected to have an inhibitory effect on cytokine storms by reducing ROS and might be an effective therapeutic drug for the COVID-19 (Sies & Parnham 2020). In the future, it is necessary to verify the effects of SARS-CoV-2 in vivo, but we can expect the development of selenium-containing compounds as therapeutic agents for a wide range of infectious diseases.

Conclusion

Selenium is a unique element for living organisms and has properties that are acting as a poison, nutrient, and medicine. Alteration of selenoproteins, which are responsible for redox regulation, has been discussed mainly on selenium intake and its hierarchy, but the involvement of expression changes in various diseases has been clarified, and now selenoproteins have become therapeutic targets. In drug discovery targeting selenoproteins, how to control selenoproteins, which play an essential role, will be the key, and understanding of lesions at the molecular level will be indispensable. In addition, it is expected to develop highly safe selenium-containing compounds with low toxicity in the development of pharmaceuticals that utilize the characteristics of selenium, especially in the provision against infectious diseases.

Declaration of interest

Yoshiro Saito is an Editor of Redox Experimental Medicine. Yoshiro Saito was not involved in the review or editorial process for this paper, on which he is listed as an author.

Funding

This work was supported in part by JSPS KAKENHI (grant number 20H00488, 20H05491, 21K19321, and 21H05270) and Japan Agency for Medical Research and Development (AMED, grant number 21ek0210144h0002 and BINDS 21am0101095j0005).

References

  • Anan Y, Nakajima G & Ogra Y 2015 Complementary use of LC-ICP-MS and LC-ESI-Q-TOF-MS for selenium speciation. Analytical Sciences 31 561564. (https://doi.org/10.2116/analsci.31.561)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Arner ES & Holmgren A 2000 Physiological functions of thioredoxin and thioredoxin reductase. European Journal of Biochemistry 267 61026109. (https://doi.org/10.1046/j.1432-1327.2000.01701.x)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Avery JC & Hoffmann PR 2018 Selenium, selenoproteins, and immunity. Nutrients 10 1203. (https://doi.org/10.3390/nu10091203)

  • Barceloux DG 1999 Selenium. Journal of Toxicology: Clinical Toxicology 37 145172. (https://doi.org/10.1081/clt-100102417)

  • Berry MJ, Banu L, Chen YY, Mandel SJ, Kieffer JD, Harney JW & Larsen PR 1991 Recognition of UGA as a selenocysteine codon in type I deiodinase requires sequences in the 3’ untranslated region. Nature 353 273276. (https://doi.org/10.1038/353273a0)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Brigelius-Flohe R & Maiorino M 2013 Glutathione peroxidases. Biochimica et Biophysica Acta 1830 32893303. (https://doi.org/10.1016/j.bbagen.2012.11.020)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Burk RF 2002 Selenium, an antioxidant nutrient. Nutrition in Clinical Care 5 7579. (https://doi.org/10.1046/j.1523-5408.2002.00006.x)

  • Burk RF & Hill KE 2015 Regulation of selenium metabolism and transport. Annual Review of Nutrition 35 109134. (https://doi.org/10.1146/annurev-nutr-071714-034250)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Burk RF, Hill KE, Motley AK, Winfrey VP, Kurokawa S, Mitchell SL & Zhang W 2014 Selenoprotein P and apolipoprotein E receptor-2 interact at the blood-brain barrier and also within the brain to maintain an essential selenium pool that protects against neurodegeneration. FASEB Journal 28 35793588. (https://doi.org/10.1096/fj.14-252874)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Cermelli C, Vinceti M, Scaltriti E, Bazzani E, Beretti F, Vivoli G & Portolani M 2002 Selenite inhibition of Coxsackie virus B5 replication: implications on the etiology of Keshan disease. Journal of Trace Elements in Medicine and Biology 16 4146. (https://doi.org/10.1016/S0946-672X(0280007-4)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Conrad M, Kagan VE, Bayir H, Pagnussat GC, Head B, Traber MG & Stockwell BR 2018 Regulation of lipid peroxidation and ferroptosis in diverse species. Genes and Development 32 602619. (https://doi.org/10.1101/gad.314674.118)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Copeland PR, Fletcher JE, Carlson BA, Hatfield DL & Driscoll DM 2000 A novel RNA binding protein, SBP2, is required for the translation of mammalian selenoprotein mRNAs. EMBO Journal 19 306314. (https://doi.org/10.1093/emboj/19.2.306)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Dagnell M, Schmidt EE & Arner ESJ 2018 The A to Z of modulated cell patterning by mammalian thioredoxin reductases. Free Radical Biology and Medicine 115 484496. (https://doi.org/10.1016/j.freeradbiomed.2017.12.029)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • de Munnik M, Lohans CT, Lang PA, Langley GW, Malla TR, Tumber A, Schofield CJ & Brem J 2019 Targeting the Mycobacterium tuberculosis transpeptidase LdtMt2 with cysteine-reactive inhibitors including ebselen. Chemical Communications 55 1021410217. (https://doi.org/10.1039/c9cc04145a)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM & Yang WS et al.2012 Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149 10601072. (https://doi.org/10.1016/j.cell.2012.03.042)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Du XB, Zheng YB, Wang Z, Chen YJ, Zhou R, Song GL, Ni JZ & Liu Q 2014 Inhibitory act of selenoprotein P on Cu+/Cu2+-induced tau aggregation and neurotoxicity. Inorganic Chemistry 53 1122111230. (https://doi.org/10.1021/ic501788v)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Fairweather-Tait SJ, Bao Y, Broadley MR, Collings R, Ford D, Hesketh JE & Hurst R 2011 Selenium in human health and disease. Antioxidants and Redox Signaling 14 13371383. (https://doi.org/10.1089/ars.2010.3275)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Flohe L 2009 The labour pains of biochemical selenology: the history of selenoprotein biosynthesis. Biochimica et Biophysica Acta 1790 13891403. (https://doi.org/10.1016/j.bbagen.2009.03.031)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Friedmann Angeli JP, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ, Herbach N, Aichler M, Walch A & Eggenhofer E et al.2014 Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nature Cell Biology 16 11801191. (https://doi.org/10.1038/ncb3064)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Fujino G, Noguchi T, Matsuzawa A, Yamauchi S, Saitoh M, Takeda K & Ichijo H 2007 Thioredoxin and TRAF family proteins regulate reactive oxygen species-dependent activation of ASK1 through reciprocal modulation of the N-terminal homophilic interaction of ASK1. Molecular and Cellular Biology 27 81528163. (https://doi.org/10.1128/MCB.00227-07)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Hadrup N & Ravn-Haren G 2020 Acute human toxicity and mortality after selenium ingestion: a review. Journal of Trace Elements in Medicine and Biology 58 126435. (https://doi.org/10.1016/j.jtemb.2019.126435)

    • Search Google Scholar
    • Export Citation
  • Hatfield DL, Tsuji PA, Carlson BA & Gladyshev VN 2014 Selenium and selenocysteine: roles in cancer, health, and development. Trends in Biochemical Sciences 39 112120. (https://doi.org/10.1016/j.tibs.2013.12.007)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Heller RA, Sun Q, Hackler J, Seelig J, Seibert L, Cherkezov A, Minich WB, Seemann P, Diegmann J & Pilz M et al.2021 Prediction of survival odds in COVID-19 by zinc, age and selenoprotein P as composite biomarker. Redox Biology 38 101764. (https://doi.org/10.1016/j.redox.2020.101764)

    • Search Google Scholar
    • Export Citation
  • Hill KE, Zhou J, McMahan WJ, Motley AK, Atkins JF, Gesteland RF & Burk RF 2003 Deletion of selenoprotein P alters distribution of selenium in the mouse. Journal of Biological Chemistry 278 1364013646. (https://doi.org/10.1074/jbc.M300755200)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Hill KE, Wu S, Motley AK, Stevenson TD, Winfrey VP, Capecchi MR, Atkins JF & Burk RF 2012 Production of selenoprotein P (Sepp1) by hepatocytes is central to selenium homeostasis. Journal of Biological Chemistry 287 4041440424. (https://doi.org/10.1074/jbc.M112.421404)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Himoto T, Yoneyama H, Kurokohchi K, Inukai M, Masugata H, Goda F, Haba R, Watababe S, Kubota S & Senda S et al.2011 Selenium deficiency is associated with insulin resistance in patients with hepatitis C virus-related chronic liver disease. Nutrition Research 31 829835. (https://doi.org/10.1016/j.nutres.2011.09.021)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Imai H, Hakkaku N, Iwamoto R, Suzuki J, Suzuki T, Tajima Y, Konishi K, Minami S, Ichinose S & Ishizaka K et al.2009 Depletion of selenoprotein GPx4 in spermatocytes causes male infertility in mice. Journal of Biological Chemistry 284 3252232532. (https://doi.org/10.1074/jbc.M109.016139)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Ingold I, Berndt C, Schmitt S, Doll S, Poschmann G, Buday K, Roveri A, Peng X, Porto Freitas F & Seibt T et al.2018 Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis. Cell 172 409 .e21422.e21. (https://doi.org/10.1016/j.cell.2017.11.048)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Jin Z, Du X, Xu Y, Deng Y, Liu M, Zhao Y, Zhang B, Li X, Zhang L & Peng C et al.2020 Structure of M(pro) from SARS-CoV-2 and discovery of its inhibitors. Nature 582 289293. (https://doi.org/10.1038/s41586-020-2223-y)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Kikuchi N, Satoh K, Kurosawa R, Yaoita N, Elias-Al-Mamun M, Siddique MAH, Omura J, Satoh T, Nogi M & Sunamura S et al.2018 Selenoprotein P promotes the development of pulmonary arterial hypertension: possible novel therapeutic target. Circulation 138 600623. (https://doi.org/10.1161/CIRCULATIONAHA.117.033113)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Kobayashi Y, Ogra Y, Ishiwata K, Takayama H, Aimi N & Suzuki KT 2002 Selenosugars are key and urinary metabolites for selenium excretion within the required to low-toxic range. PNAS 99 1593215936. (https://doi.org/10.1073/pnas.252610699)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Kohrle J 2000 The selenoenzyme family of deiodinase isozymes controls local thyroid hormone availability. Reviews in Endocrine and Metabolic Disorders 1 4958. (https://doi.org/10.1023/a:1010012419869)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Kohrle J 2013 Selenium and the thyroid. Current Opinion in Endocrinology, Diabetes, and Obesity 20 441448. (https://doi.org/10.1097/01.med.0000433066.24541.88)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Kryukov GV, Castellano S, Novoselov SV, Lobanov AV, Zehtab O, Guigo R & Gladyshev VN 2003 Characterization of mammalian selenoproteomes. Science 300 14391443. (https://doi.org/10.1126/science.1083516)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Labunskyy VM, Hatfield DL & Gladyshev VN 2014 Selenoproteins: molecular pathways and physiological roles. Physiological Reviews 94 739777. (https://doi.org/10.1152/physrev.00039.2013)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Lee BJ, Worland PJ, Davis JN, Stadtman TC & Hatfield DL 1989 Identification of a selenocysteyl-tRNA(Ser) in mammalian cells that recognizes the nonsense codon, UGA. Journal of Biological Chemistry 264 97249727. (https://doi.org/10.1016/S0021-9258(1881714-8)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Levander OA & Beck MA 1997 Interacting nutritional and infectious etiologies of Keshan disease. Insights from Coxsackie virus B-induced myocarditis in mice deficient in selenium or vitamin E. Biological Trace Element Research 56 521. (https://doi.org/10.1007/BF02778980)

    • Search Google Scholar
    • Export Citation
  • Liu Y, Zhang W, Zhao JT, Lin XY, Liu JM, Cui LW, Gao YX, Zhang TL, Li B & Li YF 2018 Selenoprotein P as the major transporter for mercury in serum from methylmercury-poisoned rats. Journal of Trace Elements in Medicine and Biology 50 589595. (https://doi.org/10.1016/j.jtemb.2018.04.013)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Low SC, Grundner-Culemann E, Harney JW & Berry MJ 2000 SECIS-SBP2 interactions dictate selenocysteine incorporation efficiency and selenoprotein hierarchy. EMBO Journal 19 68826890. (https://doi.org/10.1093/emboj/19.24.6882)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Lu J & Holmgren A 2014 The thioredoxin antioxidant system. Free Radical Biology and Medicine 66 7587. (https://doi.org/10.1016/j.freeradbiomed.2013.07.036)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Maiorino M, Conrad M & Ursini F 2018 GPx4, lipid peroxidation, and cell death: discoveries, rediscoveries, and open issues. Antioxidants and Redox Signaling 29 6174. (https://doi.org/10.1089/ars.2017.7115)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Menendez CA, Bylehn F, Perez-Lemus GR, Alvarado W & de Pablo JJ 2020 Molecular characterization of ebselen binding activity to SARS-CoV-2 main protease. Science Advances 6 eabd0345. (https://doi.org/10.1126/sciadv.abd0345)

    • Search Google Scholar
    • Export Citation
  • Mihara H, Kurihara T, Yoshimura T & Esaki N 2000 Kinetic and mutational studies of three NifS homologs from Escherichia coli: mechanistic difference between L-cysteine desulfurase and L-selenocysteine lyase reactions. Journal of Biochemistry 127 559567. (https://doi.org/10.1093/oxfordjournals.jbchem.a022641)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Misu H, Takamura T, Takayama H, Hayashi H, Matsuzawa-Nagata N, Kurita S, Ishikura K, Ando H, Takeshita Y & Ota T et al.2010 A liver-derived secretory protein, selenoprotein P, causes insulin resistance. Cell Metabolism 12 483495. (https://doi.org/10.1016/j.cmet.2010.09.015)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Misu H, Takayama H, Saito Y, Mita Y, Kikuchi A, Ishii KA, Chikamoto K, Kanamori T, Tajima N & Lan F et al.2017 Deficiency of the hepatokine selenoprotein P increases responsiveness to exercise in mice through upregulation of reactive oxygen species and AMP-activated protein kinase in muscle. Nature Medicine 23 508516. (https://doi.org/10.1038/nm.4295)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Mita Y, Nakayama K, Inari S, Nishito Y, Yoshioka Y, Sakai N, Sotani K, Nagamura T, Kuzuhara Y & Inagaki K et al.2017 Selenoprotein P-neutralizing antibodies improve insulin secretion and glucose sensitivity in type 2 diabetes mouse models. Nature Communications 8 1658. (https://doi.org/10.1038/s41467-017-01863-z)

    • Search Google Scholar
    • Export Citation
  • Mita Y, Uchida R, Yasuhara S, Kishi K, Hoshi T, Matsuo Y, Yokooji T, Shirakawa Y, Toyama T & Urano Y et al.2021 Identification of a novel endogenous long non-coding RNA that inhibits selenoprotein P translation. Nucleic Acids Research 49 68936907. (https://doi.org/10.1093/nar/gkab498)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Oo SM, Oo HK, Takayama H, Ishii KA, Takeshita Y, Goto H, Nakano Y, Kohno S, Takahashi C & Nakamura H et al.2022 Selenoprotein P-mediated reductive stress impairs cold-induced thermogenesis in brown fat. Cell Reports 38 110566. (https://doi.org/10.1016/j.celrep.2022.110566)

    • Search Google Scholar
    • Export Citation
  • Rayman MP 2012 Selenium and human health. Lancet 379 12561268. (https://doi.org/10.1016/S0140-6736(1161452-9)

  • Rayman MP & Stranges S 2013 Epidemiology of selenium and type 2 diabetes: can we make sense of it? Free Radical Biology and Medicine 65 15571564. (https://doi.org/10.1016/j.freeradbiomed.2013.04.003)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Rees K, Hartley L, Day C, Flowers N, Clarke A & Stranges S 2013 Selenium supplementation for the primary prevention of cardiovascular disease. Cochrane Database of Systematic Reviews 2013 CD009671. (https://doi.org/10.1002/14651858.CD009671.pub2/full)

    • Search Google Scholar
    • Export Citation
  • Renko K, Werner M, Renner-Muller I, Cooper TG, Yeung CH, Hollenbach B, Scharpf M, Kohrle J, Schomburg L & Schweizer U 2008 Hepatic selenoprotein P (SePP) expression restores selenium transport and prevents infertility and motor-incoordination in Sepp-knockout mice. Biochemical Journal 409 741749. (https://doi.org/10.1042/BJ20071172)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Saito Y 2020a Selenoprotein P as a significant regulator of pancreatic beta cell function. Journal of Biochemistry 167 119124. (https://doi.org/10.1093/jb/mvz061)

    • Search Google Scholar
    • Export Citation
  • Saito Y 2020b Selenoprotein P as an in vivo redox regulator: disorders related to its deficiency and excess. Journal of Clinical Biochemistry and Nutrition 66 17. (https://doi.org/10.3164/jcbn.19-31)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Saito Y 2021a Lipid peroxidation products as a mediator of toxicity and adaptive response – the regulatory role of selenoprotein and vitamin E. Archives of Biochemistry and Biophysics 703 108840. (https://doi.org/10.1016/j.abb.2021.108840)

    • Search Google Scholar
    • Export Citation
  • Saito Y 2021b Selenium transport mechanism via selenoprotein P-Its physiological role and related diseases. Frontiers in Nutrition 8 685517. (https://doi.org/10.3389/fnut.2021.685517)

    • Search Google Scholar
    • Export Citation
  • Saito Y 2021c Diverse cytoprotective actions of vitamin E isoforms – role as peroxyl radical scavengers and complementary functions with selenoproteins. Free Radical Biology and Medicine 175 121129. (https://doi.org/10.1016/j.freeradbiomed.2021.08.234)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Saito Y & Takahashi K 2002 Characterization of selenoprotein P as a selenium supply protein. European Journal of Biochemistry 269 57465751. (https://doi.org/10.1046/j.1432-1033.2002.03298.x)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Saito Y, Hayashi T, Tanaka A, Watanabe Y, Suzuki M, Saito E & Takahashi K 1999 Selenoprotein P in human plasma as an extracellular phospholipid hydroperoxide glutathione peroxidase. Isolation and enzymatic characterization of human selenoprotein p. Journal of Biological Chemistry 274 28662871. (https://doi.org/10.1074/jbc.274.5.2866)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Saito Y, Sato N, Hirashima M, Takebe G, Nagasawa S & Takahashi K 2004 Domain structure of bi-functional selenoprotein P. Biochemical Journal 381 841846. (https://doi.org/10.1042/BJ20040328)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Schomburg L, Schweizer U, Holtmann B, Flohe L, Sendtner M & Kohrle J 2003 Gene disruption discloses role of selenoprotein P in selenium delivery to target tissues. Biochemical Journal 370 397402. (https://doi.org/10.1042/BJ20021853)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Schomburg L, Schweizer U & Kohrle J 2004 Selenium and selenoproteins in mammals: extraordinary, essential, enigmatic. Cellular and Molecular Life Sciences 61 19881995. (https://doi.org/10.1007/s00018-004-4114-z)

    • Search Google Scholar
    • Export Citation
  • Schrauzer GN 2000 Selenomethionine: a review of its nutritional significance, metabolism and toxicity. Journal of Nutrition 130 16531656. (https://doi.org/10.1093/jn/130.7.1653)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Seyedali A & Berry MJ 2014 Nonsense-mediated decay factors are involved in the regulation of selenoprotein mRNA levels during selenium deficiency. RNA 20 12481256. (https://doi.org/10.1261/rna.043463.113)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Sies H & Parnham MJ 2020 Potential therapeutic use of ebselen for COVID-19 and other respiratory viral infections. Free Radical Biology and Medicine 156 107112. (https://doi.org/10.1016/j.freeradbiomed.2020.06.032)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, Fulda S, Gascon S, Hatzios SK & Kagan VE et al.2017 Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell 171 273285. (https://doi.org/10.1016/j.cell.2017.09.021)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Suzuki KT, Sasakura C & Yoneda S 1998 Binding sites for the (Hg-Se) complex on selenoprotein P. Biochimica et Biophysica Acta 1429 102112. (https://doi.org/10.1016/s0167-4838(9800221-0)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Takahashi K, Akasaka M, Yamamoto Y, Kobayashi C, Mizoguchi J & Koyama J 1990 Primary structure of human plasma glutathione peroxidase deduced from cDNA sequences. Journal of Biochemistry 108 145148. (https://doi.org/10.1093/oxfordjournals.jbchem.a123172)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Takamura T 2020 Hepatokine selenoprotein P-mediated reductive stress causes resistance to intracellular signal transduction. Antioxidants and Redox Signaling 33 517524. (https://doi.org/10.1089/ars.2020.8087)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Takebe G, Yarimizu J, Saito Y, Hayashi T, Nakamura H, Yodoi J, Nagasawa S & Takahashi K 2002 A comparative study on the hydroperoxide and thiol specificity of the glutathione peroxidase family and selenoprotein P. Journal of Biological Chemistry 277 4125441258. (https://doi.org/10.1074/jbc.M202773200)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Thomas JP, Geiger PG, Maiorino M, Ursini F & Girotti AW 1990 Enzymatic reduction of phospholipid and cholesterol hydroperoxides in artificial bilayers and lipoproteins. Biochimica et Biophysica Acta 1045 252260. (https://doi.org/10.1016/0005-2760(9090128-k)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Ursini F & Maiorino M 2020 Lipid peroxidation and ferroptosis: the role of GSH and GPx4. Free Radical Biology and Medicine 152 175185. (https://doi.org/10.1016/j.freeradbiomed.2020.02.027)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Ursini F, Bosello Travain V, Cozza G, Miotto G, Roveri A, Toppo S & Maiorino M 2022 A white paper on phospholipid hydroperoxide glutathione peroxidase (GPx4) forty years later. Free Radical Biology and Medicine 188 117133. (https://doi.org/10.1016/j.freeradbiomed.2022.06.227)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Verma S, Molina Y, Lo YY, Cropp B, Nakano C, Yanagihara R & Nerurkar VR 2008 In vitro effects of selenium deficiency on West Nile virus replication and cytopathogenicity. Virology Journal 5 66. (https://doi.org/10.1186/1743-422X-5-66)

    • Search Google Scholar
    • Export Citation
  • Vinceti M, Filippini T, Jablonska E, Saito Y & Wise LA 2022 Safety of selenium exposure and limitations of selenoprotein maximization: molecular and epidemiologic perspectives. Environmental Research 211 113092. (https://doi.org/10.1016/j.envres.2022.113092)

    • Search Google Scholar
    • Export Citation
  • Yu L, Sun L, Nan Y & Zhu LY 2011 Protection from H1N1 influenza virus infections in mice by supplementation with selenium: a comparison with selenium-deficient mice. Biological Trace Element Research 141 254261. (https://doi.org/10.1007/s12011-010-8726-x)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Zhang J, Saad R, Taylor EW & Rayman MP 2020 Selenium and selenoproteins in viral infection with potential relevance to COVID-19. Redox Biology 37 101715. (https://doi.org/10.1016/j.redox.2020.101715)

    • Search Google Scholar
    • Export Citation
  • Zhou H, Wang T, Li Q & Li D 2018 Prevention of Keshan disease by selenium supplementation: a systematic review and meta-analysis. Biological Trace Element Research 186 98105. (https://doi.org/10.1007/s12011-018-1302-5)

    • Crossref
    • Search Google Scholar
    • Export Citation

 

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    Function of representative selenoproteins. (A) Glutathione peroxidase (GPX) reduces several hydroperoxides (hydrogen peroxide, H2O2; phospholipid hydroperoxide, PL-OOH) by using glutathione (GSH). (B) Thioredoxin (TRN) reductase (TRNRD) reduces oxidized TRN by using NADPH. (C) Domain structure and function of selenoprotein P.

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    Synthetic pathway of selenocysteine (Sec) from selenium-containing amino acids. SeMet is converted to Sec by Met metabolizing enzymes (#1–#5) indistinguishable from sulphur. CBS (#4) and CSE (#5) are also known as cysteine persulphide-producing enzymes. Inorganic selenium is generated from Sec by Sec lyase and is converted to selenophosphate by SPS2. By the action of SecS, Sec is produced on tRNA from selenophosphate and phosphorylated Ser-tRNASec.

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    Translation mechanism of selenoprotein. (A) Structure of selenoprotein mRNA. (B) Mechanism of selenocysteine insertion. eEFsec, eukaryotic elongation factor for Sec translation; eIF4a3, eukaryotic initiation factor, SBP2, SECIS-binding protein 2; RPL30, ribosomal protein L30.

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    Expression regulatory mechanism of selenoprotein in the liver. The liver plays a central role in selenium metabolism. Dietary selenium can be divided into selenocysteine synthesis or excretion as selenosugar and trimethylselenonium ion, (CH3)3Se+. In the Sec synthesis system, selenium synthesized as SELENOP enters the systemic circulation. Small selenium-containing compounds bound to albumin also enter the systemic circulation.

  • Anan Y, Nakajima G & Ogra Y 2015 Complementary use of LC-ICP-MS and LC-ESI-Q-TOF-MS for selenium speciation. Analytical Sciences 31 561564. (https://doi.org/10.2116/analsci.31.561)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Arner ES & Holmgren A 2000 Physiological functions of thioredoxin and thioredoxin reductase. European Journal of Biochemistry 267 61026109. (https://doi.org/10.1046/j.1432-1327.2000.01701.x)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Avery JC & Hoffmann PR 2018 Selenium, selenoproteins, and immunity. Nutrients 10 1203. (https://doi.org/10.3390/nu10091203)

  • Barceloux DG 1999 Selenium. Journal of Toxicology: Clinical Toxicology 37 145172. (https://doi.org/10.1081/clt-100102417)

  • Berry MJ, Banu L, Chen YY, Mandel SJ, Kieffer JD, Harney JW & Larsen PR 1991 Recognition of UGA as a selenocysteine codon in type I deiodinase requires sequences in the 3’ untranslated region. Nature 353 273276. (https://doi.org/10.1038/353273a0)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Brigelius-Flohe R & Maiorino M 2013 Glutathione peroxidases. Biochimica et Biophysica Acta 1830 32893303. (https://doi.org/10.1016/j.bbagen.2012.11.020)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Burk RF 2002 Selenium, an antioxidant nutrient. Nutrition in Clinical Care 5 7579. (https://doi.org/10.1046/j.1523-5408.2002.00006.x)

  • Burk RF & Hill KE 2015 Regulation of selenium metabolism and transport. Annual Review of Nutrition 35 109134. (https://doi.org/10.1146/annurev-nutr-071714-034250)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Burk RF, Hill KE, Motley AK, Winfrey VP, Kurokawa S, Mitchell SL & Zhang W 2014 Selenoprotein P and apolipoprotein E receptor-2 interact at the blood-brain barrier and also within the brain to maintain an essential selenium pool that protects against neurodegeneration. FASEB Journal 28 35793588. (https://doi.org/10.1096/fj.14-252874)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Cermelli C, Vinceti M, Scaltriti E, Bazzani E, Beretti F, Vivoli G & Portolani M 2002 Selenite inhibition of Coxsackie virus B5 replication: implications on the etiology of Keshan disease. Journal of Trace Elements in Medicine and Biology 16 4146. (https://doi.org/10.1016/S0946-672X(0280007-4)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Conrad M, Kagan VE, Bayir H, Pagnussat GC, Head B, Traber MG & Stockwell BR 2018 Regulation of lipid peroxidation and ferroptosis in diverse species. Genes and Development 32 602619. (https://doi.org/10.1101/gad.314674.118)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Copeland PR, Fletcher JE, Carlson BA, Hatfield DL & Driscoll DM 2000 A novel RNA binding protein, SBP2, is required for the translation of mammalian selenoprotein mRNAs. EMBO Journal 19 306314. (https://doi.org/10.1093/emboj/19.2.306)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Dagnell M, Schmidt EE & Arner ESJ 2018 The A to Z of modulated cell patterning by mammalian thioredoxin reductases. Free Radical Biology and Medicine 115 484496. (https://doi.org/10.1016/j.freeradbiomed.2017.12.029)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • de Munnik M, Lohans CT, Lang PA, Langley GW, Malla TR, Tumber A, Schofield CJ & Brem J 2019 Targeting the Mycobacterium tuberculosis transpeptidase LdtMt2 with cysteine-reactive inhibitors including ebselen. Chemical Communications 55 1021410217. (https://doi.org/10.1039/c9cc04145a)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM & Yang WS et al.2012 Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149 10601072. (https://doi.org/10.1016/j.cell.2012.03.042)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Du XB, Zheng YB, Wang Z, Chen YJ, Zhou R, Song GL, Ni JZ & Liu Q 2014 Inhibitory act of selenoprotein P on Cu+/Cu2+-induced tau aggregation and neurotoxicity. Inorganic Chemistry 53 1122111230. (https://doi.org/10.1021/ic501788v)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Fairweather-Tait SJ, Bao Y, Broadley MR, Collings R, Ford D, Hesketh JE & Hurst R 2011 Selenium in human health and disease. Antioxidants and Redox Signaling 14 13371383. (https://doi.org/10.1089/ars.2010.3275)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Flohe L 2009 The labour pains of biochemical selenology: the history of selenoprotein biosynthesis. Biochimica et Biophysica Acta 1790 13891403. (https://doi.org/10.1016/j.bbagen.2009.03.031)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Friedmann Angeli JP, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ, Herbach N, Aichler M, Walch A & Eggenhofer E et al.2014 Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nature Cell Biology 16 11801191. (https://doi.org/10.1038/ncb3064)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Fujino G, Noguchi T, Matsuzawa A, Yamauchi S, Saitoh M, Takeda K & Ichijo H 2007 Thioredoxin and TRAF family proteins regulate reactive oxygen species-dependent activation of ASK1 through reciprocal modulation of the N-terminal homophilic interaction of ASK1. Molecular and Cellular Biology 27 81528163. (https://doi.org/10.1128/MCB.00227-07)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Hadrup N & Ravn-Haren G 2020 Acute human toxicity and mortality after selenium ingestion: a review. Journal of Trace Elements in Medicine and Biology 58 126435. (https://doi.org/10.1016/j.jtemb.2019.126435)

    • Search Google Scholar
    • Export Citation
  • Hatfield DL, Tsuji PA, Carlson BA & Gladyshev VN 2014 Selenium and selenocysteine: roles in cancer, health, and development. Trends in Biochemical Sciences 39 112120. (https://doi.org/10.1016/j.tibs.2013.12.007)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Heller RA, Sun Q, Hackler J, Seelig J, Seibert L, Cherkezov A, Minich WB, Seemann P, Diegmann J & Pilz M et al.2021 Prediction of survival odds in COVID-19 by zinc, age and selenoprotein P as composite biomarker. Redox Biology 38 101764. (https://doi.org/10.1016/j.redox.2020.101764)

    • Search Google Scholar
    • Export Citation
  • Hill KE, Zhou J, McMahan WJ, Motley AK, Atkins JF, Gesteland RF & Burk RF 2003 Deletion of selenoprotein P alters distribution of selenium in the mouse. Journal of Biological Chemistry 278 1364013646. (https://doi.org/10.1074/jbc.M300755200)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Hill KE, Wu S, Motley AK, Stevenson TD, Winfrey VP, Capecchi MR, Atkins JF & Burk RF 2012 Production of selenoprotein P (Sepp1) by hepatocytes is central to selenium homeostasis. Journal of Biological Chemistry 287 4041440424. (https://doi.org/10.1074/jbc.M112.421404)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Himoto T, Yoneyama H, Kurokohchi K, Inukai M, Masugata H, Goda F, Haba R, Watababe S, Kubota S & Senda S et al.2011 Selenium deficiency is associated with insulin resistance in patients with hepatitis C virus-related chronic liver disease. Nutrition Research 31 829835. (https://doi.org/10.1016/j.nutres.2011.09.021)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Imai H, Hakkaku N, Iwamoto R, Suzuki J, Suzuki T, Tajima Y, Konishi K, Minami S, Ichinose S & Ishizaka K et al.2009 Depletion of selenoprotein GPx4 in spermatocytes causes male infertility in mice. Journal of Biological Chemistry 284 3252232532. (https://doi.org/10.1074/jbc.M109.016139)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Ingold I, Berndt C, Schmitt S, Doll S, Poschmann G, Buday K, Roveri A, Peng X, Porto Freitas F & Seibt T et al.2018 Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis. Cell 172 409 .e21422.e21. (https://doi.org/10.1016/j.cell.2017.11.048)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Jin Z, Du X, Xu Y, Deng Y, Liu M, Zhao Y, Zhang B, Li X, Zhang L & Peng C et al.2020 Structure of M(pro) from SARS-CoV-2 and discovery of its inhibitors. Nature 582 289293. (https://doi.org/10.1038/s41586-020-2223-y)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Kikuchi N, Satoh K, Kurosawa R, Yaoita N, Elias-Al-Mamun M, Siddique MAH, Omura J, Satoh T, Nogi M & Sunamura S et al.2018 Selenoprotein P promotes the development of pulmonary arterial hypertension: possible novel therapeutic target. Circulation 138 600623. (https://doi.org/10.1161/CIRCULATIONAHA.117.033113)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Kobayashi Y, Ogra Y, Ishiwata K, Takayama H, Aimi N & Suzuki KT 2002 Selenosugars are key and urinary metabolites for selenium excretion within the required to low-toxic range. PNAS 99 1593215936. (https://doi.org/10.1073/pnas.252610699)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Kohrle J 2000 The selenoenzyme family of deiodinase isozymes controls local thyroid hormone availability. Reviews in Endocrine and Metabolic Disorders 1 4958. (https://doi.org/10.1023/a:1010012419869)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Kohrle J 2013 Selenium and the thyroid. Current Opinion in Endocrinology, Diabetes, and Obesity 20 441448. (https://doi.org/10.1097/01.med.0000433066.24541.88)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Kryukov GV, Castellano S, Novoselov SV, Lobanov AV, Zehtab O, Guigo R & Gladyshev VN 2003 Characterization of mammalian selenoproteomes. Science 300 14391443. (https://doi.org/10.1126/science.1083516)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Labunskyy VM, Hatfield DL & Gladyshev VN 2014 Selenoproteins: molecular pathways and physiological roles. Physiological Reviews 94 739777. (https://doi.org/10.1152/physrev.00039.2013)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Lee BJ, Worland PJ, Davis JN, Stadtman TC & Hatfield DL 1989 Identification of a selenocysteyl-tRNA(Ser) in mammalian cells that recognizes the nonsense codon, UGA. Journal of Biological Chemistry 264 97249727. (https://doi.org/10.1016/S0021-9258(1881714-8)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Levander OA & Beck MA 1997 Interacting nutritional and infectious etiologies of Keshan disease. Insights from Coxsackie virus B-induced myocarditis in mice deficient in selenium or vitamin E. Biological Trace Element Research 56 521. (https://doi.org/10.1007/BF02778980)

    • Search Google Scholar
    • Export Citation
  • Liu Y, Zhang W, Zhao JT, Lin XY, Liu JM, Cui LW, Gao YX, Zhang TL, Li B & Li YF 2018 Selenoprotein P as the major transporter for mercury in serum from methylmercury-poisoned rats. Journal of Trace Elements in Medicine and Biology 50 589595. (https://doi.org/10.1016/j.jtemb.2018.04.013)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Low SC, Grundner-Culemann E, Harney JW & Berry MJ 2000 SECIS-SBP2 interactions dictate selenocysteine incorporation efficiency and selenoprotein hierarchy. EMBO Journal 19 68826890. (https://doi.org/10.1093/emboj/19.24.6882)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Lu J & Holmgren A 2014 The thioredoxin antioxidant system. Free Radical Biology and Medicine 66 7587. (https://doi.org/10.1016/j.freeradbiomed.2013.07.036)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Maiorino M, Conrad M & Ursini F 2018 GPx4, lipid peroxidation, and cell death: discoveries, rediscoveries, and open issues. Antioxidants and Redox Signaling 29 6174. (https://doi.org/10.1089/ars.2017.7115)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Menendez CA, Bylehn F, Perez-Lemus GR, Alvarado W & de Pablo JJ 2020 Molecular characterization of ebselen binding activity to SARS-CoV-2 main protease. Science Advances 6 eabd0345. (https://doi.org/10.1126/sciadv.abd0345)

    • Search Google Scholar
    • Export Citation
  • Mihara H, Kurihara T, Yoshimura T & Esaki N 2000 Kinetic and mutational studies of three NifS homologs from Escherichia coli: mechanistic difference between L-cysteine desulfurase and L-selenocysteine lyase reactions. Journal of Biochemistry 127 559567. (https://doi.org/10.1093/oxfordjournals.jbchem.a022641)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Misu H, Takamura T, Takayama H, Hayashi H, Matsuzawa-Nagata N, Kurita S, Ishikura K, Ando H, Takeshita Y & Ota T et al.2010 A liver-derived secretory protein, selenoprotein P, causes insulin resistance. Cell Metabolism 12 483495. (https://doi.org/10.1016/j.cmet.2010.09.015)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Misu H, Takayama H, Saito Y, Mita Y, Kikuchi A, Ishii KA, Chikamoto K, Kanamori T, Tajima N & Lan F et al.2017 Deficiency of the hepatokine selenoprotein P increases responsiveness to exercise in mice through upregulation of reactive oxygen species and AMP-activated protein kinase in muscle. Nature Medicine 23 508516. (https://doi.org/10.1038/nm.4295)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Mita Y, Nakayama K, Inari S, Nishito Y, Yoshioka Y, Sakai N, Sotani K, Nagamura T, Kuzuhara Y & Inagaki K et al.2017 Selenoprotein P-neutralizing antibodies improve insulin secretion and glucose sensitivity in type 2 diabetes mouse models. Nature Communications 8 1658. (https://doi.org/10.1038/s41467-017-01863-z)

    • Search Google Scholar
    • Export Citation
  • Mita Y, Uchida R, Yasuhara S, Kishi K, Hoshi T, Matsuo Y, Yokooji T, Shirakawa Y, Toyama T & Urano Y et al.2021 Identification of a novel endogenous long non-coding RNA that inhibits selenoprotein P translation. Nucleic Acids Research 49 68936907. (https://doi.org/10.1093/nar/gkab498)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Oo SM, Oo HK, Takayama H, Ishii KA, Takeshita Y, Goto H, Nakano Y, Kohno S, Takahashi C & Nakamura H et al.2022 Selenoprotein P-mediated reductive stress impairs cold-induced thermogenesis in brown fat. Cell Reports 38 110566. (https://doi.org/10.1016/j.celrep.2022.110566)

    • Search Google Scholar
    • Export Citation
  • Rayman MP 2012 Selenium and human health. Lancet 379 12561268. (https://doi.org/10.1016/S0140-6736(1161452-9)

  • Rayman MP & Stranges S 2013 Epidemiology of selenium and type 2 diabetes: can we make sense of it? Free Radical Biology and Medicine 65 15571564. (https://doi.org/10.1016/j.freeradbiomed.2013.04.003)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Rees K, Hartley L, Day C, Flowers N, Clarke A & Stranges S 2013 Selenium supplementation for the primary prevention of cardiovascular disease. Cochrane Database of Systematic Reviews 2013 CD009671. (https://doi.org/10.1002/14651858.CD009671.pub2/full)

    • Search Google Scholar
    • Export Citation
  • Renko K, Werner M, Renner-Muller I, Cooper TG, Yeung CH, Hollenbach B, Scharpf M, Kohrle J, Schomburg L & Schweizer U 2008 Hepatic selenoprotein P (SePP) expression restores selenium transport and prevents infertility and motor-incoordination in Sepp-knockout mice. Biochemical Journal 409 741749. (https://doi.org/10.1042/BJ20071172)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Saito Y 2020a Selenoprotein P as a significant regulator of pancreatic beta cell function. Journal of Biochemistry 167 119124. (https://doi.org/10.1093/jb/mvz061)

    • Search Google Scholar
    • Export Citation
  • Saito Y 2020b Selenoprotein P as an in vivo redox regulator: disorders related to its deficiency and excess. Journal of Clinical Biochemistry and Nutrition 66 17. (https://doi.org/10.3164/jcbn.19-31)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Saito Y 2021a Lipid peroxidation products as a mediator of toxicity and adaptive response – the regulatory role of selenoprotein and vitamin E. Archives of Biochemistry and Biophysics 703 108840. (https://doi.org/10.1016/j.abb.2021.108840)

    • Search Google Scholar
    • Export Citation
  • Saito Y 2021b Selenium transport mechanism via selenoprotein P-Its physiological role and related diseases. Frontiers in Nutrition 8 685517. (https://doi.org/10.3389/fnut.2021.685517)

    • Search Google Scholar
    • Export Citation
  • Saito Y 2021c Diverse cytoprotective actions of vitamin E isoforms – role as peroxyl radical scavengers and complementary functions with selenoproteins. Free Radical Biology and Medicine 175 121129. (https://doi.org/10.1016/j.freeradbiomed.2021.08.234)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Saito Y & Takahashi K 2002 Characterization of selenoprotein P as a selenium supply protein. European Journal of Biochemistry 269 57465751. (https://doi.org/10.1046/j.1432-1033.2002.03298.x)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Saito Y, Hayashi T, Tanaka A, Watanabe Y, Suzuki M, Saito E & Takahashi K 1999 Selenoprotein P in human plasma as an extracellular phospholipid hydroperoxide glutathione peroxidase. Isolation and enzymatic characterization of human selenoprotein p. Journal of Biological Chemistry 274 28662871. (https://doi.org/10.1074/jbc.274.5.2866)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Saito Y, Sato N, Hirashima M, Takebe G, Nagasawa S & Takahashi K 2004 Domain structure of bi-functional selenoprotein P. Biochemical Journal 381 841846. (https://doi.org/10.1042/BJ20040328)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Schomburg L, Schweizer U, Holtmann B, Flohe L, Sendtner M & Kohrle J 2003 Gene disruption discloses role of selenoprotein P in selenium delivery to target tissues. Biochemical Journal 370 397402. (https://doi.org/10.1042/BJ20021853)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Schomburg L, Schweizer U & Kohrle J 2004 Selenium and selenoproteins in mammals: extraordinary, essential, enigmatic. Cellular and Molecular Life Sciences 61 19881995. (https://doi.org/10.1007/s00018-004-4114-z)

    • Search Google Scholar
    • Export Citation
  • Schrauzer GN 2000 Selenomethionine: a review of its nutritional significance, metabolism and toxicity. Journal of Nutrition 130 16531656. (https://doi.org/10.1093/jn/130.7.1653)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Seyedali A & Berry MJ 2014 Nonsense-mediated decay factors are involved in the regulation of selenoprotein mRNA levels during selenium deficiency. RNA 20 12481256. (https://doi.org/10.1261/rna.043463.113)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Sies H & Parnham MJ 2020 Potential therapeutic use of ebselen for COVID-19 and other respiratory viral infections. Free Radical Biology and Medicine 156 107112. (https://doi.org/10.1016/j.freeradbiomed.2020.06.032)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, Fulda S, Gascon S, Hatzios SK & Kagan VE et al.2017 Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell 171 273285. (https://doi.org/10.1016/j.cell.2017.09.021)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Suzuki KT, Sasakura C & Yoneda S 1998 Binding sites for the (Hg-Se) complex on selenoprotein P. Biochimica et Biophysica Acta 1429 102112. (https://doi.org/10.1016/s0167-4838(9800221-0)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Takahashi K, Akasaka M, Yamamoto Y, Kobayashi C, Mizoguchi J & Koyama J 1990 Primary structure of human plasma glutathione peroxidase deduced from cDNA sequences. Journal of Biochemistry 108 145148. (https://doi.org/10.1093/oxfordjournals.jbchem.a123172)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Takamura T 2020 Hepatokine selenoprotein P-mediated reductive stress causes resistance to intracellular signal transduction. Antioxidants and Redox Signaling 33 517524. (https://doi.org/10.1089/ars.2020.8087)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Takebe G, Yarimizu J, Saito Y, Hayashi T, Nakamura H, Yodoi J, Nagasawa S & Takahashi K 2002 A comparative study on the hydroperoxide and thiol specificity of the glutathione peroxidase family and selenoprotein P. Journal of Biological Chemistry 277 4125441258. (https://doi.org/10.1074/jbc.M202773200)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Thomas JP, Geiger PG, Maiorino M, Ursini F & Girotti AW 1990 Enzymatic reduction of phospholipid and cholesterol hydroperoxides in artificial bilayers and lipoproteins. Biochimica et Biophysica Acta 1045 252260. (https://doi.org/10.1016/0005-2760(9090128-k)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Ursini F & Maiorino M 2020 Lipid peroxidation and ferroptosis: the role of GSH and GPx4. Free Radical Biology and Medicine 152 175185. (https://doi.org/10.1016/j.freeradbiomed.2020.02.027)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Ursini F, Bosello Travain V, Cozza G, Miotto G, Roveri A, Toppo S & Maiorino M 2022 A white paper on phospholipid hydroperoxide glutathione peroxidase (GPx4) forty years later. Free Radical Biology and Medicine 188 117133. (https://doi.org/10.1016/j.freeradbiomed.2022.06.227)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Verma S, Molina Y, Lo YY, Cropp B, Nakano C, Yanagihara R & Nerurkar VR 2008 In vitro effects of selenium deficiency on West Nile virus replication and cytopathogenicity. Virology Journal 5 66. (https://doi.org/10.1186/1743-422X-5-66)

    • Search Google Scholar
    • Export Citation
  • Vinceti M, Filippini T, Jablonska E, Saito Y & Wise LA 2022 Safety of selenium exposure and limitations of selenoprotein maximization: molecular and epidemiologic perspectives. Environmental Research 211 113092. (https://doi.org/10.1016/j.envres.2022.113092)

    • Search Google Scholar
    • Export Citation
  • Yu L, Sun L, Nan Y & Zhu LY 2011 Protection from H1N1 influenza virus infections in mice by supplementation with selenium: a comparison with selenium-deficient mice. Biological Trace Element Research 141 254261. (https://doi.org/10.1007/s12011-010-8726-x)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Zhang J, Saad R, Taylor EW & Rayman MP 2020 Selenium and selenoproteins in viral infection with potential relevance to COVID-19. Redox Biology 37 101715. (https://doi.org/10.1016/j.redox.2020.101715)

    • Search Google Scholar
    • Export Citation
  • Zhou H, Wang T, Li Q & Li D 2018 Prevention of Keshan disease by selenium supplementation: a systematic review and meta-analysis. Biological Trace Element Research 186 98105. (https://doi.org/10.1007/s12011-018-1302-5)

    • Crossref
    • Search Google Scholar
    • Export Citation