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Relationship: 1765

Title

The title of the KER should clearly define the two KEs being considered and the sequential relationship between them (i.e., which is upstream and which is downstream). Consequently all KER titles take the form “upstream KE leads to downstream KE”.  More help

Binding, SH/SeH proteins involved in protection against oxidative stress leads to Protection against oxidative stress, decreased

Upstream event
Upstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help
Downstream event
Downstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

This table is automatically generated upon addition of a KER to an AOP. All of the AOPs that are linked to this KER will automatically be listed in this subsection. Clicking on the name of the AOP in the table will bring you to the individual page for that AOP. More help
AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Binding of electrophilic chemicals to SH(thiol)-group of proteins and /or to seleno-proteins involved in protection against oxidative stress during brain development leads to impairment of learning and memory adjacent Moderate Moderate Marie-Gabrielle Zurich (send email) Under development: Not open for comment. Do not cite EAGMST Under Review

Taxonomic Applicability

Select one or more structured terms that help to define the biological applicability domain of the KER. In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. Authors can indicate the relevant taxa for this KER in this subsection. The process is similar to what is described for KEs (see pages 30-31 and 37-38 of User Handbook) More help
Term Scientific Term Evidence Link
rat Rattus norvegicus NCBI
mouse Mus musculus NCBI
human Homo sapiens NCBI

Sex Applicability

Authors can indicate the relevant sex for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of the User Handbook). More help
Sex Evidence
Male
Female

Life Stage Applicability

Authors can indicate the relevant life stage for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of User Handbook). More help
Term Evidence
All life stages High

Key Event Relationship Description

Provide a brief, descriptive summation of the KER. While the title itself is fairly descriptive, this section can provide details that aren’t inherent in the description of the KEs themselves (see page 39 of the User Handbook). This description section can be viewed as providing the increased specificity in the nature of upstream perturbation (KEupstream) that leads to a particular downstream perturbation (KEdownstream), while allowing the KE descriptions to remain generalised so they can be linked to different AOPs. The description is also intended to provide a concise overview for readers who may want a brief summation, without needing to read through the detailed support for the relationship (covered below). Careful attention should be taken to avoid reference to other KEs that are not part of this KER, other KERs or other AOPs. This will ensure that the KER is modular and can be used by other AOPs. More help

Thiol (SH) and selenol (SeH) compounds exhibit reactivity toward electrophiles and oxidants and have high binding affinities for metals (Higdon, 2012; Nagy, 2013; Winterbourn, 2008; Winther, 2014). Glutathione is a thiol-containing tripeptide acting as a cofactor for the enzyme peroxidase and thus serving as an indirect antioxidant donating the electrons necessary for its decomposition of H2O2, and is also involved in many other cellular functions (Kohen, 2002). Selenoproteins contain selenocysteine amino acid residues. The selenoprotein family is composed of proteins exerting diverse functions, among them several are oxidoreductases classified as antioxidant enzymes (Labunskyy, 2014; Reeves, 2009). Relevant for this KER there are two well-studied selenoprotein families which are described to be expressed in the brain; (i) the Glutathione Peroxidase (GPx) family, involved in detoxification of hydroperoxides; (ii) the Thioredoxin Reductase (TrxR) family, involved in the regeneration of reduced thioredoxin (Pillai, 2014), but also the less studied SelH, K, S, R, W, and P selenoproteins (Pisoschi, 2015; Reeves, 2009).

As summarized in the table 1, binding to the thiol/selenol groups of the selenoproteins cited above can result in structural modifications of these proteins, which in turn inhibits their catalytic activity and thereby reduces or blocks their metabolic capacity to neutralize reactive oxygen species (Fernandes, 1996; Rajanna, 1995). Similarly, binding to the thiol group of glutathione will decrease its anti-oxidant capacity.

Figure (Poole, 2015) Structures of cysteinyl and selenocysteinyl residues within proteins. The aminoacyl groups are shown to the left, with dotted lines representing peptide bonds to the next residue on either side. Both protonated (left) and deprotonated (right) forms of these amino acids are depicted with average pKa values.

Evidence Supporting this KER

Assembly and description of the scientific evidence supporting KERs in an AOP is an important step in the AOP development process that sets the stage for overall assessment of the AOP (see pages 49-56 of the User Handbook). To do this, biological plausibility, empirical support, and the current quantitative understanding of the KER are evaluated with regard to the predictive relationships/associations between defined pairs of KEs as a basis for considering WoE (page 55 of User Handbook). In addition, uncertainties and inconsistencies are considered. More help
Biological Plausibility
Define, in free text, the biological rationale for a connection between KEupstream and KEdownstream. What are the structural or functional relationships between the KEs? For example, there is a functional relationship between an enzyme’s activity and the product of a reaction it catalyses. Supporting references should be included. However, it is recognised that there may be cases where the biological relationship between two KEs is very well established, to the extent that it is widely accepted and consistently supported by so much literature that it is unnecessary and impractical to cite the relevant primary literature. Citation of review articles or other secondary sources, like text books, may be reasonable in such cases. The primary intent is to provide scientifically credible support for the structural and/or functional relationship between the pair of KEs if one is known. The description of biological plausibility can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured (see page 40 of the User Handbook for further information).   More help

GPx family

GPxs are tetrameric enzymes. Their thiol groups can either act directly as a reductant, or catalyze reduction of hydrogen peroxide and/or phospholipid hydroperoxides through glutathione co-factors (Hanschmann, 2013, Labunskyy, 2014).

TrxR family

TxRs are homodimeric flavoenzymes, which mediate the reduction of oxidized Txn at the expense of NADPH (Birben, 2012). Inhibition of TrxR enzymes has been shown to lead to oxidative stress (Branco, 2017).

SelP

Downregulation of intracellular SelP by use of small interfering RNA (siRNA) impaired the viability of human astrocytes and made them more susceptible to hydroperoxide-induced oxidative stress, pointing to a direct contribution of SeP to ROS clearance (Steinbrenner, 2006).

Table 1

Selenoprotein family

Protein name

Normal brain function

Disruption leading to oxidative stress

Reference

Glutathione

GSH

GSH is a major endogenous antioxidant functioning directly in neutralization of free radicals and reactive oxygen compounds. GSH is the reduced form of glutathione and its SH group of cysteine is able to reduce and/or maintain reduced form of other molecules.

Disruptions leads to increased oxidative stress and apoptosis.

Hall, 1999

Dringen, 2000

 

Glutathione Peroxidase (GPx) Family

GPx1

Peroxide/ROS reduction

(Promotes neuroprotection in response to oxidative challenge).

 

Brain expression levels are highest in microglia and lower levels detected in neurons.

Brains of GPx1−/− mice are more vulnerable to mitochondrial toxin treatment, ischemia/ reperfusion, and cold-induced brain injury.

Cultured neurons from GPx1−/− mice were reported to be more susceptible to Aβ-induced oxidative stress, and addition of ebselen reversed this.

Lindenau, 1998

Klivenyi, 2000

Flentjar, 2002

Crack, 2001 and 2006

 

GPx4

Reduction of phospholipid

Hydroperoxides.

Only in neurons during normal conditions.

Brains of GPx4+/− mice were shown to have increased lipid peroxidation (a sign of oxidative stress).

Injury-induced GPx4 expression in astrocytes.

In vivo over expression of GPx4 protects against oxidative stress-induced apoptosis.

Ran, 2004

Borchert, 2006

Savaskan, 2007

Chen, 2008

 

Thioredoxin Reductase (TrxR) Family

TrxR1

TrxR2

Cytocsolic, mitochondrial, nuclear localization. Contribute to the reduction of hydrogen peroxide and oxidative stress, and regulates redox-sensitive

transcription factors that

control cellular transcription

mechanisms.

Regulate the induction of the antioxidant enzyme heme oxygenase 1 (HO-1).

Overexpression of human Trx1 and Trx2 protects retinal ganglion cells against oxidative stress-induced neurodegeneration.

Exogenously administered human rTrx ameliorates neuronal damage after transient middle cerebral artery occlusion in mice, reduces oxidative/nitrative stress and neuronal apoptosis after cerebral ischemia/reperfusion injury in mice

Gladyshev, 1996

Zhong, 2000

Hattori, 2004

Trigona, 2006

Papp, 2007

Munemasa, 2008

Arbogast, 2010

Ma, 2012

Burk, 2013

Pitts, 2014

 

 

 

Other relevant seleno- proteins

SelH

Nuclear localization. Redox sensing.

Hypersensitivity of SelH shRNA HeLa cells to paraquat- and H2O2-induced oxidative stress.

 

(Panee, 2007)(Novoselov, 2007)

(Wu, 2014)

SelK

Transmembrane protein

localized to the ER membrane.

ER homeostasis and oxidative stress response.

Protects HepG2 cells from ER stress agent-induced apoptosis.

Overexpression of SelK attenuated the intracellular reactive oxygen species level and protected cells from oxidative stress-induced toxicity in cardiomyocytes

(Shchedrina, 2011)

(Du, 2010)

(Lu, 2006)

SelS

Transmembrane protein

localized to the ER membrane. Catalyze the reduction of disulfide bonds and peroxides.

SelS overexpression increased astrocyte resistance to ER-stress and inflammatory stimuli, and suppression of SelS compromised astrocyte viability.

(Liu, 2013)

(Fradejas, 2011)

(Fradejas, 2008)

 (Gao, 2007)

MSRB1, SelR, SelX

Function in reduction of oxidized methionine residues, and actin polymerization.

Induce expression of MSRB1 protects neurons from amyloid β-protein insults in vitro and in vivo.

(Lee, 2013)

(Moskovitz, 2011)(Pillai, 2014)

SelW

Expressed in synapses. Plays an antioxidant role in cells.

Rat in vivo overexpression of SelW was shown to protect glial cells against oxidative stress caused by heavy metals and 2,20-Azobis.

Silencing of SelW made neurons more sensitive to oxidative stress.

(Reeves, 2009)

(Sun, 2001)

(Loflin, 2006)

(Raman, 2013)

(Chung, 2009)

SelP

Is important for selenium transport, distribution and retention within the brain.

Acts as a ROS-detoxifying enzyme.

Protects human astrocytes from induced oxidative.

SelP-/- mice show neurological dysfunction and that Se content and GPx activity were reduced within brain, Se supplementation to diet attenuated. neurological dysfunctions.

SelP-/- mice have reported deficits in PV-interneurons due to diminished antioxidant defense capabilities. Decreased neuronal selenoprotein synthesis may be a functional outcome of SelP

Colocalization of Sel P with amyloid plaques

 

SelP can function as an antioxidant enzyme against reactive lipid intermediates

(Steinbrenner, 2009)(Arbogast, 2010)(Zhang, 2008)

(Hill, 2003;Hill, 2004)

(Cabungcal, 2006)

(Pitts, 2012)

(Byrns, 2014)

 

 

(Schomburg, 2003)

 

(Rock, 2010)

Uncertainties and Inconsistencies
In addition to outlining the evidence supporting a particular linkage, it is also important to identify inconsistencies or uncertainties in the relationship. Additionally, while there are expected patterns of concordance that support a causal linkage between the KEs in the pair, it is also helpful to identify experimental details that may explain apparent deviations from the expected patterns of concordance. Identification of uncertainties and inconsistencies contribute to evaluation of the overall WoE supporting the AOPs that contain a given KER and to the identification of research gaps that warrant investigation (seep pages 41-42 of the User Handbook).Given that AOPs are intended to support regulatory applications, AOP developers should focus on those inconsistencies or gaps that would have a direct bearing or impact on the confidence in the KER and its use as a basis for inference or extrapolation in a regulatory setting. Uncertainties that may be of academic interest but would have little impact on regulatory application don’t need to be described. In general, this section details evidence that may raise questions regarding the overall validity and predictive utility of the KER (including consideration of both biological plausibility and empirical support). It also contributes along with several other elements to the overall evaluation of the WoE for the KER (see Section 4 of the User Handbook).  More help

Another important group of thiol-containing proteins are the metal-binging detoxifying metallothioneins. This protein family bind mercury and lead, and this binding thus serves as a protective mechanism and also protects against metal toxicity and oxidative stress (Aschner, 2006).

Lactational exposure to methylmercury (10 mg/L in drinking water) significantly increased cerebellar GSH level and GR activity. Possibly a compensatory response to mercury-induced oxidative stress (Franco, 2006).

MeHg was shown to inhibit cerebral thioredoxin reductase activity in vitro but not in brain of mice (Wagner et al., 2010). However, it has to be noted that the exposure of mice to MeHg was only 24h.

Inhibition og GR and GrX by Hg2+ and MeHg was observed on the puried protein, but not in HeLa cells incubated with the same concentrations for 24h (Carvahlo et al., 2008).

Response-response Relationship
This subsection should be used to define sources of data that define the response-response relationships between the KEs. In particular, information regarding the general form of the relationship (e.g., linear, exponential, sigmoidal, threshold, etc.) should be captured if possible. If there are specific mathematical functions or computational models relevant to the KER in question that have been defined, those should also be cited and/or described where possible, along with information concerning the approximate range of certainty with which the state of the KEdownstream can be predicted based on the measured state of the KEupstream (i.e., can it be predicted within a factor of two, or within three orders of magnitude?). For example, a regression equation may reasonably describe the response-response relationship between the two KERs, but that relationship may have only been validated/tested in a single species under steady state exposure conditions. Those types of details would be useful to capture.  More help
Time-scale
This sub-section should be used to provide information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). This can be useful information both in terms of modelling the KER, as well as for analyzing the critical or dominant paths through an AOP network (e.g., identification of an AO that could kill an organism in a matter of hours will generally be of higher priority than other potential AOs that take weeks or months to develop). Identification of time-scale can also aid the assessment of temporal concordance. For example, for a KER that operates on a time-scale of days, measurement of both KEs after just hours of exposure in a short-term experiment could lead to incorrect conclusions regarding dose-response or temporal concordance if the time-scale of the upstream to downstream transition was not considered. More help
Known modulating factors
This sub-section presents information regarding modulating factors/variables known to alter the shape of the response-response function that describes the quantitative relationship between the two KEs (for example, an iodine deficient diet causes a significant increase in the slope of the relationship; a particular genotype doubles the sensitivity of KEdownstream to changes in KEupstream). Information on these known modulating factors should be listed in this subsection, along with relevant information regarding the manner in which the modulating factor can be expected to alter the relationship (if known). Note, this section should focus on those modulating factors for which solid evidence supported by relevant data and literature is available. It should NOT list all possible/plausible modulating factors. In this regard, it is useful to bear in mind that many risk assessments conducted through conventional apical guideline testing-based approaches generally consider few if any modulating factors. More help
Known Feedforward/Feedback loops influencing this KER
This subsection should define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits? In some cases where feedback processes are measurable and causally linked to the outcome, they should be represented as KEs. However, in most cases these features are expected to predominantly influence the shape of the response-response, time-course, behaviours between selected KEs. For example, if a feedback loop acts as compensatory mechanism that aims to restore homeostasis following initial perturbation of a KE, the feedback loop will directly shape the response-response relationship between the KERs. Given interest in formally identifying these positive or negative feedback, it is recommended that a graphical annotation (page 44) indicating a positive or negative feedback loop is involved in a particular upstream to downstream KE transition (KER) be added to the graphical representation, and that details be provided in this subsection of the KER description (see pages 44-45 of the User Handbook).  More help

Domain of Applicability

As for the KEs, there is also a free-text section of the KER description that the developer can use to explain his/her rationale for the structured terms selected with regard to taxonomic, life stage, or sex applicability, or provide a more generalizable or nuanced description of the applicability domain than may be feasible using standardized terms. More help

Experimental evidences has been observed in rat, mice and human cells (Agrawal, 2015; Meinerz, 2011; Branco, 2017)

References

List of the literature that was cited for this KER description using the appropriate format. Ideally, the list of references should conform, to the extent possible, with the OECD Style Guide (OECD, 2015). More help

Agrawal, S. et al. (2015) Changes in tissue oxidative stress, brain biogenic amines and acetylcholinesterase following co-exposure to lead, arsenic and mercury in rats. Food Chem Toxicol 86, 208-216.

Arbogast, S., Ferreiro, A. (2010) Selenoproteins and protection against oxidative stress: selenoprotein N as a novel player at the crossroads of redox signaling and calcium homeostasis. Antioxid Redox Signal 12, 893-904.

Arnold AP, Khoon ST, Rabenstein DL (1986) Nuclear magnetic resonance studies of the solution chemistry of metal complexes. 23. Complexation of methylmercury by selenohydryl-containing amino acids and related molecules. Inorganic Chemistry 25 (14), 2433-2437.

Aschner, M. et al. (2006) Metallothioneins: mercury species-specific induction and their potential role in attenuating neurotoxicity. Exp Biol Med (Maywood) 231, 1468-1473.

Birben, E. et al. (2012) Oxidative stress and antioxidant defense. World Allergy Organ J 5, 9-19.

Borchert, A. et al. (2006) The role of phospholipid hydroperoxide glutathione peroxidase isoforms in murine embryogenesis. J Biol Chem 281, 19655-19664.

Branco, V. et al. (2017) Impaired cross-talk between the thioredoxin and glutathione systems is related to ASK-1 mediated apoptosis in neuronal cells exposed to mercury. Redox Biol 13, 278-287.

Burk, R.F. et al. (2013) Maternal-fetal transfer of selenium in the mouse. FASEB J 27, 3249-3256.

Byrns, C.N. et al. (2014) Mice lacking selenoprotein P and selenocysteine lyase exhibit severe neurological dysfunction, neurodegeneration, and audiogenic seizures. J Biol Chem 289, 9662-9674.

Cabungcal, J.H. et al. (2006) Glutathione deficit during development induces anomalies in the rat anterior cingulate GABAergic neurons: Relevance to schizophrenia. Neurobiol Dis 22, 624-637.

Carvalho, C.M. et al. (2008) Inhibition of the human thioredoxin system. A molecular mechanism of mercury toxicity. J Biol Chem 283, 11913-11923.

Carvalho, C.M.L. et al. (2011), Effects of selenite and chelating agents on mammalian thioredoxin reductase inhibited by mercury: Implications for treatment of mercury poisoning(. FASEB Journal, 25 (1), pp. 370-381.

Chen, L. et al. (2008) Lipid peroxidation up-regulates BACE1 expression in vivo: a possible early event of amyloidogenesis in Alzheimer's disease. J Neurochem 107, 197-207.

Chung, Y.W. et al. (2009) Antioxidative role of selenoprotein W in oxidant-induced mouse embryonic neuronal cell death. Mol Cells 27, 609-613.

Crack, P.J. et al. (2006) Lack of glutathione peroxidase-1 exacerbates Abeta-mediated neurotoxicity in cortical neurons. J Neural Transm (Vienna) 113, 645-657.

Crack, P.J. et al. (2001) Increased infarct size and exacerbated apoptosis in the glutathione peroxidase-1 (Gpx-1) knockout mouse brain in response to ischemia/reperfusion injury. J Neurochem 78, 1389-1399.

Dringen, R. (2000) Metabolism and functions of glutathione in brain. Prog Neurobiol 62, 649-671.

Du, S. et al. (2010) SelK is a novel ER stress-regulated protein and protects HepG2 cells from ER stress agent-induced apoptosis. Arch Biochem Biophys 502, 137-143.

Farina, M. et al. (2011) Oxidative stress in MeHg-induced neurotoxicity. Toxicol Appl Pharmacol 256, 405-417.

Fernandes, A.C. et al. (1996) Different effects of thiol and nonthiol ace inhibitors on copper-induced lipid and protein oxidative modification. Free Radic Biol Med 20, 507-514.

Flentjar, N.J. et al. (2002) Mice lacking glutathione peroxidase-1 activity show increased TUNEL staining and an accelerated inflammatory response in brain following a cold-induced injury. Exp Neurol 177, 9-20.

Fradejas, N. et al. (2008) SEPS1 gene is activated during astrocyte ischemia and shows prominent antiapoptotic effects. J Mol Neurosci 35, 259-265.

Fradejas, N. et al. (2011) Selenoprotein S expression in reactive astrocytes following brain injury. Glia 59, 959-972.

Franco, J.L. et al. (2006) Cerebellar thiol status and motor deficit after lactational exposure to methylmercury. Environ Res 102, 22-28.

Gao, Y. et al. (2007) Secretion of the glucose-regulated selenoprotein SEPS1 from hepatoma cells. Biochem Biophys Res Commun 356, 636-641.

Gladyshev, V.N. et al. (1996) Selenocysteine, identified as the penultimate C-terminal residue in human T-cell thioredoxin reductase, corresponds to TGA in the human placental gene. Proc Natl Acad Sci U S A 93, 6146-6151.

Hall, A.G. (1999) Review: The role of glutathione in the regulation of apoptosis. Eur J Clin Invest 29, 238-245.

Han S, Zhu M, Yuan Z, Li X (2001) A methylene blue-mediated enzyme electrode for the determination of trace mercury (II), mercury (I), methylmercury, and mercury-glutathione complex. Biosensors & Bioelectronics. 16 : 9-16.

Hanschmann, E.M. et al. (2013) Thioredoxins, glutaredoxins, and peroxiredoxins--molecular mechanisms and health significance: from cofactors to antioxidants to redox signaling. Antioxid Redox Signal 19, 1539-1605.

Hattori, I. et al. (2004) Intravenous administration of thioredoxin decreases brain damage following transient focal cerebral ischemia in mice. Antioxid Redox Signal 6, 81-87.

Higdon, A. et al. (2012) Cell signalling by reactive lipid species: new concepts and molecular mechanisms. Biochem J 442, 453-464.

Hill, K.E. et al. (2003) Deletion of selenoprotein P alters distribution of selenium in the mouse. J Biol Chem 278, 13640-13646.

Hill, K.E. et al. (2004) Neurological dysfunction occurs in mice with targeted deletion of the selenoprotein P gene. J Nutr 134, 157-161.

Khan, M.A.K., Wang, F., 2009. Mercury-selenium compounds an their toxicological significance: topward a molecular understanding of the mercury-selenium antagonism. Environ. Toxicol. Chem. 28 (8), 1567-1577.

Klivenyi, P. et al. (2000) Mice deficient in cellular glutathione peroxidase show increased vulnerability to malonate, 3-nitropropionic acid, and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. J Neurosci 20, 1-7.

Kohen, R., Nyska, A. (2002) Oxidation of biological systems: oxidative stress phenomena, antioxidants, redox reactions, and methods for their quantification. Toxicol Pathol 30, 620-650.

Labunskyy, V.M. et al. (2014) Selenoproteins: molecular pathways and physiological roles. Physiol Rev 94, 739-777.

Lee, B.C. et al. (2013) MsrB1 and MICALs regulate actin assembly and macrophage function via reversible stereoselective methionine oxidation. Mol Cell 51, 397-404.

Lindenau, J. et al. (1998) Enhanced cellular glutathione peroxidase immunoreactivity in activated astrocytes and in microglia during excitotoxin induced neurodegeneration. Glia 24, 252-256.

Liu, J., Rozovsky, S. (2013) Contribution of selenocysteine to the peroxidase activity of selenoprotein S. Biochemistry 52, 5514-5516.

Loflin, J. et al. (2006) Selenoprotein W during development and oxidative stress. J Inorg Biochem 100, 1679-1684.

Lu, C. et al. (2006) Identification and characterization of selenoprotein K: an antioxidant in cardiomyocytes. FEBS Lett 580, 5189-5197.

Ma, Y.H. et al. (2012) Thioredoxin-1 attenuates post-ischemic neuronal apoptosis via reducing oxidative/nitrative stress. Neurochem Int 60, 475-483.

Meinerz, D.F. et al. (2011) Protective effects of organoselenium compounds against methylmercury-induced oxidative stress in mouse brain mitochondrial-enriched fractions. Braz J Med Biol Res 44, 1156-1163.

Moskovitz, J. et al. (2011) Induction of methionine-sulfoxide reductases protects neurons from amyloid beta-protein insults in vitro and in vivo. Biochemistry 50, 10687-10697.

Munemasa, Y. et al. (2008) Protective effect of thioredoxins 1 and 2 in retinal ganglion cells after optic nerve transection and oxidative stress. Invest Ophthalmol Vis Sci 49, 3535-3543.

Nagy, P. (2013) Kinetics and mechanisms of thiol-disulfide exchange covering direct substitution and thiol oxidation-mediated pathways. Antioxid Redox Signal 18, 1623-1641.

Novoselov, S.V. et al. (2007) Selenoprotein H is a nucleolar thioredoxin-like protein with a unique expression pattern. J Biol Chem 282, 11960-11968.

Panee, J. et al. (2007) Selenoprotein H is a redox-sensing high mobility group family DNA-binding protein that up-regulates genes involved in glutathione synthesis and phase II detoxification. J Biol Chem 282, 23759-23765.

Papp, L.V. et al. (2007) From selenium to selenoproteins: synthesis, identity, and their role in human health. Antioxid Redox Signal 9, 775-806.

Pillai, R. et al. (2014) Selenium and selenoprotein function in brain disorders. IUBMB Life 66, 229-239.

Pisoschi, A.M., Pop, A. (2015) The role of antioxidants in the chemistry of oxidative stress: A review. Eur J Med Chem 97, 55-74.

Pitts, M.W. et al. (2014) Selenoproteins in nervous system development and function. Biol Trace Elem Res 161, 231-245.

Pitts, M.W. et al. (2012) Deletion of selenoprotein P results in impaired function of parvalbumin interneurons and alterations in fear learning and sensorimotor gating. Neuroscience 208, 58-68.

Poole, L.B. (2015) The basics of thiols and cysteines in redox biology and chemistry. Free Radic Biol Med 80, 148-157.

Qiao Y, Huang X, Chen B, He M, Hu B 2017. In vitro study on antagonism mechanism of glutathione, sodium selenite and mercuric chloride. Talanta 171 : 262-269.

Rajanna, B. et al. (1995) Modulation of protein kinase C by heavy metals. Toxicol Lett 81, 197-203.

Raman, A.V. et al. (2013) Selenoprotein W expression and regulation in mouse brain and neurons. Brain Behav 3, 562-574.

Ran, Q. et al. (2004) Transgenic mice overexpressing glutathione peroxidase 4 are protected against oxidative stress-induced apoptosis. J Biol Chem 279, 55137-55146.

Reeves, M.A., Hoffmann, P.R. (2009) The human selenoproteome: recent insights into functions and regulation. Cell Mol Life Sci 66, 2457-2478.

Rock, C., Moos, P.J. (2010) Selenoprotein P protects cells from lipid hydroperoxides generated by 15-LOX-1. Prostaglandins Leukot Essent Fatty Acids 83, 203-210.

Savaskan, N.E. et al. (2007) Role for glutathione peroxidase-4 in brain development and neuronal apoptosis: specific induction of enzyme expression in reactive astrocytes following brain injury. Free Radic Biol Med 43, 191-201.

Schomburg, L. et al. (2003) Gene disruption discloses role of selenoprotein P in selenium delivery to target tissues. Biochem J 370, 397-402.

Shchedrina, V.A. et al. (2011) Selenoprotein K binds multiprotein complexes and is involved in the regulation of endoplasmic reticulum homeostasis. J Biol Chem 286, 42937-42948.

Sugiura Y, Tamai Y, Tanaka H. (1978) Selenium protection against mercury toxicity : high binding affinity of methylmercury by selenium-containing ligands in comparison with sulfur-containing ligands. Bioinorg. Chem. 9 :167-180.

Steinbrenner, H. et al. (2006) Involvement of selenoprotein P in protection of human astrocytes from oxidative damage. Free Radic Biol Med 40, 1513-1523.

Steinbrenner, H., Sies, H. (2009) Protection against reactive oxygen species by selenoproteins. Biochim Biophys Acta 1790, 1478-1485.

Sugiura, Y., et al.(1976), Selenium protection against mercury toxicity. Binding of methylmercury by the selenohydryl-containing ligand. Journal of the American Chemical Society,  98:2339–2341.

Sun, Y. et al. (2001) Selenoprotein W in overexpressed and underexpressed rat glial cells in culture. J Inorg Biochem 84, 151-156.

Trigona, W.L. et al. (2006) Thioredoxin reductase regulates the induction of haem oxygenase-1 expression in aortic endothelial cells. Biochem J 394, 207-216.

Wagner, C., Sudati, J.H., Nogueira, C.W., Rocha, J.B.T. (2010) In vivo and in vitro inhibition of mice thioredoxin reductase by methymercury. Biometals 23, 1171-1177.

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