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Relationship: 1765

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

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

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Binding, SH/SeH proteins involved in protection against oxidative stress

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Protection against oxidative stress, decreased

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

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)	Open for citation & comment	WPHA/WNT Endorsed

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) 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. More help

Term	Scientific Term	Link
rat	Rattus norvegicus	NCBI
mouse	Mus musculus	NCBI
human	Homo sapiens	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Male
Female

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
All life stages	High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. 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 Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field 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. 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
Glutathione Peroxidase (GPx) Family	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)

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Mercury

Thiol- and selenol containing proteins have a high affinity for binding metals which contributes to the target site – brain – distribution of such toxicants (Farina, 2011).

The selenol group (-SeH) of selenocysteines is generally more reactive than thiols (-SH) towards mercury (Sugiura 1976, Khan, 2009). Methyl mercury (MeHg) can target both the GPx and TrxR proteins thereby decreasing protection against oxidative stress and therefore causing increased oxidative stress and neurotoxicity (Branco, 2017, Carvalho, 2008, Farina, 2011).

Note: The binding of HgCl₂ and MeHg is always studied in vitro on the isolated protein, whereas the effects on the activity of the proteins involved in protection against oxidative stress is mostly studied in isolated cells, mitochondrial fractions or in animals. Therefore the concentrations cannot be compared. Binding of Hg to thiol groups and to various selenium-containing proteins: Glutathione, thioredoxin reductase, thioredoxin, glutaredoxin, glutathione reductase was measured using purified proteins (Carvahlo et al., 2008, 2011; Wiederhold et al., 2010; Sugiura et al., 1978; Arnold et al., 1986; Han et al., 2001; Qiao et al., 2017).

Table 2

KE_up Binding, Thiol/seleno-proteins involved in protection against oxidative stress	KE_down Decreased protection against oxidative stress	Species; in vivo / in vitro	Stressor	Dose/ conc. + Duration of exp.	Protective/ aggravating evidence	Reference
Binding of 2.5 mol of Hg²⁺ /mol of TrX1 (Carvahlo et al., 2008)	Inhibition of TrX Inhibition of TrXR	Recombinant rat TrX HeLa and HEK293 cells	HgCl₂	IC₅₀ 7.2 nM	Selenite (5 mM)	(Carvahlo et al., 2008, 2011)
Binding of 5 mol of Hg²⁺ /mol of TrX1 (Carvahlo et al., 2008)	Inhibition of TrX Inhibition of TrXR	Recombinant rat TrX HeLa and HEK293 cells	MeHg	IC₅₀ 19.7 nM	Selenite (5 mM)	(Carvahlo et al., 2008, 2011)
Binding to GR and GrX (Carvahlo et al., 2008)	Total inhibition	Purified proteins	Hg2+	10 nM		(Carvahlo et al., 2008)
Binding to GR and GrX (Carvahlo et al., 2008)	50% of inhibition	Purified proteins	MeHg	80 nM		(Carvahlo et al. 2008)
	Inhibition of TrxR and GSH activities. TrxR activity – cytosolic: 0.7 fold; mitochondrial: 0.4 fold) TrxR1&2 expression – slight decrease, not quantified GSH – 0.7-fold	Human neuroblastoma cells (SH-SY5Y)	MeHg	1 µM		(Branco, 2017)
	Depletion of GSH levels. GSH-activity: 10µM – 0.75-fold 30µM – 0.6-fold 100µM – 0,5-fold	Mouse brain mito-chondrial-enriched fractions	MeHg	10, 30, and 100 μM 30 minutes	The co-incubation with diphenyl diselenide (100 μM)completely prevented the disruption of mitochondrial activity.	(Meinerz, 2011)
	Depleted GSH levels.	Adult male Wistar rats	mercuricchloride	30ppm in drinking water		(Agrawal, 2015)

Acrylamide (acrylamide is a common food contaminant generated by heat processing)

No literature supporting the link “SH/SeH binding leads to decreased protection against oxidative stress” for acrylamide as stressor in brain/neural tissue can be found.

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. 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).

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

See Table 2

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

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?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured 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. 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.

Wiederhold JG, Cramer CJ, Daniel K, Infante I, Bourdon B, Kretzschmar R. (2010) Equilibrium mercury isotope fractionation between dissolved Hg(II) species and thiol-bound Hg. Environ Sci Technol. 44 :4191-7. Doi : 10.1021/es100205t.

Winterbourn, C.C., Hampton, M.B. (2008) Thiol chemistry and specificity in redox signaling. Free Radic Biol Med 45, 549-561.

Winther, J.R., Thorpe, C. (2014) Quantification of thiols and disulfides. Biochim Biophys Acta 1840, 838-846.

Wu, R.T. et al. (2014) Selenoprotein H suppresses cellular senescence through genome maintenance and redox regulation. J Biol Chem 289, 34378-34388.

Zhang, Y. et al. (2008) Comparative analysis of selenocysteine machinery and selenoproteome gene expression in mouse brain identifies neurons as key functional sites of selenium in mammals. J Biol Chem 283, 2427-2438.

Zhong, L. et al. (2000) Structure and mechanism of mammalian thioredoxin reductase: the active site is a redox-active selenolthiol/selenenylsulfide formed from the conserved cysteine-selenocysteine sequence. Proc Natl Acad Sci U S A 97, 5854-5859.