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EXCLI Journal 2022;21:948-966 – ISSN 1611-2156
Received: June 16, 2022, accepted: June 28, 2022, published: July 05, 2022
948
Review article:
SELENIUM AS AN IMPORTANT FACTOR IN
VARIOUS DISEASE STATES - A REVIEW
Marek Kieliszek1* , Iqra Bano2
1 Department of Food Biotechnology and Microbiology, Institute of Food Sciences,
Warsaw University of Life Sciences, Nowoursynowska 159 C, 02-776 Warsaw, Poland
2 Department of Veterinary Physiology & Biochemistry, Shaheed Benazir Bhutto University
of Veterinary and Animals Sciences Sakrand (SBBUVAS), 67210, Sindh, Pakistan
* Corresponding author: Marek Kieliszek, Department of Food Biotechnology and
Microbiology, Institute of Food Sciences, Warsaw University of Life Sciences,
Nowoursynowska 159 C, 02-776 Warsaw, Poland; E-mails: marek_kieliszek@sggw.edu.pl
or marek-kieliszek@wp.pl
https://dx.doi.org/10.17179/excli2022-5137
This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0/).
ABSTRACT
Selenium (Se) is an element that has a pro-health effect on humans and animals. However, both the deficiency of
this element and its excess may prove harmful to the body depending on the chemical form of the selenium, the
duration of supplementation, and the human health condition. Many data indicate insufficient coverage of the
demand for selenium in humans and animals due to its low content in soils and food products. A balance in the
physiological process of the body can be achieved via the proper percentage of organically active minerals in the
feed of animals as well as human beings. Selenium is a trace mineral of great importance to the body, required
for the maintenance of a variety of its processes; primarily, selenium maintains immune endocrine, metabolic,
and cellular homeostasis. Recently, this element has been emerging as a most promising treatment option for
various disorders. Therefore, research based on Se has been increasing in recent times. The present review is de-
signed to provide up-to-date information related to Se and its different forms as well as its effects on health.
Keywords: Selenium, antioxidant, oxidative stress, selenoproteins
INTRODUCTION
Currently, selenium is one of the most
important and intensively studied micronu-
trients. This element was discovered in 1817
by the Swedish chemist J.J. Berzelius, in the
course of research on a new method of pro-
ducing sulfuric acid. During sulfur combus-
tion, a red-brown sludge obtained from py-
rite (iron sulfide) from a mine in Falun,
Sweden had been observed. Initially, this
distinctive precipitate was considered to be
the most toxic compound - arsenic, therefore,
processing of pyrite from Falun was avoided.
However, the phenomenon was found to be
interesting and was re-analyzed. During sub-
sequent studies, it was found that the sedi-
ment contained a new, previously unknown
compound with properties similar to telluri-
um. Referring to the similar properties of tel-
lurium, whose Greek name means Earth
(Tellus), selenium was given the name
meaning the Moon (Tsuji et al., 2021). Sci-
entists became interested in selenium when it
was discovered in the 1950s that increased
selenium accumulation causes muscular dys-
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949
trophy, and a deficiency of this element and
vitamin E causes acute liver necrosis in stud-
ied rats (Duntas and Benvenga, 2015). In
1973, selenium was discovered to be an im-
portant component of the active center of the
enzyme glutathione peroxidase. After less
than 20 years, researchers found that other
enzymes also contain a selenium atom in
their active centers. For example, selenocys-
teine builds the active center of iodothyro-
nine deiodase. These discoveries and the
recognition of many selenoproteins and se-
lenoenzymes were the impetus for research-
ers to start intensive research on the im-
portance of this element for the human body
(Kieliszek, 2019). The eighties and nineties
of the twentieth century were spent on re-
search into determining the total content of
selenium and its other forms in biological
materials. The results of these studies were
the starting point for explaining the metabo-
lism of selenium compounds and calculating
the daily selenium requirement for the hu-
man body. Trace mineral supplementation is
crucial for the maintenance of animal and
human health. Several trace minerals serve
as enzymatic cofactors and metallic enzymes
in various biological systems (Vural et al.,
2020). As a general rule, they activate en-
zymes that participate in the removal of cel-
lular free radicals from the body. The endo-
crine system, as well as metabolism, is di-
rectly influenced by several of these miner-
als, which are also key components of some
hormones. Thus, any change in their concen-
tration could influence the synthesis of other
hormones involved in the maintenance of re-
productive systems (Mirnamniha et al.,
2019; Arshad et al., 2021; Barchielli et al.,
2022). Selenium (Se) is one of the major
trace minerals, placed in the 34th position in
the periodic table. A growing number of re-
searchers are focusing on the role of Se in
the preservation of a wide range of bodily
processes, which has led to an increase in in-
terest in Se research. Some experts believe
that this component plays a key role in the
longevity of male fertility, serves as a regen-
eration agent, and has consequences for the
endocrine system of the animal body via
maintenance of ratios of various antioxidant
factors such as several enzymes and by-
products including glutathione peroxidase
(GPx), superoxide dismutase (SOD), malon-
dialdehyde (MDA), and catalase (CAT)
(Barchielli et al., 2022; Kieliszek et al.,
2022). According to previous studies, it has
been proven that Se also has major effects on
somatic growth in mammals and birds by in-
fluencing the insulin growth-like factor axis
(IGF), maintenance of triiodothyronine (T3),
tetraiodothyronine (T4), thioredoxin reduc-
tase (TrxR), and growth hormone (GH), re-
spectively. Research into the regulation and
functional characterization of selenoproteins
(SelPs) has helped researchers better under-
stand how Se affects human health as well as
the wide range of physiological processes
that are affected by this trace element
(Kieliszek and Błazejak, 2013). The major
SelPs and their functions in the body are
elaborated in Table 1. Eukaryotic nuclear
SelPs protect the genome from OS (oxidative
stress) by scavenging free radicals. There are
now more than 50 families of SelPs recog-
nized, most of which were discovered using
bioinformatics techniques. SELENOP seems
to be the only SelP believed to be confined
to the nucleus among the others (Ha et al.,
2019). Some SelPs belonging to the GPx and
TrxR families that are especially vulnerable
to a probable dietary Se deficit, which may
be related to a lower expression of some
SelPs. Collectively, the SelPs described
above control redox stability and protein
quality. According to recent research, the
availability of Se varies greatly throughout
the European countries with some states
lacking and others oversupplied (Benhar,
2018). The health benefits and illnesses con-
nected to a shortage of Se are explored in the
current review.
DIFFERENT FORMS OF SELENIUM
Selenium is a micronutrient, and like
other elements, circulates in nature, and Se
can be found in two distinct forms; inorganic
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950
Table 1: Mammalian Selenoproteins (SelPs) and their functions in the body
SelPs Name
Abbreviation
Functions
Reference
Glutathione
Peroxidase
GPx
Prevents oxidative stress, regulation
of antitumor immunity
Gomes Alves
Andrade et al., 2021
Iodothrionine
Deiodinase 1-3
Dio1-3
Regulation of thyroid gland secre-
tion, neuron health
Ogawa-Wong et al.,
2016
Selenoprotein H
SelH
Cell cycle regulation & cancer pre-
vention
Bertz et al., 2018
Selenoprotein I
SelI
Phospholipid biosynthesis
Mangiapane et al.,
2014
Selenoprotein K
SelK
Immunity & inflammation
Verma et al., 2011
Selenoprotein M
SelM
Maintenance of Ca2+ ions
Negro, 2008
Selenoprotein N
SelN
Growth and development of muscles
Negro, 2008
Selenoprotein O
SelO
Regulation of redox reactions
Mangiapane et al.,
2014
Selenoprotein P
Sepp1
Transportation of Se to brain and
other tissues of body
Saito, 2020
Selenoprotein S
SelS
Regulation of inflammation & redox
reactions
Yang and Liu, 2017
Selenoprotein T
SelT
Regulation of endocrine secretion
Pothion et al., 2020
Selenoprotein V
SelV
Expression of taste
Ogawa-Wong et al.,
2016
Selenoprotein W
SelW
Oxidative stress regulation, Bone
remolding
Pothion et al., 2020
Thioredoxin
Reductase 1-3
TrxR1-3
Tumor cell apoptosis, oxidative
stress, and reduction of disulfide
bonds
Zhang et al., 2021
and organic. The in-organic forms include
selenate (Na2SeO4) and selenite (Na2SeO3)
(Kieliszek and Błazejak, 2013), whereas the
organic form includes selenomethionine
(SeMet) and selenocysteine (SeCys). Both
forms of Se are known to be effective dietary
sources of the mineral. In-organic Na2SeO3
and Na2SeO4 are found in soils and are ac-
cumulated by plants, which convert them to
organic forms as well as their methylated de-
rivatives. It is estimated that skeletal muscle
stores between 28 to 46 % of the total Se
pool, making it the most important site of
storage (Hariharan and Dharmaraj, 2020). It
is possible to decrease SeCys and Na2SeO3
to produce hydrogen selenide, which is then
transformed to selenophosphate for use in
SelPs biosynthesis. On the other hand, Se is
found in higher animals and humans in the
form of SeMet, which replaces the methio-
nine in plant proteins (Hu et al., 2018). Ra-
ther than methionine, the body uses SeMet
which is more easily absorbed and may be
metabolized or incorporated into protein
(Gandin et al., 2018). As methionine intake
increases, SeMet incorporation is dimin-
ished. It is mostly present in the skeletal
muscle, erythrocyte, pancreas, liver, stom-
ach, kidney, and gastrointestinal mucosa pro-
teins; its release from body proteins is asso-
ciated with protein turnover and occurs con-
tinuously. When SeMet intake is kept con-
stant, a steady state is formed and may be
maintained throughout a broad range of in-
takes for all times (Roman et al., 2014). The
chemical structures of different forms of Se
are elaborated in Figure 1.
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951
Figure 1: The chemical structures of different selenium compounds (a: monomethylselenonium,
b: dimethylselenide, c: selenide, d: seleniumphosphate, e: selenite, f: selenate, g: selenocysteine,
h: selenomethionine)
SOURCES OF SELENIUM
Selenium is found in the atmosphere, hy-
drosphere, lithosphere, and biosphere of the
earth. Depending on the type of environ-
ment, selenium is present in different con-
centrations. Naturally occurring selenium
comes from the weathering of volcanic rocks
and the emission of dust into the atmosphere.
Additionally, by decomposing organic mat-
ter rich in selenium, microorganisms enrich
the atmosphere with selenium compounds
(Mehdi et al., 2013).
Regardless of soil thickness, the Se con-
centration in mineral soil is approximately
14 mg/kg. Only trace amounts of Se are
found in groundwater, while the concentra-
tion of Se in seawater can rise dramatically.
Se extraction from source rocks and run-off
by intensive soil fertilization with combina-
tions heavy in Se compounds are the primary
causes of seawater's greater content of Se
(Bano et al., 2021). There is a limit to how
much Se can be safely ingested by humans
according to World Health Organization
(WHO) recommendations. Several factors
influence the amount of Se in food such as
the soil and cultivating situations in which
bread and cereal crops are grown, the forage
that animals eat, and the refining of these
commodities for human consumption, all of
which affect the amount of Se present in the
final product. Also, Se may be found in both
organic and inorganic chemical forms in
foods and biological materials. When it
comes to bioavailability, the chemical form
of Se may have an impact on how it is ab-
sorbed; SeMet is more bioavailable than in-
organic Na2SeO4 or Na2SeO3 because it is
organic (Rosetta and Knight, 1995). The ef-
ficiency of selenium absorption is dependent
on the form in which SeMet> MeSeCys>Se
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952
(VI)>Se (IV) occurs (Thiry et al. 2012).
Many nations have set dietary standards to
guarantee appropriate Se consumption for
the sake of human health (Tinggi, 2008).
Based on the research by (Huang et al.,
2013) on the relationship between the doses
of this element and the occurrence of clinical
selenosis and its symptoms, EFSA experts
established the UL level (upper tolerable
level of consumption) for this element and
set the UL value at 300 μg/day for adults.
The maximum tolerable level of daily con-
sumption includes the provision of selenium
with both food and supplements. For chil-
dren and adolescents, this value was calcu-
lated on the basis of body weight and re-
duced accordingly. Both the consumption of
selenium in excess and its deficiency are tox-
ic to the human body and may have adverse
health effects (Rayman, 2017). If the rec-
ommended dose for consumption by an adult
is exceeded for a long time by more than 300
μg/day, a disease called selenosis may de-
velop (Petrović, 2021). In this case, the body
reacts by producing weakening and brittle
nails. It is also associated with substantially
increased hair loss. There may be general
weakness and fatigue of the body, mental
disorders, e.g., depression or nervousness.
Excessive consumption may also be accom-
panied by gastrointestinal disorders and skin
lesions. If the dose of selenium is well above
the standard, there is a risk of disturbing the
functioning of internal organs at one time,
which may lead to cirrhosis of the liver or
even pulmonary edema (MacFarquhar et al.,
2010).
Selenium in water, soil, and air is accu-
mulated in plant tissues and thereby intro-
duced into the food chain. Inorganic seleni-
um found in plants is less digestible than or-
ganic selenium from animal tissues, and
products of animal origin are, therefore, a
better source of selenium, i.e., meat, fish,
and dairy products. Animal products are
considered the basic source of this micronu-
trient in the diet of the European population.
People who do not eat meat satisfy their se-
lenium needs through nuts - mainly Brazil
nuts and mushrooms (Chen et al., 2021). Ce-
real products and some vegetables and fruits
are also high in this micronutrient. The most
susceptible to selenium accumulation are
cruciferous vegetables (white cabbage, Brus-
sels sprouts, cauliflower) and garlic vegeta-
bles (garlic). However, it should be remem-
bered that the content of selenium in plant
products is related to the amount of this ele-
ment in the soil in which the plant is grown.
The soils of all of Europe, including Poland,
are characterized by a low content of this el-
ement (Mirończuk-Chodakowska et al.,
2019). This means that plant-based products
are not the main source of selenium in our
diet. It is also worth noting that in the case of
soils fertilized with selenium compounds, the
selenium content in plant tissues will be
higher (Izydorczyk et al., 2021).
There are huge differences in soil Se lev-
els across the globe, and these large varia-
tions in soil Se levels are mirrored in the
wide variances in the Se status of human
populations (Yamashita et al., 2013). Several
nations have now successfully implemented
a breakthrough technological procedure
aimed at processing Se-rich food products
such as eggs, beef, and dairy. The Korean
market has pork and chicken boosted with
Se, while eggs fortified with Se are currently
available in 25 nations across the world. To
fill any micronutrient deficiency and main-
tain the body's metabolic equilibrium, it is
clear that eggs enhanced with Se might be
employed as functional meals (Bano et al.,
2021).
SELENIUM SUPPLEMENTATION
Recommended dietary intakes of Se and
other minerals are described in the dietary
reference intakes (DRIs) established by the
Food and Nutrition Board (FNB) at the Insti-
tute of Medicine of National Academies. The
term "DRI" refers to a collection of reference
values that are used to plan and assess the
nutritional intakes of healthy persons regu-
larly. These values differ depending on one's
age and gender (Yates, 1998). In different
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953
parts of the world, DRI and tolerated upper
intake levels (UL) for Se differ. For exam-
ple, in the United Kingdom (UK), men
should consume 75 g/day and women should
consume 60 g/day. Moreover, the European
Food Safety Authority (EFSA) recommends
a 55 g/day Se intake. The overconsumption
of Se can cause selenosis, a hazardous condi-
tion in which the body becomes overexposed
to Se (Stoffaneller and Morse, 2015). It is
worth noting that studies have already been
conducted on the health effects of taking ex-
cessive amounts of this element in the form
of a dietary supplement with a dose of
41.749 µg/day. 227 people participated in the
study, and their symptoms varied greatly;
only 58 % of the respondents felt nauseous,
and a little more - 61 %, noticed discolora-
tion of their nails and increased brittleness. A
majority of people participating in the study
complained about diarrhea (78 %), chronic
fatigue (75 %), and increased hair loss
(72 %), while pain in the joints affected as
many as 70 % of respondents. The vast ma-
jority of symptoms disappeared after the end
of supplementation. However, symptoms
such as fatigue and hair and nail brittleness
persisted up to 90 days after the end of the
study (MacFarquhar et al., 2010). The Se
might also become pro-oxidant at even high-
er quantities, resulting in oxidative stress
(OS) and cell damage. As a result, it is criti-
cal to keep the body's Se concentration at a
healthy level while also avoiding the harmful
consequences of an overabundance of the
mineral (Xia et al., 2021). In the early 1970s,
regulatory bodies needed to evaluate which
Se compounds may be used in animal feed,
but nothing was known about SeMet.
Na2SeO4 and Na2SeO3 were approved as
feed additives in 1974, however, the situa-
tion was unsatisfactory so, just because Se-
rich foods have been authorized by the Food
and Drug Administration (FDA) does not
always guarantee they are healthy options.
When these permissions were granted, Se
compounds such as SeMet were also missed
(Yang et al., 2022), and the only Se com-
pounds available for animal feed at the stage
of the regulatory action were the inorganic
Se compounds. The first commercially ac-
cessible "high SeYeast" appeared in the mid-
1970s. With 90 % of the Se found in com-
mercial goods being in the form of SeMet,
these products generally included between
1,000 and 2,000 μg of Se/mg (Tsuji et al.,
2021). Large-scale cancer prevention trials
began in 1983 using this SeMet-Yeast as the
Se source. An additional 200 mg of Se/day
dramatically reduced the chance of getting
prostate, lung, and colorectal cancer in this
study. The FDA authorized the use of
SeYeast in chicken broiler and layer feeds in
June of 2000 and a lengthy process of re-
search and development will lead to SeMet
or other nutritional sources ultimately replac-
ing inorganic Se compounds as feed addi-
tives (Lyons et al., 2007). Since Brazil nuts
are recognized to be one of the largest
sources of SeMet, they have been employed
extensively in the study of Se supplementa-
tion. Regular intake of Brazil nuts leads to
optimal plasma Se and erythrocyte concen-
trations as well as improved efficiency of se-
lenoenzymes antioxidant state, muscle reten-
tion, and inflammatory status (Roman et al.,
2014). Before beginning clinical trials, it is
critical to take into account genetic varia-
tions in SelPs genes as well as to pre-stratify
the population to prevent potentially varied
reactions based on the Se status of each per-
son. The nutritional Prevention of Cancer
(NPC) experiment showed that SeYeast (200
mg/day) may reduce the incidence of malig-
nancies of the uterus, prostate, lung, and co-
lon. Moreover, the Se supplementation in the
form of SeYeast (200 g/day) dramatically
boosted Se levels in healthy New Zealand
males and improved DNA stability (Ferreira
et al., 2021).
In cases of using selenium yeast as a feed
additive and dietary supplement, not even a
single accidental poisoning with this element
was reported, and lower chronic toxicity
compared to sodium selenate was found. The
first selenium yeast production process was
developed over 30 years ago and, initially,
the quantification of selenomethionine was
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954
difficult due to the poor characteristics of
yeasts and their composition. Over time,
with the use of improved methods of analy-
sis, the composition of the yeast has been
found to be more uniform than initially as-
sumed. It is selenomethionine that is the
main form of selenium in yeast cells, there-
fore, they can be treated as an excellent
source of naturally synthesized food form of
selenium (Loef et al., 2011).
In 2012, the European Food Safety Au-
thority (EFSA) Panel on additives and prod-
ucts or substances used in animal feed issued
a positive opinion on the safety and efficacy
of selenium in the selenium yeast Saccharo-
myces cerevisiae NCYC R646 (Selemax
1000/2000) as a feed additive for animals of
all species. The Panel on Additives and
Products or Substances used in Animal Feed
(FEEDAP) states that supplementation
should not exceed 0.2 mg of selenium per kg
of complete feed. Such dosing will ensure
the safety of consumers against consuming
tissues and products of animal origin that
have consumed the preparation. Additional-
ly, Selemax is believed to be an effective
source of selenium and does not change the
quality of meat measured by physical param-
eters. Due to the lack of data, the product is
considered to be potentially irritating to the
skin and eyes as well as being skin sensitiz-
ing, and due to its proteinaceous nature, it is
considered a potential respiratory sensitizer
(EFSA, 2012).
In turn, in 2020, the Panel of the Europe-
an Food Safety Authority (EFSA) for addi-
tives and products or substances used in an-
imal feed renewed the permit for the use of
selenium-enriched yeast produced by Sac-
charomyces cerevisiae CNCM I-3399 as a
feed additive for all animal species. It was
again found that the use of the additive in the
permitted amounts is safe for target species
and consumers as well as the environment
(Bampidis et al., 2020).
SELENIUM STATUS IN VARIOUS
EUROPEAN COUNTRIES
In Europe, Se intakes tend to be lower
than in the US, due to soils being a less reli-
able supply of the mineral. To assess wheth-
er these levels are enough or not, we must
first establish acceptable benchmarks against
which to measure them, however, this sub-
ject has divided opinion. There has been a
steady fall in the UK's Se intake since the
1970s, and prior government studies show
that Se consumption is low across the UK
population as a whole (Rayman, 2002). Ac-
cording to a Polish study, the Se level of the
foods consumed in Eastern Europe was four
times lower than the Se content in Spain,
which appeared to surpass the DRI and rec-
ommended daily allowance (RDA) levels of
the nutrient. Research conducted in France
and Belgium found intakes comparable to
the RDA, while studies conducted in Slove-
nia and Italy found intakes lower than the
RDA. In Europe, the results of Se status in-
vestigations show that most populations have
blood Se concentrations that fall short of the
required amount for complete plasma GPX
expression (Stoffaneller and Morse, 2015),
with a few notable exceptions, including
Austria, Hungary, Denmark, Poland, and
some of the participants in the "IMMIDIET"
study, which examined the impact of migra-
tion on dietary habits in European communi-
ties to the varying risk of coronary heart dis-
ease as a model of gene-environment interac-
tion (Iacoviello et al., 2001). The reported
serum Se levels in Albanian individuals re-
siding in Greece had the highest concentra-
tion of Se in all the European studies, at 37.4
g/L, wherein, insufficient animal protein in-
take could be the cause. The Se concentra-
tion in Estonian soils was studied and results
revealed a mean value of 0.172 mg/kg (rang-
ing from 0.010–0.443 mg/kg) (Stoffaneller
and Morse, 2015). Moreover, another re-
search suggested that Se insufficiency and
the plant-animal food chain, are linked. For
example, blood and milk samples taken from
Estonian dairy cows were discovered to be
deficient in Se (Rauhamaa et al., 2008). Se-
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955
rum or plasma Se levels are closely linked to
erythrocyte GPx activity when Se consump-
tion is low or moderately low. In populations
with low or moderate Se consumption, se-
rum or plasma Se serves as a helpful meas-
ure of status, notwithstanding the limitations
outlined above. Europe has a similar scenar-
io; Se levels are too low for GPx activity to
be fully saturated (Nève, 1995; Demircan et
al., 2021). There is some evidence to suggest
that consuming enough Se to maximize im-
mune response and minimize cancer risk is
not enough to reach levels that meet the en-
zymic or antioxidant function of Se in plas-
ma. Se intake of less than two-thirds of the
recommended daily value would exacerbate
this deficiency even more. Functional Se
markers, which indicate physiologically ef-
fective concentrations, are being explored.
The potential of Se from SeYeast to be pre-
served in the organism and reversibly re-
moved by various metabolic processes to
counteract periods of insufficient intake is
likely to be particularly valuable in areas of
low Se intake such as those found in Eastern
Europe. Se from SeYeast can be stored in the
organism and transiently cleared by normal
metabolic processes. The sale of SeYeast in
Europe should not be prohibited as a result,
especially if the criteria for upper safe limits
(such as the somewhat conservative Europe-
an Community tolerated maximum intake
threshold of 300 mg/d) are followed (Ray-
man, 2004).
THE ROLE OF SELENIUM IN
DIFFERENT DISEASES
In normal functioning, Se plays an im-
portant role and participates in the pathogen-
esis of a wide range of illnesses (Figure 2). A
healthy diet rich in Se appears to protect
against a wide range of diseases, including
cancer, cardiovascular disease, neurodegen-
erative disease, and problems with fertility,
by maintaining the body’s Se-dependent re-
dox homeostasis. This is accomplished, in
part, through the production of antioxidant
SelPs. On the other hand, even though ex-
cessive Se intake may lead to toxicity, men-
tal problems, and cancer, supra-nutritional
dosages of Se compounds can be used as
chemotherapeutic agents for their pro-
oxidant and pro-apoptotic effects on cancer
cells (Barchielli et al., 2022).
Figure 2: Effects of selenium on various health conditions
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956
Selenium as an antioxidant
Oxidative stress (OS) is a state that oc-
curs when a system's capacity to neutralize
and remove reactive oxygen species (ROS)
is outstripped. ROS are byproducts of cellu-
lar metabolism, principally created by elec-
tron leakage from mitochondrial electron ac-
ceptors and enzymes throughout oxidative
phosphorylation (Marín et al., 2020; Wang et
al., 2021). Overproduction or distribution of
ROS from endogenous sources or external
stress may lead to an antioxidant capacity
deficiency, which in turn can generate an
imbalance. Damage to lipids, proteins, or
DNA might impede signal transduction
pathways and overall cellular function if
ROS levels are not appropriately managed
(Roman et al., 2014). As a result, OS has
been linked to a wide range of human disor-
ders, including cardiovascular and neurolog-
ical diseases, cancer, and the aging process.
Chemical compounds that prevent ROS from
forming or reacting with biological struc-
tures are known as antioxidants. Enzymatic
catalysis may be used to convert inorganic
Se molecules like Na2SeO3 and Na2SeO4 to
organic forms and vice versa. ROS signaling
has two main modes of action, namely,
changes in intracellular redox status and pro-
tein oxidative modifications (Tsuji et al.,
2021). OS may be reduced by GPx and
TrxR, which work as thiol-redox systems to
reduce H2O2 and lipid hydroperoxides in the
body. One of the most important aspects of
Se is its involvement as a component of nu-
merous critical antioxidant compounds as
well as the particular oxidation properties of
the antioxidant molecule thioredoxin reduc-
tase. GPX reduces ROS metabolites to pro-
tect membrane integrity (Tinggi, 2008). Re-
search into the effects of Se and SelPs will
aid in the development of novel medicinal
approaches; more specifically, ebselen, an
organo-Se compound that mimics glutathi-
one peroxidase, has been shown to suppress
superoxide anion formation and release of
NO as well as to scavenge peroxynitrite and
protect against lipid peroxidation, which is
consistent with its proposed ability to pre-
vent the onset of OS (Zarczyńska et al.,
2013).
Selenium for brain disorders
Downregulation or damage to Se and
SelPs, which play a crucial physiological
role in neurons, astrocytes, and microglia,
may result in brain dysfunction. The Se lev-
els in the brain decline as we age, and this
decline is linked to cognitive decline
(Whanger, 2016). Moreover, Se has a role in
the prevention and treatment of Alzheimer's
disease (AD), either alone or in conjunction
with other factors. When comparing AD pa-
tients to healthy controls, one study found a
clear link between lower Se plasma concen-
trations and cognitive impairment. In the ear-
ly stages of AD, the reduction in plasma Se
levels was not related to the dietary condi-
tion. Another research suggested that the AD
brain tissue's Se levels were also markedly
lowered, particularly in the hippocampus and
in the frontal, parietal, temporal, and occipi-
tal lobes (Loef et al., 2011). In addition, it
was shown that Se therapy had a positive
impact when combined with other neuropro-
tective substances (Barchielli et al., 2022).
Na2SeO3 and natural carotenoid dicarboxylic
acid, when used together, offered superior
neuroprotection in treated rats with strepto-
zotocin (STZ) by lowering lipid peroxidation
and increasing GSH, GPX, glutathione S-
transferase (GST), and CAT activity
(Dominiak et al., 2016). Several in vitro ex-
periments have shown that Se protects the
brain against poisons that cause Parkinson's
disease symptoms to persist indefinitely in
the body. Besides, the formation of reactive
nitrogen species (RNS) was also decreased,
and the lowering of GPx levels in dopamin-
ergic neurons produced by methampheta-
mine (MA) was ameliorated by Se supple-
mentation (Navarro-Alarcon and Cabrera-
Vique, 2008). As a result of a lower serum
and erythrocyte Se concentration in epileptic
patients, it was previously believed that Se
use may be enhanced. The depletion of Se in
the brain during epilepsy is also thought to
be a significant component in the onset of
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957
seizures (Dominiak et al., 2016). As the OS
is frequently accompanied by a loss of vital
trace elements in patients with cerebral is-
chemia, it is also worth noting that Se levels
were considerably lower in the ischemic
brain compared to the control participant. Is-
chemia and reperfusion damage might bene-
fit from the scavenging properties of Se,
hence therapy utilizing Se-derived com-
pounds was recommended (Whanger, 2016).
The prefrontal cortex and hippocampus of a
rat model of ischemia/reperfusion were
shown to have increased neuron density and
reduced perineuronal and pericapillary ede-
ma after treatment with Na2SeO3 according
to more current results based on histological
examinations. Furthermore, the same study
found that inorganic Se treatment signifi-
cantly decreased the levels of inflammatory
cytokines such as interleukin-1 beta (IL-1
beta) and tumor necrosis factor alfa (TNF-
alfa) while simultaneously increasing the
levels of neurotrophic factor (NGF) in the
prefrontal cortex and hippocampus (Ramos
et al., 2015).
Selenium and thyroid diseases
In comparison to other endocrine organs,
the thyroid contains the highest Se content,
suggesting the importance of the thyroid's
actions. The maintenance of proper Se status
in humans is essential for the preservation of
thyroid health, the metabolism of thyroid
hormones (TH), and the prevention of thy-
roid disorders. Numerous clinical studies
have demonstrated that Se supplementation
has anti-inflammatory benefits for patients
with autoimmune thyroiditis, which is char-
acterized by decreased anti-thyroid peroxi-
dase supplement autoantibody (TPOAb) lev-
els and restoration of thyroid function
(Triggiani et al., 2009). The maintenance of
an optimal physiological concentration of Se
is, therefore, critical to guaranteeing appro-
priate thyroid function and, as a result, the
generation of essential regulators important
to metabolism. Several biological functions
of Se in the thyroid are known, including ac-
celerating enzymatic redox processes, regu-
lating thyroid hormone metabolism, and
guarding against oxidative DNA damage
caused by H2O2 and lipid hydroperoxides as
well as inflammation. Single nucleotide pol-
ymorphisms in SelPs genes are related to
higher risk and mortality of thyroid-
associated disorders, which reflects the im-
portance of SelPs to thyroid health (Tinggi,
2008). The polymorphisms of the GPX3 are
one example of a polymorphism that is relat-
ed to differentiated thyroid carcinoma.
Moreover, Se shortage of moderate severity
has been associated with impaired thyroid
function as well as an increase in the preva-
lence of thyroid disorders. This is because a
shortage of Se results in a decrease in both
deiodinases (DIO) and GPX enzymatic ac-
tivity. Tetraiodothyronine (T4) is converted
to its activated form, triiodothyronine (T3)
by the enzyme DIO, which becomes less ac-
tive as a result of the decreased activity of
DIO, which results in decreased active TH
production. Furthermore, a low Se status is
related to a greater risk of autoimmune thy-
roiditis, Grave's disease, and goiter (en-
largement of the thyroid gland) in women. It
is now well established that Se supplementa-
tion can have a clinically beneficial effect on
people suffering from autoimmune thyroidi-
tis and Grave's orbitopathy (Mojadadi et al.,
2021).
Selenium for reproduction
The ability to reproduce at the highest
level is dependent on several factors, includ-
ing genetics, external environmental factors,
and an individual's food. Micronutrients are
particularly important in the diet since they
are required for a variety of biological pro-
cesses, including growth and reproductive
capacity. Furthermore, even minor variations
in micronutrient concentrations can have a
significant impact on critical physiological
processes such as fertility (Zarczyńska et al.,
2013). According to certain research, there is
a link between Se level and reproductive
function in both men and women. Female
reproductive health is comprised of several
consecutive phases that result in the genera-
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958
tion of an optimally functioning egg. One of
the most important steps is folliculogenesis,
the process by which primordial ovarian fol-
licles in birth evolve into mature ovarian fol-
licles after puberty (Kieliszek and Błazejak,
2013). The multiplication of granulosa cells
is a critical phase in the formation of follicu-
logenesis, and Se has been demonstrated to
regulate the progression of granulosa cells as
well as the manufacture of one of the key
female sex hormones, 17-estradiol (E2). It
has been demonstrated in a small number of
studies that a connection between Se status,
female fertility, and Se-dependent catalytic
interaction has been established (Mojadadi et
al., 2021). In general, these studies have
found that low serum and follicular fluid
levels are associated with a higher occur-
rence of infertility in women. It has been
shown that Na2SeO3 not only promotes oo-
cyte growth but also increases the rate of cell
proliferation in theca and granulosa cells. In
support of this concept, an in vitro investiga-
tion conducted by Basini and Tamanini
(2000) showed that Na2SeO3 (5 ng/mL)
treatment induced the production of nitric
oxide (NO). This compound stimulated the
expansion of bovine granulosa cells while al-
so having some stimulatory effects on the
production of E2. These consequences could
be mitigated, at least partly, by suppressing
the generation of NO in the body (Friedman,
2011). Se is essential for the normal produc-
tion of sperm cells as well as for the matura-
tion of spermatozoa in mammals. When Se
levels are either too high or too low, sperm
production always suffers. The maturation of
spermatozoa is critical to the quality of se-
men and male fertility, hence any interrup-
tion in this process might result in lower se-
men quality and infertility. Testicular struc-
tures in male goats have been shown to be
influenced by Se supplementation; anomalies
were apparent in the mitochondrial gaps, tail,
plasma membrane, and midpiece of sperma-
tozoa from boars fed an Se deficient diet.
Overall, an insufficient supply of dietary Se
leads to poor quality semen, which eventual-
ly leads to infertility since SelPs in the testis
is involved in spermatogenesis (Bano et al.,
2019).
Selenium and embryo
The significance of Se in maternal nutri-
tion, as well as its impact on the Se status of
offspring, has recently attracted a great deal
of attention. In vertebrates, Se is delivered to
the fetus and infant through the placenta, co-
lostrum, and milk. Among bird species, Se is
transferred to the egg and then passes on to
the growing fetus and freshly fledged chick
as well as to the mother and her eggs
(Pappas et al., 2019). Se affects both non-
enzymatic and enzymatic antioxidant de-
fense mechanisms, assisting in the develop-
ment of a robust antioxidant defense for both
the mother as well as the developing embryo.
Recent human research has also demonstrat-
ed a link between parental Se status and par-
ticular outcomes in early childhood, which is
consistent with previous findings. It has been
shown that both higher and lower levels of
cord serum Se have detrimental impacts on
an infant's neurobehavioral development
(Yang et al., 2013). Moreover, the impact of
Se on large animals has been studied exten-
sively, however, most of that research has
focused on early gestational stages, with on-
ly a few studies looking at later outcomes. In
humans, studies have focused on the effects
of Se on nutrition, with only a few looking at
later consequences. Small intestine weight
was increased in six-month-old lambs gener-
ated from ewes fed with supranutritional Se
and artificially reared to minimize confusing
effects with colostral Se, but this was not ac-
companied by high jejunal cell proliferation
(Yunusova et al., 2013). In pigs, parental
supplementation with SeMet greatly enhanc-
es litter weight at weaning, and in chickens,
the addition of Se in the diets could positive-
ly affect embryo survivability, hatchability,
and development of the offspring (Kieliszek
and Błazejak, 2013).
Selenium and cancer
Selenium is of great interest in the treat-
ment and prevention of cancer (Kieliszek et
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959
al., 2017). In some cases, this micronutrient
shows an antagonistic relationship between
selenium consumption and cancer develop-
ment, such as ovarian, pancreatic, bladder,
and lung cancer. However, the therapeutic
use of selenium in cancer is a moot point.
The mechanisms leading to the death of neo-
plastic cells depend on the form of selenium,
the dose used, the duration of action, and the
characteristics of the neoplastic cells. Due to
the specificity of the discussed microele-
ment, it is referred to as "an element with
two faces". Selenium shows antioxidant
properties in small doses, and pro-oxidative
properties in large doses (Wallenberg et al.,
2014). Low selenium concentrations protect
both healthy and neoplastic cells. Cells are
protected against toxicity caused by oxida-
tive stress and support DNA repair. On the
other hand, a higher concentration of seleni-
um reduces the risk of carcinogenesis and all
kinds of cellular mutations. Selenium has a
significant impact on the expression of genes
responsible for inflammatory responses and
the remodeling of the cytoskeleton (Misra et
al., 2015). These are processes related to the
risk of cancer incidence. In vitro, selenium
inhibits the migration of neoplastic cells and
has an anti-angiogenic effect, i.e., it prevents
the formation of new blood vessels, which is
characteristic of malignant neoplasms. In
practice, inhibition of cellular mobility
means preventing the development of tumor
metastasis. This relationship has been con-
firmed in the case of breast, prostate, colon,
or lung cancer, and in the case of lymph
node metastases. Although the relationship
between selenium deficiency in the blood
and increased cancer incidence has been re-
peatedly demonstrated, little is known about
the anti-cancer mechanism of this element.
Selenium is used in anti-cancer therapy due
to its strong anti- and pro-oxidative proper-
ties. In cancer cells, the pro- and antioxidant
balance is disturbed because numerous reac-
tive oxygen species (ROS) are produced in
the process of glycolysis and the pentose cy-
cle. The way selenium acts on cancer cells
involves the production of ROS and modifi-
cation of the thiol group. This procedure
brings about effects that disrupt transcription
and changes related to the endoplasmic re-
ticulum (Zhao et al., 2020; Razaghi et al.,
2021). It is worth noting that selenium may
be helpful in the treatment of advanced
forms of cancer through its cytotoxic effect
that damages cancer cells. Selenite (IV) is
used to support the treatment of cancer in
many organs, including the lungs, uterus,
and prostate. Selenite has been shown to
have the potential to potentiate its effect on
developed prostate tumors (Fernandes and
Gandin, 2015).
Se has been studied in human clinical
studies around the world at this point. In
China, the first human trials to cure cancer
with Se have been conducted. About 20,847
people received Na2SeO3 which provided
about 30–50 mg of Se each day for eight
years. Primary liver cancer cases have
dropped considerably (Yuan et al., 2022).
Serum Se levels and the presence of breast
cancer have been linked, and these authors
suggest using Se concentrations as a predic-
tor for breast cancer. Serum Se concentra-
tions were considerably lower in breast can-
cer patients compared to healthy women in a
case-control study (Charalabopoulos et al.,
2006). GPX1 enzyme activity decreased
when SelPs levels were increased in colon-
derived HCT116 cells and MCF-7 breast
cancer cells, according to another study.
When administered orally for just 24 hours,
SelPs induced a significant increase in plas-
ma and erythrocytes concentration, plasma
oxygen radical absorbance capacity (ORAC)
levels, and erythrocytes Se concentration,
while a decrease in thioredoxin reductase 1
(TXNRD) activity and an increase in MDA
level were observed following 28 days of
treatment. Moreover, previous research has
also suggested that the plasma and serum Se
levels are typically reduced in cancer pa-
tients. In human lung cancer cells, the SeMet
has been shown to activate the tumor sup-
pressor protein p53 by transforming oxidized
p53 into the reduced form of p53. This may
help guard against cancer (Abdulah et al.,
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960
2005). Besides this, some plant-based Se
compounds have also recently been studied
for anticarcinogenic properties, with re-
searchers particularly interested in garlic, on-
ion, and broccoli. Moreover, chemotherapeu-
tic drugs can be used in combination with Se
to protect patients against the toxicity of the
treatment. Several chemotherapeutic drugs
(irinotecan, fluorouracil, oxaliplatin, and cis-
platin) had their maximum tolerated dosage
(MTD) increased when SeMet and SeCys
were added to the treatment (Yuan et al.,
2022). In order to maintain the cancer cell
selectivity of Se absorption, higher dosages
of the Se molecule may be required. There is
still a lot of work to be done in determining
the optimum doses for cancer treatment that
are safe and effective (Barchielli et al.,
2022). According to studies conducted by
Kuria et al. (2020), selenium in the recom-
mended daily dose of at least 55 μg reduces
the risk of cancer in adults. The Recom-
mended Dietary Allowances vary according
to age, for pregnant women, and while
breastfeeding. For the proper course of phys-
iological processes, this element is necessary
for the body in small amounts. Breastfeeding
women are advised to consume 70 μg of se-
lenium per day, while children aged 1 to 3
years old require a lower amount of seleni-
um, 20 μg. Children over 14 years of age and
adults require 55 μg of selenium per day
(Kuria et al., 2020).
Selenium and immunity
Immune system cells such as macro-
phages, natural killer (NK) cells, neutrophils,
and T lymphocytes rely on Se to do their
jobs properly. OS, inflammation, and the
spread of infectious diseases can all be alle-
viated or even prevented with a suitable rise
in serum Se concentration in the diet (Roman
et al., 2014). Immunoglobulin production is
increased by Se, which promotes the differ-
entiation and proliferation of lymphocytes as
well as the development of immunoglobulin
and enhances the ability of the human body
to produce antibodies such as IgM and IgG.
Immunoglobulin and antibody synthesis are
hindered by a lack of Se (Xia et al., 2021).
Broilers that received 1.50 mg/kg of dietary
SeNPs had greater IgG and IgA titers during
both the secondary and primary immunolog-
ical responses against blood cells one day af-
ter hatching. ROS produced by neutrophils
can be used to destroy bacteria. Leukotriene
B4 production, which is essential for neutro-
phil chemotaxis, is impaired by Se deficien-
cy but can be improved by Se supplementa-
tion. Nutritional Se intake has a direct and
indirect impact on NKs activity (Tsuji et al.,
2021). The cytotoxic effect of NKs has been
found in numerous investigations to be sig-
nificantly influenced by dietary Se. A study
of more than 300 North American men
found that supplementation with Se boosted
plasma Se levels, and there was a positive
association between both the plasma concen-
tration of Se and the proportion of NKs in
the bloodstream. Serum Se levels are favora-
bly associated with the number of CD16+
NKs in the blood plasma of aged adults (Xia
et al., 2021).
Selenium for bone stability
The health of the skeletal system is cru-
cial for the elderly. The ability to have a
thorough grasp of the association between Se
and bone strength is beneficial when devel-
oping early-life therapies (Zeng et al., 2013).
SelPs expressed in human embryonic osteo-
blasts would seem to protect the bone from
OS, which might also contribute to the de-
velopment of osteoporosis by suppressing
osteoblastic proliferation of bone marrow
stromal cells. Se, being a crucial ingredient
of SelPs, is far more likely to play a critical
role in the connections between Se and bone
mineral density (BMD) (Beukhof et al.,
2016). To the best of our knowledge, there
have been at least ten studies that have
looked at the relationship between nutritional
or serum Se concentrations and BMD, oste-
oporosis, or osteoporotic fractures. A lack of
Se is related to loss of bone mass in male rats
and osteoarthropathy in Kashin Beck disease
(KBD) (Yang et al., 2022). This is because
Se shortage interferes with the manufacture
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961
of many antioxidant SelPs, which compro-
mises bone metabolism and causes osteoar-
thropathy. Yao et al. (2011) investigated the
effects of supplemental Se mixed with io-
dine, which was developed for a regimen for
the KBD endemic regions, on the histology
of bones and development of plates cartilage
in Wistar rats of both sexes. They suggested
that the Se and iodine supplementation in
rats resulted in the reduction of necrosis of
the chondrocytes throughout their develop-
ment and trabecular bone formation. Addi-
tionally, they noticed increases in the bone-
to-tissue volume fraction, trabecular width,
and trabecular number, as well as decreases
in the trabecular gap between the bone and
the tissue.
Toxicity due to Selenium intake
Continuous intake of high Se-containing
foodstuffs or water can lead to Se accumula-
tion and selenosis in the body, therefore, ex-
cessive Se intake is harmful to the body
(Yang and Liu, 2017). Se toxicosis may af-
fect any kind of animal, according to experts.
While this is the case, poisoning is more
common in foods such as bovine species,
sheep and horse species, as well as other
plant herbivores that graze on plants with an
excess amount of selenium (Loh et al.,
2020). Apart from that, since most plant spe-
cies have low Se concentrations, save for
those that accumulate Se and are not tradi-
tionally used as feedstuffs, or those that grow
in seleniferous soil, the toxicity of grazing
plants is less likely to occur (Bano et al.,
2021). The effects of acute Se poisoning
might include brain problems, changes in
mental state, gastrointestinal symptoms,
breathing signs, hepatocellular necrosis, re-
nal failure, heart attacks, and other cardiac
diseases, among other symptoms. According
to certain studies, the most severe cases of
Se intoxication might cause animals to de-
velop at a slower rate than usual (Yang and
Liu, 2017). A study on Se poisoning in do-
mestic animals found that feeding naturally
occurring Se-containing foods with 25-50
mg Se/kg increased conception and fetal re-
sorption rates in cows, sheep, and horses.
The dosages would have been around 0.5–
1.5 mg Se/kg/day if big animals consume
about 2 %–3 % of their body weight. Hair
loss, lameness, degeneration of the heart,
liver, and kidneys, and fibrosis were some of
the additional side effects of such high Se
levels (MacFarquhar et al., 2010). It has been
discovered that cystic ovaries are linked to
blood Se concentrations of >108 ng/mL in
136 Holstein cows from four flocks. Milk
from control cows had higher levels of pro-
gesterone than milk from animals given Se
therapy, but no information was supplied on
how much Se each of the cows received
(Mohammed et al., 1991). Estrus cycle dura-
tion and behavior, progesterone and estrogen
profiles, and pregnancy rates were not af-
fected by alfalfa granules containing
Na2SeO4 (24 ppm) or Astragalus bisulcatus
(29 ppm) as an Se input for 88 days, from 52
days before pregnancy to day 28 of pregnan-
cy. Amounts of food consumed were not
recorded, and the report indicates that the
food supply was restricted to ensure that it
corresponded to that consumed by those in
the group with the lowest intake level. The
Water Buffalo of the Indian Punjab report
similar symptoms because of high Se levels
in soil waters (Loomba et al., 2020). If Se-
rich soils are used to produce pigs, fish, and
other grain-eating animals, then poisoning
may also occur owing to feed formulation
mistakes. It is also well known that excessive
consumption of Se by females during egg
production might have detrimental effects on
embryonic fish and birds. Se consumption in
chickens and fishes may cause mutations in
these embryos, making them particularly
vulnerable to this kind of mutation (Nasr-
Eldahan et al., 2021). Moreover, Se toxicosis
is rare in small animal pets but can happen
upon ingestion of Se possessing skincare
products or Se supplement tablets. Se toxici-
ty may be affected by a wide range of fac-
tors, but in general, an oral acute Se dosage
of 1-10 mg/kg/Bw (Body weight) is deadly
for the majority of animals. Puppies, calves,
lambs, and dogs may all die at dosages of as
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Received: June 16, 2022, accepted: June 28, 2022, published: July 05, 2022
962
little as 1 mg/kg/Bw of parenteral Se prepa-
rations, which is why these products should
never be given to young animals. Younger
animals are more vulnerable to Se poisoning,
and the chemical forms may have different
toxicity depending on the age of the animal
(Yang and Jia, 2014).
CONCLUSION
There have been significant advances in
the understanding of the import and control
of the trace element Se in cell biology, bio-
chemistry, and molecular biology in recent
years. Se toxicity, with a narrow therapeutic
window, makes it necessary to avoid over-
consumption of Se supplements. New re-
search shows the need to maintain an opti-
mal Se status for health. As far as molecular
aspects are concerned, we are eager to learn
more about Se-dependent chemoprevention.
Research into the effects of Se and SelPs will
aid in the development of novel medicinal
approaches. Specifically, ebselen, an organo-
Se compound that mimics GPX, has been
shown to suppress superoxide anion for-
mation and release of NO as well as to scav-
enge peroxynitrite and protect against lipid
peroxidation, which is consistent with its
proposed ability to prevent OS. Metabolic
processes relating to SeMet and Se remain
mostly unknown. SeCys insertion into pro-
tein is a complex process, and while many of
the variables involved have been identified,
it is still not clear how it all works. As a re-
sult, despite substantial attempts to investi-
gate the positives and negatives of Se in clin-
ical testing, key impediments remain such as
significant gaps in our understanding of the
metabolic actions of Se and SelPs. Greater
knowledge of these fundamental processes
will aid in the design and evaluation of safe
and successful human trials and contribute to
novel treatment interventions.
Acknowledgment
This study was co-financed by the
Preludium Bis 2 (2020/39/O/NZ9/00639)
from the National Science Centre (NCN),
Poland.
Conflict of interest statement
The authors declare no conflict of inter-
est.
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