An Overview of the Antioxidant and Anti-Inflammatory Activity of Selenium

Abstract

Selenium, whose name comes from the Greek word for “Selene,” has been a topic of interest as a micronutrient ever since it was described in 1817 as a by-product of sulfuric acid manufacturing. Selenium, the most important micronutrient for both humans and animals, must be consumed daily to support the body’s natural metabolism and homeostasis. The small intestine is responsible for the absorption of selenium in both its organic and inorganic forms. Selenium is then able to be widely distributed throughout the body’s diverse tissues, where it plays an important role in the regulation of the synthesis of selenoproteins. The synthesis of human selenoproteins involves the incorporation of a selenium-containing homolog of cysteine in each of the 25 selenium-containing proteins that make up this series. Many selenoproteins, including glutathione peroxidase (GPX), thioredoxin reductase (TrxR), and iodothyronine deiodinases (IDD), function as crucial cellular defenses against oxidative stress. Therefore, selenium is extremely important in boosting antioxidant defense. Recent studies have also shown that there is a close relationship between selenium and inflammation, and that selenium has regulatory effects on inflammation by affecting the expression of various cytokines. This chapter’s goal was to thoroughly review the research on how selenium is related to antioxidant and anti-inflammatory activity.

1. Introduction

Selenium, which takes its name from the Greek word “Selene,” has been attracting attention as a trace element since 1817 as a by-product of sulfuric acid [1]. Both environmental and endogenous factors affect body selenium homeostasis [2]. Selenium can be absorbed by the small intestine in both organic and inorganic forms, after which it can be distributed throughout the body and perform important biological functions, most particularly by controlling the synthesis of selenoproteins [3]. Selenoproteins play an important role in many biochemical and physiological processes in both humans and animals because of their antioxidant properties [4]. They have antioxidant and anti-inflammatory properties that help to regulate immune cell functions [5]. Twenty-five genes in the human genome are responsible for the coding of selenocysteine-containing proteins. The selenoprotein family, whose functions are known, is named according to these functions: glutathione peroxidases (GPX1, GPX2, GPX3, GPX4, and GPX6), thioredoxin reductases (TrxR1–3), iodothyronine deiodinases (DIO1–3), selenophosphate synthetase 2 (SEPHS2), methionine sulfoxide reductase B1(MSRB1), SEP15 (SELENOF), SELH (SELENOH), SELI (SELENOI), SELK (SELENOK), SELM (SELENOM), SELN (SELENON), SELO (SELENOO), SELP (SELENOP), SELS (SELENOS), SELT (SELENOT), SELV (SELENOV), and SELW (SELENOW) [6]. The primary function of multiple selenoproteins is to protect cells from oxidative damage by taking action as major antioxidants.

In this review, I want to show how selenium affects many biological effects, mostly through selenoproteins, as well as how it affects the physiological and biochemical processes it interacts with. Furthermore, the effect of deficiency and excess selenium in the body on the antioxidant and anti-inflammatory systems and the most recent findings on human health are highlighted.

1.1 Selenium requirement in the human body

Selenium is a crucial trace element required for the proper working of all organisms. It is emphasized that very high and very low selenium levels in humans are harmful to health [7]. For instance, not getting sufficient selenium can cause oxidative stress, which decreases the concentrations of selenoproteins, such as GPx and TXNRD, in the body. On the other hand, too much selenium can cause oxidative stress by oxidizing and cross-linking protein thiol groups, which causes reactive oxygen species to form [8]. The amount of this element, which varies according to bioavailability, geographical region, and nutrition, plays an important role in selenium homeostasis in the organism. It has been determined that 40–70 micrograms [9] of this element is optimal for normal biochemical and physiological processes [10, 11]. The World Health Organization suggests that adults consume 55 μg of selenium per day [12]. The US Food and Nutrition Board determined it to be 40–70 μg for men and 45–55 μg for women [13, 14, 15]. The determination of reference values for selenium in adults is based on saturation of the plasma selenoprotein P (SePP) level with adequate selenium intake. SePP saturation was reached in people with an average body weight of 58 kg who lived in areas with low selenium levels by giving them 49 microgram of selenium every day [16]. This is equivalent to getting about 1 micrograms of selenium per kilogram of body weight every day [17]. Reference values for children and teens are based on values made for adults, with their body weight and growth factors taken into account. Estimated values for selenium intake by age groups and body weights are as follows: 15 μg/day for 1 to 4 years old, 20 μg/day for 4–7 years old, 30 μg/day for 7 to 10 years old, 45 μg/day for 10 to 13 years old, and 60 μg/day for 13 to 15 years old. The estimated daily value of selenium intake for boys aged 15 to 19 is 70 micrograms, while for girls of the same age, it is 60 micrograms Daily [17]. The determination of selenium requirements in newborns and 4-month-old infants is based on the selenium content of breast milk [17]. A daily average of 750 ml of breast milk [18] results in a selenium intake of nearly 11 μg/day. An estimate of optimal selenium intake for breastfed infants between new-born and 4 months of age is 10 micrograms. However, considering the average body weight differences and solid food intake processes in infants aged 4–12 months, an estimated daily 15 micrograms was determined for infants (Table 1) [17].

	Selenium μg/day		References
Age	Male (μg)	Female (μg)
Birth–4 months	10
4–12 months	15
1–4 years	15
4–7 years	20
7–10 years	30
10–13 years	45		[17, 19]
13–15 years	60
15–19 years	70	60
19–25 years	70	60
25–51 years	70	60
51–65 years	70	60
Pregnant women		60
Lactating women		75

Table 1.

Values predicted to ensure sufficient selenium consumption.

1.2 Source of selenium in the human body

Selenium is mostly orally taken into the human organism. Plant and animal products are the main sources of this element. Selenium can be found in foods and biological materials as inorganic compounds, as well as organic compounds [20, 21]. Plants store selenium in the form of inorganic compounds called selenate (IV) or (VI) and then convert them into organic forms such as selenomethionine and selenocysteine [7]. Selenocysteine levels are high in animal-derived products [22]. Selenium is found in low concentrations in vegetables and fruits, but in high concentrations in seafood, grains, and meat products [23, 24]. On the other hand, protein-rich foods contain higher levels of selenium than foods low in protein [7]. Cereal products provide approximately 50% of the daily selenium intake, while meat, fish, and poultry products provide approximately 35%. Water and beverage products provide about 5–25% of selenium. Fruit, on the other hand, meets about 10% of the selenium demand (Table 2).

Selenium Source	Food	Selenium concentration(mg/kg)	Selenium forms	References
Meat and meat products	Beef	0.042–0.142	Selenomethionine	[19, 25]
	Lamp	0.033–0.260
	Chicken	0.081–0.142	Selenomethionine/Selenocysteine
	Pork	0.032–0.198	Selenomethionine/Selenate
	Fish	0.1–5.0	Selenomethionine/Selenite/Selenate	[19]
Milk and dairy products	Milk	0.01–0.03	Selenocysteine/Selenite
Vegetable products	Broccoli	0.5–1.0	Selenomethionine/Selenate
	Garlic	0.05–1.0	Selenomethionine/Selenocysteine
	Potatoes	0.12	Selenomethionine	[19, 25]
	Mushrooms	0.01–1.40	Selenomethionine/Selenocysteine/ Selenomethylselenocysteine	[26]
	Onions	0.02–0.05	Selenomethionine/Selenocysteine	[19]
Grain products	Bread	0.01–30	Selenomethionine/Selenate
	Cereal	0.02–35
	Lentils	0.24–0.36		[19, 25]
	Rice	0.05–0.08	Selenomethionine
Other food products	Yeast	0.6–15		[19]
	Eggs	3–25	Selenomethionine/Selenocysteine

Table 2.

Selenium concentrations in various foods.

2. The role of selenium in oxidative stress, inflammation, and immunity

Oxidative stress is a disruption of the balance between the prooxidant and antioxidant systems in the body [27, 28]. In normal circumstances, the prooxidant system and the antioxidant system work together to maintain the body’s homeostasis. However, increased prooxidant system activity and deterioration of the antioxidant system (Table 3) result in oxidative stress. The development of many chronic diseases, including diabetes [30], cancer [31], antiviral agents [32], and various aging-related and central nervous system (CNS) disorders [33], can result in high levels of reactive oxygen and nitrogen species production. In addition, reactive oxygen production causes intense lipid peroxidation in cells, causing the breakdown of cell membranes [5]. As a result, cellular homeostasis is disrupted, and human health is affected. Antioxidant activity as a free radical scavenger is linked to protecting cells from autooxidation and keeping their structure so that the immune system can work at its best [34].

	Radicals	Non- Radicals
Reactive oxygen species	O2.-, Superoxide	H2O2, Hydrogen peroxide; HOCI, Hypochlorous acid; ^1O2, Singlet oxygen; O3, Ozone
	OH., Hydroxyl
	RO2., Peroxyl
	RO., Alkoxyl
	HO2., Hydroperoxyl
	NO., Nitric oxide
	NO2., Nitrogen dioxide
Reactive nitrogen species	NO., Nitric oxide; NO2., Nitrogen dioxide	HNO2, Nitrous acid
		N2O4, Dinitrogen tetroxide
		N2O3, Dinitrogen trioxide
		ONOO-, Peroxynitrite
		ONOOH, Peroxynitrous acid
		NO2+, Nitronium cation
		ROONO, Alkyl peroxynitrites

Table 3.

Reactive oxygen and nitrogen species [29].

In the process of regulating antioxidant activities, various selenoproteins are essential players [35]. Glutathione peroxidase GSH-Px, which contains one selenium atom in each subunit, was one of the first highly effective selenoproteins [36]. The glutathione peroxidase enzyme reduces reactive oxygen and nitrogen species by converting hydrogen peroxide (H₂O₂) to water (H₂O) and organic hydroperoxides (ROOH) to alcohol (ROH) [14, 37]. The selenium dependent (GPXs 1–4) significantly detoxifies cellular peroxides that protect against reactive oxygen species [38]. Glutathione peroxidase 1 (GPX1) is the most common selenoprotein that protects the body from oxidative stress caused by reactive oxygen and nitrogen [39]. On the other hand, GPX1 may also decrease the concentration of lipid hydroperoxides and other hydroperoxides once they have been released from membrane lipids [40]. In the same way, as GPX1 does, GPX2 neutralizes H₂O₂ and fatty acid hydroperoxides [41]. This selenoprotein, which was expressed in the intestinal tract in the early 1990s, has also attracted attention with its antioxidant activities by affecting apoptosis and regulating the self-renewal of the intestinal epithelium [42]. GPX3, found in plasma and milk [38], is an important selenoprotein that serves as a source of extracellular antioxidant capacity, especially in the kidney proximal tubule epithelial cell [43], by reducing oxidative stress in the heart, liver, lungs, skeletal muscle, and thyroid gland [44, 45]. GPX4 is unique among GPXs in that it has the ability to catalyze the reduction of hydrogen peroxide and other lipid hydroperoxides in addition to reducing phospholipid hydroperoxides [46]. GPX6 enzyme expression was detected only in the embryo and olfactory epithelium [47]. In an in vivo study, supplementation of selenium-rich, rice-extracted selenoproteins to male mice modeled aging by abdominal D-galactose injection and increased GSH-Px and superoxide dismutase (SOD) enzyme activation in the liver and serum of mice compared to the control group [48]. TrxR enzymes, which function in concert with NADPH to clear the redox system in mammals, have been identified in three different forms [49]. Trx1 is responsible for the reduction of thioredoxins in the cytosol, TrxR2 for the reduction of thioredoxins in the mitochondria, and TrxR3 for the reduction of glutathione and glutaredoxin [50]. DNA synthesis, which occurs at the beginning of cellular processes, relies on the existence of selenium in the catalytic region of TrxR [51]. Furthermore, mammalian TrxRs are selenoproteins that play an essential function in many cellular processes by modulating the action of the core redox molecule thioredoxin, as well as directly reducing a variety of substrates [50]. DIOs are members of the selenoprotein family that include the three enzymes (DIO1, DIO2, and DIO3) that catalyze the activation (DIO1) and inactivation (DIO2) of the thyroid hormone thyroxine (T4), respectively [52]. DIO1 is involved in T3 production in the thyroid gland and controlling circulating T3 levels, while DIO2 and DIO3 are involved in local deiodination processing processes at the tissue and organ level [53]. Increased oxidative damage in thyroid tissue has been associated with decreased DIO and GPx activity in the organism and insufficient GPx concentration [54]. In mammals, selenophosphate synthetase 2 (SEPHS2) is a selenoprotein involved in the biosynthesis of the amino acid selenocysteine, which catalyzes the formation of selenophosphate from selenide and ATP [55, 56]. SelR, commonly referred to as methionine-R-sulfoxide reductase B1 (MsrB1), is a protein that helps reduce oxidized methionine (Met) residues (methionine sulfoxides) [57]. SelR comprises a redox effective selenoprotein containing a particular enzymatic activity that is necessary for oxidative protein repair [50]. SEP15 is the first selenoprotein [58] to be widely distributed across multiple organs including the brain, lung, testis, liver, thyroid, and kidney [59]. Sep15, belonging to the class of thiol-disulfide oxidoreductase-like selenoproteins [60], is a selenoprotein exhibiting redox activity [61]. Selenoprotein K is mainly expressed in the heart and skeletal muscle, but it is also found in other tissues such as the placenta, liver, and pancreas. Increasing levels of SELK in the organism exhibit antioxidant properties in the heart by reducing intracellular ROS levels and protecting cardiomyocytes against oxidative damage [62]. Selenoprotein M, a selenoprotein distantly related to Sep15, acts as a redox regulator with the amino acid selenocysteine [63]. SELM, induced by sodium selenite, which has prooxidant properties, has a functional role in catalyzing free radicals [64]. SELN, which is an endoplasmic reticulum glycoprotein and has important functions in muscle tissue, has been associated with myopathies [65]. SELN, which draws attention with its cell proliferation and regeneration, is significantly effective in the early embryonic development process [66]. It plays an important role in the redox system by contributing to calcium homeostasis in the organism [67] and protecting the cells from oxidative stress [68]. SelO, which is located in the mitochondria of the organism and draws attention with its feature of being the biggest selenoprotein [69], plays a role in oxidative stress by controlling S-glutathionylation levels [70]. Selenoprotein P is estimated to contain 50% of plasma selenium [71]. The plasma concentration of SELP varies depending on selenium supplementation. These changes in selenium intake, together with its concentration at the plasma SELP level, may reflect an indication of the amino acid protein residues of selenite in its molecule [72]. SELP, which exhibits antioxidant properties, has been shown to protect astrocytes [73] and endothelial cells from oxidative stress [74, 75]. In addition, it has been demonstrated that SELP prevents the oxidation of low-density lipoproteins [76]. Selenoprotein S, one of the resident proteins of the endoplasmic reticulum, is a selenoprotein involved in the reduction of reactive oxygen species and redox signaling [77]. This selenoprotein plays critical functions in protein quality control processes, cytokine modulation, and signaling [78]. Selenoprotein T is the only protein among the selenoproteins located in the membrane of the endoplasmic reticulum. The decrease in the expression of selenoprotein T, known for its suppressive effect on reactive oxygen and nitrogen species, has been shown as a possible factor in the deterioration of the antioxidant balance [79]. Selenoprotein V, which is predominantly localized in the intracellular cytoplasm, plays an important role, such as other selenoproteins, in the elimination of oxidative stress by protecting against endoplasmic reticulum stress and apoptosis caused by prooxidants [80]. Selenoprotein W, which is expressed in every tissue, is one of the well-known selenoproteins with antioxidant properties that are very important for the proper growth of the brain and embryo [81, 82].

Selenium, which plays an important role in antioxidant defense for body homeostasis, also plays an important role in the regulation of different inflammatory processes in the organism [83]. Adequate selenium supplements are essential for the immune system. For example, selenoprotein expression is affected in male mice supplemented with selenium, and immune response pathways, such as Interferon-γ and IL-6, are supported [84]. Interleukin IL-2, IL-4, IL-5, IL-13, and IL-22 cytokine levels were significantly higher in plasma and peripheral blood mononuclear cells in people who ate 200 mg of selenium-rich broccoli per serving for three days [85]. A previous study showed that increasing selenium supplements increased antigen-specific CD4⁺ T cell responses. In addition, high selenium diets increased interferon-gamma (IFN-γ) and IL-2 expression levels compared to low and moderate selenium diets [86]. The higher contents of selenium in the blood of older individuals have been shown to have a positive correlation with a higher percentage and activity of natural killer (NK) cells [87]. In patients with acute respiratory distress syndrome, intravenous selenium supplementation attenuated inflammatory responses and significantly improved respiration by restoring the antioxidant capacity of the lungs via IL-1β and IL-6 proinflammatory cytokine levels [88]. Selenium supplementation significantly affects both innate immunity (neutrophils, macrophages, and NK) and acquired immunity (T and B lymphocytes) [89]. The phagocytosis functions of macrophages and the T cell activities of the body were significantly boosted by selenium-containing proteins [90]. Selenoprotein K plays an important role in the regulation of immunity by affecting the proliferation of T cells and the transport of neutrophils as a cofactor for the enzyme involved in the maturation of proteins in the endoplasmic reticulum to support calcium influx [5, 91].

3. Conclusions

These findings suggest that adequate selenium supplements may contribute to the body’s immune homeostasis. It also shows that the selenoprotein family can prevent damage to cellular proteins by directly scavenging reactive oxygen and nitrogen species. In this respect, selenium appears to have both a protective and a therapeutic role in immune dysfunction, and further research is needed to understand the effect of selenium at different pharmacological doses, different administration methods, and in different age and gender groups. However, with new studies to be done, it is necessary to reveal the mechanisms that play a role in selenium homeostasis depending on oral or parenteral supplements in humans and animals. In addition, due to the fact that the drugs used in the treatment of chronic diseases all over the world, including in our country, have both side effects and are expensive, it leads to an increase in health costs and causes countries to determine new principles in health services. In recent years, scientists have accelerated their studies to find more accessible, inexpensive, and low side effect products such as selenium instead of expensive, prescription-only pharmacological agents with high side effects. As a result of the promising findings on the effects it creates in the organism, selenium supplements may be used as a potential pharmacological agent in the prevention of oxidative stress and regulation of inflammation in the near future.