Relationship between selenium, immunity and resistance against infection

1. Food selenium content, selenium supply and selenium needs are presented, along with methods of evaluation of selenium status. Glutathione peroxidase, a selenium-containing enzyme, is ubiquitous in the organism. 2. Some experimental studies on animal models reported a positive relationship between selenium status and resistance against infections. 3. Only one study in humans concerned the mechanisms of immune functions in selenium deficiency. Several experimental works suggest that severe selenium deficiency compromises T-cell dependent immune functions such as the blastogenic response to mitogens, but selenium deficiency was concomitant with vitamin E deficiency in most of them. Delayed hypersensitivity response is controversial in selenium-supplemented rats and guinea-pigs. 4. Selenium deficiency in animals decreases the antibody response, especially if associated with vitamin E deficiency. Low dietary selenium supplementation of healthy animals has a positive effect upon humoral responses. 5. Despite some controversies, most experimental studies on selenium-deficient animals report normal phagocytosis and an altered bactericidal capacity of neutrophils. The decrease in glutathione peroxidase activity of polymorphonuclear cells following selenium deficiency could explain some of these alterations. 6. Splenic Natural Killer cells activity is enhanced in selenium-supplemented, healthy animals.     

Effects of Selenium on Liver and Muscle Contents and Urinary Excretion of Zinc,Copper, Iron and Manganese

Selenium is a main component of glutathione peroxidase (GPX), a key antioxidant enzyme. Other elements, such as zinc, copper, manganese and iron, are also involved in the pathogenesis of oxidative damage as well as in other important metabolic pathways. The effects of selenium supplementation on the metabolism of these elements have yield controversial results .The aim of this study is to analyse the effects of selenium supplementation on liver, muscle and urinary excretion of zinc, copper, iron and manganese in a situation of oxidative stress, such as protein deficiency. The experimental design included four groups of adult male Sprague–Dawley rats, which received the Lieber–DeCarli control diet, an isocaloric 2 % protein-containing diet and another similar two groups to which selenomethionine (6 mg/l liquid diet) was added. After sacrifice (5 weeks later), muscle, liver and serum selenium were determined, as well as muscle, liver and urinary zinc, copper, manganese and iron and liver GPX activity and liver malondialdehyde. Selenium addition led to decreased liver copper, increased muscle copper, increased copper excretion and increased liver iron, whereas zinc and manganese parameters were essentially unaltered. Muscle, liver and serum selenium were all significantly correlated with liver GPX activity.     

Selenium and thyroid function in infants, children and adolescents

Selenium is an integral component of the enzymes glutathione peroxidase (GPx) and iodothyronine deiodinases. Although selenium nutrition could conceivably affect thyroid function in infants, children and adolescents, available data suggest that the effect of selenium deficiency on thyroid function is relatively modest. In patients with isolated selenium deficiency (such as patients with phenylketonuria receiving a low-protein diet), peripheral thyroid hormone metabolism is impaired but there are no changes in thyrotropin (TSH) or clinical signs of hypothyroidism, suggesting that these patients are euthyroid. Selenium supplementation may be advisable to optimize tissue GPx activity and prevent potential oxidative stress damage. In areas where combined selenium and iodine deficiencies are present (such as endemic goiter areas in Central Africa), selenium deficiency may be responsible for the destruction of the thyroid gland in myxoedematous cretins but may also play a protective role by mitigating fetal hypothyroidism. In these areas, selenium supplementation should only be advocated at the same time or after iodine supplementation. In patients with absent or decreased production of thyroid hormones and who rely solely on deiodination of exogenous L-thyroxine for generation of the active triiodothyronine (such as patients with congenital hypothyroidism), selenium supplementation may optimize thyroid hormone feedback at the pituitary level and decrease stimulation of the residual thyroid tissue.     

Relationship between selenium status,selenoproteins and COVID-19 and other inflammatory diseases: A critical review

The antioxidant effects of selenium as a component of selenoproteins has been thought to modulate host immunity and viral pathogenesis. Accordingly, the association of low dietary selenium status with inflammatory and immunodeficiency has been reported in the literature; however, the causal role of selenium deficiency in chronic inflammatory diseases and viral infection is still undefined. The COVID-19, characterized by acute respiratory syndrome and caused by the novel coronavirus 2, SARS-CoV-2, has infected millions of individuals worldwide since late 2019. The severity and mortality from COVID-19 have been associated with several factor, including age, sex and selenium deficiency. However, available data on selenium status and COVID-19 are limited, and a possible causative role for selenium deficiency in COVID-19 severity has yet to be fully addressed. In this context, we review the relationship between selenium, selenoproteins, COVID-19, immune and inflammatory responses, viral infection, and aging. Regardless of the role of selenium in immune and inflammatory responses, we emphasize that selenium supplementation should be indicated after a selenium deficiency be detected, particularly, in view of the critical role played by selenoproteins in human health. In addition, the levels of selenium should be monitored after the start of supplementation and discontinued as soon as normal levels are reached. Periodic assessment of selenium levels after supplementation is a critical issue to avoid over production of toxic metabolites of selenide because under normal conditions, selenoproteins attain saturated expression levels that limits their potential deleterious metabolic effects.     

An alloy of zinc and innate immunity: Galvanising host defence against infection

Innate immune cells such as macrophages and neutrophils initiate protective inflammatory responses and engage antimicrobial responses to provide frontline defence against invading pathogens. These cells can both restrict the availability of certain transition metals that are essential for microbial growth and direct toxic concentrations of metals towards pathogens as antimicrobial responses. Zinc is important for the structure and function of many proteins, however excess zinc can be cytotoxic. In recent years, several studies have revealed that innate immune cells can deliver toxic concentrations of zinc to intracellular pathogens. In this review, we discuss the importance of zinc status during infectious disease and the evidence for zinc intoxication as an innate immune antimicrobial response. Evidence for pathogen subversion of this response is also examined. The likely mechanisms, including the involvement of specific zinc transporters that facilitate delivery of zinc by innate immune cells for metal ion poisoning of pathogens are also considered. Precise mechanisms by which excess levels of zinc can be toxic to microorganisms are then discussed, particularly in the context of synergy with other antimicrobial responses. Finally, we highlight key unanswered questions in this emerging field, which may offer new opportunities for exploiting innate immune responses for anti‐infective development.     

The role of selenium in human conception and pregnancy

Selenium (Se) is a trace element essential for the appropriate course of vital processes in the human body. It is also a constituent of the active center of glutathione peroxidase that protects cellular membranes against the adverse effects of H₂O₂ lipid peroxides. Epidemiological surveys have demonstrated that selenium deficiency in the body may contribute to an increased risk for certain neoplasmic diseases (including colonic carcinoma, gastric carcinoma, pulmonary carcinoma and prostate carcinoma), as well as diseases of the cardiovascular, osseous and nervous systems. Apart from its cancer prevention and antioxidative activities, selenium protects the body against detrimental effects of heavy metals and determines the proper functioning of the immunological system.Furthermore, selenium plays a significant role in the undisturbed functioning of the reproductive system. Many studies have addressed correlations between its intake and fertility as well as disorders of procreation processes. Selenium deficiencies may lead to gestational complications, miscarriages and the damaging of the nervous and immune systems of the fetus. A low concentration of selenium in blood serum in the early stage of pregnancy has been proved to be a predictor of low birth weight of a newborn. A deficiency of this element may also cause infertility in men by causing a deterioration in the quality of semen and in sperm motility. For this reason, supplementation in the case of selenium deficiencies in the procreation period of both women and men is of utmost significance.     

Recent advances in clinical studies of selenium supplementation in radiotherapy

BackgroundRadiotherapy is one of the most important and common therapies for cancer patients. Selenium has been shown to be capable of reducing the side effects of radiotherapy because selenoproteins have anti-oxidative functions against reactive oxygen species that are induced by the radiation. They also function in DNA-repair and cytokine control.PurposeWe explored the benefits and risks of selenium supplementation in radiotherapy in our previous review to establish guidelines. In the current study, we expanded the search to cover recent advances in clinical studies of selenium supplementation in radiotherapy.MethodsWe conducted an initial screening in the PubMed using the MeSH terms and keywords “selenium”, “radiation”, “therapy”, and “radiotherapy” using the same methodology applied in our previous review. We identified 121 articles published between January 2013 and December 2019. We then identified eight articles (six studies) on selenium and radiotherapy by excluding 113 articles.ResultsIn selenium supplementation studies, selenium doses of 300−500 μg/day with duration of 10 days to 6 months were used. Selenium supplementation improved the selenium nutritional conditions of the patients and reduced the side effects of radiotherapy. Selenium supplementation did not reduce the effectiveness of radiotherapy, and no toxicities were reported.ConclusionThe results of our previous and current reviews showed that selenium supplementation offers specific benefits for several cancer types treated with radiotherapy. Here, we suggest a new guideline for selenium supplementation in radiotherapy. We recommend determining the selenium status of the patients before radiotherapy, and in cases of deficiency (<100 μg/L serum selenium level), selenium supplement can be beneficial.     

Selenium status in an iodine deficient population of the West Ivory Coast

Selenium is an essential trace element which is part of the active site of seleno-dependent glutathione peroxidase and type 1 deiodinase. Therefore, it plays a key role in thyroid hormone metabolism. The present work was undertaken in order to evaluate selenium status in two Ivory Coast populations: the first with high (Glanlé) and the second with low (Abidjan) prevalence of iodine deficiency. Selenium, glutathione peroxidase, glutathione reductase, glutathione and diglutathione were determined in blood and/or urine. In plasma and erythrocytes, selenium and glutathione peroxidase were dramatically low in Glanlé. Compared to Abidjan, selenium, glutathione peroxidase, vitamin E and riboflavin status were decreased whereas diglutathione was increased in Glanlé. The results clearly demonstrate a selenium deficiency and suggest an oxidant stress in Glanlé. Causes and consequences of this selenium deficiency and oxidant stress remain to be determined.     

Selenium and lung cancer: a systematic review and meta analysis

Background

Selenium is a natural health product widely used in the treatment and prevention of lung cancers, but large chemoprevention trials have yielded conflicting results. We conducted a systematic review of selenium for lung cancers, and assessed potential interactions with conventional therapies.

Methods and Findings

Two independent reviewers searched six databases from inception to March 2009 for evidence pertaining to the safety and efficacy of selenium for lung cancers. Pubmed and EMBASE were searched to October 2009 for evidence on interactions with chemo- or radiation-therapy. In the efficacy analysis there were nine reports of five RCTs and two biomarker-based studies, 29 reports of 26 observational studies, and 41 preclinical studies. Fifteen human studies, one case report, and 36 preclinical studies were included in the interactions analysis. Based on available evidence, there appears to be a different chemopreventive effect dependent on baseline selenium status, such that selenium supplementation may reduce risk of lung cancers in populations with lower baseline selenium status (serum<106 ng/mL), but increase risk of lung cancers in those with higher selenium (≥121.6 ng/mL). Pooling data from two trials yielded no impact to odds of lung cancer, OR 0.93 (95% confidence interval 0.61–1.43); other cancers that were the primary endpoints of these trials, OR 1.51 (95%CI 0.70–3.24); and all-cause-death, OR 0.93 (95%CI 0.79–1.10). In the treatment of lung cancers, selenium may reduce cisplatin-induced nephrotoxicity and side effects associated with radiation therapy.

Conclusions

Selenium may be effective for lung cancer prevention among individuals with lower selenium status, but at present should not be used as a general strategy for lung cancer prevention. Although promising, more evidence on the ability of selenium to reduce cisplatin and radiation therapy toxicity is required to ensure that therapeutic efficacy is maintained before any broad clinical recommendations can be made in this context.     

Increased inflammatory response in aged mice is associated with age-related zinc deficiency and zinc transporter dysregulation

Aging is a complex process associated with physiological changes in numerous organ systems. In particular, aging of the immune system is characterized by progressive dysregulation of immune responses, resulting in increased susceptibility to infectious diseases, impaired vaccination efficacy and systemic low-grade chronic inflammation. Increasing evidence suggest that intracellular zinc homeostasis, regulated by zinc transporter expression, is critically involved in the signaling and activation of immune cells. We hypothesize that epigenetic alterations and nutritional deficits associated with aging may lead to zinc transporter dysregulation, resulting in decreases in cellular zinc levels and enhanced inflammation with age. The goal of this study was to examine the contribution of age-related zinc deficiency and zinc transporter dysregulation on the inflammatory response in immune cells. The effects of zinc deficiency and age on the induction of inflammatory responses were determined using an in vitro cell culture system and an aged mouse model. We showed that zinc deficiency, particularly the reduction in intracellular zinc in immune cells, was associated with increased inflammation with age. Furthermore, reduced Zip 6 expression enhanced proinflammatory response, and age-specific Zip 6 dysregulation correlated with an increase in Zip 6 promoter methylation. Furthermore, restoring zinc status via dietary supplementation reduced aged-associated inflammation. Our data suggested that age-related epigenetic dysregulation in zinc transporter expression may influence cellular zinc levels and contribute to increased susceptibility to inflammation with age.     

Low serum selenium concentration as a possible factor for persistent goiter in Iranian school children

Selenium deficiency can have adverse effect on thyroid metabolism and response to iodine supplementation. The aim of this study was to determine relationship between prevalence of goiter, thyroid hormone profile, urinary iodine and serum selenium concentrations in Iranian schoolchildren. In a cross- sectional study, 1188 schoolchildren in the age group of 8-13 years were evaluated for goiter prevalence. Urine and serum samples were collected from 500 children and assayed for urinary iodine concentration, thyroid hormone profile and serum selenium concentration. The overall goiter prevalence was 39.6% and the median urinary iodine excretion, indicated to an adequate iodine intake. The mean serum selenium concentration was 119.1 +/- 31 mug/l with significant difference between boys and girls (108.4 +/- 26.2 mug/l vs 127.7 +/- 32.1 mug/l). An increase in free T4 concentration was observed in those with a lower selenium level and there was a significant relationship between the presence or absence of goiter and serum selenium concentration. Selenium supplementation may be an advisable measure to optimize thyroid hormone metabolism and decrease the prevalence of goiter in schoolchildren with low serum selenium concentration.     

Increased hair selenium concentration in hyperlipidemic patients

Selenium is an essential trace element with potential anti‐atherogenic and antioxidant effects. Experimental data suggest that selenium might be beneficial in the prevention of atherosclerosis and its complications, whereas human epidemiological studies have yielded conflicting results. Data on hair selenium status in hyperlipidemic patients are still lacking. Therefore, we analysed selenium concentrations by X‐ray fluorescence in the hair of 81 statin‐naïve patients with newly diagnosed Fredrickson‐type IIa and IIb hyperlipoproteinemia and compared their data with 43 healthy volunteers. We also assessed the frequency of other classical risk factors of atherosclerosis. Hair selenium levels were found to be significantly higher in hyperlipidemic patients compared with volunteers with normal lipid levels. Also, a significantly increased number of traditional atherosclerosis risk factors were observed in hyperlipidemic patients with hair selenium concentrations above the median in contrast to those with below. Our results suggest that high hair selenium status might be associated with adverse blood lipid profile together with an increased number of traditional risk factors in a selenium‐deplete population. These findings warrant further investigations to study the impact of selenium supplementation on the incidence of cardiovascular events.     

Selenium in human nutrition: dietary intakes and effects of supplementation

The dietary selenium intakes of a young couple residing in Southern California were determined to be 107 and 99 micrograms/day for the husband and the wife, respectively, on the basis of a 30 day study. For other young adult Californians, the selenium intakes were estimated from 90 to 168 micrograms/day. The highest intakes were observed in individuals subsisting on diets rich in whole wheat grain cereal products and seafoods. The selenium concentrations in whole blood of the subjects under study correlated with the dietary selenium intakes directly (P less than 0.001). The administration of 150 micrograms of selenium/day in the form of commercially available supplements increases the blood selenium concentrations. After 3 weeks of supplementation, the selenium concentrations in whole blood of our subjects reached 0.21 micrograms/ml. Prolonged supplementation at higher Se dosage levels causes further increases of the blood concentrations: Two individuals who had been ingesting 350 and 600 micrograms/day for 18 months exhibited blood selenium levels of 0.35 and 0.62 micrograms/ml. The blood selenium concentration of all subjects declined slowly after cessation of supplementation. Selenium uptake from the supplements was not affected by the joint administration of zinc supplements at 15 mg zinc/day. Glutathione peroxidase blood levels did not correlate with blood Se concentrations.     

The role of selenium in thyroid hormone metabolism.

In animals, decreases in selenium-containing glutathione peroxidase activity and the resultant impairment of peroxide metabolism can account for many, but not all of the biochemical and clinical changes caused by selenium deficiency. Recently, however, type I iodothyronine 5'-deiodinase has also been shown to be a selenium-containing enzyme. This explains the impairment of thyroid hormone metabolism caused by selenium deficiency in animals with a normal vitamin E status. Since iodothyronine 5'-deiodinases are essential for the production of the active thyroid hormone 3,5,3'-triiodothyronine, some of the consequences of selenium deficiency may result from thyroid changes rather than inability to metabolise peroxides. In particular, the impaired thyroid hormone metabolism may be responsible for decreased growth and resistance to cold stress in selenium-deficient animals. A further consequence of the role of selenium in thyroid hormone metabolism is the exacerbation of some of the thyroid changes in iodine deficiency by a concurrent selenium deficiency. Selenium status may therefore have a major influence on the outcome of iodine deficiency in both human and animal populations.     

Selenium

Selenium is increasingly recognized as a versatile anticarcinogenic agent. Its protective functions cannot be solely attributed to the action of glutathione peroxidase. Instead, selenium appears to operate by several mechanisms, depending on dosage and chemical form of selenium and the nature of the carcinogenic stress. In a major protective function, selenium is proposed to prevent the malignant transformation of cells by acting as a “redox switch” in the activation-inactivation of cellular growth factors and other functional proteins through the catalysis of oxidation-reduction reactions of critical SH groups or SS bonds. The growth-modulatory effects of selenium are dependent on the levels of intracellular GSH and the oxygen supply. In general, growth inhibition is achieved by the Se-mediated stimulation of cellular respiration. Selenium appears to inhibit the replication of tumor viruses and the activation of oncogenes by similar mechanisms. However, it may also alter carcinogen metabolism and protect DNA against carcinogen-induced damage. In additional functions of relevance to its anticarcinogenic activity, selenium acts as an acceptor of biogenic methyl groups, and is involved in the detoxification of metals and of certain xenobiotics. In its interactions with transformed cells at higher concentrations, it may induce effects ranging from metabolic and phenotypical changes, and partial renormalization to selective cytotoxicity owing to reversible or irreversible inhibition of protein and DNA synthesis. Selenium also has immunopotentiating properties. It is required for optimal macrophage and NK cell function. Its protective effects are influenced by synergistic and antagonistic dietary and environmental factors. The latter include a variety of toxic heavy metals and xenobiotic compounds, but they are also influenced by essential elements, such as zinc. The exposure to antagonistic factors must be minimized for the full expression of its anticarcinogenic potential.     

Selenium and zinc levels in surgical patients receiving total parenteral nutrition

The zinc and selenium levels of 40 surgical patients were monitored pre-and post-TPN. The initial selenium level was low normal, and the initial zinc level was also low. Both selenium and zinc are potent antioxidants involved in cellular defense against free radicals. Surgical patients are at risk for selenium and zinc deficiencies secondary to both increased needs and losses. TPN blood work protocols should include monitoring of selenium and zinc with supplementation of the nutrient solutions, as required.     

Effect of supplementation with organic selenium on mercury status as measured by mercury in pubic hair.

The purpose of this study was to evaluate the effect of four months of yeast-based selenium supplementation on selenium and mercury status in subjects with low serum selenium. The study was carried out in Rakvere, Estonia. Pubic hair mercury, serum selenium and blood selenium concentrations in 23 subjects (serum selenium < 90 micrograms/l) were investigated before and after selenium supplementation. Thirteen subjects were randomized into the selenium supplementation group and ten into the placebo group. The selenium supplementation group received daily 100 micrograms of selenomethionine. Selenium supplementation reduced pubic hair mercury level by 34% (p = 0.005) and elevated serum selenium by 73% and blood selenium by 59% in the supplemented group (p < 0.001 for both). The study indicates that mercury accumulation in pubic hair can be reduced by dietary supplementation with small daily amounts of organic selenium in a short range of time.     

Influence of macro and micro minerals in the peri-parturient period on fertility in dairy cattle

Infertility in dairy cattle is a complex, multi-factorial problem that cannot be evaluated in isolation of other diseases and disorders. Clearly there is a role for the prevention of problems in the peri-parturient period, in particular hypocalcaemia, mastitis, lameness and retained placenta (RP), that all have a negative impact on the subsequent fertility of the cow. Minerals, trace elements and vitamins play a vital role in the prevention of these disorders at this time. Macro minerals are involved in the acid base status of the dairy cow and influence calcium metabolism. The use of anionic salts in combination with adequate calcium and magnesium supplementation may help to improve dry matter intakes and reduce negative energy balance in the post-calving period as well as prevent hypocalcaemia. Vitamin E and zinc are effective in prevention of mastitis that occurs predominantly in the first weeks of lactation, through enhanced antioxidant function and keratinisation of the teat canal. Lameness in dairy cattle also occurs mainly in lactation though most of the original insults to the hoof can occur prior to calving. Zinc and biotin are implicated in improving keratinisation of the hoof and prevention of this disease. Organic forms of zinc are retained better than inorganic sources and may provide greater benefit in disease prevention. Retained placenta can be reduced by prevention of hypocalcaemia and also adequate selenium status of the dairy cow. Selenium yeast is known to have higher retention in tissues and may play an important role in ensuring sufficient selenium is available to the cow for reduction of disease.     

Zinc intervention on macrophages and lymphocytes response

Normal zinc levels are essential for the development and maintenance of immune functions; Zn deficiency is detrimental to the embryo and offspring of experimental animals, especially concerning immune development. It is known that Zn supplementation improves immune responses. To further explore the relation between Zn administration and the metal in vitro effects, we studied zinc (500 mg/l) supplementation impact on lymphocytes and macrophages and zinc in vitro effects, in BALB/c mice supplemented from gestation to lactation. Results show a significant increase in proliferation (assessed by 3H incorporation) in lymphocytes exposed to Zn (0.1 mM) in vitro, in 3-wk-old mice; this effect is annulled when the supplementation period is lengthened, indicating saturation of the mechanisms involved in zinc induced stimulation. Macrophages functional capacity assessed by erythrophagocytosis was also improved by Zn supplementation and furthermore by the in vitro exposure to the metal, in mice 3 wk old, this was also depressed by Zn accumulation due to the supplementation period extension (9 weeks). Results show an improvement in the immune parameters analysed due to zinc supplementation and to zinc in vitro exposure. Results also suggest the accumulation of zinc as a result of prolonged supplementation periods, suppresses the cells response to zinc in vitro.     

Mechanistic aspects of the interaction between selenium and arsenic

Selenium is an essential trace element for humans and other animals, and there is mounting evidence for the efficacy of certain forms of selenium as cancer-chemopreventive compounds. However, over the years, numerous elements such as As, Cu, Zn, Cd, Hg, Sn, Pb, Ni, Co, Sb, Bi, Ag, Au, and Mo have been found to inhibit anti-carcinogenic effects of selenium, which may affect the anti-carcinogenic activity of selenium. The interaction between selenium and arsenic has been one of the most extensively studied. The proposed mechanisms of this interaction include the increase of biliary excretion and direct interaction/precipitation of selenium and arsenic, and their effects on zinc finger protein function, cellular signaling and methylation pathways. This article focuses on these proposed mechanisms and how anti-carcinogenic effects of selenium may be affected by arsenic.