Selenium and Tropical Diseases

Selenium and clinical trials: New therapeutic evidence for multiple diseases Carmen Sanmartín*, Daniel Plano, María Font and Juan Antonio Palop Department of Organic and Pharmaceutical Chemistry, University of Navarra, Irunlarrea 1, E-31008, Pamplona, Spain. • Address correspondence to this author at the Department of Organic and Pharmaceutical Chemistry, Faculty of Pharmacy, University of Navarra, Irunlarrea, 1, E-31008, Pamplona, Spain. E-mail: [email protected] Abstract The understanding of the essential role of selenium (Se) in human health has increased substantially in recent decades. Micronutrient deficiencies are very common in the general population and may be even more common in patients with different pathologies due to genetic or environmental causes and prescription drug use. Selenium is used by people in the prevention and/or treatment of different disorders including cardiovascular disease, osteoarthritis, rheumatoid arthritis, hypothyroidism, stroke, atherosclerosis, cancer susceptibility and treatment, HIV, AIDS, neuronal diseases such as Alzheimer or amyotrophic lateral sclerosis, pancreatitis, depression, and diabetes amongst others. Several mechanisms have been suggested to mediate the biological effects of Se and these include antioxidant defence systems, synthesis and stability of metabolites that act as intermediates implicated in diverse selenoproteins expression pathways oxidative metabolism, immune system modulation, DNA intercalators, kinase regulation, enzymatic cofactor, and gene expression. A number of clinical trials in recent years have provided convincing evidence of the central role of this element, either alone or in combination with other micronutrients or antioxidants, in the prevention and treatment of multiple diseases. Based on these studies this review focuses on the advances made so far in the study of mechanisms and applications of selenium compounds that could be suitable for chronic diseases. Keywords: Arthritic, Cancer, Cardiovascular, Depression, Diabetes,, HIV, Mechanism, Neurodegeneration, Pancreatitis, Selenium, Thyroid, Trials, Tropical diseases 2 Introduction Although the element selenium (Se) was identified nearly 40 years ago, some of the main biochemical features have only emerged in the last five years. Selenium has a known beneficial role and appropriate amounts of this element are required for optimal human health [1, 2]. The bioavailability of Se varies according to the source and nutritional status of the subject, with significantly higher availability found for organic Se forms. In the last decade there has been increasing interest in a number of Se compounds because of their environmental, biological and toxicological properties, particularly for their multiple activities in the prevention and treatment of diseases [3]. Many of the physiological roles of Se are directly attributed to its presence within at least 25 proteins, named selenoproteins, which are collectively essential for life and are predominantly in the form of the amino acids selenomethionine (SeMet) and selenocysteine (Sec) [4]. These amino acids are present in foods such as bread, cereals, nuts, meat, fish, and other seafood, but the amount and the type of selenium in foods varies greatly and depends on the Se content of the soil, geographical location, seasonal changes, protein content and food processing and composition. Not all selenoproteins are enzymes involved in regulating cellular reactive oxygen species (ROS) and, furthermore, the list of selenoprotein functions and properties is expanding at rapidly. However, several selenoproteins have been characterized as antioxidant enzymes, serving to mitigate damage caused by ROS. Selenoproteins such as glutathione peroxidases (GPX), thioredoxin reductases (TrxR) and iodothyronine deiodinases (DI) [5-7] are involved in redox reactions (Figure 1). The first selenoprotein to be identified was glutathione peroxidase 1 (GPX1) of the GPX family, where sequently became one of the most fully characterized groups of selenoproteins. Specifically, the Se-dependent GPX enzyme does not recycle glutathione, reducing lipid peroxidation by catalyzing the reduction of peroxides, including hydrogen peroxide. GPXs are well known to be the major components of the human antioxidant defence. TrxR enzymes are oxidoreductases that use NADPH to catalyze the reduction of oxidized thioredoxin (Trx). TrxR system acts as electron donor and catalyzes the reduction of protein disulfides being the major mechanism by which a reduced environment is maintained within cells, particularly serving to maintain reduced cysteine groups. The DI family of selenoproteins consists of three enzymes: types 1, 2 and 3 (D1, 2, and 3; or DIO 1, 2, and 3). Thyroid hormone action is initiated by the activation of the T4 prohormone to T3. This conversion is carried out by D1 or D2, which catalyze an outer ring monodeiodination reaction. Thus, thyroid 3 hormone metabolism is dependent upon the combined actions of the three deiodinases and is regulated mainly through D2 stability in response to changes in iodine supply, to cold exposure, and to changes in thyroid gland function. Oxidative stress appears to be a major factor in aging and has been implicated in numerous diseases such as Alzheimer’s, diabetes and cancer. Figure 1. Roles for selenoproteins in regulating oxidative stress and redox status of signalling molecules. Figure from Reeves & Hoffmann, 2009 with permission from Cellular and Molecular Life Sciences. Other important selenoproteins include selenoproteins H, I, M, Sep15, N, O, P, R, S, T, and W. Of these associated enzymes, selenoprotein P (SelP) is also involved in the regulation of other human diseases such as Alzheimer’s. This observation, coupled with the lower level of circulating SelP during inflammatory conditions like sepsis and Crohn’s disease, may have important implications for potential links between Se status, inflammation and neurological disorders [7]. In addition, antitumorigenic effects of Se compounds have been described in a variety of in vitro and animal models, suggesting that supplemental Se in human diets may reduce the risk of cancer. The action of selenoenzymes in reducing DNA damage, oxidative stress reduction, reduced inflammation, detoxification, improved immune response, increased tumour suppressor protein p53, inactivation of protein kinase C, alteration of DNA methylation, cell cycle arrest, induction of apoptosis of cancer cells, inhibition of angiogenesis etc. have been postulated as potential mechanisms of action [8-12]. The anticarcinogenic role of selenoproteins on various types of cancer has been demonstrated, with the focus not only on prostate and colorectal tumours, which are the most cited in the literature. Some recent clinical trials, however, have cast doubt on the anticancer effects of Se. The contradictory findings and 4 consequent controversy could be due to the lack of understanding of the mechanisms underlying Se biology. Selenium and cardiovascular diseases Cardiovascular disease (CVD) is the leading cause of death in the United States, Europe, and Japan [13]. Multiple lines of evidence indicate that Se-based biochemical systems may reduce the risk of CVD. For example, Se deficiency has been shown to decrease GPX activity and increase levels of blood lipid peroxides and other ROS [14, 15]. The oxidation caused by ROS is a major cause of cellular damage and death and has been implicated in CVD. Many selenocompounds have been investigated, with the focus on several antioxidant mechanisms including ROS scavenging (Figure 2) [16]. Figure 2. Chemical structures for selenocompounds and CVD. 5 Another hypothesis related to the involvement of Se in CVD is that selenoproteins can help to reduce levels of oxidative stress, which would otherwise increase oxidation of circulating lipoprotein particles, induce vascular and tissue damage, and cause vascular endothelial injury. An important pathology that may cause CVD is hypertension, which is a lifestyle-related disease that is strongly influenced by the excessive intake of salt, smoking, alcohol consumption, obesity, and stress. If the symptoms of hypertension continue long term, serious conditions such as heart disease and cerebral hemorrhage can occur. Few studies have concerned [17, 18] the association between the use of nutritional supplements such as Se and hypertension, the prevention of coronary heart disease and stroke and these have yielded conflicting results (positive, neutral and negative) with inconsistent findings. For example, a study carried out in the United States concluded that high serum Se concentrations were associated with a higher prevalence of hypertension. On the other hand, in spontaneously hypertensive rats (SHR), increased Se intake was clearly associated with an increase in seleno antioxidant enzyme activity and a decrease in cardiac oxidative injury [19]. Dietary Se intake was further correlated with a reduction in disease severity and mortality in the SHR. Nawrot et al. [20] reported an association between low blood Se levels and blood pressure readings in a group of Flemish men. Interestingly, this association was not observed in the women in this study group of 710 randomly selected individuals living in 6 rural districts of Belgium from 1991 to 1995 [21]. These observations emphasise the importance of maintaining adequate dietary Se in individuals at higher risk of developing congestive heart failure (CHF). CHF is a clinical syndrome that features a failing heart together with signs and symptoms arising from renal retention of salt and water, mediated by attendant neurohormonal activation, and which prominently includes the renin-angiotensinaldosterone system. This condition may be particularly relevant in ageing populations, hypertensive individuals, or in countries where the Se content of food is falling. In summary, the study showed that the majority of CHF patients do not meet dietary reference values for energy and a range of nutrients, and that nutrient intake was lower than that of a comparison group of healthy individuals. There was also some evidence of dietary inadequacy being increased in those individuals with more severe symptoms. In light of the prevalence of CHF and the associated morbidity and mortality, the nutritional strategies to promote dietary adequacy are important areas for further research [22]. Another important pathology linked to CVD is atherosclerosis. The underlying cause of coronary artery disease, which is the leading cause of death in most parts of the world, is a multifactorial disease. Several mechanisms participate in the initial manifestation and progression of this condition and these mainly involve the triad: 6 hyperlipidemia, oxidative stress, and inflammation. It is generally accepted that elevated levels of cholesterol, i.e. mainly low density lipoprotein (LDL) cholesterol, provide a higher substrate concentration for lipid peroxidation by ROS. The addition of antioxidants to a diet supplemented with cholesterol has been found to decrease the levels of plasma lipid peroxidation products as well as the severity of atherosclerotic lesions in rabbits. Se has antioxidant properties and is essential for the expression of several peroxidases and redox enzyme systems, like GPX, which protect cells from oxidative stress. Dhingra et al. [23] reported that Se supplementation in the diet decreases the serum levels of total cholesterol in cholesterol-fed rats. One particular organoselenium compound, diphenyl diselenide (DPDS) (Figure 2), has been shown to inhibit human LDL oxidation in vitro and this phenomenon was related to its thiol-peroxidase activity [24]. A recent study revealed [25] that oral administration of this derivative can have beneficial effects on serum total cholesterol and on several parameters related to oxidative stress in hypercholesterolaemic rabbits. In addition, this compound was able to lower plasma lipid concentrations in mice [26] with hyperlipidaemia induced by Triton. On the other hand, it has been shown that selenocompounds in different oxidation states, such as ebselen (Figure 2) and sodium selenite (Figure 2), can play a role in the pathogenesis of atherosclerosis through histamine signalling modulation [27]. The levels of histamine in blood are increased in stable coronary artery disease and in acute coronary syndrome and are associated with atherosclerosis by involving several receptor pathways. Binding of histamine to receptors on endothelial cells results in a prolonged increase in cytosolic calcium concentration, which is deleterious to cells. The mechanism of action for these compounds involves the modulation of the thiol/disulfide state. Another potential cause of atherosclerosis is the oxidation of LDL. Among several mechanisms suggested to explain how LDL is oxidized in vivo, 12/15-lipoxygenase (LO) has been proposed to play a major role. ebselen (Figure 2), which has been widely used as a hydroperoxide reducing agent, was able to reduce other oxidation products that might be formed, such as cholesteryl ester hydroperoxides [28, 29]. Many years ago experimental studies indicated that the modification of oxidative status can provoke other cardiopathologies. The generation of ROS produced during ischemia can mediate in cellular damage produced in angina pectoris, acute coronary syndrome and acute myocardial infarction [30]. The relevance of Se supplementation is related to the expression and activity of GPX, mainly GPX-1. In vivo studies in knockout and transgenic mice showed that GPX-1 can modulate vascular function [31]. In a double-blind assay [32] with 669 patients supplemented with sodium selenite during 12 ± 1 weeks, it was 7 observed that this compound increased GPX-1 protein expression dose-dependently and provoked a cardioprotective effect. A similar effect was observed for Se-methyl-selenocysteine hydrochloride (Figure 2). However, SeMet (Figure 2) did not give rise to this effect on GPX-1 activity. In 2010, the same authors [33] concluded that low Se concentration was associated with future cardiovascular death in patients with acute coronary syndrome. On the other hand, Xun et al. [34], in a study carried out on 5115 Americans aged 18-30, did not observe any association between toenail Se levels and the manifestation of atherosclerosis as well as the implication of Se and the risk of CVD. In conclusion, these studies indicate the essential protective effects of Se in CVD but the results are conflicting and demonstrate the need for further investigations into the mechanism of Se activity. Selenium and arthritic diseases Arthritis is a disease characterized by damage to joints, which leads to chronic debilitating pain and stiffness. Osteoarthritis (OA), which is the most common form of arthritis, is characterized by the progressive loss of articular hyaline cartilage (leading to narrowing of the joint space) along with underlying bony changes surrounding the joint (i.e., osteophytes, sclerosis and subchondral cysts). Rheumatoid arthritis (RA) is an autoimmune condition of unknown etiology that can be described as a chronic inflammatory polyarthritis with progressive erosion of tissues within and surrounding the joint. Until the 1990s patients with RA were initially treated with aspirin or other non-steroidal antiinflammatory drugs (NSAIDs); disease modifying anti-rheumatic drugs (DMARDs), such as methotrexate, were introduced only as the disease progressed. Combined treatment with more than one DMARD was reserved for patients with the most severe symptoms. The outcome for most patients was functional deterioration with progressive damage. However, innovations in drugs, better tools for monitoring treatment, and tight control strategies have improved the outlook for patients with RA [3537]. Numerous drugs are available for the treatment of RA. These include gold compounds, NSAIDs, penicillamine, sulphasalasine, chloroquine, glucocorticoids, and methotrexate as an immunosuppressant [38]. In recent years, a few studies have focussed on the possible role of trace elements in the etiology and pathogenesis of RA. The mechanism(s) by which cells play a role in RA pathogenesis has been the subject of intense research. The changes in trace element levels are part of the immune defence system of an organism and are induced by the hormone-like substances interleukin-1 (IL-1), tumour necrosis factor(TNF- ), and interleukin-6 (IL-6). Se is a cofactor of GPX, an important antioxidant enzyme for the 8 removal of lipid hydroperoxides and hydrogen peroxide [39]. In patients with RA, the serum Se level was lower relative to controls [40]. This fact confirms the previous results reported by Köse et al. [41] from a study of Se levels in 60 patients with RA with respect to healthy controls. In 2000 Helgeland et al. [42] hypothesized that consumption of Se was inversely associated with the risk of developing juvenile arthritis in patients. Recently, it has been reported that gold complexes [43] are able to interact with mammalian proteins that contain Sec residues. The use of gold (I) complexes (Figure 3) for the treatment of RA has attracted considerable attention, although the exact biochemical mechanism for the therapeutic action of these drugs has not been well documented. However, a considerable amount of experimental evidence indicates that these compounds exert their therapeutic effects by inhibiting certain enzyme activities or affecting inflammatory functions. Mammalian selenoenzymes such as GPX, DI and TrxR contain Sec residues at the active site. Gold(I) compounds such as GTG and AUR (Figure 3) inhibit the GPX activity by reacting with the Sec residue to form stable gold-selenolate complexes. It has also been shown that gold compounds can undergo ligand displacement reactions with GSH to produce the goldGSH complex [Au(SG)2]-, which reacts with the selenol group to produce the corresponding Sec-Se-AuSG complex. Because of the fact the sensitivity of a particular gold(I) complex towards the differents proteins depends of the ligands attached to the Au(I) center, the right modification of the ligand is determinant for binding to the catalytically essential active site residues of enzymes and it is important to develop gold(I) compounds that can modulate the inhibition of key enzymes involved in antioxidant defense such as GPX, whose inhibition may have a detrimental effect on the peroxide metabolism. Figure 3. Gold compounds Other important drugs used for the treatment of RA are NSAIDs. NSAIDs block the activity of cyclooxygenases (COX), namely COX-1 and COX-2, which catalyze the production of leukotrienes (LTs) as arachidonic acid metabolites. COX-2 is mainly present in inflammatory cells, while COX-1 is an enzyme constitutively expressed in most cell types and that acts as a cytoprotective in areas such as the gastrointestinal mucosa and kidney. Some of the most significant side effects associated with all currently available NSAIDs are gastrointestinal haemorrhage, ulceration and kidney failure. In order to reduce 9 these problems a new target is emerging based on the combination between 5-LO/COX inhibition, with the aim of interfering with two pathways – the production of prostaglandins and the biosynthesis of LTs. In addition, many NSAIDs have the potential to reduce the level of ROS such as hydroxyl radicals, which support inflammatory processes in RA. The well-known Se-containing compound ebselen (Figure 2) has been reported as an antioxidant, an inactivator of reactive radicals and a potent inhibitor of lipid peroxidase. Related to that compound Scholz et al. [44] described a new series of diaryl isoselenazoles (Figure 4) that combine dual COX/LO inhibitors with the potential radical scavenging potency of the Se moiety. Some of compounds were equipotent to celecoxib with regard to COX-2 inhibition but more potent with regard to the COX-1 inhibition. One of these compounds included COX-1, COX-2 and 5-LO inhibitory activities and weak hydroxyl radical scavenger potency. Figure 4. Diarylisoselenazoles Recently, several studies have suggested an important role for Se in maintaining normal cartilage metabolism and potentially preventing OA [45], however the exact mechanism remains unclear. Some authors have hypothesized that Se, in SeMet form (Figure 2), could block proinflammatory gene expression induced by physiological doses of IL-1 . It was also reported that SeMet induced nitric oxide (NO) and prostaglandin E2 (PGE2) production through modulation of inducible nitric oxide synthase (iNOS) and COX-2 gene expression in primary chondrocytes. Another important pathology related to osteoarthritis and which shares similar pathological features is Kashin-Beck Disease (KBD), the etiology of which is unknown. KBD is characterized by focal chondronecrosis in the deep zone and impaired endochondral ossification, which results in a secondary chronic osteoarthritis and impaired skeletal development. This disease occurs primarily in Se-deficient areas. With the aim of validating the importance of Se deficiency along with the genetic variabilities in the pathogenesis of this illness, Shi et al. [46] examined a total of 129 patients with KBD and these were distributed into groups. Two healthy control groups, one of which originated from an area where KBD was not endemic and the other one from an area where this disease was endemic. The latter group corresponded to subjects with a genetic modification on chromosomes 2 and 11. All of the subjects were treated with different Se concentrations 10 and the susceptibility loci were calculated. The results suggest that genetic factors are more important than environmental factors. However, and taking into account that many of the effects of Se are mediated through its role as a constituent of Se-containing proteins, Xiong et al. [47] studied the relation between KBD risk and four selenoprotein genetic polymorphisms in Chinese patients. These selenoproteins were related to GPXs, TrxRRs and SelP, which are responsible for antioxidative defence, and the DI family, which is responsible for maintaining a circulating level of thyroid hormone and regulation of bone metabolism. Some work has been carried out on the relationship between selenoprotein gene polymorphisms and osteoarthropathy risk. The results of the study demonstrated that modification of GPX-1 might be a genetic risk factor in the development of KBD. In addition, alteration of NF- B p65 and p53 mRNA expression suggests that apoptosis signalling might be activated in KBD patients. At present there is no convincing evidence that Se [48] is effective in the treatment of any type of arthritis. Selenium and thyroid diseases Thyroxine or 3,3',5,5'-tetraiodothyronine (T4), a major hormone secreted by the follicular cells of the thyroid gland, is produced on thyroglobulin (Tg) by the thyroid peroxidase (TPO)/H2O2/iodide system. TPO, which is responsible for the synthesis of thyroid hormones, is synthesized on polysomes and inserted into the membrane of the endoplasmic reticulum. TPO is then transported to the Golgi, where it is subjected to terminal glycosylation and packaged into transport vesicles along with Tg. TPO catalyzes two very different types of reactions in the thyroid gland: iodination and coupling. The role of Se in the thyroid gland is now well established. In fact, the thyroid contains more Se per gram of tissue than any other organ and Se, like iodine, is an essential trace element for normal thyroid function and thyroid hormone homeostasis [49]. Therefore, the thyroid gland requires an adequate supply of iodine and Se for the efficient production of thyroid hormones. In the thyroid gland, Se is a component of selenocysteine, the 21st amino acid, which, in turn, is a part of the active site of several selenoenzymes [50]. Therefore, Se, acting through the expression of specific selenoproteins, has many biological actions that are important in maintaining normal thyroid function. Although the function of many of these selenoproteins remains to be elucidated, the important roles for at least three selenoenzymes in human thyroid tissues have been defined. The type-I ID-1 is the most important selenoenzyme and this catalyzes the deiodination of thyroxine to activate the thyroid hormones and links the thyroid status with Se and iodine levels. The other two major selenoenzymes present in the thyroid gland are the antioxidant enzyme GPX and the redox enzyme TrxRR. The role of GPX in the gland is to protect the thyroid cells from 11 oxidative damage by catalyzing the reduction of H2O2 with the help of thiol co-substrates such as glutathione (GSH). The human TrxRR also plays important roles in the detoxification of ROS in the thyroid gland. It should be mentioned that both GPX and TrxRR are up-regulated during the thyroid hormone synthesis, indicating that these enzymes provide the thyrocytes with protection from peroxidative damage [50, 51]. Of all the aforementioned examples, in recent years there has been renewed interest in Se analogues of antithyroid drugs of MMI (2, MSeI), PTU (5, PSeU) and MTU (7, MSeU) (Figure 5). The initial assumption for the selection of the Se analogues was that the Se compounds may exhibit much higher inhibitory activity towards ID-1 compared with their sulfur analogues due to their high nucleophilic character. As these compounds are expected to react with the selenenyl iodide intermediate of ID-1, the formation of an Se-Se bond may occur more readily than the formation of an Se-S bond [52]. In addition to their inhibitory action, the Se analogues may have a significant effect on H2O2. There are numerous examples of Se compounds that mimic the action of GPX by catalytically reducing H2O2 and organic peroxides with the help of thiol co-substrates [53]. Since the discovery that ebselen (Figure 2) exhibits significant antioxidant activity by mimicking the active site of GPX, several groups have pursued the design and synthesis of low molecular weight GPX mimics, either by modifying the basic structure of ebselen or by incorporating some structural features of the native enzyme. The synthetic GPX mimics reported in the literature include benzoselenazolinones, selenenamide, diaryl selenide, various diselenides, hydroxyalkyl selenides, a selenocysteine derivative, and a selenenate ester (Figure 5). 12 Figure 5. Chemical structures for selenocompounds and thyroid diseases It was reported that Se supplementation shows promising potential for enhancing GPX and other selenoprotein activity in various pathological thyroid conditions [54] although the efficacy of Se supply frequently depends on the bioavailability of the compounds used. For example, SeMet has excellent bioavailability and lower toxicity and it is therefore is more applicable for long-term administration. In fact, the introduction of elemental Se in nano-sized particles (Nano-Selenium) produced a highly effective molecular compound that, when compared with SeMet or Na2SO3, showed a similar efficacy in increasing antioxidant GPX and TrxR activities [55]. In spite of this finding, the essential role of Se in the regulation of thyroid function and its importance in thyroid pathogenesis are evident, as proven by the fact that severe Se deficiency contributes to the manifestation of myxedematous cretinism [56]. It has also been reported that Se supplementation decreases thyroid peroxidase antibody concentrations in adult patients with autoimmune thyroiditis, but this is not the case in children or adolescents [57]. Zagrodzki et al. [58] reported that some selenoenzymes such as ID are the most promising targets for diagnoses and possibly therapy of thyroid tumours. Another important disease related to the autoimmune thyroid process is Hashimoto’s thyroiditis (HT), which is characterized by diffuse or nodular goiter with euthyroidism, subclinical hypothyroidism and permanent hypothyroidism [59]. There is some evidence to suggest that Se supplementation could be useful as a coadjuvant therapy to levothyroxine [60] in the treatment of this illness. One such piece of evidence is the significant decrease in thyroid peroxidase autoantibody titers in patients after three months of supplementation with this trace element. In addition, a correlation was observed between Se, sex hormone secrection and thyroid function in a group of patients with HT [61]. It is also relevant that pregnant women who are positive for thyroid peroxidase antibodies are candidates for developing thyroid dysfunction. However, patients who ingested Se supplements during pregnancy and in the postpartum period showed reduced thyroid inflammatory activity [62, 63]. Evaluation of the total sum of emerging data indicates the need to maintain optimal "selenostasis" through adequate selenium intake for the prevention of thyroid disorders. Selenium and cancer It is well understood that Se is an essential micronutrient for normal functioning of the body and results obtained from epidemiological studies, laboratory bioassays and human clinical intervention support a protective role(s) of Se against cancer development. A literature survey revealed that most of the 13 experimental work on the evaluation of Se as a cancer chemopreventive agent was carried out using inorganic Se such as sodium selenite (Na2SeO3) as the Se source. Studies also indicate that inorganic Se compounds are more toxic than organoselenium compounds. Therefore, there has been growing interest in the synthesis of organoselenium compounds that could be used as antitumoral agents. Several mechanisms have been suggested to mediate the anticancer effects of Se. The major mechanisms are as follows: reduction of DNA damage, oxidative stress, inflammation; induction of phase II conjugating enzymes that detoxify carcinogens; enhancement of immune response; incorporation into selenoproteins; alteration in DNA methylation status of tumour suppressor genes; inhibition of cell cycle and angiogenesis; induction of apoptosis and kinase modulation (Figure 6). Studies performed in vitro have shown that both the dose and the chemical form of Se compounds are critical factors in cellular responses [64-69]. Figure 6. Relationship between selenium and DNA damage in cancer prevention. Figure from Tabassum et al., 2010, with permission from Cancer Treatment Reviews. Among the multiple cancer types and their relation with Se, prostate cancer (PC) has been one of the most widely studied. Several large prospective studies into the association between Se levels and PC risk have been published and almost all the studies established a significantly reduced risk of PC in healthy men and men with advanced PC or those with a baseline prostatic specific antigen (PSA) level of >4 ng/mL [70]. Recently, Corcoran et al. [71] reported a study in which sodium selenate was administered as an oral capsule to 19 patients to determine the maximum tolerated dose in order to study the pharmacokinetic 14 profile. This compound showed modest efficacy as an anti-angiogenic agent in a mode consistent with single-agent studies of other anti-angiogenic agents, such as Bevacizumab, Sorafenib and Sunitinib, but provoked a decrease in PSA levels in patients with prostate cancer. The combination of this compound with conventional cytotoxic agents – in particular Docetaxel – as well as with other anti-angiogenics with different modes of action is worthy of consideration. The combination of Se and a drug such as Genistein was assayed by Kumi-Diaka et al. [72] for the treatment of PC. The data obtained from the study indicate that this combination may have chemopreventive value and may be adjuvant to the standard therapy for prostate tumours. Evidence has also been obtained to support the ingestion of Se [73] during PC prostate cancer radiotherapy through the protection of healthy tissues and the reduction of the side effects of the treatment. The administration of Se as SeMet (Figure 2) in conjunction with silymarin (SM) [74] to 37 patients after radical prostatectomy (RP) had a positive effect on the organism by significantly improving the lipid parameters and increasing the blood Se level. These findings suggest that a dietary intervention with an SM-Se combination could benefit patients by reducing PC progression. In spite of the evidence outlined above, there is some controversy related to the hypotheses that Se and other compounds, such as Vitamin E, decrease PC incidence either individually or in combination. For example, Dunn et al. [75] reported that neither Se nor Vitamin E (SELECT), alone or together, prevented PC in a study carried out on a heterogeneous population of healthy men. Stratton et al. [76] also observed that Se supplementation to 140 men distributed into a placebo group and two groups that received different amounts of Se did not show a protective effect in subjects with localized PC. Ledesma et al. [77] later proposed that the problem with the results of SELECT studies is a lack of appropriate in vivo studies on these agents using effective doses and formulations. Ramoutar et al. [78] reinforced the proposal that the anticancer properties of small molecules containing Se greatly depend on the experimental conditions and this would explain the contradictory literature data for their efficacy. However, research on prevention and treatment strategies has included nutritional Se status, and there is some evidence that Se may affect not only cancer risk but also progression and metastasis. Thus, it has been demonstrated in ovine pulmonary adenocarcinoma (OPA), as an animal model for studying lung cancer [79], that the different Se status has an impact on Sedependent metabolic functions (e.g. activity of specific selenoenzymes). One of these enzymes, TrxR [80], which is induced in tumour cells and preneoplastic cells, is modulated in its expression by Se. It has also been reported that some compounds, including Se, extracted from wild mushrooms exhibited antitumour potential [81]. Other mechanisms of action have been reported for selenocompounds. For 15 example, SeMet (Figure 2) induces ROS generation associated with the induction of apoptosis, which is affected by the Akt/TOR/ROS pathway in A549 lung carcinoma cells [82]. On the other hand, in this same cell line various Sec prodrugs, including selenocystine (Secys), methylseleninic acid (MSA), 1,4phenylenebis(methylene)selenocyanate (p-XSC) and SeMet (Figure 7), were tested as cytotoxic agents. The cytotoxic effects of some of these compounds were modulated by TrxR through mitochondrial dysfunction [83]. Furthermore, administration of these compounds to 40 patients with end-stage cancer led to an increase in the predicted survival in 76% of cases [84]. Another seleno derivative with Akt3 signalling modulation is isoselenocyanate-4 (ISC-4) (Figure 7), a compound in which the alkyl chain is four carbon atoms long. The repeated topical application of this compound reduced tumour cell expansion and development in animals by 80% by decreasing signalling, which leads to a 3-fold increase in apoptosis rates [85]. In view of importance of the length of the alkyl chain containing the selenocyanate active group on the biological activity, Roy et al. [86] carried out a study on normal Swiss albino mice with molecules that combine naphthalimide compounds, which have high antitumour activity, and a selenocyanate group (Figure 7). These compounds inhibited oxidative stress to a greater extent than sodium selenite. The importance of the selenocyanate group in cancer is indisputable. Recently, Desai et al. [87] described novel selenium compounds (SeISA-1 and SeISA-2, Figure 7) based on histone deacetylase (HDAC) inhibitors that are structurally related to hydroxamic acid (SAHA). SAHA is under clinical trials for both haematological and nonhematological malignancies and is approved for the treatment of cutaneous T-cell lymphoma. SeISA-1 and SeISA-2 both showed a markedly increased inhibitory effect on HDAC (more than 20-fold) in comparison to SAHA. Moreover, this compound also inhibited ERK and PI3K-Akt signalling in lung cancer cells [88]. It is remarkable that Se or its derivatives can act synergistically with other cancer therapies. For example, sodium selenite was proven to reduce the side effects of adjuvant hormone therapy [89] in a study carried out on 129 patients. In fact, a significant reduction in plasma levels of selenium was observed in 209 patients undergoing radiotherapy [90], which suggests that the nutritional status of this element should be considered. 16 Figure 7. Chemical structures of seleno compounds with anticancer activity Selenium and HIV Human immunodeficiency virus (HIV) infection is a major global health problem and nutritional disorders are often present in HIV +/ acquired immunodeficiency syndrome (AIDS) patients. In terms of personal, social and economic tolls, HIV/AIDS ranks among the top five global causes of death now and for the foreseeable future. Human immunodeficiency virus-1 (HIV-1) is an RNA viral infection that is affected by host Se status. Deficiencies in micronutrients such as Se present a problem among HIV-1seropositive individuals, particularly in regions of the world where resources for fighting HIV-1 infection are limited. Among HIV-1-infected individuals, lower serum Se concentrations have been associated with greater HIV-1 disease progression, higher related mortality and progressive decrease in the antioxidant ability [91-93] (Figure 8). 17 Figure 8. Molecular basis of a link between four biochemical pathways involved in HIV-induced metabolic abnormalities: (1) antioxidants (Se, GPX, GSH) vs. ROS mediated oxidative stress (left); (2) tryptophan oxidation via the indoleamine-2,3-dioxygenase (IDO) (right) (3) arginine metabolism, and (4) the poly(ADP-ribose) polymerase (PARP) complex. Figure from Taylor, 2010 with permission from Toxicology. Several studies have provided evidence to support the anti-HIV-1 effects of Se supplementation. Cohort studies have shown an association between Se deficiency and progression to AIDS and mortality [94]. In a study carried out on 915 pregnant women in Tanzania, Se supplements such as SeMet [95] reduced diarrhoeal morbidity and reduced viral load in two separate small trials carried out in American adults [96]. In addition, the combination of Se and aspirin [97] in vivo showed an inhibition of HIV production through inhibition of the transcription factor. In this study 32 patients were selected – 23 females and 9 males aged between 22 and 52 years – and an improvement in the quality of life was observed. However, multiple micronutrient supplementation (14 micronutrients) to 847 children in Uganda attending HIV clinics was well tolerated, but it did not significantly alter mortality [98]. In spite of this finding, Harthill [99] recently confirmed the importance of selenium deficiency in the evolution of viral infectious diseases (VIDs) considering that viral mutation rates diminished and immunocompetence improved with Se supplementation. In 2011 Mariath et al. [100] studied the possible role of Se status during pregnancy. Related to the synthesis of novel seleno derivatives based on AZT, an anti-AIDS drug and 2',3'dideoxynucleosides (ddNs), which have been considered as representative in developing nucleoside reverse transcriptase (RT) inhibitors, Jeong et al. [101] described the synthesis of 4'-selenonucleosides (Figure 9). These compounds have been considered as possible AZT substitutes because of the bioisosteric relationship between 4'-oxonucleosides and 4'-selenonucleosides (Figure 9). In 2010, the same authors [102] described some structural modifications and synthesized 4'-selenothymidine and 4'seleno-AZT (Figure 9). Figure 9. Seleno nucleosides 18 Selenium and neurodegenerative diseases One of the most prevalent neurodegenerative diseases is Alzheimer’s disease (AD). This condition is characterized by dementia that typically begins with subtle and poorly recognized failure of memory, which slowly becomes more severe and, eventually, incapacitating. Other common findings include confusion, poor judgment, language disturbance, agitation, withdrawal, and hallucinations. In some cases seizures, Parkinsonian features, increased muscle tone, myoclonus, incontinence, and mutism occur [103]. Se is a vital trace element that is enriched in the brain; its levels decline with age and particularly low levels have been linked to cognitive impairment and AD. Short-term administration of Se improves memory deficits in an acute rat model of dementia and reduces tau phosphorylation in WT rats. Therefore, Se has been attributed neuroprotective properties, but the underlying mechanism and its therapeutic potential remain elusive [104, 105]. Vural et al. [106] carried out a study on 50 patients with AD and suggested that peripheral antioxidant and trace element levels can be used as markers of central nervous system-dependency. Antioxidant and trace element changes were observed in plasma levels, with a decrease seen in patients with AD – a change that may lead to oxidative damage. Similarly, Cardoso et al. [107] carried out a study on a group of elderly patients with AD (n = 28) and corroborated that AD patients showed significantly lower Se levels in plasma, erythrocytes and nails when compared with the control group. The hypothesis related to the importance of Se, through its antioxidant potential, in providing neuroprotection was previously demonstrated in a model of neurodegeneration intracerebroventricular-streptozotocin (ICV-STZ) [108]. In other degenerative processes that affect the striato nigral system (SN), such as Parkinson’s disease (PD), Se had shown a protective effect in animal models. An association between PD and plasma Se was not observed in a study on 1,012 participants, although lower levels of this element were linked with decreased performance in neurological tests of coordination among older adults [109]. It is well known that Se mediates its biological function mainly through selenoproteins and that the decreased expression of several of them is associated with neurodisorders (Figure 10) [110], especially neuron damage induced by oxidative stress. 19 Figure 10. Function of ROS in the aging brain as a consequence of selenium status. Solid arrows, promote ROS; dash arrows, suppress ROS. Figure adapted from Zhang et al. 2010 with permission from Mechanisms of Ageing and Development. Specifically, SelP is essential for neuronal survival and function. SelP may act directly as an antioxidant to prevent oxidative stress, or it may provide Se for the biosynthesis of other antioxidant selenoproteins such as GPX and TrxR [111]. SelP-mediated neuroprotection may have important ramifications for other disorders in addition to AD ie Parkinson, epilepsy. SelP expression increases with dietary Se supplementation, suggesting that such supplementation might be used in the treatment or prevention of AD. Additionally, the measurement of SelP levels in cerebral spinal fluid could potentially become a prognostic tool to better predict disease progression [112]. In fact, treatment of AD with a cholinesterase inhibitor (donepezil) combined with a supplement complex named Formula F, which contains the most common antioxidants, including Se, reduced the oxidative stress level in brain and this fact improved the prognosis of the illness [113]. As a continuation of the efforts aimed at corroborating the role of Se as an antioxidant in relation to neurodegenerative diseases, Yoo et al. [114] suggested the involvement of glutathione peroxidase 4 (GPX4) acting through the removal of lipid hydroperoxides in AD. In view of relevance of Se in these pathologies, some authors have investigated the synthesis of new molecules containing Se. A variety of compounds are emerging due to their selective activity at subtypes of a variety of ion channels, receptors, transporters, and other targets of pharmacologic interest, and these include marine toxins that have been postulated to be potential pharmacotherapeutics for multiple disorders, including AD and PD. In 2010 Raffa [115] described a novel synthesis of analogues of the native peptides related to Conus venom, a predatory marine cone. The new molecules incorporate diselenium bonds between Sec residues in place of disulfide bonds between cysteine residues (native peptides). This molecular change leads to either the retention of selectivity or an increase in selectivity, probably as a consequence of the greater hydrophobicity of the diselenide bond. Other groups have worked towards the 20 synthesis of better GPX mimics. All of these mimics with Se-N bonds have been developed on the assumption that the enzyme GPX may have a cyclic selenenamide structure in its oxidized form and the peptidic nitrogen atoms may function similarly in the formation of cyclic selenenamide species in the natural enzyme GPX. The most promising drug in this class is ebselen [1,2-phenyl-1,2-benzoisoselenazol3-(2H)-one] (Figure 2). Taking these premises into consideration, various organoselenium compounds containing heteroatoms such as nitrogen in close proximity to the selenium have been synthesized in order to study their GPX activity. In this regard, Hassan et al. [116] reported the synthesis of a heterocyclic diselenide with an imino residue close to Se, namely hydroxybenzylidenamino)ethyl)phenyl)diselanyl)phenyl)ethylimino)methyl)phenol 2-[1-(2-(2-(2-(1-(2(Compound A) (Figure 11). This compound showed promising antioxidant potential against Fe(II)-induced lipid peroxidation in vitro in the low micromolar range and caused low or negligible toxicity in rats. This compound also exhibited high thiol peroxidase activity, which was even higher than that of DPDS (Figure 2). Figure 11. Selenocompound and neurodegenerative disease Other mechanisms of action have been postulated for Se compounds in relation to AD. For example, sodium selenate acts as a specific agonist for the key phosphatase PP2A, which is involved in regulating tau protein phosphorylation. This phenomenon was observed in a transgenic TAU441 mice model. In addition, this compound exhibited excellent oral bioavailability and favourable central nervous system penetrating properties [117, 118]. Organoselenium compounds also have effects on another neurological damage. For example, it has been observed that ebselen reduces the neuronal death by 48-59% in the gerbil hippocampal CA1 region induced by ischemia/reperfusion [119]. A significant neuroprotective effect on ischemia/reperfusion via suppression of oxidative stress was observed in a study carried out on 50 rats treated with a ginkgo biloba extract (EGb761) and Se alone or in combination during 14 days [120]. There is also evidence to suggest that Se functions through associations with other substances. For example, a Se-enriched diet provided 21 during 4 to 9 months to a transgenic mice reduced amyloid beta peptide plaques and minimized DNA and RNA oxidation [121]. Selenium and depression Depression is one of the most common mental disorders and it causes enormous personal and economic burden. In its early stages, however, it is the most manageable of mental disorders. One of the treatments for bipolar disorder and resistant depression is the use of lithium salts. Major side effects of long-term lithium therapy include thyroid abnormalities (mainly presented as hypothyroidism and goiter), weight gain, oedema, gastrointestinal pain, diarrhoea, tremor, polyuria, and renal tubular damage [122]. In order to evaluate the association between exposure to lithium and thyroid function, 202 women were selected and exposed to lithium via drinking water and other environmental sources. One of the markers of thyroid function was Se, which was measured in urine. Se was positively associated with T4 and inverse associated with TSH, findings that suggest and confirm that Se may have a beneficial effect on thyroid function [123] and can reduce the side effects of lithium. One problem associated with depression is suicidal behaviour, mainly in adolescents, which coexists with alcohol and drug abuse. Alcohol abuse may lead to the deficiency of micronutrients – including Se, which is a potent protective agent for neurons through the expression of selenoproteins. As a result, supplementation of the diet with this mineral could form part of the treatment plan for adolescents with depression and alcohol misuse [124]. Another time during which women frequently suffer from depression is the perinatal period. Perinatal depression refers to major and minor episodes during pregnancy or within the first 12 months after delivery. Some studies with primigravid pregnant women have shown that inadequate intake of certain nutrients such as Se can increase the risk of maternal depression [125, 126]. On the other hand, it is well known that Se and Se compounds display neuroprotective activities mediated at least in part by their antioxidant actions. Oxidative damage has been implicated in psychiatric disorders and the development of novel therapeutic strategies based on antioxidant compounds is of great interest. A review of the evidence supports the view that Se compounds should be investigated as potential novel therapeutic agents for these disorders. One of the compounds studied is 3,3'- ditrifluoromethyldiphenyldiselenide (Figure 12), which is structurally related to DPDS and has been shown to protect rat hippocampal neurons from damage induced by oxygen–glucose deprivation. The administration of the fluoro derivative to apomorphine induced stereotype in mice, an animal model of psychosis, indicated a significantly reduced apomorphine-induced stereotyped behaviour [127]; the 22 biomarker used was the expression of selenium-binding protein-1 (SELENBP-1) because this expression was significantly up-regulated in patients with schizophrenia [128]. More recently, in a study carried out with 34 schizophrenic patients, 33 bipolar disorder patients and 34 normal subjects, Kanazawa et al. [129] confirmed that elevated SELENBP-1 is a consistent feature in the schizophrenic brain and, for this reason, may have a potential role as a biomarker. As an extension of this study, these authors [130] employed a sample of over 2,400 individuals of Han Chinese descent living in Taiwan where all had a positive family history. The results obtained corroborated the altered expression of SELENBP-1 in schizophrenia patients. Figure 12. 3,3'-ditrifluoromethyldiphenyldiselenide Selenium and diabetes Diabetes mellitus (DM) is a heterogeneous metabolic disorder characterized by the presence of hyperglycaemia. Recent data indicate that 12.9% of the adult U.S. population aged > 20 years have DM, of which 39.8% remain undiagnosed. Type 2 DM (T2DM) comprises 90% of all cases of DM syndrome. A major risk factor for developing T2DM is excessive adiposity and for this reason self-care is believed to play an important role in DM management [131]. Several micronutrients have beneficial effects in healthy subjects and also in diabetes. In particular, copper, zinc, Se, iron and manganese are essential components of metalloenzymes such as glutathione peroxidase. A cross-sectional study on almost 9,000 American adults, along with another analysis, showed a positive link between high Se levels and diabetes [18, 132]. In a study carried out on 76 T2DM patients with slight-to-severe diabetes complications, all of whom were non-smokers and had no other chronic or infectious diseases, and 12 healthy volunteers indicated the association of some elements with the progress of disease and its complications [133]. In spite of this, the association between the concentration of Se in plasma and T2DM is a matter of debate. Stranges et al. [134] performed a study on 7,182 women from Northern Italy and observed that increased dietary Se intake was associated with an increased risk of T2DM. In another study with 140 subjects distributed in three groups (46 as placebo, 47 received Se 200 g/day and 47 received Se 800 g/day), the changes in serum glucose levels were not statistically significantly different on comparing the placebo group and the treatment groups [135]. However, it was observed that the combination of low doses of insulin and Se in diabetic rats was 23 effective in the control of blood glucose accompanied by a correction of glucose transporter (GLUT4) distribution [136]. Another important consideration is that diabetes is a significant risk factor for atherosclerosis and both the incidence and mortality of cardiovascular disease are increased in patients with diabetes. Several mechanisms have been proposed to explain why diabetic patients are at an increased risk of such vascular disorders. These include an excessive concentration of glucose causing glycation of various proteins, a decrease in the level of oxygen dissociation in erythrocytes, an increase in platelet aggregation, an increase in the level of very low density lipoproteins and a decrease in high density lipoprotein (HDL) cholesterol and inflammation processes that play a central role in the development of atherosclerotic diseases. However, the mechanism is still unclear. Li et al. [137] studied human umbilical vein endothelial cells (HUVECs) and provided experimental support for the hypothesis that Se may have an anti-atherosclerosis effect in diabetic patients, in part by inhibiting high glucose (HG), advanced glycation end products (AGE), high insulin (HI) and H2O2 induced expression of COX-2 and P-selectin in vascular endothelial cells. This effect was at least partially mediated through the modulation of the p38 signalling pathway. Other researchers affirmed that cardiovascular complications result from multiple parameters where the imbalance between the production of ROS and reactive nitrogen species (RNS) is responsible for the pathology. A strategy based on the control of oxidative stress can therefore antagonize cardiovascular dysfunction during diabetes [138]. Oxidative stress has also been studied as a determinant factor in insulin resistance, acting through Forkhead box class O (FoxO) transcription factors that regulate the expression of intra- and extracellular antioxidant enzymes, such as manganese superoxide dismutase [139]. Another parameter studied in the Se-diabetes relationship is whether patients with diabetes present a different plasma selenoprotein status. An association was observed between individual selenoprotein concentrations, the presence of diabetes, and some of its main parameters. The study involved 40 patients with T2DM, who were treated with oral hypoglycemic drugs, and the control group included 15 healthy subjects with normal glucose tolerance, as assessed by an oral glucose tolerance test. The GPX, SelP, SeAlb, and total Se mean concentrations were determined and an association was found between the individual selenoprotein concentrations and the presence of diabetes [140]. Recently, Labunskyy et al. [141] suggested that the supplemental intake of Se above the appropriate level may increase the risk of T2DM, mainly through the elevated expression of a selective group of selenoproteins. Another prospective avenue of Se function in the protection against diabetes is its potential as a regulator of the antioxidant enzyme GPX-1, whose lack of activity accelerates 24 atherosclerosis. In a study carried out on diabetic mice it was demonstrated that administration of the synthetic antioxidant ebselen (Figure 2) to diabetic apoE-deficient mice attenuated lesion formation in most regions of the aorta, suggesting that ebselen is an effective antiatherogenic agent against diabetic macrovascular disease [142]. In 2010 the same authors [143] confirmed this effect and found that ebselen limits the development of two major diabetic vascular complications, namely diabetes-associated atherosclerosis and diabetic nephropathy in ApoE/GPX-1deficient mice, with the renoprotective effect mediated via pathways that include the modulation of p38, JNK, and IKK. Selenium and pancreatitis Acute pancreatitis (AP) is a disease with high morbidity and mortality. In the absence of specific effective therapy, management revolves around supportive care. The clinical course of an attack of AP varies from a short period of hospitalization with supportive care to prolonged hospitalization and admittance to an Intensive Care Unit (ICU) due to the development of systemic inflammatory response syndrome (SIRS), multiorgan failure (MOF), and septic complications. Overall, in about 15-20% of patients, AP progresses to a severe illness with a prolonged disease course. These severely ill patients may develop organ failure and/or local complications such as pancreatic necrosis. In patients with necrotizing pancreatitis, the mortality is close to 17%, with a mortality of 12% in the case of sterile necrosis and up to 30% in infected necrosis [144, 145]. Corroborative evidence for the involvement of oxidative stress mediators in pancreatitis is derived from studies that have demonstrated up-regulation of the oxidative stress response genes c-fos, heme oxygenase and metallothionein during experimental acute pancreatitis. These genetic changes are paralleled in the clinical state by depletion of serum antioxidants during acute pancreatitis, with the degree of depletion corresponding to the severity of the disease [146]. The ability of Se to act as an antioxidant is well known and, in a study carried out by Vaona et al. [147] on 38 patients with chronic pancreatitis and 48 healthy subjects acting as control, lower serum selenium levels were observed in patients with chronic pancreatitis than in control subjects. Se supplementation therefore improved antioxidant status in patients with severe AP [148]. Indeed, this element is frequently used as a nutritional support in AP [149] in enteral or parenteral nutrition [150]. Selenium and amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease. This illness is invariably fatal due to the absence of any effective therapy and is characterized by an incidence of around 25 2 cases/100,000/year. A range of antioxidant medications are available and have been studied. These include Se alone or in combination with L-methionine and Vitamin E [151] but there is insufficient evidence for their efficacy. However, it has been demonstrated that dietary intake of inorganic Se through drinking water increases the risk of ALS [152]. The results of other studies have reinforced this idea, mainly associated with high levels of inorganic hexavalent Se [153], although metal exposure alone is not sufficient to develop ALS [154]. Recently, Maraldi et al. [155] examined in vitro a human neuron cell line treated with sodium selenite, sodium selenate and SeMet, while monitoring changes in ROS and RNS and antioxidant protein content. The results supported the biological plausibility of the hypothesis, indicated by epidemiologic studies, that Se overexposure may increase the risk of neurodegenerative diseases such as ALS. Selenium and tropical diseases Clinical and epidemiological studies affirm that selenium plays an important role in tropical diseases such as tuberculosis, leishmania, philariasis, and chagas, acting as a preventive agent or in diagnosis and prognosis. Recent studies have addressed the importance of selenium in oxidative status and antioxidant defence capabilities during the course of infection and progression of such illnesses in human patients and experimental models. For this reason, one of the most relevant mechanisms of action proposed concerns selenoproteins, i.e. GPX, an enzyme that protects against oxidative stress and modulates the redox processes [156]. In addition, it was observed that low Se levels were positively correlated with an increased susceptibility to infections and Se supplementation is proposed as an adjuvant therapy for treatment of these chronic diseases [157-159]. In the case of tuberculosis there is limited evidence related to this effect, but in a study carried out on 3,393 patients it was found that oral nutritional supplements may help people with tuberculosis to gain weight [157]. However, the effectiveness of supplementary antioxidant micronutrients for the prevention of kwashiorkor in 2,372 pre-school children in developing countries was unclear [158]. In cardiomyopathy and digestive disorders associated with chagas an effect was observed in the experimental mouse model. This effect could be analogous to the slow changes that occur during the early chronic phase of T. cruzi infection in humans; therefore, Se supplementation might be useful to halt disease progression in patients at this stage of infection. Se supplementation, in combination with specific anti-trypanosomal agents and/or other antioxidants, could provide a superior therapeutic protocol to modulate the inflammatory, immunological, and antioxidant responses involved in intestinal and cardiac disturbances caused by T. cruzi infection [159]. Recently, the specific effects of 26 selenoprotein Sel K deficiency in several different types of immune cells [160] have emerged, although further studies involving Sel K structure and function are necessary in order to better understand the role of this selenoprotein in immune responses. In spite of the results outlined above, references related to the synthesis and biological evaluation of novel selenium-containing derivatives against these diseases are scarce. In recent years our research team has been interested in the design and synthesis of organoselenium compounds as a new class of agents for the treatment of neglected tropical diseases. During the current year we have reported two general structures with leishmanicidal activity, both of which correspond to symmetrical compounds. The first are alkyl imidoselenocarbamates (alkyl isoselenourea) (Figure 13), which showed a moderate effect in vitro [161], and the second are selenocyanates and diselenides (Figure 13) [162]. It is remarkable that some of these compounds showed stronger in vitro antileishmanial activity than edelfosine and miltefosine, which were used as reference drugs, and combined high potency and low cytotoxicity against Jurkat and THP-1 cells. Figure 13. General structures for selenocompounds with leishmanicidal activity Conclusions and future direction It is clear from the epidemiological data discussed above that Se is an effective approach factor in human diseases and development. This fact has stimulated clinical trials to investigate the efficacy of Se alone or in Se-containing compounds as an attractive therapeutic lead for the treatment of multiple diseases. In this review we have summarized information from 162 references, of which 141 were published from 2008 to the present. These references merely hint at the hundreds of other citations available due to the ever increasing amount of work carried out in this field. The studies discussed above suggest the following preliminary considerations: 27 1) There are numerous studies that support the use of Se in human multiple diseases since it modulates antioxidant properties. Of particular interest is the role of this trace element in CVD, thyroid disease, cancer, neurological diseases, depression, diabetes, pancreatitis and tropical diseases. 2) Many recent studies have provided insights into the functional roles and significance of individual selenoproteins, but not all are well characterized. There are many functional and regulatory aspects of selenoproteins that remain unknown. The role of selenoproteins should be carefully examined to establish whether supplementation is advisable for the treatment or prevention of a specific disease in spite of the fact that Se status has been shown to affect the expression of individual selenoproteins differently. Many of these proteins, such as GPX, TrxR, and SelP, modulate the redox status systems. The DI family is responsible for maintaining a circulating level of thyroid hormone. 3) There is some controversy over whether Se administration predisposes one to diabetes and other metabolic effects. Knowledge of the effect of Se status on gene expression and metabolism obtained by using animal models is critical to predict accurately the effect of Se supplementation. In some diseases, i.e. ALS, the dietary intake of inorganic Se or hexavalent Se also increases the risk for this pathology. 4) Additional experimental evidence is needed to provide new insights into the role of Se and of specific selenoproteins in human biology, especially to clarify the underlying mechanisms linking Se to chronic disease endpoints. Prospective epidemiological studies and randomized clinical trials must be conducted to investigate the link between Se exposure and health effects across different ranges of exposure and in different populations. This would help to determine the optimal level of Se intake in the general population that can maximize health benefits while avoiding potential chronic toxic effects. Abbreviations AD Alzheimer’s disease AGE advanced glycation end products AIDS acquired immunodeficiency syndrome ALS amyotrophic lateral sclerosis AP acute pancreatitis CHF Congestive heart failure COX cyclooxygenase CVD Cardiovascular disease 28 ddNs 2´,3´-dideoxynucleosides DIO deiodinase DM Diabetes mellitus DMARDs disease modifying anti-rheumatic drugs DPDS diphenyl diselenide FoxO forkhead box class O GPX1 glutathion peroxidase 1 HDL high density lipoprotein HG high glucose HIV human immunodeficiency virus HT Hashimoto’s thyroiditis HUVEC human umbilical vein endothelial cells ICU intensive care unit ICV-STZ intracerebroventricular streptozotozin ID iodothyronine deiodinase IL-1 interleukin-1 IL-6 interleukin-6 iNOS inducible nitric oxide synthase ISC-4 isoselenocyanate-4 KBD Kashin-Beck disease LDL low density lipoprotein LO lipooxygenase LTs leukotrienes MOF multiorgan failure MSA methylseleninic acid NO nitric oxide NSAIDs non-steroidal anti-inflammatory drugs OA osteoarthritis OPA ovine pulmonary adenocarcinoma PC prostate cancer 29 PD Parkinson disease PGE2 prostaglandin E2 PSA prostatic specific antigen p-XSC 1,4-phenylenebis(methylene)selenocyanate RA rheumatoid arthritis RNS reactive nitrogen species ROS reactive oxygen species RP radical prostatectomy RT reverse transcriptase Se selenium Sec selenocysteine Secys selenocystine Sel K Selenoprotein K SelP selenoprotein P SeMet selenomethionine SHR spontaneously hypertensive rats SIRS systemic inflammatory response syndrome SM silymarin SN nigral system T2DM type 2 diabetes mellitus T4 3,3´,5,5´-tetraiodothyronine Tg thyroglobulin TNF-a tumour factor necrosis-a TPO thyroid peroxidase Trx oxidized thioredoxin TrxR thioredoxin reductase VIDs viral infectious diseases Acknowledgments 30 The authors wish to express their gratitude to the University of Navarra Research Plan (Plan de Investigación de la Universidad de Navarra, PIUNA), CAN Foundation and to the Ministerio de Ciencia e Innovación, Spain (SAF 2009-07744) for financial support for the project. 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