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Oxidation of glutathione and superoxide generation by inorganic and organic selenium compounds

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Abstract

The carcinostatic activities of selenium (Se) compounds have been shown to be composition and concentration dependent. Several studies have indicated that the ratios between glutathione (GSH) and Se may play an important role in Se catalysis and toxicity. The present study examined the catalytic effect of three selenium compounds on GSH oxidation using lucigenin-dependent chemiluminescence (CL) as an indirect measure of superoxide generation. Various GSH:Se ratios were assayed for the glutathione oxidase activity of selenite, selenocystamine and diselenodipropionic acid. CL emitted from the reaction of selenite with GSH increased more rapidly and was greater than those from the diselenides, but the diselenide CL reactions were sustainable. Both selenite- and diselenide-induced CL were markedly suppressed by superoxide dismutase (SOD). Iodoacetic acid (IAc) effectively inhibited CL generated from selenite-, selenocystamine- and diselenodipropionic acid-catalyzed GSH oxidation. These results suggest that GSH oxidation catalyzed by selenite, and the diselenides selenocystamine and diselenodipropionic acid, generated the superoxide radical in which the CL was inhibited by SOD. Furthermore, CL inhibition by IAc suggests that the catalytic species producing superoxide were the GSSe(-) or RSe(-) anion. This redox chemistry may be responsible for selenite and organoselenium toxicity and apoptosis, making possible the design and synthesis of organoselenium-containing pharmaceuticals.

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... In the presence of GSH, inorganic selenite, but not selenate, also generates superoxide as first reported by Seko et al. and later in 1991, Yan et al. showed the generation of O2 •− by various organic selenium compounds in the presence of GSH and other thiols [16,17]. In this study, we labeled Tz (Herceptin ® ) with reduceable selenides (RSe − ) using a Se-BHR and report the redox cycling by Se-Tz but not Tz in the presence of GSH at 37 °C in Figure 3. ...
... •− by various organic selenium compounds in the presence of GSH and other thiols [16,17]. In this study, we labeled Tz (Herceptin ® ) with reduceable selenides (RSe − ) using a Se-BHR and report the redox cycling by Se-Tz but not Tz in the presence of GSH at 37 • C in Figure 3. ...
... •− ) using an in vitro Lucigenin Chemiluminescent assay (Figure 3) at 37 • C degrees as previous described by Chen et al. [16]. (Figure 1) were grown in tissue culture flasks in a humidified atmosphere of 95% air and 5% CO 2 at 37 • C. Growth medium was renewed every 2 or 3 days and cell densities were maintained at 1 × 10 5 cells/mL before passage. ...
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Her/2+ breast cancer accounts for ~25% mortality in women and overexpression of Her/2 leads to cell growth and tumor progression. Trastuzumab (Tz) with Taxane is the preferred treatment for Her/2+ patients. However, Tz responsive patients often develop resistance to Tz treatment. Herein, redox selenides (RSe-) were covalently linked to Tz using a selenium (Se)-modified Bolton–Hunter Reagent forming Seleno-Trastuzumab (Se-Tz; ~25 µgSe/mg). Se-Tz was compared to Tz and sodium selenite to assess the viability of JIMT-1 and BT-474 cells. Comparative cell viability was examined by microscopy and assessed by fluorometric/enzymatic assays. Se-Tz and selenite redox cycle producing superoxide (O2•−) are more cytotoxic to Tz resistant JIMT-1 and Tz sensitive BT-474 cells than Tz. The results of conjugating redox selenides to Tz suggest a wider application of this technology to other antibodies and targeting molecules.
... Selenium species act as pro-oxidants as well [13]. For example, superoxide was generated in aerobic mixtures containing selenite or diselenides and glutathione (GSH) [14][15][16][17]. Selenium pro-oxidant properties significantly contribute to its toxicity [13,18]. ...
... Hydroxyl radical (HO Å ) or hydroxyl-like radicals are formed in this reaction as well that was supported by DNA damage, although its exact origin remains unknown [19,20]. Alternatively, in the case of selenite/ GSH mixture, the reactive selenium species responsible for the superoxide generation were attributed to glutathione perselenide (GS-Se À ) [14]. Selenols are also capable of producing reactive oxygen species via their rapid reaction with dioxygen [21][22][23]. ...
... Most of these species are not experimentally identified with the exception of selenodiglutathione (GS-Se-SG; reaction (4)) [39] and glutathione-S-selenite (GS-SeO 2 À ; reaction (1)) [40][41][42]. Earlier works suggest strong reducing properties of glutathione perselenide (GS-Se À ; reaction (7)) [14,43,44] as well as of selenium nanoparticles [45]. We exclude contribution of selenium nanoparticles to the direct production of HO Å , because the hydroxylation of TA in selenite/GSH system is accelerated upon increase in [GSH] up to 0.5 mM (Fig. 8B) and regeneration of selenium from selenite or other selenium oxidation products is fast that provides the rate saturation at lower [GSH]. ...
Article
The present study examined generation of hydroxyl radical (HO•) in aqueous aerobic solutions (pH 7.1) containing selenite (SeO3²⁻) and glutathione (GSH) using terephthalic acid (TA) scavenging HO• to give highly fluorescent 2-hydroxyterephthalic acid (TA-OH). The highest reaction rate and yield of TA-OH were observed in a micromolar concentration range of selenite at [GSH] = 0.5 mM. Accumulation of TA-OH was substantially lower in the case of other selenium species (viz. selenomethionine, selenocystine and selenate) and their mixtures with GSH. Addition of superoxide dismutase notably increased the rate of TA-OH formation, whereas catalase inhibited the reaction. Mixture of other thiols (i.e., cysteine or cysteamine) with SeO3²⁻ hydroxylates TA as well, although the rate of the reaction is lower than in the case of GSH. The mechanism consists of the rapid reduction of SeO3²⁻ by GSH to Se(0), reversible formation of glutathione perselenide (GS-Se⁻) and its further reaction with hydrogen peroxide to give HO•.
... 7 Sodium selenite is known as one of the most redox-active Se compounds in inducing ROS production and a potent Se compound for inhibiting cancer cell proliferation for a long time. 8,9 Administration of sodium selenite via ip injection is highly effective in inhibiting PC in mice bearing murine hepatocarcinoma 22 cells (H22 cells). The potential mechanisms involve the selective accumulation of Se in cancer cells in the form of selenium nanoparticles (SeNPs) and the abundant production of ROS. 10 A previous study found that intraperitoneal administration of SeNPs is an effective and safe approach for preventing the proliferation of cancer cells in the peritoneal cavity. ...
... 11,34,35 Since intracellular selenium levels increased more than one hundred times in H22 cells of peritoneal cavity post therapeutic doses of selenium were delivered by ip injection, 11,12 the molar ratio of GSH/Se in H22 cells from mice ranged from 1 to 4. SeNPs could be used as a superior Se species in such a low ratio of GSH/Se because SeNPs that present higher redox activity than selenite when reducing equivalents are limited. 8,12 Yet, sufficient reducing equivalents could enhance ROS production especially when the molar ratio of GSH/Se is at the range of 25.7−257. 8 Indeed, we found that both GSH and NAC dose-dependently induced ROS production in chemical systems at the ratio of 20 and 100 ( Figure 7A,B). ...
... 8,12 Yet, sufficient reducing equivalents could enhance ROS production especially when the molar ratio of GSH/Se is at the range of 25.7−257. 8 Indeed, we found that both GSH and NAC dose-dependently induced ROS production in chemical systems at the ratio of 20 and 100 ( Figure 7A,B). When the ratio of GSH/Se was set at 1, which is known as an inadequate reducing equivalent circumstance, NAC dose-dependently enhanced ROS production ( Figure 7C); when the ratio of NAC/Se was set at 1, GSH also enhanced ROS production in a dose-dependent manner ( Figure 7D). ...
Article
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Peritoneal carcinomatosis (PC) has an extremely poor prognosis, which leads to a significantly decreased overall survival in patients with peritoneal implantation of cancer cells. Administration of sodium selenite by intraperitoneal injection is highly effective in inhibiting PC. Our previous study found that selenium nanoparticles (SeNPs) have higher redox activity and safety than sodium selenite. In the present study, we examined the therapeutic effect of SeNPs on PC and elucidated the potential mechanism. Our results revealed that intraperitoneal delivery of SeNPs to cancer cells in the peritoneal cavity of mice at a tolerable dose was beneficial for prolonging the survival time of mice, even better than the optimal dose of cisplatin. The underlying mechanism involved in SeNP-induced reactive oxygen species (ROS) production caused protein degradation and apoptotic response in cancer cells. Interestingly, N-acetyl-l-cysteine (NAC), recognized as a ROS scavenger, without reducing the efficacy of SeNPs, enhanced ROS production and cytotoxicity. The effect of NAC was associated with the following mechanisms: (1) the thiol groups in NAC can increase the biosynthesis of endogenous glutathione (GSH), thus increasing the production of SeNP-induced ROS and cytotoxicity and (2) redox cycling of SeNPs was directly driven by thiol groups in NAC to produce ROS. Moreover, NAC, without increasing the systematic toxicity of SeNPs, decreased SeNP-induced lethality in healthy mice. Overall, we demonstrated that SeNPs exert a potential cytotoxicity effect by inducing ROS production in cancer cells; NAC effectively heightens the property of SeNPs in vitro and in vivo.
... Ganther proposed a possible mechanism of the reaction between sodium selenite and GSH [23], which is evidence for Se directly influencing peroxide removal. Later, investigators found that superoxide (O 2 •-), one of the reactive oxygen species, was CAT CAT detectable during this reaction [24,25,26,27]. This idea comes to a totally opposite direction from the protective role of Se. ...
... Selenite and GSH are proposed to react with oxygen being reduced to produce O 2 ▪- [23,24,25,26,27]. Studies on the reaction rates from different ratios of GSH to selenite were a good start to know more about the reaction kinetics (Figure 3.2). ...
... Similar to selenite, SeM and GSH are thought to react with each other and oxygen is also consumed in this process [24,27]. The reaction rates, which were observed as OCRs, were also studied on SeM and GSH (Figure 3.3). ...
... 3 The more toxic Se compounds include inorganic selenite, methylselenide and the diselenides; selenocystamine and diselenodipropionic acid among others and all have been shown to generate superoxide by oxidation of reduced Glutathione (GSH) and other thiol oxidations. 1,2,4 Selenium's cytotoxicity, like various sulfide toxicities, can be attributed to its lower catalytic selenide ionization, H 2 Se, HSe-, pKa, 3.8. Ionized allyl sulfides and allyl selenides have been shown to be the cause for apoptosis in cancer cells. ...
... In purely aqueous buffer systems SOD quenches O 2 -. and the CL activity of both S and Se redox cycling compounds. 4 In final consideration of the CL activity of alcohols, noteworthy are the catalytic studies of S and Se analogs by Sharma et al. 8 and by the animal Se toxicity studies of Schwarz et al. 22 In both circumstances, there are clear structural catalytic/toxicity functional relationships within a series of similar S and Se compounds differing only in the R substitution. Similar functional relationships appear here with alcohols as generally shown for the catalytic and non-catalytic alcohols. ...
... Superoxide anion is the main radical originated after Se (IV) treatments in microalgae and plants (Schiavon et al., 2012;X. Sun et al., 2014b;Gupta and Gupta, 2017), fish cell lines (Misra and Niyogi, 2009), birds (Hoffman, 2002) and diverse cancer cell lines (Spallholz, 1997;Chen et al., 2007;Misra et al., 2010;Weekley et al., 2014;Řezáčová et al., 2016). In T. thermophila we have detected strong peroxides generation associated to both selenite and selenate exposures, and their toxicity seems to be associated with the selenium concentration. ...
... In acellular systems (Cui et al., 2008), it has been found that selenite can be an active catalyst for the sulphydryl compounds oxidation, such as glutathione (GSH). Besides, it has been revealed, at least in cancer cells, that Se (IV) and some selenium organic compounds can oxide GSH (Chen et al., 2007). Some GSH dependent enzymes, as glutathione peroxidases, are well-known selenoproteins which are present in diverse organisms (Lu and Holmgren, 2009), and they have a relevant role as antioxidants. ...
Article
Selenium is an essential micronutrient but at high concentrations can produce severe cytotoxicity and genomic damage. We have evaluated the cytotoxicity, ultrastructural and mitochondrial alterations of the two main selenium inorganic species; selenite and selenate, in the eukaryotic microorganism Tetrahymena thermophila. In this ciliate, selenite is more toxic than selenate. Their LC 50 values were calculated as 27.65 μM for Se(IV) and 56.88 mM for Se(VI). Significant levels of peroxides/hydroperoxides are induced under low-moderate selenite or selenate concentrations. Se(VI) exposures induce an immediate mitochondrial membrane depolarization. Selenium treated cells show an intense vacuolization and some of them present numerous discrete and small electrondense particles, probably selenium deposits. Mitochondrial fusion, an intense swelling in peripheral mitochondria and mitophagy are detected in selenium treated cells, especially in those exposed to Se (IV). qRT-PCR analysis of diverse genes, encoding relevant antioxidant enzymes or other proteins, like metallothioneins, involved in an environmental general stress response, have shown that they may be crucial against Se(IV) and/or Se (VI) cytotoxicity.
... So what causes the toxicity of Se? Some insight into the toxicology of Se may be garnered from studies of the anticancer properties of Se compounds [129][130][131][132][133]. Oxidative stress and apoptosis occurs when mammalian cells are treated with SeO 3 2− [124,[134][135][136][137][138][139][140][141][142][143]. Superoxide (O 2 − •) is known to be produced when SeO 3 2− reacts with GSH [144]. ...
... Superoxide (O 2 − •) is known to be produced when SeO 3 2− reacts with GSH [144]. In Vitro evidence demonstrated that non-enzymatic reduction of SeO 3 2− by GSH rapidly yields GSSeSG and O 2 − • [135,[144][145][146][147]. Additionally, apoptosis is known to be induced by ROS like O 2 − • [3]. ...
Article
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There are no two main-group elements that exhibit more similar physical and chemical properties than sulfur and selenium. Nonetheless, Nature has deemed both essential for life and has found a way to exploit the subtle unique properties of selenium to include it in biochemistry despite its congener sulfur being 10,000 times more abundant. Selenium is more easily oxidized and it is kinetically more labile, so all selenium compounds could be considered to be “Reactive Selenium Compounds” relative to their sulfur analogues. What is furthermore remarkable is that one of the most reactive forms of selenium, hydrogen selenide (HSe⁻ at physiologic pH), is proposed to be the starting point for the biosynthesis of selenium-containing molecules. This review contrasts the chemical properties of sulfur and selenium and critically assesses the role of hydrogen selenide in biological chemistry.
... It is from such reactions that the oxidative stress causing toxicity and the death of the Polo horses from selenite likely involved extensive hemolysis. The selenopersulfide anion catalyst is seen in reactions with selenite and GSH; and as the selenide or selenoate anion upon reduction in many diselenides experimentally using luminometry that measures superoxide [28]. Toxicity of selenium compounds was seen in early oral comparisons of selenium toxicity in mice, from a large library of mono-and diselenides as reported by Schwarz [29]. ...
... We use a chemiluminescent cocktail of GSH and Lucigenin (bis-N-methylacridinium nitrate) and a water-jacketed luminometer to routinely measure superoxide. Additionally, quantitatively superoxide dismutase (SOD) [28,37] as well as iodoacetate, quenches the above and similar selenide or selenoate reactions with thiols confirming the generation of superoxide. In vitro and/or ex vivo a probe for superoxide, dihydroethidium (DHE) and its florescence, comes from the reaction of DHE with superoxide; Lambda Ex, 380 nm; 500 nm, Lambda Em, 580 nm. ...
Article
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Selenium is generally known as an antioxidant due to its presence in selenoproteins as selenocysteine, but it is also toxic. The toxic effects of selenium are, however, strictly concentration and chemical species dependent. One class of selenium compounds is a potent inhibitor of cell growth with remarkable tumor specificity. These redox active compounds are pro-oxidative and highly cytotoxic to tumor cells and are promising candidates to be used in chemotherapy against cancer. Herein we elaborate upon the major forms of dietary selenium compounds, their metabolic pathways, and their antioxidant and pro-oxidant potentials with emphasis on cytotoxic mechanisms. Relative cytotoxicity of inorganic selenite and organic selenocystine compounds to different cancer cells are presented as evidence to our perspective. Furthermore, new novel classes of selenium compounds specifically designed to target tumor cells are presented and the potential of selenium in modern oncology is extensively discussed.
... selenite, CysSeSeCys and MeSeA) are capable of producing ROS in vitro and thus ROS generation is usually attributed to redox cycling of selenolates with GSH and oxygen. [216][217][218] MeSeCys and SeMet, which do not generate superoxide in vivo, may be capable of generating ROS in cells where they can be cleaved to MeSe À . 217 ...
... Selenite-mediated ROS generation occurs in concert with a reduction in GSH levels and increased levels of GSSG and has been associated with oxidative stress leading to DNA strand breaks and apoptosis in cancer cells. 219 Superoxide, generated by selenolates, 218 is generally held to induce selenite-mediated apoptosis, but other species may be involved. Shen et al. found that the selenite-induced apoptosis in human hepatoma cells was inhibited by superoxide dismutase 219 and Kim et al. observed that superoxide dismutase, but not catalase overexpression, prevented autophagic cell death in selenite-treated malignant glioma cells; 220 but Park et al. recently reported that superoxide dismutase had no effect on selenite-induced apoptosis in human lung cancer cells. ...
Article
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The biological activity of selenium is dependent upon its speciation. We aim to integrate selenium speciation and metabolism into a discussion of the mechanisms by which selenium exerts its biological activity. First, we present the current status of selenium in the prevention of cancer, cardiovascular and neurodegenerative diseases with particular attention paid to the results of major chemoprevention trials involving selenium supplementation. A comprehensive review of the current understanding of the metabolism of common dietary selenium compounds - selenite, selenomethionine, methylselenocysteine and selenocystine - is presented, with discussion of the evidence for the various metabolic pathways and their products. The antioxidant, prooxidant and other mechanisms of the dietary selenium compounds have been linked to their disease prevention and treatment properties. The evidence for these various mechanisms - in vitro, in cells and in vivo - is evaluated with emphasis on the selenium metabolites involved. We conclude that dietary selenium compounds should be considered prodrugs, whose biological activity will depend on the activity of the various metabolic pathways in, and the redox status of, cells and tissues. These factors should be considered in future laboratory research and in selecting selenium compounds for trials of disease prevention and treatment by selenium supplementation.
... Additionally, • O 2 − is produced when SeO 3 2− reacts with GSH [14,17,65,66] and the following stoichiometry has been proposed [17]: ...
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Selenium compounds exert their antioxidant activity mostly when the selenium atom is incorporated into selenoproteins. In our work, we tested the possibility that selenite itself interacts with thiols to form active species that have reducing properties. Therefore, we studied the reduction of 2-(4-carboxyphenyl)-4,5-dihydro-4,4,5,5-tetramethyl-1H-imidazol-1-yloxy-3-oxide radical (•cPTIO), damage of plasmid DNA (pDNA), modulation of rat hemodynamic parameters and tension of isolated arteries induced by products of interaction of selenite with thiols. We found that the products of selenite interaction with thiols had significant reducing properties that could be attributed mainly to the selenide and that selenite had catalytic properties in the access of thiols. The potency of thiols to reduce •cPTIO in the interaction with selenite was cysteine > homocysteine > glutathione reduced > N-acetylcysteine. Thiol/selenite products cleaved pDNA, with superoxide dismutase enhancing these effects suggesting a positive involvement of superoxide anion in the process. The observed •cPTIO reduction and pDNA cleavage were significantly lower when selenomethionine was used instead of selenite. The products of glutathione/selenite interaction affected several hemodynamic parameters including rat blood pressure decrease. Notably, the products relaxed isolated mesenteric artery, which may explain the observed decrease in rat blood pressure. In conclusion, we found that the thiol/selenite interaction products exhibited significant reducing properties which can be used in further studies of the treatment of pathological conditions caused by oxidative stress. The results of decreased rat blood pressure and the tension of mesenteric artery may be perspective in studies focused on cardiovascular disease and their prevention.
... However, growing studies indicated that inorganic Se-induced oxidative stress can also result in Se toxicity in plants (Van Hoewyk, 2013). The mechanism underlying this stress involves the pro-oxidant capacity of Se to cause the oxidation of thiols (e.g., GSH), and the generation of hydrogen peroxide (H 2 O 2 ) and superoxide free radicals (O 2 •-) (Chen et al., 2007;Qu et al., 2023). Therefore, the antioxidant capacity of plants may be involved in detoxifying Se-induced toxicity. ...
... Beyond this level, the increase in blood Se does not reflect an increase in selenoprotein levels or activity, but rather non-specific binding of selenomethionine in place of methionine in albumin and other serum proteins (Hill et al., 1996;Tinkov et al., 2020). Selenite and methyl-selenol continue to produce superoxide (O 2 ) in vitro when reduced glutathione is present (Chen et al., 2007). Reactive oxygen species can increase insulin resistance and affect the function of the islet β-cell under conditions of oxidative stress (Evans et al., 2003). ...
Article
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Background Currently, over 2 billion people worldwide suffer from obesity, which poses a serious health risk. More and more attention is being given to the effects of trace elements on obesity in recent years. Synergistic or antagonistic interactions among these elements can adversely or positively impact human health. However, epidemiological evidence on the relationship between trace element exposure levels and obesity has been inconclusive. Methods Baseline data of 994 participants from the Cohort of Elderly Health and Environment Controllable Factors were used in the present study. ICP-MS was used to measure the concentrations of 10 trace elements in the whole blood of the older population. Binary logistic regression, restricted cubic splines (RCS) models, and Bayesian kernel machine regression (BKMR) models were employed to assess single, nonlinear, and mixed relationships between 10 trace element levels and three types of obesity based on body mass index (BMI), waist circumference (WC), and body fat percentage (BFP) in the elderly. Results Based on BMI, WC and BFP, 51.8% of the included old population were defined as general overweight/obesity, 67.1% as abdominal obesity, and 36.2% as having slightly high/high BFP. After multivariable adjustment, compared with the lowest tertile, the highest tertile of blood selenium (Se) concentration was associated with an increased risk of all three types of obesity. Additionally, compared with the lowest tertile, higher tertiles of strontium (Sr) concentrations were associated with a lower risk of general overweight/obesity and having slightly high/high BFP, and the highest tertile of barium (Ba) was associated with a lower risk of having slightly high BFP, while higher tertiles of arsenic (As) concentrations were associated with an increased risk of having slightly high/high BFP, and the highest tertile of manganese (Mn) was associated with a higher risk of abdominal obesity. BKMR analyses showed a strong linear positive association between Se and three types of obesity. Higher blood levels of trace element mixture were associated with increased obesity risks in a dose–response pattern, with Se having the highest value of the posterior inclusion probability (PIP) within the mixture. Conclusions In this study, we found higher Se levels were associated with an elevated risk of obesity and high levels of Ba, Pb and Cr were associated with a decreased risk of obesity. Studies with larger samples are needed to confirm these findings.
... 35 Oxidation of -thiol compounds, found on the surface of microorganisms and all bodily fluids, by selenium results in generation of reactive oxygen species (ROS), which in turn cause oxidative stresses, DNA damage, and death of microbial cells. 36 It is pertinent to mention that organoselenium incorporated in denture base material is safe for human mucosal cells. The safety of selenium is attributed to the formation of covalent bonds between selenium molecules and several compounds used in medical and dental materials, such as silicone and resin polymers. ...
Article
Purpose: Denture Stomatitis, a chronic mucosal inflammation associated with Candida albicans, is common among denture wearers. Several health conditions have been linked to chronic Candida infections. The complex, multifactorial nature of denture stomatitis requires the continuous pursuit of effective long-term solutions. The present in vitro study investigated the effect of incorporating organoselenium into 3D-printed denture base resin on Candida albicans adhesion and biofilm formation. Materials and methods: Thirty disks were fabricated using 3D-printed denture base resin and assigned to 3 experimental groups (10/group): disks without organoselenium (control), disks with 0.5% organoselenium (0.5%SE), and disks with 1% organoselenium (1%SE). Each disk was incubated with approximately 1 × 106 cells/mL of Candida albicans for 48 hours. Microbial viability (CFU/mL) was quantified by the spread plate method, while Confocal laser scanning microscopy and scanning electron microscope were performed for quantifying the biofilm thickness and examining biofilm morphology, respectively. Data were analyzed using One-way ANOVA with Tukey's multiple comparisons test. Results: CFU/mL was significantly (P<0.05) higher in Control when compared with 0.5%SE and 1%SE, but no significant difference between 0.5%SE and 1%SE. A similar trend was observed with biofilm thickness except that there was no significant difference between the Control and 0.5%SE. There was C. albicans biofilm adhesion on the Control disks, with yeast cells and hyphae formation, whereas on 0.5%SE and 1%SE, there was inhibition of yeast cells transition to hyphae formation. Conclusions: Incorporation of organoselenium into 3D-printed denture base resin was effective in reducing Candida albicans biofilm formation and growth on denture base material. This article is protected by copyright. All rights reserved.
... The connection between ROS and Se stress is evident as early as the Se metabolism: glutathione reduces selenite to selenide, which results in superoxide anion (Chen et al. 2007). This can enhance the transcription of antioxidant response genes (Van Hoewyk et al. 2008) and the metabolism of antioxidants (Dimkovikj and Van Hoewyk 2014). ...
Chapter
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Though higher plants essentially do not require selenium (Se) in their physiological processes, it has been proven that Se at lower dosages (few μM) may be beneficial for the development and stress tolerance of plants against both abiotic and biotic stress factors. At the same time, beyond the optimal concentration, Se can act as a prooxidant provoking the imbalance of redox homeostasis and results in hormonal and nutritional disorders. Due to its chemical similarity to sulphur (S), Se may be the constituent of several organic compounds like selenoamino acids (e.g. selenocysteine, SeCys) which can replace S-contaning amino acids making dysfunctional proteins as a consequence of Se toxicity. To avoid incorporation into proteins, mainly in case of excess Se, plants may convert SeCys into elemental Se or to volatile dimethyl-selenide (DMSe) in non-accumulators or dimetyl-diselenide (DMDSe) in hyperaccumulator species and evaporate it through the stomata. This chapter summarizes the previous and recent scientific results regarding the background mechanisms of Se toxicity and tolerance in order to provide a state-of-the-art overview about Se toxicity and tolerance in higher plants.
... [22] Seleno-L-cystine, the basic structural feature of 17FSe2, belongs to a group of selenium molecules that may generate superoxide radicals when in contact with GSH. [23] We investigated whether the chemical modification of 17FSe2 influences the J o u r n a l P r e -p r o o f generation of superoxide radicals in the presence of GSH and compared it with L-selenocystine. The presence, generation, and abundance of superoxide radicals between the diselenium compounds (17FSe2, seleno-L-cystine) and GSH were measured using a lucigenin probe. ...
Article
Radiation resistance of cancer cells represents one of the major challenges in cancer treatment. The novel self-assembled fluoralkylated diselenide nanoparticles (fluorosomes) based on seleno-l-cystine (17FSe2) possess redox-active properties that autocatalytically decompose hydrogen peroxide (H2O2) and oxidize the intracellular glutathione (GSH) that results in regulation of cellular oxidative stress. Alkylfluorinated diselenide nanoparticles showed a significant cytotoxic and radiosensitizing effect on cancer cells. The EL-4 tumor-bearing C56BL/6 mice treated with 17FSe2 followed by fractionated radiation treatment (4 × 2Gy) completely suppressed tumor growth. Our results suggest that described diselenide system behaves as a potent radiosensitizer agent targeting tumor growth and preventing tumor recurrence.
... The selenite-mediated ROS generation (e.g. the generation of superoxide, hydrogen peroxide, hydroxyl radicals) by the drug itself and its metabolites was observed in several studies and has been associated with oxidative stress leading to DNA strand breaks and apoptosis in various cancer cell types [37][38][39]. In addition, it has been described for a number of cancer cell lines that selenite induced mitochondria mediated apoptosis. ...
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Sodium selenite is often given to moderate the side effects of cancer therapy to enhance the cellular defence of non-cancerous cells. To determine whether sodium selenite during radiotherapy protects not only normal cells but also cancer cells, which would imply a reduction of the desired effect of irradiation on tumour during radiotherapy, the effect of the combined treatment of irradiation and sodium selenite was investigated. Human bronchial cells from carcinoma (A549) and normal tissue (BEAS-2B) were treated with sodium selenite and effects on growth and in combination with radiation on metabolic activity and cell cycle distribution were studied. The influence on radiosensitivity was determined via colony forming assays using different solvents of sodium selenite and treatment schedules. It was shown that sodium selenite inhibits growth and influences cell cycle distribution of both normal and tumour cells. Metabolic activity of normal cells decreased more rapidly compared to that of cancer cells. The influence of sodium selenite on radiation response depended on the different treatment schedules and was strongly affected by the solvent of the agent. It could be shown that the effect of sodium selenite on radiation response is strongly dependent on the respective experimental in vitro conditions and ranges from lead to an initially suspected but ultimately no real radioprotection to radiosensitizing up to no effect in one and the same cell line. This might be a reason for controversially described cell responses to radiation under the influence of sodium selenite in studies so far.
... Expecting to follow a similar mechanism, DSePA has been studied for hepatic metabolism using S9 fraction (prepared from rat liver homogenate consisting of both microsomal and cytosolic enzymes, and therefore a source of wide variety of metabolic enzymes like phase I, phase II and cysteine conjugate β-lyase) [80].The results have revealed that DSePA undergoes β-elimination and oxidative transformation reactions through cysteine conjugate β-lyase and cytochrome P450 family of enzymes, respectively [77]. Additionally, DSePA also undergoes reduction by GSH under cell free conditions producing superoxide radical and therefore is expected to be a prooxidant [81]. However, it is important to understand that the reaction conditions inside a living cell are much more complex due to the presence of several types of reductants and oxidants with varying concentrations and the pathological state of cell. ...
Article
Background Extensive research is being carried out globally to design and develop new selenium compounds for various biological applications such as antioxidants, radio-protectors, anti-carcinogenic agents, biocides, etc. In this pursuit, 3,3′-diselenodipropionic acid (DSePA), a synthetic organoselenium compound, has received considerable attention for its biological activities. Scope of review This review intends to give a comprehensive account of research on DSePA so as to facilitate further research activities on this organoselenium compound and to realize its full potential in different areas of biological and pharmacological sciences. Major conclusions It is an interesting diselenide structurally related to selenocystine. It shows moderate glutathione peroxidase (GPx)-like activity and is an excellent scavenger of reactive oxygen species (ROS). Exposure to radiation, as envisaged during radiation therapy, has been associated with normal tissue side effects and also with the decrease in selenium levels in the body. In vitro and in vivo evaluation of DSePA has confirmed its ability to reduce radiation induced side effects into normal tissues. Administration of DSePA through intraperitoneal (IP) or oral route to mice in a dose range of 2 to 2.5 mg/kg body weight has shown survival advantage against whole body irradiation and a significant protection to lung tissue against thoracic irradiation. Pharmacokinetic profiling of DSePA suggests its maximum absorption in the lung. General significance Research work on DSePA reported in fifteen years or so indicates that it is a promising multifunctional organoselenium compound exhibiting many important activities of biological relevance apart from radioprotection.
... In contrast, excessive production of ROS gives rise to the activation of events that lead to death in several cell types [27]. Several studies have suggested that the anticancer functions of selenium compounds involve the production of O 2 • − [12,16,30,51,52]. Selenium compounds such as SS, selenium dioxide, diselenides, and selenocysteine react with cysteine residues of reduced GSH ultimately leads to the generation of O 2 • − [52,53]. ...
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Ferroptosis is a novel form of programmed cell death characterized by an iron-dependent increase in reactive oxygen species (ROS). However, the role of ROS in the regulation of ferroptosis remains elusive. In this study, for the first time, we demonstrate that sodium selenite (SS), a well-established redox-active selenium compound, is a novel inducer of ferroptosis in a variety of human cancer cells. Potent ferroptosis inhibitors, such as ferrostatin-1 (Fer-1) and deferoxamine (DFO), rescue cells from SS-induced ferroptosis. Furthermore, SS down-regulates ferroptosis regulators; solute carrier family 7 member 11 (SLC7A11), glutathione (GSH), and glutathione peroxidase 4 (GPx4), while it up-regulates iron accumulation and lipid peroxidation (LPO). These SS-induced ferroptotic responses are achieved via ROS, in particular superoxide (O2⁻) generation. Antioxidants such as superoxide dismutase (SOD) and Tiron not only scavenged O2⁻ production, but also markedly rescued SLC7A11 down-regulation, GSH depletion, GPx4 inactivation, iron accumulation, LPO, and ferroptosis. Moreover, iron chelator DFO significantly reduces the O2⁻ production, indicating a positive feedback regulation between O2⁻ production and iron accumulation. Taken together, we have identified SS as a novel ferroptosis inducing agent in various human cancer models.
... To further explore the link between Sfp1 and the glutathione redox system, a sodium selenite sensitivity assay was performed to detect alterations in cellular glutathione content. Glutathione is involved in selenite-induced oxidative stress and reacts with selenite to yield superoxide, causing cell death [43]. Therefore, cells containing a high level of glutathione are more sensitive to sodium selenite. ...
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Candida albicans is a commensal that inhabits the skin and mucous membranes of humans. Because of the increasing immunocompromised population and the limited classes of antifungal drugs available, C. albicans has emerged as an important opportunistic pathogen with high mortality rates. During infection and therapy, C. albicans frequently encounters immune cells and antifungal drugs, many of which exert their antimicrobial activity by inducing the production of reactive oxygen species (ROS). Therefore, antioxidative capacity is important for the survival and pathogenesis of C. albicans. In this study, we characterized the roles of the zinc finger transcription factor Sfp1 in the oxidative stress response against C. albicans. A sfp1-deleted mutant was more resistant to oxidants and macrophage killing than wild-type C. albicans and processed an active oxidative stress response with the phosphorylation of the mitogen-activated protein kinase (MAPK) Hog1 and high CAP1 expression. Moreover, the sfp1-deleted mutant exhibited high expression levels of antioxidant genes in response to oxidative stress, resulting in a higher total antioxidant capacity, glutathione content, and glutathione peroxidase and superoxide dismutase enzyme activity than the wild-type C. albicans. Finally, the sfp1-deleted mutant was resistant to macrophage killing and ROS-generating antifungal drugs. Together, our findings provide a new understanding of the complex regulatory machinery in the C. albicans oxidative stress response.
... Only Se-HuSA showed a statistically significant (p < 0.05) Caspase-3 increase in comparison to the control cells. Se-Apo-Tf and Se-Holo-Tf induced an approximately 0.50 and 0.75 fold increase in Caspase 3 respectively, which was higher but not statistically significant (p > 0.05) from control cells [11,[13][14][15][16][17][18]. For futher cytotoxic assessment of the selenium conjugated proteins, ...
... Furthermore, it controls several processes involving the cellular antioxidative defense, the regulation of the level of thyroid hormones and energy metabolism (Rayman, 2000;Falandysz, 2008). However, the effects of Se are finely controlled by dose and form (Chen, Boylan, Wu, & Spallholz, 2007;Wang et al., 2018). Elemental Se as well as selenite (SeO 3 2− ) and selenate (SeO 4 2− ) are already toxic at low concentrations, in contrast to the selenoamino acids, selenopeptides and selenoproteins which are characterized by a high bioavailability and relatively lower toxicity even at high concentrations (> 800 μg d −1 ) (Whanger, Vendeland, Park, & Xia, 1996). ...
... Anticancerogenic effect of selenium depends on the protection of DNA against damage and improvement its reparative capabilities. A decrease in number of mutations (72), induction of apoptosis through the activation of caspase-3, and modulation of glutathione and mitochondrial functions were evidenced in experimental studies (73). An inverse association between serum selenium level and occurrence of advanced CRC was also found in active smokers (74). ...
Article
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Colorectal cancer (CRC) is the third most prevalent neoplasm worldwide and fourth most frequent reason of cancer-related death throughout the world. About 70% of malignant tumors are related to lifestyle and environmental factors, and better knowledge of their significance might reduce the prevalence of CRC. The cyclooxygenase-2 (COX-2) inhibitory and other direct and indirect pathways of aspirin are translated to inhibition proliferation and enhanced apoptosis of cancer cells. Many studies showed the benefits of aspirin in reducing the risk of CRC development, cancer-related mortality and adenoma prevalence rate in general population, but not in high risk populations. The role of sulindac in CRC prevention is uncertain and the use of this drug is rather uncommon. Celecoxib - COX-2 selective inhibitor- showed efficacy in decreasing of colon adenoma recurrence only in some studies. The protective role of microelements is controversial. The beneficial effects of supplementation of selenium, calcium, folic acid, methionine, antioxidant supplements and probiotics are still not certain. A high energy diet consisting of red meat, animal fat, highly processed foods and unsaturated fats increases the risk of CRC. Carcinogenic role of fat and cholesterol depends on increased production of primary bile acids. The importance of milk and dairy products in CRC prevention is controversial. Fruits, vegetables and grain are considered to have protective effects against adenoma and CRC. Excessive alcohol consumption, smoking, physical inactivity are considered as important CRC risk factors. This article briefly summarizes current state of knowledge about the role of pharmacological and dietary prevention of colorectal cancer. Moreover, it indicates that despite many studies some aspects of this issue are not clear and require future studies.
... Furthermore it is known that the reaction of selenite with glutathione produces superoxide anions within the first minutes of the reaction [30,33] as indicated in Eq. 1. ...
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Background In many works, the chemical composition of bacterially-produced elemental selenium nanoparticles (Se⁰-nanoparticles) was investigated using electron dispersive X-ray analysis. The results suggest that these particles should be associated with organic compounds. However, a complete analysis of their chemical composition is still missing. Aiming at identifying organic compounds associated with the Se⁰-nanoparticles produced by the purple phototrophic bacteria Rhodospirillum rubrum and Rhodobacter capsulatus (α group of the proteobacteria), we used MALDI-TOF spectrometry. Results This technic revealed that numerous signals obtained from particles produced by both species of bacteria were from metabolites of the photosynthetic system. Furthermore, not only bacteriochlorophyll a, bacteriopheophytin a, and bacteriopheophorbide a, which are known to accumulate in stationary phase cultures of these bacteria grown phototrophically in the absence of selenite, were identified. The particles were also associated with intermediary metabolites of the bacteriochlorophyll a biosynthesis pathway such as protoporphyrin IX, protoporphyrin IX monomethyl ester, bacteriochlorophyllide a and, most likely, Mg-protoporphyrin IX-monomethyl ester, as well as with oxidation products of the substrates of protochlorophyllide reductase and chlorin reductase. Conclusion Accumulation of intermediary metabolites of the bacteriochlorophyll biosynthesis pathway in these purple phototrophic bacteria was attributed to inhibition of oxygen-sensitive enzymes involved in this pathway. Consistent with this interpretation it has been reported that these bacteria reduce selenite intracellularly, that they contain high levels of glutathione and that the reduction of selenite with glutathione is a very fast reaction accompanied by the production of reactive oxygen species. As many enzymes involved in the biosynthesis of bacteriochlorophyll contain [Fe-S] clusters in their active site, which are known to be degraded in the presence of reactive oxygen species as well as in the presence of molecular oxygen, we concluded that the substrates of these enzymes accumulate in cells during selenite reduction. Association of metabolites of bacteriochlorophyll biosynthesis and degradation with the Se⁰-nanoparticles produced by Rhodospirillum rubrum and Rhodobacter capsulatus is proposed to result from coating of the nanoparticles with the intracytoplasmic membrane of these bacteria, where the photochemical apparatus is concentrated. Electronic supplementary material The online version of this article (10.1186/s12866-018-1209-5) contains supplementary material, which is available to authorized users.
... Painter (1941) reported that the selenite toxicity is related to the oxidation of endogenous thiol. More recently, it has been suggested that Se-mediated thiol oxidation cause reactive oxygen species (ROS) (Stewart et al., 1998;Chen et al., 2007;Plano et al., 2010), and oxidative stress can be a factor related to Se-induced toxicity (Kitahara et al., 1993;Shen et al., 2001;Kim et al., 2007;Xiang et al., 2009). Therefore, Se can be bioaccumulate in tissues and increase the production of ROS to damage the biological molecules such as lipid or protein or DNA. ...
... Increased ROS lead to convert the reduced GSH to its oxidized form in the cell and may cause the imbalance of antioxidant and pro-oxidants in the cells. Similarly, Chen et al. (2007) reported that sodium selenite provoked oxidation of GSH with superoxide generation. Zuo et al. (2004) reported that sodium selenite exerted ROS mediated oxidative stress and the cellular GSH decrease in NB4 cells. ...
Article
Purpose of this study is to investigate mechanism/s of cyto-protection by selenium (Na2SeO3; Se4+) against cadmium (CdCl2; Cd2+)-induced cytotoxicity using PC12 cells. In addition, Se (5, 10, 20 and 40 μM) and Cd (2.5, 5 and 10 μM)-induced cytotoxicity is determined. Cytotoxicity assays and western blot analyses confirmed that Se (≥10 μM) promotes autophagic cell death via inhibition of mTOR activation and p62 accumulation due to increase of cellular oxidative stress. On the other hand, co-presence of non-toxic Se (5 μM) and toxic Cd (5 μM) showed to increase cell viability, glutathione and glutathione peroxidase 1 (GPx1) levels, and to decrease DNA fragmentation and lactate dehydrogenase (LDH) activity compared to Cd-treated (5 μM) cells alone. Furthermore, western blot analyses of cytochrome c and ERK1 indicated that Cd-induced apoptotic cell death in PC12 cells. However, the co-exposure of Se with Cd significantly decreases the release of cytochrome c into cytosol from mitochondria, and up-regulates ERK1 protein to inhibit Cd-induced apoptosis. In conclusion, Se (≥10 μM) possess cytotoxicity in PC12 cells; however, co-presence of Se (5 μM) with Cd (5 μM) protects against Cd-induced apoptosis in PC12 cells due to inhibition of Cd-induced oxidative stress and subsequently suppression of mitochondrial apoptosis pathway.
... Increased ROS lead to convert the reduced GSH to its oxidized form in the cell and may cause the imbalance of antioxidant and pro-oxidants in the cells. Similarly, Chen et al. (2007) reported that sodium selenite provoked oxidation of GSH with superoxide generation. Zuo et al. (2004) reported that sodium selenite exerted ROS mediated oxidative stress and the cellular GSH decrease in NB4 cells. ...
Presentation
The 28th Annual Scientific Meeting of the Japan Society for Biomedical Research on Trace Elements Sendai, July 30, 2017
... Numerous mushroom species have been shown to have the ability to absorb and retain trace elements, among which is selenium (Se), an essential micronutrient which can enhance immune functioning, protect cell membranes from oxidative stress, and participate in the biosynthesis of thyroid hormone, energy metabolism and gene expression [9][10][11][12]. However, the effect depends on its form and concentration because at higher amounts and especially in elemental form Se could be toxic [13]. The ability to transform inorganic Se forms into organic forms, which are more appropriate for animals and humans, is a significant feature of mushrooms [14]. ...
Article
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The aim of the study was an assessment of the antioxidant, antifungal and cytotoxic potentials of L. betulinus and T. hirsuta mycelia extracts and the effect of selenium on these activities. Extracts of L. betulinus were twice as efficient in DPPH• scavenging as those of T. hirsuta. The phenol content in Se-enriched L. betulinus extracts was higher than in non-enriched extracts, in contrast to the effect of Se-enrichment on T. hirsuta extracts, and a direct correlation between the amount and DPPH• scavenging effect was observed. Ethanol extracts exhibited fungistatic but not fungicidal activity against a range of micromycetes, and mycelium enrichment with selenium inhibited this effect. Although the extracts showed low cytotoxic activity against HeLa and LS174 cells, T. hirsuta extracts, especially those enriched with selenium, had better potential. L. betulinus extracts showed better antioxidant and antifungal activity than T. hirsuta extracts which were more active cytotoxic agents. The presence of selenium stimulated antioxidant and cytotoxic, and inhibited antifungal activity in L. betulinus, while in T. hirsuta its effect was slight.
... Numerous mushroom species have been shown to have the ability to absorb and retain trace elements, among which is selenium (Se), an essential micronutrient which can enhance immune functioning, protect cell membranes from oxidative stress, and participate in the biosynthesis of thyroid hormone, energy metabolism and gene expression [9][10][11][12]. However, the effect depends on its form and concentration because at higher amounts and especially in elemental form Se could be toxic [13]. The ability to transform inorganic Se forms into organic forms, which are more appropriate for animals and humans, is a significant feature of mushrooms [14]. ...
Article
The aim of the study was an assessment of the antioxidant, antifungal and cytotoxic potentials of L. betulinus and T. hirsuta mycelia extracts and the effect of selenium on these activities. Extracts of L. betulinus were twice as efficient in DPPH• scavenging as those of T. hirsuta. The phenol content in Se-enriched L. betulinus extracts was higher than in non-enriched extracts, in contrast to the effect of Se-enrichment on T. hirsuta extracts, and a direct correlation between the amount and DPPH• scavenging effect was observed. Ethanol extracts exhibited fungistatic but not fungicidal activity against a range of micromycetes, and mycelium enrichment with selenium inhibited this effect. Although the extracts showed low cytotoxic activity against HeLa and LS174 cells, T. hirsuta extracts, especially those enriched with selenium, had better potential. L. betulinus extracts showed better antioxidant and antifungal activity than T. hirsuta extracts which were more active cytotoxic agents. The presence of selenium stimulated antioxidant and cytotoxic, and inhibited antifungal activity in L. betulinus, while in T. hirsuta its effect was slight.
... Methylselenol can in turn be formed via cleavage of MSC (or through other Sec-conjugates) by selenocysteine Se-conjugated β-lyase or through the reduction of MSA. Excessive amount of selenide or methylselenol can however be deleterious to the cell, as these forms readily oxidize and can lead to the production of superoxide and other reactive oxygen species with add-on toxic effects [118,119]. Importantly, monomethylated selenium compounds, are direct precursors of putative active anticancer metabolite methylselenol [113]. The relative ability to produce this metabolite should be readily considered in the development of new selenium compounds for cancer therapy. ...
... Additionally, selenite is a pro-oxidant that can induce oxidative stress and the accumulation of ROS in a wide-range of plants, as recently reviewed [20]. In plants, selenate can be reduced to selenite enzymatically; however, the subsequent non-enzymatic reduction of selenite is likely mediated by glutathione [21], which is known to generate superoxide [22]. Recently, human cells treated with selenite induced the accumulation of mitochondrial superoxide and rapidly changed mitochondrial morphology [23]. ...
Article
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Background Human requirements for dietary selenium are met mainly by crops. However, excessive uptake of selenium in plants can restrict growth, and its toxicity has been postulated to target roots. Selenite toxicity can be attributed to its assimilation into selenocysteine, which can replace cysteine to yield malformed selenoproteins. Additionally, selenite has pro-oxidant properties. In this study, the effects of selenite on root tissue in Brassica napus (canola) were investigated to better understand its mode of toxicity and the metabolic adjustments needed to mediate a selenite-response.ResultsSelenite induced the rapid formation of mitochondrial superoxide, which led to decreased aconitase activity and involvement of the alternative oxidase pathway. Although selenite altered primary metabolism, as observed by the increased amino acids and decreased TCA cycle metabolites, increased glucose presumably supported higher respiratory rates and ATP levels reported in this study. Additionally, evidence is presented indicating that selenite suppressed the ubiquitin-proteasome pathway, and induced the pentose phosphate pathway needed to maintain antioxidant metabolism. Selenite treatment also elevated glutathione concentration and coincided with increased levels of ¿-glutamyl cyclotransferase, which may possibly degrade selenium metabolites conjugated to glutathione.Conclusion Collectively, the data indicate that selenite necessitates the reconfiguration of metabolic pathways to overcome the consequences of mitochondrial oxidative stress in root tissue. Efforts to mitigate the detrimental effects of selenite-induced oxidative stress may ultimately improve selenium tolerance and accumulation in crops.
... Mechanisms explaining cardiometabolic associations are incompletely understood. Organic Se species were shown to generate superoxides in vitro [15]. Release of hydrogen peroxide, a second messenger in the insulin signaling pathway, may be disrupted by high GPx activity [16]. ...
Article
Recent studies have raised concern over possible associations between high selenium (Se) status and excess adiposity, known to be linked to adverse cardio-metabolic outcomes. Studies of Se status in relation to adiposity are scarce in the UK. This study examined cross-sectional associations of anthropometric indices with Se-status biomarkers in a nationally representative sample of 1045 (577 female, 468 male) British Caucasian adults aged 19-64 who participated in the 2000-2001 National Diet and Nutrition Survey. Median (1(st), 3(rd) Quartile) values for whole-blood glutathione peroxidase [GPx] activity, plasma and erythrocyte Se concentrations were 120.0 (103.0, 142.4) nmol·mgHb(-1)·min(-1), 1.08 (0.98, 1.20) µmol/L and 1.62 (1.38, 1.91) µmol/L, respectively. For males, values were 119.0 (100.0, 141.0) nmol·mgHb(-1)·min(-1), 1.09 (0.99, 1.22) µmol/L and 1.54 (1.34, 1.79) µmol/L, respectively; for females 121.0 (105.0, 145.0) nmol·mgHb(-1)·min(-1), 1.07 (0.97, 1.18) µmol/L and 1.71 (1.43, 1.99) µmol/L, respectively. Multivariate adjusted mean differences (95%CI) in whole-blood GPx between the highest (>30kg/m(2)) and lowest (<25kg/m(2)) categories of body mass index [BMI] and highest (96.5-139.2cm) and lowest (52.2-78.1cm) quartiles of waist circumference [WC] were -7.9 (-13.2, -2.7) nmol·mgHb(-1)·min(-1) and -9.7 (-16.2, -3.2) nmol·mgHb(-1)·min(-1), respectively. Difference (95%CI) in plasma Se between the 3(rd) (87.5-96.4cm) and lowest quartiles of WC was -0.04 (-0.08, -0.03) µmol/L. Difference (95%CI) in RBC Se between the highest (0.91-1.11) and lowest (0.53-0.76) quartiles of waist-to-hip ratio [WHR] was 0.10 (0.00, 0.20) µmol/L. Similar results were observed in gender and menopausal-status subgroup analyses. The inverse association between plasma Se and WC and the positive association between RBC Se and WHR will need confirmation. Findings suggest associations between low whole-blood GPx activity and higher measures of general and central adiposity. Further experimental and randomised studies are needed to deduce mechanisms and infer causality.
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Hydrogen selenide (H2Se) as one of the endogenous gaseous signaling molecules for antibacterial gas therapy, faces limitations such as high‐dose toxicity and short half‐life. Herein, a polymeric H2Se delivery nanogel (H2Se‐NG) incorporated with aldehyde‐modified selenobenzamide (SeAs) is designed for multidrug resistant (MDR) related healthcare‐associated infections (HAIs) treatment. H2Se‐NG facilitates a dual‐cascade responsive release of H2Se over 72 h, effectively addressing the safety issues caused by the rapid hydrolysis of traditional inorganic H2Se delivery methods. In vitro and in vivo studies demonstrate that nontoxic doses of H2Se‐NG at 150 µg mL⁻¹ not only eliminated over 99% of MDR bacteria and their biofilm within 8 h while reducing levels of proinflammatory cytokines postinfection. Additionally, RNA sequencing results reveal that the released H2Se induces oxidative stress at infection site, kills biofilm‐embedded methicillin‐resistant Staphylococcus aureus (MRSA) and leads biofilm elimination by activating biofilm dispersion genes, suggesting the potential of H2Se‐NG as a promising strategy in antibacterial gas therapy.
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The strategic combination of more than one therapeutic modality has emerged as the smart tool for anticancer therapy. Herein, we have synthesized and characterized a new iron(III) complex-functionalized selenium nanowire...
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Selenium (Se) is an essential element for maintaining human health. The biological effects and toxicity of Se compounds in humans are related to their chemical forms and consumption doses. In general, organic Se species, including selenoamino acids such as selenomethionine (SeMet), selenocystine (SeCys2), and Se-methylselenocysteine (MSC), could provide greater bioactivities with less toxicity compared to those inorganics including selenite (Se IV) and selenate (Se VI). Plants are vital sources of organic Se because they can accumulate inorganic Se or metabolites and store them as organic Se forms. Therefore, Se-enriched plants could be applied as human food to reduce deficiency problems and deliver health benefits. This review describes the recent studies on the enrichment of Se-containing plants in particular Se accumulation and speciation, their functional properties related to human health, and future perspectives for developing Se-enriched foods. Generally, Se’s concentration and chemical forms in plants are determined by the accumulation ability of plant species. Brassica family and cereal grains have excessive accumulation capacity and store major organic Se compounds in their cells compared to other plants. The biological properties of Se-enriched plants, including antioxidant, anti-diabetes, and anticancer activities, have significantly presented in both in vitro cell culture models and in vivo animal assays. Comparatively, fewer human clinical trials are available. Scientific investigations on the functional health properties of Se-enriched edible plants in humans are essential to achieve in-depth information supporting the value of Se-enriched food to humans.
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A series of seleno-biotin analogs were synthesized and their anticancer activity and mode of action were assessed using ovarian cancer cells. Compound 2, out of the other analogs, in direct comparison to biotin alone, more effectively reduced the cell viability and induced apoptosis in ovarian cancer cell lines in a dose dependent manner as demonstrated by the cell viability assay, trypan blue dye exclusion assay, Annexin V/7-AAD, and Caspase 3/7 apoptosis assays. Furthermore, compound 2 showed efficacy better than 5-fluorouracil (5-FU) and similar to cisplatin, in vitro; notably it was more cytotoxic to drug-resistant Hey A8 cells than cisplatin. The cytotoxicity of compound 2 was primarily mediated by reactive oxygen species (ROS) as demonstrated by DCFDA based ROS estimation. Biotin receptors (BR) saturation and the use of a BR negative cell line showed a significant decline in the cytotoxic ativity of the compound 2, confirming that its activity is BR-mediated. These experiments demonstrated that selenium modified biotin which contains an ester linked redox cycling selenocyanate group has the potential for human therapeutic applications against ovarian and other cancers over-expressing BR.
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To understand the effects of micronutrients have particular biological functions that are involved mainly in the antioxidant system, which has essential implications for the development of diseases, this study investigated how vitamin E, selenium, and their combination affect lipid, protein, carbohydrate, and malondialdehyde (MDA) content; antioxidant enzyme (catalase [CAT], superoxide dismutase [SOD], glutathione-S-transferase [GST]) activity; and the total hemocyte count (THC) in larvae of Galleria mellonella L. fed different diets. Diet 1 (100 µg of selenium) significantly decreased carbohydrate and lipid content. Diets 2 (100 µg of vitamin E), 3 (100 µg of selenium and vitamin E each), and 5 (Tween 80) did not significantly affect protein and carbohydrate content. Diet 2 significantly increased the lipid content compared to diet 4 (control). Diet 1 increased CAT, SOD, and GST activity and MDA content (highest at 27.64 nmol/mg protein). Diet 2 significantly decreased SOD activity and MDA content compared to other diets. Diet 1 significantly decreased the THC compared to other diets. These results suggested that selenium changes oxidative stress parameters, energy reserves, and THC in G. mellonella. These changes could be a physiological adaptation against selenium-induced oxidative stress. Vitamin E could play a protective role in selenium toxicity.
Chapter
Colloidal selenium, was first used to treat cancer as early as 1911 in both humans and mice. Selenium was identified as the toxic component in forage plants of sheep, cattle, and horses in the 1930s. The animal toxicity of selenium compounds was determined to be from the metabolism by animals of the elevated concentrations of Se-methylselenocysteine and selenomethionine in plants. The metabolism of both Se-methylselenocysteine and selenomethionine by animals gives rise to the metabolite, methylselenide (CH3Se-), which if in sufficient concentration oxidizes thiols and generates superoxide and other reactive oxygen species. Cancer cells that may overly express methionine gamma-lyase, or beta-lyase (methioninase), by induced viral genomic expression, are susceptible to free radical-induced apoptosis from selenomethionine or Se-methylselenocysteine supplementation.
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Stable and controllable nitric oxide (NO) release at the physiological level from biomedical materials remains to be a challenge for the NO-based therapy. NO-generating polymers have great potential to achieve this goal because they can catalytically decompose endogenous S-nitrosothiols (RSNOs) into NO. However, the current catalytic surfaces based on such polymers often suffer from loss of catalytic sites, which can influence the stability of NO release in the long-term application. In this work, we proposed a novel strategy to enhance the catalytic stability of NO-catalytic materials by incorporating catalytic sites into polymer backbone. Selenium-containing polyurethane (PU-Se) was synthesized by using catalyst 2, 2’-diselenodiethanol (SeDO) as chain extender. A series of PU/PU-Se blend films were prepared to investigate the effect of PU-Se content on the catalytic properties. The blend films exhibited excellent catalytic activity, and also showed outstanding catalytic stability in comparison with PU coated by diselenide/dopamine (PU-PDA-Se). Among these blend films, PU-Se-10 gave a stable NO release rate of 5.05 × 10-10 mol cm-2 min-1 after exposure to PBS buffer for 30 days. Moreover, the PU/PU-Se films demonstrated enhanced anti-platelets effects, low hemolysis ratio, excellent biocompatibility, and similar mechanical properties to PU. It is expected the newly designed PU-Se has great potential in generating stable NO release at the physiological level for the long-term application of blood-contacting medical devices.
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The metalloid element, selenium (Se) is in many ways special and perhaps because of this its research in human and plant systems is of great interest. Despite its non-essentiality, higher plants take it up and metabolize it via sulfur pathways, but higher amounts of Se cause toxic symptoms in plants. However, the molecular mechanisms of selenium phytotoxicity have been only partly revealed; the data obtained so far point out that Se toxicity targets the plant proteome. Besides seleno- and oxyproteins, nitroproteins are also formed due to Se stress. In order to minimize proteomic damages induced by Se, certain plants are able to redirect selenocysteine away from protein synthesis thus preventing Se-protein formation. Additionally, the damaged or malformed selenoproteins, oxyproteins and nitroproteins may be removed by proteasomes. Based on the literature this review sets Se toxicity mechanisms into a new concept and it draws attention to the importance of Se-induced protein-level changes.
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We have previously demonstrated that selenium nanoparticles (SeNPs) administered via oral route possess similar capacities of increasing selenoenzyme activities as the extensively examined sodium selenite, selenomethionine and methylselenocysteine, and yet display the lowest toxicity among these selenium compounds in mouse models. However, the low toxicity of SeNPs found in mammalian systems would lead to the interpretation that the punctate distribution of elemental selenium found in cultured cancer cells subjected to selenite treatment that triggers marked cytotoxicity represents a detoxifying mechanism. The present study found that SeNPs could be reduced by the thioredoxin- or glutaredoxin-coupled glutathione system to generate ROS. Importantly, ROS production by SeNPs in these systems was more efficient than by selenite, which has been recognized as the most redox-active selenium compound for ROS production. This is because multiple steps of reduction from selenite to selenide anion are required; whereas only a single step reduction from the elemental selenium atom to selenide anion is needed to trigger redox cycling with oxygen to produce ROS. We thus speculated that accumulation of SeNPs in cancer cells would result in a strong therapeutic effect, rather than serves a detoxification function. Indeed, we showed herein that preformed SeNPs generated a potent therapeutic effect in a mouse model due to rapid, massive and selective accumulation of SeNPs in cancer cells. Overall, for the first time, we demonstrate that SeNPs have a stronger pro-oxidant property than selenite and hyper-accumulation of SeNPs in cancer cells can generate potent therapeutic effects.
Article
In this study, we investigated the role of glutathione (GSH) and phytochelatins (PCs) on the detoxification of selenite using Arabidopsis thaliana. The wild-type (WT) of Arabidopsis thaliana and its mutants (glutathione deficient Cad 2–1 and phytochelatins deficient Cad 1–3) were separately exposed to varying concentrations of selenite and arsenate and jointly to both toxicants to determine their sensitivities. The results of the study revealed that, the mutants were about 20-fold more sensitive to arsenate than the WT, an indication that the GSH and PCs affect arsenate detoxification. On the contrary, the WT and both mutants showed a similar level of sensitivity to selenite, an indication that the GSH and PCs do not significantly affect selenite detoxification. However, the WT is about 8 times more sensitive to selenite than to arsenate, and the mutants were more resistant to selenite than arsenate by a factor of 2. This could not be explained by the accumulation of both elements in roots and shoots in exposure experiments. The co-exposure of the WT indicates a synergistic effect with regards to toxicity since selenite did not induce PCs but arsenic and selenium compete in their PC binding as revealed by speciation analysis of the root extracts using HPLC–ICP–MS/ESI–MS. In the absence of PCs an antagonistic effect has been detected which might suggest indirectly that the formation of Se glutathione complex prevent the formation of detrimental selenopeptides. This study, therefore, revealed that PC and GSH have only a subordinate role in the detoxification of selenite.
Article
Selenium assimilation in plants is facilitated by several enzymes that participate in the transport and assimilation of sulfate. Manipulation of genes that function in sulfur metabolism dramatically affects selenium toxicity and accumulation. However, it has been proposed that selenite is not reduced by sulfite reductase. Instead, selenite can be non-enzymatically reduced by glutathione, generating selenodiglutathione and superoxide. The damaging effects of superoxide on iron-sulfur clusters in cytosolic and mitochondrial proteins are well known. However, it is unknown if superoxide damages chloroplastic iron-sulfur proteins. The goals of this study were twofold: to determine whether decreased activity of sulfite reductase impacts selenium tolerance in Arabidopsis, and to determine if superoxide generated from the glutathione-mediated reduction of selenite damages the iron-sulfur cluster of ferredoxin. Our data demonstrate that knockdown of sulfite reductase in Arabidopsis does not affect selenite tolerance or selenium accumulation. Additionally, we provide in vitro evidence that the non-enzymatic reduction of selenite damages the iron-sulfur cluster of ferredoxin, a plastidial protein that is an essential component of the photosynthetic light reactions. Damage to ferredoxin's iron-sulfur cluster was associated with formation of apo-ferredoxin and impaired activity. We conclude that if superoxide damages iron-sulfur clusters of ferredoxin in planta, then it might contribute to photosynthetic impairment often associated with abiotic stress, including toxic levels of selenium.
Article
Selenite can enhance selenium nutrition level of crops, but excessive selenite may be toxic to plant growth. To elucidate the mechanisms underlying the role of selenite in production and detoxification of oxidative toxicity, peanut seedlings were developed with sodium selenite (0, 3, and 6 mg/L). The effects of selenite on antioxidant capacity, transcript levels of antioxidant enzyme genes, and enzyme activities in hypocotyl were investigated. The CuZn-SOD, GSH-Px, GST, and APX gene expression levels and their enzyme activities in selenite treatments were 1.0 to 3.6 folds of the control. Selenite also significantly increased the glutathione and ascorbate concentrations by mediating the ascorbate-glutathione cycle, and the selenite-induced hydrogen peroxide may act as a second messenger in the signaling pathways. Our work has revealed a complex antioxidative response to selenite in peanut seedling. Understanding these mechanisms may help future research in increasing selenite tolerance and selenium accumulation in peanut and other crops.
Article
Juvenile Pagrus major (mean length 15.8±1.6cm, and mean weight 90.4±4.7g) were exposed for 4weeks with waterborne selenium concentration (0, 50, 100, 200, and 400μgL(-1)). In oxidative stress indicators, liver and gill superoxide dismutase (SOD) activity and glutathione S-transferase (GST) activity were markedly elevated after 4weeks exposure. Similarly, glutathione (GSH) level in liver and gill was also increased in response to the highest Se exposure after 4weeks exposure. In neurotoxicity, AChE activity was inhibited in brain and muscle tissues by waterborne Se exposure. In the non-specific immune responses, lysozyme activity of plasma and kidney was significantly increased by waterborne Se exposure. Peroxidase activity and anti-protease activity were decreased at high Se concentration. The results suggest that waterborne Se exposure can induce significant oxidative stress, inhibition of AChE activity, and immunological alterations. Copyright © 2015 Elsevier Ltd. All rights reserved.
Article
Organoselenium chemistry has proven to be a powerful tool for organic synthesis over several decades. Nevertheless, the use of selenating reagents has often been limited by a generally bad reputation surrounding selenium toxicity and its potential impact on the environment. In this review we would like to stress some aspects that will encourage the reader to discover an unexpected “Green Side” to this element and the chemistry connected with its organic derivatives.
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Selenocystamine (RSe-SeR) was shown to catalyze the oxygen-mediated oxidation of excess GSH to glutathione disulfide, at neutral pH and ambient PO2. This glutathione oxidase activity required the heterolytic reduction of the diselenide bond, which produced two equivalents of the selenolate derivative selenocysteamine (RSe-), via the transient formation of a selenenylsulfide intermediate (RSe-SG). Formation of RSe- was the only reaction observed in anaerobic conditions. At ambient PO2, the kinetics and stoichiometry of GSSG production as well as that of GSH and oxygen consumptions demonstrated that RSe- performed a three-step reduction of oxygen to water. The first step was a one-electron transfer from RSe- to dioxygen, yielding superoxide and a putative selenyl radical RSe., which decayed very rapidly to RSe-SeR. In the second step, RSe- reduced superoxide to hydrogen peroxide through a much faster one-electron transfer, also associated with the decay of RSe. to RSe-SeR. The third step was a two-electron transfer from RSe- to hydrogen peroxide, again much faster than oxygen reduction, which resulted in the production of RSe-SG, presumably via a selenenic acid intermediate (RSeOH) which was trapped by excess GSH. This third step was studied on exogenous hydroperoxide in anaerobic conditions, and it could be eliminated from the glutathione oxidase cycle in the presence of excess catalase. The role of RSe- as a one- and two-electron reductant was confirmed by competitive carboxymethylation with iodoacetate. RSe- was able to rapidly reduce ferric cytochrome c to its ferrous derivative. The overall rate of catalytic glutathione oxidation was GSH concentration dependent and oxygen concentration independent. Excess glutathione reductase and NADPH increased the catalytic oxidation of GSH, probably by switching the rate-limiting step from selenylsulfide to diselenide cleavage. When GSH was substituted for dithiothreitol, it was shown to reduce RSe-SeR to RSe- in a fast and quantitative reaction, and selenocystamine behaved as a dithiothreitol oxidase, whose catalytic cycle was dependent on oxygen concentration. The oxidase cycle of glutathione was inhibited by mercaptosuccinate, while that of dithiothreitol was not affected. When mercaptosuccinate was substituted for GSH, a stable selenenylsulfide was formed. These observations suggest that electrostatic interactions affect the reductive cleavage of diselenide and selenenylsulfide linkages. This study illustrates the ease of one-electron transfers from RSe- to a variety of reducible substrates. Such free radical mechanisms may explain much of the cytotoxicity of alkylselenols, and they demonstrate that selenocystamine is a poor catalytic model of the enzyme glutathione peroxidase.
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Lucigenin is most noted for its wide use as a chemiluminescent detector of superoxide anion radical (O2-.) production by biological systems. However, its validity as a O2-.-detecting probe has recently been questioned in view of its ability to undergo redox cycling in several in vitro enzymatic systems, which produce little or no O2-.. Whether and to what extent lucigenin redox cycling occurs in systems that produce significant amounts of O2-. has not been carefully investigated. We examined and correlated three end points, including sensitive measurement of lucigenin-derived chemiluminescence (LDCL), O2 consumption by oxygen polarography, and O2-. production by 5-(diethoxyphosphoryl)-5-methyl-1-pyrroline-N-oxide spin trapping to characterize the potential of lucigenin to undergo redox cycling and as such to act as an additional source of O2-. in various enzymatic and cellular systems. Marked LDCL was elicited at lucigenin concentrations ranging from 1 to 5 microM in all of the O2-.-generating systems examined, including xanthine oxidase (XO)/xanthine, lipoamide dehydrogenase/ NADH, isolated mitochondria, mitochondria in intact cells, and phagocytic NADPH oxidase. These concentrations of lucigenin were far below those that stimulated additional O2 consumption or O2-. production in the above systems. Moreover, a significant linear correlation between LDCL and superoxide dismutase-inhibitable cytochrome c reduction was observed in the XO/ xanthine and phagocytic NADPH oxidase systems. In contrast to the above O2-.-generating systems, no LDCL was observed at non-redox cycling concentrations of lucigenin in the glucose oxidase/glucose and XO/NADH systems, which do not produce a significant amount of O2-.. Thus, LDCL still appears to be a valid probe for detecting O2-. production by enzymatic and cellular sources.
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In recent years, the role of selenium in the prevention of a number of degenerative conditions including cancer, inflammatory diseases, thyroid function, cardiovascular disease, neurological diseases, aging, infertility, and infections, has been established by laboratory experiments, clinical trials, and epidemiological data. Most of the effects in these conditions are related to the function of selenium in antioxidant enzyme systems. Replenishing selenium in deficiency conditions appears to have immune-stimulating effects, particularly in patients undergoing chemotherapy. However, increasing the levels of selenoprotein antioxidant enzymes (glutathione peroxidase, thioredoxin reductase, etc.) appears to be only one of many ways in which selenium-based metabolites contribute to normal cellular growth and function. Animal data, epidemiological data, and intervention trials have shown a clear role for selenium compounds in both prevention of specific cancers and antitumorigenic effects in post-initiation phases of cancer.
Chapter
Increased lipid peroxidation caused by selenite treatment was observed in vivo (Dougherty and Hoekstra 1982) and in vitro (Bunyan et al. 1960; Stacey and Klaassen 1981; Seko 1986). In vitro treatment of cells with selenite resulted in the decreased content of reduced glutathione and NADPH (Tsen and Collier 1960; Anundi et al. 1984), which are important in protecting cells against oxidation. However, the decrease in GSH concentration did not always relate to cell damage (Tsen and Collier 1960; Seko 1986) or lipid peroxidation (Seko 1986) in erythrocyte suspension. On the other hand, the importance of GSH (Young et al. 1981) or reactive sulfhydryls of hemoglobin (Seko 1986) have been considered to play an important role in selenite induced in vitro hemolysis. In order to estimate the relationship between GSH and the selenite-induced lipid peroxidation, we have examined the active oxygen generation in the mixture of selenite and GSH by using luminol- or lucigenin-dependent chemiluminescence (CL) as an indicator.
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Recent studies have implicated apoptosis as one of the most plausible mechanisms of the chemopreventive effects of selenium compounds, and reactive oxygen species (ROS) as important mediators in apoptosis induced by various stimuli. In the present study, we demonstrate that Se-methylselenocysteine (MSC), one of the most effective selenium compounds at chemoprevention, induced apoptosis in HL-60 cells and that ROS plays a crucial role in MSC-induced apoptosis. The uptake of MSC by HL-60 cells occurred quite early, reaching the maximum within 1 h. The dose-dependent decrease in cell viability was observed by MSC treatment and was coincident with increased DNA fragmentation and sub-G1 population. 50 μM of MSC was able to induce apoptosis in 48% of cell population at a 24 h time point. Moreover, the release of cytochrome c from mitochondria and the activation of caspase-3 and caspase-9 were also observed. The measurement of ROS by dichlorofluorescein fluorescence revealed that dose- and time-dependent increase in ROS was induced by MSC. N-acetylcysteine, glutathione, and deferoxamine blocked cell death, DNA fragmentation, and ROS generation induced by MSC. Moreover, N-acetylcysteine effectively blocked caspase-3 activation and the increase of the sub-G1 population induced by MSC. These results imply that ROS is a critical mediator of the MSC-induced apoptosis in HL-60 cells.
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The element selenium (Se) was recognized only 40 years ago as being essential in the nutrition of animals and humans. It is recognized as being an essential component of a number of enzymes, in which it is present as the amino acid selenocysteine. Se compounds have also been found to inhibit tumorigenesis in a variety of animal models, and recent studies indicate that supplemental Se in human diets may reduce cancer risk. The antitumorigenic activities have been associated with Se intakes that correct nutritionally deficient status in animals, as well as higher intakes that are substantially greater than those associated with maximal expression of the selenocysteine-containing enzymes. Therefore, it is proposed that while some cancer protection, particularly that involving antioxidant protection, involves selenoenzymes, specific Se metabolites, which are produced in significant amounts at relatively high Se intakes, also discharge antitumorigenic functions. According to this two-stage model of the roles of Se in cancer prevention, individuals with nutritionally adequate Se intakes may benefit from Se supplementation. Evidence for chemoprevention by Se and for the apparent mechanisms underlying these effects is reviewed to the end of facilitating the development of the potential of Se compounds as cancer chemopreventive agents.
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Selenium is considered to be one of the most promising micronutrients for cancer prevention and therapy, based on evidence from epidemiological studies, laboratory-based research and clinical trial intervention. There are ample reports of selenium methionine and sodium selenite's ability to induce apoptosis in various cancers in vitro. There are a few reports in the literature on the effects of selenium on established glioma cell lines but none on biopsy-derived short-term brain tumour cultures. In this in vitro study the effects of a range of concentrations (2-10 microg/ml) of sodium selenite were investigated in one low-passage culture of biopsy-derived glioma cells (IPSB-18, an anaplastic astrocytoma, P 18-22) and a normal human brain cell culture (CC2565, P11). Results from 2 viability assays, 3[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and sulphorodamine B (SRB) consistently showed that the IC50 for selenium in the astrocytoma was approximately 5 microg/ml whilst the normal brain cells were unaffected by selenium in the range of concentrations studied. Time-lapse video microscopy revealed that, while at 4 microg/ml selenium, the time taken to achieve 100% cell death was 17 h, with increasing concentrations of selenium from 6 to 8 microg/ml and finally at 10 microg/ml the IPSB-18 cells rounded up and died much more quickly. The time taken to achieve 100% cell death was 7 h, 7 h and 6 h, respectively, suggesting that the effect was similar at higher concentrations. Flow cytometry indicated that cell death was by apoptosis. RT-PCR results showed downregulation of the gene expression of 6 matrix metalloproteases (MMP2, 9, 14, 15, 16, 24), their inhibitors, TIMPs and epidermal growth factor receptor, in IPSB-18 cells treated with 2, 4 and 8 microg/ml of selenium. Collectively, the data in this study suggests that selenium, not only induces tumour cell-specific apoptosis but also has anti-invasive potential.
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Selenite at 10-5-10-6 M is an effective catalyst for the reduction of cytochrome c by glutathione (GSH). Selenocystine was more effective and selenate less effective than selenite. Selenomethionine had no catalytic effect. A strong catalysis of selenite on the reduction of cytochrome c was still observed when mercaptoethylamine or cysteine replaced GSH as the thiol, but smaller catalytic effects of Se were seen when thioglycolate or mercaptoethanol was used in lieu of GSH. Cysteine was a more active reductant for cytochrome c than GSH either in the presence or absence of Se. Dithiothreitol and 2,3-dimercaptopropanol were both potent reducing agents for cytochrome c without Se, but a catalytic effect due to Se could still be demonstrated with these dithiols. Cyanide at 5 × 10-6 M caused a 50% inhibition in Se-catalyzed reduction of cytochrome c by GSH. Selenocyanate was a relatively poor catalyst for the reduction of cytochrome c by GSH. Cd2+ and Hg2+ were moderately good inhibitors of Se-catalyzed reduction of cytochrome c by GSH, but arsenite had little or no inhibitory effect even at levels as high as 10-2 M. A mechanism for the selenite-catalyzed reduction of cytochrome c by GSH is presented which involves the formation of a selenopersulfide intermediate. Selenium may act in vivo as selenopersulfide to facilitate the transfer of electrons from sulfhydryl groups to cytochrome c.
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Cysteine and glutathione reduce selenocystine to selenocysteine, with reaction equilibriums attained rapidly. The extent of reduction is reported as a function of the concentrations of the sulfhydryl compounds, and equilibrium constants are given. The implications of the results are discussed in terms of their possible significance to the function of selenium in biological systems.
Article
Rat erythrocytes were incubated in vitro with various selenium compounds at 37 degrees. Hemolysis occurred with some selenium compounds but not with corresponding sulfur analogues. Selenite induced more rapid loss of intracellular glutathione (GSH) than did selenocystine but was less hemolytic. Cystine caused neither loss of intracellular GSH nor hemolysis. Addition of GSH to the incubation medium enhanced hemolysis by selenite and selenium dioxide but inhibited hemolysis by selenocystine. Inclusion of glucose in the incubation medium also inhibited selenocystine-induced lysis of erythrocytes from both selenium-supplemented rats and selenium-deficient rats. The results suggest a relationship between the oxidation of intracellular GSH and the hemolysis by selenocystine, selenite and selenium dioxide.
Article
Selenium toxicity was first confirmed in 1933 to occur in livestock that consumed plants of the genus Astragalus, Xylorrhiza, Oonopsis, and Stanleya in the western regions of the United States. In 1957 selenium was identified as an essential nutrient for laboratory rats and soon thereafter for chickens and sheep. Essentiality for mammalian species was established in 1973 with the discovery that the enzyme glutathione peroxidase contained selenium. During this same period of time, human epidemiological evidence suggested that selenium possessed anticarcinogenic effects. Since the 1970s, many animal studies have confirmed the human epidemiologic evidence that selenium compounds possess carcinostatic activity. Less progress has been made in explaining why many of these compounds of selenium are toxic and why these same compounds are carcinostatic. In 1988 the observation was made that oxidation of glutathione by selenite produced superoxide, opening a new area for selenium research. This present paper, drawing information from the literature on selenium metabolism in plants and animals, selenium toxicology, selenium cytotoxicity, and selenium carcinostatic activity in animals over the last sixty years, sets forth a probable biochemical catalytic mechanism that encompasses both selenium toxicity and selenium carcinostatic activity. The thesis presented here for scrutiny is that compounds of selenium are toxic owing to their prooxidant catalytic activity to produce superoxide (O2.-), hydrogen peroxide, and very likely other cascading oxyradicals. The toxicity of selenium compounds is countered by plant and animal methylation reactions and antioxidant defenses. As carcinostasis is mostly known to occur at supranutritional levels of selenium in animals, carcinostasis appears to be directly correlated to selenium toxicity. The catalytic toxic selenium specie appears to be the metabolic selenide (RSe-) anion.
Article
Univalent oxidation of luminol and univalent reduction of lucigenin must precede reaction with O2.- if that reaction is to lead to luminescence. The assumption that luminol or lucigenin, per se, reacts with O2.- in a way leading to luminescence is incorrect, and leads to misinterpretation of results. The chemical reactions leading to the O2(.-)-dependent luminescences of luminol and of lucigenin are discussed.
Article
Sodium selenite, sodium selenate, selenocystine and selenomethionine were tested for their abilities to generate superoxide by the oxidation of glutathione and other thiols in the absence and presence of cells of the human mammary tumor cell line HTB123/DU4475. Free radical generation was measured by lucigenin- or luminol-amplified chemiluminescence. In the absence of tumor cells, lucigenin-dependent chemiluminescence was observed from the reaction of selenite with the thiols glutathione, 2-mercaptoethanol and L-cysteine, but not with oxidized glutathione. Superoxide dismutase, catalase, and glutathione peroxidase all suppressed the observed chemiluminescence; but when these enzymes were heat inactivated they had little suppressive inhibition on chemiluminescence. Luminol-dependent chemiluminescence from the reaction of selenite with glutathione was much less than that observed by lucigenin-amplified chemiluminescence. In the presence of the HTB123/DU4475 mammary tumor cells, lucigenin-dependent chemiluminescence was observed from the reactions of selenite and selenocystine with glutathione which were 5 and 23 times greater than their respective reactions with glutathione in the absence of tumor cells. The enhanced chemiluminescence generated by selenite and selenocystine in the presence of the tumor cells was also suppressed by superoxide dismutase, catalase and glutathione peroxidase. These data suggest that a free radical, the superoxide anion (O2-), and H2O2 are produced from the reaction of selenite and selenocystine with glutathione. These free radical reactions may account for the toxicity of selenite and selenocystine in vitro in comparison to a near absence of acute tumor cell toxicity and superoxide generation by selenate and selenomethionine with thiols. Enhanced chemiluminescence in the presence of tumor cells may be an expression of cellular selenium metabolism and the capability of cells to form selenium metabolites that more easily oxidize glutathione and other thiols producing reactive free radicals and peroxides.
Article
Eight naturally occurring prenylflavonoids were tested for their antiplatelet activities in rabbit platelet suspension. Cyclomorusin and artomunoxanthone showed strong inhibition of platelet-activating factor (PAF; 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) induced platelet aggregation. Cyclomulberrin, dihydroisocycloartomunin, cyclocommunol and cyclocommunin showed strong inhibition of arachidonic acid (AA)- and collagen-induced platelet aggregation. Cyclomorusin also inhibited markedly collagen-induced platelet aggregation. Cyclocommunin, dihydroisocycloartomunin and cyclomulberrin also showed slight but significant antiplatelet effects on the aggregation induced by PAF. Of the compounds tested, cyclocommunin exhibited the most potent inhibition of platelet aggregation induced by collagen (IC50 = 14.4 microM) and AA (IC50 = 12.5 microM). Thromboxane B2 formation caused by AA was suppressed by cyclocommunin and artomunoxanthone.
Article
A selenium (Se)-containing immunoconjugate of a human anti-erythrocyte membrane antibody (Ab-Se) has been synthesized via oxidation of the carbohydrate moieties of the antibody and covalent coupling with selenocystamine. The isolated Ab-Se immunoconjugate is shown to be more hemolytic than is selenocystamine when expressed on equivalent selenium basis. Native antibody preincubated with the human erythrocytes prevented hemolysis induced by the Ab-Se immunoconjugate. As observed microscopically, the Ab-Se immunoconjugate caused extensive damage to the erythrocyte membrane and lysis. The cytotoxicity of Se toward the human erythrocytes is believed to be caused initially by the localized generation of superoxide (O2.-) within the cell membrane. This is the first demonstration of site-directed immunoselectivity of Se cytotoxicity and demonstrates the potential for a free radical pharmacology based on localized Se-generated O2.-.
Article
Selenium, both organic and inorganic forms, inhibit mammary tumorigenesis in vivo and mammary cell growth in vitro. In the present study, sodium selenite was compared to methylselenocysteine (MSC) for their individual effects on cell growth, cdc2/cdk2 kinase activities and the levels of cyclins D1, E and A bound to cdk2 in a mouse mammary epithelial cell culture model. Selenite arrested the growth of cells in S-G2-M phase in contrast to MSC which arrested or delayed the cells in G1. In MSC-treated cells there was a 57% drop in the cdk2 kinase activity accompanied by a 73.5% decrease in cyclin E-cdk2 content as compared to the control cells. Selenite treatment increased the cdk2 kinase activity by 30% without any appreciable change in either of the cyclins D1, E or A bound to cdk2 when compared to the control cells. These data support the hypothesis that selenite and MSC have distinct modes of action in the inhibition of cell growth in vitro. Selenite has a strong genotoxic effect on the tumor cells; in contrast, MSC appears to inhibit cell growth via specific inhibition of cell cycle regulatory proteins.
Article
Selenium (Se) and many of its compounds are among the most toxic of nutrients. Selenium toxicity was first described in range animals in the western United States in the 1930's which consumed "selenium accumulator" plants of the genus Astragalus, Xylorrhiza, Oonopsis, and Stanleya. Selenites and selenates from the soil accumulate in these plants primarily as methylated selenium compounds and plants evolve dimethyldiselenide and dimethylselenide. Dietary selenium, primarily as selenomethionine and selenocysteine for humans fulfill the dietary requirement for selenoenzymes and proteins. In humans and animals excessive dietary selenium may be toxic. In vitro, selenium compounds such as selenite, selenium dioxide and diselenides react with thiols, such as glutathione, producing superoxide and other reactive oxygen species. This catalytic reaction of selenium compounds with thiols likely accounts for selenium toxicity to cells ex vivo and in vivo where the major glutathione producing organ, the liver, is also the major target organ of selenium toxicity. Selenium enzymes and selenoethers that do not readily form a selenide (RSe-) anion and compounds such as Ebselen where selenium is sequestered, are not toxic. Methylation of selenium by both plants and animals serves to detoxify selenium by generating methylselenides. Alternatively, full reduction of Se to elemental selenium (Se0) as done by some bacteria and the formation of heavy metal selenides such as Ag2Se or Hg2Se, results in a non-catalytic non-toxic form of selenium. This catalytic prooxidant attribute of some selenium compounds appears to account for its toxicity when such activity exceeds plant and animal methylation reactions and antioxidant defenses. This prooxidant activity may also account for cellular apoptosis and may provide a useful pharmaceutical application for selenium compounds as antibacterial, antiviral, antifungal and anticancer agents.
Article
The article reviews the progress in basic research of selenium and cancer prevention during the past decade. Special emphasis is placed on the following four major areas of discussion: 1) chemical forms of selenium and anticarcinogenic activity; 2) selenium-enriched food; 3) in vitro effects of selenite vs. monomethylated selenium; and 4) aromatic selenium compounds. It is clear that basic research has contributed new knowledge to our understanding of selenium biochemistry, anticancer efficacy and regulation of cell growth. Some of this information could be ready for incorporation into the design of a second-generation selenium trial in humans.
Article
The cancer chemopreventive effect of selenium cannot be fully accounted for by the role of selenium as a component of the antioxidant enzyme glutathione peroxidase, which suggests that chemoprevention occurs by another mechanism. Several studies have shown that thiol oxidation and free radical generation occur as a consequence of selenium catalysis and toxicity. In the present study, we evaluated three different selenium compounds; selenite, selenocystamine, and selenomethionine to determine the relative importance of the prooxidative effects of these compounds with regard to their ability to induce apoptosis. The experimental results suggest that, in addition to supporting an increased activity of glutathione peroxidase, an antioxidant function that the three selenium compounds did with equal efficacy, catalytic selenite, and selenocystamine generated 8-hydroxydeoxyguanosine DNA adducts, induced apoptosis and were found to be cytotoxic in mouse keratinocytes. The noncatalytic selenomethionine was not cytotoxic, did not generate 8-hydroxydeoxyguanosine adducts and did not induce cellular apoptosis at any of the selenium concentrations studied. In keratinocytes, apoptosis may be initiated by superoxide (O2*-) and oxidative free radicals that are generated by selenite and selenocystamine, but not by selenomethionine.
Article
The relevance of lucigenin (bis-N-methylacridinium nitrate)-amplified chemiluminescence (CL) as a specific assay for superoxide ion has recently been disputed (S. I. Liochev and I. Fridovich, Arch. Biochem. Biophys. 337, 115-120, 1997). These authors suggested that the redox cycling of lucigenin can lead to the formation of additional amount of superoxide ion. However, thermodynamic consideration shows that the equilibrium for the reaction O*-2 + Luc2+ if O2 + Luc*+ is completely shifted to the right (Keq = 10(6)); therefore, the redox cycling of lucigenin is of no importance. This conclusion is supported by the study of the effects of lucigenin on cytochrome c reduction by xanthine oxidase. It was found that lucigenin did enhance the rate of cytochrome c reduction with xanthine as a substrate, but it did not increase the rate of xanthine oxidation. When NADH was used as a substrate, lucigenin inhibited the SOD-dependent component of cytochrome c reduction and enhanced both the SOD-independent cytochrome c reduction and NADH oxidation, being a sole acceptor of an electron from the enzyme. All these findings indicate the extremely low probability of lucigenin redox cycling. In our opinion, lucigenin-amplified CL remains the most sensitive and highly specific test for superoxide formation in biological systems.
Article
Selenocysteine-containing enzymes that have been identified in mammals include the glutathione peroxidase family (GPX1, GPX2, GPX3, and GPX4), one or more iodothyronine deiodinases and two thioredixin reductases. Selenoprotein P, a glycoprotein that contains 10 selenocysteine residues per 43 kDa polypeptide and selenoprotein W, a 10 kDa muscle protein, are unidentified as to function. Levels of all of these selenocysteine-containing proteins in various tissues are affected to different extents by selenium availability. Increased amounts of selenoproteins observed in response to selenium supplementation were shown in several studies to correlate with increases in the corresponding mRNA levels. In general, selenoprotein levels in brain are less sensitive to dietary selenium fluctuation than the corresponding selenoprotein levels in other tissues.
Article
We investigated the relationship between active oxygen species (AOS) generation and cultured vascular endothelial cellular damage caused by simultaneous exposure to selenium compounds and sulfhydryl compounds such as cysteine (Cys) or reduced glutathione (GSH). Selenium compounds, selenite, selenate or selenomethionine (SeMet), are added to total parenteral nutrition (TPN) and intravenously administered. We confirmed by luminol dependent chemiluminescence, an indicator of AOS generation, that selenite generates AOS in the presence of clinical concentrations of sulfhydryl compounds, 0.5 mM Cys or 0.5 mM GSH, and that the amount of AOS generated reaches the maximum when their mole ratio is 1:50. However, AOS generation was not observed after simultaneous administration of various concentrations of selenate or SeMet with sulfhydryl compounds. Moreover, simultaneous exposure to 10 microM selenite and sulfhydryl compounds was found to result in significant increases in the [3H]-adenine and lactate dehydrogenase (LDH) release rates from cells, a significant decrease in the amount of cellular protein, and enhancement of cellular damage as compared with after exposure to selenite alone. However, simultaneous exposure to 10 microM selenate or 10 microM SeMet together with sulfhydryl compounds did not induce cellular damage. These findings revealed that selenite generates AOS and causes cellular damage in the presence of sulfhydryl compounds. Accordingly, it seems better to choose selenate or SeMet instead of selenite when a selenium compound is to be added to TPN.
Article
The present study examined the mammary cancer chemopreventive activity of Se-methylselenocysteine, Se-propylselenocysteine and Se-allylselenocysteine in the rat methylnitrosourea (MNU) model. Each compound was supplemented in the diet at a level of 2 ppm Se for the entire duration of the experiment after MNU dosing. Se-Allylselenocysteine was the most active and caused a reduction in total tumor yield by 86%. Se-Methylselenocyteine and Se-propylselenocysteine were similar but less effective, and both produced a decrease of about 50% in tumorigenesis. All three compounds were very well absorbed through the gastrointestinal tract. However, more selenium was excreted in urine after gavaging with Se-propylselenocysteine or Se-allylselenocysteine compared with Se-methylselenocysteine. Analysis of selenium in the mammary gland and other organs showed that tissue selenium levels did not appear to be correlated with differences in chemopreventive activity. A lyase activity capable of catalyzing scission of the Se-alkyl group from the remainder of the amino acid was demonstrated. This activity was found to be high in liver and kidney, but relatively low in mammary gland and intestine. Minimal variations in enzyme activity towards each of the substrates were observed. Our results support the concept that Se-alkylselenoamino acids could be used as precursors for delivering the Se-alkyl moiety and that intrinsic chemical differences in the Se-alkyl substituent of the test compounds are likely to be important determinants of their biological effects.
Article
The exact role of superoxide radicals (O(2)(*)(-)) in apoptosis is still a matter of debate. The main objective of the present study is to evaluate the apoptotic signalling pathway initiated by O(2)(*)(-). The reductive reaction of sodium selenite with glutathione was used as the intracellular O(2)(*)(-)-generating system. When cells were exposed to 5 to 25 microM selenite, a temporal pattern of apoptotic events was observed following the elevation of O(2)(*)(-), in which cytochrome c release and mitochondrial depolarization preceded caspase-3 activation and DNA fragmentation. The simultaneous treatment with N-acetylcysteine and 4-hydroxy-2,2,6, 6-tetramethylpiperidine-N-oxyl markedly reduced O(2)(*)(-) level and suppressed the mitochondrial changes and the downstream apoptotic events. Moreover, pretreatment with cyclosporin A plus trifluoperazine, two mitochondrial permeability transition (MPT) inhibitors, was capable of attenuating O(2)(*)(-)-mediated cytochrome c release and mitochondrial depolarization, and subsequently inhibiting apoptosis. Thus, the present results provide convincing evidence that O(2)(*)(-) generated from the reductive reaction of selenite with GSH is capable of triggering a mitochondria-dependent apoptotic pathway. Such knowledge may not only help to obtain a better understanding of the apoptotic effect of selenite per se, but of the role of O(2)(*)(-) in initiation and execution of apoptosis.
Article
Collectively, results from epidemiologic studies, laboratory bioassays, and human clinical intervention trials clearly support a protective role of selenium against cancer development. Several hypotheses have been proposed to explain these observations. Increased genomic instability, either inherent or induced by exogenous agents (mutagens or carcinogens), has been considered as a primary event leading to neoplastic transformation. This report deals specifically with the evidence for a role of selenium in the inhibition of carcinogen-induced covalent DNA adduct formation and retardation of oxidative damage to DNA, lipids and proteins, and for modulating cellular and molecular events that are critical in cell growth inhibition and in the multi-step carcinogenesis process. At present, the bulk of our knowledge on the role of selenium on genetic stability is based primarily on animal data and from studies conducted in in vitro systems. Studies performed in vitro showed that the dose and form of selenium compounds are critical factors with regard to cellular responses. Inorganic (at doses up to 10microM) and organic selenium compounds (at doses equal to or greater than 10microM) elicit distinctly different cellular responses. The recommended daily allowance (RDA) is 50-70 microgramSe per day for healthy adults; with 40 microgramSe as minimum requirement. Less than 11 microgramSe will definitely put people at risk of deficiency that would be expected to cause genetic damage. Daily doses of 100-200 microgramSe inhibited genetic damage and cancer development in humans. About 400 microgramSe per day is considered an upper limit. Clearly, doses above the RDA are needed to inhibit genetic damage and cancer. However, it has been hypothesized that the intake of excessive doses of selenium may cause oxidative damage, leading to genomic instability. The use of a cocktail consisting of selenium, and other vitamins and minerals appears to be a promising approach to inhibit genetic damage and the development of cancer. It is the author's recommendation that development of mechanism-based hypotheses that can be tested in pilot studies in different populations prior to a large-scale clinical trial in humans, is of paramount importance in order to better understand the role of selenium on genetic stability and cancer.
Article
Methylselenol from selenium metabolism is postulated to be and most experimental evidence now indicates that it is the selenium metabolite responsible for the dietary chemoprevention of cancers. Using the recombinant enzyme methioninase, methylselenol-generating chemiluminesence by superoxide (O2*-) is shown to be catalytically produced from L-selenomethionine and D,L-selenoethionine, but not from methionine or L-Se-methylselenocysteine (SeMC). Methylselenol enzymaticaly generated by methioninase activity from the substrate selenomethionine arises from an initial putative selenium radical as measured by chemiluminesence in the absence of glutathione (GSH). In the presence of GSH, superoxide was generated as measured by chemiluminesence and superoxide dismutase inhibition of chemiluminescence. Ascorbic acid also quenched the chemiluminesence from the activity of methioninase with selenomethionine. Methylselenol and other redox cycling selenium compounds are almost assuredly accountable for inducing cell-cycle arrest and apoptosis in cancer cells in vitro and in vivo. Methylselenol generated from selenomethionine by methioninase is catalytic alone in oxidizing thiols, i.e. GSH, generating superoxide and inducing oxidative stress in direct proportion to its concentration. Se-methylselenocysteine in vivo is very likely carcinostatic in like manner to selenomethionine by generating methylselenol from other enzymatic activity, i.e. beta-lyase or amino acid oxidases.
Article
Although the average daily dietary selenium (Se) intake in the United States is consistently above the adult RDA of 55 μg Se/day, supranutritional supplements of 200 μg Se/day have been shown to provide chemopreventive benefits against several cancers, particularly prostate cancer. The hypothesis herein contends that selenium compounds with the greatest anticarcinogenic potency are likely to be sodium selenite with Se in the +4 oxidation state and methylseleninic acid. These compounds exert their cancer chemopreventive effects by directly oxidizing critical thiol-containing cellular substrates, and are more effective than the more frequently preferred (used) supplements of selenomethionine and Se–methylselenocysteine that lack oxidation capability. Selenate (+6 Se) the immediate precursor of selenite (+4 Se) can be metabolically reduced, and although less potent than the +4 Se compounds cited above, appears to be a more effective anticarcinogen than organic forms of dietary selenium.
Article
Selenium (Se) is a dietary essential trace element with important biological roles. Accumulating evidence indicates that Se compounds possess anticancer properties. Se is specifically incorporated into proteins in the form of selenocysteine and non-specifically incorporated as selenomethionine in place of methionine. The effects of Se compounds on cells are strictly compositional and concentration-dependent. At supranutritional dietary levels, Se can prevent the development of many types of cancer. At higher concentrations, Se compounds can be either cytotoxic or possibly carcinogenic. The cytotoxicity of Se is suggested to be associated with oxidative stress. Accordingly, sodium selenite, an inorganic Se compound, was reported to induce DNA damage, particularly DNA strand breaks and base damage. In this review we summarize the various activities of Se compounds and focus on their relation to DNA damage and repair. We discuss the use of Saccharomyces cerevisiae for identification of the genes involved in Se toxicity and resistance.
Article
Although silicone hydrogel materials have produced many corneal health benefits to patients wearing contact lenses, bacteria that cause acute red eye or corneal ulcers are still a concern. A coating that inhibits bacterial colonization while not adversely affecting the cornea should improve the safety of contact lens wear. A covalent selenium (Se) coating on contact lenses was evaluated for safety using rabbits and prevention of bacterial colonization of the contact lenses in vitro. Contact lenses coated with Se were worn on an extended-wear schedule for up to 2 months by 10 New Zealand White rabbits. Corneal health was evaluated with slit-lamp biomicroscopy, pachymetry, electron microscopy, and histology. Lenses worn by the rabbits were analyzed for protein and lipid deposits. In addition, the ability of Se to block bacterial colonization was tested in vitro by incubating lenses in a Pseudomonas aeruginosa broth followed by scanning electron microscopy of the contact lens surface. The covalent Se coating decreased bacterial colonization in vitro while not adversely affecting the corneal health of rabbits in vivo. The Se coating produced no noticeable negative effects as observed with slit-lamp biomicroscopy, pachymetry, electron microscopy, and histology. The Se coating did not affect protein or lipid deposition on the contact lenses. The data from this pilot study suggest that a Se coating on contact lenses might reduce acute red eye and bacterial ulceration because of an inhibition of bacterial colonization. In addition, our safety tests suggest that this positive effect can be produced without an adverse effect on corneal health.
Article
Selenomethionine (SeMet) is the chemical form or major component of selenium used for cancer chemoprevention in several clinical trials. However, evidence from experimental studies indicates that SeMet has weaker anticancer effects than most other forms of selenium. Recent studies showed that the anticancer activity of SeMet can be enhanced by methioninase (METase), indicating that SeMet metabolites are responsible for its anticancer activity. In the present study, we showed that wild-type p53-expressing LNCaP human prostate cancer cells were more sensitive to cotreatment with SeMet and METase than p53-null PC3 human prostate cancer cells. SeMet and METase cotreatment significantly increased levels of superoxide and apoptosis in LNCaP cells. Cotreatment with SeMet and METase resulted in increased levels of phosphorylated p53 (Ser15), total p53, Bax, and p21(Waf1) proteins. LNCaP cells treated with SeMet and METase also showed p53 translocation to mitochondria, decreased mitochondrial membrane potential, cytochrome c release into the cytosol, and activation of caspase-9. The effects of SeMet and METase were suppressed by pretreatment with a synthetic superoxide dismutase mimic or by knockdown of p53 via RNA interference. Reexpression of wild-type p53 in PC3 cells resulted in increases in superoxide production, apoptosis, and caspase-9 activity and a decrease in mitochondrial membrane potential following cotreatment with SeMet and METase. Our study shows that apoptosis induced by SeMet plus METase is superoxide mediated and p53 dependent via mitochondrial pathway(s). These results suggest that superoxide and p53 may play a role in cancer chemoprevention by selenium.
Article
Selenium is a promising chemopreventive agent for prostate cancer, possibly via an induction of apoptosis. Earlier studies have shown that selenite induces DNA single strand breaks (SSBs), reactive oxygen species (ROS), p53 Ser-15 phosphorylation and caspase-dependent and -independent apoptosis, whereas a methylselenol precursor methylseleninic acid (MSeA) induces caspase-mediated apoptosis regardless of p53 status. Here we address three main questions: What types of ROS are induced by selenite vs. MSeA in LNCaP (p53 wild type, androgen-responsive) and DU145 (mutant p53, androgen-independent) prostate cancer cells? Does ROS generation depend on androgen signaling? What are the relationships among ROS, DNA SSBs, p53 and caspases? We show that selenite (5 microM) induced superoxide and hydrogen peroxide in LNCaP cells much more than in DU145 cells and the ROS generation was not affected by physiological androgen stimulation. MSeA (10 microM) induced apoptosis without either type of ROS in both cell lines. In LNCaP cells, we established superoxide as a primary mediator for selenite-induced DNA SSBs, p53 activation and caspase-mediated apoptosis. Furthermore a p53-dominant negative mutant attenuated selenite-induced ROS, leading to a proportionate protection against apoptosis. The results support the p53-mitochondria axis in a feedback loop for sustaining superoxide production to lead to efficient caspase-mediated apoptosis by selenite. In contrast, caspase-mediated apoptosis induced by MSeA does not involve ROS induction. Since p53 is frequently mutated or deleted in prostate cancer and many other cancers, our results suggest that genotoxic vs. nongenotoxic classes of selenium may exert differential apoptosis efficacy depending on the p53 status of the cancer cells.
Article
Oxidative stress has been linked with apoptosis in germ cells and with male infertility. However, the molecular mechanism of oxidative-stress-mediated apoptosis in germ cells has not been clearly defined so far. Because of the involvement of CDC2 and cyclin B1 in cell cycle regulation and their plausible role in apoptosis, the present study aimed to investigate the possibility that selenium (Se)-induced oxidative-stress-mediated modulations of these cell cycle regulators cause DNA damage and apoptosis in germ cells. To create different Se status (deficient, adequate and excess), male Balb/c mice were fed yeast-based Se-deficient diet (Group I) and a deficient diet supplemented with Se as sodium selenite (0.2 and 1 ppm Se in Groups II and III, respectively) for a period of 8 weeks. After the completion of the diet feeding schedule, a significant decrease in Se levels and glutathione peroxidase activity was observed in the Se-deficient group (Group I), whereas the Se-excess group (Group III) demonstrated an increase in Se levels. Increased levels of lipid peroxidation were seen in both Groups I and III when compared to Group II, indicating oxidative stress. The mRNA and protein expressions of both CDC2 and cyclin B1 were found to be significantly decreased in Groups I and III. A decrease in the immunohistochemical localization of these proteins was also observed in spermatogenic cells. The mRNA expressions of apoptotic factors such as Bcl-2, Bax, caspase-3 and caspase-9 were found to be increased in Groups I and III. A decrease in CDC2 kinase activity was also seen in these groups. Increased apoptosis was observed in Group I and Group III animals by terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labeling assay indicating oxidative-stress-mediated DNA damage. These findings suggest the effect of Se-induced oxidative stress on the cell cycle regulators and apoptotic activity of germ cells, thus providing new dimensions to molecular mechanisms underlying male infertility.
Article
Converging data from epidemiological, ecological, and clinical studies have shown that selenium (Se) can decrease the risk for some types of human cancers. Induction of apoptosis is considered an important cellular event that can account for the cancer preventive effects of Se. Prior to occurrence of apoptosis, Se compounds alter the expression and/or activities of signaling molecules, mitochondria-associated factors, transcriptional factors, tumor suppressor genes, and cellular reduced glutathione. Mechanistic studies have demonstrated that the methylselenol metabolite pool has many desirable attributes of chemoprevention, whereas the hydrogen selenide pool with excess of selenoprotein synthesis can lead to DNA single-strand breaks. To elucidate the effects of Se on cytotoxic events, it should be remembered that the chemical forms and the dose of Se, and the experimental system used, are determinants of its biological activities. This mini-review focuses on elucidation of the molecular mechanisms of cancer prevention by Se with the apoptotic approach.
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