Selenium is an essential trace element co-translationally incorporated into selenoproteins with important biological functions. Health benefits have long been associated with selenium supplementation. However, cytotoxicity is observed upon excessive selenium intake. The aim of this study is to investigate the metabolic pathways underlying the response to the selenium-containing amino acids selenomethionine and selenocysteine in a normal human breast epithelial cell model. We show that both selenomethionine and selenocystine inhibit the proliferation of non-cancerous MCF-10A cells in the same concentration range as cancerous MCF-7 and Hela cells, which results in apoptotic cell death. Selenocystine exposure in MCF-10A cells caused a severe depletion of free low molecular weight thiols, which might explain the observed upregulation of the expression of the oxidative stress pathway transcription factor NRF2. Both selenomethionine and selenocystine induced the expression of target genes of the unfolded protein response (GRP78, ATF4, CHOP). Using a redox-sensitive fluorescent probe targeted to the endoplasmic reticulum (ER), we show that both selenoamino acids shifted the ER redox balance towards an even more oxidizing environment. These results suggest that alteration of the redox state of the ER may disrupt protein folding and cause ER stress-induced apoptosis in MCF-10A cells exposed to selenoamino acids.

The SLC7A11/xCT cystine and glutamate antiporter has emerged as an attractive target for cancer therapy due to its selective overexpression in multiple cancers and its role in preventing ferroptosis. Utilizing pharmacological and genetic approaches in hepatocellular carcinoma cell lines, we demonstrate that overexpression of SLC7A11 engenders hypersensitivity towards l-selenocystine, a naturally occurring diselenide that bears close structural similarity to l-cystine. We find that the abundance of SLC7A11 positively correlates with sensitivity to l-selenocystine, but surprisingly, not to Erastin, an inhibitor of SLC7A11 activity. Our data indicate that SLC7A11 acts as a transport channel for l-selenocystine, which preferentially incites acute oxidative stress and damage eventuating to cell death in cells that highly express SLC7A11. Hence, our findings raise the prospect of l-selenocystine administration as a novel strategy for targeting cancers that up-regulate SLC7A11 expression.

BACKGROUND: To protect from toxicity at supra-essential doses of selenium, it is important to determine dose levels at which adverse effects occur.
METHODS: We identified relevant literature on the repeated dosage of selenium and extracted dose descriptors on reported endpoints, except on genotoxicity/carcinogenicity.
RESULTS: Selenium forms with toxicological data were organic ones: selenomethionine, selenocystine/selenocysteine; and inorganic ones, including selenite (SeO32-), selenate (SeO42-), selenium sulphide (SeS2), selenide (Se2-) and selenium nanoparticles. Clinical signs of selenium toxicity in humans include a garlicky-smelling breath, hair loss, and nail changes. One human study showed increased mortality following daily ingestion of 300 µg Se per day for 5 years, equal to a lowest-observed-adverse-effect level (LOAEL) of ∼4.3 µg/kg bw/days. The corresponding no-observed-adverse-effect level (NOAEL) was ∼2.9 µg Se/kg bw/day. One study reported an increased risk of type 2 diabetes after ∼2.9 µg Se/kg bw/day, but other studies with similar doses found no increases in mortality or incidence of type 2 diabetes. NOAELs on affected body weight in animal studies were 0.24-1.2 mg Se/kg bw/day. Other endpoints of selenium toxicity in animals include hepatotoxicity with a NOAEL as low as 2 µg/kg bw/day in rats, as well as gastrointestinal, cardiovascular, and reproductive toxicities with NOAELs of 0.6 (gastrointestinal), 0.08, and 0.4 (cardiovascular) and ≥ 0.04 mg Se/kg bw/day (reproductive), respectively.
CONCLUSIONS: Dose descriptors describing selenium toxicity were as low as 2-3 µg Se/kg bw/day.

BACKGROUND: Human Adenovirus (HAdV) can cause severe respiratory symptoms in people with low immunity and there is no targeted treatment for adenovirus infection. Anti-adenoviral drugs have high clinical significance for inhibiting adenovirus infection. Selenium (Se) plays an important role in anti-oxidation, redox signal transduction, and redox homeostasis. The excellent biological activity of Se is mainly achieved by being converted into selenocystine (SeC). Se participates in the active sites of various selenoproteins in the form of SeC. The ability of SeC to resist the virus has raised high awareness due to its unique antioxidative activity in recent years. The antiviral ability of the SeC was determined by detecting the infection rate of the virus in the cells.
METHODS: The experiment mainly investigated the antiviral mechanism of SeC by locating the virus in the cell, detecting the generation of ROS, observing the DNA status of the cell, and monitoring the mitochondrial membrane potential.
RESULTS: In the present study, SeC was designed to resist A549 cells infections caused by HAdV-14. SeC could prevent HAdV-14 from causing cell apoptosis-related to DNA damage. SeC significantly inhibited ROS generation and protect the cells from oxidative damage induced by ROS against HAdV-14. SeC induced the increase of antiviral cytokines such as IL-6 and IL-8 by activating the Jak2 signaling pathway, and repaired DNA lesions by suppressing ATR, p53, and PARP signaling pathways.
CONCLUSIONS: SeC might provide an effective selenium species with antiviral properties for the therapies against HAdV-14.

Overproduction of reactive oxygen species (ROS) and cumulative oxidative stress induce the degeneration of neuromelanin-containing dopaminergic neurons in the substantia nigra pars compacta (SNpc) of PD patients. Due to its redox property, melanin-like polydopamine (PDA) has been studied for its ability to remove ROS with a series of antioxidant enzyme mimetic activities including superoxide dismutase (SOD) and catalase (CAT). Glutathione peroxidase (GPx) is important for maintaining ROS metabolic homeostasis, but only a few GPx-like nanozymes have been studied for in vivo therapy. As we know, selenocysteine is essential for the antioxidant activity of GPx. Hence, we co-synthesized PDA with selenocystine (SeCys) to prepare a nanocomposite (PDASeCys) with GPx-like activity. The results showed that the PDASeCys nanocomposite has the same CAT and SOD enzymatic activities as PDA but better free radical scavenging efficiency and additional GPx enzymatic activity than PDA. In the 1-methyl-4-phenyl-pyridine ion (MPP+)-induced PD cell model, PDASeCys could increase intracellular GPx levels effectively and protect SH-SY5Y neuronal cells from oxidative stress caused by MPP+. In vivo, the PDASeCys nanocomposite effectively inhibited 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinium (MPTP)-induced Parkinson-related symptoms of mice when it was injected into the substantia nigra (SN). This polydopamine-based nanocomposite containing selenocystine with a variety of enzymatic activities including GPx-like activity synthesized by a one-pot method provides convenience and safety in the neuromelanin-like nanozyme-based therapeutic strategy for oxidative stress-induced PD.

Chemo and siRNA synergic treatments for tumors is a promising new therapeutic trend. Selenocystine, a selenium analog of cysteine, has been considered a potential antitumor agent due to its redox perturbing role. In this study, we developed a nanocarrier for siRNA based on a selenocystine analog engineered polyetherimide and achieved traceable siRNA delivery and the synergic killing of tumor cells. Notably, we applied the label-free Schiff base fluorescence mechanism, which enabled us to trace the siRNA delivery and to monitor the selenocystine analogs\' local performance. A novel selenocystine-derived fluorescent Schiff base linker was used to crosslink the polyetherimide, thereby generating a traceable siRNA delivery vehicle with green fluorescence. Moreover, we found that this compound induced tumor cells to undergo senescence. Together with the delivery of a siRNA targeting the anti-apoptotic BCL-xl/w genes in senescent cells, it achieved a synergistic inhibition function by inducing both senescence and apoptosis of tumor cells. Therefore, this study provides insights into the development of label-free probes, prodrugs, and materials towards the synergic strategies for cancer therapy.

BACKGROUND: Selenium is a trace element traditionally ingested either in its organic form via food or in its inorganic form through nutritional supplements, while selenium formulated as nanoparticles is a putative long-acting alternative. To understand the physiology and toxicology of the different selenium formulations, it is important to determine how their selenium content is absorbed, distributed, metabolised and excreted; therefore, we reviewed their biokinetics following oral exposure.
METHODS: We retrieved and reviewed the literature on the absorption, distribution, metabolism, and excretion of oral exposure to different forms of selenium.
RESULTS: Selenium in both the organic form (containing carbon to selenium chemical bonds) and the inorganic form is absorbed into the blood in humans. The mean normal blood level of many studies was 139 μg/L. There are indications that selenium from organic sources is more bioavailable than selenium from inorganic sources. Selenium is distributed throughout the body, including in breast milk. The elimination of selenium mainly involves the faecal and urinary pathways, whereas breath, saliva and hair are minor contributors. Urinary metabolites include trimethylselenium ions, selenosugars and Se-methylselenoneine.
CONCLUSIONS: Selenium is absorbed to a high extent, and selenium from organic sources is more bioavailable than from inorganic sources. Selenium, as expected as an essential trace element, is distributed throughout the body. Selenium is extensively metabolised, and various excretion metabolites have been identified in both urine and breath, while some selenium is also excreted via faeces.

Cadmium ion (Cd2+) is a common environmental pollutant with high biotoxicity. Interestingly, the Cd2+ biotoxicity can be alleviated by the coexisting selenite (SeO32-), which induces the formation of cadmium selenide-rich nanoparticles (CdSe NPs) under the function of thiol-capping peptides. However, the detailed biochemical mechanisms by which Cd and Se are synergistically transformed into CdSe NPs in living organisms remain unclear so far. Here, we shed light on the molecular basis of such biotransformation processes in Caenorhabditis elegans by focusing on the roles of several key thiol-capping peptides. By monitoring the compositional and structural changes of the Cd and Se species and the genetic-level responses of nematodes, we revealed the specific roles of glutathione (GSH) and phytochelatins (PCs) in mediating the CdSe NP formation. With the aid of in vitro bioassembly assay and density functional theory calculations, the detailed Cd-Se interaction pathways were further deciphered: the ingested Cd binds predominantly to GSH and PCs in sequence, then further interacts with selenocysteine to form tetrahedral-structured PC2-Cd2-Sec2 complex, and ultimately grows into CdSe NPs. This work provides molecular-level insights into the Cd-Se interaction in C. elegans and lays a basis for controlling the ecological and health risks of heavy metals in polluted environment.

Bacteria are increasingly relying on biofilms to develop resistance to antibiotics thereby resulting in their failure in treating many infections. In spite of continuous research on many synthetic and natural compounds, ideal anti-biofilm molecule is still not found thereby warranting search for new class of molecules. The current study focuses on exploring anti-biofilm potential of selenocystine against respiratory tract infection (RTI)-causing bacteria. Anti-bacterial and anti-biofilm assays demonstrated that selenocystine inhibits the growth of bacteria in their planktonic state, and formation of biofilms while eradicating preformed-biofilm effectively. Selenocystine at a MIC50 as low as 42 and 28 μg/mL effectively inhibited the growth of Klebsiella pneumonia and Pseudomonas aeruginosa. The antibacterial effect is further reconfirmed by agar cup diffusion assay and growth-kill assay. Selenocystine showed 30-60% inhibition of biofilm formation in K. pneumonia, and 44-70% in P. aeruginosa respectively. It also distorted the preformed-biofilms by degrading the eDNA component of the Extracellular Polymeric Substance matrix. Molecular docking studies of selenocystine with quorum sensing specific proteins clearly showed that through the carboxylic acid moiety it interacts and inhibits the protein function, thereby confirming its anti-biofilm potential. With further validation selenocystine can be explored as a potential candidate for the treatment of RTIs.

UNASSIGNED: Inflammatory bowel disease (IBD) is characterized by chronic relapsing inflammation of the gastrointestinal tract. Oxidative stress plays a pivotal role in the pathogenesis of IBD. Selenium-containing amino acids reportedly have anti-oxidative and anti-inflammatory properties, but it remains unknown if selenium-containing amino acids can be used to treat IBD. This study aimed to investigate the effects of two selenium-containing amino acids - selenocysteine and selenocystine - on oxidative stress and chronic inflammation in a mouse model of dextran sulfate sodium (DSS)-induced IBD.
UNASSIGNED: C57BL/6 mice were randomly assigned to the following six groups: control, DSS, DSS+selenocysteine, DSS+selenocystine, DSS+sodium selenite, and DSS+N-acetylcysteine (NAC). IBD was induced by 3% DSS. Pro-inflammatory cytokines [interleukin-1β (IL-1β), monocyte chemotactic protein 1 (MCP-1), IL-6, and tumor necrosis factor-α (TNF-α)] and markers for oxidative and anti-oxidative stress [malondialdehyde (MDA), reactive oxygen species (ROS), superoxide dismutase (SOD), and glutathione peroxidase (GPx)] were measured using immunohistochemical analysis.
UNASSIGNED: Selenocysteine and selenocystine significantly attenuated IBD-related symptoms, including preventing weight loss, decreasing disease activity index (DAI) scores, and increasing colon length. Selenocysteine and selenocystine significantly ameliorated the DSS-induced oxidative stress, as demonstrated by a reduction in ROS and MDA activity and an increase in SOD and GPx activity. IL-1, MCP-1, IL-6, and TNF-α levels were significantly increased in the IBD mice, while treatment with the selenium-containing amino acids significantly reduced the levels of these pro-inflammatory cytokines. In vivo safety analysis showed minimal side effects of the selenium-containing amino acids.
UNASSIGNED: We found that selenocysteine and selenocystine ameliorated DSS-induced IBD via reducing oxidative stress and intestinal inflammation, indicating that selenium-containing amino acids could be a novel therapeutic option for patients with IBD.