Special Issue of “Optimal Selenium Status and Selenoproteins in Health”

Molecular Mechanisms by Which Selenoprotein K Regulates Immunity and Cancer Abstract Many of the 25 members of the selenoprotein family function as enzymes that utilize their selenocysteine (Sec) residues to catalyze redox-based reactions. However, some selenoproteins likely do not exert enzymatic activity by themselves and selenoprotein K (SELENOK) is one such selenoprotein family member that uses its Sec residue in an alternative manner. SELENOK is an endoplasmic reticulum (ER) transmembrane protein that has been shown to be important for ER stress and for calcium-dependent signaling. Molecular mechanisms for the latter have recently been elucidated using knockout mice and genetically manipulated cell lines. These studies have shown that SELENOK interacts with an enzyme in the ER membrane, DHHC6 (letters represent the amino acids aspartic acid, histidine, histidine, and cysteine in the catalytic domain), and the SELENOK/DHHC6 complex catalyzes the transfer of acyl groups such as palmitate to cysteine residues in target proteins, i.e., palmitoylation. One protein palmitoylated by SELENOK/DHHC6 is the calcium channel protein, the inositol 1,4,5-trisphosphate receptor (IP3R), which is acylated as a means for stabilizing the tetrameric calcium channel in the ER membrane. Factors that lower SELENOK levels or function impair IP3R-driven calcium flux. This role for SELENOK is important for the activation and proliferation of immune cells, and recently, a critical role for SELENOK in promoting calcium flux for the progression of melanoma has been demonstrated. This review provides a summary of these findings and their implications in terms of designing new therapeutic interventions that target SELENOK for treating cancers like melanoma.

Systems Biology of Selenium and Complex Disease Abstract Selenium is an essential trace element for maintenance of overall health, whose deficiency and dyshomeostasis have been linked to a variety of diseases and disorders. The majority of previous researches focused on characterization of genes encoding selenoproteins or proteins involved in selenium metabolism as well as their functions. Many studies in humans also investigated the relationship between selenium and complex diseases, but their results have been inconsistent. In recent years, systems biology and “-omics” approaches have been widely used to study complex and global variations of selenium metabolism and function in physiological and different pathological conditions. The present paper reviews recent progress in large-scale and systematic analyses of the relationship between selenium status or selenoproteins and several complex diseases, mainly including population-based cohort studies and meta-analyses, genetic association studies, and some other omics-based studies. Advances in ionomics and its application in studying the interaction between selenium and other trace elements in human health and diseases are also discussed.

New Directions for Understanding the Codon Redefinition Required for Selenocysteine Incorporation Abstract The fact that selenocysteine (Sec) is delivered to the elongating ribosome by a tRNA that recognizes a UGA stop codon makes it unique and a thorn in the side of what was originally thought to be a universal genetic code. The mechanism by which this redefinition occurs has been slowly coming to light over the past 30 years, but key questions remain. This review seeks to highlight the prominent mechanistic questions that will guide the direction of work in the near future. These questions arise from two major aspects of Sec incorporation: (1) novel functions for the Sec insertion sequence (SECIS) that resides in all selenoprotein mRNAs and (2) the myriad of RNA-binding proteins, both known and yet to be discovered, that act in concert to modify the translation elongation process to allow Sec incorporation.

Role of Selenoproteins in Bacterial Pathogenesis Abstract The trace element selenium is an essential micronutrient that plays an important role in maintaining homeostasis of several tissues including the immune system of mammals. The vast majority of the biological functions of selenium are mediated via selenoproteins, proteins which incorporate the selenium-containing amino acid selenocysteine. Several bacterial infections of humans and animals are associated with decreased levels of selenium in the blood and an adjunct therapy with selenium often leads to favorable outcomes. Many pathogenic bacteria are also capable of synthesizing selenocysteine suggesting that selenoproteins may have a role in bacterial physiology. Interestingly, the composition of host microbiota is also regulated by dietary selenium levels. Therefore, bacterial pathogens, microbiome, and host immune cells may be competing for a limited supply of selenium. Elucidating how selenium, in particular selenoproteins, may regulate pathogen virulence, microbiome diversity, and host immune response during a bacterial infection is critical for clinical management of infectious diseases.

Selenoproteins of the Human Prostate: Unusual Properties and Role in Cancer Etiology Abstract The prostate is an important organ for the maintenance of sperm health with prostate cancer being a common disease for which there is a critical need to distinguish indolent from aggressive disease. Several selenium-containing proteins have been implicated in prostate cancer risk or outcome due to either enzyme function, the reduced levels of these proteins being associated with cancer recurrence after prostatectomy or their corresponding genes containing single-nucleotide polymorphisms associated with increased risk. Moreover, experimental data obtained from the manipulation of either cultured cells or animal models have indicated that some of these proteins are contributing mechanistically to prostate cancer incidence or progression. Among these are selenocysteine-containing proteins selenoprotein P (SELENOP), glutathione peroxidase (GPX1), and selenoprotein 15 (SELENOF); and the selenium-associated protein selenium-binding protein 1 (SBP1). Genotyping of some of the genes for these proteins has identified functional single-nucleotide polymorphisms that are associated with prostate cancer risk and the direct quantification of these proteins in human prostate tissues has not only revealed associations to clinical outcomes but have also identified unique properties that are different from what is observed in other tissue types. The location of GPX1 in the nucleus and SELENOF in the plasma membrane of prostate epithelial cells indicates that these proteins may have functions in normal prostate tissue that are distinct from that of the other tissue types.

From Selenium Absorption to Selenoprotein Degradation Abstract Selenium is an essential dietary micronutrient. Ingested selenium is absorbed by the intestines and transported to the liver where it is mostly metabolized to selenocysteine (Sec). Sec is then incorporated into selenoproteins, including selenoprotein P (SELENOP), which is secreted into plasma and serves as a source of selenium to other tissues of the body. Herein, we provide an overview of the biology of selenium from its absorption and distribution to selenoprotein uptake and degradation, with a particular focus on the latter. Molecular mechanisms of selenoprotein degradation include the lysosome-mediated pathway for SELENOP and endoplasmic reticulum–mediated degradation of selenoproteins via ubiquitin-activated proteasomal pathways. Ubiquitin-activated pathways targeting full-length selenoproteins include the peroxisome proliferator–activated receptor gamma–dependent pathway and substrate-dependent ubiquitination. An alternate mechanism is utilized for truncated selenoproteins, in which cullin-RING E3 ubiquitin ligase 2 targets the defective proteins for ubiquitin-proteasomal degradation. Selenoproteins, particularly SELENOP, may have their Sec residues reutilized for new selenoprotein synthesis via Sec decomposition. This review will explore these aspects in selenium biology, providing insights to knowledge gaps that remain to be uncovered.

Selenium and Other Elements in Wheat ( Triticum aestivum ) and Wheat Bread from a Seleniferous Area Abstract The objective of the present study was to assess the levels of Se, as well as other essential and toxic trace elements in wheat grains and traditional Roti-bread from whole-grain flour in a seleniferous area of Punjab (India) using inductively-coupled plasma mass-spectrometry. Wheat grain and bread selenium levels originating from seleniferous areas exceeded the control values by a factor of more than 488 and 179, respectively. Se-rich wheat was also characterized by significantly increased Cu and Mn levels. Se-rich bread also contained significantly higher levels of Cr, Cu, I, Mn, and V. The level of Li and Sr was reduced in both Se-enriched wheat and bread samples. Roti bread from Se-enriched wheat was also characterized by elevated Al, Cd, and Ni, as well as reduced As and Hg content as compared to the respective control values. Se intake with Se-rich bread was estimated as more than 13,600% of RDA. Daily intake of Mn with both Se-unfortified and Se-fortified bread was 133% and 190% of RDA. Therefore, Se-rich bread from wheat cultivated on a seleniferous area of Punjab (India) may be considered as a potent source of selenium, although Se status should be monitored throughout dietary intervention.

The Functional Analysis of Selenium-Related Genes and Magnesium-Related Genes in the Gene Expression Profile Microarray in the Peripheral Blood Mononuclear Cells of Keshan Disease Abstract Keshan disease (KD) is an endemic cardiomyopathy with high mortality. Selenium (Se) deficiency is closely related to KD, while magnesium (Mg) plays many critical roles in the cardiovascular function. The molecular mechanism of KD pathogenesis is still unclear. Until now, we have not found any studies investigating the association between Se- or Mg-related genes and KD. In this study, oligonucleotide microarray analysis was used to identify the differentially expressed genes in the peripheral blood mononuclear cells between KD patients and normal controls. Next, human metabolome database (HMDB) was used to screen Se- and Mg-related genes. Function classification, gene pathway, and interaction network of Se- and Mg-related genes in KD peripheral blood mononuclear cells were defined by FunRich (functional enrichment analysis tool). Among 83 differentially expressed genes, five Se-related (DIO2, GPX1, GPX2, GPX4, and GPX7) and five Mg-related (ACSL6, EYA4, IDH2, PPM1A, and STK11) genes were recognized from HMDB. Two significant biological processes (energy pathways and metabolism), one molecular function (peroxidase activity), one biological pathway (glutathione redox reactions I), and one gene interaction network were constituted from Se-related and Mg-related genes. Se-related gene DIO2 and Mg-related genes STK11 and IDH2 may have key roles in the myocardial dysfunction of KD. However, we still have not obtained any interaction between Se-related gene and Mg-related gene. The interactions between RPS6KB1, PTEN, ATM, HSP90AA1, SNRK, PRKAA2, SMARCA4, HSPA1A, and STK11 may play important roles in the abnormal cardiac function of KD.

Comparison and Risk Assessment for Trace Heavy Metals in Raw Pu-erh Tea with Different Storage Years Abstract This research conducted an exploration of the content of microelements (As, Cr, Cd, Pb, Cu, Zn, Mn, and Hg) in raw Pu-erh tea with different storage years. The contents of As, Cr, Cd, Pb, Cu, Zn, Mn, and Hg were 0.14, 0.82, 0.02, 0.52, 14.59, 33.51, 564.02, and 0.01 μg/g, respectively, and were all less than the national standard limit values in China. The target hazard quotients (THQs) of each heavy metal were all lower than 1, and the value of combined risk hazard index (HI) of all to adults was 0.221, which presents no health risk when consumed properly by adults of the raw Pu-erh tea infusions. Interestingly, there was no significant correlation between the heavy metal element (As, Cr, Cd, Pb, Cu, Zn, Mn, and Hg) contents and the THQ values of raw Pu-erh tea samples and storage years; the correlation coefficients (R2) range from 0.01 to 0.33 and from 0.01 to 0.57, respectively. The result showed that the storage years showed no effect on the exposure risk of heavy metals; the heavy metal elements in tea samples come from the atmosphere and soil.