Selenoprotein P1 as a biomarker of insulin resistance in pediatric obesity:Insights and implications

This editorial discusses the findings of Elbarky et al on the role of selenoprotein P1(SEPP1)in pediatric obesity and insulin resistance.Their study uncovered si-gnificantly lower SEPP1 Levels in children who were obese compared with hea-lthy peers,demonstrating a negative correlation between SEPP1 levels and mea-sures of adiposity and insulin resistance.These findings suggest that SEPP1 is a biomarker useful in the early identification of insulin resistance in pediatric populations.This editorial emphasizes the clinical implications of the study and calls for further research to validate and explore the role of SEPP1 in metabolic health.

Advances in Extraction of Selenoproteins Biosyntheses in Plant

Selenium（Se） is an essential trace element in many organisms, its biological function is mainly in the form of selenoproteins, and plant selenoproteins have antioxidant, anti-cancer, and immunity enhancing effects. This study reviewed the existing forms of selenium in plants, selenoproteins classification and selenoproteins extraction methods and proposed future research directions.

Selenoprotein P mRNA expression in human hepatic tissues

AIM: To investigate the expression of selenoprotein P mRNA (SePmRNA) in tissues of normal liver, liver cirrhosis and hepatocellular carcinoma (HCC), and its relationship with HCC occurrence and development. METHODS: The expression of SePmRNA in tissues of normal liver, liver cirrhosis and HCC were detected by in situ hybridization using a cDNA probe. RESULTS: The enzyme digesting products of PBluescript-H uman Selenoprotein P were evaluated by electrophoresis. The positive expression of SePmRNA was found in the tissues of normal liver, liver cirrhosis and HCC. The expression of SeP mRNA was found in hepatic interstitial substance, especially in endothelial cells and lymphocytes of vasculature. The positive rate of SePmRNA in normal liver tissue was 84.6% (11/13) and the positive signals appeared in the nucleus and cytoplasm, mostly in the nucleolus, and the staining granules were larger in the nucleolus and around the nucleus. The positive rate of SePmRNA in liver cirrhosis tissue was 45.0% (9/20) and the positive signals were mainly in the nucleolus and cytoplasm, being less around the nucleus and inner nucleus than that in normal liver tissue. The positive rate of SePmRNA in HCC tissue was 30.0% (9/30) and the positive signals were in the cytoplasm, but less in the nucleus. CONCLUSION: SePmRNA expression in the tissues of normal liver and HCC is significantly different (84.6% vs 30.0%, P = 0.003), suggesting that SeP might play a role in the occurrence and development of HCC.

Selenoprotein W cDNAs From Five Species of Animals

The nucleotide sequences of the open reading frames of cDNAs for selenoprotein W from skeletal muscle of rat, mouse, sheep, rhesus monkey and human are reported. Theoretical translation of the coding sequences indicated highly similar proteins of 88 (mouse and rat) or 87 (human, monkey and sheep) amino acids. In 73 of 88 positions the specified amino acids are identical for all five proteins. TGA encoding selenocysteine is the 13th codon of all the cDNAs. The rnouse, rat and sheep open reading frames terminate with TGA but the human and rhesus monkey coding regions terminate with TAA. The encoded amino acid sequences are identical for the rat and mouse proteins, and for the human and monkey proteins. The similarity of the cDNAs continues in the 3' noncoding regions through the putative selenocysteine insertion sequence (SEClS) elements which are required for correct interpretation of the selenocysteine codon. The region between the SECIS elements and the polyadenylation signals showed much lower similarity. The cloned rat gene for selenoprotein W is 5000 bases long,with the 663 bases of the cDNA in six exons. The transcription start site was identified by nuclease protection assay to be 16 bases upstream of the longest cDNA clone. A canonical TATA box occurs 150 bases upstream, but the assay did not indicate the presence of longer mRNAs

Biological Functions of Selenoprotein Iodothyronine Deiodinase and its Expression in Osteoarthritis

Objective Iodothyronine deiodinases(DIOs)are important selenoproteins that play a key role in the bone and joint diseases.Osteoarthritis(OA)is the most prevalent joint disease especially in elders.This bioinformatic analysis was performed to explore the role of DIOs in OA pathogenesis.Methods The biological functions of selenoprotein DIOs were analyzed by bioinformatic techniques,mcluding GenCLip 3.0,Database for Annotation,Visualization and Integrated Discovery(DAVID),STRING,Cytoscape,and Network Analyst.The expression of DIOs in the healthy individuals and OA patients was determined by mining OA-related microarray data in the gene expression omnibus(GEO)database of National Center for Biotechnology Information and performing a Meta-analysis of the data with Review Manager 5.3.Results Cluster analysis revealed that the function of the DIOs was associated with thyroid hormone receptor and iodothyronine;GO analysis showed that DIOs were mainly involved in biological processes,such as ethanol metabolism and phenol-containing compound metabolism and primarily involved in the cytochrome P450 metabolism of exogenous organisms and thyroid hormone signaling;SULT1A1 was the core node of the PPI network;miRNAs and thyroid hormones had some iterations with DIO1 and DI02;Meta-analysis showed that DIO3 expression was significantly up-regulated in OA patients(SMD=0.31,95%CI:0.03,0.59,P=0.03).Conclusions The main biological functions of DIOs were closely associated with the regulation of thyroid hormone.And the up-regulated expression of DIO3 may have crucial impact on the occurrence of OA.

Selenocysteine tRNAs as Central Components of Selenoprotein Biosynthesis in Eukaryotes

Selenocysteine (Sec) tRNAs serve as carrier molecules for the biosynthesis of Sec from serine and to donate Sec to protein in response to specific UGA codons. In this study, we describe the current status of Sec tRNAs in higher animals and further we exarnine: (i) the Sec tRNA population in Drosophila; (ii) transcription of the Sec tRNA in vivo (in Xenopus oocytes) and in vitro (in Xenopus oocyte extracts); (iii) the effect of selenium on the Sec tRNA population in various rat tissues following replenishment of extremely selenium deficient rats with this element; and (iv) the biosynthesis of the modified bases on Sec tRNA in Xenopus oocytes

Selenoprotein expression is regulated at multiple levels in prostate cells

Selenium supplementation in a population with low basal blood selenium levels has been reported to decrease the incidence of several cancers including prostate cancer. Based on the clinical findings, it is likely that the antioxidant function of one or more selenoproteins is responsible for the chemopreventive effect, although low molecular weight seleno-compounds have also been posited to selectively induce apoptosis in transformed cells. To address the effects of selenium supplementation on selenoprotein expression in prostate cells, we have undertaken an analysis of antioxidant selenoprotein expression as well as selenium toxicity in non-tumorigenic prostate epithelial cells （RWPE- 1 ） and prostate cancer cells （LNCaP and PC-3）. Our results show that two of the glutathione peroxidase family members （GPX1 and GPX4） are highly induced by supplemental selenium in prostate cancer cells but only slightly induced in RWPE-1 cells. In addition, GPX 1 levels are dramatically lower in PC-3 cells as compared to RWPE- 1 or LNCaP cells. GPX2 protein and mRNA, however, are only detectable in RWPE-1 cells. Of the three selenium compounds tested （sodium selenite, sodium selenate and selenomethionine）, only sodium selenite shows toxicity in a physiological range of selenium concentrations. Notably and in contrast to previous studies, RWPE-1 cells were significantly more sensitive to selenite than either of the prostate cancer cell lines. These results demonstrate that selenoproteins and selenium metabolism are regulated at multiple levels in prostate cells.

Selenoproteins synergistically protect porcine skeletal muscle from oxidative damage via relieving mitochondrial dysfunction and endoplasmic reticulum stress

Background The skeletal muscle of pigs is vulnerable to oxidative damage,resulting in growth retardation.Selenoproteins are important components of antioxidant systems for animals,which are generally regulated by dietary selenium(Se)level.Here,we developed the dietary oxidative stress(DOS)-inducing pig model to investigate the protective effects of selenoproteins on DOS-induced skeletal muscle growth retardation.Results Dietary oxidative stress caused porcine skeletal muscle oxidative damage and growth retardation,which is accompanied by mitochondrial dysfunction,endoplasmic reticulum(ER)stress,and protein and lipid metabolism disorders.Supplementation with Se(0.3,0.6 or 0.9 mg Se/kg)in form of hydroxy selenomethionine(OH-SeMet)linearly increased muscular Se deposition and exhibited protective effects via regulating the expression of selenotranscriptome and key selenoproteins,which was mainly reflected in lower ROS levels and higher antioxidant capacity in skeletal muscle,and the mitigation of mitochondrial dysfunction and ER stress.What’s more,selenoproteins inhibited DOS induced protein and lipid degradation and improved protein and lipid biosynthesis via regulating AKT/mTOR/S6K1 and AMPK/SREBP-1 signalling pathways in skeletal muscle.However,several parameters such as the activity of GSH-Px and T-SOD,the protein abundance of JNK2,CLPP,SELENOS and SELENOF did not show dose-dependent changes.Notably,several key selenoproteins such as MSRB1,SELENOW,SELENOM,SELENON and SELENOS play the unique roles during this protection.Conclusions Increased expression of selenoproteins by dietary OH-SeMet could synergistically alleviate mitochondrial dysfunction and ER stress,recover protein and lipid biosynthesis,thus alleviate skeletal muscle growth retardation.Our study provides preventive measure for OS-dependent skeletal muscle retardation in livestock husbandry.

Selenium and Iodine Deficiencies and Selenoprotein Function

This paper reviews some recent findings on the interactions between selenium deficiency and iodine deficency. Both micronutrients can control the levels of selenoprotein mRNAs, particularly in the thyroid and brain. When selenium and iodine supplies are limiting the compensatory mechanisms work to minimise adverse effects on thyroid hormone metabolsm and thus neurological developtnent. The mechanisms for regulation of selenoproteins in selenium and iodine deficiency are however very tissue-specific. For example, unlike the brain and thyroid,brown adipose tissue is unable to retain selenoproteins in selenium and iodine deficiency and is therefore at greater risk from injurious effects of the deficiencies.

RNA and Protein Requirements for Eukaryotic Selenoprotein Synthesis

Selenium has been recognized as an essential nutrient in animals since the 1950s. Demonstration of the role of dietary selenium in protection from oxidative stress foIlowed in the early 1970s, and was largely attributed to its presence as an integral part of cellular glutathione peroxidase. However, the functions of this enzyme did not explain many of the other effects of selenium deficiency. The identification of other mammalian selenoproteins during the last few years has provided new insights into the functions of this trace nutrient. The discovery that type 1 deiodinase (D1) is a selenoenzyme, in addition to unveiling an essential role for selenium in thyroid hormone action, has had more far-reaching implications. Studies of this protein opened the door for investigation of the requirements for eukaryotic selenoprotein synthesis,and the features that distinguish this pathway from the corresponding prokaryotic pathway.Selenium is present in a number of prokaryotic and eukaryotic proteins in the form of the unusual amino acid, selenocysteine. Incorporation of selenocysteine into these proteins requires a novel translation step in which UGA specifies selenocysteine insertion. Since UGA codons are typically recognized as translation stop signals, an intriguing question is raised: How does a cell recognize and distinguish a UGA selenocysteine codon from a UGA stop codon? In this review, we will focus on what is known about selenocysteine incorporation in eukaryotes, briefly summarizing initial studies and discussing a few recent advances in our understanding of this unique 'recoding' process

Two New Selenoproteins Found in the Prostatic Glandular Epithelium and in the Spermatid Nuclei

After labeling of rats in vivo with 75Se and protein separation by sodium dodecyl sulfatepolyacrylamide gel electrophoresis more than 25 Se-containing bands could be distinguished.Of those proteins which were detected only in certain compartments and might therefore have tissue-specific functions, two were chosen for detailed investigation.A 15 kDa-protein was found in the prostatic epithelium where it accounted for about two thirds of the protein-bound 75Se. It was mainly present in the cytosol but was not released into the prostatic secretion. After gel chromatography it was found in the fraction which contained proteins with molecular masses of about 300 kDa. Using two-dimensional electrophoresis a plvalue of about 4. 5 was determined.In the testis a specific Se-containing 34 kDa-protein was observed which appeared after the onset of puberty. It was localized in the spermatid nuclei where it contained about 80% of the Se tracer present and was found to be bound to the DNA. After extraction it partly disintegrated into a 20 kDa-protein.Both compounds contain Se in the form of selenocysteine. The fact that their formation had priority over that of glutathione peroxidase during insufficient Se intake is an indication of their biological significance. Special interest in the prostatic epithelial selenoprotein derives from a possible inverse relationship between the Se status and the incidence of prostate cancer observed in epidemiological studies, whereas with the 34 kDa-selenoprotein its appearance during the condensation phase of the spermatid nuclei might suggest its participation in some processes of sperm maturation

Ebola viral selenoproteins:a metallomics analysis

Ebola virus infection is the present public health problem.The trend of worldwide epidemic becomes the serious consideration for this infection.The Ebola virus infection has main clinical manifestation as acute febrile illness with hemorrhagic episode.The problem of hemostatic disturbance can be seen.Focusing on the palhophysiology.selenium plays an important role in the blood clotting regulation.The study on the selenoprotein of the Ebola virus can be useful for further understanding on the pathology of the infection.Here,the authors use metallomics analysis for assessment of Ebola virus genome.According to this study,the selenoprotein portion within Ebola virus genome can be detected at position 1046-1115.

Maternal reproductive health: Expression patterns of antioxidant enzyme selenoproteins of post-implantation embryos conceived by ethanol-treated murine mothers supplemented with α-tocopherol

Objective:To investigate if the protective effect ofα-tocopherol against the impact of ethanol on brain morphogenesis involved the activity of the selenoproteins phospholipid hydroperoxide glutathione peroxidase (PHGPx;GPx4) and selenoprotein P (SelPP) that have roles against oxidative stress.Methods:Forty female mice were randomly assigned into natural control (CON), positive control (ETOH), low-, medium-, and high-α-tocopherol-supplemented-ethanol groups (LTOC, MTOC, HTOC, respectively). CON received drinking water without ethanol while ETOH, LTOC, MTOC and HTOC groups received 20% ethanol in drinking water. The supplemented groups were given respective dosages ofα-tocopherol, 0.410, 0.819, and 1.640 mg/g body weight, at day 14 before mating onwards to the day 9 of gestation. At 10.5 ED of gestation (1100 h), the pregnant females were sacrificed by cervical dislocation and the embryos were harvested. Total RNA were extracted, cDNA synthesis and qRT- PCR analyses were carried out.Results: The level of expression of PHGPx in the positive control was significantly lower than that of the natural control. Among the threeα-tocopherol-supplemented groups, only the medium dose- group was significantly higher than the positive control. The level of expression of SelPP in the positive control was significantly lower than those of the natural control, the low- and medium- dose -tocopherol supplemented groups. In the high dose-α-tocopherol supplemented group, the level of expression was not significantly different from the positive control but significantly lower than the natural control.Conclusions: The activity of the selenoproteins PHGPx and SelPP are involved in the internetwork of antioxidative enzymes with vitamin E when given up to a medium dose only and is one of the possible pathways of shielding embryonic development against the impact of ethanol on brain morphogenesis. This study strengthens the impact of dietaryα-tocopherol and Selenium supplement during the critical period of pregnancy.

Identification of selenocyst-eine insertion sequence(SECIS) element in eukaryotic selenoproteins by RNA Draw program

The computer program RNA Draw was used to identify the secondary structures in the 3’untranslated regions (3’UTRs) of the mRNAs from 46 eukaryotic seleno-proteins among 7 species. The program found one or two possible SECIS elements in these selenoproteins. The SECIS element consists of a stem-loop or hairpin structure with three conserved sequences of AUGA-(A)AA-GA. SECIS element was not found by the RNA Draw program in randomly selected non-selenoproteins. The results showed that SECIS element is the unique character of the genes ofeukaryotic selenoproteins. Thus it is possible to use RNA Draw to search the SECIS elements in gene bank for potential new selenoproteins.

Determination of optimal dietary selenium levels by full expression of selenoproteins in various tissues of broilers from 1 to 21 d of age

The current NRC dietary selenium(Se)requirement(0.15 mg/kg)of broilers is primarily based on growth performance data reported in 1986.Our study aimed to determine optimal dietary Se levels of broilers fed a practical corn-soybean meal diet for the full expression of selenoproteins in various tissues.A total of 384 one-d-old male broilers(n=8 replicates/diet)were fed a basal corn-soybean meal diet or the basal diet supplemented with 0.1,0.2,0.3,0.4 or 0.5 mg Se/kg in the form of Na_(2)SeO_(3) for 21 d.Regression analysis was conducted to evaluate the optimal dietary Se levels using broken-line,quadratic or asymptotic models.The activity of glutathione peroxidase(GPX)in the plasma,liver,kidney and pancreas,iodothyronine deiodinase(DIO)in the plasma,liver and pancreas,and thioredoxin reductase(Txnrd)in the liver and pancreas,the mRNA levels of Gpx1,Gpx4,Dio1,selenoprotein(Seleno)h,Selenop and Selenou in the liver,Gpx4,Dio1,Txnrd1,Txnrd2,Selenoh,Selenop and Selenou in the kidney,and Gpx1,Gpx4,Selenoh and Selenou in the pancreas,and the protein levels of GPX4 in the liver and kidney of broilers were influenced(P<0.05)by added Se levels,and increased quadratically(P<0.05)with the increase of added Se levels.The estimates of optimal dietary Se levels were 0.07 to 0.36 mg/kg based on the fitted broken-line,quadratic or asymptotic models(P<0.001)of the aforementioned selenoprotein expression in the plasma,liver and kidney,and 0.09 to 0.46 mg/kg based on the fitted broken-line models(P<0.001)of the aforementioned selenoprotein expression in the pancreas.The results indicate that the optimal dietary Se levels would be 0.36 mg/kg to support the full expression of selenoproteins in the plasma,liver and kidney,and 0.46 mg/kg to support the full expression of selenoproteins in the pancreas of broilers fed a practical corn-soybean meal diet from 1 to 21 d of age.

Determination of optimal dietary selenium levels by full expression of selenoproteins in various tissues of broilers from 22 to 42 d of age

The current NRC dietary selenium(Se)requirement(0.15 mg/kg)of broilers from 22 to 42 d of age is primarily based on a previous study reported in 1986,which might not be applicable to modern classes of rapidly growing broilers.The present experiment was conducted to determine the optimal dietary Se level for meeting metabolic and functional Se requirements of broilers fed a corn-soybean meal diet from 22 to 42 d of age.A total of 336 Arbor Acres male broilers at 22 d old were randomly assigned to 1 of 6 treatments with 7 replicates and fed a basal corn-soybean meal diet(control,containing 0.014 mg Se/kg)and the basal diet supplemented with 0.10,0.20,0.30,0.40,or 0.50 mg Se/kg from Na_(2)SeO_(3) for 21 d.The results showed that the Se concentrations in plasma,liver,kidney,pancreas,breast and thigh muscles,the activity of glutathione peroxidase(GPX)in plasma,liver and kidney,the mRNA expression levels of Gpx4,selenoprotein(Seleno)h and Selenou in liver,Selenop and Selenoh in kidney,and the protein expression levels of GPX4 in the liver and kidney of broilers were affected(P<0.05)by supplemental Se level,and increased quadratically(P<0.05)with the increase of supplemental Se level.The estimates of optimal dietary Se levels were 0.10 to 0.49 mg/kg based on the fitted broken-line or asymptotic models(P<0.0001)of the above Se concentration indices,and 0.08 to 0.37 mg/kg based on the fitted brokenline,quadratic or asymptotic models(P<0.007)of the above selenoprotein expression indices.These results indicate that the optimal dietary Se levels would be 0.49 mg/kg to support the maximum Se concentrations and 0.37 mg/kg to support the full expression of selenoproteins in plasma and various tissues of broilers fed a corn-soybean meal diet from 22 to 42 d of age.

New selenoproteins identified in silico from the genome of Anopheles gambiae

Selenoprotein is biosynthesized by the incorporation of selenocysteine into proteins,where the TGA codon in the open reading frame does not act as a stop signal but is translated into selenocysteine.The dual functions of TGA result in mis-annotation or lack of selenoproteins in the sequenced genomes of many species.Available computational tools fail to correctly predict selenoproteins.Thus,we devel-oped a new method to identify selenoproteins from the genome of Anopheles gambiae computationally.Based on released genomic information,several programs were edited with PERL language to identify selenocysteine insertion sequence(SECIS)element,the coding potential of TGA codons,and cys-teine-containing homologs of selenoprotein genes.Our results showed that 11365 genes were termi-nated with TGA codons,918 of which contained SECIS elements.Similarity search revealed that 58 genes contained Sec/Cys pairs and similar flanking regions around in-frame TGA codons.Finally,7 genes were found to fully meet requirements for selenoproteins,although they have not been anno-tated as selenoproteins in NCBI databases.Deduced from their basic properties,the newly found se-lenoproteins in the genome of Anopheles gambiae are possibly related to in vivo oxidation tolerance and protein regulation in order to interfere with anopheles' vectorial capacity of Plasmodium.This study may also provide theoretical bases for the prevention of malaria from anopheles transmission.

A Method for Identification of Selenoprotein Genes in Archaeal Genomes

The genetic codon UGA has a dual function： serving as a terminator and encoding selenocysteine. However, most popular gene annotation programs only take it as a stop signal, resulting in misannotation or completely missing selenoprotein genes. We developed a computational method named Asec-Prediction that is specific for the prediction of archaeal selenoprotein genes. To evaluate its effectiveness, we first applied it to 14 archaeal genomes with previously known selenoprotein genes, and Asec-Prediction identified all reported selenoprotein genes without redundant results. When we applied it to 12 archaeal genomes that had not been researched for selenoprotein genes, Asec-Prediction detected a novel selenoprotein gene in Methanosarcina acetivorans. Further evidence was also collected to support that the predicted gene should Asec-Prediction is effective be a real selenoprotein gene. for the prediction of archaeal The result shows that selenoprotein genes.

Role of selenoprotein M knockdown in the melatonin antagonism of nickel-induced apoptosis and endoplasmic reticulum stress in mouse heart

The aim of this study was to investigate the role of selenoprotein M(SelM)in endoplasmic reticulum stress and apoptosis in nickel-exposed mouse hearts and to explore the detoxifying effects of melatonin.At 21 d after intraperitoneal injection of nickel chloride(NiCl_(2))and/or melatonin into male wild-type(WT)and SelM knockout(KO)C57BL/6J mice,NiCl_(2)was found to induce changes in the microstructure and ultrastructure of the hearts of both WT and SelM KO mice,which were caused by oxidative stress,endoplasmic reticulum stress,and apoptosis,as evidenced by decreases in malondialdehyde(MDA)content and total antioxidant capacity(T-AOC)activity.Changes in the messenger RNA(mRNA)and protein expression of genes related to endoplasmic reticulum stress(activating transcription factor 4(ATF4),inositol-requiring protein 1(IRE1),c-Jun N-terminal kinase(JNK),and C/EBP homologous protein(CHOP))and apoptosis(B-cell lymphoma-2(Bcl-2),Bcl-2-associated X protein(Bax),Caspase-3,Caspase-9,and Caspase-12)were also observed.Notably,the observed damage was worse in SelM KO mice.Furthermore,melatonin alleviated the heart injury caused by NiCl_(2)in WT mice but could not exert a good protective effect in the heart of SelM KO mice.Overall,the findings suggested that the antioxidant capacity of SelM,as well as its modulation of endoplasmic reticulum stress and apoptosis,plays important roles in nickel-induced heart injury.

Carrimycin,a first in-class anti-cancer agent,targets selenoprotein H to induce nucleolar oxidative stress and inhibit ribosome biogenesis

Carrimycin is a synthetic macrolide antibiotic that has been shown to have anti-cancer activity;however,its exact mechanism of action and molecular target were previously unknown.It was recently elucidated that Isovalerylspiramycin I(ISP I),the active component of carrimycin,targets selenoprotein H(SelH),a nucleolar reactive oxygen species-scavenging enzyme in the selenoprotein family.ISP I treatment accelerates SelH degradation,resulting in oxidative stress,disrupted ribosomal biogenesis,and apoptosis in tumor cells.Specifically,ISP I disrupts the association between RNA polymerase I and ribosomal DNA in the nucleolus.This inhibits ribosomal RNA transcription and subsequent ribosomal assembly,which prevents cancer cells from sustaining elevated rates of protein synthesis and cellular proliferation that are necessary for tumor growth and malignancy.In this review,we(1)describe the historical categorization and evolution of anti-cancer agents,including macrolide antibiotics,(2)outline the discovery of SelH as a target of ISP I,and(3)summarize the ways in which carrimycin has been used both clinically and at the bench to date and propose additional potential therapeutic uses.