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Sequence analysis of the Zaire ebolavirus (EBOV) polymerase (L gene) mRNA, using online tools, identified a highly ranked −1 programmed ribosomal frameshift (FS) signal including an ideal slippery sequence heptamer (UUUAAAA), with an overlapping coding region featuring two tandem UGA codons, immediately followed by an RNA region that is the inverse complement (antisense) to a region of the mRNA of the selenoprotein iodothyronine deiodinase II (DIO2). This antisense interaction was confirmed in vitro via electrophoretic gel shift assay, using cDNAs at the EBOV and DIO2 segments. The formation of a duplex between the two mRNAs could trigger the ribosomal frameshift, by mimicking the enhancing role of a pseudoknot structure, while providing access to the selenocysteine insertion sequence (SECIS) element contained in the DIO2 mRNA. This process would allow the −1 frame UGA codons to be recoded as selenocysteine, forming part of a C-terminal module in a low abundance truncated isoform of the viral polymerase, potentially functioning in a redox role. Remarkably, 90 bases downstream of the −1 FS site, an active +1 FS site can be demonstrated, which, via a return to the zero frame, would enable the attachment of the entire C-terminal of the polymerase protein. Using a construct with upstream and downstream reporter genes, spanning a wildtype or mutated viral insert, we show significant +1 ribosomal frameshifting at this site. Acting singly or together, frameshifting at these sites (both of which are highly conserved in EBOV strains) could enable the expression of several modified isoforms of the polymerase. The 3D modeling of the predicted EBOV polymerase FS variants using the AI tool, AlphaFold, reveals a peroxiredoxin-like active site with arginine and threonine residues adjacent to a putative UGA-encoded selenocysteine, located on the back of the polymerase "hand". This module could serve to protect the viral RNA from peroxidative damage. [ABSTRACT FROM AUTHOR]

Impaired sensitivity to thyroid hormones encompasses disorders with defective transport of hormones into cells, reduced hormone metabolism, and resistance to hormone action. Mediated by heritable single-gene defects, these rare conditions exhibit different patterns of discordant thyroid function associated with multisystem phenotypes. In this context, challenges include ruling out other causes of biochemical discordance, making a diagnosis using clinical features together with the identification of pathogenic variants in causal genes, and managing these rare disorders with a limited evidence base. For each condition, the present guidelines aim to inform clinical practice by summarizing key clinical features and useful investigations, criteria for molecular genetic diagnosis, and pathways for management and therapy. Specific, key recommendations were developed by combining the best research evidence available with the knowledge and clinical experience of panel members, to achieve a consensus.

Radiation-induced heart disease (RIHD), characterized by severe oxidative stress and immune dysregulation, is a serious condition affecting cancer patients undergoing thoracic radiation. Unfortunately, clinical interventions for RIHD are lacking. Selenium (Se) is a trace element with excellent antioxidant and immune-modulatory properties. However, its application in heart radioprotection remains challenging. Herein, we developed a novel bioactive Cordyceps militaris-based Se oral delivery system (Se@CM), which demonstrated superior radioprotection effects in vitro against X-ray-induced damage in H9C2 cells through suppressing excessive ROS generation, compared to the radioprotectant Amifostine. Moreover, Se@CM exhibited exceptional cardioprotective effects in vivo against X-ray irradiation, reducing cardiac dysfunction and myocardial fibrosis by balancing the redox equilibrium and modulating the expression of Mn-SOD and MDA. Additionally, Se@CM maintained immuno-homeostasis, as evidenced by the upregulated population of T cells and M2 macrophages through modulation of selenoprotein expression after irradiation. Together, these results highlight the remarkable antioxidant and immunity modulation properties of Se@CM and shed light on its promising application for cardiac protection against IR-induced disease. This research provides valuable insights into developing effective strategies for preventing and managing RIHD.

Selenocysteine (Sec) is an essential amino acid that distinguishes itself from cysteine by a selenium atom in place of a sulfur atom. This single change imparts distinct chemical properties to Sec which are crucial for selenoprotein (Sec-containing protein) function. These properties include a lower pKa, enhanced nucleophilicity, and reversible oxidation. However, studying Sec incorporation in proteins is a complex process. While we find Sec in all domains of life, each domain has distinct translation mechanisms. These mechanisms are unique to canonical translation and are composed of Sec-specific enzymes and an mRNA hairpin to drive recoding of the UGA stop codon with Sec. In this review, we highlight the obstacles that arise when investigating Sec insertion, and the role that Sec has in proteins. We discuss the strategic methods implemented in this field to address these challenges. Though the Sec translation system is complex, a remarkable amount of information has been obtained and specialized tools have been developed. Continued studies in this area will provide a deeper understanding on the role of Sec in the context of proteins, and the necessity that we have for maintaining this complex translation machinery to make selenoproteins. [ABSTRACT FROM AUTHOR]

Background/Objectives: As a hyperaccumulator of selenium (Se), Cardamine violifolia (Cv) and its peptide extract could ameliorate the negative effects of a high-fat diet (HFD). However, the effects of the coaccumulation of cadmium (Cd) in Se-enriched Cv (Cv2) and the potential confounding effect on the roles of enriched Se remain unknown. We aimed to investigate whether Cv2 could alleviate HFD-induced lipid disorder and liver damage. Methods: Three groups of 31-week-old female mice were fed for 41 weeks (n = 10–12) with a control Cv-supplemented diet (Cv1D, 0.15 mg Se/kg, 30 µg Cd/kg, and 10% fat calories), a control Cv-supplemented HFD (Cv1HFD, 45% fat calories), and a Cv2-supplemented HFD (Cv2HFD, 1.5 mg Se/kg, 0.29 mg Cd/kg, and 45% fat calories). Liver and serum were collected to determine the element concentrations, markers of liver injury and lipid disorder, and mRNA and/or protein expression of lipid metabolism factors, heavy metal detoxification factors, and selenoproteins. Results: Both Cv1HFD and Cv2HFD induced obesity, and Cv2HFD downregulated Selenoi and upregulated Dio3 compared with Cv1D. When comparing Cv2HFD against Cv1HFD, Cv2 increased the liver Se and Cd, the protein abundance of Selenoh, and the mRNA abundance of 10 selenoproteins; reduced the serum TG, TC, and AST; reduced the liver TG, lipid droplets, malondialdehyde, and mRNA abundance of Mtf1 and Mt2; and differentially regulated the mRNA levels of lipid metabolism factors. Conclusions: Cv2 alleviated HFD-induced lipid dysregulation and liver damage, which was probably associated with its unique Se speciation. However, further research is needed to explore the interaction of plant-coenriched Se and Cd and its effects on health. [ABSTRACT FROM AUTHOR]

The onset of Alzheimer's disease (AD) is significantly influenced by oxidative stress. Trace element selenium (Se) can be incorporated into selenoproteins to participate in redox regulation. In our previous study, it was found that brain-targeting chlorogenic acid-modified selenium nanoparticles (SeNPs) could effectively relieve oxidative stress in AD. However, the main mechanism of polyphenol-decorated SeNPs on antioxidant enzymes such as glutathione peroxidase is still unknown. Dihydromyricetin (DMY) is one polyphenol that has neuroprotective effects through antioxidant activities. In this study, chitosan (CS) was introduced as a stabilizer for the synthesis of a brain-targeted peptide (Tg: TGNYKALHPHNG) and DMY-modified SeNPs (Tg-CS/DMY@SeNPs). Tg-CS/DMY@SeNPs could improve the solubility of DMY and exhibited better free radical scavenging ability than DMY. Meanwhile, Tg-CS/DMY@SeNPs significantly enhanced the activity of antioxidant enzymes, which effectively inhibited ROS accumulation in Aβ aggregate-induced PC12 cells. More importantly, Tg-CS/DMY@SeNPs could activate the Nrf2/Keap-1 signaling pathway to regulate the activity of antioxidant enzymes, especially selenophenase glutathione peroxidase in the brain and liver of APP/PS1 mice. In that case, Tg-CS/DMY@SeNPs also prevented oxidative damage-induced apoptosis by inhibiting the Caspase-3 signaling pathway in the brain and liver of APP/PS1 mice. Finally, Tg-CS/DMY@SeNPs remarkably improved cognitive disorders in the APP/PS1 mice. These results indicated that Tg-CS/DMY@SeNPs exhibited promising therapeutic effects in the antioxidant therapy of AD. [ABSTRACT FROM AUTHOR]

Cognitive deficits associated with oxidative stress and the dysfunction of the central nervous system are present in some neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. Selenium (Se), an essential microelement, exhibits cognition-associated functions through selenoproteins mainly owing to its antioxidant property. Due to the disproportionate distribution of Se in the soil, the amount of Se varies greatly in various foods, resulting in a large proportion of people with Se deficiency worldwide. Numerous cell and animal experiments demonstrate Se deficiency-induced cognitive deficits and Se supplementation-improved cognitive performances. However, human studies yield inconsistent results and the mechanism of Se in cognition still remains elusive, which hinder the further exploration of Se in human cognition. To address the urgent issue, the review summarizes Se-contained foods (plant-based foods, animal-based foods, and Se supplements), brain selenoproteins, mechanisms of Se in cognition (improvement of synaptic plasticity, regulation of Zn2+ level, inhibition of ferroptosis, modulation of autophagy and de novo synthesis of L-serine), and effects of Se on cognitive deficits, as well as consequently sheds light on great potentials of Se in the prevention and treatment of cognitive deficits. [ABSTRACT FROM AUTHOR]

Introduction: fertility is necessary for hatchability of broiler breeder eggs. Roosters as half part of the fertility have a great role and with increasing age fertility is declined. It has been revealed that phospholipid fraction of the avian spermatozoa membranes has high proportion of polyunsaturated fatty acids (PUFA) and it is the reason why the spermatozoa are susceptible to free radical damages. To maintain sperm fertilizing ability, an antioxidant defense system is a crucial point. In avian semen the antioxidant system consists of natural antioxidants together with enzymes that have antioxidant characteristics such as glutathione peroxidase (GPx) and selenoprotein P (SEPP1) protects sperm against free radicals and their destructive metabolites. Antioxidants such as vitamin E and selenium (Se) have remarkable roles in avian reproduction. To gain great reproductive performances in breeders, optimum level of antioxidant in diet is thought to be necessary. By using additives such as selenium (Se) we can help delaying this reduction through antioxidant properties of Se. Replacing inorganic Se by new source of Se like the nano form in poultry diets can improve the fertility of broiler breeder eggs. This research was conducted to investigate the effect of Nano-Selenium (NanoSe) in comparison with sodium selenite on serum selenoprotein p (SEPP1) and glutathione peroxidase (GPx) content in broiler breeder roosters. Material and Method: A total of thirty Arbor Acres broiler breeder roosters (40 wks.) were randomly divided into five experimental groups. Each of which included 3 replicates of 2 birds. According to the arbor acres broiler breeder manual, the amount of 160 grams of diet was allocated daily for each rooster which had 12% crude protein and 2800 kcal/kg metabolizable energy. After one-week adaptation, birds were fed the corn-soybean meal-based basal diet (T1) supplemented with 0.3 mg/kg Sodium Selenite (T2), 0.15 mg/kg nano-Se (T3), 0.3 mg/kg nano-Se (T4) and 0.6 mg/kg nano-Se (T5). The duration of feeding experiment was four weeks. After the adaptation period, a 2.5 ml of blood sample was taken from each rooster. Two weeks later, in the middle of the research, blood sampling was done again from each bird. Four weeks after the treatment was done at the end of experiment, the roosters were humanely euthanized by cervical dislocation, the 3rd and last sampling was implemented at the end of experiment that as in the previous sampling was done, the blood samples were centrifuged and separated serum was stored in -20°C . Then serum concentration of the antioxidant “SEPP1” was measured by ELISA method and “GPx” was analyzed using a spectrophotometry kit. Results and discussion: By increasing the level of nanoselenium in diet, the serum concentration of SEPP1 and GPx also increases (P < 0.05) and using 0.6 mg/kg nano-Se in the diet reached the highest value. Based on a consideration of all experiment indexes, in this research, 0.6 mg/kg is suggested to be the best level of supplementation of nano-Se, and nano-Se showed higher contents of serum SEPP1 and GPx at the same amounts of nano-Se and sodium selenite supplementation. In conclusion, dietary supplementation of nano-Se was more effective than sodium selenite on serum SEPP1 and GPx concentration of tested selenoproteins in broiler breeder males. [ABSTRACT FROM AUTHOR]

Selenium is an essential trace element in our diet, crucial for the composition of human selenoproteins, which include 25 genes such as glutathione peroxidases and thioredoxin reductases. The regulation of the selenoproteome primarily hinges on the bioavailability of selenium, either from dietary sources or cell culture media. This selenium-dependent control follows a specific hierarchy, with "housekeeping" selenoproteins maintaining constant expression while "stress-regulated" counterparts respond to selenium level fluctuations. This study investigates the variability in fetal bovine serum (FBS) selenium concentrations among commercial batches and its effects on the expression of specific stress-related cellular selenoproteins. Despite the limitations of our study, which exclusively used HEK293 cells and focused on a subset of selenoproteins, our findings highlight the substantial impact of serum selenium levels on selenoprotein expression, particularly for GPX1 and GPX4. The luciferase reporter assay emerged as a sensitive and precise method for evaluating selenium levels in cell culture environments. While not exhaustive, this analysis provides valuable insights into selenium-mediated selenoprotein regulation, emphasizing the importance of serum composition in cellular responses and offering guidance for researchers in the selenoprotein field. [ABSTRACT FROM AUTHOR]

The genus Acanthamoeba comprises facultative pathogens, causing Acanthamoeba keratitis (AK) and granulomatous amoebic encephalitis (GAE). In both diseases, treatment options are limited, and drug development is challenging. This study aimed to investigate the role of the large thioredoxin reductase selenoprotein of Acanthamoeba (AcTrxR-L) as a potential drug target assessing the effects of the thioredoxin reductase inhibitors auranofin, TRi-1, and TRi-2 on AcTrxR-L activity and on the viability of Acanthamoeba trophozoites. Recombinant expression and purification of AcTrxR-L as a selenoprotein allowed assessments of its enzymatic activity, with reduction of various substrates, including different thioredoxin isoforms. Auranofin demonstrated potent inhibition towards AcTrxR-L, followed by TRi-1, and TRi-2 exhibiting lower effectiveness. The inhibitors showed variable activity against trophozoites in culture, with TRi-1 and TRi-2 resulting in strongly impaired trophozoite viability. Cytotoxicity tests with human corneal epithelial cells revealed lower susceptibility to all compounds compared to Acanthamoeba trophozoites, underscoring their potential as future amoebicidal agents. Altogether, this study highlights the druggability of AcTrxR-L and suggests it to be a promising drug target for the treatment of Acanthamoeba infections. Further research is warranted to elucidate the role of AcTrxR-L in Acanthamoeba pathogenesis and to develop effective therapeutic strategies targeting this redox enzyme.

Oxidative stress plays a critical role in the development of chronic ocular conditions including cataracts, age-related macular degeneration, and diabetic retinopathy. There is a need to explore the potential of topical antioxidants to slow the progression of those conditions by mediating oxidative stress and maintaining ocular health. Selenium has attracted considerable attention because it is a component of selenoproteins and antioxidant enzymes. The application of selenium to a patient can increase selenoprotein expression, counteracting the effect of reactive oxygen species by increasing the presence of antioxidant enzymes, and thus slowing the progression of chronic ocular disorders. Oxidative stress effects at the biomolecular level for prevalent ocular conditions are described in this review along with some of the known defensive mechanisms, with a focus on selenoproteins. The importance of selenium in the eye is described, along with a discussion of selenium studies and uses. Selenium's antioxidant and anti-inflammatory qualities may prevent or delay eye diseases. Recent breakthroughs in drug delivery methods and nanotechnology for selenium-based ocular medication delivery are enumerated. Different types of selenium may be employed in formulations aimed at managing ocular oxidative stress conditions. [ABSTRACT FROM AUTHOR]

Selenium is an important and essential trace element in organisms, but its effects on organisms are also a "double-edged sword". Selenium deficiency or excess can endanger the health of humans and animals. In order to thoroughly understand the nutritional value and toxicity hazards of selenium, researchers have conducted many studies on the model animal zebrafish. However, there is a lack of induction and summary of relevant research on which selenium acts on zebrafish. This paper provides a review of the reported studies. Firstly, this article summarizes the benefits of selenium on zebrafish from three aspects: Promoting growth, Enhancing immune function and anti-tumor ability, Antagonizing some pollutants, such as mercury. Then, three aspects of selenium toxicity to zebrafish are introduced: nervous system and behavior, reproductive system and growth, and damage to some organs. This article also describes how different forms of selenium compounds have different effects on zebrafish health. Finally, prospects for future research directions are presented. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to analyze the methylation pattern of deoxyribonucleic acid (CpG) sites in the DIO3_FA26 promoter region of patients with heart failure (HF) and explore the correlation between differential CpG methylation levels and various clinical parameters. Methods: Peripheral blood specimens were collected from 20 patients with HF and 20 healthy individuals. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was used to identify and detect the CpG sites in the DIO3_FA26 promoter region. CpG methylation levels were compared between patients with HF and healthy controls and patients with HF with different levels of cardiac function. Results: The methylation level of DIO3_FA26_CpG_17.18 in patients with HF was significantly lower than that in the healthy control group (P = 0.0002). Among patients with HF and cardiac function levels of I/II and III/IV, methylation levels of DIO3_FA26_CpG_24.25.26.27 (P = 0.0168) were significantly lower in those with III/IV cardiac function compared to those with I/II cardiac function. Conclusion: The methylation level of DIO3_FA26_CpG_17.18 is significantly reduced in patients with HF, and that of DIO3_FA26_CpG_24.25.26.27 is significantly decreased in patients with III/IV cardiac function. Variations in DIO3_FA26 methylation levels influence coagulation, liver and kidney functions, and routine blood indexes, including D-dimer, albumin, calcium, and hemoglobin. This study provides clinical evidence for the involvement of DIO3_FA26 methylation in the occurrence and development of HF and proposes novel targets for HF prevention and treatment.

Sulfide-releasing compounds reduce reperfusion injury by decreasing mitochondria-derived reactive oxygen species production. We previously characterised ammonium tetrathiomolybdate (ATTM), a clinically used copper chelator, as a sulfide donor in rodents. Here we assessed translation to large mammals prior to clinical testing. In healthy pigs an intravenous ATTM dose escalation revealed a reproducible pharmacokinetic/pharmacodynamic (PK/PD) relationship with minimal adverse clinical or biochemical events. In a myocardial infarction (1-h occlusion of the left anterior descending coronary artery)-reperfusion model, intravenous ATTM or saline was commenced just prior to reperfusion. ATTM protected the heart (24-h histological examination) in a drug-exposure-dependent manner (r2 = 0.58, p

Abnormal levels of reactive oxygen species (ROS) and the hypoxic microenvironment within bone defects are important factors that impede bone repair processes. Herein, an innovative ultrasound‐modulatable hydrogel platform with selenoprotein‐mediated antioxidant effects to promote bone injury repair is presented. This hydrogel platform encapsulates oxygen‐enriched selene‐incorporated thin‐shell silicon within methacrylate gelatin (O2‐PSSG). The resultant construct orchestrates the modulation of the bone‐defect microenvironment, thereby expediting the course of bone regeneration. Ultrasound (US) is used to regulate the pore size of the hydrogel to release selenium‐containing nanoparticles and promote the in situ synthesis of efficient intracellular selenoproteins and hydrogen peroxide consumption. As expected, O2‐PSSG rapidly releases selenocystine ([Sec]2) under US control to scavenge reactive oxygen species and maintain the homeostasis of bone marrow mesenchymal stem cells (BMSCs). Over time, the action of the system by selenoprotein increases the activation of Wnt/β‐catenin pathways and promotes the differentiation of BMSCs. Consequently, O2‐PSSG potentiates the antioxidant proficiency of BMSCs both in vitro and in vivo, alleviates hypoxic environments, promotes osteogenic differentiation, and expedites cranial bone repair in rat models. In summary, this study suggests that the designed and constructed US‐responsive antioxidant hydrogel is a promising prospective strategy for addressing bone defects and fostering bone regeneration. [ABSTRACT FROM AUTHOR]

Selenocysteine, the 21st amino acid specified by the genetic code, is a rare selenium-containing residue found in the catalytic site of selenoprotein oxidoreductases. Selenocysteine is analogous to the common cysteine amino acid, but its selenium atom offers physical–chemical properties not provided by the corresponding sulfur atom in cysteine. Catalytic sites with selenocysteine in selenoproteins of vertebrates are under strong purifying selection, but one enzyme, glutathione peroxidase 6 (GPX6), independently exchanged selenocysteine for cysteine <100 million years ago in several mammalian lineages. We reconstructed and assayed these ancient enzymes before and after selenocysteine was lost and up to today and found them to have lost their classic ability to reduce hydroperoxides using glutathione. This loss of function, however, was accompanied by additional amino acid changes in the catalytic domain, with protein sites concertedly changing under positive selection across distant lineages abandoning selenocysteine in glutathione peroxidase 6. This demonstrates a narrow evolutionary range in maintaining fitness when sulfur in cysteine impairs the catalytic activity of this protein, with pleiotropy and epistasis likely driving the observed convergent evolution. We propose that the mutations shared across distinct lineages may trigger enzymatic properties beyond those in classic glutathione peroxidases, rather than simply recovering catalytic rate. These findings are an unusual example of adaptive convergence across mammalian selenoproteins, with the evolutionary signatures possibly representing the evolution of novel oxidoreductase functions. [ABSTRACT FROM AUTHOR]

Selenium has been proven to influence several biological functions, showing to be an essential micronutrient. The functional studies demonstrated the benefits of a balanced selenium diet and how its deficiency is associated with diverse diseases, especially cancer and viral diseases. Selenium is an antioxidant, protecting the cells from damage, enhancing the immune system response, preventing cardiovascular diseases, and decreasing inflammation. Selenium can be found in its inorganic and organic forms, and its main form in the cells is the selenocysteine incorporated into selenoproteins. Twenty-five selenoproteins are currently known in the human genome: glutathione peroxidases, iodothyronine deiodinases, thioredoxin reductases, selenophosphate synthetase, and other selenoproteins. These proteins lead to the transport of selenium in the tissues, protect against oxidative damage, contribute to the stress of the endoplasmic reticulum, and control inflammation. Due to these functions, there has been growing interest in the influence of polymorphisms in selenoproteins in the last two decades. Selenoproteins' gene polymorphisms may influence protein structure and selenium concentration in plasma and its absorption and even impact the development and progression of certain diseases. This review aims to elucidate the role of selenoproteins and understand how their gene polymorphisms can influence the balance of physiological conditions. In this polymorphism review, we focused on the PubMed database, with only articles published in English between 2003 and 2023. The keywords used were "selenoprotein" and "polymorphism". Articles that did not approach the theme subject were excluded. Selenium and selenoproteins still have a long way to go in molecular studies, and several works demonstrated the importance of their polymorphisms as a risk biomarker for some diseases, especially cardiovascular and thyroid diseases, diabetes, and cancer. [ABSTRACT FROM AUTHOR]

Selenium (Se) is a naturally occurring essential micronutrient that is required for human health. The existing form of Se includes inorganic and organic. In contrast to the inorganic Se, which has low bioavailability and high cytotoxicity, organic Se exhibits higher bioavailability, lower toxicity, and has a more diverse composition and structure. This review presents the nutritional benefits of Se by listing and linking selenoprotein (SeP) functions to evidence of health benefits. The research status of SeP from foods in recent years is introduced systematically, particularly the sources, biochemical transformation and speciation, and the bioactivities. These aspects are elaborated with references for further research and utilization of organic Se compounds in the field of health. [ABSTRACT FROM AUTHOR]

Background: The antioxidant enzyme GPX3 is a selenoprotein that transports selenium in blood and maintains its levels in peripheral tissues. Aberrant GPX3 expression is strongly linked to the development of some tumors. However, there is a scarcity of studies examining the pan-cancer expression patterns and prognostic relevance of GPX3. Methods: GPX3 expression levels in normal tissues and multiple tumors were analyzed using TCGA, CCLE, GTEx, UALCAN and HPA databases. Forest plots and KM survival curves were utilized to evaluate the correlation between GPX3 expression and the outcome of tumor patients. The prognostic value of GPX3 in LGG was assessed utilizing the CGGA datasets, and that in STAD was tested by TCGA and GEO databases. A nomogram was then constructed to predict OS in STAD using R software. Additionally, the impact of GPX3 on post-chemoradiotherapy OS in patients with LGG and STAD was evaluated using the KM method. The multiplicative interaction of GPX3 expression, chemotherapy and radiotherapy on STAD and LGG was analyzed using logistic regression models. The correlation of GPX3 with the immune infiltration, immune neoantigens and MMR genes were investigated in TCGA cohort. Results: GPX3 exhibited downregulation across 21 tumor types, including STAD, with its decreased expression significantly associated with improved OS, DFS, PFS and DSS. Conversely, in LGG, low levels of GPX3 expression were indicative of a poorer prognosis. Univariate and multivariate Cox models further identified GPX3 as an independent predictor of STAD, and a nomogram based on GPX3 expression and other independent factors showed high level of predictive accuracy. Moreover, low GPX3 expression and chemotherapy prolonged the survival of STAD. In LGG patients, chemoradiotherapy, GPX3 and chemotherapy, and GPX3 and chemoradiotherapy may improve prognosis. Our observations reveal a notable connection between GPX3 and immune infiltration, immune neoantigens, and MMR genes. Conclusions: The variations in GPX3 expression are linked to the controlling tumor development and could act as a promising biomarker that impacts the prognosis of specific cancers like STAD and LGG.

Vascular diseases, a leading cause of death in human, are strongly associated with pathological damage to blood vessels. The selenoprotein (Sel) have been reported to play important roles in vascular disease. However, the role of SelO in vascular disease has not been conclusively investigated. The present experiment was to investigate the regulatory mechanism of the effect of SelO on the permeability of vascular endothelial. The H.E staining, FITC-Dextran staining, Dil-AC-LDL staining and FITC-WGA staining showed that vascular structure was damaged, and intercellular junctions were disrupted with selenium (Se)-deficient. Immunohistochemistry, qPCR and Western blot revealed decreased expression of the adhesion plaque proteins vinculin, talin and paxillin, decreased expression of the vascular connectivity effector molecules connexin, claudin-1 and E-cadherin and increased expression of JAM-A and N-cadherin, as well as decreased expression of the ZO-1 signaling pathways ZO-1, Rock, rhoGEF, cingulin and MLC-2. In a screening of 24 Sel present in mice, SelO showed the most pronounced changes in vascular tissues, and a possible association between SelO and vascular intercellular junction effectors was determined using IBM SPSS Statistics 25. Silencing of SelO, vascular endothelial intercellular junction adverse effects present. The regulatory relationship between SelO and vascular endothelial intercellular junctions was determined. The results showed that Se deficiency lead to increased vascular endothelial permeability and vascular tissue damage by decreasing SelO expression, suggesting a possible role for SelO in regulating vascular endothelial permeability.

Thioredoxin reductase (TXNRD) is a selenoprotein that plays a crucial role in cellular antioxidant defense. Previously, a distinctive guiding bar motif was identified in TXNRD1, which influences the transfer of electrons. In this study, utilizing single amino acid substitution and Excitation-Emission Matrix (EEM) fluorescence spectrum analysis, we discovered that the guiding bar communicates with the FAD and modulates the electron flow of the enzyme. Differential Scanning Fluorimetry (DSF) analysis demonstrated that the aromatic amino acid in guiding bar is a stabilizer for TXNRD1. Kinetic analysis revealed that the guiding bar is vital for the disulfide reductase activity but hinders the selenocysteine-independent reduction activity of TXNRD1. Meanwhile, the guiding bar shields the selenocysteine residue of TXNRD1 from the attack of electrophilic reagents. We also found that the inhibition of TXNRD1 by caveolin-1 scaffolding domain (CSD) peptides and compound LCS3 did not bind to the guiding bar motif. In summary, the obtained results highlight new aspects of the guiding bar that restrict the flexibility of the C-terminal redox motif and govern the transition from antioxidant to pro-oxidant.

Selenium is an essential trace element in humans, critical to the normal physiology in all animal species. The main form of selenium in food is selenomethionine, selenocysteine and a variety of organic compounds, while inorganic salts mainly occur in food supplements. In animals and humans, selenium occurs as selenocysteine in selenoproteins encoded by 25 genes (specific selenium pool). Several selenoproteins are part of the antioxidant enzyme system and serve as oxido-reductases and in thyroid hormone regulation. SelenoproteinP (SELENOP) transports selenium to peripheral tissues, is the main plasma selenoprotein, and has been used as biomarker of selenium status and intake. SELENOP in plasma represents a saturable pool of selenium and is maximised at a selenium concentration in plasma of about 110 µg/L or an intake of selenomethionine at about 1.2 µg/kg body weight in adults. In Finland, with an estimated selenium intake of 88 µg/day in men and 68 µg/day in women, the average selenium concentration in plasma is about 110 µg/L. Imported wheat from selenium rich areas is an important dietary source in Norway. Dietary intakes in the Nordic and Baltic area vary from 39 to 88 µg/day in men and 22 to 68 µg/day in women, the highest levels were from Finland. Most intervention trials on the effect of selenium supplementation on health outcomes have been carried out in ‘selenium-replete’-populations and show no beneficial effect, which from a nutritional point of view would rather not be expected. Some intervention studies conducted in populations low in selenium have showed a beneficial effect. Observational studies suggest an inverse relationship between selenium status and risk of cardiovascular diseases (CVDs), cancer and all-cause mortality, and some other outcomes at low levels of intake (

Abstract Ferroptosis has emerged as an attractive strategy in cancer therapy. Understanding the operational networks regulating ferroptosis may unravel vulnerabilities that could be harnessed for therapeutic benefit. Using CRISPR‐activation screens in ferroptosis hypersensitive cells, we identify the selenoprotein P (SELENOP) receptor, LRP8, as a key determinant protecting MYCN‐amplified neuroblastoma cells from ferroptosis. Genetic deletion of LRP8 leads to ferroptosis as a result of an insufficient supply of selenocysteine, which is required for the translation of the antiferroptotic selenoprotein GPX4. This dependency is caused by low expression of alternative selenium uptake pathways such as system Xc−. The identification of LRP8 as a specific vulnerability of MYCN‐amplified neuroblastoma cells was confirmed in constitutive and inducible LRP8 knockout orthotopic xenografts. These findings disclose a yet‐unaccounted mechanism of selective ferroptosis induction that might be explored as a therapeutic strategy for high‐risk neuroblastoma and potentially other MYCN‐amplified entities.

Background: Keshan disease (KD) is a fatal dilated cardiomyopathy that is mainly endemic through northeast to southwest China's low-selenium belt. KD may result in adverse outcomes such as heart enlargement, heart failure, and cardiogenetic death. Results: The nutritional biogeochemical etiology theory has been acknowledged as one of the primary etiology hypotheses for KD, primarily suggesting that selenium deficiency and coxsackie virus infection are the main causes of KD. The element selenium, which has antioxidant and immune-enhancing effects, is a component of selenoprotein. The prevention and treatment of KD are impacted by selenium supplementation. The pathogenesis of KD is associated with related genetic polymorphisms and gene mutations, such as SEPHS2, SCN5A, GPX-1, and ALAD. Conclusion: The pathogenic mechanism has not yet been completely explored. ALAD gene may be a causative locus for KD, and selenium supplementation reversed the pathological process of KD.

ABSTRACT: Selenium (i.e., Se) is a trace element that is vital in poultry nutrition, and optimal forms and levels of Se are critical for poultry productivity and health. This study aimed to compare the effects of sodium selenite (SS), yeast selenium (SY), and methionine selenium (SM) at selenium levels of 0.15 mg/kg and 0.30 mg/kg on production performance, egg quality, egg selenium content, antioxidant capacity, immunity and selenoprotein expression in laying hens. The trial was conducted in a 3 × 2 factorial arrangement, and a total of 576 forty-three-wk-old Hyland Brown laying hens were randomly assigned into 6 treatment groups, with diets supplemented with 0.15 mg Se/kg and 0.3 mg Se/kg of SS, SY and SM for 8 wk, respectively. Results revealed that SM increased the laying rate compared to SS and SY (P < 0.05), whereas different selenium levels had no effect. Organic selenium improved egg quality, preservation performance, and selenium deposition compared to SS (P < 0.05), while SY and SM had different preferences for Se deposition in the yolk and albumen. Also, organic selenium enhanced the antioxidant capacity and immune functions of laying hens at 0.15 mg Se/kg, whereas no obvious improvement was observed at 0.30 mg Se/kg. Moreover, SY and SM increased the mRNA expression of most selenoproteins compared to SS (P < 0.05), with SM exhibiting a more pronounced effect. Correlation analysis revealed a strong positive association between glutathione peroxidase 2 (GPx2), thioredoxin reductases (TrxRs), selenoprotein K (SelK), selenoprotein S (SelS), and antioxidant and immune properties. In conclusion, the use of low-dose organic selenium is recommended as a more effective alternative to inorganic selenium, and a dosage of 0.15 mg Se/kg from SM is recommended based on the trail conditions.

Selenocysteine (Sec), the 21st amino acid, is structurally similar to cysteine but with a sulfur to selenium replacement. This single change retains many of the chemical properties of cysteine but often with enhanced catalytic and redox activity. Incorporation of Sec into proteins is unique, requiring additional translation factors and multiple steps to insert Sec at stop (UGA) codons. These Sec-containing proteins (selenoproteins) are found in all three domains of life where they often are involved in cellular homeostasis (e.g., reducing reactive oxygen species). The essential role of selenoproteins in humans requires us to maintain appropriate levels of selenium, the precursor for Sec, in our diet. Too much selenium is also problematic due to its toxic effects. Deciphering the role of Sec in selenoproteins is challenging for many reasons, one of which is due to their complicated biosynthesis pathway. However, clever strategies are surfacing to overcome this and facilitate production of selenoproteins. Here, we focus on one of the 25 human selenoproteins, selenoprotein M (SELENOM), which has wide-spread expression throughout our tissues. Its thioredoxin motif suggests oxidoreductase function; however, its mechanism and functional role(s) are still being uncovered. Furthermore, the connection of both high and low expression levels of SELENOM to separate diseases emphasizes the medical application for studying the role of Sec in this protein. In this review, we aim to decipher the role of SELENOM through detailing and connecting current evidence. With multiple proposed functions in diverse tissues, continued research is still necessary to fully unveil the role of SELENOM. [ABSTRACT FROM AUTHOR]

α-lipoic acid (LA) is an essential cofactor for mitochondrial dehydrogenases and is required for cell growth, metabolic fuel production, and antioxidant defense. In vitro, LA binds copper (Cu) with high affinity and as an endogenous membrane permeable metabolite could be advantageous in mitigating the consequences of Cu overload in human diseases. We tested this hypothesis in 3T3-L1 preadipocytes with inactivated Cu transporter Atp7a; these cells accumulate Cu and show morphologic changes and mitochondria impairment. Treatment with LA corrected the morphology of Atp7a-/-cells similar to the Cu chelator bathocuproinedisulfonate (BCS) and improved mitochondria function; however, the mechanisms of LA and BCS action were different. Unlike BCS, LA did not decrease intracellular Cu but instead increased selenium levels that were low in Atp7a-/- cells. Proteome analysis confirmed distinct cell responses to these compounds and identified upregulation of selenoproteins as the major effect of LA on preadipocytes. Upregulation of selenoproteins was associated with an improved GSH:GSSG ratio in cellular compartments, which was lowered by elevated Cu, and reversal of protein oxidation. Thus, LA diminishes toxic effects of elevated Cu by improving cellular redox environment. We also show that selenium levels are decreased in tissues of a Wilson disease animal model, especially in the liver, making LA an attractive candidate for supplemental treatment of this disease. [ABSTRACT FROM AUTHOR]

Selenium (Se) is an essential micronutrient, and animals biosynthesize selenoproteins from various selenocompounds such as inorganic salts and organic selenocompounds as a Se source. In addition to the inorganic and organic forms of Se, it is also known that elemental Se is biologically synthesized at the nanoscale in nature. Biologically synthesized Se nanoparticles (Se-NPs), i.e., biogenic Se-NPs (Se-BgNPs), have not been fully investigated as a Se source compared with the other forms of Se. In this study, we evaluated the nutritional availability of Se-BgNPs biosynthesized in E. coli and revealed that Se-BgNPs were less assimilated into selenoproteins in rats as a Se source than inorganic Se salt or chemically synthesized Se-NPs. Se-BgNPs showed tolerance toward digestion and low absorbability in gut, which resulted in the low nutritional availability. Se-BgNPs seem to be coated with a biomaterial that functions to reduce their toxicity toward E. coli and at the same time lowers their availability to animals. [ABSTRACT FROM AUTHOR]

Glutathione peroxidase (GPx) is an important antioxidant enzyme. Selenocysteine (Sec)-containing GPxs (Sec-GPxs) are usually superior to their conventional cysteine-containing counterparts (Cys-GPxs), which make up the majority of the natural GPxs but display unsuitable activity and stability for industrial applications. This study first heterologously expressed and characterized a Cys-GPx from Lactococcus lactis (LlGPx), systematically exchanged all the three Cys to Sec and introduced an extra Sec. The results showed that the insertion of Sec at the active site could effectively increase the enzyme activity and confer a lower optimal pH value on the mutants. The double mutant C36U/L157U increased by 2.65 times (5.12 U/mg). The thermal stability of the C81U mutant was significantly improved. These results suggest that site-directed Sec incorporation can effectively improve the enzymatic properties of LlGPx, which may be also used for the protein engineering of other industrial enzymes containing catalytic or other functional cysteine residues. [ABSTRACT FROM AUTHOR]

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.

Oxidative stress plays a critical role in the development of chronic ocular conditions including cataracts, age-related macular degeneration, and diabetic retinopathy. There is a need to explore the potential of topical antioxidants to slow the progression of those conditions by mediating oxidative stress and maintaining ocular health. Selenium has attracted considerable attention because it is a component of selenoproteins and antioxidant enzymes. The application of selenium to a patient can increase selenoprotein expression, counteracting the effect of reactive oxygen species by increasing the presence of antioxidant enzymes, and thus slowing the progression of chronic ocular disorders. Oxidative stress effects at the biomolecular level for prevalent ocular conditions are described in this review along with some of the known defensive mechanisms, with a focus on selenoproteins. The importance of selenium in the eye is described, along with a discussion of selenium studies and uses. Selenium’s antioxidant and anti-inflammatory qualities may prevent or delay eye diseases. Recent breakthroughs in drug delivery methods and nanotechnology for selenium-based ocular medication delivery are enumerated. Different types of selenium may be employed in formulations aimed at managing ocular oxidative stress conditions.

With the increasing of global mean surface air temperature, heat stress (HS) induced by extreme high temperature has become a key factor restricting the poultry industry. Liver is the main metabolic organ of broilers, HS induces liver damage and metabolic disorders, which impairs the health of broilers and affects food safety. As an essential trace element for animals, selenium (Se) involves in the formation of antioxidant system, and its biological functions are generally mediated by selenoproteins. However, the mechanism of Se against HS induced liver damage and metabolic disorders in broilers is inadequate. Therefore, we developed the chronic heat stress (CHS) broiler model and investigated the potential protection mechanism of organic Se (selenomethionine, SeMet) on CHS induced liver damage and metabolic disorders. In present study, CHS caused liver oxidative damage, and induced hepatic lipid accumulation and glycogen infiltration of broilers, which are accompanied by mitochondrial dysfunction, abnormal mitochondrial tricarboxylic acid (TCA) cycle and endoplasmic reticulum (ER) stress. Dietary SeMet supplementation increased the hepatic Se concentration and exhibited protective effects via promoting the expression of selenotranscriptome and several key selenoproteins (GPX4, TXNRD2, SELENOK, SELENOM, SELENOS, SELENOT, GPX1, DIO1, SELENOH, SELENOU and SELENOW). These key selenoproteins synergistically improved the antioxidant capacity, and mitigated the mitochondrial dysfunction, abnormal mitochondrial TCA cycle and ER stress, thus recovered the hepatic triglyceride and glycogen concentration. What's more, SeMet supplementation suppressed lipid and glycogen biosynthesis and promoted lipid and glycogen breakdown in liver of broilers exposed to CHS though regulating the AMPK signals. Overall, our present study reveals a potential mechanism that Se alleviates environment HS induced liver damage and glycogen and lipid metabolism disorders in broilers, which provides a preventive and/or treatment measure for environment HS-dependent hepatic metabolic disorders in poultry industry.

Selenium, a trace mineral with various biological functions, has become a focal point in prostate cancer research. This review aims to present a comprehensive overview of selenium's involvement in prostate cancer, covering its impact on prevention, development, treatment, and underlying mechanisms. Observational studies have revealed a link between selenium levels and selenoproteins with prostate cancer progression. However, randomized controlled studies have shown that selenium supplementation does not prevent prostate cancer (HR: 0.95; 95% CI 0.80–1.13). This discrepancy might be attributed to selenoprotein single nucleotide polymorphisms. In the context of combinatorial therapy, selenium has demonstrated promising synergistic potential in the treatment of prostate cancer. Emerging evidence highlights the significant role of selenium and selenoproteins in prostate cancer, encompassing AR signaling, antioxidative properties, cell death, cell cycle regulation, angiogenesis, epigenetic regulation, immunoregulation, epithelial–mesenchymal transformation, and redox signal. In conclusion, selenium's diverse properties make it a promising trace mineral in prostate cancer prevention, development, and treatment and as a platform for exploring novel agents. [ABSTRACT FROM AUTHOR]

The current guidelines suggest routine screening for non-alcoholic fatty liver disease (NAFLD) in patients with polycystic ovary syndrome (PCOS). Hepatokines seem to be promising surrogate endpoints for the diagnosis and severity of NAFLD. PCOS has its onset in adolescence and its metabolic sequalae begin during the same period. There are scarce data on the hepatokine profile of adolescent PCOS patients. This case–control study examined the serum profile of the hepatokines sex hormone-binding globulin (SHBG), selenoprotein P, fibroblast growth factor 21 (FGF21), and fetuin A in a sample of adolescent PCOS patients, and their association to metabolic and hormonal parameters. The selenoprotein P and SHBG serum concentrations were significantly decreased in PCOS patients vs. the controls (median (IQR), 2.47 (0.40) vs. 2.66 (0.36) μg/mL, p = 0.025; mean ± SD, 41.71 ± 19.41 vs. 54.94 ± 22.12 nmol/L, p = 0.011, respectively), whereas selenoprotein P was significantly and positively associated with testosterone (r = 0.325, p = 0.007) and the free androgen index (r = 0.361, p = 0.002). The SHBG demonstrated multiple significant negative correlations with adverse metabolic parameters. Among the PCOS patients, the FGF21 concentrations were significantly higher in those with NAFLD, whereas a 1 pg/mL increase in the FGF21 concentration increased the odds of NAFLD diagnosis by liver ultrasound by 1%, suggesting FGF21 as a potential biomarker for hepatic disease in females with PCOS in adolescence. Fetuin A was the least differentiated hepatokine between the PCOS patients and controls with the least associations with metabolic and hormonal parameters. [ABSTRACT FROM AUTHOR]

Background: Neurodegenerative diseases (NDs) have posed significant challenges to public health, and it is crucial to understand their mechanisms in order to develop effective therapeutic strategies. Recent studies have highlighted the potential role of selenium in ND pathogenesis, as it plays a vital role in maintaining cellular homeostasis and preventing oxidative damage. However, a comprehensive analysis of the association between selenium and NDs is still lacking. Method: Five public databases, namely PubMed, Web of Science, EMBASE, Cochrane and Clinical Trials, were searched in our research. Random model effects were chosen, and Higgins inconsistency analyses (I2), Cochrane's Q test and Tau2 were calculated to evaluate the heterogeneity. Result: The association of selenium in ND patients with Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD) was studied. A statistically significant relationship was only found for AD patients (SMD = −0.41, 95% CI (−0.64, −0.17), p < 0.001), especially for erythrocytes. However, no significant relationship was observed in the analysis of the other four diseases. Conclusion: Generally, this meta-analysis indicated that AD patients are strongly associated with lower selenium concentrations compared with healthy people, which may provide a clinical reference in the future. However, more studies are urgently needed for further study and treatment of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Ferroptosis has emerged as an attractive strategy in cancer therapy. Understanding the operational networks regulating ferroptosis may unravel vulnerabilities that could be harnessed for therapeutic benefit. Using CRISPR‐activation screens in ferroptosis hypersensitive cells, we identify the selenoprotein P (SELENOP) receptor, LRP8, as a key determinant protecting MYCN‐amplified neuroblastoma cells from ferroptosis. Genetic deletion of LRP8 leads to ferroptosis as a result of an insufficient supply of selenocysteine, which is required for the translation of the antiferroptotic selenoprotein GPX4. This dependency is caused by low expression of alternative selenium uptake pathways such as system Xc−. The identification of LRP8 as a specific vulnerability of MYCN‐amplified neuroblastoma cells was confirmed in constitutive and inducible LRP8 knockout orthotopic xenografts. These findings disclose a yet‐unaccounted mechanism of selective ferroptosis induction that might be explored as a therapeutic strategy for high‐risk neuroblastoma and potentially other MYCN‐amplified entities. Synopsis: The low‐density lipoprotein receptor (LRP8) was identified as a critical suppressor of ferroptosis in MYCN‐amplified neuroblastoma. Blocking selenium/selenocysteine uptake mechanisms via LRP8 offers a selective strategy to induce ferroptosis and disrupt GPX4 function. Ferroptosis, a cell death modality, is gaining interest as a therapeutic approach against challenging tumors.GPX4 is crucial for suppressing ferroptosis, but suitable in vivo inhibitors are lacking, limiting translation to cancer therapies.Genome‐wide and single‐cell CRISPR‐activation screens reveal LRP8 as a critical ferroptosis suppressor in MYCN‐amplified neuroblastoma.Blocking selenium/selenocysteine uptake via LRP8 disrupts GPX4 function and selectively induces ferroptotic cell death.LRP8 dependency emerges as the result of the low system Xc− activity suggesting that targeting LRP8 could be explore in other entities such as AML and lymphoma. [ABSTRACT FROM AUTHOR]

Selenium deficiency can affect the level of selenoprotein in organs and tissues and cause inflammation. However, the mechanism of selenium deficiency on jejunal injury in chickens remains unclear. In this study, we established a selenium deficiency model in chickens by feeding a low selenium diet and observed ultrastructural and pathological changes in the jejunum. The expression levels of 25 selenoproteins, the levels of oxidative stress, tight junction (TJ) proteins, and antimicrobial peptides (AMP), as well as the expression levels of factors related to inflammatory signaling pathways, were examined in the intestine and analyzed using principal component analysis (PCA). The results of PCA and quantitative real-time PCR (qRT-PCR) showed that selenium deficiency mainly affected the expression of antioxidant selenoproteins in chicken jejunum, especially glutathione peroxidases, thioredoxin reductase, and iodothyronine deiodinase, thus weakening the antioxidant function in the intestine and inducing oxidative stress. We also found disruption of intestinal TJ structures, a significant reduction in TJ protein expression, and downregulation of antimicrobial peptide levels, suggesting that selenium deficiency led to damage of the intestinal barrier. In addition, a significant increase in inflammatory cell infiltration and expression of inflammatory factors was observed in the jejunum, indicating that selenium deficiency induces inflammatory injury. In conclusion, selenium deficiency downregulates antioxidant selenoproteins levels, induces oxidative stress, decreases intestinal AMP levels, and leads to inflammatory injury and disruption of the intestinal barrier in the jejunum. These results shed new light on the molecular mechanisms of intestinal damage caused by selenium deficiency. [ABSTRACT FROM AUTHOR]

The epitranscriptomic writer Alkylation Repair Homolog 8 (ALKBH8) is a transfer RNA (tRNA) methyltransferase that modifies the wobble uridine of selenocysteine tRNA to promote the specialized translation of selenoproteins. Using Alkbh8 deficient (Alkbh8def) mice, we have investigated the importance of epitranscriptomic systems in the response to naphthalene, an abundant polycyclic aromatic hydrocarbon and environmental toxicant. We performed basal lung analysis and naphthalene exposure studies using wild type (WT), Alkbh8de f and Cyp2abfgs-null mice, the latter of which lack the cytochrome P450 enzymes required for naphthalene bioactivation. Under basal conditions, lungs from Alkbh8def mice have increased markers of oxidative stress and decreased thioredoxin reductase protein levels, and have reprogrammed gene expression to differentially regulate stress response transcripts. Alkbh8def mice are more sensitive to naphthalene induced death than WT, showing higher susceptibility to lung damage at the cellular and molecular levels. Further, WT mice develop a tolerance to naphthalene after 3 days, defined as resistance to a high challenging dose after repeated exposures, which is absent in Alkbh8def mice. We conclude that the epitranscriptomic writer ALKBH8 plays a protective role against naphthalene-induced lung dysfunction and promotes naphthalene tolerance. Our work provides an early example of how epitranscriptomic systems can regulate the response to environmental stress in vivo.

Selenium (Se)-enriched lactic acid bacteria (LAB) are live bacteria preparations that accumulate and bio-transform inorganic Se into organic Se forms including Se-nanoparticles (SeNPs), Se-amino acids and selenoproteins. Se-enriched LAB can play the dual role of organic Se supplement and probiotic effects, and have great applications in the food and biomedical fields. Therefore, more and more attentions have been paid on the Se-enriched LAB. This paper firstly summarized the factors affecting the Se-enrichment efficiency of Se-enriched LAB, then discussed the metabolic mechanisms and physiological functions of Se-enriched LAB, and finally reviewed their applications in food production, in order to provide a guidance for the theoretical and practical implementation of Se-enriched LAB. We concluded that 1) both biomass and the amount of Se enrichment should be used as dual indicators to screen Se-enriched LAB and comprehensively optimize the influencing factors including initial Se concentration, pH, inoculation amount, species of LAB to ensure the Se enrichment efficiency. 2) The metabolic mechanism underlining Se-enriched LAB needs to be further revealed, which will facilitate the production of higher value Se compounds by LAB. 3) The proven physiological functions of Se-enriched LAB include 5 categories: antioxidant activity, antibacterial activity, improving the physical function of animals, detoxification and disease prevention. However, the application of Se-enriched LAB in medical field currently still lacks clinical research, and convincing clinical evidence of effectiveness for Se-enriched LAB on human being must be established. 4) The application in the food field will benefit from the stable existence in the food system of Se-enriched LAB and public acceptance, which come before the various health benefits. In any case, the great potential value of Se-enriched LAB formulations deserves further comprehensive exploration and development.

There will be generated some adverse conditions in the process of acquculture farming with the continuous improvement of the intensive degree of modern aquaculture, such as crowding stress, hypoxia, and malnutrition, which will easily lead to oxidative stress. Se is an effective antioxidant, participating and playing an important role in the antioxidant defense system of fish. This paper reviews the physiological functions of selenoproteins in resisting oxidative stress in aquatic animals, the mechanisms of different forms of Se in anti-oxidative stress in aquatic animals and the harmful effects of lower and higher levels of Se in aquaculture. To summarize the application and research progress of Se in oxidative stress in aquatic animals and provide scientific references for its application in antioxidative stress in aquaculture. [ABSTRACT FROM AUTHOR]

Selenium is a trace mineral that is essential for health. After being obtained from food and taken up by the liver, selenium performs various physiological functions in the body in the form of selenoproteins, which are best known for their redox activity and anti-inflammatory properties. Selenium stimulates the activation of immune cells and is important for the activation of the immune system. Selenium is also essential for the maintenance of brain function. Selenium supplements can regulate lipid metabolism, cell apoptosis, and autophagy, and have displayed significant alleviating effects in most cardiovascular diseases. However, the effect of increased selenium intake on the risk of cancer remains unclear. Elevated serum selenium levels are associated with an increased risk of type 2 diabetes, and this relationship is complex and nonlinear. Selenium supplementation seems beneficial to some extent; however, existing studies have not fully explained the influence of selenium on various diseases. Further, more intervention trials are needed to verify the beneficial or harmful effects of selenium supplementation in various diseases. [ABSTRACT FROM AUTHOR]

Selenium is an essential trace element to maintain good health. This retrospective study investigated the prevalence of selenium deficiency and its effect on overt hepatic encephalopathy (OHE) in patients with chronic liver disease (CLD). Patients who underwent serum selenium level measurement between January 2021 and April 2022 were enrolled. The factors associated with selenium deficiency (≤10 µg/dL) and the association between selenium deficiency and OHE were analyzed. Among 98 eligible patients, 24% were observed to have selenium deficiency, with a median serum selenium level of 11.8 µg/dL. The serum selenium levels were significantly lower in patients with cirrhosis than in those with chronic hepatitis (10.9 µg/dL vs. 12.4 µg/dL; p = 0.03). The serum selenium levels were negatively correlated with mac-2 binding protein glycan isomer, the FIB-4 index, albumin-bilirubin (ALBI) score, and Child–Pugh score. The ALBI score remained significantly associated with selenium deficiency (odds ratio, 3.23; 95% confidence interval [CI], 1.56–6.67). During a median follow-up period of 2.9 months, nine patients experienced OHE. Selenium deficiency was associated with OHE (hazard ratio, 12.75; 95% CI, 2.54–70.22). Selenium deficiency is highly prevalent in patients with CLD and is associated with an increased risk of OHE development. [ABSTRACT FROM AUTHOR]

Intrauterine growth retardation (IUGR) causes oxidative stress in the skeletal muscle. Serine and selenoproteins are involved in anti-oxidative processes; however, whether IUGR affects selenium status and whether serine has beneficial effects remain elusive. Here, we investigated the effects of serine administration on selenium nutritional status and oxidative stress in the longissimus dorsi muscle of piglets with IUGR. Six newborn Min piglets having normal birth weight were administered saline, and 12 IUGR piglets were either administered saline or 0.8% serine. The results showed a lower selenium content in skeletal muscle in IUGR piglets, which was restored after serine administration. IUGR piglets showed a disturbed expression of genes encoding selenoproteins, with decreased expression of GPX2, GPX4, TXNRD1, and TXNRD3 and increased expression of DIO1, DIO2, SELF, SELM, SELP, and SELW. Notably, serine administration restored the expression levels of these genes. In accordance with the changes in gene expression, the activity of GPX, TXNRD, and DIO and the content of GSH and SELP were also altered, whereas serine administration restored their contents and activities. Moreover, we observed severe oxidative stress in the skeletal muscle of IUGR piglets, as indicated by decreased GSH content and increased MDA and PC content, whereas serine administration alleviated these changes. In conclusion, our results indicate that IUGR piglets showed a disturbed expression of genes encoding selenoproteins, accompanied by severe oxidative stress. Serine administration can improve selenium status, oxidative stress, and mitochondrial function in the longissimus dorsi muscle of piglets with IUGR. These results suggest that serine could potentially be used in the treatment of IUGR in piglets. [ABSTRACT FROM AUTHOR]

Effects of selenoproteins on many renal diseases have been reported. However, their role in renal ischemia–reperfusion (I/R) injury is unclear. The present study was performed to investigate the impact of ebselen and renal I/R injury on the expression of selenoproteins. Sprague–Dawley rats were pretreated with or without ebselen (10 mg/kg) through a daily single oral administration from 3 days before renal I/R surgery. RT-qPCR (real-time quantitative PCR) was performed to determine the mRNA expression of 25 selenoprotein genes in the renal tissues. The expression levels of two selenoproteins, including GPX3 (glutathione peroxidase 3) and DIO1 (iodothyronine deiodinase 1), were evaluated by Western blot or/and IHF (immunohistofluorescence) assays. Furthermore, renal function, renal damage, oxidative stress, and apoptosis were assessed. The results showed that in renal I/R injury, the mRNA levels of 15 selenoprotein genes (GPX1, GPX3, GPX4, DIO1, DIO2, TXNRD2, TXNRD3, SEPHS2, MSRB1, SELENOF, SELENOK, SELENOO, SELENOP, SELENOS, and SELENOT) were decreased, whereas those of eight selenoprotein genes (GPX2, GPX6, DIO3, TXNRD1, SELENOH, SELENOM, SELENOV, and SELENOW) were increased. I/R also induced a reduction in the expression levels of GPX3 and DIO1 proteins. In addition, our results indicated that ebselen reversed the changes in those selenoprotein genes, excluding SELENOH, SELENOM, SELENOP, and SELENOT, in renal I/R injury and alleviated I/R-induced renal dysfunction, tissue damage, oxidative stress, and apoptosis. To our knowledge, this is the first study to investigate the changes of 25 mammalian selenoprotein genes in renal I/R injury kidneys. The present study also provided more evidence for the roles of ebselen against renal I/R injury. [ABSTRACT FROM AUTHOR]

Selenoprotein glutathione peroxidases (GPX), like ubiquitously expressed GPX1 and the ferroptosis modulator GPX4, enact antioxidant activities by reducing hydroperoxides using glutathione. Overexpression of these enzymes is common in cancer and can be associated with the development of resistance to chemotherapy. GPX1 and GPX4 inhibitors have thus shown promise as anti-cancer agents, and targeting other GPX isoforms may prove equally beneficial. Existing inhibitors are often promiscuous, or modulate GPXs only indirectly, so novel direct inhibitors identified through screening against GPX1 and GPX4 could be valuable. Here, we developed optimized glutathione reductase (GR)-coupled GPX assays for the biochemical high-throughput screen (HTS) of almost 12,000 compounds with proposed mechanisms of action. Initial hits were triaged using a GR counter-screen, assessed for isoform specificity against an additional GPX isoform, GPX2, and were assessed for general selenocysteine-targeting activity using a thioredoxin reductase (TXNRD1) assay. Importantly, 70% of the GPX1 inhibitors identified in the primary screen, including several cephalosporin antibiotics, were found to also inhibit TXNRD1, while auranofin, previously known as a TXNRD1 inhibitor, also inhibited GPX1 (but not GPX4). Additionally, every GPX1 inhibitor identified (including omapatrilat, tenatoprazole, cefoxitin and ceftibuten) showed similar inhibitory activity against GPX2. Some compounds inhibiting GPX4 but not GPX1 or GPX2, also inhibited TXNRD1 (26%). Compounds only inhibiting GPX4 included pranlukast sodium hydrate, lusutrombopag, brilanestrant, simeprevir, grazoprevir (MK-5172), paritaprevir, navitoclax, venetoclax and VU0661013. Two compounds (metamizole sodium and isoniazid sodium methanesulfate) inhibited all three GPXs but not TXNRD1, while 2,3-dimercaptopropanesulfonate, PI4KIII beta inhibitor 3, SCE-2174 and cefotetan sodium inhibited all tested selenoproteins (but not GR). The detected overlaps in chemical space suggest that the counter screens introduced here should be imperative for identification of specific GPX inhibitors. With this approach, we could indeed identify novel GPX1/GPX2- or GPX4-specific inhibitors, thus presenting a validated pipeline for future identification of specific selenoprotein-targeting agents. Our study also identified GPX1/GPX2, GPX4 and/or TXNRD1 as targets for several previously developed pharmacologically active compounds.

The global understanding of selenium (Se) in plant biology mainly comes from the fields of medicine and animal science, while the research on Se in plant biology in the field of plant science lags behind. This paper summarized the physiological functions of Se in plants. These studies indicate that Se can promote plant seed development and growth and plant photosynthesis, increase plant economic yield and quality, and enhance plant antioxidant capacity and resistance to stress. However, its effects have a "dual" character, and its concentration or dosage range is very narrow. At appropriate concentrations, Se has an important impact on the physiological processes of plants and is a beneficial element for many plants to maintain health and good growth and development. [ABSTRACT FROM AUTHOR]