Selenoprotein Research Articles

Selenoprotein S (SELENOS) is a potential prognostic biomarker for brain lower grade glioma

BackgroundSelenium, an essential micronutrient, primarily exists as selenocysteine in various selenoproteins. Selenoprotein S (SELENOS) is crucial in the development of human cancer. This study aimed to explore the correlation between SELENOS gene expression and the prognosis of brain lower-grade glioma (LGG). MethodsSELENOS protein and mRNA expression in human normal and tumor tissues were explored through the HPA database. SELENOS expression differences between normal and tumor tissues, along with its prognostic significance in gliomas, were analyzed using the TCGA, GTEx datasets, while the CGGA dataset was used to further assess its prognostic potential in a Chinese cohort. The association between SELENOS expression and tumor immune infiltration was also assessed. Multivariate and univariate Cox models were used to screen for clinicopathological parameters associated with SELENOS expression. The GDSC datasets was utilized to explore the connection between SELENOS and chemotherapeutic responses in LGG. A protein-protein interaction network for SELENOS was created. SELENOS expression in LGG cell lines were determined by Western blotting and qRT-PCR, and its functions were ascertained by routine in vitro experiments. ResultsSELENOS was upregulated in 11 cancers and downregulated in 10 cancers relative to the corresponding normal tissues, and correlated significantly with the prognosis, especially for GBM, LGG and GBMLGG. Furthermore, It displayed a positive correlation with immune cell infiltration levels in LGG. Multivariate and Univariate Cox analyses confirmed that the impact of SELENOS on the prognosis of LGG is the combined result of factors such as age and tumor grade. The expression of SELENOS was significantly negatively correlated with temozolomide IC50 in LGG. We found that SELENOS interacts with 10 proteins, which are upregulated in LGG compared to human normal tissues. The expression of these interactors is positively correlated with SELENOS expression and LGG survival/prognosis. In vitro experiments confirmed the aberrant expression of SELENOS in LGG cell lines, and siRNA-mediated knockdown of SELENOS reduced the proliferation, viability, invasion and migration of LGG cells, and induced apoptosis. ConclusionsSELENOS is a potential prognostic marker and therapeutic target for LGG, and its low expression is associated with favorable prognosis in LGG.

Loss of SELENOW aggravates muscle loss with regulation of protein synthesis and the ubiquitin-proteasome system

Sarcopenia is characterized by accelerated muscle mass and function loss, which burdens and challenges public health worldwide. Several studies indicated that selenium deficiency is associated with sarcopenia; however, the specific mechanism remains unclear. Here, we demonstrated that selenoprotein W (SELENOW) containing selenium in the form of selenocysteine functioned in sarcopenia. SELENOW expression is up-regulated in dexamethasone (DEX)–induced muscle atrophy and age-related sarcopenia mouse models. Knockout (KO) of SELENOW profoundly aggravated the process of muscle mass loss in the two mouse models. Mechanistically, SELENOW KO suppressed the RAC1-mTOR cascade by the interaction between SELENOW and RAC1 and induced the imbalance of protein synthesis and degradation. Consistently, overexpression of SELENOW in vivo and in vitro alleviated the muscle and myotube atrophy induced by DEX. SELENOW played a role in age-related sarcopenia and regulated the genes associated with aging. Together, our study uncovered the function of SELENOW in age-related sarcopenia and provides promising evidence for the prevention and treatment of sarcopenia.

Selenoprotein W modulates tau homeostasis in an Alzheimer’s disease mouse model

Lower selenium levels are observed in Alzheimer’s disease (AD) brains, while supplementation shows multiple benefits. Selenoprotein W (SELENOW) is sensitive to selenium changes and binds to tau, reducing tau accumulation. However, whether restoration of SELENOW has any protective effect in AD models and its underlying mechanism remain unknown. Here, we confirm the association between SELENOW downregulation and tau pathology, revealing SELENOW’s role in promoting tau degradation through the ubiquitin‒proteasome system. SELENOW competes with Hsp70 to interact with tau, promoting its ubiquitination and inhibiting tau acetylation at K281. SELENOW deficiency leads to synaptic defects, tau dysregulation and impaired long-term potentiation, resulting in memory deficits in mice. Conversely, SELENOW overexpression in the triple transgenic AD mice ameliorates memory impairment and tau-related pathologies, featuring decreased 4-repeat tau isoform, phosphorylation at Ser396 and Ser404, neurofibrillary tangles and neuroinflammation. Thus, SELENOW contributes to the regulation of tau homeostasis and synaptic maintenance, implicating its potential role in AD.

Association between Human Blood Proteome and the Risk of Myocardial Infarction.

The objective of this study is to estimate the causal relationship between plasma proteins and myocardial infarction (MI) through Mendelian randomization (MR), predict potential target-mediated side effects associated with protein interventions, and ensure a comprehensive assessment of clinical safety. From 3 proteome genome-wide association studies (GWASs) involving 9775 European participants, 331 unique blood proteins were screened and chosed. The summary data related to MI were derived from a GWAS meta-analysis, incorporating approximately 61,000 cases and 577,000 controls. The assessment of associations between blood proteins and MI was conducted through MR analyses. A phenome-wide MR (Phe-MR) analysis was subsequently employed to determine the potential on-target side effects of protein interventions. Causal mediators for MI were identified, encompassing cardiotrophin-1 (CT-1) (odds ratio [OR] per SD increase: 1.16; 95% confidence interval [CI]: 1.13-1.18; p = 1.29 ), Selenoprotein S (SELENOS) (OR: 1.16; 95% CI: 1.13-1.20; p = 4.73 ), killer cell immunoglobulin-like receptor 2DS2 (KIR2DS2) (OR: 0.93; 95% CI: 0.90-0.96; p = 1.08 ), vacuolar protein sorting-associated protein 29 (VPS29) (OR: 0.92; 95% CI: 0.90-0.94; p = 8.05 ), and histo-blood group ABO system transferase (NAGAT) (OR: 1.05; 95% CI: 1.03-1.07; p = 1.41 ). In the Phe-MR analysis, memory loss risk was mediated by CT-1, VPS29 exhibited favorable effects on the risk of 5 diseases, and KIR2DS2 showed no predicted detrimental side effects. Elevated genetic predictions of KIR2DS2 and VPS29 appear to be linked to a reduced risk of MI, whereas an increased risk is associated with CT-1, SELENOS, and NAGAT. The characterization of side effect profiles aids in the prioritization of drug targets. Notably, KIR2DS2 emerges as a potentially promising target for preventing and treating MI, devoid of predicted detrimental side effects.

The selenoprotein from selenium-rich glutinous rice improves spleen immune protection by inhibiting the NF-κB pathway

Moderate amounts of selenium supplementation have a positive effect on the immune response. Selenium deficiency status can lead to reduced immunity, but the benefits of a natural selenium-rich diet for selenium deficiency are unknown. In this experiment, low selenium feed (0.02 mg Se/kg diet) was given to the mice for 5 weeks and selenium supplementation with selenoprotein (SeP) for 4 weeks, and the selenium-deficient mouse model was successfully established. SeP supplementation had significant protective effects, including increased antioxidant capacity and alleviation of inflammatory damage. SeP markedly elevated the activities of thioredoxin reductase (TrxR) and glutathione peroxidase (GSH-Px) in the serum, kidney, liver, and spleen of selenium-deficient mice. SeP can restore the condition of damaged spleen tissue, raise the spleen index in mice, and encourage an increase in immunoglobulin (IgA, IgG, and IgM) content. The levels of catalase (CAT), total antioxidant capacity (T-AOC), GSH-Px, and cytokines (IL-1β, IL-6, and TNF-α) were all significantly elevated by SeP. SeP showed superior immunomodulatory effects over inorganic selenium (Na2SeO3). Together, these results suggest that SeP may be a potential dietary selenium supplement that can reduce symptoms of spleen damage caused by selenium deficiency.

Chronic Aroclor 1260 exposure alters the mouse liver proteome, selenoproteins, and metals in steatotic liver disease

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) continues to increase due in part to the obesity epidemic and to environmental exposures to metabolism disrupting chemicals. A single gavage exposure of male mice to Aroclor 1260 (Ar1260), an environmentally relevant mixture of non-dioxin-like polychlorinated biphenyls (PCBs), resulted in steatohepatitis and altered RNA modifications in selenocysteine tRNA 34 weeks post-exposure. Unbiased approaches identified the liver proteome, selenoproteins, and levels of 25 metals. Ar1260 altered the abundance of 128 proteins. Enrichment analysis of the liver Ar1260 proteome included glutathione metabolism and translation of selenoproteins. Hepatic glutathione peroxidase 4 (GPX4) and Selenoprotein O (SELENOO) were increased and Selenoprotein F (SELENOF), Selenoprotein S (SELENOS), Selenium binding protein 2 (SELENBP2) were decreased with Ar1260 exposure. Increased copper, selenium (Se), and zinc and reduced iron levels were detected. These data demonstrate that Ar1260 exposure alters the (seleno)proteome, Se, and metals in MASLD-associated pathways.

Abstract 2980: Exploiting the selenoproteome in uveal melanoma

Abstract Uveal melanoma (UM) is a common intraocular malignancy arising from GNAQ/GNA11 mutations in uveal tract melanocytes. Although primary UM is treatable by radiation and enucleation, half of patients will develop liver metastasis. Unfortunately, patients with metastatic UM have a poor prognosis of approximately one-year - underscoring metastatic UM as one of the deadliest cancers. A strong prognostic indicator for UM liver metastases is a deletion or inactivation of the deubiquitinase BAP1, yet its specific role in disease progression is unclear. Intriguingly, upon BAP1 loss of function, the cysteine importer SLC7A11 is up regulated. Imported cysteine can be converted into glutathione serving as a cofactor for antioxidant enzymes like GPX4, a selenoprotein (SeP). SePs are a protein family characterized by having at least one selenocysteine - a selenium (Se) containing amino acid. Interestingly, the liver serves as a major hub for Se transport via Selenoprotein P (SEPP). The selenocysteine rich SEPP is secreted by hepatocytes and catabolized in recipient cells facilitating synthesis of de novo SeP. Here we hypothesize that mutant BAP1 UM utilizes the liver’s Se rich microenvironment to augment selenoproteome expression to stave off oxidative stress. Using publicly available datasets, we found patients with mutant BAP1 UM have increased expression of antioxidants proteins and genes associated with SeP expression. In a panel of BAP1 expressing and deficient UM cells, we found that BAP1 deficient cells have increased expression of SePs, suggesting a predisposition to resist oxidative stress. In the presence of exogenous Se, UM cell lines upregulate SeP expression indicating the importance of selenium availability for SeP expression. In addition, a hepatocyte cell line, and an ex vivo liver slice co-culture model was used to confirm that SEPP was produced in the liver slices and was associated with increased SeP expression in UM cells. Furthermore, we found that BAP1 null UM cells were more susceptible to GPX4 inhibition compared to wild type cells, suggesting a reliance on SeP expression. Taken together, these findings suggest that the liver associated selenoproteome expression may underpin an oxidative stress-associated therapeutic vulnerability in UM liver metastases. Citation Format: Alyssa Sanders, Camille Cunanan, Edward Hartsough. Exploiting the selenoproteome in uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2980.

The role of selenium in autoimmune thyroiditis

Selenium (Se) is an essential trace element of fundamental importance for human health. Se is incorporated into selenoproteins (SPs) which are endowed with pleiotropic effects including antioxidant and anti-inflammatory effects and active production of thyroid hormones. It has also been suggested that Se plays a crucial role in the pathogenesis of various human diseases. The therapeutic effects of supplementation with Se have already been described in various thyroid diseases. However, there are still conflicting results regarding the optimal dose of Se to administer and the duration of treatment, efficacy, and safety. The highly beneficial effects of supplementation with Se have been observed in subjects with thyroid disease in the hyperthyroid phase. In line with these observations, clinical studies have shown that in patients with Basedow's disease (BD) and autoimmune thyroiditis (AT), treatment with a combination of antithyroid drugs and Se restores the euthyroid state faster than administration of antithyroid drugs alone. However, the efficacy of this therapeutic approach remains to be better evaluated.

Metabolomic analysis reveals biogenic selenium nanoparticles improve the meat quality of thigh muscle in heat-stressed broilers is related to the regulation of ferroptosis pathway

Heat stress (HS) causes oxidative damage and abnormal metabolism of muscle, thus impairing the meat quality in broilers. Selenium is an indispensable element for enhancing antioxidant systems. In our previous study, we synthesized a novel type of biogenic selenium nanoparticles synthesized with alginate oligosaccharides (SeNPs-AOS), and found that the particle size of Se is 80 nm and the Se content is 8% in the SeNPs-AOS; and dietary 5 mg/kg SeNPs-AOS has been shown to be effective against HS in broilers. However, whether SeNPs-AOS can mitigate HS-induced the impairment of thigh muscle quality in broilers is still unclear. Therefore, the purpose of this study was to investigate the protective effects of dietary SeNPs-AOS on meat quality, antioxidant capacity, and metabolomics of thigh muscle in broilers under HS. A total of 192 twenty-one-day-old Arbor Acres broilers were randomly divided into 4 groups with 6 replicates per group (8 broilers per replicate) according to a 2 × 2 experimental design: thermoneutral group (TN, broilers raised under 23±1.5°C); TN+SeNPs-AOS group (TN group supplemented 5 mg/kg SeNPS-AOS); HS group (broilers raised under 33 ± 2°C for 10 h/d); and HS + SeNPs-AOS group (HS group supplemented 5 mg/kg SeNPS-AOS). The results showed that HS increased the freezing loss, cooking loss, and malondialdehyde (MDA) content of thigh muscle, whereas decreased the total superoxide dismutase (T-SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) activities, as well as downregulated the mRNA expression of SOD2, CAT, GPX3, nuclear factor erythroid 2-related factor 2 (Nrf2), selenoprotein S (SELENOS), solute carrier family 7 member 11 (SLC7A11), GPX4, and ferroportin 1 (Fpn1) of thigh muscle (P < 0.05). Dietary SeNPS-AOS reduced the b* value, elevated the pH0min value and the activities of T-SOD, GSH-Px, glutathione S-transferase (GST) and the mRNA expression levels of GSTT1, GSTA3, GPX1, GPX3, ferritin heavy polypeptide-1 (FTH1), and Fpn1 of thigh muscle in broilers under HS (P < 0.05). Nontargeted metabolomics analysis identified a total of 79 metabolites with significant differences among the four groups, and the differential metabolites were mainly enriched in 8 metabolic pathways including glutathione metabolism and ferroptosis (P < 0.05). In summary, dietary 5 mg/kg SeNPs-AOS (Se content of 8%) could alleviate HS-induced impairment of meat quality by improving the oxidative damage, metabolic disorders and ferroptosis of thigh muscle in broilers challenged with HS. Suggesting that the SeNPs-AOS may be used as a novel nano-modifier for meat quality in broilers raised in thermal environment.

Selenoproteins in Health.

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.

Biogenic Selenium Nanoparticles Synthesized Using Alginate Oligosaccharides Attenuate Heat Stress-Induced Impairment of Breast Meat Quality via Regulating Oxidative Stress, Metabolome and Ferroptosis in Broilers.

Selenium (Se) is an indispensable trace element with versatile functions in antioxidant defense in poultry. In our previous study, we synthesized a novel type of biogenic selenium nanoparticle based on alginate oligosaccharides (SeNPs-AOS), and found that the particles are sized around 80 nm with an 8% Se content, and the dietary addition of 5 mg/kg of SeNPs-AOS could effectively alleviate the deleterious effects of heat stress (HS) in broilers, but it is still unclear whether SeNPs-AOS can improve the meat quality. Therefore, the aim of this study was to evaluate the protective effects of SeNPs-AOS on breast meat quality in heat-stressed broilers, and explore the relevant mechanisms. Birds at the age of 21 days were randomly divided into four groups with six replicates per group (eight broilers per replicate) according to a 2 × 2 experimental design, using HS (33 ± 2 °C, 10 h/day vs. thermoneutral, TN, under 23 ± 1.5 °C) and SeNPs-AOS (5 mg/kg feed vs. no inclusion) as variables. The results showed that dietary SeNPs-AOS decreased the cooking loss (p < 0.05), freezing loss (p < 0.001), and shear force (p < 0.01) of breast muscle in heat-stressed broilers. The non-targeted metabolomics analysis of the breast muscle identified 78 differential metabolites between the HS and HS + SeNPs-AOS groups, mainly enriched in the arginine and proline metabolism, β-alanine metabolism, D-arginine and D-ornithine metabolism, pantothenate, and CoA biosynthesis pathways (p < 0.05). Meanwhile, supplementation with SeNPs-AOS increased the levels of the total antioxidant capacity (T-AOC), the activities of catalase (CAT) and glutathione peroxidase (GSH-Px), and decreased the content of malondialdehyde (MDA) in the breast muscle (p < 0.05) in broilers under HS exposure. Additionally, SeNPs-AOS upregulated the mRNA expression of CAT, GPX1, GPX3, heme oxygenase-1 (HO-1), masculoaponeurotic fibrosarcoma G (MafG), MafK, selenoprotein W (SELENOW), SELENOK, ferritin heavy polypeptide-1 (FTH1), Ferroportin 1 (Fpn1), and nuclear factor erythroid 2-related factor 2 (Nrf2) (p < 0.05), while it downregulated Kelch-like ECH-associated pro-36 tein 1 (Keap1) and prostaglandin-endoperoxide Synthase 2 (PTGS2) expression (p < 0.05) in broilers under HS. These findings demonstrated that the dietary addition of SeNPs-AOS mitigated HS-induced oxidative damage and metabolite changes in the breast muscle of broilers, which may be related to the regulation of the Nrf2 signaling pathway and selenoprotein synthesis. In addition, SeNPs-AOS upregulated the breast muscle gene expression of anti-ferroptosis-related molecules in broilers under HS, suggesting that SeNPs-AOS can be used as novel Se supplements against HS in broilers.

Regorafenib activates oxidative stress by inhibiting SELENOS and potentiates oxaliplatin-induced cell death in colon cancer cells

Colorectal cancer (CRC) is the third most common cancer, and is one of the leading causes of cancer-related death worldwide. At the time of diagnosis, about 20% of patients with CRC present metastatic disease. Regorafenib, an oral multi-kinase inhibitor, has been demonstrated the efficacy and tolerability in patients with metastatic CRC. Oxaliplatin is a frontline treatment regimen for CRC, and combination treatments with oxaliplatin and other chemotherapeutic agents exert superior therapeutic effects. However, side effects and drug resistance limited their further clinical application. Here, we found that combined treatment with regorafenib and oxaliplatin synergistically enhanced anti-tumor activities in CRC by activating reactive oxygen species (ROS) mediated endoplasmic reticulum (ER) stress, C-Jun-amino-terminal kinase (JNK) and p38 signaling pathways. Regorafenib promoted ROS production by suppressing the expression of selenoprotein S (SELENOS). Knocking down SELENOS sensitized ROS-mediated anti-tumor effects of regorafenib in CRC cells. Furthermore, mouse xenograft models demonstrated that synergistic anti-tumor effects of combined treatment with regorafenib and oxaliplatin. This study provided solid experimental evidences for the combined treatment with regorafenib and oxaliplatin in CRC.

Selenium modulates AR/IGF-1R/EGFR and TROP2 signaling pathways and improves anticancer efficacy in murine mammary carcinoma 4T1

The micronutrient selenium (Se) has been shown to exert potential anticancer properties. This study aimed to evaluate the effects of Se (in Se yeast form) on the selenoproteins (SELENO), AR/IGF-1R/EGFR, PI3K/Akt/mTOR and Ras/Raf/ERK cascades, and immune checkpoint blockade in TNBC murine 4T1 cells. We also assessed the effects of combination treatment with chemotherapeutic doxorubicin and Se on trophoblast cell surface antigen 2 (TROP2) levels. Compared with the control groups, cells incubated with Se (0.25, 0.5, 0.75, 1.0, 1.5 µg Se/mL) have lower viability, raised intracellular Se concentrations and SELENO expression, and higher malondialdehyde products in a dose-dependent manner. Se induced the inactivation of AR/IGF-1R/EGFR and downregulation of the PI3K/Akt/mTOR and Ras/Raf/ERK signaling molecules. Se-treated cells also exhibited decreased mitochondrial membrane potential, reduced levels of the cell cycle regulatory protein cyclin D1, cancer stemness, metastatic and EMT-related markers, and increased apoptosis. Subsequently, Se treatment significantly suppressed PD-1/PD-L1 and CTLA-4 mRNA levels and proteins. Doxorubicin decreased 4T1 cell viability and TROP2 expression levels, but the addition of Se to doxorubicin contributed to further reductions. Similar responses to Se treatment were also observed in the human MDA-MB-231 and MCF-7 breast cancer cells. These results show that Se upregulates SELENO and anti-AR/IGF-1R/EGFR signaling in TNBC cells, thus inducing oxidative stress-dependent apoptosis and cell cycle arrest, stemness, EMT, and metastasis, as well as blocking the immune checkpoint molecules. TROP2 down-regulation with Se is also a potential anti-TNBC therapeutic target.

Study the Effect of Selenium Supplementations on the Liver, Kidney and Thyroid Gland Activities in Male Rats

The liver, kidney, and thyroid glands are main vital in biochemical and physiological activities in animals and humans. In this study, we examined the effects of adding selenium supplementation on the improvement activity of many glands such as the liver, kidney, and thyroid after cadmium chloride administration (induced toxicity) in male rabbits. This study included 16 male rabbits divided into four groups, the 1st group (CON) was control and administration normal fed and drinking water, the 2nd group (NC ) was negative control group that administration of 1ml of cadmium chloride (100ppm) with normal fed, the 3rd group (S1) was administration of 1ml of sodium selenite, and 4th group (S2) was administration of 5ml of selenium and all groups continuous for same style up to 8th week of experiment. Antioxidant and oxidative stress status was investigated by measuring the levels of T-AOC and MDA. The liver was assessed by estimation of ALT, AST, TP, and TB while kidney was assessed by calculation of blood CRI and UR and the thyroid gland assessed by measurement of serum T3 and T4. The levels of selenoprotein (SeP) mg/l were assessed by HPLC for standard and S2 group. The results of present study shows highly statistical differences between four group when compare the mean±SD of the levels of ALT,AST,TP,TB,CRI,UR,T3, and T4 (p-value &lt;0.005). In conclusion, this study showing highly ability of selenium supplementation to lowering the levels of the markers of liver, kidney, and thyroid gland and work as protective factor from toxicity induced by cadmium in male rabbits.

Selenium-enriched Cardamine violifolia improves growth performance with potential regulation of intestinal health and antioxidant function in weaned pigs.

This study was conducted to evaluate the effects of different Selenium (Se) sources on growth performance, intestinal function and antioxidant status of weaned piglets. A total of 300 weaned pigs were randomly allocated to 5 treatment groups with 5 replicates of 12 pigs/pen. The control group was corn-soybean basal diet without any additional Se supplement. The experimental diets were supplemented with 0.3 mg/kg of Se from sodium selenite (SS), Se-enriched yeast (SEY), Se-enriched Cardamine violifolia (SEC) and 0.3+0.3 mg/kg of Se from SEY and SEC, respectively. The trial lasted for 4 weeks. The results showed that diets supplementation with SEY, SEC or SEY+SEC could improve average daily gain and reduce feed/gain ratio during the entire study. Compared with the control group, SEC or SEY+SEC improved intestinal morphology, indicated by greater villus height and villus height/ crypt depth ratio. In addition, SEC or SEY+SEC also increased maltase and lactase activities as well as tight junction protein expression. Different Se sources decreased malondialdehyde (MDA) concentration and improved superoxide dismutase (SOD) activity in serum. In the jejunum, SEY or SEC reduced MDA concentration and increased total antioxidant capacity (T-AOC) compared with the control group. Moreover, SEY+SEC increased the antioxidant parameters including SOD and T-AOC in the jejunum. Dietary SEY or SEC supplementation significantly increased the mRNA expression of selenoproteins including thioredoxin reductase 1 (TXNRD1), selenoprotein I (SELENOI), selenoprotein S (SELENOS), and selenoprotein P (SELENOP) in the jejunum. In conclusion, organic Se sources, especially Cardamine violifolia, improve growth performance, potentially by regulating intestinal function, antioxidant capacity and selenoprotein expression in piglets.

Selenoprotein K Is Essential for the Migration and Phagocytosis of Immature Dendritic Cells.

Selenoprotein K (SELENOK) is an endoplasmic reticulum stress (ERS)-regulated protein required for the calcium (Ca2+) flux-mediated migration of T cells and neutrophils, and the migration and phagocytosis of macrophages and microglia. However, the effect of SELENOK on the regulation of the immune function of dendritic cells (DCs), including immature DCs (imDCs) and mature DCs (mDCs), is still unclear. In this study, imDCs prepared from SELENOK knockout mice were used to evaluate the effect of SELENOK on the migration and phagocytosis of imDCs. The results showed that ERS-induced downregulation of imDCs phenotypic markers led to a reduction in Ras homolog gene family member A (RhoA)-dependent migration and enhanced Ca2+/CD205-mediated phagocytosis. SELENOK deficiency-induced upregulation of selenoprotein S (SELENOS) attenuated ERS levels in imDCs. An increase in Ca2+ levels resulted in increased migration and decreased phagocytosis with or without ERS conditions. The migration was RhoA-dependent, and Ca2+ or CD205 was associated with regulating phagocytosis in imDCs. Our study found that SELENOK is required for imDC migration and phagocytosis.

Comparative Proteomic Analysis Reveals the Effect of Selenoprotein W Deficiency on Oligodendrogenesis in Fear Memory.

The essential trace element selenium plays an important role in maintaining brain function. Selenoprotein W (SELENOW), the smallest selenoprotein that has been identified in mammals, is sensitive to selenium levels and abundantly expressed in the brain. However, its biological role in the brain remains to be clarified. Here, we studied the morphological and functional changes in the brain caused by SELENOW deficiency using its gene knockout (KO) mouse models. Histomorphological alterations of the amygdala and hippocampus, specifically in the female SELENOW KO mice, were observed, ultimately resulting in less anxiety-like behavior and impaired contextual fear memory. Fear conditioning (FC) provokes rapidly intricate responses involving neuroplasticity and oligodendrogenesis. During this process, the females generally show stronger contextual FC than males. To characterize the effect of SELENOW deletion on FC, specifically in the female mice, a Tandem mass tag (TMT)-based comparative proteomic approach was applied. Notably, compared to the wildtype (WT) no shock (NS) mice, the female SELENOW KO NS mice shared lots of common differentially expressed proteins (DEPs) with the WT FC mice in the hippocampus, enriched in the biological process of ensheathment and oligodendrocyte differentiation. Immunostaining and Western blotting analyses further confirmed the proteomic results. Our work may provide a holistic perspective of gender-specific SELENOW function in the brain and highlighted its role in oligodendrogenesis during fear memory.

Selenoprotein S regulates tumorigenesis of clear cell renal cell carcinoma through AKT/ GSK3β/NF-κB signaling pathway

Clear cell renal cell carcinoma (ccRCC) is one of the most lethal genitourinary tumors with rapid progression and metastasis. Selenoprotein S (SELS), which is broadly expressed in human tissues, has been reported to be involved in ER homeostasis and inflammation. However, the biological roles of SELS in ccRCC remain unclear. In this study, we found that SELS expression was significantly higher in ccRCC and correlated with multiple clinicopathological features. Overexpression of SELS could promote cell proliferation and inhibit apoptosis in 786-O cells, whereas silence of SELS elicited opposite effect. Further mechanistic studies revealed that SELS enhanced cell proliferation and inhibited apoptosis through activating AKT/GSK3β/NF-κB signaling pathway. Besides, SELS could stabilize c-Myc by preventing ubiquitin–proteasome-mediated degradation. Interestingly, we found that SELS could also inhibit migration of ccRCC cell likely through repressing epithelial–mesenchymal transition (EMT). Collectively, our findings suggested that SELS promoted tumor progression, and inhibited apoptosis and migration through AKT/GSK3β/NF-κB signaling pathway and EMT in ccRCC.

Maternal Organic Selenium Supplementation Relieves Intestinal Endoplasmic Reticulum Stress in Piglets by Enhancing the Expression of Glutathione Peroxidase 4 and Selenoprotein S.

Endoplasmic reticulum (ER) stress, which can be induced by reactive oxygen species (ROS) and multiple factors, is associated with numerous intestinal diseases. The organic selenium source 2-hydroxy-4-methylselenobutanoic acid (HMSeBA), has been proved to decrease intestinal inflammation and autophagy by improving the expression of selenoproteins. However, it remains unclear whether HMSeBA could alleviate intestinal ER stress by decreasing excessive production of ROS products. This study was conducted to investigate the effect of maternal HMSeBA supplementation on the regulation of intestinal ER stress of their offspring and the regulatory mechanism. Sows were supplemented with HMSeBA during gestation and jejunal epithelial (IPEC-J2) cells were treatment with HMSeBA. Results showed that maternal HMSeBA supplementation significantly upregulated mRNA level of selenoprotein S (SELS) in the jejunum of newborn and weaned piglets compared with the control group, while decreased the gene expression and protein abundance of ER stress markers in the jejunum of LPS challenged weaned piglets. In addition, HMSeBA treatment significantly increased the expression of glutathione peroxidase 4 (GPX4) and SELS, while decreased ROS level and the expression of ER stress markers induced by hydrogen peroxide (H2O2) in IPEC-J2 cells. Furthermore, knockdown of GPX4 did not enhance the ERS signal induced by H2O2, but the lack of GPX4 would cause further deterioration of ER stress signal in the absence of SELS. In conclusion, maternal HMSeBA supplementation might alleviate ROS induced intestinal ER stress by improving the expression of SELS and GPX4 in their offspring. Thus, maternal HMSeBA supplementation might be benefit for the intestinal health of their offspring.

Sodium selenite attenuates zearalenone-induced apoptosis through inhibition of endoplasmic reticulum stress in goat trophoblast cells.

Zearalenone (ZEL)-induced apoptosis in different cells is mediated by various molecular mechanisms, including endoplasmic reticulum (ER) stress. Selenium, an inorganic micronutrient, has several cytoprotective properties, but its potential protective action against ZEL-induced apoptosis in trophoblast cells and the precise mechanisms remain unclear. In this study, we investigated the effects of sodium selenite, a predominant chemical form of selenium, on cell viability, apoptosis, and progesterone (P4) production in ZEL-treated goat trophoblast cell line and explored the underlying molecular mechanisms. ZEL treatment repressed cell viability and promoted apoptosis, which was accompanied by an enhancement of the activity of caspase 3, a key executioner of apoptosis. ZEL treatment was involved in the upregulation of malonaldehyde (MDA) levels and was implicated in the reduction of the protein expression of selenoprotein S (SELS), thereby triggering protein expression of ER stress biomarkers (glucose-regulated protein 78 (GRP78) and CCAAT/enhancer-binding protein homologous protein (CHOP)). However, sodium selenite attenuates these adverse effects, including increases in apoptotic rate, caspase 3 activity, MDA, GRP78, and CHOP expression and decreases in SELS expression in cells treated with ZEL or Thapsigargin (Tg, an ER stress agonist). Simultaneously, 4-phenylbutyric acid (4-PBA, an ER stress antagonist) treatment significantly alleviated the ZEL-induced deleterious effects on cells in response to ZEL, similarly to sodium selenite. In addition, sodium selenite supplementation effectively rescued the ZEL-induced decrease in P4 production in ZEL-treated cells. In summary, these findings suggest that ZEL triggers apoptosis in goat trophoblast cells by downregulating SELS expression and activating the ER stress signaling pathway and that sodium selenite protects against these detrimental effects. This study provides novel insights into the benefits of using selenium against ZEL-induced apoptosis and cellular damage.