The Dynamics of Methylation Concentrations in Glutathione Peroxidase 3 Promoter from Patients with Chronic Heart Failure and Their Association with Key Clinical Parameters.

OBJECTIVE: This study investigated changes in methylation concentrations within the glutathione peroxidase 3 (GPX3) promoter region among patients diagnosed with chronic heart failure (CHF). Peripheral blood samples were collected from 20 CHF patients and 20 healthy individuals for analysis. METHODS: Using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, methylation concentrations of 11 CpG sites within the GPX3 promoter region were quantified. RESULTS: Results showed a significant increase in methylation at the GPX3_FA10_CpG_24 site in patients with CHF compared with the control group (P < 0.05). Furthermore, a nonlinear dose-response relationship was observed between methylation concentrations at this site and key clinical parameters including serum apolipoprotein A-1, D-dimer, chlorine, potassium, and sodium (Na) (P < 0.05). CONCLUSIONS: These findings suggest that aberrant methylation of the GPX3 promoter may impact disease progression by influencing physiological functions such as blood lipids, coagulation, and electrolytes. Further investigations are warranted to elucidate the role of GPX3 promoter methylation in CHF pathogenesis, potentially contributing valuable insights for its prevention, diagnosis, and treatment.

Deciphering the associations of selenium distribution in serum GPx-3 and selenoprotein P with cardiovascular risk factors in a healthy population with moderate levels of selenium: The ATTICA study.

BACKGROUND: Selenium (Se) is an essential micronutrient, important for human health. The relationship of Se with cardiovascular risk factors is still inconclusive, especially regarding the role of different selenoproteins. The present study evaluated the relation of total serum Se as well as its distribution in plasma selenoproteins, namely glutathione peroxidase 3 (GPx3) and selenoprotein P (SelP) with cardiovascular risk factors in a sex-specific manner, in a healthy population with moderate levels of Se. METHODS: A sub-sample from the ATTICA Study's database, consisting of 398 participants (160 females and 238 males) with data on Se and selenoproteins levels, was considered. GPx3, SelP and the main non-specific serum selenium containing protein, selenoalbumin (SeAlb) were simultaneously determined in human plasma by high-performance liquid chromatography (HPLC) coupled with inductively coupled plasma mass spectrometry (ICP-MS) at baseline. RESULTS: Participants that belong to the highest tertiles of GPx3 and SelP presented the lowest blood pressure. Homocysteine was inversely associated with SelP and its ratio SelP/TSe in both sexes. In males, the lowest tertile of GPx3 showed lower adiponectin levels (0.66 ± 0.21 µg/mL) in comparison to the 2nd tertile of GPx3 (p=0.002), SelP was inversely associated with visceral adipose index (VAI) (-2.29 ± 0.81, p=0.005). Particularly, in males, the middle tertile of SelP had the lowest VAI values. Regarding females, lower Lp(a) concentration by 11.96 ± 5.84 mg/dL was observed in low SelP levels while higher leptin concentration by 2.30 ± 0.73 µg/L and lower fibrinogen concentration by 27.32 ± 13.30 mg/dL was detected in low GPx3 levels. CONCLUSION: Circulating selenoproteins exert differentiated effects on cardiovascular risk factors, some of them in a sex-specific manner.

Characterization of selenium-containing broccoli (Brassica oleracea L. var. italica planch) proteins and evaluation of antioxidant activity by electron spin resonance.

Selenoproteins found in selenium (Se)-enriched vegetables play a vital role in maintaining human health. In this study, four Se-containing broccoli proteins (Se-BP: albumin, globulin, prolamin, and glutelin) were continuous extracted by Osborne method. Three ultrafiltered fractions were subsequently obtained from the glutelin hydrolysate, composed of Se-contained broccoli peptides (Se-Bp) with different molecular weights (MW), namely, < 1 kDa, 1-3 kDa, and 3-10 kDa. Glutelin exhibited the highest protein yield (65.60 ± 1.07%), purity (78.39 ± 0.95%), nutritional value, organic Se content (88.05 ± 0.32% of total Se content), and Se speciation distribution (selenocystine, selenomethionine, methylselenocysteine, and selenoethionine). Additionally, the antioxidant activity of different MW of Se-Bp was assessed using electron spin resonance spectroscopy. The results revealed that antioxidant activity of the candidate peptide is dependent upon its Se content, amino acid composition, and MW, especially Se-Bp with MW of 1-3 kDa displayed the strongest free radical scavenging ability.

Maternal selenium deficiency during pregnancy in association with autism and ADHD traits in children: The Odense Child Cohort.

BACKGROUND: Selenoproteins regulate pathways controlling neurodevelopment, e.g., redox signaling and thyroid hormone metabolism. However, studies investigating maternal selenium in relation to child neurodevelopmental disorders are scarce. METHODS: 719 mother-child pairs from the prospective population-based Odense Child Cohort study in Denmark were included. Three selenium biomarkers, i.e. concentrations of serum selenium, selenoprotein P (SELENOP), and activity of glutathione peroxidase 3 (GPX3), along with serum copper, zinc and iron were measured in early third trimester (at 28.9+/-0.8 weeks of pregnancy). ADHD and ASD traits in children were assessed systematically using the established Child Behaviour Checklist at 5 years of age, based on a Danish reference cohort with cut-off at 90th percentile. Multivariable regression models adjusted for biologically relevant confounders were applied. RESULTS: 155 of 719 (21.6 %) children had ASD traits and 59 of 719 (8.2 %) children had traits of ADHD at 5 years of age. In crude and adjusted models, all three selenium biomarkers associated inversely with ADHD traits. For ADHD, fully adjusted OR for 10 µg/L increment in selenium was 0.76 (95 % CI 0.60, 0.94), for one mg/L increment in SELENOP was 0.73 (0.56, 0.95), and for 10 U/L increment in GPx3 was 0.93 (0.87,1.00). Maternal total selenium was inversely associated with child ASD traits, OR per 10 µg/L increment was 0.85 (0.74, 0,98). SELENOP and GPx3 were not associated with ASD traits. The associations were specific to selenium, as other trace elements such as copper, zinc, or iron were not associated with the outcomes. CONCLUSIONS: The results provide coherent evidence for selenium deficiency as a risk factor for ADHD and ASD traits in an environment with borderline supply, the causality of which should be elucidated in a randomized controlled trial.

The Regulation of Selenoproteins in Diabetes: A New Way to Treat Diabetes.

Selenium is an essential micronutrient required for the synthesis and function of selenoproteins, most of which are enzymes involved in maintaining oxidative balance in the body. Diabetes is a group of metabolic disorders characterized by high blood glucose levels over a prolonged period of time. There are three main types of diabetes: type 1, type 2, and gestational diabetes. This review summarizes recent advances in the field of diabetes research with an emphasis on the roles of selenoproteins on metabolic disturbance in diabetes. We also discuss the interaction between selenoproteins and glucose and lipid metabolism to provide new insights into the prevention and treatment of diabetes.

Rapid Selenoprotein Activation by Selenium Nanoparticles to Suppresses Osteoclastogenesis and Pathological Bone Loss.

Osteoclast hyperactivation stands as a significant pathological factor contributing to the emergence of bone disorders driven by heightened oxidative stress levels. The modulation of the redox balance to scavenge reactive oxygen species emerges as a viable approach to addressing this concern. Selenoproteins, characterized by selenocysteine (SeCys2) as the active center, are crucial for selenium-based antioxidative stress therapy for inflammatory diseases. This study reveals that surface-active elemental selenium (Se) nanoparticles, particularly lentinan-Se (LNT-Se), exhibit enhanced cellular accumulation and accelerated metabolism to SeCys2, the primary active Se form in biological systems. Consequently, LNT-Se demonstrates significant inhibition of osteoclastogenesis. Furthermore, in vivo studies underscore the superior therapeutic efficacy of LNT-Se over SeCys2, potentially attributable to the enhanced stability and safety profile of LNT-Se. Specifically, LNT-Se effectively modulates the expression of the selenoprotein GPx1, thereby exerting regulatory control over osteoclastogenesis inhibition, and the prevention of osteolysis. In summary, these results suggest that the prompt activation of selenoproteins by Se nanoparticles serves to suppress osteoclastogenesis and pathological bone loss by upregulating GPx1. Moreover, the utilization of bioactive Se species presents a promising avenue for effectively managing bone disorders.

The redox-active defensive Selenoprotein T as a novel stress sensor protein playing a key role in the pathophysiology of heart failure.

Maladaptive cardiac hypertrophy contributes to the development of heart failure (HF). The oxidoreductase Selenoprotein T (SELENOT) emerged as a key regulator during rat cardiogenesis and acute cardiac protection. However, its action in chronic settings of cardiac dysfunction is not understood. Here, we investigated the role of SELENOT in the pathophysiology of HF: (i) by designing a small peptide (PSELT), recapitulating SELENOT activity via the redox site, and assessed its beneficial action in a preclinical model of HF [aged spontaneously hypertensive heart failure (SHHF) rats] and against isoproterenol (ISO)-induced hypertrophy in rat ventricular H9c2 and adult human AC16 cardiomyocytes; (ii) by evaluating the SELENOT intra-cardiomyocyte production and secretion under hypertrophied stimulation. Results showed that PSELT attenuated systemic inflammation, lipopolysaccharide (LPS)-induced macrophage M1 polarization, myocardial injury, and the severe ultrastructural alterations, while counteracting key mediators of cardiac fibrosis, aging, and DNA damage and restoring desmin downregulation and SELENOT upregulation in the failing hearts. In the hemodynamic assessment, PSELT improved the contractile impairment at baseline and following ischemia/reperfusion injury, and reduced infarct size in normal and failing hearts. At cellular level, PSELT counteracted ISO-mediated hypertrophy and ultrastructural alterations through its redox motif, while mitigating ISO-triggered SELENOT intracellular production and secretion, a phenomenon that presumably reflects the extent of cell damage. Altogether, these results indicate that SELENOT could represent a novel sensor of hypertrophied cardiomyocytes and a potential PSELT-based new therapeutic approach in myocardial hypertrophy and HF.

Selenium, diabetes, and their intricate sex-specific relationship.

Selenium (Se) is an essential trace element, which is inserted as selenocysteine (Sec) into selenoproteins during biosynthesis, orchestrating their expression and activity. Se is associated with both beneficial and detrimental health effects; deficient supply or uncontrolled supplementation raises concerns. In particular, Se was associated with an increased incidence of type 2 diabetes (T2D) in a secondary analysis of a randomized controlled trial (RCT). In this review, we discuss the intricate relationship between Se and diabetes and the limitations of the available clinical and experimental studies. Recent evidence points to sexual dimorphism and an association of Se deficiency with gestational diabetes mellitus (GDM). We highlight the emerging evidence linking high Se status with improved prognosis in patients with T2D and lower risk of macrovascular complications.

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.

Se Alleviated Pb-Caused Neurotoxicity in Chickens: SPS2-GPx1-GSH-IL-2/IL-17-NO Pathway, Selenoprotein Suppression, Oxidative Stress, and Inflammatory Injury.

Lead (Pb), a heavy metal environmental pollutant, poses a threat to the health of humans and birds. Inflammation is one of the most common pathological phenomena in the case of illness and poisoning. However, the underlying mechanisms of inflammation remain unclear. The cerebellum and the thalamus are important parts of the nervous system. To date, there have been no reports of Pb inducing inflammation in animal cerebellums or thalami. Selenium (Se) can relieve Pb poisoning. Therefore, we aimed to explore the mechanism by which Se alleviates Pb toxicity to the cerebellums and thalami of chickens by establishing a chicken Pb or/and Se treatment model. Our results demonstrated that exposure to Pb caused inflammatory damage in cerebellums and thalami, evidenced by the characteristics of inflammation, the decrease in anti-inflammatory factors (interleukin (IL)-2 and interferon-γ (INF-γ)), and the increase in pro-inflammatory factors (IL-4, IL-6, IL-12ß, IL-17, and nitric oxide (NO)). Moreover, we found that the IL-2/IL-17-NO pathway took part in Pb-caused inflammatory injury. The above findings were reversed by the supplementation of dietary Se, meaning that Se relieved inflammatory damage caused by Pb via the IL-2/IL-17-NO pathway. In addition, an up-regulated oxidative index malondialdehyde (MDA) and two down-regulated antioxidant indices (glutathione (GSH) and total antioxidant capacity (TAC)) were recorded after the chickens received Pb stimulation, indicating that excess Pb caused an oxidant/antioxidant imbalance and oxidative stress, and the oxidative stress mediated inflammatory damage via the GSH-IL-2 axis. Interestingly, exposure to Pb inhibited four glutathione peroxidase (GPx) family members (GPx1, GPx2, GPx3, and GPx4), three deiodinase (Dio) family members (Dio1, Dio2, and Dio3), and fifteen other selenoproteins (selenophosphate synthetase 2 (SPS2), selenoprotein (Sel)H, SelI, SelK, SelM, SelO, SelP1, SelPb, SelS, SelT, SelU, and selenoprotein (Sep)n1, Sepw1, Sepx1, and Sep15), suggesting that Pb reduced antioxidant capacity and resulted in oxidative stress involving the SPS2-GPx1-GSH pathway. Se supplementation, as expected, reversed the changes mentioned above, indicating that Se supplementation improved antioxidant capacity and mitigated oxidative stress in chickens. For the first time, we discovered that the SPS2-GPx1-GSH-IL-2/IL-17-NO pathway is involved in the complex inflammatory damage mechanism caused by Pb in chickens. In conclusion, this study demonstrated that Se relieved Pb-induced oxidative stress and inflammatory damage via the SPS2-GPx1-GSH-IL-2/IL-17-NO pathway in the chicken nervous system. This study offers novel insights into environmental pollutant-caused animal poisoning and provides a novel theoretical basis for the detoxification effect of Se against oxidative stress and inflammation caused by toxic pollutants.