Effect of High-Dose Selenium on Postoperative Organ Dysfunction and Mortality in Cardiac Surgery Patients: The SUSTAIN CSX Randomized Clinical Trial.

Importance: Selenium contributes to antioxidative, anti-inflammatory, and immunomodulatory pathways, which may improve outcomes in patients at high risk of organ dysfunctions after cardiac surgery. Objective: To assess the ability of high-dose intravenous sodium selenite treatment to reduce postoperative organ dysfunction and mortality in cardiac surgery patients. Design, Setting, and Participants: This multicenter, randomized, double-blind, placebo-controlled trial took place at 23 sites in Germany and Canada from January 2015 to January 2021. Adult cardiac surgery patients with a European System for Cardiac Operative Risk Evaluation II score-predicted mortality of 5% or more or planned combined surgical procedures were randomized. Interventions: Patients were randomly assigned (1:1) by a web-based system to receive either perioperative intravenous high-dose selenium supplementation of 2000 µg/L of sodium selenite prior to cardiopulmonary bypass, 2000 µg/L immediately postoperatively, and 1000 µg/L each day in intensive care for a maximum of 10 days or placebo. Main Outcomes and Measures: The primary end point was a composite of the numbers of days alive and free from organ dysfunction during the first 30 days following cardiac surgery. Results: A total of 1416 adult cardiac surgery patients were analyzed (mean [SD] age, 68.2 [10.4] years; 1043 [74.8%] male). The median (IQR) predicted 30-day mortality by European System for Cardiac Operative Risk Evaluation II score was 8.7% (5.6%-14.9%), and most patients had combined coronary revascularization and valvular procedures. Selenium did not increase the number of persistent organ dysfunction-free and alive days over the first 30 postoperative days (median [IQR], 29 [28-30] vs 29 [28-30]; P = .45). The 30-day mortality rates were 4.2% in the selenium and 5.0% in the placebo group (odds ratio, 0.82; 95% CI, 0.50-1.36; P = .44). Safety outcomes did not differ between the groups. Conclusions and Relevance: In high-risk cardiac surgery patients, perioperative administration of high-dose intravenous sodium selenite did not reduce morbidity or mortality. The present data do not support the routine perioperative use of selenium for patients undergoing cardiac surgery. Trial Registration: ClinicalTrials.gov Identifier: NCT02002247.

Sodium selenite inhibits proliferation and metastasis through ROS-mediated NF-κB signaling in renal cell carcinoma.

BACKGROUND: Sodium selenite (SSE) has been reported to exert anti-tumor effects in several cancer cells. However, the underlying mechanisms in renal cancer are yet to be elucidated. The effects of SSE on the proliferation, metastasis, and apoptosis of renal cancer cells, as well as its mechanism, were investigated in this study. METHODS: ACHN and 786-O renal cancer cells were treated with different concentrations of SSE, MTT, and colony formation assays were used to detect the proliferation ability of cells. The migration of cells was detected using scratch-wound-healing and transwell-migration assays. The effect of SSE on apoptosis was assessed by AnnexinV-FITC/PI double staining. Besides, Western blotting was employed to detect the protein-expression level and elucidate the underlying pathways. We also made subcutaneous xenografts in athymic mice to verify the effect of SSE on tumor growth in vivo. RESULTS: Our results demonstrated that treatment with SSE resulted in significant inhibition of cell proliferation and migration. Flow cytometry and Western blot confirmed that SSE induced apoptosis via the endogenous apoptotic pathway. We also confirmed that SSE treatment causes an increase in intracellular reactive oxygen species (ROS) levels, resulting in the inhibition of nuclear transcription factor-κB (NF-κB) signaling. Modulation of the ROS level by the chemical inhibitor N-acetyl-cysteine reversed the effect of SSE on cells. Similarly, subcutaneous xenografts in athymic mice models showed that SSE inhibits tumor growth in vivo. CONCLUSION: These results indicate that SSE inhibits proliferation and migration and induces apoptosis via ROS mediated inhibition of NF-κB signaling in renal cancer cells.

Delayed increase of plasma selenoproteins and absence of side effect induced by infusion of pharmacological dose of sodium selenite in septic shock: Secondary analysis of a multicenter, randomized controlled trial.

BACKGROUND: In sepsis, neutrophil respiratory bursts participate in endothelium damage, the first step to multiple organ failure. In plasma two antioxidant selenoenzymes, which protect the endothelium, decrease: selenoprotein-P, and to a lesser extent glutathione peroxidase (GPX3). Sodium selenite (Na2SeO3) is a Se donor, but also an oxidant chemotherapy drug depending on its concentration. In a previous published study, Na2SeO3 continuous infusion in septic shock patients at a pharmacological dose of 4 mg1 Se/day on day-1, followed by a high nutritional dose of 1 mg Se/day during 9 days, showed no beneficial effect on weaning of catecholamine nor on survival. In this ancillary study, we report clinical and biological effects of such continuous infusion of Na2SeO3. METHODS: This was a multicenter, placebo-controlled, double-blind study on 60 patients. Na2SeO3 or placebo in continuous infusion as described above. Evolution with time of plasma Se, selenoprotein-P, GPX3, Organ dysfunction (sequential organ failure assessment SOFA scores, including PaO2/FiO2, for respiratory failure, and plasma lactate) and quality of life at 6 months (by SF36 scores) were analyzed using two-way (time, treatment) non-parametric repeated-measures analysis of variance (Friedman test). MAIN RESULTS: At baseline, plasma Se was about a quarter of reference values. From baseline to day-4 plasma Se, selenoprotein-P and GPX3 significantly increased by 3.9, 2.7 and 1.8 respectively in the Na2SeO3 group as compared with placebo and remained elevated by 2.3, 2.7 and 2.1 at day-14 respectively (p < 0.001). Na2SeO3 did not affect global and organ by organ SOFA Scores and plasma lactate concentration at day-1 and later up to day-14. The evolution of PaO2/FiO2 until day-14 was similar in the two groups. Quality of life in the surviving patients at 6 months was similar between the two groups. CONCLUSION: Continuous infusion of Na2SeO3 at 4 mg Se at day-1 seems to have neither beneficial nor toxic effect at day-1 or later and induces a late increase of selenoprotein-P at day-4. Preclinical studies are required to confirm the use of Na2SeO3 as a cytotoxic drug against neutrophils and protection of the endothelium by selenoprotein-P.

Sodium Selenite Modulates IDO1/Kynurenine, TLR4, NF-κB and Bcl2/Bax Pathway and Mitigates Acetic Acid-Induced Colitis in Rat.

BACKGROUND/AIMS: Colitis is a main presentation of inflammatory bowel disease (IBD) and yet, has no definitive cure. Currently, corticosteroids, anti-tumor necrosis factor (anti-TNF) agents and 5-aminosalicylic acid derivatives are prescribed for management of colitis. Except their failure rate, they are not always tolerated because of their severe adverse effects. Additive formulas with fewer adverse effects may improve the treatment of colitis. METHODS: In this study, colitis was induced with intra-rectal injection of three concentrations of acetic acid (4, 6 and 8 v/v). Each group received sodium selenite (0.5 mg/kg) or saline, gavaged on days 0 and 1 for treatment. Two days after induction of colitis, rats were sacrificed and the end part of their colons were resected for macroscopic and microscopic evaluation and molecular measurement. RESULTS: Sodium selenite improved macroscopic and microscopic view of the colon, decreased cryptitis, crypt abscess and inflammatory cells infiltration and partly maintained mucosal structure. Sodium selenite markedly reduced tissue levels of malondialdehyde (MDA), TNF-α and interferon γ (INF-γ) and decreased myeloperoxidase (MPO) activity. Treatment with sodium selenite also significantly downregulated IL17, IL22, indoleamine 2,3-dioxygenase (IDO1), and kynurenine levels. Western blotting revealed that sodium selenite prevented apoptosis by increasing bcl2/Bax ratio. Furthermore, our findings showed that sodium selenite significantly downregulated the upstream inflammatory molecules such as nuclear factor kappa B (NF-κB) and toll-like receptor 4 (TLR4) in colitis. CONCLUSION: These findings show that sodium selenite alleviates inflammatory response and oxidative stress and protects against colitis.

Selenium ameliorates mercuric chloride-induced brain damage through activating BDNF/TrKB/PI3K/AKT and inhibiting NF-κB signaling pathways.

Mercuric chloride (HgCl2), a heavy metal compound, causes neurotoxicity of animals and humans. Selenium (Se) antagonizes heavy metal-induced organ damage with the properties of anti-oxidation and anti-inflammation. Nevertheless, the molecular mechanism underlying the protective effects of sodium selenite (Na2SeO3) against HgCl2-induced neurotoxicity remains obscure. Therefore, the present study aimed to explore the protective mechanism of Na2SeO3 on HgCl2-induced brain damage in chickens. Morphological observations showed that Na2SeO3 alleviated HgCl2-induced brain tissues damage. The results also showed that Na2SeO3 decreased the protein expression of S100 calcium binding protein B (S100B), and increased the levels of nerve growth factors (NGF), doublecortin domain containing 2 (DCDC2), as well as neurotransmitter to reverse HgCl2-induced brain dysfunction. Further, Na2SeO3 attenuated HgCl2-induced oxidative stress by decreasing the level of malondialdehyde (MDA) and increasing the activities of total superoxide dismutase (T-SOD), glutathione peroxidase (GSH-Px), and total antioxidant capacity (T-AOC). Mechanistically, Na2SeO3 activated the brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase receptor type B (TrKB)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway and suppressed the nuclear factor kappa B (NF-κB) signaling pathway to inhibit apoptosis and inflammation caused by HgCl2 exposure. In summary, Na2SeO3 ameliorated HgCl2-induced brain injury via inhibiting apoptosis and inflammation through activating BDNF/TrKB/PI3K/AKT and suppressing NF-κB pathways.

Protective effects of sodium selenite on insulin secretion and diabetic retinopathy in rats with type 1 diabetes mellitus.

The aim of the present study was to determine the effects of sodium selenite on pancreatic ß cells and diabetic retinopathy in type 1 diabetes mellitus (T1DM) rats. Diabetes was induced by administration of streptozotocin (STZ) and both diabetic and control animals were treated with sodium selenite to measure body weight, food and water intake as well as blood glucose level. Additionally, immunohistochemistry was performed to detect the levels of insulin secretion in pancreatic ß cells. Apoptosis level of pancreatic cells in rats was determined by apoptosis kit. Retinal tissues were stained with hematoxylin-eosin and the area of retinal capillary was measured by Image-Pro Plus 6.0 software. Food and water intake coupled with blood glucose level were increased while body weight of rats was decreased in STZ group. After treatment with sodium selenite, High-Sel group and Low-Sel group showed decreased food intake coupled with blood glucose level and concomitantly increased body weight (vs. STZ group). Of note, the insulin secretion in pancreatic ß cells as well as serum insulin levels were strikingly heightened while apoptosis level of pancreatic tissues was lowered in the High-Sel group (vs. STZ and Low-Sel groups). Additionally, both High-Sel and Low-Sel groups showed a small area of retinal capillary (vs. STZ group). Sodium selenite could promote the levels of insulin secretion in pancreatic ß cells of T1DM rats, and concomitantly ameliorate diabetic retinopathy.

Antitumor Effects of Selenium.

Functions of selenium are diverse as antioxidant, anti-inflammation, increased immunity, reduced cancer incidence, blocking tumor invasion and metastasis, and further clinical application as treatment with radiation and chemotherapy. These functions of selenium are mostly related to oxidation and reduction mechanisms of selenium metabolites. Hydrogen selenide from selenite, and methylselenol (MSeH) from Se-methylselenocyteine (MSeC) and methylseleninicacid (MSeA) are the most reactive metabolites produced reactive oxygen species (ROS); furthermore, these metabolites may involve in oxidizing sulfhydryl groups, including glutathione. Selenite also reacted with glutathione and produces hydrogen selenide via selenodiglutathione (SeDG), which induces cytotoxicity as cell apoptosis, ROS production, DNA damage, and adenosine-methionine methylation in the cellular nucleus. However, a more pronounced effect was shown in the subsequent treatment of sodium selenite with chemotherapy and radiation therapy. High doses of sodium selenite were effective to increase radiation therapy and chemotherapy, and further to reduce radiation side effects and drug resistance. In our study, advanced cancer patients can tolerate until 5000 µg of sodium selenite in combination with radiation and chemotherapy since the half-life of sodium selenite may be relatively short, and, further, selenium may accumulates more in cancer cells than that of normal cells, which may be toxic to the cancer cells. Further clinical studies of high amount sodium selenite are required to treat advanced cancer patients.

Selenium triggers Nrf2-AMPK crosstalk to alleviate cadmium-induced autophagy in rabbit cerebrum.

Cadmium (Cd) is a toxic heavy metal that accumulates in the brain and causes a series of histopathological changes. Selenium (Se) exerts a crucial function in protecting damage caused by toxic heavy metals, but its potential mechanism is rarely studied. The main purpose of this study is to explore the protective effects of Se on Cd-induced oxidative stress and autophagy in rabbit cerebrum. Forty rabbits were randomly divided into four groups and treated as follows: Control group, Cd (1 mg/kg⋅BW) group, Se (0.5 mg/kg⋅BW) group and Cd (1 mg/kg⋅BW)+Se (0.5 mg/kg⋅BW) group, with 30 days feeding management. Our results suggested that Se treatment significantly suppressed the Cd-induced degenerative changes including cell necrosis, vacuolization, and atrophic neurons. In addition, Se decreased the contents of MDA and H2O2 and increased the activities of CAT, SOD, GST, GSH and GSH-Px, alleviating the imbalance of the redox system induced by Cd. Furthermore, Cd caused the up-regulation of the mRNA levels of autophagy-related genes (ATG3, ATG5, ATG7, ATG12 and p62), AMPK (Prkaa1, Prkaa2, Prkab1, Prkab2, Prkag2, Prkag3) and Nrf2 (Nrf2, HO-1 and NQO1) signaling pathway, and the expression levels of LC3II/LC3I, p-AMPK/AMPK, Beclin-1, Nrf2 and HO-1 proteins, which were alleviated by Se, indicated that Se inhibited Cd-induced autophagy and Nrf2 signaling pathway activation. In conclusion, our study found that Se antagonized Cd-induced oxidative stress and autophagy in the brain by generating crosstalk between AMPK and Nrf2 signaling pathway.

The solvent and treatment regimen of sodium selenite cause its effects to vary on the radiation response of human bronchial cells from tumour and normal tissues.

Sodium selenite is often given to moderate the side effects of cancer therapy to enhance the cellular defence of non-cancerous cells. To determine whether sodium selenite during radiotherapy protects not only normal cells but also cancer cells, which would imply a reduction of the desired effect of irradiation on tumour during radiotherapy, the effect of the combined treatment of irradiation and sodium selenite was investigated. Human bronchial cells from carcinoma (A549) and normal tissue (BEAS-2B) were treated with sodium selenite and effects on growth and in combination with radiation on metabolic activity and cell cycle distribution were studied. The influence on radiosensitivity was determined via colony forming assays using different solvents of sodium selenite and treatment schedules. It was shown that sodium selenite inhibits growth and influences cell cycle distribution of both normal and tumour cells. Metabolic activity of normal cells decreased more rapidly compared to that of cancer cells. The influence of sodium selenite on radiation response depended on the different treatment schedules and was strongly affected by the solvent of the agent. It could be shown that the effect of sodium selenite on radiation response is strongly dependent on the respective experimental in vitro conditions and ranges from lead to an initially suspected but ultimately no real radioprotection to radiosensitizing up to no effect in one and the same cell line. This might be a reason for controversially described cell responses to radiation under the influence of sodium selenite in studies so far.

Selenium Ameliorates Ibuprofen Induced Testicular Toxicity by Redox Regulation: Running Head: Se protects against NSAID induced testicular toxicity.

Despite the Cox inhibitory anti-inflammatory and antipyretic effects of most widely used non-steroidal anti-inflammatory drugs (NSAIDs), such as Ibuprofen, their chronic use is associated with a plethora of patho-physiological insults. One such toxic effect on testicular tissues is not well studied and the underlying molecular mechanisms remain unexplored. Thus, the current study is designed to evaluate the antioxidant properties of essential trace element selenium (Se) to ameliorative Ibuprofen associated testicular toxic effects. Adult male Wistar rats were divided into 3 groups and fed on diets containing different concentrations of sodium selenite, viz. 0.01 mg/kg (Se- deficient), 0.2 mg/kg (Se-adequate), or 0.5 mg/kg (Se- supplemented) for 8 weeks. After diet feeding schedule, each group was divided into two subgroups i.e., with or without the treatment of Ibuprofen (120 mg/kg Bw). The protective effect of Se was evaluated by measuring testicular Se and selenoproteins status, spermatogenic markers, histopathology and testicular redox status. Ibuprofen diminished seminal volume, sperm count, sperm motility, which correlated well increased testicular reactive oxygen species. Se deficiency exacerbated these detrimental effects of ibuprofen by increasing oxidative stress. Alternatively, Se supplementation through antioxidant enzymes mediated protective effects. Se as essential antioxidant selenoproteins ameliorates Ibuprofen induced male reproductive toxicity.

The Involvement of Mitochondrial Biogenesis in Selenium Reduced Hyperglycemia-Aggravated Cerebral Ischemia Injury.

Selenium has been shown to possess antioxidant and neuroprotective effects by modulating mitochondrial function and activating mitochondrial biogenesis. Our previous study has also suggested that selenium protected neurons against glutamate toxicity and hyperglycemia-induced damage by regulating mitochondrial fission and fusion. However, it is still not known whether the mitochondrial biogenesis is involved in selenium alleviating hyperglycemia-aggravated cerebral ischemia reperfusion (I/R) injury. The object of this study is to define whether selenium protects neurons against hyperglycemia-aggravated cerebral I/R injury by promoting mitochondrial biogenesis. In vitro oxygen deprivation plus high glucose model decreased cell viability, enhanced reactive oxygen species production, and meanwhile stimulated mitochondrial biogenesis signaling. Pretreated with selenium significantly decreased cell death and further activated the mitochondrial biogenesis signaling. In vivo 30 min of middle cerebral artery occlusion in the rats under hyperglycemic condition enhanced neurological deficits, enlarged infarct volume, exacerbated neuronal damage and oxidative stress compared with normoglycemic ischemic rats after 24 h reperfusion. Consistent to the in vitro results, selenium treatment alleviated ischemic damage in hyperglycemic ischemic animals. Furthermore, selenium reduced the structural changes of mitochondria caused by hyperglycemic ischemia and further promoted the mitochondrial biogenesis signaling. Selenium activates mitochondrial biogenesis signaling, protects mitochondrial structure integrity and ameliorates cerebral I/R injury in hyperglycemic rats.

Selenium supplementation in the prevention of coronavirus infections (COVID-19).

Selenium (Se) is a ubiquitous element akin to sulfur (S) existing in the Earth crust in various organic and inorganic forms. Selenium concentration varies greatly depending on the geographic area. Consequently, the content of selenium in food products is also variable. It is known that low Se is associated with increased incidence of cancer and heart diseases. Therefore, it is advisable to supplement diet with this element albeit in a proper form. Although blood increased concentrations of Se can be achieved with various pharmacological preparations, only one chemical form (sodium selenite) can offer a true protection. Sodium selenite, but not selenate, can oxidize thiol groups in the virus protein disulfide isomerase rendering it unable to penetrate the healthy cell membrane. In this way selenite inhibits the entrance of viruses into the healthy cells and abolish their infectivity. Therefore, this simple chemical compound can potentially be used in the recent battle against coronavirus epidemic.

Therapeutic potential of sodium selenite in letrozole induced polycystic ovary syndrome rat model: Targeting mitochondrial approach (selenium in PCOS).

Polycystic ovary syndrome (PCOS) is the most common endorinopathy in fertile women with heterogeneous reproductive and metabolic phenotypes and unknown etiology. This study was undertaken to investigate the beneficial effect of selenium in management of letrozole induced PCOS and its role in modulating mitochondrial dynamics, and its associated signals. Twenty four adult female rats were enrolled and randomly divided into four equal groups; control group received 0.5% w/v carboxymethyl cellulose (CMC); PCOS group received letrozole (1 mg/kg, daily) in 0.5% CMC for 21 days. From day 22 to day 36, after letrozole PCOS induction, the (PCOS +Metformin) group received metformin (2 mg/kg, daily) while (PCOS + sodium selenite) group received sodium selenite (0.1 mg/kg, daily). All doses were given via oral gavage. At the study end, serum hormone levels, lipid profile and HOMA-IR were assessed. Ovaries were dissected, used for histopathological evaluation, immunohistochemical detection of B-cell lymphoma-2 (Bcl-2), and its associated X protein (Bax) expression, measurement of redox status, mitochondrial dynamics markers and citrate synthase (CS) activity. Furthermore Mitofusins 2 (Mfn2) and dynamin related protein 1 (Drp1) mRNA expression was assessed by real time PCR. Selenium treatment of PCOS rats succeeded, comparable to metformin, to greatly improve the PCOS associated endocrine and metabolic phenotypes and histopathological changes, mostly through modulating mitochondrial dynamics, anti-apoptotic action, alleviating oxidative stress and mitochondrial dysfunction. So, selenium could provide a novel therapeutic strategy for PCOS.

Sodium Selenite Alleviates Breast Cancer-Related Lymphedema Independent of Antioxidant Defense System.

Long-term surveillance is necessary to identify patients at risk of developing secondary lymphedema after breast cancer surgery. We assessed how sodium selenite supplementation would affect breast cancer-related lymphedema (BCRL) symptoms and parameters in association with antioxidant effects. A randomized, double-blind, controlled trial was conducted on 26 participants with clinical stage II to III BCRL. The control group (CTRL, n = 12) and selenium group (SE, n = 14) underwent five sessions of 0.9% saline and 500 µg sodium selenite (Selenase®) IV injections, respectively, within 2 weeks. All patients were educated on recommended behavior and self-administered manual lymphatic drainage. Clinical diagnosis on lymphedema by physicians, bioimpedance data, blood levels of oxidative markers, including glutathione (GSH), glutathione disulfide (GSSG), malondialdehyde (MDA), glutathione peroxidase activity (GSH-Px), and serum oxygen radical absorbance capacity (ORAC) levels, were investigated at timelines defined as baseline, 2-week, and follow-up. Sodium selenite increased whole blood selenium concentration in the SE group. Compared to the baseline, at 2 weeks, 75.0% of participants in clinical stage showed improvement, while there was no change in the CTRL group. At follow-up, 83.3% and 10.0% of the SE and CTRL, respectively, showed stage changes from III to II (p = 0.002). Extracellular water (ECW) ratios were significantly reduced at 2 weeks and follow-up, only in the SE group. Blood GSH, GSSG, GSH/GSSG ratio, MDA, and ORAC levels did not change by selenium supplementation. Sodium selenite improved diagnostic stages of BCRL along with ECW ratios, although the beneficial effect might not be related to its antioxidant activity. Selenite's effect on lymphedema may be associated with non-antioxidant properties, such as anti-inflammation and immune function. Further mechanistic research using a larger population is needed.

Immune function testing in sepsis patients receiving sodium selenite.

PURPOSE: We examined in a longitudinal study the role of sodium selenite in sepsis patients in strengthening the immune performance in whole blood samples using immune functional assays. MATERIALS AND METHODS: This was a sub-study from a randomized, double blinded multicenter clinical trial (SISPCT) registered with www.clinicaltrials.gov (NCT00832039) and with data collected at our center. Full blood samples were incubated with various recall antigens and the supernatants were measured for their cytokine concentrations as markers for immune response. Data from days 0, 4, 7, 14, and 21 (from sepsis onset) were analyzed using a generalized least squares model in R to appropriately take the longitudinal structure and the missing values into account. RESULTS: From the 76 patients enrolled in the study at our center, 40 were randomized to selenium therapy and 36 to placebo. The analyses of immune response assay data showed no statistical difference between the selenium and placebo groups at each of the time points. There was however an overall dampening of cytokine release, which tended to recover over time in both groups. CONCLUSION: Selenium has long been an adjuvant therapy in treating sepsis. Recently, it was proven to not have beneficial effects on the mortality outcome. Using data from our center in this sub-cohort study, we identified no relative improvement in cytokine release of stimulated blood immune cells ex vivo from patients with selenium therapy over a three-week period. This offers a potential explanation for the lack of beneficial effects of selenium in sepsis patients.

Protective Role of Selenium Against Hemolytic Anemia Is Mediated Through Redox Modulation.

Selenium (Se), an essential trace element and potent nutritional antioxidant, exerts its biological effects through incorporation into selenoproteins like glutathione peroxidase (GPx). Modest decrement in the levels of GPx could be partly responsible for peroxidation of RBCs, which results into hemolytic anemia. Therefore, it is hypothesized that dietary Se, as selenoproteins (GPx), can maintain the homeostasis in RBCs and regulate the erythropoiesis by preventing oxidative stress-mediated hemolysis. Se-deficient (0.01 ppm), Se-adequate (0.1 ppm sodium selenite), and Se-supplemented (0.5 ppm sodium selenite) status were created in Balb/c mice by feeding yeast-based diets for 8 weeks and established by measuring Se levels in plasma and activities, expressions of Se-dependent selenoproteins. Fifty percent of mice from each differential Se group were treated with phenylhydrazine (PHZ, 20 mg/kg, i.p.) to induce hemolytic anemia. Results indicated that PHZ-treated Se-deficient animals demonstrated increased hemolysis, abnormal RBC morphology, increase in Heinz bodies and reticulocytes, and denaturation of hemoglobin to globin precipitates and methemoglobin. Se supplementation protected against these hemolytic changes and makes RBCs less fragile. These findings were consistent with dietary Se concentration-dependent changes in activity and expression of GPx indicating that ROS-mediated oxidative stress is integral to hemolysis. Protective effects of Se supplementation against increased levels of ROS, protein carbonyls, and peroxide damage to membrane lipids and enzymatic antioxidants validated these observations. In conclusion, dietary Se supplementation protected the RBCs against hemolysis by mitigating ROS-mediated oxidative stress.

A protocol update for the Selenium Treatment and Chagasic Cardiomyopathy (STCC) trial.

Several studies evaluating clinical forms of chronic Chagas disease show that about one-third of patients present cardiac involvement. Heart failure, sudden death and cardioembolic stroke are the main mechanisms of death in Chagas heart disease. The impact of specific etiologic treatment on the prognosis of patients with chronic Chagas heart disease is very limited regardless of the presence or absence of heart failure. Patients with symptomatic Chagas heart disease present serum selenium (Se) levels lower than patients without Chagas heart disease. Moreover, Se supplementation in animal models showed promising results. The aim of this trial is to estimate the effect of Se treatment on prevention of heart disease progression in patients with Chagas cardiomyopathy. However, we had to introduce some protocol modifications in order to keep trial feasibility, as follows: the primary outcome was restricted to left ventricular ejection fraction as a continuous variable, excluding disease progression; the follow-up period was decreased from 5 years to 1 year, an adjustment that might increase the participation rate of our study; the superior age limit was increased from 65 to 75 years; and diabetes mellitus was no longer considered an exclusion criterion. All of these protocol modifications were extensively debated by the research team enrolled in the design, recruitment and conduction of the clinical trial to guarantee a high scientific quality. TRIAL REGISTRATION: Clinical Trials.gov, NCT00875173 . Registered on 20 October 2008.

From epidemiology to treatment: Aspirin's prevention of brain and breast-cancer and cardioprotection may associate with its metabolite gentisic acid.

BACKGROUND: Epidemiological studies indicate that aspirin consumption reduces the risk of tumors, which is especially relevant for colonic adenoma and carcinoma. Similar observations were made for glial brain tumors and breast cancers, yet the results are inconsistent. Gentisic acid (GA) is a minor catabolite of aspirin; yet humans carrying CYP2C9-variants incapable to catabolize aspirin to GA do not benefit from aspirin in prevention against colonic adenoma. GA blocks binding of Fibroblastic Growth Factor to its receptor and its sulphonate metabolite dobesilic acid blocks growth of C6 glioblastoma in vivo. GA is also an endogenously produced siderophore in mammalians for the transport of iron, a trace element which stimulates tumor growth and enhances anthracycline cardiotoxicity. MATERIALS AND METHODS: In this study, we assessed whether GA exerts direct antitumor activity on C6 glioma cells in vitro (cytotoxicity, colony growth, 3H-thymidine labeling analysis of DNA synthesis); and whether it can modify growth of Ehrlich breast ascites carcinoma (EAC) and solid tumors (EST) in vivo. GA and antitumoral trace element selenium block 12-lipoxygenase activity and aspirin's paradoxical inflammatory effects are seen in selenium-deficient humans; thus, we also investigated antitumor interactions between GA and sodium selenite. Lastly, we evaluated whether GA could protect against doxorubicin cardiotoxicity due to its function to chelate iron. RESULTS: Clinically achievable doses of GA blocked growth, colony formation and DNA synthesis of C6 glioma in vitro with high significance. GA enhanced the survival of EAC-bearing mice at a dosage of 0.4 mg/mice/day, in which 33% of the treated animals survived more than 3-weeks, when all untreated mice succumbed to their tumors. Selenium decreased EST volumes initially, yet increased tumor volumes at later stages in surviving mice. GA alone reduced solid tumor growth and did not modify selenite antineoplasticity initially, but blocked the late tumor-stimulating effects of selenite. Lastly, doxorubicin-induced cardiac myofibrillary and endothelial damage and hyalinization necrosis were attenuated with GA treatment. CONCLUSIONS: GA highly merits to be studied in further animal models as an anticancer and chemoprotective drug.

Sodium selenite ameliorates both intestinal and extra-intestinal changes in acetic acid-induced colitis in rats.

Selenium and its derivatives including sodium selenite (sod sel) belong to the group of essential trace elements needed for proper health and nutrition. They are fairly safe and possess antioxidant and anti-inflammatory properties. The aim of present investigation was to elucidate the effect of sod sel on experimental colitis model in rats. Colitis was induced by intrarectal instillation of 4% (v/v) acetic acid. Two hours later, sod sel was given to rats on a daily basis for 15 consecutive days. Clinical symptoms, colon mass index, spleen weight inflammatory markers, hematological, biochemical, macroscopic, and histological changes were determined. Sod sel markedly ameliorated colitis as evidenced by a significant decrease in macroscopic and microscopic score, disease activity index, colon mass index, and spleen weight. Treatment with sod sel attenuated oxidative stress in the colon by normalizing the colonic content of nitric oxide, malondialdehyde, and reduced glutathione, as well as the activities of catalase, superoxide dismutase, and junctional adhesion molecule (JAM-a). In addition, it significantly reduced colonic myeloperoxidase content, the intercellular adhesion molecule (ICAM-1), and the proinflammatory cytokines; TNF-α, IL-1ß. Moreover, sod sel normalized hematological parameters, serum transaminases, and kidney and liver function enzymes. The current study indicates that sod sel was effective in ameliorating the intestinal and extra-intestinal manifestation in acetic acid-induced colitis through its antioxidant, anti-inflammatory, and immunomodulatory effects.