Long-term study of ovine pulmonary adenocarcinogenesis in sheep with marginal vs. sufficient nutritional selenium supply: Results from computed tomography,pathology, immunohistochemistry,JSRV-PCR and lung biochemistry

The impact of selenium (Se) in carcinogenesis is still debatable due to inconsistent results of observational studies, recent suspicion of diabetic side effects and e.g. dual roles of glutathione peroxidases (GPx). Previously, our group introduced long-term studies on lung carcinogenesis using the jaagtsiekte sheep retrovirus (JSRV) induced ovine pulmonary adenocarcinoma (OPA) as an innovative animal model. The present report describes the results of sufficient (0.2 mg Se/kg dry weight (dw)) vs. marginal (<0.05 mg Se/kg dw) nutritional Se supply on cancer progression over a two-year period in 16 animals. Computed tomography (CT) evaluation of lung cancer progression, final pathological examination, evidence of pro-viral JSRV-DNA in lung, lymph nodes and broncho-alveolar lavage cells as well as biochemical analysis of Se, GPx1 and thioredoxin reductase (TrxR) activity in lung tissue were recorded. Additionally, immunohistochemical determination of GPx1 expression in unaffected and neoplastic lung cells was implemented.The feeding regime caused significant differences in Se concentration and GPx1 activity in lung tissue between groups, whereas TrxR activity remained unaffected. JSRV was evident in broncho-alveolar lavage cells, lung tissue and lung lymph nodes. Quarterly executed CT could not demonstrate differences in lung cancer proliferation intensity. Necropsy and histopathology substantiated CT findings. Immunohistochemical analysis of GPx1 in lung tissue suggested a coherency of GPx1 immunolabelling intensity in dependence of tumour size.It was concluded that the model proved to be suitable for long-term studies of lung cancer proliferation including the impact of modifiable nutritional factors. Proliferation of OPA was unaffected by marginal vs. sufficient nutritional Se supply.     

Dietary selenium requirements based on tissue selenium concentration and glutathione peroxidase activities in old female rats

Dietary nutrient requirements for older animals have been studied far less than have requirements for young growing animals. To determine dietary selenium (Se) requirements in old rats, we fed female weanling rats a Se-deficient diet (0.007 μg Se/g) or supplemented rats with graded levels of dietary Se (0–0.3 μg Se/g) as Na₂SeO₃ for 52 weeks. At no point did Se deficiency or level of Se supplementation have a significant effect (P>0.05) on growth. To determine Se requirements, Se response curves were determined for 7 Se-dependent parameters. We found that minimum dietary Se requirements in year-old female rats were at or below 0.05 μg Se/g diet based on liver Se, red blood cell glutathione peroxidase (Gpx1) activity, plasma Gpx3 activity, liver and kidney Gpx1 activity, and liver and kidney Gpx4 activity. In conclusion, this study found that dietary Se requirements in old female rats were decreased at least 50% relative to requirements found in young, rapidly growing female rats. Collectively, this indicates that the homeostatic mechanisms related to retention and maintenance of Se status are still fully functional in old female rats.     

Statins inhibit expression of thioredoxin reductase 1 in rat and human liver and reduce tumour development

BackgroundStatins have been reported to have anti-carcinogenic properties in addition to their cholesterol-lowering effects, but the mechanism is unknown. Thioredoxin reductases (TrxR) are selenium-containing enzymes of great importance for carcinogenesis and their levels are increased in neoplastic cells. The aim of the present study was to investigate if statin treatment is associated with alterations in the hepatic expression of TrxR.MethodsHuman liver biopsies from a study where patients had been randomised to statin treatment or placebo were analysed. In addition we used liver tissue from a human liver bank where statin treated subjects were compared with non-treated. We also used tissue from a rat liver cancer model in which we have previously shown anti-carcinogenic effects of statins. Real-time PCR and activity assay were used to determine TrxR-levels and activity in tissue extracts.ResultsIn humans 80 mg atorvastatin treatment for 4 weeks (n = 6) was associated with 85% lower levels of TrxR1 and TrxR2 compared to placebo-treated patients (n = 8) (p = 0.03). In liver biopsies from a human donor liver bank 3 statin treated subjects had 90% lower expression of TrxR1 than 15 non-treated subjects (p = 0.04). Statin treatment was associated with 45% lower expression and activity of TrxR1 in a rat model for liver cancer (p = 0.03). There was a clear correlation between inhibition of carcinogenesis and decreased TrxR1-levels (p = 0.003).ConclusionStatin treatment decreases the hepatic expression of TrxR1 in humans and rats. Suppression of TrxR1 expression could explain possible anti-carcinogenic effects of statins. In addition, decreased levels of TrxR1 during statin treatment may shed light on the mechanism of other side-effects of statins.     

Simvastatin inhibits the core promoter of the TXNRD1 gene and lowers cellular TrxR activity in HepG2 cells

Thioredoxin reductase 1 (TrxR1) is a selenocysteine-containing redox-active enzyme that is thought to be important during carcinogenesis. We have recently shown that treatment with statins, HMGCoA reductase inhibitors, reduces the levels of TrxR1 in liver of both rat and human. The reduced TrxR1 levels were correlated with inhibited hepatocarcinogenesis in a rat model. The aim of the present study was to investigate if statins affect the activity of the human TXNRD1 core promoter, which guides expression of TrxR1, and if the effects by statins on TrxR1 expression in liver could be reproduced in a cellular model system. We found that simvastatin and fluvastatin decreased cellular TrxR activity in cultured human liver-derived HepG2 cells with approximately 40% (p < 0.05). Simvastatin, but not fluvastatin or atorvastatin, also reduced the TXNRD1 promoter activity in HepG2 cells by 20% (p < 0.01). In line with this result, TrxR1 mRNA levels decreased with about 25% in non-transfected HepG2 cells upon treatment with simvastatin (p < 0.01). Concomitant treatment with mevalonate could not reverse these effects of simvastatin, indicating that other mechanisms than HMGCoA reductase inhibition was involved. Also, simvastatin did not inhibit sulforaphane-derived stimulation of the TXNRD1 core promoter activity, suggesting that the inhibition by simvastatin was specific for basal and not Nrf2-activated TrxR1 expression. In contrast to simvastatin, the two other statins tested, atorvastatin or fluvastatin, did not influence the TrxR1 mRNA levels. Thus, our results reveal a simvastatin-specific reduction of cellular TrxR1 levels that at least in part involves direct inhibitory effects on the basal activity of the core promoter guiding TrxR1 expression.     

Trace mineral status and liver and blood parameters in sheep without mineral supply compared to local roe deer (Capreolus capreolus) populations

General health, clinical-chemical blood analysis and copper (Cu), zinc (Zn), selenium (Se) and vitamin E concentrations in plasma and liver tissue (wet weight, ww) of two extensive grazing sheep flocks without mineral supply were compared to the status of local roe deer (Capreolus capreolus) populations (liver samples). Both sheep flocks were classified as healthy except for a remarkable variation in body weight and a slight foot rot infection in one flock. Hematology of sheep was normal, and total protein and creatinine as well as activities of creatin kinase, aspartat-amino-transferase, alkaline phosphatase and gamma-glutamyl-transferase in plasma were within reference levels. The mean of glutamate dehydrogenase (13.8 U/l) was slightly elevated in one flock. Mean liver concentrations of Zn (38.9 and 43.5 mg/kg ww) and Cu (111 and 87.5 mg/kg ww) in sheep flocks were higher compared to the respective roe deer populations (27.5 and 36.3 mg Zn/kg ww; 18.3 and 28.6 mg Cu/kg ww). This is supposed to be caused by differences in Cu and Zn metabolism in sheep and roe deer. Selenium deficiency was diagnosed in liver samples of both sheep flocks (0.21 and 0.23 mg/kg ww). There were neither significant differences compared to roe deer (0.21 and 0.27 mg Se/kg ww) nor differences depending on location. Correlations between plasma and liver concentrations of Cu, Zn and Se were not significant in sheep. Means of vitamin E in liver samples (30.6 and 41.8 mg/kg ww) were higher in roe deer populations. This may be caused by the opportunity of selective browsing for wild ruminants, which allows access to younger plants which are higher in vitamin E.     

Differential regulation of expression of cytosolic and mitochondrial thioredoxin reductase in rat liver and kidney

Adequate supply of selenium (Se) is critical for synthesis of selenoproteins through selenocysteine insertion mechanism. To explore this process we investigated the expression of the cytosolic and mitochondrial isoenzymes of thioredoxin reductase (TrxR1 and TrxR2) in response to altered Se supply. Rats were fed diets containing different quantities of selenium and the levels of TrxR1 and TrxR2 protein and their corresponding mRNAs were determined in liver and kidney. Expression of the two isoenzymes was differentially affected, with TrxR1 being more sensitive to Se depletion than TrxR2 and greater changes in liver than kidney. In order to determine if the selenocysteine incorporation sequence (SECIS) element was critical in this response liver and kidney cell lines (H4 and NRK-52E) were transfected with reporter constructs in which expression of luciferase required read-through at a UGA codon and which contained either the TrxR1 or TrxR2 3'UTR, or a combination of the TrxR1 5' and 3'UTRs. Cell lines expressing constructs with the TrxR1 3'UTR demonstrated no response to restricted Se supply. In comparison the Se-deficient cells expressing constructs with the TrxR2 3'UTR showed considerably less luciferase activity than the Se-adequate cells. No disparity of response to Se supply was observed in the constructs containing the different TrxR1 5'UTR variants. The data show that there is a prioritisation of TrxR2 over TrxR1 during Se deficiency such that TrxR1 expression is more sensitive to Se supply than TrxR2 but this sensitivity of TrxR1 was not fully accounted for by TrxR1 5' or 3'UTR sequences when assessed using luciferase reporter constructs.     

The relationship between fetal and maternal selenium concentrations in sheep and goats

In this study, biological samples (slaughterhouse material) were collected from 30 sheep and 36 goats and classified according to gestational stage into either early or late gestation. Samples consisted of allantoic fluid, amniotic fluid, fetal liver, fetal kidney, fetal thyroid gland, maternal plasma and liver to determine selenium (Se) concentrations throughout gestation. The Se concentrations in the allantoic fluid, fetal liver and kidney increased significantly (p < 0.01) during late gestation. Concurrently, the Se concentrations in amniotic fluid, maternal plasma and liver decreased significantly (p < 0.01) over time. Significant (p < 0.01) positive relationships were recorded between the age of the fetus and Se concentrations in the allantoic fluid (r = 0.57–0.75), fetal liver (r = 0.43–0.59) and kidney (r = 0.80–0.81) in both sheep and goats. A significant (p < 0.05) positive relationships were also recorded between the Se concentrations in the allantoic fluid and fetal liver (r = 0.35–0.37), the maternal plasma and liver Se concentrations (r = 0.37–0.57) between sheep and goats. A significant (p < 0.05) negative correlation was recorded between the Se concentrations in the allantoic fluid with maternal plasma of sheep (r = −0.41) as well as between the fetal liver and maternal liver Se (r = −0.22 to 0.50) and a negative correlation (r = −0.42 to 0.43) (p < 0.01) between Se concentrations in the fetal liver and amniotic fluid in both sheep and goats, respectively. Se concentration in the fetal liver was significantly (p < 0.01) higher than that of the kidney and thyroid. In the thyroid gland no morphological differences were noted. Strong fetal–maternal relationships in Se concentration were evident throughout the gestational period and dams seem to sacrifice Se levels in order to maintain that in the fetus. Se concentrations in the amniotic and allantoic fluids could be used as a possible indicator of the Se status of the fetus throughout gestation.     

Effects of selenium supplementation on selenium status of farmed fallow deer in outdoor pens

The study investigated the effects of selenium (Se) supplementation on Se status in farmed fallow deer. Fallow deer were housed on grass pasture and adapted to consume ∼200 g of pelleted grain daily. Animals were divided into two groups. One group received pelleted grain enriched with sodium selenate for 12 weeks (Se+ group, N = 10). Se intake for the first 7 weeks was 0.18 mg/kg dry matter (DM) and 0.32 mg/kg DM for the subsequent 5 weeks. The control group was fed pelleted grain without extra Se (Se− group, N = 9, 0.06-0.08 mg/kg DM). Blood samples were collected at the beginning and the end of the experiment. After the animals were slaughtered, tissue samples were collected for analysis of Se concentrations and Se-dependent glutathione peroxidase 1 (GPx1) activity. In addition, Se-independent α-glutathione-S-transferase (α-GST) activity was analyzed in liver tissue. Se supplementation significantly increased Se levels in plasma and in tissues as follows: liver > spleen > skeletal muscle > myocardium > kidney. Se supplementation also significantly increased GPx1 activity in tissues in the following order: liver > skeletal muscle > spleen = myocardium > kidneys. However, hepatic α-GST activity did not differ between Se+ and Se− groups. As expected, Se supplementation increased blood and tissue Se concentrations and GPx1 activity, which suggests a better antioxidant status. However, the activity of α-GST, an important Se-independent antioxidant enzyme, was not altered, presumably because GPx provided an adequate antioxidant capacity even though Se intake was low.     

Ovine pulmonary adenocarcinoma as an animal model of progressive lung cancer and the impact of nutritional selenium supply

Jaagsiekte sheep retrovirus (JSRV) is known to induce ovine pulmonary adenocarcinoma (OPA). Several studies have suggested an influence of selenium (Se) status on cancer progression. Thus, combining OPA with a defined Se supply might serve as a suitable animal model to study the impact of Se on lung cancer progression.16 naturally JSRV-infected sheep were divided into 2 treatment groups receiving (a) <0.05 and (b) 0.2 mg Se/kg dry matter in diet, respectively. Computed tomography (CT) was performed repeatedly and evaluated using a CT-OPA-score system. Liver biopsies were taken three-monthly, blood samples were collected biweekly to study treatment effects on Se concentrations and glutathione peroxidase (GPx) activity. Cell pellets from bronchoalveolar lavage fluid (BALF) were tested for JSRV by PCR to approve the infection. To date, four animals of the ongoing study have been euthanised. Autopsy and histopathology were performed and correlated to CT analysis.JSRV was detected in BALF cell pellets. Progression of lung tumours was monitored successfully by repeated CT examinations, enabling the detection of even small nodules or increased lung density. Histopathology revealed bronchioloalveolar adenocarcinoma in lung areas suspicious to be OPA from CT evaluation. Score-based analysis of CT images for quantifying tumour progression proved as a valuable tool.Se concentration and GPx activity increased in liver and serum of group b and verified the efficiency of different feeding regime.In conclusion, OPA along with CT, autopsy/histopathology, trace element and enzyme activity analysis provide a suitable large animal model to examine the impact of Se supply on lung tumourigenesis.     

Inhibition of thioredoxin reductase 1 by porphyrins and other small molecules identified by a high-throughput screening assay

The selenoprotein thioredoxin reductase 1 (TrxR1) has in recent years been identified as a promising anticancer drug target. A high-throughput assay for discovery of novel compounds targeting the enzyme is therefore warranted. Herein, we describe a single-enzyme, dual-purpose assay for simultaneous identification of inhibitors and substrates of TrxR1. Using this assay to screen the LOPAC¹²⁸⁰ compound collection we identified several known inhibitors of TrxR1, thus validating the assay, as well as several compounds hitherto unknown to target the enzyme. These included rottlerin (previously reported as a PKCδ inhibitor and mitochondrial uncoupler) and the heme precursor protoporphyrin IX (PpIX). We found that PpIX was a potent competitive inhibitor of TrxR1, with a K_i = 2.7 μM with regard to Trx1, and in the absence of Trx1 displayed time-dependent irreversible inhibition with an apparent second-order rate constant (k_inact) of (0.73 ± 0.07) × 10^? 3 μM^? 1 min^? 1. Exogenously delivered PpIX was cytotoxic, inhibited A549 cell proliferation, and was found to also inhibit cellular TrxR activity. Hemin and the ferrochelatase inhibitor NMPP also inhibited TrxR1 and showed cytotoxicity, but less potently compared to PpIX. We conclude that rottlerin-induced cellular effects may involve targeting of TrxR1. The unexpected finding of PpIX as a TrxR1 inhibitor suggests that such inhibition may contribute to symptoms associated with conditions of abnormally high PpIX levels, such as reduced ferrochelatase activity seen in erythropoietic protoporphyria. Finally, additional inhibitors of TrxR1 may be discovered and further characterized based upon the new high-throughput TrxR1 assay presented here.     

Hydroxytyrosol prevents metabolic impairment reducing hepatic inflammation and restoring duodenal integrity in a rat model of NAFLD

The potential mechanisms of action of polyphenols in nonalcoholic fatty liver disease (NAFLD) are overlooked. Here, we evaluate the beneficial therapeutic effects of hydroxytyrosol (HT), the major metabolite of the oleuropein, in a nutritional model of insulin resistance (IR) and NAFLD by high-fat diet. Young male rats were divided into three groups receiving (1) standard diet (STD; 10.5% fat), (2) high-fat diet (HFD; 58.0% fat) and (3) HFD + HT (10 mg/kg/day by gavage). After 5 weeks, the oral glucose tolerance test was performed, and at 6th week, blood sample and tissues (liver and duodenum) were collected for following determinations. The HT-treated rats showed a marked reduction in serum AST, ALT and cholesterol and improved glucose tolerance and insulin sensitivity, reducing homeostasis model assessment index. HT significantly corrected the metabolic impairment induced by HFD, increasing hepatic peroxisome proliferator-activated receptor PPAR-α and its downstream-regulated gene fibroblast growth factor 21, the phosphorylation of acetyl-CoA carboxylase and the mRNA carnitine palmitoyltransferase 1a. HT also reduced liver inflammation and nitrosative/oxidative stress decreasing the nitrosylation of proteins, reactive oxygen species production and lipid peroxidation. Moreover, HT restored intestinal barrier integrity and functions (fluorescein isothiocyanate-dextran permeability and mRNA zona occludens ZO-1). Our data demonstrate the beneficial effect of HT in the prevention of early inflammatory events responsible for the onset of IR and steatosis, reducing hepatic inflammation and nitrosative/oxidative stress and restoring glucose homeostasis and intestinal barrier integrity.     

Expression of fibroblast growth factor 21 in patients with biliary atresia

Fibroblast growth factor 21 is a critical circulating adipokine involving in metabolic disorders and various liver diseases. This study was performed to investigate whether FGF21 is also associated with the pathophysiology of biliary atresia. Serum FGF21 levels were measured in 57 BA patients and 20 age matched healthy controls. We also examined hepatic FGF21 mRNA expression and FGF21 protein levels in liver tissues obtained from 15 BA patients undergoing liver transplantation and 5 cases of pediatric donation after cardiac death donor without liver diseases by RT-PCR and Western blotting. Patients with BA showed significantly higher serum FGF21 levels than those without BA (554.7 pg/mL [83–2300] vs. 124.5 pg/mL [66–270], P < 0.05). Patients with BA also had significantly higher FGF21 mRNA and protein levels in hepatic tissues than control subjects. Serum FGF21 expression increased corresponding to the severity of liver fibrosis. Furthermore, serum FGF21 levels dropped significantly in BA patients within 6 months after liver transplantation and approached baseline in healthy controls (P > 0.05). In vivo, FXR knockout could significantly abrogate cholestasis induced FGF21 expression. FGF21 levels in serum and liver tissue increased significantly in BA patients. In vivo, cholestasis could induce FGF21 expression in FXR dependent manner.     

Protective effect of combined therapy with dithiothreitol,zinc and selenium protects acute mercury induced oxidative injury in rats

The present study was undertaken to establish mode of action, comparative therapeutic efficacy and safety evaluation of dithiothreitol (DTT) supplemented with Zn and Se against dimethylmercury in rats. Adult male albino rats of Sprague-Dawley strain (150 ± 10 g, n = 6 per group) were exposed a bolus dose of dimethylmercury (10 mg/kg, p.o.) for once only followed by DTT (15.4 mg/kg, i.p.) along with the combination of antioxidants Zn and Se (2 mmol/kg and 0.5 mg/kg, p.o.) after 72 h of toxicant administration for three days. The results showed a significant (P ≤ 0.05) increase in the activities of AST, ALT, alkaline phosphatase, lactate dehydrogenase, in serum after toxicant administration. This was accompanied by histopathological observations. A significant rise was observed in lipid peroxidation level and mercury ion concentration however reduced glutathione content decreased in liver, kidney and brain. A significant (P ≤ 0.05) decrease in the activity of acetyl cholinesterase was also seen in different regions of brain. Combined treatment of DTT along with Zn and Se significantly (P ≤ 0.05) recouped the alterations in the enzymatic activities of serum and reversed the tissue biochemical and histopathological changes of liver, kidney and brain. Our results demonstrate that combined treatment of thiol chelator (DTT) along with antioxidants (Zn and Se) plays an important role against dimethylmercury induced tissue damage and hepatic, nephro and neurotoxicity.     

Serum selenium levels of the very low birth weight premature newborn infants with bronchopulmonary dysplasia

BackgroundThe selenium (Se) is an essential trace element that has a critical role in synthesis and activity of a number of selenoproteins with protective properties against free radical damage. This study was conducted to detect the serum Se concentration in very low birth weight (VLBW) preterm infants and its association with bronchopulmonary dysplasia (BPD).Materials and methodsCord blood Se concentration was determined in 54 neonates with gestation age 30 week or less. Another sample was obtained from these infants at day 28 of birth and serum Se levels were measured by atomic absorption spectrophotometer. All neonates were followed for oxygen dependency at 28 day after birth and 36 week postmenstrual age.ResultsThe mean cord blood Se concentration in studied neonates was 64.78 ± 20.73 μg L^?1. Serum Se concentration was 60.33 ± 26.62 μg L^?1 at age 28-day. No significant correlation was observed for serum Se concentration at birth and at one month after birth (r = ?0.04, p = 0.72). BPD was diagnosed in 25 neonates (46%). The mean serum Se concentration at one month was 57.16 ± 29.68 μg L^?1 in patients with BPD (25 cases) and 63.27 ± 23.6 μg L^?1 in 29 patients without BPD (p = 0.40).ConclusionIn our study, serum Se concentration at 28 day of birth was lower than cord blood levels in preterm neonates, but we have not found significant difference among patients who had BPD or not with respect to serum Se concentrations at this age.     

IL-10 deficiency augments acute lung but not liver injury in hemorrhagic shock

In hemorrhagic shock and trauma, patients are prone to develop systemic inflammation with remote organ dysfunction, which is thought to be caused by pro-inflammatory mediators. This study investigates the role of the immuno-modulatory cytokine IL-10 in the development of organ dysfunction following hemorrhagic shock. Male C57/BL6 and IL-10 KO mice were subjected to volume controlled hemorrhagic shock for 3 h followed by resuscitation. Animals were either sacrificed 3 or 24 h after resuscitation. To assess systemic inflammation, serum IL-6, IL-10, KC, and MCP-1 concentrations were measured with the Luminex? multiplexing platform; acute lung injury (ALI) was assessed by pulmonary myeloperoxidase (MPO) activity and lung histology and acute liver injury was assessed by hepatic MPO activity, hepatic IL-6 levels, and serum ALT levels. There was a trend towards increased IL-6 and KC serum levels 3 h after resuscitation in IL-10 KO as compared to C57/BL6 mice; however this did not reach statistical significance. Serum MCP-1 levels were significantly increased in IL-10 KO mice 3 and 24 h following resuscitation as compared to C57/BL6 mice. In IL-10 KO mice, pulmonary MPO activity was significantly increased 3 h following resuscitation and after 24 h histological signs of acute lung injury were more apparent than in C57/BL6 mice. In contrast, no significant differences in any liver parameters were detected between IL-10 KO and C57/BL6 mice. Our data indicate that an endogenous IL-10 deficiency augments acute lung but not liver injury following hemorrhagic shock.     

The effects of di(2-ethylhexyl) phthalate and/or selenium on trace element levels in different organs of rats

Di(2-ethylhexyl)phthalate (DEHP), a widely used plasticizer for synthetic polymers, is known to have endocrine disruptive potential, reproductive toxicity, and induces hepatic carcinogenesis in rodents. Selenium (Se) is a component of several selenoenzymes which are essential for cellular antioxidant defense and for the functions of mammalian reproductive system. The present study was designed to investigate the effects of DEHP exposure on trace element distribution in liver, testis, and kidney tissues and plasma of Se-deficient and Se-supplemented rats. Se deficiency was produced by feeding 3-week old Sprague-Dawley rats with ≤0.05 mg Se/kg diet for 5 weeks, and supplementation group were on 1 mg Se/kg diet. DEHP treated groups received 1000 mg/kg dose by gavage during the last 10 days of feeding period. Se, zinc (Zn), copper (Cu), iron (Fe) and manganese (Mn) levels were measured by inductively coupled plasma mass spectrometry (ICP-MS). Se supplementation caused significant increases in hepatic, renal, and testicular Se levels. With DEHP exposure, plasma Se and Zn, kidney Se, Cu and Mn levels were significantly decreased. Besides, liver Fe decreased markedly in all the DEHP-treated groups. Liver and kidney Mn levels decreased significantly in DEHP/SeD group compared to both DEHP and SeD groups. These results showed the potential of DEHP exposure and/or different Se status to modify the distribution pattern of essential trace elements in various tissues, the importance of which needs to be further evaluated.     

Serum selenium and selenoprotein P in patients with silicosis

ObjectivesSelenoprotein P (SeP) is a selenium (Se) supply protein, which is an antioxidant micronutrient considered to be vital for human health. The aim of this study was to assess the serum selenium status in patients with silicosis.MethodsWe conducted a retrospective case–control study where serum samples from a total of 78 patients (males with a median age of 73.5 years old) with silicosis and 20 healthy controls (males with a median age of 72.5 years old) were assayed for Se and SeP. They underwent medical and job history taking, lung function testing, and chest radiography examinations. Levels of serum Se were measured using electrothermal atomic absorption spectrophotomerty, while levels of SeP were assessed with sandwich Enzyme Immunoassay. Spearman's rank correlation test was carried out to evaluate the relationship between Se and SeP. The Mann–Whitney test was used to evaluate differences in serum Se and SeP between study groups.ResultsThe median serum Se and SeP concentrations were significantly lower in cases (74.0 μg/l and 4.2 mg/l, respectively) compared with controls (116.0 μg/l and 5.8 mg/l, respectively). In both cases and controls, serum Se was positively correlated with serum SeP (rho = 0.781, p < 0.001 and rho = 0.768, p < 0.001, respectively). Serum Se and SeP levels were significantly lower in patients classified in category four compared with those who were classified in category two or three.ConclusionsSerum Se and SeP concentrations were found to be at inadequate levels in patients with silicosis, and decreased significantly with the severity of the disease.     

Suppression of acute ethanol-induced hepatic steatosis by docosahexaenoic acid is associated with downregulation of stearoyl-CoA desaturase 1 and inflammatory cytokines

Excessive alcohol consumption can lead to hepatic steatosis. Omega-3 (n-3) polyunsaturated fatty acids (PUFA) have been shown to be effective in reducing hepatic accumulation of triglycerides (TG) by downregulation of TG biosynthesis in the liver. The aim of this study was to examine whether supplementation with the n-3 PUFA, docosahexaenoic acid (DHA), can effectively reduce acute alcohol-induced hepatic steatosis. Acute alcohol-induced hepatic steatosis was generated in 9-week-old male mice (C57BL/6J) by oral gavage of ethanol (4.7 g/kg BW) diluted in water (60%, v/v), with or without DHA (250 mg/kg BW), every 12 h for 3 administrations. Compared to the control (ethanol-alone) group, animals supplemented with DHA were protected against ethanol-induced TG accumulation in the liver. Accordingly, hepatic stearoyl-CoA desaturase-1 (SCD-1) expression, serum alanine aminotransferase (ALT) activity, and the levels of inflammatory cytokines (such as IL-6 and TNF-α) in the liver were significantly reduced, whereas the expression of heme oxygenase-1 (HO-1), an enzyme that can improve cell survival in liver tissue, was markedly increased in DHA-supplemented mice compared to the control animals. There were no differences in serum TG level and hepatic production of reactive oxygen species (ROS) between the two groups. Our findings demonstrate that DHA supplementation protects against acute ethanol-induced hepatic steatosis, which may be associated with reduced expression of SCD-1 and inflammatory cytokines.