Selenium-deficient Diet Research Articles

P-317 - Preparation of selenium-deficient mouse model and its glutathione peroxidase activity

Relatively young (8-week-old) selenium deficient (SeD) mouse model was prepared using SeD diet. Selenium (Se), which is an essential trace element, has important roles in the biological redox regulation system as the catalytic center of glutathione peroxidases (GSH-Px). Mice were fed on torula yeast based SeD diet (F2SeDD, Oriental Yeast Co., Ltd., Tokyo) and ultra-pure water (mili-Q water). Several different timings for starting SeD diet were demonstrated and weekly time course of liver GSH-Px activities after starting SeD diet were monitored. Postweaning (4-week-old or older) start of SeD diet gives relatively older (> 8-week-old) SeD mice. The same procedure which was reported for a Se-deficient rat model (Matsumoto et al., Biol. Pharm. Bull. 23, 641–644, 2000.) could not prepared Se-deficient mouse model due to neonatal death. Starting SeD diet to the mother mouse from 2 weeks after giving birth could give 8-week-old SeD mouse model (SeD-trial-2w). Tissue GSH-Px activities of 8-week-old SeD-trial-2w group were almost non, while the normal group (fed on normal diet, MB-1) and SeC group (fed on SeD diet+1.5 mg Se in drinking water) could keep GSH-Px activity. This SeD-trial-2w mouse model can be proposed for an H2O2-induced oxidative stress model for future experiments.

FGF8 and FGFR3 are up-regulated in hypertrophic chondrocytes: Association with chondrocyte death in deep zone of Kashin-Beck disease

ObjectiveThe aim of this study was to investigate FGF8 and FGFR3 expression in clinical samples of Kashin–Beck disease (KBD), an endemic osteochondropathy found in China, as well as in pre-clinical models of this disease. MethodCartilage was collected from the hand phalanges of five patients with KBD and from five healthy children. Sprague-Dawley rats were administered a selenium-deficient diet for four weeks prior to exposure to the T-2 toxin. ATDC5 cells were differentiated into hypertrophic chondrocytes for twenty-one days, and then treated with 3-morpholinosydnonimine (SIN-1) (0, 1, 3, or 5 mM) for 24 h. FGF8 and FGFR3 were visualized using immunohistochemistry; protein levels were assessed by western blotting, and mRNA levels were determined by real-time RT-PCR. ResultsIncreased staining of FGF8 and FGFR3 was observed in the cartilage of children with KBD compared to normal children. Both increased FGF8 and FGFR3 staining, as well as protein levels, were also observed in the cartilage of rats fed normal or Se-deficient diets plus T-2 toxin exposure, compared to those in rats fed with normal or Se-deficient diets alone. SIN-1 treatment of hypertrophic chondrocytes (ATCD5 cells) increased FGF8 and FGFR3 protein and mRNA levels in a dose-dependent manner. ConclusionOur data indicate that SIN-1 induces FGF8 and FGFR3 overexpression and this is involved in the abnormal terminal differentiation and degradation of the ECM in cartilage. FGF8 and FGFR3 may therefore play an important role in the onset of deep zone necrosis and pathogenesis in KBD in adolescent children.

Effect of Seleno-L-methionine on Oxidative Stress in the Pancreatic Islets of a Short-Term Induced Diabetic Mouse Model in Insufficient Selenium Status.

The protective effects of seleno-L-methionine (SeMet) on oxidative stress in pancreatic islets were investigated with a short-term nicotinamide (NA) and streptozotocin (STZ)-induced diabetic mouse model. ICR mice were intraperitoneally injected twice with 100 mg/kg STZ and 120 mg/kg NA at a 1-d interval and were then orally administered 158 µg Se/kg SeMet with free access to a selenium-deficient diet for 5 weeks. Administration of SeMet significantly improved the levels of glycated hemoglobin (HbA1c), non-fasting and oral glucose tolerance-tested (OGTT) blood glucose, plasma adiponectin and hepatic glycogen that deteriorated by NA/STZ treatment. However, supplementary SeMet did not restore non-fasting plasma insulin levels in NA/STZ treatment group and significantly suppressed OGTT plasma insulin levels in the control group. Although SeMet significantly suppressed 8-hydroxy-2'-deoxyguanosine density in pancreatic islets, SeMet did not restore insulin density. The hepatic and pancreatic mRNA levels of glutathione peroxidase 1 (GPX1) increased by NA/STZ treatment or SeMet administration. These results suggest that although a physiological level of SeMet improves glucose tolerance by exhibiting insulin-mimetic activity in a short-term induced diabetic mouse model under insufficient Se status, the suppression of pancreatic oxidative stress with the induction GPX1 by SeMet supplementation is unlikely to restore insulin storage and secretion.

Increased Chondrocyte Apoptosis in Kashin-Beck Disease and Rats Induced by T-2 Toxin and Selenium Deficiency

ObjectiveTo investigate chondrocyte apoptosis and the expression of biochemical markers associated with apoptosis in Kashin-Beck disease (KBD) and in an established T-2 toxin- and selenium (Se) deficiency-induced rat model. MethodsCartilages were collected from the hand phalanges of five patients with KBD and five healthy children. Sprague-Dawley rats were administered a selenium-deficient diet for 4 weeks prior to T-2 toxin exposure. The apoptotic chondrocytes were observed by terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Caspase-3, p53, Bcl-2, and Bax proteins in the cartilages were visualized by immunohistochemistry, their protein levels were determined by Western blotting, and mRNA levels were determined by real-time reverse transcription polymerase chain reaction. ResultsIncreased chondrocyte apoptosis was observed in the cartilages of children with KBD. Increased apoptotic and caspase-3-stained cells were observed in the cartilages of rats fed with normal and Se-deficient diets plus T-2 toxin exposure compared to those in rats fed with normal and Se-deficient diets. Caspase-3, p53, and Bax proteins and mRNA levels were higher, whereas Bcl-2 levels were lower in rats fed with normal or Se-deficiency diets supplemented with T-2 toxin than the corresponding levels in rats fed with normal diet. ConclusionT-2 toxin under a selenium-deficient nutritional status induces chondrocyte death, which emphasizes the role of chondrocyte apoptosis in cartilage damage and progression of KBD.

Human selenoprotein P and S variant mRNAs with different numbers of SECIS elements and inferences from mutant mice of the roles of multiple SECIS elements.

Dynamic redefinition of the 10 UGAs in human and mouse selenoprotein P (Sepp1) mRNAs to specify selenocysteine instead of termination involves two 3′ UTR structural elements (SECIS) and is regulated by selenium availability. In addition to the previously known human Sepp1 mRNA poly(A) addition site just 3′ of SECIS 2, two further sites were identified with one resulting in 10–25% of the mRNA lacking SECIS 2. To address function, mutant mice were generated with either SECIS 1 or SECIS 2 deleted or with the first UGA substituted with a serine codon. They were fed on either high or selenium-deficient diets. The mutants had very different effects on the proportions of shorter and longer product Sepp1 protein isoforms isolated from plasma, and on viability. Spatially and functionally distinctive effects of the two SECIS elements on UGA decoding were inferred. We also bioinformatically identify two selenoprotein S mRNAs with different 5′ sequences predicted to yield products with different N-termini. These results provide insights into SECIS function and mRNA processing in selenoprotein isoform diversity.

Individual effects of different selenocompounds on the hepatic proteome and energy metabolism of mice

BackgroundSelenium (Se) exerts its biological activity largely via selenoproteins, which are key enzymes for maintaining the cellular redox homeostasis. However, besides these beneficial effects there is also evidence that an oversupply of Se might increase the risk towards developing metabolic disorders. To address this in more detail, we directly compared effects of feeding distinct Se compounds and concentrations on hepatic metabolism and expression profiles of mice. MethodsMale C57BL6/J mice received either a selenium-deficient diet or diets enriched with adequate or high doses of selenite, selenate or selenomethionine for 20weeks. Subsequently, metabolic parameters, enzymatic activities and expression levels of hepatic selenoproteins, Nrf2 targets, and additional redox-sensitive proteins were analyzed. Furthermore, 2D-DIGE-based proteomic profiling revealed Se compound-specific differentially expressed proteins. ResultsWhereas heterogeneous effects between high concentrations of the Se compounds were observed with regard to body weight and metabolic activities, selenoproteins were only marginally increased by high Se concentrations in comparison to the respective adequate feeding. In particular the high-SeMet group showed a unique response compromising higher hepatic Se levels in comparison to all other groups. Accordingly, hepatic glutathione (GSH) levels, glutathione S-transferase (GST) activity, and GSTpi1 expression were comparably high in the high-SeMet and Se-deficient group, indicating that compound-specific effects of high doses appear to be independent of selenoproteins. ConclusionsNot only the nature, but also the concentration of Se compounds differentially affect biological processes. General significanceThus, it is important to consider Se compound-specific effects when supplementing with selenium.

Long-Term Selenium-Deficient Diet Induces Liver Damage by Altering Hepatocyte Ultrastructure and MMP1/3 and TIMP1/3 Expression in Growing Rats

The effects of selenium (Se)-deficient diet on the liver were evaluated by using growing rats which were fed with normal and Se-deficient diets, respectively, for 109days. The results showed that rats fed with Se-deficient diet led to a decrease in Se concentration in the liver, particularly among male rats from the low-Se group. This causes alterations to the ultrastructure of hepatocytes with condensed chromatin and swelling mitochondria observed after low Se intake. Meanwhile, pathological changes and increased fibrosis in hepatic periportal were detected by hematoxylin and eosin and Masson's trichrome staining in low-Se group. Furthermore, through immunohistochemistry (IHC) staining, higher expressions of metalloproteinases (MMP1/3) and their tissue inhibitors of metalloproteinases (TIMP1/3) were observed in the hepatic periportal of rats from the low-Se group. However, higher expressions of MMP1/3 and lower expressions of TIMP1/3 were detected in hepatic central vein and hepatic sinusoid. In addition, upregulated expressions of MMP1/3 and downregulated expressions of TIMP1/3 at the messenger RNA (mRNA) and protein levels also appeared to be relevant to low Se intake. In conclusion, Se-deficient diet could cause low Se concentration in the liver, alterations of hepatocyte ultrastructure, differential expressions of MMP1/3 and TIMP1/3 as well as fibrosis in the liver hepatic periportal.

Effects of selenium supplementation on the oxidative state of acute heat stress-exposed quails.

This study aimed to evaluate the effect of heat stress (HS) and selenium supplementation on markers of stress, meat quality and gene expression. For this, meat quails of 42days of age were fed a diet that either met [0.33mg/kg, nutritional demand for selenium (SS)] or did not meet [0.11mg/kg, selenium deficient (SD)] the nutritional demands for selenium during the 7days of evaluation. In addition, the animals were kept at either a thermal comfort temperature (25°C) or exposed to HS (38°C for 24h). Glutathione synthetase (GSS), glutathione reductase (GSR) and uncoupling protein (UCP) gene expression were influenced by the interaction between temperature and diet. Animals subjected to HS and fed the SS diet exhibited the highest GSS and GSR gene expression. In terms of UCP gene expression, the lowest values were observed in HS animals on the SD diet. Glutathione peroxidase 7 (GPX7) gene expression, body temperature (BT) and creatine kinase (CK) activity were influenced by both selenium supplementation and HS. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) activity and creatinine content all were influenced by the diet/environment interaction. The highest AST activity, ALT activity and creatinine levels were observed in animals that were both on the SD diet and exposed to HS. HS animals also exhibited an increased heterophil/lymphocyte ratio and lower triiodothyronine (T3) hormone levels than birds that remained at the comfortable temperature. Animals subjected to HS and fed with selenium supplemented diet showed better results regarding gene expression and, thus, better results for the activities of enzymes used as stress markers, which could be due to the higher antioxidant capacity provided by the action of the studied genes.

Selenoprotein Expression in Macrophages Is Critical for Optimal Clearance of Parasitic Helminth Nippostrongylus brasiliensis

The plasticity of macrophages is evident in helminthic parasite infections, providing protection from inflammation. Previously we demonstrated that the micronutrient selenium induces a phenotypic switch in macrophage activation from a classically activated (pro-inflammatory; M1/CAM) toward an alternatively activated (anti-inflammatory; M2/AAM) phenotype, where cyclooxygenase (COX)-dependent cyclopentenone prostaglandin J2 (15d-PGJ2) plays a key role. Here, we hypothesize that dietary selenium modulates macrophage polarization toward an AAM phenotype to assist in the increasing clearance of adult Nippostrongylus brasiliensis, a gastrointestinal nematode parasite. Mice on a selenium-adequate (0.08 ppm) diet significantly augmented intestinal AAM presence while decreasing adult worms and fecal egg production when compared with infection of mice on selenium-deficient (<0.01 ppm) diet. Further increase in dietary selenium to supraphysiological levels (0.4 ppm) had very little or no impact on worm expulsion. Normal adult worm clearance and enhanced AAM marker expression were observed in the selenium-supplemented Trsp(fl/fl)Cre(WT) mice that express selenoproteins driven by tRNA(Sec) (Trsp), whereas N. brasiliensis-infected Trsp(fl/fl)Cre(LysM) selenium-supplemented mice showed a decreased clearance, with lowered intestinal expression of several AAM markers. Inhibition of the COX pathway with indomethacin resulted in delayed worm expulsion in selenium-adequate mice. This was rescued with 15d-PGJ2, which partially recapitulated the effect of selenium supplementation on fecal egg output in addition to increasing markers of AAMs in the small intestine. Antagonism of PPARγ blocked the effect of selenium. These results suggest that optimal expression of selenoproteins and selenium-dependent production of COX-derived endogenous prostanoids, such as Δ(12)-PGJ2 and 15d-PGJ2, may regulate AAM activation to enhance anti-helminthic parasite responses.

Use of Organic Selenium Supplements in Soybean Meal- Based Diets for Juvenile Yellowtail Kingfish (Seriolalalandi)

Sustainable aquaculture, from both ecological and economic perspectives, demands a substantial reduction of the amount of fishmeal used in aqua feed. Instead, plant-derived protein feed stuff, which provide a nutritious diet offer a promising alternative for inclusion in aqua feed. In this study, the effects of organic selenium supplementation in low and high soybean meal-based practical diets for yellowtail kingfish (Seriola lalandi) were evaluated over a 60-day feeding experiment. The juvenile yellowtail kingfish (initial weight 5.02 ± 0.04 g fish −1 ) were fed five iso-nitrogenous and iso-caloric diets containing 49% crude protein and 22 MJ kg −1 gross energy. The control diet(C) includes 46% fishmeal, whereas the other diets used soybean meal to replace 25% and 75% of the fishmeal protein, both without and with organic selenium supplementation (SBM 25 , SBM 25+Se , SBM 75 , and SBM 75+Se ). Fish were fed ad libitum two times a day at 09:00 and 15:00 hours. No differences were observed in feed intake among dietary treatment groups (P > 0.05). Organic selenium-supplemented diets improved final weight; however, final weight was significantly reduced when fish were fed high soybean meal diets (P < 0.05). Organic selenium supplementation had a significant effect on specific growth rate at low soybean meal diets, but did not affect specific growth rate when fish were fed high soybean meal diets. Selenium accumulation in fish fillet was strongly correlated with selenium concentration in the diets. While fish fed the SBM 25+Se diets had significantly higher glutathione peroxidase activity than those fed other diets, the lowest glutathione peroxidase activity was found in fish fed SBM 75 diets. Histologically, selenium-deficient diets induced myopathy and alterations in tissue structure were most prevalent in fish fed the SBM 75 diet. The findings of this study indicate that, with Se supplementation, soybean meal could supply 25% of the protein in yellowtail kingfish diets.

Selenium deficiency induced damages and altered expressions of metalloproteinases and their inhibitors (MMP1/3, TIMP1/3) in the kidneys of growing rats

Selenium is an essential trace element for the maintenance of structures and functions of kidney. To evaluate the effects of low selenium on the kidneys of growing rats, newborn rats were fed with selenium deficient and normal diets respectively for 109 days. As a result, rats fed with low selenium diets resulted in a decline in the body weight and the concentration of selenium in the kidney, especially the male rats from the low selenium groups. Moreover, the ultrastructure of glomerulus and tubules were damaged in low selenium group: the glomeruli were observed with hyperplasia of mesangial cells, fusion of podocyte foot processes and thickening of basement membrane; and the tubules were observed with vacuolar degenerated epithelial cells, increased edema fluid or protein solution between cells, microvilli edema, increased cell gaps and decreased cell links. Furthermore, the pathological changes in selenium deficient group included the increase of fibers around renal hilum aorta and in the renal collecting duct, and shed of cells in the proximal convoluted tubules. In addition, up-regulated expressions of matrix metalloproteinases (MMP1/3) and down-regulated expressions of their inhibitors (TIMP1/3) at the mRNA and protein levels were also appeared to be relevant to low selenium. The results suggested that low selenium in diet may cause low selenium concentration in the kidney of growing rat and lead to damages of the ultrastructure and extracellular matrix (ECM) of kidney.

셀레늄 결핍식이를 먹인 쥐를 대상으로 유기셀레늄의 생체이용률에 대한 연구

본 연구는 세리신을 이용해 만든 유기셀레늄의 생체이용률을 알아보고자 하였다. 그 결과를 요약하면 다음과 같다. 항산화지표인 환원형 글루타티온은 셀레늄 처치로 인해 증가되었는데 유기셀레늄에 의한 증가는 무기셀레늄에 비해 큰 경향이었으며, 또한 혈중 과산화 지질도 유기셀레늄이 무기셀레늄에 비해 낮은 값을 나타내어 유기셀레늄은 무기셀레늄에 비해 항산화력 향상에 더 기여하는 것으로 나타났다. 셀레늄 결핍식이로 인해 저하된 셀레늄 흡수율과 보유율은 셀레늄 처치로 증가되는데, 특히 유기셀레늄 처치로 인한 흡수율과 보유율이 높아 생체 내 이용률은 증대될 것으로 사료되며 이는 항산화력 향상에 영향을 미칠 것으로 사료된다. 혈청과 간의 셀레늄의 농도는 셀레늄 처치로 유의하게 증가되는데 셀레늄 형태 중 유기셀레늄에 의한 증가가 가장 컸으나 통계적으로 유의한 수준은 아니었다. 결론적으로 본 연구의 결과 무기질을 함유한 펩타이드는 무기질의 생체이용률을 증가시키는 것으로 나타났는데 세리신을 이용한 유기화 형태로 섭취될 경우 혈액과 장기의 침착뿐 아니라 흡수율과 보유율 증가에 관여하여 각 무기질의 효능을 증진시키는 것으로 나타났다.

Involvement of caspases and their upstream regulators in myocardial apoptosis in a rat model of selenium deficiency-induced dilated cardiomyopathy

Keshan disease is an endemic dilated cardiomyopathy (DCM) which is closely related with selenium-deficient diet in China. In the previous study, we reported that the low selenium status plays a pivotal role in the myocardial apoptosis in the DCM rats, however, the underlying mechanism remains unclear. The present study aimed to determine whether the intrinsic, extrinsic pathways and the upstream regulators were involved in the myocardial apoptosis of selenium deficiency-induced DCM rats. Therefore, the rat model of endemic DCM was induced by a selenium-deficient diet for 12 weeks. Accompanied with significant dilation and impaired systolic function of left ventricle, an enhanced myocardial apoptosis was detected by TUNEL assay. Western blot analysis showed remarkably increased protein levels of cleaved caspase-3, caspase-8, caspase-9, and cytosolic cytochrome c released from the mitochondria. In addition, the immunoreactivities of p53 and Bax were significantly up-regulated, while the anti-apoptotic Bcl-2 family members Bcl-2 and Bcl-XL were down-regulated. Furthermore, appropriate selenium supplement for another 4 weeks could partially reverse all the above changes. In conclusion, the intrinsic, extrinsic pathways and the upstream regulators such as p53, Bax, Bcl-2, and Bcl-XL were all involved in selenium deficiency-induced myocardial apoptosis.

Direct interaction between selenoprotein P and tubulin.

Selenium (Se), an essential trace element for human health, mainly exerts its biological function via selenoproteins. Among the 25 selenoproteins identified in human, selenoprotein P (SelP) is the only one that contains multiple selenocysteines (Sec) in the sequence, and has been suggested to function as a Se transporter. Upon feeding a selenium-deficient diet, mice lacking SelP develop severe neurological dysfunction and exhibit widespread brainstem neurodegeneration, indicating an important role of SelP in normal brain function. To further elucidate the function of SelP in the brain, SelP was screened by the yeast two-hybrid system from a human fetal brain cDNA library for interactive proteins. Our results demonstrated that SelP interacts with tubulin, alpha 1a (TUBA1A). The interaction between SelP and tubulin was verified by fluorescence resonance energy transfer (FRET) and co-immunoprecipitation (co-IP) assays. We further found that SelP interacts with the C-terminus of tubulin by its His-rich domain, as demonstrated by FRET and Isothermal Titration Calorimetry (ITC) assays. The implications of the interaction between SelP and tubulin in the brain and in Alzheimer’s disease are discussed.

Mice Lacking Selenoprotein P and Selenocysteine Lyase Exhibit Severe Neurological Dysfunction, Neurodegeneration, and Audiogenic Seizures

Selenoproteins are a unique family of proteins, characterized by the co-translational incorporation of selenium as selenocysteine, which play key roles in antioxidant defense. Among selenoproteins, selenoprotein P (Sepp1) is particularly distinctive due to the fact that it contains multiple selenocysteine residues and has been postulated to act in selenium transport. Within the brain, Sepp1 delivers selenium to neurons by binding to the ApoER2 receptor. Upon feeding a selenium-deficient diet, mice lacking ApoER2 or Sepp1 develop severe neurological dysfunction and exhibit widespread brainstem neurodegeneration, indicating an important role for ApoER2-mediated Sepp1 uptake in normal brain function. Selenocysteine lyase (Scly) is an enzyme that plays an important role in selenium homeostasis, in that it catalyzes the decomposition of selenocysteine and allows selenium to be recycled for additional selenoprotein synthesis. We previously reported that constitutive deletion of Scly results in neurological deficits only when mice are challenged with a low selenium diet. To gain insight into the relationship between Sepp1 and Scly in selenium metabolism, we created novel transgenic mice constitutively lacking both genes (Scly(-/-)Sepp1(-/-)) and characterized the neurobehavioral phenotype. We report that deletion of Scly in conjunction with Sepp1 further aggravates the phenotype of Sepp1(-/-) mice, as these mice needed supraphysiological selenium supplementation to survive, and surviving mice exhibited impaired motor coordination, audiogenic seizures, and brainstem neurodegeneration. These findings provide the first in vivo evidence that Scly and Sepp1 work cooperatively to maintain selenoprotein function in the mammalian brain.

Effect of injectable sodium selenite on the level of stress biomarkers in male aardi goats

The aim of the present study was to evaluate the effects of sodium selenite (SS) injection on plasma concentrations of selenium (Se), glutathione peroxidase (GSH-Px); Malondialdehyde (MDA), and cortisol. A total of twenty seven male Aardi goats were randomly divided into three equal groups; group I (control, fed selenium deficient diet), II (injected with 0.01 mg SS/kg body weight) and III (injected with 0.05 mg SS/kg body weight). Plasma selenium levels differed significantly between treatment and control groups from week one to week three. Level of GSH-Px also differed significantly between the groups. Cortisol varied according to selenium supplementation in week one, two and three. Sodium selenite injection significantly increased Se levels in plasma of Aardi goats as compared with the control group. In conclusion, sodium selenite treatment to Aardi goats minimized the stress level in male Aardi goats, and it was difficult from the experimental design to recommend one of the two doses as therapeutic or preventive anti stress protocols.

Effects of administering sodium selenite, methylseleninic acid, and seleno-L-methionine on glucose tolerance in a streptozotocin/nicotinamide-induced diabetic mouse model.

The effects of administering the selenocompounds, sodium selenite, methylseleninic acid (MSA), and seleno-L-methionine (SeMet) on glucose tolerance were compared in the nicotinamide (NA) and streptozotocin (STZ)-induced diabetic mouse model. ICR mice were intraperitoneally treated twice with STZ (100 mg/kg) 15 min after an injection of NA (120 mg/kg) at a 1-d interval. Non-fasting blood glucose levels were then monitored weekly while orally administering the selenocompounds at 158 µg Se/kg body weight with free access to a selenium-deficient diet for 5 weeks. The mean body weights of NA/STZ-induced diabetic mice were partly restored by the administration of selenocompounds, while SeMet led to a higher selenium content and glutathione peroxidase 1 activity in the pancreas. Non-fasting and oral glucose tolerance-tested blood glucose levels, which were elevated by NA/STZ, were significantly suppressed by the administration of SeMet. These results suggest that SeMet may improve glucose tolerance in a NA/STZ-induced mild diabetic mouse model by increasing bioavailability in the pancreas.

Increased levels of IL-6, IL-1β, and TNF-α in Kashin–Beck disease and rats induced by T-2 toxin and selenium deficiency

The objective of this study is to investigate the possible role of inflammatory mediators such as IL-6, IL-1β, and TNF-α in Kashin-Beck disease (KBD) children and rats fed with T-2 toxin under a selenium-deficient nutrition status in order to determine possible mechanism underlying KBD. Sprague-Dawley rats were administered a selenium-deficient diet for 4 weeks prior to their exposure to T-2 toxin for 4 weeks. The morphology of joint cartilages of KBD children and rats was examined by light microscopy, and the expression of proteoglycans was determined by histochemical staining. The serum levels of IL-6, IL-1β, and TNF-α were determined by enzyme-linked immunosorbent assay. IL-6, IL-1β and TNF-α were localized by immunohistochemistry, and their mRNA levels were detected by real-time RT-PCR. The serum levels of IL-6 were significantly elevated in rats fed with selenium-deficient, T-2 toxin, and T-2 toxin plus selenium-deficient diets compared to those in the normal diet, while the serum levels of IL-1β and TNF-α were significantly increased only in the T-2 toxin plus selenium-deficient diet group. IL-6, IL-1β and TNF-α protein and mRNA levels in cartilage were significantly higher in rats with diets of T-2 toxin and T-2 toxin plus selenium deficiency than in rats fed normal or selenium-deficient diet. While staining for the cytokines in cartilages of KBD children was significantly higher than that in controls. T-2 toxin under a selenium-deficient nutritional status induces increased levels of IL-6, IL-1β, and TNF-α in serum and cartilages, which may account for the pathological mechanism underlying the cartilage damage in KBD.

Elevated amyloid-β plaque deposition in dietary selenium-deficient Tg2576 transgenic mice

Selenium-containing proteins (e.g., glutathione peroxidases) are important antioxidants in neuronal defense against oxidative stress. In this study, the production of amyloid-β (Aβ) plaques in the brain of the Tg2576 transgenic mice was investigated under dietary selenium-deficient conditions. The 16-week-old mice were fed a selenium-deficient diet (0.004 μg-selenium g(-1)-diet) or a selenium-adequate diet (0.386 μg-selenium g(-1) diet) for 76 weeks. The selenium concentrations of the organs/tissues in the selenium-deficient diet-fed mice were significantly decreased in comparison to those in the selenium-adequate diet-fed mice; 1.7% of that in the selenium-adequate diet-fed mice in the liver and 43% of that in the selenium-adequate diet-fed mice in the brain. The Aβ plaques formed in the brain were fluorescently stained with thioflavin T, and then the obtained images of the brain slices were qualitatively analyzed. The feeding of the selenium-deficient diet to the Tg2576 transgenic mice resulted in more than a two-fold increase in the total area of the Aβ plaques in comparison to that of the selenium-adequate diet. The elevated Aβ plaque deposition in the selenium-deficient mice can be explained as a consequence of decrease in the selenium concentration, which suggests that the selenium status is associated with the production and/or the clearance of the Aβ peptide. The selenium-deficiency could possibly promote the onset and/or progression of Alzheimer's disease (AD) dementia, if the Aβ peptides initiate a sequence of events that lead to AD dementia. Consequently, the results shown here suggest that AD has an important relation with the selenium status in vivo.

Abstract 1401: Dietary selenium and metastasis in a mouse model

Abstract The skeleton is a common site for breast cancer metastasis. Once breast cancer cells enter the bone microenvironment, they alter the homeostasis of the bone remodeling system in favor of osteoclasts, which results in osteolysis. Breast cancer cells induce an osteoblast inflammatory response resulting in the production of IL-6, IL-8, MCP-1, and COX-2, known to promote osteoclastogenesis. Therefore, down-regulation of the inflammatory response of the osteoblasts brought about by breast cancer cells may reduce the activation of osteoclasts and decrease osteolysis. IL-6, MCP-1, COX-2 are regulated by a common transcription factor, NF-κB which is sensitive to intracellular redox status; its activation can be inhibited by cellular antioxidant enzymes. Two major antioxidant enzymes, glutathione peroxidase and thioredoxin reductase are selenoenzymes. Their dependence on selenium (Se) offers a way to increase their expression and activity, block NF-κB activation and thus inhibit the expression of its target genes. The hypothesis was that inhibition of NF-κB through dietary selenium would prevent the osteoblast inflammatory response and metastasis. To test the effect of dietary selenium in breast cancer progression, one of five diets: three selenium supplementation diets (sodium selenite, selenomethionine, and methylseleninic acid) or a selenium-deficient or a selenium adequate diet was fed to Balb/c mice for 3 months before inoculation of a metastatic breast cancer cell line 4T1.2luc into the mammary gland. The growth and metastasis of the tumors were followed by IVIS imaging. After 4 weeks, organs were collected and prepared for Q-PCR analysis of the luciferase gene as an indicator of metastatic burden. There was no significant difference in the development or growth of the primary breast tumor and the metastatic patterns between mice receiving the selenium-deficient or selenium-adequate diets. On the other hand, selenium supplementation diets were shown to affect breast cancer progression differently. Mice with sodium selenite supplementation developed the most metastasis (15/15) and showed higher incidence of breast cancer kidney and bone metastasis. The selenomethionine supplementation diet (3ppm) reduced breast cancer primary tumor growth and decreased overall tumor burden in major organs, such as lung, liver, kidney and femur. Taken together, this study showed that dietary selenium affected tumor growth and metastasis and that the selenomethionine supplementation diet offered the most protective effect on breast cancer progression. Support: American Institute for Cancer Research with supplemental support from the National Foundation for Cancer Research. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1401. doi:1538-7445.AM2012-1401