Multiomics analyses reveal a critical role of selenium in controlling T cell differentiation in Crohn’s disease

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Biomarkers of Selenium Status

The essential trace element, selenium (Se), has multiple biological activities, which depend on the level of Se intake. Relatively low Se intakes determine the expression of selenoenzymes in which it serves as an essential constituent. Higher intakes have been shown to have anti-tumorigenic potential; and very high Se intakes can produce adverse effects. This hierarchy of biological activities calls for biomarkers informative at different levels of Se exposure. Some Se-biomarkers, such as the selenoproteins and particularly GPX3 and SEPP1, provide information about function directly and are of value in identifying nutritional Se deficiency and tracking responses of deficient individuals to Se-treatment. They are useful under conditions of Se intake within the range of regulated selenoprotein expression, e.g., for humans <55 μg/day and for animals <20 μg/kg diet. Other Se-biomarkers provide information indirectly through inferences based on Se levels of foods, tissues, urine or feces. They can indicate the likelihood of deficiency or adverse effects, but they do not provide direct evidence of either condition. Their value is in providing information about Se status over a wide range of Se intake, particularly from food forms. There is need for additional Se biomarkers particularly for assessing Se status in non-deficient individuals for whom the prospects of cancer risk reduction and adverse effects risk are the primary health considerations. This would include determining whether supranutritional intakes of Se may be required for maximal selenoprotein expression in immune surveillance cells. It would also include developing methods to determine low molecular weight Se-metabolites, i.e., selenoamino acids and methylated Se-metabolites, which to date have not been detectable in biological specimens. Recent analytical advances using tandem liquid chromatography-mass spectrometry suggest prospects for detecting these metabolites.     

Monomethylarsonous acid inhibited endogenous cholesterol biosynthesis in human skin fibroblasts

Human exposure to arsenic in drinking water is a widespread public health concern, and such exposure is known to be associated with many human diseases. The detailed molecular mechanisms about how arsenic species contribute to the adverse human health effects, however, remain incompletely understood. Monomethylarsonous acid [MMA(III)] is a highly toxic and stable metabolite of inorganic arsenic. To exploit the mechanisms through which MMA(III) exerts its cytotoxic effect, we adopted a quantitative proteomic approach, by coupling stable isotope labeling by amino acids in cell culture (SILAC) with LC-MS/MS analysis, to examine the variation in the entire proteome of GM00637 human skin fibroblasts following acute MMA(III) exposure. Among the ~ 6500 unique proteins quantified, ~ 300 displayed significant changes in expression after exposure with 2 μM MMA(III) for 24 h. Subsequent analysis revealed the perturbation of de novo cholesterol biosynthesis, selenoprotein synthesis and Nrf2 pathways evoked by MMA(III) exposure. Particularly, MMA(III) treatment resulted in considerable down-regulation of several enzymes involved in cholesterol biosynthesis. In addition, real-time PCR analysis showed reduced mRNA levels of select genes in this pathway. Furthermore, MMA(III) exposure contributed to a distinct decline in cellular cholesterol content and significant growth inhibition of multiple cell lines, both of which could be restored by supplementation of cholesterol to the culture media. Collectively, the present study demonstrated that the cytotoxicity of MMA(III) may arise, at least in part, from the down-regulation of cholesterol biosynthesis enzymes and the resultant decrease of cellular cholesterol content.     

硒蛋白对糖尿病小鼠血糖、Ca~(2 )转运以及NO系统影响的实验研究

目的研究硒蛋白对糖尿病小鼠血糖、Ca2 转运及NO系统的调控作用。方法体重(203±17)g昆明种雄性小鼠,腹腔注射200mgkgbw,2%的四氧嘧啶造糖尿病(DM)模型。实验分6组正常对照组(Ⅰ)、正常 硒蛋白组(Se100μgkgbw)(Ⅱ)、糖尿病对照组(Ⅲ)、DM 硒蛋白低剂量组(Se100μgkgbw)(Ⅳ)、DM 硒蛋白高剂量组(Se300μgkgbw)(Ⅴ)、DM 亚硒酸钠组(Se100μgkgbw)(Ⅵ)。结果Ⅴ组血糖(204±63)mmolL明显低于Ⅲ组(453±33)mmolL,P<005;肾脏三磷酸腺苷酶(Ca2 ATPase)活性,Ⅴ组090±05明显高于Ⅲ组(035±01)μmol(h·mgprot),P<005;一氧化氮合酶(NOS)活性,Ⅴ组(250±43)Uml明显低于Ⅲ组(352±44)Uml,P<005。结论补硒剂量为Se300μgkgbw的硒蛋白能够显著的降低糖尿病小鼠血糖、提高肾脏Ca2 ATPase活性和降低血浆NOS活性。     

硒蛋白抑制肿瘤的动物试验

目的采用自富硒豌豆中提取的硒蛋白进行抑瘤试验。方法受试硒蛋白制成经酶解和非酶解两种形式，给接种了小鼠肉瘤S180和小鼠肝癌HAC的ICR纯系小鼠分组饲以不同剂量和两种形式的硒蛋白口服液。结果两种硒蛋白液对S180的生长均有一定的抑制作用，大剂量组的抑制率分别达52．24％和55．88％，与对照组有显著差异（P〈0．001）。两种硒蛋白使HAC荷瘤鼠的存活期分别可延长37．30％和27．78％。与对照组相比有显著差异（P〈0．001）。结论饲用酶解硒蛋白的HAC荷瘤鼠其存活期高于饲用非酶解硒蛋白而与5-Fu相当。     

Molecular clues into the pathogenesis of statin-mediated muscle toxicity

The pathophysiology of statin-mediated muscle dysfunction is poorly defined. Reductions in skeletal muscle membrane cholesterol were initially thought to account for the range of myopathic reactions, e.g., myalgia, elevated serum creatine kinase, or rhabdomyolysis. This assumption however, does not consider a potential role of the isoprenoids in the pathophysiology of statin myopathy. The observation that derangements in mevalonate kinase (MK), but not more distal enzymes of cholesterologenesis, are associated with a skeletal myopathy suggests a critical role for the isoprenoids in the maintenance of muscle. Statins also deplete the isoprenoid pool by inhibiting the enzyme, beta-hydroxy-beta-methylglutaryl coenzyme A reductase, which is upstream of MK. Identifying candidate proteins that are both dependent on isoprenoid-mediated modification and associated with muscle disease, when genetically mutated, offers further insight into potential mechanisms of statin myopathy. For example, lamin A/C, selenoprotein N, alpha- and beta-dystroglycan, and cytoskeletal G-proteins all require isoprenylation for optimal function. Understanding the pleiotropic effects of protein prenylation, and the potential consequences of a generalized insufficiency of this form of protein modification, may help clarify the molecular pathogenesis of statin myopathy.     

大鼠脱碘酶、硒蛋白P和硒蛋白W正常表达所需的最低饲料硒水平

目的　研究能满足大鼠脱碘酶、硒蛋白 P和硒蛋白 W合成所需的饲料硒水平。方法　以低硒酵母合成饲料加不同剂量的亚硒酸钠配成硒水平分别为 0 .0 1、0 .0 2、0 .0 3、0 .0 4、0 .0 5、0 .0 6、0 .1 0和 0 .2 0 mg/kg的 8种饲料喂养雄性 wistar断乳大鼠。 2 0周时杀死大鼠取其组织 ,分别对各种组织中的 型、 型和 型脱碘酶、硒蛋白 P的 m RNA以及硒蛋白 W的 m RNA的水平进行测定。结果　能满足大鼠各组织 型、 型和 型脱碘酶发挥最佳活性时的最低饲料硒水平为0 .0 5mg/kg,而硒蛋白 P的 m RNA以及硒蛋白 W的 m RNA正常表达所需的最低饲料硒水平分别为 0 .0 5和 0 .0 6mg/kg。结论　饲料硒水平达到 0 .1 mg/kg可满足大鼠脱碘酶、硒蛋白 P和硒蛋白 W的合成。     

大鼠脑中血浆硒蛋白P

对缺硒雄性ＳＤ大鼠腹腔内注射７５Ｓｅ标记的亚硒酸钠，２４ｈ后抽去血液，进行灌洗，取脑组织，进行免疫沉淀分析，Ｓｅｐｈａｃｒｙｌ２００柱分离，８Ｆ１１免疫亲和柱吸附及ＳＤＳ－ＰＡＧＥ和放射自显影，结果均表明脑中存在有血浆硒蛋白Ｐ。     

Serum concentrations of trace elements in patients with Crohn's disease receiving enteral nutrition

We investigated the trace element status in Crohn's disease (CD) patients receiving enteral nutrition, and evaluated the effects of trace element-rich supplementation. Thirty-one patients with CD were enrolled in this study. All patients were placed on an enteral nutrition regimen with Elental(R) (Ajinomoto pharmaceutical. Ltd., Tokyo, Japan). Serum selenium, zinc and copper concentrations were determined by atomic absorption spectroscopy. Serum selenoprotein P levels were determined by an ELISA system. Average serum levels of albumin, selenium, zinc and copper were 4.1 +/- 0.4 g/dl, 11.2 +/- 2.8 microg/dl, 71.0 +/- 14.8 microg/dl, and 112.0 +/- 25.6 microg/dl, respectively. In 9 patients of 31 CD patients, serum albumin levels were lower than the lower limit of the normal range. Serum selenium, zinc and copper levels were lower than lower limits in 12 patients, 9 patients and 1 patient, respectively. Serum selenium levels significantly correlated with both serum selenoprotein P levels and glutathione peroxidase activity. Supplementation of selenium (100 microg/day) and zinc (10 mg/day) for 2 months significantly improved the trace element status in CD patients. In conclusion, serum selenium and zinc levels are lower in many CD patients on long-term enteral nutrition. In these patients, supplementation of selenium and zinc was effective in improving the trace element status.