微量营养素补充对孕妇和中老年人群抗氧化能力及免疫功能影响的研究
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摘要
尽管人们的生活水平不断提高,仍有相当一部分人群维生素和矿物质等微量营养素的摄入量处在边缘缺乏甚至缺乏的状态,尤其是处在特殊生理状态的孕妇和中老年人群,是营养不良的高发人群。而有研究证实,充足的维生素和矿物质的摄入是调节机体的氧化应激水平,维持免疫系统正常功能所必需的。妊娠期妇女随着胎盘发育成熟,胎盘富含的血管暴露于高氧分压,胎盘富含的线粒体在呼吸链中释放出大量的电子,使机体氧化应激增强,免疫功能受损。而中老年人群随着年龄增长,机体抗氧化防御体系功能下降,氧化损伤加剧。因此,通过合理补充微量营养素,可以达到改善营养状况,促进健康的效果。本研究分别选取孕妇和中老年人群作为研究对象,通过补充铁、叶酸、视黄醇或维生素E(VE)等微量营养素,观察其对机体抗氧化能力及免疫功能等方面的改善作用。
     首先选取妊娠中期(12-24周)妇女166名,根据其血红蛋白和血清铁蛋白水平分为铁营养状况不同的4组,收集各组孕妇红细胞,制备红细胞膜。通过检测红细胞膜SOD等抗氧化酶活性、MDA水平及膜流动性等指标,对比分析不同铁营养状况孕妇的抗氧化能力。结果显示,与非贫血孕妇比较,贫血孕妇红细胞膜SOD、GSH-Px活性下降,MDA水平升高;当孕妇Hb水平超过130g/L时,其抗氧化能力和细胞功能与Hb在110~130/L的孕妇无显著差别。提示铁营养状况改善可提高机体的抗氧化能力。基于上述实验结果,又进一步观察了补充铁及维生素A对贫血孕妇铁营养状况改善及免疫功能的影响。选取妊娠中期贫血(Hb<110g/L)妇女186名,随机分为4组,分别给予安慰剂(C组)、60mg铁(I组)、60mg铁+0.4mg叶酸(IF组)、60mg铁+0.4mg叶酸+2.0mg视黄醇(IFR组)补充2个月,分别检测各组孕妇Hb、血浆铁蛋白、VA、叶酸等营养状况指标及IL-2、淋巴细胞增殖活性等免疫指标。结果发现3个营养素补充组铁营养状况均明显改善,IL-2水平、淋巴细胞增殖活性也明显提高。而且联合补充铁、叶酸和视黄醇组孕妇铁营养状况及免疫功能均较单独补铁组改善效果好。可见,补充铁、VA等微量营养素可有效改善贫血孕妇营养状况,并促进机体免疫功能。因此,我们又针对中老年人群易发生营养不良的生理特点,继续观察了补充VE对中老年人群抗氧化能力的改善效果。选取55-70岁的中老年人180名,随机分为:安慰剂对照组和100、200、300 mg/d VE补充组,干预时间4个月。干预前后分别采集空腹静脉血,分离血浆和红细胞,同时制备红细胞膜。检测各组血浆SOD、MDA等指标,并分析红细胞溶血度及膜流动性。结果表明每天补充100、200和300mg VE组血浆VE水平明显升高,脂质过氧化产物(MDA)生成减少,而SOD活性也降低,但3组间无显著差异。与对照组比较,每天补充200和300mg VE可有效降低红细胞溶血度,提高红细胞膜流动性。
     综上可见,缺铁性贫血会导致孕妇细胞抗氧化能力和细胞功能降低,随着铁营养状况的改善,孕妇抗氧化能力逐渐升高,细胞功能改善;当孕妇Hb≥130g/L时,抗氧化能力和细胞功能与Hb值在110~130g/L的孕妇比较并无明显差异。对贫血孕妇联合补充铁、叶酸和视黄醇比单独补铁更有利于改善铁营养状况,提高IL-2水平和淋巴细胞增殖活性。对于中老年人群,每天补充100~300mg维生素E可有效减轻机体的氧化损伤,200~300mg/d VE还可明显改善红细胞膜功能。
Although there is a rising of living standards, the intake of vitamins and minerals of large parts of the population are marginally adequate, or even clearly deficient, especially pregnant women and middle-aged and elderly people, who are in special physiological status have higer risk of malnutrition. It's proved that adequate intakes of vitamins and trace elements are required for regulating oxidative stress and the immune system to function efficiently. During pregnancy, as the placenta matures, its vascular exposes to high maternal oxygen partial pressure and its abundant mitochondrial mass favors the production of reactive oxygen species (ROS). So, the oxidative stress increases and immune function is damaged. With age, the antioxidative activity decreases and oxidative damage exacerbates. Therefore, micronutrients supplementation can improve nutrition status and promote health. This study chose the above two population as subjects, and investigated the improvement in antioxidative activity and immune function after supplementation with iron, folic acid, retinol or vitamin E.
     First,166 pregnant women (12-24w gestation) were randomized into 4 groups according to the Hb and serum ferritin levels. Erythrocytes of each group were collected and erythrocyte membrane was prepared. Indicators including SOD, MDA and fliudity of erythrocyte membrane et al. were measured, the results showed that compared with the non-anemic pregnant women, activities of SOD and GSH-Px of erythrocyte membrane in anemic pregnant women decreased, the level of MDA increased and the membrane fliudity also decreased. For those pregnant women whose Hb levels are more than 130g/L, the antioxidative activity and cell function have no significant difference compared with those pregnant women whose Hb levels are 110-130 g/L. It is indicated that with the improvement of iron status, the antioxidative activity increased. Based on the above results, we further investigated the effect of iron and retinol supplementation on iron status and immune function of anemic pregnant women. We randomly allocated 186 anemic pregnant women(12-24w gestation) into four groups. Group C was the placebo group, I was supplemented daily with 60 mg iron as ferrous sulfate, IF with 60 mg iron and 0.4 mg folic acid, IFR with 60 mg iron,0.4 mg folic acid and 2.0 mg retinol. Nutrition status biomarkers including hemoglobin concentration, erythrocyte protoporphyrin (EP), plasma ferritin, plasma retinol, plasma folic acid and immune indexes including IL-2 and lymphocyte proliferation were measured. After the 2 months trial, compared with group C, there were considerable increases of iron status in Hb and plasma ferritin in the I, IF and IFR groups, IL-2 levels and lymphocyte proliferation also increased significantly. Iron combined folic acid and retinol supplementation was more beneficial to improving iron status and immune function during pregnancy than iron alone. This shows that micronutrients (iron, retinol, et al.) supplementation can effectively improve nutrition status of anemic pregnant women and promote the immune function. Taking the elderly population's physiological characteristics into account, they are vulnerable to malnutrition. Therefore, we analyzed the effect of vitamin E supplementation on the antioxidant capacity in the elderly population.180 middle-aged and elderly people(55-70 yrs) were randomly allocated into 4 groups:placebo control group and 100,200,300mg/d VE supplement groups. The intervention period was 4 months. Plasma and erythrocyte membrane were collected for measurement at baseline and after the intervention. The concentration of plasma MDA and activity of plasma SOD were determined. Erythrocyte hemolysis and membrane fluidity were detected too. The plasma VE concentration increased significantly in the three VE supplement groups after 4 months of supplementation. Plasma MDA was reduced and SOD activity was reduced too, while there were no significant differences between the three supplement groups. Compared with group C,200 or 300mg/d VE supplementation decreased erythrocyte hemolysis and elevated erythrocyte membrane fliudity.
     Results of these studies confirmed that IDA (Hb<110g/L) can decrease antioxidative activity and cell functions of pregnant women. With the improvement of iron status, the antioxidative activity and cell functions of pregnant women are increased gradually. The high level of hemoglobin which is above 130g/L does not have additional effect on the antioxidative activity and cell functions. Iron combined folic acid and retinol supplementation was more beneficial to improving iron status, IL-2 and lymphocyte proliferation during pregnancy than iron alone. For middle-aged and elderly people, supplementation of 100-300mg/d VE can effectively alleviate oxidative damage and 200-300mg/d VE can improve erythrocyte function.
引文
1. Ames BN. Increasing longevity by tuning up metabolism. To maximize human health and lifespan, scientists must abandon outdated models of micronutrients. TMBO,2005; 6(S1):S20-S24.
    2. Ferns G, Williams J, Forster L, et al. Cholesterol standardized plasma vitamin E levels are reduced in patients with severe angina pectoris. Int J Exp Pathol.2000; 81(1):57-62.
    3. Kostner K, Hornykewycz S, Yang P, et al. Is oxidative stress causally linked to unstable angina pectoris? A study in 100 CAD patients and matched controls. Cardiovasc Res.1997; 36(3): 330-336.
    4. Riemersma RA, Wood DA, Macintyre CC, et al. Risk of angina pectoris and plasma concentrations of vitamins A, C, and E and carotene. Lancet,1991; 337(8732):1-5.
    5. Lee IM, Cook N, Gaziano JM, et al. Vitamin E in the primary prevention of cardiovascular disease and cancer:the Women's Health Study:a randomized controlled trial. JAMA,2005; 294(1): 56-65.
    6. Bobak M, Brunner E, Miller NJ, et al. Could antioxidants play a role in high rates of coronary heart disease in the Czech Republic? Eur J Clin Nutr,1998; 52(9):632-636.
    7. Rajasekhar D, Srinivasa Rao PV, Latheef SA, et al. Association of serum antioxidants and risk of coronary heart disease in South Indian population. Indian J Med Sci,2004; 58(11):465-471.
    8.葛可佑总主编.中国营养科学全书,2004年10月第1版,人民卫生出版社。
    9. Cordero Z, Drogan D, Weikert C, et al. Vitamin E and risk of cardiovascular diseases:a review of epidemiologic and clinical trial studies. Crit Rev Food Sci Nutr,2010; 50(5):420-440.
    10. Shekelle PG, Morton SC, Jungvig LK, et al. Effect of supplemental vitamin E for the prevention and treatment of cardiovascular disease. J Gen Intern Med,2004; 19(4):380-389.
    11. Hense HW, Stender M, Bors W, et al. Lack of an association between serum vitamin E and myocardial infarction in a population with high vitamin E levels. Atherosclerosis,1993; 103(1): 21-28.
    12. Virtamo J, Rapola J, Ripatti S, et al. Effect of vitamin E and beta carotene on the incidence of primary nonfatal myocardial infarction and fatal coronary heart disease. Arch Intern Med,1998; 158(6):668-675.
    13. Lonn E, Bosch J, Yusuf S, et al. Effects of long-term vitamin E supplementation on cardiovascular events and cancer:a randomized controlled trial. JAMA,2005; 293 (11):1338-1347.
    14. Valko M, Leibfritz D, Moncol J, et al. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol,2007; 39(1):44-84.
    15. Halliwell B. Free radicals and antioxidants:a personal view. Nutr Rev,1994; 52 (8 pt 1):253-265.
    16. Thomas DR. Vitamins in aging, health, and longevity. Clin Interv Aging.2006; 1(1):81-91.
    17. Wakimoto P, Block G. Dietary intake, dietary patterns, and changes with age:an epidemiological perspective. J Gerontol A Biol Sci Med Sci,2001; 56(2):65-80.
    18. Cetin E, Top EC, Sahin G, et al. Effect of vitamin E supplementation with exercise on cognitive functions and total antioxidant capacity in older people. J Nutr Health Aging.2010;14(9):763-769.
    19. Yusuf S, Dagenais G, Pogue J, et al. Vitamin E supplementation and cardiovascular events in high-risk patients, The Heart Outcomes Prevention Evaluation Study Investigators. NEngl J Med, 2000; 342(3):154-160.
    20. Leppala JM, Virtamo J, Fogelholm R, et al. Controlled trial of alpha-tocopherol and betacarotene supplements on stroke incidence and mortality in malesmokers. Arterioscler Thromb Vasc Biol, 2000; 20(1):230-235.
    21. Vina J, Gomez-Cabrera MC, Borras C. Fostering antioxidant defences:up-regulation of antioxidant genes or antioxidant supplementation? Br J Nutr,2007; 98 Suppl 1:S36-S40.
    22. Ames BN, Atamna H, Killilea DW. Mineral and vitamin deficiencies can accelerate the mitochondrial decay of aging. Mol Aspects Med,2005; 26(4-5):363-378.
    23.潘迎,武明辉,谢争等.北京市孕产妇贫血患病率分析.中国妇幼保健,2007,22(10):1364-1366.
    24. Ma AG, Chen XC, Wang Y, et al. The multiple vitamin status of Chinese pregnant women with anemia and nonanemia in the last trimester. J Nutr Sci Vitaminol (Tokyo).2004;50(2):87-92.
    25. Wintergerst ES, Maggini S, Hornig DH. Contribution of selected vitamins and trace elements to immune function. Ann Nutr Metab.2007; 51(4):301-23.
    26. Castellani ML, Shaik-Dasthagirisaheb YB, Tripodi D, et al. Interrelationship between vitamins and cytokines in immunity. J Biol Regul Homeost Agents,2010; 24(4):385-390.
    27. Mora JR, Iwata M, von Andrian UH. Vitamin effects on the immune system:vitamins A and D take centre stage. Nat Rev Immunol,2008; 8(9):685-698.
    28. Ertesvag A, Engedal N, Naderi S, et al. Retinoic acid stimulates the cell cycle machinery in normal T cells:involvement of retinoic acid receptor-mediated IL-2 secretion. J Immunol, 2002;169(10):5555-5563.
    29. Kontic-Vucinic O, Sulovic N, Radunovic N. Micronutrients in women's reproductive health: Ⅱ. Minerals and trace elements. Int J Fertil Womens Med,2006; 51(3):116-124.
    30. Ziaei S, Norrozi M, Faghihzadeh S, et al. A randomised placebo-controlled trial to determine the effect of iron supplementation on pregnancy outcome in pregnant women with haemoglobin>or=13.2 g/dl. BJOG,2007; 114(6):684-688.
    31.聂松青,礴惠卿,林克椿.蜂王精对大鼠红细胞膜流动性的影响.北京医学院学报,1983;15(4):249-252.
    32. Milman N, Bergholt T, Eriksen L, et al. Iron requirements and iron balance during pregnancy. Is iron supplementation needed for pregnant women? Ugeskr Laeger,1997; 159(41):6057-6062.
    33. Knutson MD, Walter PB, Ames BN, et al. Both iron deficiency and daily iron supplements increase lipid peroxidation in rats. J Nutr,2000; 130(2):621-628.
    34. Meral A, Tuncel P, Surmen-Gur E. Lipid peroxidation and antioxidant status in beta-thalassemia. Pediatr Hematol Oncol,2000; 17(8):687-693.
    35.李文丽,海春旭,梁欣,等.维生素A和E对梭曼中毒大鼠过氧化物酶的影响.第四军医大学学报,2002;23(1):56-58.
    36. Walter PB, Knutson MD, Paler-Martinez A, et al. Iron deficiency and iron excess damage mitochondria and mitochondial DNA in rats. Proc Natl Acad Sci USA,2002; 99(4):2264-2269.
    37. Knutson MD, Walter PB, Ames BN, et al. Both Iron Deficiency and Daily Iron Supplements Increase Lipid Peroxidation in Rats. J Nutr.2000; 130(3):621-628.
    38.李英哲,黄连珍,周丽玲.维生素A缺乏对大鼠脂质过氧化和抗氧化系统的影响.营养学报,2001:23(1):1-4.
    39. Anichkov DA, Maksina AG, Shostak NA. Relationships between erythrocyte membrane properties and components of metabolic syndrome in women. Med Sci Monit,2005; 11(4):203-210.
    40. Benderitter M, Vincent-Genod L, Pouqet JP, et al. The cell membrane as a biosensor of oxidative stress induced by raiation exposure:a multiparameter investigation. Radiat Res,2003; 159(4): 471-483.
    41. Steer P, Alam MA, Wadsworth J, et al. Relation between maternal haemoglobin concentration and birth weight in different ethnic groups. BMJ,1995; 310 (6978):489-491.
    42. Bondevik GT, Lie RT, Ulstein M, et al. Maternal hematological status and risk of low birth weight and preterm delivery in Nepal. Acta Obstet Gynecol Scand,2001; 80(5):402-408.
    1. Ma AG, Schouten EG, Wang Y, et al. Anemia prevalence among pregnant women and birth weight in five areas in China. Med Prin Pract,2009;18(5):368-372.
    2. Ma AG, Chen XC, Wang Y, et al. The multiple vitamin status of Chinese pregnant women with anemia and nonanemia in the last trimester. J Nutr Sci Vitaminol (Tokyo),2004;50(2):87-92.
    3. Christian P, West KP, Jr Khatry SK, et al. Night blindness of pregnancy in rural Nepal:nutritional and health risks. Int J Epidemiol,1998; 27(2):231-237.
    4. Bhaskaram P. Immunobiology of mild micronutrient deficiencies. Br J Nutr,2001; 85(suppl 2): S75-S80.
    5. Stephensen CB. Vitamin A, infection, and Immune function. Annu Rev Nutr,2001; 21:167-192.
    6. Engedal N, Ertesvag A, Blomhoff HK. Survival of activated human T lymphocytes is promoted by retinoic acid via induction of IL-2. Int Immunol,2004; 16(3):443-453.
    7. Ross AC. Vitamin A status:relationship to immunity and the antibody response. Proc Soc Exp Biol Med,1992; 200(3):303-320.
    8. Semba RD. Vitamin A, immunity, and infection. Clin Infect Dis,1994;19(3):489-499.
    9. Chandra RK, Saraya AK. Impaired immunocompetence associated with iron deficiency. Paediatrics,1975; 86(6):899-902.
    10. Sipahi T, Akar N, Egin T, et al. Serum interleukin-2 and interleukin-6 levels in iron deficiency anemia. Pediatr Hematol Oncol.1998;15(1):69-73.
    11. Wang JX, Liu GH, Fan YZ, et al. Effects of cytotoxic T lymphocytes on hepatoma cell line SMMC-7721 induced by different subsets of dendritic cells in vitro. Hepatobiliary Pancreat Dis Int,2006; 5(3):422-427.
    12. Ma A, Chen X, Zheng M, et al. Iron status and dietary intake of Chinese pregnant women with anaemia in the third trimester. Asia Pac J Clin Nutr,2002; 11(3):171-175.
    13. Seck BC, Jackson RT. Multiple contributors to iron deficiency and anemia in Senegal. Int J Food Sci Nutr,2010; 61(2):204-216.
    14. Kuvibidila SR, Porretta C, Surendra Baliga B, et al. Reduced thymocyte proliferation but not increased apoptosis as a possible cause of thymus atrophy in iron-deficient mice. Br J Nutr,2001; 86(2):157-162.
    15. Bhaskaram P. Micronutrient malnutrition, infection, and immunity:an overview. Nutr Rev,2002; 60(5 pt 2):S40-S45.
    16. Golding S, Young P. Iron requirements of human lymphocytes:Relative contributions of intra-and Extra-cellular iron. Scand J Immunol,1995; 41(3):229-236.
    17. Dhur A, Galan P, Hercberg S. Effect of decreased food consumption during iron deficiency upon growth rate and iron status indicators in the rat. Ann Nutr Metab,1990; 34(5):280-287.
    18. Artac H, Coskun M, Karadogan I, et al. Transferrin receptor in proliferation of T lymphocytes in infants with iron deficiency. Int J Lab Hematol,2007; 29(4):310-315.
    19. Semba RD, Kumwenda N, Taha TE, et al. Impact of vitamin A supplementation on anaemia and plasma erythropoietin concentrations in pregnant women:a controlled clinical trial. Eur J Haematol,2001; 66(6):389-395.
    20. Engedal N, Gjevik T, Blomhoff R,et al. All-trans retinoic acid stIRulates IL-2-mediated proliferation of human T lymphocytes:early induction of cyclin D3. J Immunol,2006;177(5): 2851-2861.
    21. Ahmad SM, Haskell MJ, Raqib R, et al. Vitamin A status is associated with T-cell responses in Bangladeshi men. Br J Nutr,2009; 102(6):797-802.
    22. Ertesvag A, Austenaa LM, Carlsen H, et al. Retinoic acid inhibits in vivo interleukin-2 gene expression and T-cell activation in mice. Immunology,2009; 126(4):514-522.
    23. Ren A, Zhang L, Li Z, et al. Awareness and use of folic acid, and blood folate concentrations among pregnant women in northern China:an area with a high prevalence of neural tube defects. Reprod Toxicol,2006;22(3):431-436.
    24. CDC. Use of vitamins containing folic acid among women of childbearing age:United States. MMWR Morb Mortal Wkly Rep,2004; 53(36):847-850.
    1. Shiva Shankar Reddy CS, Subramanyam MV, Vani R, et al. In vitro models of oxidative stress in rat erythrocytes:effect of antioxidant supplements. Toxicol In Vitro,2007; 21(8):1355-1364.
    2. Armutcu F, Coskun O, Gurel A,et al. Vitamin E protects against acetone-induced oxidative stress in rat red blood cells.Cell Biol Toxicol,2005; 21(1):53-60.
    3. Fantappie O, Lodovici M, Fabrizio P, et al. Vitamin E protects DNA from oxidative damage in human hepatocellular carcinoma cell lines. Free Radic Res,2004; 38(7):751-759.
    4. Radimer K, Bindewald B, Hughes J, et al. Dietary supplement use by US adults:data from the National Health and Nutrition Examination Survey,1999-2000. Am J Epidemiol,2004; 160(4): 339-349.
    5. Miller ER 3rd, Pastor-Barriuso R, Dalal D, et al. Meta-Analysis:High-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med,2005; 142 (1):37-46.
    6. Gerss J, Kopcke W. The questionable association of vitamin E supplementation and mortality--inconsistent results of different meta-analytic approaches. Cell Mol Biol (Noisy-le-grand),2009; 55 Suppl:OLl111-1120.
    7. David R Thomas. Vitamins in aging, health, and longevity. Clinical Interventions in Aging,2006; 1(1):81-91.
    8.聂松青,礴惠卿,林克椿.蜂王精对大鼠红细胞膜流动性的影响.北京医学院学报,1983;15(4):249-252.
    9. Engin KN. Alpha-tocopherol:looking beyond an antioxidant. Mol Vis,2009; 15:855-860.
    10. Tsuchiya M, Asada A, Kasahara E, et al. Antioxidant protection of propofol and its recycling in erythrocyte membranes. Am J Respir Crit Care Med,2002; 165(1):54-60.
    11. Burton GW. Vitamin E:molecular and biological function. Proc Nutr Soc,1994; 53(2):251-262.
    12. Pearson P, Lewis SA, Britton J, et al. The pro-oxidant activity of high-dose vitamin E supplements in vivo. BioDrugs,2006; 20(5):271-273.
    13. Harman D. Aging:overview. Ann N Y Acad Sci,2001; 928:1-21.
    14. Motta S, Letellier C, Ropert M, et al. Protecting effect of vitamin E supplementation on submaximal exercise-induced oxidative stress in sedentary dogs as assessed by erythrocyte membrane fluidity and paraoxonase-1 activity. Vet J,2009; 181(3):288-295.
    15. Schwenke DC, Behr SR. Alpha-tocopherol and probucol reduce autoantibody titer to MDA-LDL in hypercholesterolemic rabbits. Free Radical Biol. Med,2001; 31(6):778-789.
    16. Meagher EA, Barry OP, Lawson JA, et al. Effects of vitamin E on lipid peroxidation in healthy persons. JAMA,2001; 285:1178-1182.
    17. Shirpoor A, Salami S, Khadem-Ansari MH, et al. Cardioprotective effect of vitamin E:rescues of diabetes-induced cardiac malfunction, oxidative stress, and apoptosis in rat. J Diabetes Complications,2009; 23(5):310-316.
    18. Yerer MB, Aydogan S. The in vivo antioxidant effectiveness of alpha-tocopherol in oxidative stress induced by sodium nitroprusside in rat red blood cells. Clin Hemorheol Microcirc,2004; 30(3-4):323-329.
    19. Dandapat J, Chainy GB, and Rao KJ. Dietary vitamin-E modulates antioxidant defence system in giant fresh water prawn, Macrobrachium rosenbergii. Comp Biochem Physiol Toxicol Pharmacol, 2000; 127(1):101-115.
    20. Deyhim F, Gonzales C, Garcia C, et al. Vitamin E dose not modulate plasma lipid profile or C-reactive protein despite suppressing oxidative stress orchiectomized rats. J Med Food,2007; 10(3):559-562.
    21. Aslan L, and Meral I. Effect of oral vitamin E supplementation on oxidative stress in guinea-pigs with short-term hypothermia. Cell Biochem Funct,2007; 25(6):711-715.
    22. Huang W-P, Chan P, Chen Y-J, et al. Changes of superoxide dismutase in cultured rat aortic smooth muscle cells(A7r5) by an incubation of vitamin E. Pharmacology,1999; 59(5):275-282.
    23. De Oliveira S, and Saldanha C. An overview about erythrocyte membrane. Clin Hemorheol Microcirc,2010; 44(1):63-74.
    24. Wang J, Huang CJ, Chow CK. Red cell vitamin E and oxidative damage:a dual role of reducing agents. Free Radic Res,1996; 24(4):291-298.
    25. Borst JW, Visser NV, Kouptsova O, et al. Oxidation of unsaturated phospholipids in membrane bilayer mixtures is accompanied by membrane fluidity changes. Biochimica et Biophysica Acta, 2000; 1487(1):61-73.
    26. Cazzola R, Russo-Volpe S, Cervato G, et al. Biochemical assessments of oxidative stress, erythrocyte membrane fluidity and antioxidant status in professional soccer players and sedentary controls. Eur J Clin Invest,2003; 33(10):924-930.
    27. Cazzola R, Rondanelli M, Russo-Volpe S, E, et al. Decreased membrane fluidity and altered susceptibility to peroxidation and lipid composition in overweight and obese female erythrocytes. J Lipid Res,2004; 45(10):1846-1851.
    28. Babu N. Influence of hypercholesterolemia on deformability and shape parameters of erythrocytes in hyperglycemic subjects. Clin Hemorheol and Microcirc,2009; 41(3):169-177.
    29. Yawata Y. Cell Membrance:The Red Blood Cell as a modeal. Wiley,2003.
    30. Clarke MW, Burnett JR, Croft KD. Vitamin E in human health and disease. Crit Rev Clin Lab Sci, 2008; 45(5):417-450.
    31.李永华,马爱国,杜珍,等.维生素E、C和β-胡萝卜素对老年人细胞氧化损伤影响的研究.营养学报,2007;29(6):535-539.
    32.丁航,刘慧明,梁统,等.侧柏叶中黄酮类化合物对H2O2诱导的人红细胞氧化作用的影响.实用临床医学,2003;4(3):23-24.
    33. Sies H, Murphy ME. Role of tocopherols in the protection of biological systems against oxidative damage. J Photochem Photobiol B,1991; 8(2):211-218.
    1. McCann JC, Ames BN. An overview of evidence for a causal relation between iron deficiency during development and deficits in cognitive or behavioral function. Am J Clin Nutr,2007; 85(4): 931-945.
    2. Ames BN. Low micronutrient intake may accelerate the degenerative diseases of aging through allocation of scarce micronutrients by triage. Proc Natl Acad Sci USA,2006; 103(47): 17589-17594.
    3. Meydani M. Nutrition interventions in aging and age-associated disease. Ann N Y Acad Sci,2001; 928:226-235.
    4. Fenech M, Ferguson LR. Vitamins/minerals and genomic stability in humans. Mutat Res,2001; 475(1-2):1-6.
    5. Vina J, Gomez-Cabrera MC, Borras C. Fostering antioxidant defences:up-regulation of antioxidant genes or antioxidant supplementation? Br J Nutr.2007; 98 Suppl 1:S36-S40.
    6. Ames BN, Atamna H, Killilea DW. Mineral and vitamin deficiencies can accelerate the mitochondrial decay of aging. Mol Aspects Med,2005; 26(4-5):363-378.
    7. Han SN, Meydani M, Wu D, et al. Effect of long-term dietary antioxidant supplementation on influenza virus infection. J Gerontol A Biol Sci Med Sci,2000; 55(10):B496-B503.
    8. de la Asuncion JG, del Olmo ML, Sastre J, et al. AZT treatment induces molecular and ultrastructural oxidative damage to muscle mitochondria. Prevention by antioxidant vitamins. J Clin Invest,1998; 102(1):4-9.
    9. Naidu KA. Vitamin C in human health and disease is still a mystery? An overview. Nutr J,2003; 2:7.
    10. Bjelakovic G, Nikolova D, Gluud LL, et al. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention:systematic review and meta-analysis. JAMA, 2007; 297(8):842-857.
    11. Miller E, Pastor-Barriuso R, Dalal D, et al. Meta-analysis:high dose vitamin E supplementation may increase all-cause mortality. Ann Intern Med,2005; 142(1):37-46.
    12. The HOPE and HOPE-TOO Trial Investigators. Effects of long-term vitamin E supplementation on cardiovascular events and cancer:a randomised controlled trial. JAMA,2005; 293(11): 1338-1347.
    13. Gonzalez-Correa JA, Arrebola MM, Guerrero A, et al. Antioxidant and antiplatelet effects of the alpha-tocopherol-aspirin combination in type 1-like diabetic rats. Life Sciences,2006; 79(15): 1405-1412.
    14. Mustacich DJ, Leonard SW, Devereaux MW, et al. α-tocopherol regulationoh hepatic cytochrome P450s and ABC transportersin rats. Free Rad Biol Med,2006; 41(7):1069-1078.
    15. Brown KM, Morrice PC, Duthie GG. Erythrocyte vitamin E and plasma ascorbate concentrations in relation to erythrocyte peroxidation in smokers and nonsmokers. Dose response to vitamin E supplementation. Am J Clin Nutr,1997; 65(2):496-502.
    16. Winterbone MS, Sampson MJ, Saha S, et al. Pro-oxidant effect of a-tocopherol in patients with Type 2 Diabetes after an oral glucose tolerance test-a randomized controlled trial. Cardiovasc Diabetol,2007; 6:8.
    17. Brigelius-Flohe R. Vitamin E:the shrew waiting to be tamed. Free Radic Biol Med,2009; 46(5):543-54.
    18. Evans HM and Bishop KS. On the existence of a Hitherto Unrecognized Dietary Factor Essential for Reproduction. Science,1922; 56:650-651.
    19. Sies H, Murphy ME. Role of tocopherols in the protection of biological systems against oxidative damage. J Photochem Photobiol B,1991; 8(2):211-218.
    20. Ciocouu M, Badescu M, Paduraru I. Protecting antioxidative efects of vitamins E and C in experimental physical stress. J Physiol Biochem,2007; 63(3):187-194.
    21. Jurczuk M, Brzoska MM, Moniuszko-Jakoiuk J. Hepatic and renal concentrations of vitamins E and C inlead- and ethanol-exposed rats. An assessment of their involvement in the mechanisms of peroxidative damage. Food Chem Toxicol,2007; 45(8):1478-1486.
    22. Andersen HR, Andersen O. Effects of dietary alpha-tocopherol and beta-carotene on lipid peroxidation induced by methyl mercuric chloride in mice. Pharmacol Toxicol,1993; 73(4): 192-201.
    23. Huang HY, Helzlsouer KJ, Appel LJ. The effects of vitamin C and vitamin E on oxidative DNA damage:results from a randomized controlled trial. Cancer Epidemiol Biomarkers Prev,2000; 9(7):647-652.
    24. Huang HY, Appel LJ, Croft KD, et al. Effects of vitamin C and vitamin E on in vivo lipid peroxidation:results of a randomized controlled trial. Am J Clin Nutr,2002; 76(3):549-555.
    25. Schmidt MC, Askew EW, Roberts DE, et al. Oxidative stress in humans training in a cold, moderate altitude enviroment and their response to a phytochemical antioxidant supplement. Wilderness Environ Med,2002; 13(2):94-105.
    26. Gomez-Cabrera MC, Borras C, Pallardo FV, et al. Decreasing xanthine oxidase-mediated oxidative stress prevents useful cellular adaptations to exercise in rats. J Physiol,2005; 567(ptl): 113-120.
    27. Halliwell B. Free radicals and antioxidants:a personal view. Nutr Rev,1994; 52(8 pt 1):253-265.
    28. Valko M, Leibfritz D, Moncol J, et al. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol,2007; 39(1):44-84.
    29. Borras C, Sastre J, Garcia-Sala D, et al. Mitochondria from females exhibit higher antioxidant gene expression and lower oxidative damage than males. Free Radic Biol Med,2003; 34(5): 546-552.
    30. Chappell LC, Seed PT, Briley AL, et al. Effect of antioxidants on the occurrence of pre-eclampsiain women at increased risk:a randomised trial. Lancet,1999; 354(9181):810-816.
    31. Mares-Perlman JA, Lyle BJ, Klein R, et al. Vitamin supplement use and incident cataracts in a population-based study. Arch Ophthalmol,2000; 118(11):1556-1563.
    32. Belda JI, Roma J, Vilela C, et al. Serum vitamin E levels negatively correlate with severity of age-related macular degeneration. Mech Ageing Dev,1999; 107(2):159-164.
    33. Jain SK, McVie R, Smith T. Vitamin E supplementation restores glutathione and malondialdehyde to normal concentrationsin erythrocytes of type 1 diabetic children. Diabetes Care,2000; 23(9):1389-1394.
    34. Sano M, Ernesto C, Thomas RG, et al.A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer'sdisease. The Alzheimer's Disease Cooperative Study. N Engl J Med, 1997; 336(17):1216-1222.
    35. Pfluger P, Kluth D, Landes N, et al. Vitamin E:underestimated as an antioxidant. Redox Rep, 2004; 9(5):249-254.
    36. Stocker R, Keaney JF Jr. Role of oxidative modifications in atherosclerosis. Physiol Rev,2004; 84(4):1381-1478.
    37. Stocker R. Vitamin E. Novartis Found Symp,2007; 282:77-87.
    38. Vivekananthan DP, Penn MS, Sapp SK, et al. Use of antioxidant vitamins for the prevention of cardiovascular disease:meta-analysis of randomised trial. Lancet,2003; 361(9374):2017-2023.
    39. Meydani SN, Leka LS, Fine BC, et al. Vitamin E and respiratory tract infections in elderly nursing home resident:a randomized controlled trial. JAMA,2004; 292(7):828-836.
    40. Han SN, Meydani M, Wu D, et al. Effect of long-term dietary antioxidant supplementation on influenza virus infection. J Gerontol A Biol Sci Med Sci,2000; 55(10):B496-B503.
    41. Kaliora AC, Dedoussis GV, Schmidt H. Dietary antioxidants in preventing atherogenesis. Atheroselerosis,2006; 187(1):1-17.
    42. Steinhubl SR. Have antioxidants failed in clinical trials?. Am J Cardiol,2008; 101(10A):14-19.
    43. Stephens NG, Parsons A, Schofield PM, et al. Randomised controlled trial of vitamin E in patients with coronary disease:Cambridge Heart Antioxidant Study (CHAOS).Lancet,1996; 347(9004):781-786.
    44. Fand JC, Kinlay S, Beltrame J, et al. Effect of vitamins C and E on progression of transplant-associated arteriosclerosis:a randomised trial. Lancet,2002; 359(9312):1108-1113.
    45. Kamal-Eldin A, Appelqvist LA. The chemistry and antioxidant properties of tocopherols and tocotrienols. Lipids,1996; 31(7):671-701.
    46. Lea CH. On the antioxidant activities of the tocopherols. Ⅱ.influence of substrate, temperature and level of oxidation. J Sci Food Agric,1960; 11:212-218.
    47. Bowry VW, Ingold KU, Stocher R. Vitamin E in human low-density lipoprotein. Bilchem J,1992; 288(pt2):341-344.
    48. Eder K, Flaker D, Hirche F, et al. Excess dietary vitamin E lowers the activities of antioxidative enzymes in erythrocytes of rats fed salmon oil. J Nutr,2002; 132(11):3400-3404.
    49. Record IR, Jannes M. Iron, alpha-tocpherol, oxidative damage and micronucleus formation in rat splenocytes. Cancer Lett,2000; 160(2):125-131.
    50. Blasiak J, Bloc E, Wozniak K, et al. Genotoxicity of idarubicin and its modulation by vitamins C and E and amifostine. Chem Biol Interact,2002; 140(1):1-18.
    51. Bowry VM, Stocker R. Tocopherol-mediated peroxidation:the prooxidant effect of vitamin E on the radical-initiated oxidation of human low-density lipoprotein. J Am Chem Soc,1993; 115: 6029-6044.
    52. Hicks M, Gebicki JM. Inhibition of peroxidation in linoleic acid membranes by nitroxide radicals, butylated hydroxy toluene and a-tocopherol. Arch Biochem Bilphys,1981; 210(1):56-63.
    53. Clarke MW, Burnett JR, Croft KD. Vitamin E in human health and disease. Crit Rev Clin Lab Sci, 2008; 45(5):417-450.
    54. Navab M, Ananthramaiah GM, Reddy ST, et al. The oxidation hypothesis of atherogenesis:the role of oxidized phospholipids and HDL. J Lipid Res,2004; 45(6):993-1007.
    55. Kushi LH, Folsom AR, Prineas RJ, et al. Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women. N,1996; 334(18):1156-1162.
    56. Rimm EB, Stampfer MJ, Ascherio A, et al. Vitamin E consumption and the risk of coronary disease in men. N Engl J Med,1993; 328(20):1450-1456.
    57. Stampfer MJ, Hennekens CH, Manson JE, et al. Vitamin E consumption and the risk of coronary heart disease in women. N Engl J med,1993; 328(20):1444-1449.
    58. Radimer K, Bindewald B, Hughes J, et al. Dietary supplement use by US adults:data from the National Health and Nutrition Examination Survey,1999-2000. Am J Epidemiol,2004; 160(4): 339-349.
    59. Gey KF, Pusk A P. Plasma vitamins E and A inversely correlated to mortality from ischemic heart disease in Cross-cultural epidemiology. Ann NY Acad Sci,1989,570:268-282.
    60. Stampfer MJ, Hennekens CH, Manson JE, et al. Vitamin E consumption and the risk of coronary disease in women. N Engl J Med,1993; 328(20):1444-1449.
    61. Collaborative Group of the Primary Prevention Project. Low-dose aspirin and vitamin E in people at cardiovascular risk:a randomized trial in general practice. Lancet,2001; 357(9250):89-95.
    62. Cook NR, Albert CM, Gaziano JM, et al. A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular events in women:results from the Women's Antioxidant Cardiovascular Study. Arch Intern Med,2007; 167(15):1610-1618.
    63. GISSI-Preventione I. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction:results of the GISSI-Prevenzione trial. Lancet,1999; 354(9177): 447-455.
    64. Lee IM, CookNR, Gaziano JM, et al. Vitamin E in the primary prevention of cardiovascular disease and cancer:the Women's Health Study:a randomized controlled trial. JAMA,2005; 294(1):56-65.
    65. Leppala JM, Virtamo J, Fogelholm R, et al. Controlled trial of alpha-tocopherol and beta-carotene supplements on stroke incidence and mortality in male smokers. Arterioscler Thromb Vasc Biol, 2000; 20(1):230-235.
    66. Sesso HD, Buring JE, Christen WG, et al. Vitamins E and C in the prevention of cardiovascular disease in men:the Physicians' Health Study Ⅱ randomized controlled trial. JAMA,2008; 300(18):2123-2133.
    67. Yusuf S, Dagenais G, Pogue J, et al. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med, 2000; 342(3):154-160.
    68. Vivekananthan DP, Penn MS, Sapp SK, et al. Use of antioxidant vitamins for the prevention of cardiovascular disease:meta-analysis of randomised trials. Lancet,2003; 361(9374):2017-2023.
    69. Eidelman RS, Hollar D, Hebert PR, et al. Randomized trials of vitamin E in the treatment and prevention of cardiovascular disease. Arch Intern Med 2004; 164(14):1552-1556.
    70. Tonk M, Haan J. A review of genetic causes of ischemic and hemorrhagic stroke. J Neurol Sci, 2007; 257(1-2):273-279.
    71. Straus SE, Majumdar SR, McAlister FA. New evidence for stroke prevention:scientific review. JAMA,2002; 288(11):1388-1395.
    72. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease:meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ 2009; 338(10.1136):b1665.
    73. Zhang H, Thijs L, Staessen JA. Blood pressure lowering for primary and secondary prevention of stroke. Hypertension,2006; 48(2):187-195.
    74. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet,2005; 366(9493):1267-1278.
    75. Meagher EA, Barry OP, Lawson JA, et al. Effects of vitamin E on lipid peroxidation in healthy persons. JAMA,2001; 285(9):1178-1182.
    76. Halliwell B. Antioxiants and human disease:a general introduction. Nutr Rev,1997; 55(1):S49-52.
    77. Gon Y, Sasada T, Matsui M, et al. Expression of thioredoxin in bleomycin-injured airway epithelium:possible role of protection against bleomycin induced epithelial injury. Life Sci, 2001;68(16):1877-1888.
    78. Husain K, Whitworth C, Somani SM, et al. Carboplatin-induced oxidative stress in rat cochlea. Hear Res,2001;159(1-2):14-22.
    79. Chen X, Mikhail SS, Ding YW, et al. Effects of vitamin E and selenium supplementation on esophageal adenocarcinogenesis in a surgical model with rats. Carcinogenesis,2000; 21(8): 1531-1536.
    80. Cognault S, Jourdan ML, Germain E, et al. Effect of an a-linolenic acid diet on rat mammary tumor growth depends on the dietary oxidative status. Nutr Cancer,2000; 36(1):33-41.
    81. Leonetti C, Biroccio A, Gabellini C, et al. Alpha-tocopherol protects against cisplatin-induced toxicity without interfering with antitumor efficacy. Int J Cancer,2003; 104(2):243-250.
    82. Woodson K, Triantos S. Long-term alpha-tocopherol supplementation is associated with lower serum vascular endothelial growth factor levels. Anticancer Res,2002; 22(1 A):375-378.
    83. Blot WJ, Li JY, Taylor PR, et al. Nutrition intervention trials in Linxian, China:supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst,1993; 85(18):1483-1492.
    84. Traber MG, Sies H. Vitamin E in humans:demand and delivery. Annu Rev Nutr.1996; 16:321-347.
    85. Wu D, Meydani SN. Age-associated changes in immune and inflammatory responses:impact of vitamin E intervention. J Leukoc Biol,2008; 84(4):900-914.
    86. Meydani SN, Barklund MP, Liu S, et al. Vitamin E supplementation enhances cell-mediated immunity in healthy elderly subjects. Am J Clin Nutr,1990; 52(3):557-563.
    87. Meydani SN, Meydani M, Verdon Cp, et al. Vitamin E supplementation suppresses prostaglandin E1 (2) synthesis and enhances the immune response of aged mice. Mech Ageing Dev,1986; 34(): 191-201.
    88. Meydani SN, Meydani M, Blumberg JB, et al. Vitamin E supplementation and in vivo immune response in healthy elderly subjects. A randomized controlled trial. JAMA,1997; 277(17):1380-1386.
    89. Sakai S, Moriguchi S. Long-term feeding of high vitamin E diet improves the decreased mitogen response of rat splenic lymphocytes with aging. J Nutr Sci Vitaminol,1997; 43(1):113-122.
    90. Wintergerst ES, Maggini S, Hornig DH. Contribution of selected vitamins and trace elements to immune function. Ann Nutr Metab,2007;51(4):301-323.
    91. Chavance M, Herbeth B, Mikstachi T, et al. Nutritional support improves antibody response to influenza virus vaccine in the elderly. Br Med J,1985; 291(6505):1348-1349.
    92. Campbell D, Bunker VW, Thomas AJ,et al. Selenium and vitaminE status of healthy and institutionalized elderly subjects:analysis of plasma, erythrocytes and platelets. Br J Nutr,1989; 62(1):221-227.
    93. De la Fuente M, Hernanz A, Guayerbas N, et al. Vitamin E ingestion improves several immune functions in elderly men and women. Free Radic Res,2008; 42(3):272-280.
    94. De Waart FG, Portengen L, Doekes G, et al. Effect of 3 months vitamin E supplementation on indices of the cellular and humoral immune response in elderly subjects. Br J Nutr,1997; 78(5): 761-774.
    95. Munoz M, Villar I, Garcia-Erce JA. An update on iron physiology. World J Gastroenterol, 2009; 15(37):4617-26.
    96. Munoz Gomez M, Campos Garriguez A, Garcia Erce JA,et al. Fisiopathology of iron metabolism: diagnostic and therapeutic implications. Nefrologia,2005; 25(1):9-19.
    97. Siah CW, Ombiga J, Adams LA, et al. Normal iron metabolism and the pathophysiology of iron overload disorders. Clin Biochem Rev,2006; 27(1):5-16.
    98. Andrews NC. Disorders of iron metabolism. N Engl J Med,1999; 341(26):1986-1995.
    99. Beard JL. Iron biology in immune function, muscle metabolism and neuronal functioning. J Nutr, 2001; 131(2s-2):568S-580S.
    100. Oppenheimer SJ. Iron and its relation to immunity and infectious disease. J Nutr,2001; 131(2s-2): 616S-635S.
    101. Beaumont C, Delaby C. Recycling iron in normal and pathological states. Semin Hematol,2009; 46(4):328-338.
    102. Lee PL, Beutler E. Regulation of hepcidin and iron-overload disease. Annu Rev Pathol,2009; 4: 489-515.
    103. Cadenas E, Davies KJA. Mitochondrial free radical generation, oxidative stress, and aging. Free Radic Biol Med,2000; 29(3-4):222-230.
    104. Jomova K, Vondrakova D, Lawson M, et al. Metals, oxidative stress and neurodegenerative disorders. Mol Cell Biochem,2010;345(1-2):91-104.
    105. Liochev SI, Friedovich I. How does superoxide dismutase protect against tumor necrosis factor:a hypothesis informed by effect of superoxide on "free" iron. Free Radic Biol Med,1997; 23(4): 668-671.
    106. Casanueva E, Viteri FE. Iron and oxidative stress in pregnancy. J Nutr,2003; 133(5 Suppl 2): 1700S-1708S.
    107. Parkkila S, Waheed A, Britton RS, et al. Association of the transferrin receptor in human placenta with HFE the protein defective in hereditary hemocromatosis. Proc Natl Acad Sci USA,1997; 94(24):13198-13202.
    108. Green P, Eviatar JM, Sirota P, et al. Secondary hemochromatosis due to prolonged iron ingestion. Isr J Med Sci,1989; 25(4):650-651.
    109. Lund EK, Fairweather-Tait SJ, Warf SG, et al. Chronic exposure to high levels of dietary iron fortification increases lipid peroxidation in the mucosa of the rat large intestine. J Nutr,2001; 131(11):2928-2931.
    110. Abraham SC, Yardley JH, Wu TT. Erosive injury to the upper gastrointestinal tract in patients receiving iron medication:an underrecognized entity. Am J Surg Pathol,1999; 23(10): 1241-1247.
    111. Srigiridhar K, Nair KM, Subramanian R, et al. Oral repletion of iron induces free radical mediated alterations in the gastrointestinal tract of rat. Mol Cell Biochem,2001; 219(1-2):91-98.
    112. Srigiridhar K, Nair KM. Supplementation with alpha-tocopherol or a combination of alpha-tocopherol and ascorbic acid protects the gastrointestinal tract of iron-deficient rats against iron-induced oxidative damage during iron repletion. Br J Nutr,2000; 84(2):165-173.
    113. Srigiridhar K, Nair KM. Iron-deficient intestine is more susceptible to peroxidative damage during iron supplementation in rats. Free Radic Biol Med,1998; 25(6):660-665.
    114. Srigiridhar K, Nair KM. Protective effects of antioxidant enzymes and GSH in vivo on iron mediated lipid peroxidation in gastrointestinal tract of rat. Ind J Biochim Biophys,1997; 34(4): 402-405.
    115. Viteri FE, Liu XN, Martin A, et al. True absorption and retention of supplemental iron is more efficient when administered every-threedays rather than daily to iron-normal and iron-deficient rats.J Nutr,1995; 125(1):82-91.
    116. Viteri FE. Iron supplementation for the control of iron deficiency in populations at risk. Nutr Rev, 1997; 55(6):195-209.
    117. Breuer W, Ronson A, Slotki IN, et al. The assessment of serum nontransferrin-bound iron in chelation therapy and iron supplementation. Blood,2000; 95(9):2975-2982.
    118. Gutteridge JM, Mumby S, Koizumi M, et al. "Free" iron in neonatal plasma activates aconitase: evidence for biologically reactive iron. Biochem Biophys Res Commun,1996; 229(3):806-809.
    119. Buonocore G, Zani S, Perrone S, et al. Intraerythrocyte nonprotein-bound iron and plasma malondialdehyde in the hypoxic newborn. Free Radic Biol Med,1998; 25(7):766-770.
    120. Knutson MD, Walter PB, Ames BN, et al. Daily iron supplements promote abnormal iron accumulation and lipid peroxidation in rats. J Nutr,2000; 130(3):621-628.
    121. Walter PB, Knutson MD, Paler-Martinez A, et al. Iron defic iency and iron excess damage mitochondria and mitochondrial DNA in rats. Proc Natl Acad Sci USA,2002; 99(4):2264-2269.
    122. Schaible UE, Kaufmann SH. Iron and microbial infection. Nat Rev Microbiol,2004; 2(12): 946-953.
    123. Sazawal S, Black RE, Ramsan M, et al. Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting:community-based, randomised, placebo-controlled trial. Lancet,2006; 367(9505):133-143.
    124. Gangaidzo IT, Moyo VM, Mvundura E, et al. Association of pulmonary tuberculosis with increased dietary iron. J Infect Dis,2001; 184(7):936-939.
    125. Magnus SA, Hambleton IR, Moosdeen F, et al. Recurrent infections in homozygous sickle cell disease. Arch Dis Child,1999; 80(6):537-541.
    126. WanachiwanawinW. Infections in E-beta thalassemia. J Pediatr Hematol Oncol,2000; 22(6): 581-587.
    127. Oppenheimer SJ. Iron and its relation to immunity and infectious disease. J Nutr,2001; 131(2s-2): 616S-635S.
    128. Brock JH, Mulero V. Cellular and molecular aspects of iron and immune function. Proc Nutr Soc, 2000; 59(4):537-540.
    129. Walker EM, Walker SM. Effects of iron overload on the immune system. Ann Clin Lab Sci,2000; 30(4):354-365.
    130. Thorson JA, Smith KM, Gomez F, et al. Role of iron in T cell activation:Th-1 clones differ from Th-2 clones in their sensitivity to inhibition for DNA synthesis caused by IGG Mabs against transferrin receptor and iron chelators desferrioxamine. Cell Immunol,1991; 134(1):126-127.
    131. Beard JL. Iron biology in immune function, muscle metabolism and neuronal functioning. J Nutr, 2001; 131(2s-2):568S-580S.
    132. Ahluwalia N, Sun J, Krause D, et al. Immune function is impaired in iron-deficient home-bound, older women. Am J Clin Nutr,2004; 79(3):516-521.
    133. Nyakeriga AM, Troye-Blomberg M, Dorfman JR, et al. Iron deficiency and malaria among children living in the coast of Kenya. J Infect Dis,2004; 190(3):439-447.
    134. Gera T, Sachdev HPS. Effect of iron supplementation on incidence on infectious illness in children:systematic review:BMJ,2002; 325(7373):1142-1151.
    135. English M, Snow RW. Iron and folic acid supplementation and malaria risk. Lancet,2006; 367(9505):90-91.
    136. Marx JJ. Iron and infection:competition between host and microbes for a precious element. Best Pract Res Clin Haematol,2002; 15(2):411-426.
    137. Radtke AL, O'Riordan MX. Intracellular innate resistance to bacterial pathogens. Cell Microbiol, 2006; 8(11):1720-1729.
    138. van der Strate BW, Beljaars L, Molema G, et al. Antiviral activities of lactoferrin. Antiviral Res, 2001; 52(3):225-239.
    139. Fischer R, Debbabi H, Dubarry M, et al. Regulation of physiological and pathological Thl and Th2 responses by lactoferrin. Biochem Cell Biol,2006; 84():303-311.
    140. Macedo MF, de Sousa M, Ned RM, et al. Transferrin is required for early T-cell differentiation. Immunology,2004; 112(4):543-549.
    141. Vidal S, Gros P, Skamene E. Natural resistance to infection with intracellular parasites:molecular genetics identifies Nrampl as the Bcg/Ity/Lsh locus. J Leukoc Biol,1995; 58(4):382-390.
    142. Jabado N, Cuellar-Mata P, Grinstein S, et al. Iron chelators modulate the fusogenic properties of Salmonella-containingphagosomes. Proc Natl Acad Sci USA,2003; 100(10):6127-6132.
    143. Peyssonnaux C, Zinkernagel AS, Datta V, et al. TLR4-dependent hepcidin expression by myeloid cells in response to bacterial pathogens. Blood,2006; 107(9):3727-3732.
    144. Flo TH, Smith KD, Sato S, et al. Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 2004; 432:917-921.
    145. Lesbordes-Brion JC, Viatte L, Bennoun M, et al. Targeted disruption of the hepcidin 1 gene results in severe hemochromatosis. Blood,2006; 108(4):1402-1405.
    146. Lin L, Goldberg YP, Ganz T. Competitive regulation of hepcidin mRNA by soluble and cell-associated hemojuvelin. Blood,2005; 106(8):2884-2889.
    147. Nemeth E, Rivera S, Gabayan V, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest,2004; 113(9):1271-1276.
    148. Wang L, Cherayil BJ. Ironing out the wrinkles in host defense:interactions between iron homeostasis and innate immunity. J Innate Immun,2009; 1(5):455-464.
    149. Collins HL, Kaufmann SH, Schaible UE. Iron chelation via deferoxamine exacerbates experimental salmonellosis via inhibition of the nicotinamide adenine dinucleotide phosphate oxidase-dependent respiratory burst. J Immunol,2002; 168(7):3458-3463.
    150. Dlaska M, Weiss G. Central role of transcription factor NF-IL6 for cytokine and iron-mediated regulation of murine inducible nitric oxide synthase expression. J Immunol,1999; 162(10): 6171-6177.
    151. Vallabhapurapu S, Karin M. Regulation and function of NF-kappa B transcription factors in the immune system. Annu Rev Immunol,2009; 27:693-733.
    152. Bubici C, Papa S, Dean K et al. Mutual cross-talk between reactive oxygen species and NF-kappaB:molecular basis and biological significance. Oncogene,2006; 25(51):6731-6748.
    153. Chen L, Xiong S, She H, et al. Iron causes interactions of TAK1, p21ras and phosphatidylinositol-3-kinase in caveolae to activate I-kappaB kinase in hepatic macrophages. J Biol Chem,2007; 282(8):5582-5588.
    154. Nizet V, Johnson RS. Interdependence of hypoxic and innate immune responses. Nat Rev Immunol,2009; 9(9):609-617.
    155. Hartmann H, Eltzschig HK, Wurz H, et al. Hypoxia-independent activation of HIF-1 by enterobacteriaceae and their siderophores. Gastroenterology,2008; 134(3):756-767.
    156. Bonilla FA, Oettgen HC. Adaptive immunity. J Allergy Clin Immunol,2010; 125(suppl 2): S33-S40.
    157. Ned RM, Swat W, Andrews NC. Transferrin receptor 1 is differentially required in lymphocyte development. Blood,2003;102(10):3711-3718.
    158. Hamill RL, Woods JC, Cook BA. Congenital atransferrinemia. A case report and review of the literature. Am J Clin Pathol,1991; 96(2):215-218.
    159. Kemp JD, Thorson JA, Gomez F, et al. Inhibition of lymphocyte activation with anti-transferrin receptor Mabs:a comparison of three reagents and further studies of their range of effects and mechanism of action. Cell Immunol,1989; 122(1):218-230.
    160. De Sousa M. Lymphoid cell positioning:a new proposal for the mechanism of control of lymphoid cell migration. Symp Soc Exp Biol,1978; 32:393-410.
    161. Porto G, De Sousa M. Iron overload and immunity. World J Gastroenterol,2007; 13(35): 4707-4715.
    162. Neckers LM, Cossman J. Transferrin receptor induction in mitogen-stimulated human T lymphocytes is required for DNA synthesis and cell division and is regulated by interleukin 2. Proc Natl Acad Sci USA,1983; 80(11):3494-3498.
    163. Vezzoni P, Levi S, Gabri E, et al. Ferritins in malignant and non-malignant lymphoid cells. Br J Haematol,1986; 62(1):105-110.
    164. De Sousa M. T lymphocytes and iron overload:novel correlations of possible significance to the biology of the immunological system. Mem Inst Oswaldo Cruz 1992; 87 Suppl 5:23-29.
    165. Walker EM Jr, Walker SM. Effects of iron overload on the immune system. Ann Clin Lab Sci, 2000; 30(4):354-365.
    166. Grady RW, Akbar AN, Giardina PJ, et al. Disproportionate lymphoid cell subsets in thalassaemia major:the relative contributions of transfusion and splenectomy. Br J Haematol,1985; 59(4): 713-724.
    167. Palace VP, Khaper N, Qin Q, et al. Antioxidant potentials of vitamin A and carotenoids and their relevance to heart disease. Free Radic Biol Med,1999; 26(5-6):746-761.
    168. Chen S, Wang K, Wan YJ. Retinoids activate RXR/CAR-mediated pathway and induce CYP3A. Biochem Pharmacol,2010; 79(2):270-276.
    169. Jameel NM, Thirunavukkarasu C, Wu T, et al. p38-MAPK-and caspase-3-mediated superoxide-induced apoptosis of rat hepatic stellate cells:reversal by retinoic acid. J Cell Physiol, 2009; 218(1):157-166.
    170. Lee HP, Casadesus G, Zhu X, et al. All-trans-retinoic acid as a novel therapeutic strategy for Alzheimer's disease. Expert Rev Neurother,2009; 9(11):1615-1621.
    171. Zulet MA, Puchau B, Hermsdorff HH, et al. Vitamin A intake is inversely related with adiposity in healthy young adults. J Nutr Sci Vitaminol,2008; 54(5):347-352.
    172. Basu TK, Basualdo C. Vitamin A homeostasis and diabetes mellitus. Nutrition,1997; 3(9): 804-806.
    173. Puolakkainen M, Lee A, Nosaka T,et al. Retinoic acid inhibits the infectivity and growth of Chlamydia pneumoniae in epithelial and endothelial cells through different receptors. Microb Pathog,2008; 44(5):410-416.
    174. Enqedal N, Auberqer P, Blomhoff HK. Retinoic acid regulates Fas-induced apoptosis in Jurkat T cells:reversal of mitogen-mediated repression of Fas DISC assembly. J Leukoc Biol,2009; 85(3):469-480.
    175. Benammar C, Hichami A, Yessoufou A, et al. Zizyphus lotus L. (Desf.) modulates antioxidant activity and human T-cell proliferation. BMC Complement Altern Med,2010; 10:54-62.
    176. Duriancik DM, Hoag KA. Vitamin A deficiency alters splenic dendritic cell subsets and increases CD8(+)Gr-l(+) memory T lymphocytes in C57BL/6J mice. Cell Immunol,2010; 265(2):56-163.
    177. Ovsyannikova IG, Dhiman N, Haralambieva IH, et al. Rubella vaccine-induced cellular immunity: evidence of associations with polymorphisms in the Toll-like, vitamin A and D receptors, and innate immune response genes. Hum Genet,2010; 127(2):207-221.
    178. Ahmad SM, Haskell MJ, Raqib R, et al. Markers of innate immune function are associated with vitamin A stores in men. J Nutr,2009; 139(2):377-385.
    179. Manicassamy S, Pulendran B. Retinoic acid dependent regulation of immune responses by dendritic cells and macrophages.Semin Immunol,2009; 21(1):22-27.
    180. Xiao S, Jin H, Korn T, et al. Retinoic acid increases Foxp3+ regulatory T cells and inhibits development of Th17 cells by enhancing TGF-(3-driven Smad3 signaling and inhibiting IL-6 and IL-23 receptor expression. J Immunol,2008; 181(4):2277-2284.
    181. Stroes ES, van Faassen EE, Yo M, et al. Folic acid reverts dysfunction of endothelial nitric oxide synthase. Circ Res,2000; 86(11):1129-1134.
    182. Verhaar MC, Wever RM, Kastelein JJ, et al.5-Methyltetrahydrofolate, the active form of folic acid, restores endothelial function in familial hypercholesterolemia. Circulation,1998; 97(3): 237-241.
    183. Halsted CH, Villanueva JA, Devlin AM, et al. Folate deficiency disturbs hepatic methionine metabolism and promotes liver injury in the ethanol-fed micropig. Proc Natl Acad Sci USA,2002; 99(15):10072-10077.
    184. Wilmink HW, Stroes ES, Erkelens WD, et al. Influence of folic acid on postprandial endothelial dysfunction. Arterioscler Thromb Vasc Biol,2000; 20(1):185-188.
    185. Durand P, Prost M, Blache D. Pro-thrombotic effects of a folic acid deficient diet in rat platelets and macrophages related to elevated homocysteine and decreased n-3 polyunsaturated fatty acids. Atherosclerosis,1996; 121 (2):231-243.
    186. Henning SM, Swendseid ME, Ivandic BT, et al. Vitamins C, E and A and heme oxygenase in rats fed methyl/folate-deficient diets. Free Rad Biol Med,1997; 23(6):936-942.
    187. Doshi SN, McDowell IF, Moat SJ, et al. Folate improves endothelial function in coronary artery disease:an effect mediated by reduction of intracellular superoxide? Arterioscler Thromb Vasc Biol,2001; 21(7):1196-1202.
    188. Marletta MA. Nitric oxide synthase:aspects concerning structure and catalysis. Cell,1994; 78(6):927-930.
    189. Xia Y, Tsai AL, Berka V, et al. Superoxide generation from endothelial nitric-oxide synthase:a Ca2+/calmodulin-dependent and tetrahydrobiopterin regulatory process. J Biol Chem,1998; 273(40):25804-25808.
    190. Stroes E, Hijmering M, van Zandvoort M, et al. Origin of superoxide production by endothelial nitric oxide synthase. FEBS Lett,1998; 438(3):161-164.
    191. Pritchard KA, Groszek L, Smalley DM, et al. Native low-density lipoprotein increases endothelial cell nitric oxide synthase generation of superoxide anion. Circ Res,1995; 77(3):510-518.
    192. Vasquez-Vivar J, Kalyanaraman B, Martasek P, et al. Superoxide generation by endothelial nitric oxide synthase:the influence of cofactors. Proc Natl Acad Sci USA,1998; 95(16):9220-9225.
    193. Stroes E, Kastelein J, Cosentino F, et al. Tetrahydrobiopterin restores endothelial function in hypercholesterolemia. J Clin Invest,1997; 99(1):41-46.
    194. Tiefenbacher CP, Chilian WM, Mitchell M, et al. Restoration of endothelium-dependent vasodilation after reperfusion injury by tetrahydrobiopterin.Circulation,1996; 94(6):1423-1429.
    195. Heller R, Unbehaun A, Schellenberg B, et al. L-ascorbic acid potentiates endothelial nitric oxide synthesis via a chemical stabilization of tetrahydrobiopterin. J Biol Chem.2001; 276(1):40-47.
    196. Smith I, Hyland K, Kendall B. Clinical role of pteridine therapy in tetrahydrobiopterin deficiency. J Inherit Metab Dis.1985; 8(suppl 1):39-45.
    197. Troen AM, Mitchell B, Sorensen B, et al. Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women. J Nutr,2006; 136(1): 189-194.
    198. Courtemanche C, Elson-Schwab I, Mashiyama ST, et al. Folate deficiency inhibits the proliferation of primary human CD8+ T lymphocytes in vitro. J Immunol,2004; 173(5): 3186-3192.
    199. Courtemanche C, Huang AC, Elson-Schwab I, et al. Folate deficiency and ionizing radiation cause DNA breaks in primary human lymphocytes:a comparison. FASEB J,2004; 18 (1): 209-211.
    200. Hansen G, Berry G, Dekruyff RH, et al. Allergen-specific Thl cells fail to counterbalance Th2 cell-induced airway hyperreactivity but cause severe airway inflammation. J Clin Invest, 1999;103(2):175-183.
    201. Lucey DR, Clerici M, Shearer GM. Type 1 and type 2 cytokine dysregulation in human infectious, neoplastic, and inflammatory diseases. Clin Microbiol Rev,1996; 9(4):532-562.

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