Roles of vitamins in stem cells

  • Carlos Godoy-Parejo
  • Chunhao Deng
  • Yumeng Zhang
  • Weiwei Liu
  • Guokai ChenEmail author


Stem cells can differentiate to diverse cell types in our body, and they hold great promises in both basic research and clinical therapies. For specific stem cell types, distinctive nutritional and signaling components are required to maintain the proliferation capacity and differentiation potential in cell culture. Various vitamins play essential roles in stem cell culture to modulate cell survival, proliferation and differentiation. Besides their common nutritional functions, specific vitamins are recently shown to modulate signal transduction and epigenetics. In this article, we will first review classical vitamin functions in both somatic and stem cell cultures. We will then focus on how stem cells could be modulated by vitamins beyond their nutritional roles. We believe that a better understanding of vitamin functions will significantly benefit stem cell research, and help realize their potentials in regenerative medicine.


Vitamin Cell culture Vitamin A Vitamin B3 Vitamin C Vitamin E Embryogenesis Stem cells 



This work was supported by the Science and Technology Development Fund of Macau SAR (FDCT/131/2014/A3, FDCT/056/2015/A2 and FDCT/0059/2019/A1) and University of Macau Multiyear Research Grant (MYRG2018-00135-FHS).

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.


  1. 1.
    Combs GF (1992) The vitamins: fundamental aspects in nutrition and health. Can Vet J 40:813–814Google Scholar
  2. 2.
    Funk C (1912) The preparation from yeast and certain foodstuffs of the substance the deficiency of which in diet occasions polyneuritis in birds. J Physiol 43:395–400. CrossRefGoogle Scholar
  3. 3.
    Fall CHD, Yajnik CS, Rao S et al (2003) Micronutrients and fetal growth. Am Soc Nutr Sci 133:1747S–1756SGoogle Scholar
  4. 4.
    Semba RD (2012) The discovery of the vitamins. Int J Vitam Nutr Res 82:310–315. CrossRefPubMedGoogle Scholar
  5. 5.
    Schnellbaecher A, Binder D, Bellmaine S, Zimmer A (2019) Vitamins in cell culture media: stability and stabilization strategies. Biotechnol Bioeng 116:1537–1555. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Arigony ALV, de Oliveira IM, Machado M et al (2013) The influence of micronutrients in cell culture: a reflection on viability and genomic stability. Biomed Res Int 2013:597282. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Blaner WS (2013) The fat-soluble vitamins 100 years later: where are we now? J Lipid Res 54:1716–1718. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Mcculloch EA, Till JE (1960) The radiation sensitivity of normal mouse bone marrow cells, determined by quantitative marrow transplantation into irradiated mice. Radiat Res 13:115–125CrossRefPubMedGoogle Scholar
  9. 9.
    Singh VK, Saini A, Kalsan M et al (2016) Describing the stem cell potency: the various methods of functional assessment and in silico diagnostics. Front Cell Dev Biol. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Conboy IM, Rando TA (2005) Aging, stem cells and tissue regeneration: lessons from muscle. Cell Cycle 4:407–410. CrossRefPubMedGoogle Scholar
  11. 11.
    Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2:663–676. CrossRefGoogle Scholar
  12. 12.
    Trounson A, Dewitt ND (2016) Pluripotent stem cells progressing to the clinic. Nat Rev 17:194–200. CrossRefGoogle Scholar
  13. 13.
    Thomson JA, ItsKovitz-Eldor J, Shapiro SS et al (1998) Embryonic stem cell lines derived from human blastocysts. Science 282:1145–1147. CrossRefPubMedGoogle Scholar
  14. 14.
    Xu C, Inokuma MS, Denham J et al (2001) Feeder-free growth of undifferentiated human embryonic stem cells. Nat Biotechnol 19:971–974. CrossRefPubMedGoogle Scholar
  15. 15.
    Xu C, Rosler E, Jiang J et al (2005) Basic fibroblast growth factor supports undifferentiated human embryonic stem cell growth without conditioned medium. Stem Cells 23:315–323. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Wang L, Schulz TC, Sherrer ES et al (2007) Self-renewal of human embryonic stem cells requires insulin-like growth factor-1 receptor and ERBB2 receptor signaling. Blood 110:4111–4120. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Ludwig TE, Levenstein ME, Jones JM et al (2006) Derivation of human embryonic stem cells in defined conditions. Nat Biotechnol 24:185–187. CrossRefPubMedGoogle Scholar
  18. 18.
    D’Aniello C, Cermola F, Patriarca EJ, Minchiotti G (2017) Vitamin C in stem cell biology: impact on extracellular matrix homeostasis and epigenetics. Stem Cells Int 2017:1–16. CrossRefGoogle Scholar
  19. 19.
    Meng Y, Ren Z, Xu F et al (2018) Nicotinamide promotes cell survival and differentiation as kinase inhibitor in human pluripotent stem cells. Stem Cell Rep 11:1347–1356. CrossRefGoogle Scholar
  20. 20.
    Ross SA, McCaffery PJ, Drager UC, De Luca LM (2000) Retinoids in embryonal development. Physiol Rev 80:1021–1054. CrossRefPubMedGoogle Scholar
  21. 21.
    Zhang J, Gao Y, Yu M et al (2015) Retinoic acid induces embryonic stem cell differentiation by altering both encoding RNA and microRNA expression. PLoS One 10:1–17. CrossRefGoogle Scholar
  22. 22.
    Combs GF, McClung JP (2017) The vitamins : fundamental aspects in nutrition and healthGoogle Scholar
  23. 23.
    Hill MJ (1997) Intestinal flora and endogenous vitamin synthesis. Eur J Cancer Prev Suppl 1:S43–S45. CrossRefGoogle Scholar
  24. 24.
    Yano M, Fujita A (1958) Synthesis of vitamins by intestinal bacteria in man and the effect of cellulose. VI. Synthesis of folic acid. J Vitaminol (Kyoto) 2:209–215. CrossRefGoogle Scholar
  25. 25.
    Stacpoole PW (2012) The pyruvate dehydrogenase complex as a therapeutic target for age-related diseases. Aging Cell 11:371–377. CrossRefPubMedGoogle Scholar
  26. 26.
    Zhou ZH, McCarthy DB, O’Connor CM et al (2002) The remarkable structural and functional organization of the eukaryotic pyruvate dehydrogenase complexes. Proc Natl Acad Sci 98:14802–14807. CrossRefGoogle Scholar
  27. 27.
    Murad S, Grove D, Lindberg KA et al (1981) Regulation of collagen synthesis by ascorbic acid. Biochemistry 78:2879–2882Google Scholar
  28. 28.
    Vasta JD, Raines RT (2016) Human collagen prolyl 4-hydroxylase is activated by ligands for its iron center. Biochemistry 55:3224–3233. CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Nytko KJ, Maeda N, Schläfli P et al (2011) Vitamin C is dispensable for oxygen sensing in vivo. Blood 117:5485–5493. CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Rebouche CJ (1991) Ascorbic acid and carnitine biosynthesis. Am J Clin Nutr 54:1147S–1152S. CrossRefPubMedGoogle Scholar
  31. 31.
    Delanghe JR, Langlois MR, De Buyzere ML et al (2011) Vitamin C deficiency: more than just a nutritional disorder. Genes Nutr 6:341–346. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Jackson GR, Morgan BC, Werrbach-Perez K, Perez-Polo JR (1991) Antioxidant effect of retinoic acid on PC12 rat pheochromocytoma. Int J Dev Neurosci 9:161–170. CrossRefPubMedGoogle Scholar
  33. 33.
    Law WC, Rando RR (1989) The molecular basis of retinoic acid induced night blindness. Biochem Biophys Res Commun 161:825–829CrossRefPubMedGoogle Scholar
  34. 34.
    Narbaitz R (1987) Role of vitamin D in the development of the chick embryo. J Exp Zool Suppl 1:15–23PubMedGoogle Scholar
  35. 35.
    Sylvester Paul W (2005) Mechanisms mediating the antiproliferative and apoptotic effects of vitamin E in mammary cancer cells. Front Biosci 10:699–709. CrossRefPubMedGoogle Scholar
  36. 36.
    Stenflo J, Fernlund P, Egan W, Roepstorff P (1974) Vitamin K dependent modifications of glutamic acid residues in prothrombin. Proc Natl Acad Sci 71:2730–2733. CrossRefPubMedGoogle Scholar
  37. 37.
    Vermeer C (1990) γ-Carboxyglutamate-containing proteins and the vitamin K-dependent carboxylase. Biochem J 266:625–636. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Morgan JF, Morton HJ, Parker RC (1949) Nutrition of animal cells in tissue culture. I. Initial studies on a synthetic medium. Proc Soc Exp Bio Med 73:1–8CrossRefGoogle Scholar
  39. 39.
    Eagle BH (1955) The minimum vitamin requirements of the L and HeLa cells in tissue culture, the production of specific vitamin deficiencies, and their cure. J Exp Med 102:595–600CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Eagle H (1959) Amino acid metabolism in mammalian cell cultures. Science 130:432–437. CrossRefPubMedGoogle Scholar
  41. 41.
    Dulbecco R, Freeman G (1959) Plaque production by the polyoma virus. Virology 8:396–397. CrossRefPubMedGoogle Scholar
  42. 42.
    Ham RG (1963) An improved nutrient solution for diploid Chinese hamster and human cell lines. Exp Cell Res 29:515–526. CrossRefPubMedGoogle Scholar
  43. 43.
    Ham RG (1965) Clonal growth of mammalian cells in a chemically defined, synthetic medium. Proc Natl Acad Sci 53:288–293CrossRefPubMedGoogle Scholar
  44. 44.
    Dakshinamurti K, Chalifour L, Bhullar RP (1985) Requirement for biotin and the function of biotin in cells in culture. Ann N Y Acad Sci 447:38–55. CrossRefPubMedGoogle Scholar
  45. 45.
    Fehling C, Jägerstad M, Åkesson B et al (1978) Effects of vitamin B12 deficiency on lipid metabolism of the rat liver and nervous system. Br J Nutr 39:501–513. CrossRefPubMedGoogle Scholar
  46. 46.
    Takahashi-Iñiguez T, García-Hernandez E, Arreguín-Espinosa R, Flores ME (2012) Role of vitamin B12 on methylmalonyl-CoA mutase activity. J Zhejiang Univ Sci B 13:423–437. CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Barnes D, Sato G (1979) Growth of a human mammary tumour cell line in a serum-free medium. Nature 281:388–389CrossRefPubMedGoogle Scholar
  48. 48.
    Yao T, Asayama Y (2017) Animal-cell culture media: history, characteristics, and current issues. Reprod Med Biol 16:99–117. CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Akopian V, Andrews PW, Beil S et al (2010) Comparison of defined culture systems for feeder cell free propagation of human embryonic stem cells. In Vitro Cell Dev Biol Anim 46:247–258. CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Chen G, Gulbranson DR, Hou Z et al (2011) Chemically defined conditions for human iPS cell derivation and culture. Nat Methods 8:424–429. CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Hasegawa K, Yasuda S, Teo J-L et al (2012) Wnt signaling orchestration with a small molecule DYRK inhibitor provides long-term xeno-free human pluripotent cell expansion. Stem Cells Transl Med 1:18–28. CrossRefPubMedGoogle Scholar
  52. 52.
    Elwyn D, Weissbach A, Henry SS, Sprinson DB (1955) The biosynthesis of choline from serine and related compounds. J Biol Chem 213:281–295PubMedGoogle Scholar
  53. 53.
    Penry JT, Manore MM (2008) Choline: an important micronutrient for maximal endurance-exercise performance? Int J Sport Nutr Exerc Metab 18:191–203. CrossRefPubMedGoogle Scholar
  54. 54.
    Dominguez-Salas P, Moore SE, Cole D et al (2013) DNA methylation potential: dietary intake and blood concentrations of one-carbon metabolites and cofactors in rural African women. Am J Clin Nutr 97:1217–1227. CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Parthasarathy LK, Ratnam L, Seelan S et al (2006) Mammalian inositol 3-phosphate synthase: its role in the biosynthesis of brain inositol and its clinical use as a psychoactive agent BT—biology of inositols and phosphoinositides: subcellular biochemistry. In: Majumder AL, Biswas BB (eds) Springer. US, Boston, pp 293–314Google Scholar
  56. 56.
    Deranieh RM, He Q, Caruso JA, Greenberg ML (2013) Phosphorylation regulates myo-inositol-3-phosphate synthase a novel regulatory mechanism of inositol biosynthesis. J Biol Chem 288:26822–26833. CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Eagle H, Oyama VI, Levy I, Freeman A (1956) Myo-inositol as an essential growth factor for normal and malignant human cells in tissue culture. Science 123:845–847CrossRefPubMedGoogle Scholar
  58. 58.
    Berridge MJ, Irvine RF (1984) Inositol trisphosphate, a novel second messenger in cellular signal transduction. Nature 312:315–321. CrossRefPubMedGoogle Scholar
  59. 59.
    Holub BJ (1986) Metabolism and function of myo-inositol and inositol phospholipids. Annu Rev Nutr 6:563–597. CrossRefPubMedGoogle Scholar
  60. 60.
    Conquer JA, Tierney MC, Zecevic J et al (2000) Fatty acid analysis of blood plasma of patients with Alzheimer’s disease, other types of dementia, and cognitive impairment. Lipids 35:1305–1312. CrossRefPubMedGoogle Scholar
  61. 61.
    Lazzarin N, Vaquero E, Exacoustos C et al (2009) Low-dose aspirin and omega-3 fatty acids improve uterine artery blood flow velocity in women with recurrent miscarriage due to impaired uterine perfusion. Fertil Steril 92:296–300. CrossRefPubMedGoogle Scholar
  62. 62.
    Swanson D, Block R, Mousa SA (2012) Omega-3 fatty acids EPA and DHA: health benefits throughout life. Adv Nutr 3:1–7. CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Su KP, Huang SY, Chiu TH et al (2008) Omega-3 fatty acids for major depressive disorder during pregnancy: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 69:644–651. CrossRefPubMedGoogle Scholar
  64. 64.
    Shearer MJ (1995) Vitamin K. Lancet 345:229–234. CrossRefPubMedGoogle Scholar
  65. 65.
    Olson JA, Hayaishi O (1965) The enzymatic cleavage of β-carotene into vitamin A by soluble enzymes of rat liver and intestine. Proc Natl Acad Sci 54:1364–1370CrossRefPubMedGoogle Scholar
  66. 66.
    Kin R, Kam T, Deng Y et al (2015) Retinoic acid synthesis and functions in early embryonic development. Cell Biosci 2:1–14. CrossRefGoogle Scholar
  67. 67.
    Duester G (2008) Retinoic acid synthesis and signaling during early organogenesis. Cell 134:921–931. CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Sharow KA, Temkin B, Asson-batres MANN (2012) Retinoic acid stability in stem cell cultures. Int J Dev Biol 56:273–278. CrossRefPubMedGoogle Scholar
  69. 69.
    Chen L, Yang M, Dawes J, Khillan JS (2007) Suppression of ES cell differentiation by retinol (vitamin A) via the overexpression of Nanog. Differentiation 75:682–693. CrossRefPubMedGoogle Scholar
  70. 70.
    Chen L, Khillan JS (2010) A novel signaling by vitamin A/retinol promotes self renewal of mouse embryonic stem cells by activating PI3K/Akt signaling pathway via insulin-like growth factor-1 receptor. Stem Cells 28:57–63. CrossRefPubMedGoogle Scholar
  71. 71.
    Khillan JS (2014) Vitamin A/retinol and maintenance of pluripotency of stem cells. Nutrients 6:1209–1222. CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Mosher KI, Schaffer DV (2018) Proliferation versus differentiation: redefining retinoic acid’s role. Stem Cell Rep 10:1673–1675. CrossRefGoogle Scholar
  73. 73.
    Zhang S, Sun J, Pan S et al (2011) Retinol (vitamin A) maintains self-renewal of pluripotent male germline stem cells (mGSCs) from adult mouse testis. J Cell Biochem 112:1009–1021. CrossRefPubMedGoogle Scholar
  74. 74.
    Balmer JE, Blomhoff R (2002) Gene expression regulation by retinoic acid. J Lipid Res 43:1773–1808. CrossRefPubMedGoogle Scholar
  75. 75.
    Del Corral RD, Olivera-Martinez I, Goriely A et al (2003) Opposing FGF and retinoid pathways control ventral neural pattern, neuronal differentiation, and segmentation during body axis extension. Neuron 40:1673–1675. CrossRefGoogle Scholar
  76. 76.
    Li X, Fok KL, Guo J et al (2018) Retinoic acid promotes stem cell differentiation and embryonic development by transcriptionally activating CFTR. Biochim Biophys Acta Mol Cell Res 1865:605–615. CrossRefPubMedGoogle Scholar
  77. 77.
    Cheong HS, Lee HC, Park BL et al (2010) Epigenetic modification of retinoic acid-treated human embryonic stem cells. BMB Rep 43:830–835. CrossRefPubMedGoogle Scholar
  78. 78.
    Lee ER, Murdoch FE, Fritsch MK (2007) High histone acetylation and decreased polycomb repressive complex 2 member levels regulate gene specific transcriptional changes during early embryonic stem cell differentiation induced by retinoic acid. Stem Cells 25:2191–2199. CrossRefPubMedGoogle Scholar
  79. 79.
    Urvalek AM, Gudas LJ (2014) Retinoic acid and histone deacetylases regulate epigenetic changes in embryonic stem cells. J Biol Chem 289:19519–19530. CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Bar-El Dadon S, Reifen R (2017) Vitamin A and the epigenome. Crit Rev Food Sci Nutr 57:2404–2411. CrossRefPubMedGoogle Scholar
  81. 81.
    Szarc vel Szic K, Ndlovu MN, Haegeman G, Vanden Berghe W (2010) Nature or nurture: Let food be your epigenetic medicine in chronic inflammatory disorders. Biochem Pharmacol 80:1816–1832. CrossRefPubMedGoogle Scholar
  82. 82.
    Janesick A, Wu SC, Blumberg B (2015) Retinoic acid signaling and neuronal differentiation. Cell Mol Life Sci 72:1559–1576. CrossRefPubMedGoogle Scholar
  83. 83.
    Zile MH (1998) Vitamin A and embryonic development: an overview. Am Soc Nutr Sci 128:455–458Google Scholar
  84. 84.
    Maden M (2001) Vitamin A and the developing embryo. Postgrad Med J 77:489–491CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Hale F (1933) Pigs born without eye balls. J Hered 24:105–106. CrossRefGoogle Scholar
  86. 86.
    Kalter H, Warkany J (1959) Experimental production of congenital malformations in mammals by metabolic procedure. Physiol Rev 39:69–115. CrossRefPubMedGoogle Scholar
  87. 87.
    Noma T, Glick A, Geiser A et al (1991) Molecular cloning and structure of the human transforming growth factor-β2 gene promoter. Growth Factors. CrossRefPubMedGoogle Scholar
  88. 88.
    Pendaries V, Verrecchia F, Michel S, Mauviel A (2003) Retinoic acid receptors interfere with the TGF-β/Smad signaling pathway in a ligand-specific manner. Oncogene 22:8212–8220. CrossRefPubMedGoogle Scholar
  89. 89.
    Brown JM, Robertson KE, Wedden SE, Tickle C (1997) Alterations in Msx 1 and Msx 2 expression correlate with inhibition of outgrowth of chick facial primordia induced by retinoic acid. Anat Embryol (Berl) 195:203–207. CrossRefGoogle Scholar
  90. 90.
    Gonzalez SMDC, Ferland LH, Robert B, Abdelhay E (1998) Structural and functional analysis of mouse Msx1 gene promoter: sequence conservation with human MSX1 promoter points at potential regulatory elements. DNA Cell Biol 17:561–572. CrossRefPubMedGoogle Scholar
  91. 91.
    Ghatpande SK, Zhou HR, Cakstina I et al (2010) Transforming growth factor β2 is negatively regulated by endogenous retinoic acid during early heart morphogenesis. Dev Growth Differ 52:433–455. CrossRefPubMedGoogle Scholar
  92. 92.
    Zile MH (2010) Vitamin A-not for your eyes only: requirement for heart formation begins early in embryogenesis. Nutrients 2:532–550. CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Heller LC, Li Y, Abrams KL, Rogers MB (2002) Transcriptional regulation of the Bmp2 gene. J Biol Chem 274:1394–1400. CrossRefGoogle Scholar
  94. 94.
    Shannon SR, Moise AR, Trainor PA et al (2017) New insights and changing paradigms in the regulation of vitamin A metabolism in development. Wiley Interdiscip Rev Dev Biol 6:1–28. CrossRefGoogle Scholar
  95. 95.
    Collins SJ (2002) The role of retinoids and retinoic acid receptors in normal hematopoiesis. Leukemia 16:1896–1905. CrossRefPubMedGoogle Scholar
  96. 96.
    Rönn RE, Guibentif C, Moraghebi R et al (2015) Retinoic acid regulates hematopoietic development from human pluripotent stem cells. Stem Cell Rep 4:269–281. CrossRefGoogle Scholar
  97. 97.
    Cabezas-Wallscheid N, Buettner F, Sommerkamp P et al (2017) Vitamin A-retinoic acid signaling regulates hematopoietic stem cell dormancy. Cell 169:807–823.e19. CrossRefPubMedGoogle Scholar
  98. 98.
    Chanda B, Ditadi A, Iscove NN, Keller G (2013) Retinoic acid signaling is essential for embryonic hematopoietic stem cell development. Cell 155:215–227. CrossRefPubMedGoogle Scholar
  99. 99.
    Cabezas-Wallscheid N, Klimmeck D, Hansson J et al (2014) Identification of regulatory networks in HSCs and their immediate progeny via integrated proteome, transcriptome, and DNA methylome analysis. Cell Stem Cell 15:507–522. CrossRefPubMedGoogle Scholar
  100. 100.
    Li L, Dong J, Yan L et al (2017) Single-cell RNA-Seq analysis maps development of human germline cells and gonadal niche interactions. Cell Stem Cell 20:858–873.e4. CrossRefPubMedGoogle Scholar
  101. 101.
    Koshimizu U, Watanabe M, Nakatsuji N (1995) Retinoic acid is a potent growth activator of mouse primordial germ cells in vitro. Dev Biol 168:683–685CrossRefPubMedGoogle Scholar
  102. 102.
    Nayernia K, Nolte J, Michelmann HW et al (2006) In vitro-differentiated embryonic stem cells give rise to male gametes that can generate offspring mice. Dev Cell 11:125–132. CrossRefPubMedGoogle Scholar
  103. 103.
    Sandell LL, Sanderson BW, Moiseyev G et al (2007) RDH10 is essential for synthesis of embryonic retinoic acid and is required for limb, craniofacial, and organ development. Genes Dev 21:1113–1124. CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Farjo KM, Moiseyev G, Nikolaeva O et al (2011) RDH10 is the primary enzyme responsible for the first step of embryonic vitamin A metabolism and retinoic acid synthesis. Dev Biol 357:347–355. CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Billings SE, Pierzchalski K, Tjaden NEB et al (2013) The retinaldehyde reductase DHRS3 is essential for preventing the formation of excess retinoic acid during embryonic development. FASEB J 27:4877–4889. CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Takahashi K, Tanabe K, Ohnuki M et al (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872. CrossRefGoogle Scholar
  107. 107.
    Yu J, Vodyanik MA, Smuga-Otto K et al (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318:1917–1920. CrossRefGoogle Scholar
  108. 108.
    Wang W, Yang J, Liu H et al (2011) Rapid and efficient reprogramming of somatic cells to induced pluripotent stem cells by retinoic acid receptor gamma and liver receptor homolog 1. Proc Natl Acad Sci 108:18283–18288. CrossRefPubMedGoogle Scholar
  109. 109.
    Yang J, Wang W, Ooi J et al (2015) Signalling through retinoic acid receptors is required for reprogramming of both mouse embryonic fibroblast cells and epiblast stem cells to induced pluripotent stem cells. Stem Cells 33:1390–1404. CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Hou P, Li Y, Zhang X et al (2013) Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds. Science 341:651–654. CrossRefPubMedGoogle Scholar
  111. 111.
    Shu J, Wu C, Wu Y et al (2013) Induction of pluripotency in mouse somatic cells with lineage specifiers. Cell 153:963–975. CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    De Angelis MT, Parrotta EI, Santamaria G, Cuda G (2018) Short-term retinoic acid treatment sustains pluripotency and suppresses differentiation of human induced pluripotent stem cells. Cell Death Dis 9:1–13. CrossRefGoogle Scholar
  113. 113.
    Hore TA, Von Meyenn F, Ravichandran M et al (2016) Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms. Proc Natl Acad Sci 113:12202–12207. CrossRefPubMedGoogle Scholar
  114. 114.
    Garten A, Petzold S, Barnikol-Oettler A et al (2010) Nicotinamide phosphoribosyltransferase (NAMPT/PBEF/visfatin) is constitutively released from human hepatocytes. Biochem Biophys Res Commun 391:376–381. CrossRefPubMedGoogle Scholar
  115. 115.
    Mullangi R, Srinivas NR (2011) Niacin and its metabolites: role of LC–MS/MS bioanalytical methods and update on clinical pharmacology. An overview. Biomed Chromatogr 25:218–237. CrossRefPubMedGoogle Scholar
  116. 116.
    Saini JS, Corneo B, Miller JD et al (2018) Nicotinamide ameliorates disease phenotypes in a human iPSC model of age-related macular degeneration. Cell Stem Cell 20:635–647. CrossRefGoogle Scholar
  117. 117.
    Mitchell SJ, Bernier M, Aon MA et al (2018) Nicotinamide improves aspects of healthspan, but not lifespan, in mice. Cell Metab 27:667–676.e4. CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Parsons XH, Teng YD, Parsons JF et al (2011) Efficient derivation of human cardiac precursors and cardiomyocytes from pluripotent human embryonic stem cells with small molecule induction. J Vis Exp. CrossRefPubMedPubMedCentralGoogle Scholar
  119. 119.
    Nostro MC, Sarangi F, Yang C et al (2015) Efficient generation of NKX6-1+ pancreatic progenitors from multiple human pluripotent stem cell lines. Stem Cell Rep 4:591–604. CrossRefGoogle Scholar
  120. 120.
    Son MJ, Son M-Y, Seol B et al (2013) Nicotinamide overcomes pluripotency deficits and reprogramming barriers. Stem Cells 31:1121–1135. CrossRefPubMedGoogle Scholar
  121. 121.
    Sato T, Stange DE, Ferrante M et al (2011) Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett’s epithelium. Gastroenterology 141:1762–1772. CrossRefGoogle Scholar
  122. 122.
    Bartfeld S, Bayram T, van de Wetering M et al (2015) In vitro expansion of human gastric epithelial stem cells and their responses to bacterial infection. Gastroenterology 148:126–136.e6. CrossRefPubMedGoogle Scholar
  123. 123.
    Urbischek M, Rannikmae H, Foets T et al (2019) Organoid culture media formulated with growth factors of defined cellular activity. Sci Rep 9:6193. CrossRefPubMedPubMedCentralGoogle Scholar
  124. 124.
    Peled T, Shoham H, Aschengrau D et al (2012) Nicotinamide, a SIRT1 inhibitor, inhibits differentiation and facilitates expansion of hematopoietic progenitor cells with enhanced bone marrow homing and engraftment. Exp Hematol 40:342–355. CrossRefPubMedGoogle Scholar
  125. 125.
    Bosch-Presegué L, Vaquero A (2015) Sirtuin-dependent epigenetic regulation in the maintenance of genome integrity. FEBS J 282:1745–1767. CrossRefPubMedGoogle Scholar
  126. 126.
    Kuchmerovska T, Shymanskyy I, Donchenko G et al (2004) Poly(ADP-ribosyl)ation enhancement in brain cell nuclei is associated with diabetic neuropathy. J Diabetes Complicat 18:198–204. CrossRefPubMedGoogle Scholar
  127. 127.
    Avalos JL, Bever KM, Wolberger C (2005) Mechanism of sirtuin inhibition by nicotinamide: altering the NAD+ cosubstrate specificity of a Sir2 enzyme. Mol Cell 17:855–868. CrossRefPubMedGoogle Scholar
  128. 128.
    de Picciotto NE, Gano LB, Johnson LC et al (2016) Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice. Aging Cell 15:522–530. CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Nadtochiy SM, Wang YT, Nehrke K et al (2018) Cardioprotection by nicotinamide mononucleotide (NMN): involvement of glycolysis and acidic pH. J Mol Cell Cardiol 121:155–162. CrossRefPubMedPubMedCentralGoogle Scholar
  130. 130.
    Wang X, Hu X, Yang Y et al (2016) Nicotinamide mononucleotide protects against β-amyloid oligomer-induced cognitive impairment and neuronal death. Brain Res 1643:1–9. CrossRefPubMedGoogle Scholar
  131. 131.
    Vannini N, Campos V, Girotra M et al (2019) The NAD-booster nicotinamide riboside potently stimulates hematopoiesis through increased mitochondrial clearance. Cell Stem Cell 24:405–418.e7. CrossRefPubMedGoogle Scholar
  132. 132.
    Belenky P, Racette FG, Bogan KL et al (2007) Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/Meu1 pathways to NAD+. Cell 129:473–484. CrossRefPubMedGoogle Scholar
  133. 133.
    Linster CL, Van Schaftingen E (2007) Vitamin C: biosynthesis, recycling and degradation in mammals. FEBS J 274:1–22. CrossRefPubMedGoogle Scholar
  134. 134.
    Stone I (1972) The natural history of ascorbic acid in the evolution of the mammals and primates and its significance for present day man. J Orthomol Psychiatry 1:82–89Google Scholar
  135. 135.
    Andrews FE, Driscoll PJ (1977) Stability of ascorbic acid in orange juice exposed to light and air during storage. J Am Diet Assoc 71:140PubMedGoogle Scholar
  136. 136.
    Austria R, Semenzato A, Bettero A (1997) Stability of vitamin C derivatives in solution and topical formulations. J Pharm Biomed Anal 15:795–801. CrossRefPubMedGoogle Scholar
  137. 137.
    Lee WJ, Kim SL, Choe YS et al (2015) Magnesium ascorbyl phosphate regulates the expression of inflammatory biomarkers in cultured sebocytes. Ann Dermatol 27:376–382. CrossRefPubMedPubMedCentralGoogle Scholar
  138. 138.
    Meves A, Stock SN, Beyerle A et al (2002) Vitamin C derivative ascorbyl palmitate promotes ultraviolet-B-induced lipid peroxidation and cytotoxicity in keratinocytes. J Investig Dermatol 119:1103–1108. CrossRefPubMedGoogle Scholar
  139. 139.
    Frei B, England L, Ames BN (1989) Ascorbate is an outstanding antioxidant in human blood plasma. Proc Natl Acad Sci USA 86:6377–6381. CrossRefPubMedGoogle Scholar
  140. 140.
    Carcamo JM, Pedraza A, Borquez-Ojeda O et al (2004) Vitamin C is a kinase inhibitor: dehydroascorbic acid inhibits IκBα kinase β. Mol Cell Biol 24:6645–6652. CrossRefPubMedPubMedCentralGoogle Scholar
  141. 141.
    Bowie AG, O’Neill LAJ (2000) Vitamin C inhibits NF-κB activation by TNF via the activation of p38 mitogen-activated protein kinase. J Immunol 165:7180–7188. CrossRefPubMedGoogle Scholar
  142. 142.
    Hurrel R, Egli I (2010) Iron bioavailability and dietary reference values. Am J Clin Nutr 91:1461–1467. CrossRefGoogle Scholar
  143. 143.
    Ma Y, Chapman J, Levine M et al (2014) High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy. Sci Transl Med. CrossRefPubMedPubMedCentralGoogle Scholar
  144. 144.
    Bram S, Froussard P, Guichard M et al (1980) Vitamin C preferential toxicity for malignant melanoma cells. Nature 284:629–631. CrossRefPubMedGoogle Scholar
  145. 145.
    Bishun N, Basu TK, Metcalfe S, Williams DC (1978) The effect of ascorbic acid (vitamin C) on two tumor cell lines in culture. Oncology 35:160–162. CrossRefPubMedGoogle Scholar
  146. 146.
    Hinman A, Holst CR, Latham JC et al (2018) Vitamin E hydroquinone is an endogenous regulator of ferroptosis via redox control of 15-lipoxygenase. PLoS One 13:1–22. CrossRefGoogle Scholar
  147. 147.
    Stockwell BR, Angeli JPF (2017) Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell 171:273–285. CrossRefPubMedPubMedCentralGoogle Scholar
  148. 148.
    Cimmino L, Neel BG, Aifantis I (2018) Vitamin C in stem cell reprogramming and cancer. Trends Cell Biol 28:698–708. CrossRefPubMedPubMedCentralGoogle Scholar
  149. 149.
    Rahman F, Fontes M (2013) Ascorbic acid, myelination and associated disorders. PharmaNutrition 1:98–100. CrossRefGoogle Scholar
  150. 150.
    Podratz JL, Rodriguez E, Windebank AJ (2001) Role of the extracellular matrix in myelination of peripheral nerve. Glia 35:35–40CrossRefPubMedGoogle Scholar
  151. 151.
    Passage E, Norreel JC, Noack-Fraissignes P et al (2004) Ascorbic acid treatment corrects the phenotype of a mouse model of Charcot–Marie–Tooth disease. Nat Med 10:396–401. CrossRefPubMedGoogle Scholar
  152. 152.
    Pareyson D, Reilly MM, Schenone A et al (2011) Ascorbic acid in Charcot–Marie–Tooth disease type 1A (CMT-TRIAAL and CMT-TRAUK): a double-blind randomised trial. Lancet Neurol 10:320–328. CrossRefPubMedPubMedCentralGoogle Scholar
  153. 153.
    Chojkier M, Houglum K, Solis-Herruzo J, Brenner DA (1989) Stimulation of collagen gene expression by ascorbic acid in human fibroblasts. J Biol Chem 246:16957–16962Google Scholar
  154. 154.
    Esteban MA, Wang T, Qin B et al (2010) Vitamin C enhances the generation of mouse and human induced pluripotent stem cells. Cell Stem Cell 6:71–79. CrossRefPubMedGoogle Scholar
  155. 155.
    Zhao Y, Yin X, Qin H et al (2008) Two supporting factors greatly improve the efficiency of human iPSC generation. Cell Stem Cell 3:475–479. CrossRefPubMedGoogle Scholar
  156. 156.
    Marión RM, Strati K, Li H et al (2009) A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity. Nature 460:1149–1153. CrossRefPubMedPubMedCentralGoogle Scholar
  157. 157.
    Shi Y, Zhao Y, Deng H (2010) Powering reprogramming with vitamin C. Cell Stem Cell 6:1–2. CrossRefPubMedGoogle Scholar
  158. 158.
    Shi Y (2007) Histone lysine demethylases: emerging roles in development, physiology and disease. Nat Rev Genet 8:829CrossRefPubMedGoogle Scholar
  159. 159.
    Chung TL, Brena RM, Kolle G et al (2010) Vitamin C promotes widespread yet specific DNA demethylation of the epigenome in human embryonic stem cells. Stem Cells 28:1848–1855. CrossRefPubMedGoogle Scholar
  160. 160.
    Irizarry RA, Ladd-Acosta C, Wen B et al (2009) The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet 41:178CrossRefPubMedPubMedCentralGoogle Scholar
  161. 161.
    Rahman F, Bordignon B, Culerrier R et al (2017) Ascorbic acid drives the differentiation of mesoderm-derived embryonic stem cells. Involvement of p38 MAPK/CREB and SVCT2 transporter. Mol Nutr Food Res. CrossRefPubMedGoogle Scholar
  162. 162.
    Takahashi T, Lord B, Schulze PC et al (2003) Ascorbic acid enhances differentiation of embryonic stem cells into cardiac myocytes. Circulation 107:1912–1916. CrossRefPubMedGoogle Scholar
  163. 163.
    Cao N, Liu Z, Chen Z et al (2012) Ascorbic acid enhances the cardiac differentiation of induced pluripotent stem cells through promoting the proliferation of cardiac progenitor cells. Cell Res 22:219–236. CrossRefPubMedGoogle Scholar
  164. 164.
    Chepda T, Cadau M, Girin P et al (2002) Monitoring of ascorbate at a constant rate in cell culture: effect on cell growth. In Vitro Cell Dev Biol Anim 37:26.;2 CrossRefGoogle Scholar
  165. 165.
    Hata R-I, Senoo H (1989) l-ascorbic acid 2-phosphate stimulates collagen accumulation, cell proliferation, and formation of a three-dimensional tissuelike substance by skin fibroblasts. J Cell Physiol 138:8–16. CrossRefPubMedGoogle Scholar
  166. 166.
    Senoo H, Hata R (1994) Extracellular matrix regulates and l-ascorbic acid 2-phosphate further modulates morphology, proliferation, and collagen synthesis of perisinusoidal stellate cells. Biochem Biophys Res Commun 200:999–1006. CrossRefPubMedGoogle Scholar
  167. 167.
    Fujisawa K, Hara K, Takami T et al (2018) Evaluation of the effects of ascorbic acid on metabolism of human mesenchymal stem cells. Stem Cell Res Ther 9:1–12. CrossRefGoogle Scholar
  168. 168.
    Potdar PD, D’Souza SB (2010) Ascorbic acid induces in vitro proliferation of human subcutaneous adipose tissue derived mesenchymal stem cells with upregulation of embryonic stem cell pluripotency markers Oct4 and SOX 2. Hum Cell 23:152–155. CrossRefPubMedGoogle Scholar
  169. 169.
    Choi K-M, Seo Y-K, Yoon H-H et al (2008) Effect of ascorbic acid on bone marrow-derived mesenchymal stem cell proliferation and differentiation. J Biosci Bioeng 105:586–594. CrossRefPubMedGoogle Scholar
  170. 170.
    Narita Y, Yamawaki A, Kagami H et al (2008) Effects of transforming growth factor-beta 1 and ascorbic acid on differentiation of human bone-marrow-derived mesenchymal stem cells into smooth muscle cell lineage. Cell Tissue Res 333:449–459. CrossRefPubMedGoogle Scholar
  171. 171.
    Vater C, Kasten P, Stiehler M (2011) Culture media for the differentiation of mesenchymal stromal cells. Acta Biomater 7:463–477. CrossRefPubMedGoogle Scholar
  172. 172.
    Xiao G, Wang D, Benson MD et al (1998) Role of the α2-integrin in osteoblast-specific gene expression and activation of the Osf2 transcription factor. J Biol Chem 273:32988–32994. CrossRefPubMedGoogle Scholar
  173. 173.
    Franceschi RT, Iyer BS, Cui Y (1994) Effects of ascorbic acid on collagen matrix formation and osteoblast differentiation in murine MC3T3-E1 cells. J Bone Miner Res 9:843–854. CrossRefPubMedGoogle Scholar
  174. 174.
    Castrén E, Sillat T, Oja S et al (2015) Osteogenic differentiation of mesenchymal stromal cells in two-dimensional and three-dimensional cultures without animal serum. Stem Cell Res Ther 6:1–13. CrossRefGoogle Scholar
  175. 175.
    Barlian A, Judawisastra H, Alfarafisa NM et al (2018) Chondrogenic differentiation of adipose-derived mesenchymal stem cells induced by L-ascorbic acid and platelet rich plasma on silk fibroin scaffold. PeerJ 6:e5809. CrossRefPubMedPubMedCentralGoogle Scholar
  176. 176.
    Chang Z, Huo L, Li P et al (2015) Ascorbic acid provides protection for human chondrocytes against oxidative stress. Mol Med Rep 12:7086–7092. CrossRefPubMedGoogle Scholar
  177. 177.
    Huijskens MJAJ, Walczak M, Sarkar S et al (2015) Ascorbic acid promotes proliferation of natural killer cell populations inculture systems applicable for natural killer cell therapy. Cytotherapy 17:613–620. CrossRefPubMedGoogle Scholar
  178. 178.
    Huijskens MJAJ, Walczak M, Koller N et al (2014) Technical Advance: ascorbic acid induces development of double-positive T cells from human hematopoietic stem cells in the absence of stromal cells. J Leukoc Biol 96:1165–1175. CrossRefPubMedGoogle Scholar
  179. 179.
    Kennedy M, Keller G (2007) Development of hemangioblast defines the onset of hematopoiesis in ES cell differentiation cultures. Blood 12:3521–3528. CrossRefGoogle Scholar
  180. 180.
    Agathocleous M, Meacham CE, Burgess RJ et al (2017) Ascorbate regulates haematopoietic stem cell function and leukaemogenesis. Nature 549:476–481. CrossRefPubMedPubMedCentralGoogle Scholar
  181. 181.
    Minor EA, Court BL, Young JI, Wang G (2013) Ascorbate induces ten-eleven translocation (Tet) methylcytosine dioxygenase-mediated generation of 5-hydroxymethylcytosine. J Biol Chem 288:13669–13674. CrossRefPubMedPubMedCentralGoogle Scholar
  182. 182.
    Chen J, Guo L, Zhang L et al (2013) Vitamin C modulates TET1 function during somatic cell reprogramming. Nat Genet 45:1504–1509. CrossRefPubMedGoogle Scholar
  183. 183.
    Shi DQ, Ali I, Tang J, Yang WC (2017) New insights into 5hmC DNA modification: generation, distribution and function. Front Genet 8:1–11. CrossRefGoogle Scholar
  184. 184.
    Lee Chong T, Ahearn EL, Cimmino L (2019) Reprogramming the epigenome with vitamin C. Front Cell Dev Biol 7:1–13. CrossRefGoogle Scholar
  185. 185.
    Anderson OS, Sant KE, Dolinoy DC (2012) Nutrition and epigenetics: an interplay of dietary methyl donors, one-carbon metabolism, and DNA methylation. J Nutr Biochem 23:853–859. CrossRefPubMedPubMedCentralGoogle Scholar
  186. 186.
    Martin EM, Fry RC (2018) Environmental influences on the epigenome: exposure-associated DNA methylation in human populations. Annu Rev Public Health 39:309–333. CrossRefPubMedGoogle Scholar
  187. 187.
    Clare CE, Brassington AH, Kwong WY, Sinclair KD (2019) One-carbon metabolism: linking nutritional biochemistry to epigenetic programming of long-term development. Annu Rev Anim Biosci 7:263–287. CrossRefPubMedGoogle Scholar
  188. 188.
    Wang T, Chen K, Zeng X et al (2011) The histone demethylases Jhdm1a/1b enhance somatic cell reprogramming in a vitamin-C-dependent manner. Cell Stem Cell 9:575–587. CrossRefGoogle Scholar
  189. 189.
    Tsukada YI, Fang J, Erdjument-Bromage H et al (2006) Histone demethylation by a family of JmjC domain-containing proteins. Nature 439:811–816. CrossRefPubMedGoogle Scholar
  190. 190.
    Ito S, Shen L, Dai Q et al (2011) Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333:1300–1303. CrossRefPubMedPubMedCentralGoogle Scholar
  191. 191.
    Wu H, Zhang Y (2014) Reversing DNA methylation: mechanisms, genomics, and biological functions. Cell 156:45–68. CrossRefPubMedPubMedCentralGoogle Scholar
  192. 192.
    Yang Q, Liang X, Sun X et al (2016) AMPK/α-ketoglutarate axis dynamically mediates DNA demethylation in the Prdm16 promoter and brown adipogenesis. Cell Metab 24:542–554. CrossRefPubMedPubMedCentralGoogle Scholar
  193. 193.
    Yin R, Mao SQ, Zhao B et al (2013) Ascorbic acid enhances tet-mediated 5-methylcytosine oxidation and promotes DNA demethylation in mammals. J Am Chem Soc 135:10396–10403. CrossRefPubMedGoogle Scholar
  194. 194.
    Clifton IJ, McDonough MA, Ehrismann D et al (2006) Structural studies on 2-oxoglutarate oxygenases and related double-stranded β-helix fold proteins. J Inorg Biochem 100:644–669. CrossRefPubMedGoogle Scholar
  195. 195.
    He X-B, Kim M, Kim S et al (2015) Vitamin C facilitates dopamine neuron differentiation in fetal MIdbrain through TET1- and JMJD3-dependent epigenetic control manner. Stem Cells 33:1320–1332. CrossRefPubMedPubMedCentralGoogle Scholar
  196. 196.
    Koh KP, Yabuuchi A, Rao S et al (2011) Tet1 and Tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells. Cell Stem Cell 8:200–213. CrossRefPubMedPubMedCentralGoogle Scholar
  197. 197.
    Evans HM, Bishop KS (1922) On the existence of a hitherto unrecognized dietary factor essential for reproduction. Science 56:650–651. CrossRefPubMedGoogle Scholar
  198. 198.
    Brigelius-Flohé R, Traber MG (1999) Vitamin E: function and metabolism. FASEB J 13:1145–1155. CrossRefPubMedGoogle Scholar
  199. 199.
    Traber MG, Atkinson J (2007) Vitamin E, antioxidant and nothing more. Free Radic Biol Med 43:4–15. CrossRefPubMedPubMedCentralGoogle Scholar
  200. 200.
    Torquato P, Ripa O, Giusepponi D et al (2016) Analytical strategies to assess the functional metabolome of vitamin E. J Pharm Biomed Anal 124:399–412. CrossRefPubMedGoogle Scholar
  201. 201.
    Peh HY, Tan WSD, Liao W, Wong WSF (2016) Vitamin E therapy beyond cancer: tocopherol versus tocotrienol. Pharmacol Ther 162:152–169. CrossRefPubMedGoogle Scholar
  202. 202.
    Aggarwal V, Kashyap D, Sak K et al (2019) Molecular mechanisms of action of tocotrienols in cancer: recent trends and advancements. Int J Mol Sci 20:656. CrossRefPubMedCentralGoogle Scholar
  203. 203.
    Ling MT, Luk SU, Al-Ejeh F, Khanna KK (2011) Tocotrienol as a potential anticancer agent. Carcinogenesis 33:233–239. CrossRefPubMedGoogle Scholar
  204. 204.
    Davies MJ, Forni LG, Willson RL (1988) Vitamin E analogue Trolox C. E.s.r. and pulse-radiolysis studies of free-radical reactions. Biochem J 255:513–522PubMedPubMedCentralGoogle Scholar
  205. 205.
    Compadre CM, Singh A, Thakkar S et al (2014) Molecular dynamics guided design of tocoflexol: a new radioprotectant tocotrienol with enhanced bioavailability. Drug Dev Res 75:10–22. CrossRefPubMedGoogle Scholar
  206. 206.
    Neuzil J, Weber T, Terman A et al (2004) Vitamin E analogues as inducers of apoptosis: implications for their potential antineoplastic role. Redox Rep 6:143–151. CrossRefGoogle Scholar
  207. 207.
    Zf M (2002) Final report on the safety assessment of tocopherol, tocopheryl acetate, tocopheryl linoleate, tocopheryl linoleate/oleate, tocopheryl nicotinate, tocopheryl succinate, dioleyl tocopheryl methylsilanol, potassium ascorbyl tocopheryl phosphate, and tocophe. Int J Toxicol 21:51–116. CrossRefGoogle Scholar
  208. 208.
    Lee E, Choi M-K, Lee Y-J et al (2006) Alpha-tocopheryl succinate, in contrast to alpha-tocopherol and alpha-tocopheryl acetate, inhibits prostaglandin E 2 production in human lung epithelial cells. Carcinogenesis 27:2308–2315. CrossRefPubMedGoogle Scholar
  209. 209.
    Li Z-T, Wang L-M, Yi L-R et al (2017) Succinate ester derivative of δ-tocopherol enhances the protective effects against (60)Co γ-ray-induced hematopoietic injury through granulocyte colony-stimulating factor induction in mice. Sci Rep 7:40380. CrossRefPubMedPubMedCentralGoogle Scholar
  210. 210.
    Frei B, Stocker R, Ames BN (1988) Antioxidant defenses and lipid peroxidation in human blood plasma. Proc Natl Acad Sci 85:9748–9752. CrossRefPubMedGoogle Scholar
  211. 211.
    Dhitavat S, Rivera ER, Rogers E, Shea TB (2001) Differential efficacy of lipophilic and cytosolic antioxidants on generation of reactive oxygen species by amyloid-β. J Alzheimer’s Dis 3:525–529. CrossRefGoogle Scholar
  212. 212.
    Zingg J-M (2015) Vitamin E: a role in signal transduction. Annu Rev Nutr 35:135–173. CrossRefPubMedGoogle Scholar
  213. 213.
    Boscoboinik D, Szewczyk A, Henseys C, Ami A (1991) Inhibition of cell proliferation by a-tocopherol. role of protein kinase C. J Biol Chem 266:6188–6194PubMedGoogle Scholar
  214. 214.
    Ricciarelli R, Tasinato A, Clément S et al (1998) Alpha-tocopherol specifically inactivates cellular protein kinase C alpha by changing its phosphorylation state. Biochem J 334(Pt 1):243–249. CrossRefPubMedPubMedCentralGoogle Scholar
  215. 215.
    Abdala-Valencia H, Berdnikovs S, Cook-Mills JM (2012) Vitamin E isoforms differentially regulate intercellular adhesion molecule-1 activation of PKCα in human microvascular endothelial cells. PLoS One 7:e41054–e41054. CrossRefPubMedPubMedCentralGoogle Scholar
  216. 216.
    Boscoboinik D, Szewczyk A, Azzi A (1991) α-Tocopherol (vitamin E) regulates vascular smooth muscle cell proliferation and protein kinase C activity. Arch Biochem Biophys 286:264–269. CrossRefPubMedGoogle Scholar
  217. 217.
    Ferri P, Cecchini T, Ambrogini P et al (2006) α-tocopherol affects neuronal plasticity in adult rat dentate gyrus: the possible role of PKCδ. J Neurobiol 66:793–810. CrossRefPubMedGoogle Scholar
  218. 218.
    Samant GV, Sylvester PW (2006) γ-Tocotrienol inhibits ErbB3-dependent PI3K/Akt mitogenic signalling in neoplastic mammary epithelial cells. Cell Prolif 39:563–574. CrossRefPubMedGoogle Scholar
  219. 219.
    Shin-Kang S, Ramsauer VP, Lightner J et al (2011) Tocotrienols inhibit AKT and ERK activation and suppress pancreatic cancer cell proliferation by suppressing the ErbB2 pathway. Free Radic Biol Med 51:1164–1174. CrossRefPubMedGoogle Scholar
  220. 220.
    Bhatti FU, Mehmood A, Latief N et al (2017) Vitamin E protects rat mesenchymal stem cells against hydrogen peroxide-induced oxidative stress in vitro and improves their therapeutic potential in surgically-induced rat model of osteoarthritis. Osteoarthr Cartil 25:321–331. CrossRefPubMedGoogle Scholar
  221. 221.
    Garg S, Sadhukhan R, Banerjee S et al (2019) Gamma-tocotrienol protects the intestine from radiation potentially by accelerating mesenchymal immune cell recovery. Antioxidants (Basel, Switzerland) 8:57. CrossRefGoogle Scholar
  222. 222.
    Wilankar C, Khan NM, Checker R et al (2011) Gamma-tocotrienol induces apoptosis in human T cell lymphoma through activation of both intrinsic and extrinsic pathways. Curr Pharm Des 17:2176–2189CrossRefPubMedGoogle Scholar
  223. 223.
    Ahmed RA, Alawin OA, Sylvester PW (2016) γ-Tocotrienol reversal of epithelial-to-mesenchymal transition in human breast cancer cells is associated with inhibition of canonical Wnt signalling. Cell Prolif 49:460–470. CrossRefPubMedGoogle Scholar
  224. 224.
    Lin TP, Hom Yun Kit, Richards J, Nandi S (1991) Effects of antioxidants and reduced oxygen tension on rat mammary epithelial cells in culture. In Vitro Cell Dev Biol Anim 27A:191–196. CrossRefGoogle Scholar
  225. 225.
    Offord EA, Gautier J-C, Avanti O et al (2002) Photoprotective potential of lycopene, β-carotene, vitamin E, vitamin C and carnosic acid in UVA-irradiated human skin fibroblasts. Free Radic Biol Med 32:1293–1303. CrossRefPubMedGoogle Scholar
  226. 226.
    Dhein S, Kabat A, Olbrich A et al (2003) Effect of chronic treatment with vitamin E on endothelial dysfunction in a type I in vivo diabetes mellitus model and in vitro. J Pharmacol Exp Ther 305:114–122. CrossRefPubMedGoogle Scholar
  227. 227.
    Steiner M, Li W, Ciaramella JM et al (1997) Dl-alpha-tocopherol, a potent inhibitor of phorbol ester induced shape change of erythro- and megakaryoblastic leukemia cells. J Cell Physiol 172:351–360.;2-N CrossRefPubMedGoogle Scholar
  228. 228.
    Pazdro R, Burgess JR (2012) Differential effects of α-tocopherol and N-acetyl-cysteine on advanced glycation end product-induced oxidative damage and neurite degeneration in SH-SY5Y cells. Biochim Biophys Acta Mol Basis Dis 1822:550–556. CrossRefGoogle Scholar
  229. 229.
    Faedmaleki F, Shirazi FH, Ejtemaeimehr S et al (2016) Study of silymarin and vitamin E protective effects on silver nanoparticle toxicity on mice liver primary cell culture. Acta Med Iran 54:85–95PubMedGoogle Scholar
  230. 230.
    Tangney CC, Shekelle RB, Raynor W et al (1987) Intra- and interindividual variation in measurements of beta-carotene, retinol, and tocopherols in diet and plasma. Am J Clin Nutr 45:764–769. CrossRefPubMedGoogle Scholar
  231. 231.
    Winklhofer-Roob BM, van’t Hof MA, Shmerling DH (1997) Reference values for plasma concentrations of vitamin E and A and carotenoids in a Swiss population from infancy to adulthood, adjusted for seasonal influences. Clin Chem 43:146–153PubMedGoogle Scholar
  232. 232.
    High KP, Legault C, Sinclair JA et al (2002) Low plasma concentrations of retinol and α-tocopherol in hematopoietic stem cell transplant recipients: the effect of mucositis and the risk of infection. Am J Clin Nutr 76:1358–1366. CrossRefPubMedGoogle Scholar
  233. 233.
    Borel P, Moussa M, Reboul E et al (2007) Human plasma levels of vitamin E and carotenoids are associated with genetic polymorphisms in genes involved in lipid metabolism. J Nutr 137:2653–2659. CrossRefPubMedGoogle Scholar
  234. 234.
    Brewer GJ, Torricelli JR, Evege EK, Price PJ (1993) Optimized survival of hippocampal neurons in B27-supplemented neurobasal™, a new serum-free medium combination. J Neurosci Res 35:567–576. CrossRefGoogle Scholar
  235. 235.
    Brewer GJ, Cotman CW (1989) Survival and growth of hippocampal neurons in defined medium at low density: advantages of a sandwich culture technique or low oxygen. Brain Res 494:65–74. CrossRefPubMedGoogle Scholar
  236. 236.
    Spector AA, Mathur SN, Kaduce TL (1980) Lipid nutrition and metabolism of cultured mammalian cells. Prog Lipid Res 19:155–186. CrossRefPubMedGoogle Scholar
  237. 237.
    Bhatti FUR, Kim SJ, Yi A-K et al (2018) Cytoprotective role of vitamin E in porcine adipose-tissue-derived mesenchymal stem cells against hydrogen-peroxide-induced oxidative stress. Cell Tissue Res 374:111–120. CrossRefPubMedGoogle Scholar
  238. 238.
    El Alami M, Viña-Almunia J, Gambini J et al (2014) Activation of p38, p21, and NRF-2 mediates decreased proliferation of human dental pulp stem cells cultured under 21% O2. Stem Cell Rep 3:566–573. CrossRefGoogle Scholar
  239. 239.
    Malakoutikhah M, Satarian L, Kiani S, Javan M (2015) Alpha-tocopherol increases the proliferation of induced pluripotent stem cell derived neural progenitor cells. Physiol Pharmacol 19:90–98Google Scholar
  240. 240.
    Wu Y, Viana M, Thirumangalathu S, Loeken MR (2012) AMP-activated protein kinase mediates effects of oxidative stress on embryo gene expression in a mouse model of diabetic embryopathy. Diabetologia 55:245–254. CrossRefPubMedGoogle Scholar
  241. 241.
    Santander N, Lizama C, Parga MJ et al (2017) Deficient vitamin E uptake during development impairs neural tube closure in mice lacking lipoprotein receptor SR-BI. Sci Rep 7:5182. CrossRefPubMedPubMedCentralGoogle Scholar
  242. 242.
    Huang Y-H, Sharifpanah F, Becker S et al (2016) Impact of arachidonic acid and the leukotriene signaling pathway on vasculogenesis of mouse embryonic stem cells. Cells Tissues Organs 201:319–332. CrossRefPubMedGoogle Scholar
  243. 243.
    Sauer H, Bekhite MM, Hescheler J, Wartenberg M (2005) Redox control of angiogenic factors and CD31-positive vessel-like structures in mouse embryonic stem cells after direct current electrical field stimulation. Exp Cell Res 304:380–390. CrossRefPubMedGoogle Scholar
  244. 244.
    Na L, Wartenberg M, Nau H et al (2003) Anticonvulsant valproic acid inhibits cardiomyocyte differentiation of embryonic stem cells by increasing intracellular levels of reactive oxygen species. Birth Defects Res Part A Clin Mol Teratol 67:174–180. CrossRefPubMedGoogle Scholar
  245. 245.
    Wo Y, Zhu D, Hu Y et al (2008) Reactive oxygen species involved in prenylflavonoids, icariin and icaritin, initiating cardiac differentiation of mouse embryonic stem cells. J Cell Biochem 103:1536–1550. CrossRefPubMedGoogle Scholar
  246. 246.
    Sauer H, Neukirchen W, Rahimi G et al (2004) Involvement of reactive oxygen species in cardiotrophin-1-induced proliferation of cardiomyocytes differentiated from murine embryonic stem cells. Exp Cell Res 294:313–324. CrossRefPubMedGoogle Scholar
  247. 247.
    Boland MJ, Nazor KL, Loring JF (2014) Epigenetic regulation of pluripotency and differentiation. Circ Res 115:311–324. CrossRefPubMedPubMedCentralGoogle Scholar
  248. 248.
    Depeint F, Bruce WR, Shangari N et al (2006) Mitochondrial function and toxicity: role of B vitamins on the one-carbon transfer pathways. Chem Biol Interact 163:113–132. CrossRefPubMedGoogle Scholar
  249. 249.
    Malavolta M (2016) Molecular basis of nutrition and aging. Academic Press, LondonGoogle Scholar
  250. 250.
    Ragsdale SW (2008) Catalysis of methyl group transfers involving tetrahydrofolate and B(12). Vitam Horm 79:293–324. CrossRefPubMedPubMedCentralGoogle Scholar
  251. 251.
    Locasale JW (2013) Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat Rev Cancer 13:572–583. CrossRefPubMedPubMedCentralGoogle Scholar
  252. 252.
    Yamazoe H, Kobori M, Murakami Y et al (2006) One-step induction of neurons from mouse embryonic stem cells in serum-free media containing vitamin B12 and heparin. Cell Transpl 15:135–145. CrossRefGoogle Scholar
  253. 253.
    Bannister DW, O’Neill IE, Whitehead CC (1983) The effect of biotin deficiency and dietary protein content on lipogenesis, gluconeogenesis and related enzyme activities in chick liver. Br J Nutr 50:291–302. CrossRefPubMedGoogle Scholar
  254. 254.
    Mock DM, Stratton SL, Horvath TD et al (2011) Urinary excretion of 3-hydroxyisovaleric acid and 3-hydroxyisovaleryl carnitine increases in response to a leucine challenge in marginally biotin-deficient humans. J Nutr 141:1925–1930. CrossRefPubMedPubMedCentralGoogle Scholar
  255. 255.
    Huskisson E, Maggini S, Ruf M (2007) The role of vitamins and minerals in energy metabolism and well-being. J Int Med Res 35:277–289. CrossRefPubMedGoogle Scholar
  256. 256.
    Cascante M, Centelles JJ, Veech RL et al (2000) Role of thiamin (vitamin B-1) and transketolase in tumor cell proliferation. Nutr Cancer 36:150–154. CrossRefPubMedGoogle Scholar
  257. 257.
    Shi L, Tu BP (2015) Acetyl-CoA and the regulation of metabolism: mechanisms and consequences. Curr Opin Cell Biol 33:125–131. CrossRefPubMedPubMedCentralGoogle Scholar
  258. 258.
    Janssen JJE, Grefte S, Keijer J, de Boer VCJ (2019) Mito-nuclear communication by mitochondrial metabolites and its regulation by B-vitamins. Front Physiol 10:78CrossRefPubMedPubMedCentralGoogle Scholar
  259. 259.
    Xuemei L, Jing Y, Bei X et al (2013) Retinoic acid improve germ cell differentiation from human embryonic stem cells. Iran J Reprod Med 11:905–912PubMedPubMedCentralGoogle Scholar
  260. 260.
    Rasouli-Ghahroudi AA, Akbari S, Najafi-Alishah M, Bohloli M (2017) The effect of vitamin K2 on osteogenic differentiation of dental pulp stem cells: an in vitro study. Regen Reconstr Restor 2:26–29. CrossRefGoogle Scholar
  261. 261.
    Cortes M, Chen MJ, Stachura DL et al (2016) Developmental vitamin D availability impacts hematopoietic stem cell production. Cell Rep 17:458–468. CrossRefPubMedPubMedCentralGoogle Scholar
  262. 262.
    Trüeb RM (2016) Serum biotin levels in women complaining of hair loss. Int J Trichology 8:73–77. CrossRefPubMedPubMedCentralGoogle Scholar
  263. 263.
    Cuerq C, Peretti N, Chikh K et al (2014) Overview of the in vitro stability of commonly measured vitamins and carotenoids in whole blood. Ann Clin Biochem 52:259–269. CrossRefPubMedGoogle Scholar
  264. 264.
    El-Heis S, Crozier SR, Robinson SM et al (2016) Higher maternal serum concentrations of nicotinamide and related metabolites in late pregnancy are associated with a lower risk of offspring atopic eczema at age 12 months. Clin Exp Allergy 46:1337–1343. CrossRefPubMedPubMedCentralGoogle Scholar
  265. 265.
    Kathman JV, Kies C (1984) Pantothenic acid status of free living adolescent and young adults. Nutr Res 4:245–250. CrossRefGoogle Scholar
  266. 266.
    Puebla C, Cisterna BA, Salas DP et al (2016) Linoleic acid permeabilizes gastric epithelial cells by increasing connexin 43 levels in the cell membrane via a GPR40- and Akt-dependent mechanism. Biochim Biophys Acta 1861:439–448. CrossRefPubMedPubMedCentralGoogle Scholar
  267. 267.
    Belal SA, Sivakumar AS, Kang DR et al (2018) Modulatory effect of linoleic and oleic acid on cell proliferation and lipid metabolism gene expressions in primary bovine satellite cells. Anim Cells Syst (Seoul) 22:324–333. CrossRefGoogle Scholar
  268. 268.
    Figueroa V, Sáez PJ, Salas JD et al (2013) Linoleic acid induces opening of connexin26 hemichannels through a PI3K/Akt/Ca2+-dependent pathway. Biochim Biophys Acta Biomembr 1828:1169–1179. CrossRefGoogle Scholar
  269. 269.
    Walocko FM, Eber AE, Keri JE et al (2017) The role of nicotinamide in acne treatment. Dermatol Ther 30:e12481. CrossRefGoogle Scholar
  270. 270.
    Bains P, Kaur M, Kaur J, Sharma S (2018) Nicotinamide: mechanism of action and indications in dermatology. Indian J Dermatol Venereol Leprol 84:234–237. CrossRefPubMedGoogle Scholar
  271. 271.
    Gale EAM, Group* TENDIT (ENDIT) (2003) Intervening before the onset of Type 1 diabetes: baseline data from the European Nicotinamide Diabetes Intervention Trial (ENDIT). Diabetologia 46:339–346. CrossRefGoogle Scholar
  272. 272.
    Lenglet A, Liabeuf S, Guffroy P et al (2013) Use of nicotinamide to treat hyperphosphatemia in dialysis patients. Drugs R D 13:165–173. CrossRefPubMedPubMedCentralGoogle Scholar
  273. 273.
    Janssens GO, Rademakers SE, Terhaard CH et al (2012) Accelerated radiotherapy with carbogen and nicotinamide for laryngeal cancer: results of a phase III randomized trial. J Clin Oncol 30:1777–1783. CrossRefPubMedGoogle Scholar
  274. 274.
    Starr P (2015) Oral nicotinamide prevents common skin cancers in high-risk patients, reduces costs. Am Health Drug Benefits 8:13–14PubMedPubMedCentralGoogle Scholar
  275. 275.
    Jonas WB, Rapoza CP, Blair WF (1996) The effect of niacinamide on osteoarthritis: a pilot study. Inflamm Res 45:330–334. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Centre of Reproduction, Development and Aging, Faculty of Health SciencesUniversity of MacauTaipaChina
  2. 2.Bioimaging and Stem Cell Core Facility, Faculty of Health SciencesUniversity of MacauTaipaChina
  3. 3.Institute of Translational Medicine, Faculty of Health SciencesUniversity of MacauTaipaChina

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