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Modulation of Oxidative Stress Responses by Vitamin E, or Vitamin A plus Vitamin C Treatment in Human Retinal Pigment Epithelial Cells

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DOI: 10.4236/ns.2015.712056    4,447 Downloads   4,822 Views   Citations


The purpose of this study was to characterize the potential of vitamins to protect the retinal pig-ment epithelium (RPE) from oxidative stress (OS). We have previously shown that OS induces the expression of AP1 transcription factors (FOSB, CFOS and ATF3), but is modulated by pretreatment with vitamin C (200 μM). We propose that OS-induced AP1 expression can be used as a biomarker of OS to test the efficacy of vitamins to limit the impact of OS in the RPE. Here we examined the efficacy of vitamin E or combined vitamin A plus vitamin C to modulate OS-induced AP1 expression in the RPE. We pretreated human ARPE-19 cells with vitamin E (0 - 7.5 μM) or with combined vitamin A (10 or 15 μM) plus vitamin C (50 or 100 μM) for 3 days prior to exposure to 500 μM H2O2 OS for 1 - 4 h. AP1 expression was assessed using qRT-PCR. Pretreatment with ≥2.5 μM vitamin E significantly decreased OS-induced AP1 expression at 1 - 4 h OS, compared to controls. Lower doses of vitamin E were ineffective at modulating OS responses. Pretreatment with 100 μM vitamin C combined with 15 μM vitamin A protected RPE cells from OS-induced AP1 expression. There is an additive and potentially protective effect of 100 μM vitamin C and 15 μM vitamin A on FOSB expression at 4 h, and a potentially protective effect of 100 μM vitamin C and 15 μM vitamin A on CFOS expression at 1 h OS. A protective effect was also seen with 15 μM vitamin A pretreatment alone on ATF3 expression. Thus, “sub-therapeutic” levels of multiple vitamins may protect RPE cells better than higher doses of a single vitamin. This OS-induced AP1 expression biomarker assay may be useful to identify complex antioxidant formulations as therapeutics for degenerative diseases that are thought to be caused by OS, like age-related macular degeneration.

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The authors declare no conflicts of interest.

Cite this paper

Yin, J. , Winborn, C. , Thomas, F. , Tran, Q. , Lang, J. and Chaum, E. (2015) Modulation of Oxidative Stress Responses by Vitamin E, or Vitamin A plus Vitamin C Treatment in Human Retinal Pigment Epithelial Cells. Natural Science, 7, 558-570. doi: 10.4236/ns.2015.712056.


[1] Halliwell, B., Hu, M.L., Louie, S., Duvall, T.R., Tarkington, B.K., Motchnik, P. and Cross, C.E. (1992) Interaction of Nitrogen Dioxide with Human Plasma. Antioxidant Depletion and Oxidative Damage. FEBS Letters, 313, 62-66.
[2] Winkler, B.S., Boulton, M.E., Gottsch, J.D. and Sternberg, P. (1999) Oxidative Damage and Age-Related Macular Degeneration. Molecular Vision, 5, 32-59.
[3] Jarrett, S.G. and Boulton, M.E. (2012) Consequences of Oxidative Stress in Age-Related Macular Degeneration. Molecular Aspects of Medicine, 33, 399-417.
[4] Tokarz, P., Kaarniranta, K. and Blasiak, J. (2013) Role of Antioxidant Enzymes and Small Molecular Weight Antioxidants in the Pathogenes Is of Age-Related Macular Degeneration (AMD). Biogerontology, 14, 461-482.
[5] Age-Related Eye Disease Study Research Group (2001) A Randomized, Placebo-Controlled, Clinical Trial of High- Dose Supplementation with Vitamins C and E, Beta Carotene, and Zinc for Age-Related Macular Degeneration and Vision Loss: AREDS Report No. 8. Archives of Ophthalmology, 119, 1417-1436.
[6] Age-Related Eye Disease Study Research Group, SanGio-vanni, J.P., Chew, E.Y., Clemons, T.E., Ferris 3rd, F.L., Gensler, G., Lindblad, A.S., Milton, R.C., Seddon, J.M. and Sperduto, R.D. (2007) The Relationship of Dietary Carotenoid and Vitamin A, E, and C Intake with Age-Related Mac-ular Degeneration in a Case-Control Study: AREDS Report No. 22. Archives of Ophthalmology, 125, 1225-1232.
[7] Amann, P.M., Eichmuller, S.B., Schmidt, J. and Bazhin, A.V. (2011) Regulation of Gene Expression by Retin-oids. Current Medicinal Chemistry, 18, 1405-1412.
[8] Dawson, M.I. and Xia, Z. (2012) The Retinoid X Receptors and Their Ligands. Biochimica et Biophysica Acta, 1821, 21-56.
[9] Salbert, G., Fanjul, A., Piedrafita, F.J., Lu, X.P., Kim, S.J., Tran, P. and Pfahl, M. (1993) Retinoic Acid Receptors and Retinoid X Receptor-Alpha Down-Regulate the Transforming Growth Factor-Beta 1 Promoter by Antagonizing AP-1 Activity. Molecular Endocrinology, 7, 1347-1356.
[10] Pfahl, M. and Piedrafita, F.J. (2003) Retinoid Targets for Apoptosis Induction. Oncogene, 22, 9058-9062.
[11] Abate, C., Patel, L., Rauscher 3rd, F.J. and Curran, T. (1990) Redox Regulation of Fos and Jun DNA-Binding Activity in Vitro. Science, 249, 1157-1161.
[12] Benkoussa, M., Brand, C., Delmotte, M.H., Formstecher, P. and Lefebvre, P. (2002) Retinoic Acid Receptors Inhibit AP1 Activation by Regulating Extracellular Signal-Regulated Kinase and CBP Recruitment to an AP1-Responsive Promoter. Molecular and Cellular Biology, 22, 4522-4534.
[13] Froeschle, A., Carnac, G., Alric, S., Montarras, D., Pinset, C., Rochette-Egly, C. and Bonnieu, A. (1996) RXR Alpha Is Essential for Mediating the All-Trans Retinoic Acid-Induced Growth Arrest of C2 Myogenic Cells. Oncogene, 12, 411-421.
[14] Ding, Y., Qiao, A., Wang, Z., Goodwin, J.S., Lee, E.S., Block, M.L., Allsbrook, M., McDonald, M.P. and Fan, G.H. (2008) Retinoic Acid Attenuates Beta-Amyloid Deposition and Rescues Memory Deficits in an Alzheimer’s Disease Transgenic Mouse Model. The Journal of Neuroscience, 28, 11622-11634.
[15] Maden, M. (2007) Retinoic Acid in the Development, Regeneration and Maintenance of the Nervous System. Nature Reviews Neuroscience, 8, 755-765.
[16] Malaspina, A. and Michael-Titus, A.T. (2008) Is the Modulation of Ret-inoid and Retinoid-Associated Signaling a Future Therapeutic Strategy in Neurological Trauma and Neurodegeneration? Journal of Neurochemistry, 104, 584-595.
[17] Chang, H.J., Park, J.S., Lee, E.K., Kim, M.H., Baek, M.K., Kim, H.R., Jeong, H.G., Choi, S.Y. and Jung, Y.D. (2009) Ascorbic Acid Suppresses the 2,3,7,8-Tetrachloridibenxo-p-Dioxin (TCDD)-Induced CYP1A1 Expression in Human HepG2 Cells. Toxicology in Vitro, 23, 622-626.
[18] Duarte, T.L. and Lunec, J. (2005) Review: When Is an Antioxidant Not an Antioxidant? A Review of Novel Actions and Reactions of Vitamin C. Free Radical Research, 39, 671-686.
[19] May, J.M. (1999) Is Ascorbic Acid an Antioxidant for the Plasma Membrane? The FASEB Journal, 13, 995-1006.
[20] Lane, D.J. and Lawen, A. (2009) Ascorbate and Plasma Membrane Electron Transport—Enzymes vs Efflux. Free Radical Biology and Medicine, 47, 485-495.
[21] Thompson, D.A. and Gal, A. (2003) Vitamin A Metabolism in the Retinal Pigment Epithelium: Genes, Mutations, and Diseases. Progress in Retinal and Eye Research, 22, 683-703.
[22] Azzi, A. (2004) The Role of Al-pha-Tocopherol in Preventing Disease. European Journal of Nutrition, 43, I/18-25.
[23] Azzi, A., Ricciarelli, R. and Zingg, J.M. (2002) Non-Antioxidant Molecular Functions of Alpha-Tocopherol (Vitamin E). FEBS Letters, 519, 8-10.
[24] Burton, G.W. and Ingold, K.U. (1989) Vitamin E as an in Vitro and in Vivo Antioxidant. Annals of the New York Academy of Sciences, 570, 7-22.
[25] Traber, M.G. (2007) Vitamin E Regulatory Mecha-nisms. Annual Review of Nutrition, 27, 347-362.
[26] Yamauchi, J., Iwamoto, T., Kida, S., Masushige, S., Yamada, K. and Esashi, T. (2001) Tocopherol-Associated Protein Is a Ligand-Dependent Transcriptional Activator. Biochemical and Biophysical Research Communications, 285, 295-299.
[27] Darwiche, N., Bazzi, H., El-Touni, L., Abou-Lteif, G., Doueiri, R., Hatoum, A., Maalouf, S. and Gali-Muhtasib, H. (2005) Regulation of Ultraviolet B Radiation-Mediated Activation of AP1 Signaling by Retinoids in Primary Keratinocytes. Radiation Research, 163, 296-306.
[28] Kagan, D.B., Liu, H. and Hutnik, C.M. (2012) Efficacy of Various Anti-oxidants in the Protection of the Retinal Pigment Epithelium from Oxidative Stress. Clinical Ophthalmology, 6, 1471-1476.
[29] Rozanowska, M., Bakker, L., Boulton, M.E. and Rozanowski, B. (2012) Concentration Dependence of Vitamin C in Combinations with Vitamin E and Zeaxanthin on Light-Induced Toxicity to Retinal Pigment Epithelial Cells. Photochemistry and Photobiology, 88, 1408-1417.
[30] Loke, W.M., Proudfoot, J.M., McKinley, A.J. and Croft, K.D. (2006) Augmentation of Monocyte Intracellular Ascorbate in Vitro Protects Cells from Oxidative Damage and Inflammatory Responses. Biochemical and Biophysical Research Communications, 345, 1039-1043.
[31] Chen, J.Y., Penco, S., Ostrowski, J., Balaguer, P., Pons, M Starrett, J.E., Reczek, P., Chambon, P. and Gronemeyer, H. (2006) RAR-Specific Agonist/Antagonists Which Dissociate Transactivation and AP1 Transrepression Inhibit Anchorage-Independent Cell Proliferation. The EMBO Journal, 14, 1187-1197.
[32] Dedieu, S. and Lefebvre, P. (2006) Retinoids Interfere with the AP1 Signalling Pathway in Human Breast Cancer Cells. Cellular Signalling, 18, 889-898.
[33] Amstad, P.A., Krupitza, G. and Cerutti, P.A. (1992) Mecha-nism of c-Fos induction by Active Oxygen. Cancer Research, 52, 3952-3960.
[34] Devary, Y., Gottlieb, R.A., Lau, L.F. and Karin, M. (1991) Rapid and Preferential Activation of the c-Jun Gene during the Mammalian UV Response. Molecular and Cellular Biology, 11, 2804-2811.
[35] Geller, S.F. and Stone, J. (2003) Quantitative PCR Analysis of FosB mRNA Expression after Short Duration Oxygen and Light Stress. Advances in Experimental Medicine and Biology, 533, 249-257.
[36] Karin, M. (1995) The Regulation of AP-1 Activity by Mitogen-Activated Protein Kinases. The Journal of Biological Chemistry, 270, 16483-16486.
[37] Morris, B.J. (1995) Stimulation of Immediate Early Gene Ex-pression in Striatal Neurons by Nitric Oxide. The Journal of Biological Chemistry, 270, 24740-24744.
[38] Cavigelli, M., Li, W.W., Lin, A., Su, B., Yoshioka, K. and Karin, M. (1996) The Tumor Promoter Arsenite Stimulates AP-1 Activity by Inhibiting a JNK Phosphatase. The EMBO Journal, 15, 6269-6279.
[39] Karin, M. and Shaulian, E. (2001) AP-1: Linking Hydrogen Peroxide and Oxidative Stress to the Control of Cell Proliferation and Death. IUBMB Life, 52, 17-24.
[40] Lallemand, D., Spyrou, G., Yaniv, M. and Pfarr, C.M. (1997) Variations in Jun and Fos Protein Expression and AP-1 Activity in Cycling, Resting and Stimulated Fibroblasts. Oncogene, 14, 819-830.
[41] Morgan, J.I. and Curran, T. (1991) Stimulus-Transcription Coupling in the Nervous System: Involvement of the Inducible Proto-Oncogenes Fos and Jun. Annual Review of Neuroscience, 14, 421-451.
[42] Xanthoudakis, S. and Curran, T. (1992) Identification and Characterization of Ref-1, a Nuclear Protein That Facilitates AP-1 DNA-Binding Activity. The EMBO Journal, 11, 653-665.
[43] Zhou, L.Z., Johnson, A.P. and Rando, T.A. (2001) NF Kappa B and AP-1 Mediate Transcriptional Responses to Oxidative Stress in Skeletal Muscle Cells. Free Radical Biology & Medicine, 31, 1405-1416.
[44] Shaulian, E. and Karin, M. (2002) AP-1 as a Regulator of Cell Life and Death. Nature Cell Biology, 4, E131-E136.
[45] Shaulian, E. and Karin, M. (2001) AP-1 in Cell Proliferation and Survival. Oncogene, 20, 2390-2400.
[46] Chaum, E., Yin, J., Yang, H., Thomas, F. and Lang, J.C. (2009) Quantitative AP-1 Gene Regulation by Oxidative Stress in the Human Retinal Pigment Epithelium. Journal of Cellular Biochemistry, 108, 1280-1291.
[47] Yin, J., Thomas, F., Lang, J.C. and Chaum, E. (2011) Modulation of Oxidative Stress Responses in the Human Retinal Pigment Epithelium Following Treatment with Vitamin C. Journal of Cellular Physiology, 226, 2025-2032.
[48] Yang, H., Yang, X., Lang, J.C. and Chaum, E. (2006) Tissue Culture Methods Can Strongly Induce Immediate Early Gene Expression in Retinal Pigment Epithelial Cells. Journal of Cellular Biochemistry, 98, 1560-1569.
[49] Gao, S., Qin, T., Liu, Z., Caceres, M.A., Ronchi, C.F., Chen, C.Y., Yeum, K.J., Taylor, A., Blumberg, J.B., Liu, Y. and Shang, F. (2011) Lutein and Zeaxanthin Supplementation Reduces H2O2-Induced Oxidative Damage in Human Lens Epithelial Cells. Molecular Vision, 17, 3180-3190.
[50] Hothorn, T., Bretz, F. and Westfall, P. (2008) Simultaneous Inference in General Parametric Models. Biometrical Journal, 50, 346-363.
[51] Van Belle, G., Fisher, L.D., Heagerty, P.J. and Lumley, T. (2004) Biostatistics: A Methodology for the Health Sciences. Wiley, Hoboken.
[52] Kunter, M., Nachtsheim, C., Neter, J. and Li, W. (2005) Applied Linear Statistical Models. McGraw-Hill/Irvin, Boston.
[53] Montgomery, D.C. (2001) Design and Analysis of Experiments. Wiley, Hoboken.
[54] Chew, E.Y., Clemons, T.E., Agron, E., Sperduto, R.D., Sangiovanni, J.P., Kurinij, N. and Davis, M.D., Age-Related Eye Disease Study Research Group (2013) Long-Term Effects of Vitamins C and E, Beta-Carotene, and Zinc on Age-Related Macular Degeneration: AREDS Report No. 35. Ophthalmology, 120, 1604.e4-1611.e4.
[55] Kagan, V.E., Serbinova, E.A., Forte, T., Scita, G. and Packer, L. (1992) Recycling of Vitamin E in Human Low Density Lipoproteins. The Journal of Lipid Research, 33, 385-397.
[56] Niki, E. (1987) Interaction of Ascorbate and Alpha-Tocopherol. Annals of the New York Academy of Sciences, 498, 186-199.
[57] Niki, E., Saito, T., Kawakami, A. and Kamiya, Y. (1984) Inhibition of Oxidation of Methyl Linoleate in Solution by Vitamin E and Vitamin C. The Journal of Biological Chemistry, 259, 4177-4182.
[58] Ford, E.S., Schleicher, R.L., Mokdad, A.H., Ajani, U.A. and Liu, S. (2006) Distribution of Serum Concentrations of α-Tocopherol and γ-Tocopherol in the US Population. The American Journal of Clinical Nutrition, 84, 375-383.
[59] Hosomi, A., Goto, K., Kondo, H., Iwatsubo, T., Yokota, T., Ogawa, M., Arita, M., Aoki, J., Arai, H. and Inoue K. (1998) Localization of Alpha-Tocopherol Transfer Protein in Rat Brain. Neuroscience Letters, 256, 159-162.
[60] Morley, S., Cecchini, M., Zhang, W., Virgulti, A., Noy, N., Atkinson, J. and Manor, D. (2008) Mechanisms of Ligand Transfer by the Hepatic Tocopherol Transfer Protein. The Journal of Biological Chemistry, 283, 17797-17804.
[61] Shichiri, M., Takanezawa, Y., Rotzoll, D.E., Yoshida, Y., Kokubu, T., Ueda, K., Tamai, H. and Arai, H. (2010) ATP-Binding Cassette Transporter A1 Is Involved in Hepatic Alpha-Tocopherol Secretion. The Journal of Nutritional Biochemistry, 21, 451-456.
[62] Thakur, V., Morley, S. and Manor, D. (2010) Hepatic Alpha-Tocopherol Transfer Protein: Ligand-Induced Protection from Proteasomal Degradation. Biochemistry, 49, 9339-9344.
[63] Ouahchi, K., Arita, M., Kayden, H., Hentati, F., Ben Hamida, M., Sokol, R., Arai, H., Inoue, K., Mandel, J.L. and Koenig, M. (1995) Ataxia with Isolated Vitamin E Deficiency Is Caused by Mutations in the Alpha-Tocopherol Transfer Protein. Nature Genetics, 9, 141-145.
[64] Yokota, T., Igarashi, K., Uchihara, T., Jishage, K., Tomita, H., Inaba, A., Li, Y., Arita, M., Suzuki, H., Mizusawa, H. and Aria, H. (2001) Delayed-Onset Ataxia in Mice Lacking Alpha-Tocopherol Transfer Protein: Model for Neuronal Degeneration Caused by Chronic Oxidative Stress. Proceedings of the National Academy of Sciences of the United States of America, 98, 15185-15190.
[65] Yokota, T., Shiojiri, T., Gotoda, T. and Arai, H. (1996) Retinitis Pigmentosa and Ataxia Caused by a Mutation in the Gene for the Alpha-Tocopherol-Transfer Protein. The New England Journal of Medicine, 335, 1770-1771.
[66] Yokota, T., Uchihara, T., Kumagai, J., Shiojiri, T., Pang, J.J., Arita, M., Arai, H., Hayashi, M., Kiyosawa, M., Okeda, R. and Mizusawa, H. (2000) Postmortem Study of Ataxia with Retinitis Pigmentosa by Mutation of the Alpha-Tocopherol Transfer Protein Gene. Journal of Neurology, Neurosurgery & Psychiatry, 68, 521-525.
[67] Tanito, M., Yoshida, Y., Kaidzu, S., Chen, Z.H., Cynshi, O., Jishage, K., Niki, E. and Ohira, A. (2007) Acceleration of Age-Related Changes in the Retina in Alpha-Tocopherol Transfer Protein Null Mice Fed a Vitamin E-Deficient Diet. Investigative Ophthalmology & Visual Science, 48, 396-404.
[68] Robison Jr., W.G., Kuwabara, T. and Bieri, J.G. (1979) Vitamin E Deficiency and the Retina: Photoreceptor and Pigment Epithelial Changes. Investigative Ophthalmology & Visual Science, 18, 683-690.
[69] Robison Jr., W.G., Kuwabara, T. and Bieri, J.G. (1980) Deficiencies of Vitamins E and A in the Rat. Retinal Damage and Lipofuscin Accumulation. Investigative Ophthalmology & Visual Science, 19, 1030-1037.
[70] Etzl, R.P., Vrekoussis, T., Kuhn, C., Schulze, S., Poschl, J.M., Makrigiannakis, A., Jeschke, U. and Rotzoll, D.E. (2012) Oxidative Stress Stimulates Alpha-Tocopherol Transfer Protein in Human Trophoblast Tumor Cells BeWo. Journal of Perinatal Medicine, 40, 373-378.
[71] Ulatowski, L., Dreussi, C., Noy, N., Barnholtz-Sloan, J., Klein, E. and Manor, D. (2012) Expression of the Alpha-Tocopherol Transfer Protein Gene Is Regulated by Oxidative Stress and Common Single-Nucleotide Polymorphisms. Free Radical Biology & Medicine, 53, 2318-2326.
[72] Titchenell, P.M., Lin, C.M., Keil, J.M., Sundstrom, J.M., Smith, C.D. and Antonetti, D.A. (2012) Novel Atypical PKC Inhibitors Prevent Vascular Endothelial Growth Factor-Induced Blood-Retinal Barrier Dysfunction. Biochemical Journal, 446, 455-467.
[73] Azzi, A., Breyer, I., Feher, M., Ricciarelli, R., Stocker, A., Zimmer, S. and Zingg, J. (2001) Nonantioxidant Functions of Alpha-Tocopherol in Smooth Muscle Cells. Journal of Nutrition, 131, 378S-381S.
[74] Ricciarelli, R., Tasinato, A., Clement, S., Ozer, N.K., Boscoboinik, D. and Azzi, A. (1998) Alpha-Tocopherol Specifically Inactivates Cellular Protein Kinase C Alpha by Changing Its Phosphorylation State. Biochemical Journal, 334, 243-249.
[75] Azzi, A., Boscoboinik, D., Clement, S., Ozer, N., Ricciarelli, R. and Stocker, A. (1999) Vitamin E Mediated Response of Smooth Muscle Cell to Oxidant Stress. Diabetes Research and Clinical Practice, 45, 191-198.
[76] Feng, Z., Liu, Z., Li, X., Jia, H., Sun, L., Tian, C., Jia, L. and Liu, J. (2010) Alpha-Tocopherol Is an Effective Phase II Enzyme Inducer: Protective Effects on Acrolein-Induced Oxidative Stress and Mitochondrial Dysfunction in Human Retinal Pigment Epithelial Cells. The Journal of Nutritional Biochemistry, 21, 1222-1231.
[77] Niture, S.K., Khatri, R. and Jaiswal, A.K. (2013) Regulation of Nrf2—An Update. Free Radical Biology & Medicine, 66, 36-44.
[78] Maziere, C., Conte, M.A., Degonville, J., Ali, D. and Maziere, J.C. (1999) Cellular Enrichment with Polyunsaturated Fatty Acids Induces an Oxidative Stress And activates the Transcription Factors AP1 and NFkappaB. Biochemical and Biophysical Research Communications, 265, 116-122.
[79] Catani, M.V., Rossi, A., Costanzo, A., Sabatini, S., Levrero, M., Melino, G. and Avigliano, L. (2001) Induction of Gene Expression via Activator Protein-1 in the Ascorbate Protection against UV-Induced Damage. Biochemical Journal, 356, 77-85.
[80] Hoshikawa, Y., Kanki, K., Ashla, A.A., Arakaki, Y., Azumi, J., Yasui, T., Tezuka, Y., Matsumi, Y., Tsuchiya, H., Kurimasa, A., Hisatome, I., Hirano, T., Fujimoto, J., Kagechika, H., Shomori, K., Ito, H. and Shiota, G. (2011) c-Jun N-Terminal Kinase Activation by Oxidative Stress Suppresses Retinoid Signaling through Proteasomal Degradation of Retinoic Acid Receptor Alpha Protein in Hepatic Cells. Cancer Science, 102, 934-941.
[81] Mehta, K. (2003) Retinoids as Regulators of Gene Transcription. Journal of Biological Regulators & Homeostatic Agents, 17, 1-12.
[82] Rohrdanz, E. and Kahl, R. (1998) Alterations of Antioxidant Enzyme Expression in Response to Hydrogen Peroxide. Free Radical Biology & Medicine, 24, 27-38.
[83] Tate Jr., D.J., Miceli, M.V. and Newsome, D.A. (1995) Phagocytosis and H2O2 Induce Catalase and Metallothionein Gene Expression in Human Retinal Pigment Epithelial Cells. Investigative Ophthalmology & Visual Science, 36, 1271- 1279.
[84] Palczewski, K. (2010) Retinoids for Treatment of Retinal Diseases. Trends in Pharmacological Sciences, 31, 284-295.
[85] Sharoni, Y., Danilenko, M., Dubi, N., Ben-Dor, A. and Levy, J. (2004) Carotenoids and Transcription. Archives of Biochemistry and Biophysics, 430, 89-96.
[86] DiSepio, D., Sutter, M., Johnson, A.T., Chandraratna, R.A. and Nagpal, S. (1999) Identification of the AP1-Antagon- ism Domain of Retinoic Acid Receptors. Molecular Cell Biology Research Communications, 1, 7-13.
[87] Schule, R., Rangarajan, P., Yang, N., Kliewer, S., Ransone, L.J., Bolado, J., Verma, I.M. and Evans, R.M. (1991) Retinoic Acid Is a Negative Regulator of AP-1-Responsive Genes. Proceedings of the National Academy of Sciences of the United States of America, 88, 6092-6096.
[88] Zhou, X.F., Shen, X.Q. and Shemshedini, L. (1999) Ligand-Activated Retinoic Acid Receptor Inhibits AP-1 Transactivation by Disrupting c-Jun/c-Fos Dimerization. Molecular Endocrinology, 13, 276-285.
[89] Du, Y.H., Hirooka, K., Miyamoto, O., Bao, Y.Q., Zhang, B, An, J.B. and Ma, J.X. (2013) Retinoic Acid Suppresses the Adhesion and Migration of Human Retinal Pigment Epithelial Cells. Experimental Eye Research, 109, 22-30.
[90] Dutta, A., Sen, T. and Chatterjee, A. (2010) All-Trans Retinoic Acid (ATRA) Downregulates MMP-9 by Modulating Its Regulatory Molecules. Cell Adhesion & Migration, 4, 409-418.
[91] Diaz, B.V., Lenoir, M.C., Ladoux, A., Frelin, C., Demarchez, M. and Michel, S. (2000) Regulation of Vascular Endothelial Growth Factor Expression in Human Keratinocytes by Retinoids. The Journal of Biological Chemistry, 275, 642-650.
[92] Perusek, L. and Maeda, T. (2013) Vitamin A Derivatives as Treatment Options for Retinal Degenerative Diseases. Nutrients, 5, 2646-2666.
[93] Harrison, E.H. (2012) Mechanisms Involved in the Intestinal Absorption of Dietary Vitamin A and Provitamin A Carotenoids. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids, 1821, 70-77.
[94] von Lintig, J. (2012) Provitamin A Metabolism and Functions in Mammalian Biology. The American Journal of Clinical Nutrition, 96, 1234S-1244S.

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