NeuroMolecular Medicine

, Volume 19, Issue 2–3, pp 436–451 | Cite as

Combination of EPA with Carotenoids and Polyphenol Synergistically Attenuated the Transformation of Microglia to M1 Phenotype Via Inhibition of NF-κB

  • Nurit Hadad
  • Rachel LevyEmail author
Original Paper


Microglia activation toward the M1 phenotype has been reported to contribute to the neurodegenerative processes and cognition alterations due to the release of pro-inflammatory mediators and cytokines. The aim of the present research was to assess the effectiveness of free fatty acids omega-3 preparations: eicosapentaenoic acid (EPA) or/and docosahexaenoic acid (DHA), carotenoids and phenolics combinations, in inhibiting the release of inflammatory mediators from activated microglia. Preincubation of BV-2 microglia cells with each of the FFAs omega-3 preparations in a range of 0.03–2 μM together with Lyc-O-mato® (0.1 μM), Carnosic acid (0.2 μM) with or without Lutein (0.2 μM), 1 h before addition of lipopolysaccharide (LPS) for 16 h caused a synergistic inhibition of nitric oxide (NO) production with a rank order of EPA > Ropufa (EPA/DHA 2/1) > Krill (EPA/DHA 1.23/1). The optimal inhibitory combinations of EPA (0.125 μM) with the phytonutrients caused a synergistic inhibition of prostaglandin E2 (PGE2) release, IL-6 secretion, superoxide and NO production and prevention of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) upregulation and elevated CD40 expression in microglia exposed to LPS or interferon-γ (IFN-γ), representing infection or inflammation, respectively. The presence of the combination caused a synergistic increase in the release of the anti-inflammatory cytokine IL-10. The inhibitory effects by the combinations of EPA with the phytonutrients were mediated by the inhibition of the redox-sensitive NF-κB activation and detected by its phosphorylated p-65 on serine 536 in microglia stimulated by either LPS or IFN-γ. In addition, phosphorylated CREB on serine 133 which was shown to be involved in the induction of iNOS was inhibited by the combinations in stimulated cells. In conclusion, the results suggest that low concentrations of EPA with the phytonutrients are very efficient in inhibiting the transformation of microglia to M1 phenotype and may prevent cognition deficit.


Microglia EPA Lycopene NOX2-NADPH oxidase Pro-inflammatory mediators Carnosic acid Lutein NF-κB 



This work was supported in part by a grant from Lycored Ltd. Beer-Sheva, Israel. Lycored Ltd. did not have any role in the performance of the experiments or in the analysis and interpretation of the data presented in this paper. We thank Dr. Sergio Lamprecht for assistance in editing the English text.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no competing interests.


  1. Anderle, P., Farmer, P., Berger, A., & Roberts, M. A. (2004). Nutrigenomic approach to understanding the mechanisms by which dietary long-chain fatty acids induce gene signals and control mechanisms involved in carcinogenesis. Nutrition, 20, 103–108.CrossRefPubMedGoogle Scholar
  2. Arun, P., Brown, M., Ehsanian, R., Chen, Z., & Waes, C. V. (2009). Nuclear NF-κB p65 phosphorylation at serine 276 by protein kinase A contributes to the malignant phenotype of head and neck cancer. Clinical Cancer Research, 15(19), 5974–5984.CrossRefPubMedPubMedCentralGoogle Scholar
  3. Aruoma, O., Halliwell, B., Aeschbach, R., & Loligers, J. (1992). Antioxidant and pro-oxidant properties of active rosemary constituents: Carnosol and carnosic acid. Xenobiotica, 22, 257–268.CrossRefPubMedGoogle Scholar
  4. Azad, N., Rasoolijazi, H., Joghataie, M. T., & Soleimani, S. (2011). Neuroprotective effects of carnosic acid in an experimental model of Alzheimer’s disease in rats. Cell Journal, 13, 39–44.PubMedPubMedCentralGoogle Scholar
  5. Barnham, K., Masters, C., & Bush, A. (2004). Neurodegenerative diseases and oxidative stress. Nature Reviews Drug Discovery, 3, 205–214.CrossRefPubMedGoogle Scholar
  6. Bozic, I., Savic, D., Laketa, D., Bjelobaba, I., Milenkovic, I., Pekovic, S., et al. (2015). Benfotiamine attenuates inflammatory response in LPS stimulated BV-2 microglia. PLoS ONE, 10, 118372–118395.Google Scholar
  7. Britton, G. (1995). Structure and properties of carotenoids in relation to function. The FASEB Journal, 9, 1551–1558.PubMedGoogle Scholar
  8. Calder, P. C. (2012a). Long-chain fatty acids and inflammation. Proceedings of the Nutrition Society, 71(2), 284–289.CrossRefPubMedGoogle Scholar
  9. Calder, P. C. (2012b). Mechanisms of action of (n-3) fatty acids. Journal of Nutrition, 142, 592S–599S.CrossRefPubMedGoogle Scholar
  10. Chen, K., Huang, J., Gong, W., Zhang, L., Yu, P., & Wang, J. M. (2006). CD40/CD40L dyad in the inflammatory and immune responses in the central nervous system. Cellular & Molecular Immunology, 3(3), 163–169.Google Scholar
  11. Chu, A. J., Walton, M. A., Prasad, J. K., & Seto, A. (1999). Blockade by polyunsaturated n-3 fatty acids of endotoxin-induced monocytic tissue factor activation is mediated by the depressed receptor expression in THP-1 cells. Journal of Surgical Research, 87, 217–224.CrossRefPubMedGoogle Scholar
  12. Chuang, D. Y., Simonyi, A., Kotzbauer, P. T., Gu, Z., & Sun, G. Y. (2015). Cytosolic phospholipase A2 plays a crucial role in ROS/NO signaling during microglial activation through the lipoxygenase pathway. Journal of Neuroinflammation, 12, 199.CrossRefPubMedPubMedCentralGoogle Scholar
  13. Cianciulli, A., Salvatore, R., Porro, C., Trotta, T., & Panaro, M. A. (2016). Folic acid is able to polarize the inflammatory response in LPS activated microglia by regulating multiple signaling pathways. Mediators of Inflammation, 2016, 5240127.CrossRefPubMedPubMedCentralGoogle Scholar
  14. Clinton, S. (1998). Lycopene: Chemistry, biology, and implications for human health and disease. Nutrition Reviews, 56, 35–51.CrossRefPubMedGoogle Scholar
  15. Colton, C., & Wilcock, D. M. (2010). Assessing activation states in microglia. CNS & Neurological Disorders: Drug Targets, 9, 174–191.CrossRefGoogle Scholar
  16. Conquer, J. A., Tierney, M. C., Zecevic, J., Bettger, W. J., & Fisher, R. H. (2000). Fatty acid analysis of blood plasma of patients with Alzheimer’s disease, other types of dementia, and cognitive impairment. Lipids, 35(12), 1305–1312.CrossRefPubMedGoogle Scholar
  17. Corsi, L., Dongmo, B. M., & Avallone, R. (2015). Supplementation of omega 3 fatty acids improves oxidative stress in activated BV2 microglial cell line. International Journal of Food Sciences and Nutrition, 66, 293–299.CrossRefPubMedGoogle Scholar
  18. da Silva, T. M., Munhoz, R. P., Alvarez, C., Naliwaiko, K., Kiss, A., Andreatini, R., et al. (2008). Depression in Parkinson’s disease: A double-blind, randomized, placebo-controlled pilot study of omega-3 fatty-acid supplementation. Journal of Affective Disorders, 111, 351–359.CrossRefPubMedGoogle Scholar
  19. Doolaege, E. H., Raes, K., De Vos, F., Verhe, R., & De Smet, S. (2011). Absorption, distribution and elimination of carnosic acid, a natural antioxidant from Rosmarinus officinalis, in rats. Plant Foods for Human Nutrition, 66, 196–202.CrossRefPubMedGoogle Scholar
  20. Dyall, S. C. (2015). Long-chain omega-3 fatty acids and the brain: A review of the independent and shared effects of EPA, DPA and DHA. Front Aging Neurosci, 7, 52–67.CrossRefPubMedPubMedCentralGoogle Scholar
  21. Eilander, A., Hundscheid, D. C., Osendarp, S. J., Transler, C., & Zock, P. L. (2007). Effects of n-3 long chain polyunsaturated fatty acid supplementation on visual and cognitive development throughout childhood: A review of human studies. Prostaglandins Leukotrienes and Essential Fatty Acids, 76, 189–203.CrossRefGoogle Scholar
  22. Feart, C., Peuchant, E., Letenneur, L., Samieri, C., Montagnier, D., Fourrier-Reglat, A., et al. (2008). Plasma eicosapentaenoic acid is inversely associated with severity of depressive symptomatology in the elderly: Data from the Bordeaux sample of the Three-City Study. American Journal of Clinical Nutrition, 87, 1156–1162.PubMedGoogle Scholar
  23. Garcia-Alonso, F. J., Jorge-Vidal, V., Ros, G., & Periago, M. J. (2012). Effect of consumption of tomato juice enriched with n-3 polyunsaturated fatty acids on the lipid profile, antioxidant biomarker status, and cardiovascular disease risk in healthy women. European Journal of Nutrition, 51, 415–424.CrossRefPubMedGoogle Scholar
  24. Hadad, N., & Levy, R. (2012). The synergistic anti-inflammatory effects of lycopene, lutein, β-carotene, and carnosic acid combinations via redox-based inhibition of NF-κB signaling. Free Radical Biology and Medicine, 53(7), 1381–1391.CrossRefPubMedGoogle Scholar
  25. Hazan, I., Dana, R., Granot, Y., & Levy, R. (1997). Cytosolic phospholipase A2 and its mode of activation in human neutrophils by opsonized zymosan: Correlation between 42/44 kDa mitogen-activated protein kinase, cytosolic phospholipase A2 and NADPH oxidase. Biochemical Journal, 326, 867–876.CrossRefPubMedPubMedCentralGoogle Scholar
  26. Hazan-Eitan, Z., Weinstein, Y., Hadad, N., Konforty, A., & Levy, R. (2006). Induction of Fc gammaRIIA expression in myeloid PLB cells during differentiation depends on cytosolic phospholipase A2 activity and is regulated via activation of CREB by PGE2. Blood, 108, 1758–1766.CrossRefPubMedGoogle Scholar
  27. Hazan-Halevy, I., & Levy, R. (2000). Activation of cytosolic phospholipase A2 by opsonized zymosan in human neutrophils requires both ERK and p38 MAP-kinase. Advances in Experimental Medicine and Biology, 479, 115–123.CrossRefPubMedGoogle Scholar
  28. Itakura, H., Yokoyama, M., Matsuzaki, M., Saito, Y., Origasa, H., Ishikawa, Y., et al. (2011). Relationships between plasma fatty acid composition and coronary artery disease. Journal of Atherosclerosis and Thrombosis, 18, 99–107.CrossRefPubMedGoogle Scholar
  29. Jack, C., Ruffini, F., Bar-Or, A., & Antel, J. P. (2005). Microglia and multiple sclerosis. Journal of Neuroscience Research, 81, 363–373.CrossRefPubMedGoogle Scholar
  30. Johnson, E. J. (2014). Role of lutein and zeaxanthin in visual and cognitive function throughout the lifespan. Nutrition Reviews, 72, 605–612.CrossRefPubMedGoogle Scholar
  31. Kohman, R. A. (2012). Aging microglia: Relevance to cognition and neural plasticity. Methods in Molecular Biology, 934, 193–218.CrossRefPubMedGoogle Scholar
  32. Koscso, B., Csoka, B., Selmeczy, Z., Himer, L., Pacher, P., Virag, L., et al. (2012). Adenosine augments IL-10 production by microglial cells through an A2B adenosine receptor-mediated process. The Journal of Immunology, 188(1), 445–453.CrossRefPubMedGoogle Scholar
  33. Kucuk, O., Sarkar, F., Sakr, W., Djuric, Z., Pollak, M., Khachik, F., et al. (2001). Phase II randomized clinical trial of lycopene supplementation before radical prostatectomy. Cancer Epidemiology, Biomarkers and Prevention, 10, 861–868.PubMedGoogle Scholar
  34. Kurtys, E., Eisel, U. L., Verkuyl, J. M., Broersen, L. M., Dierckx, R. A., & de Vries, E. F. (2016). The combination of vitamins and omega-3 fatty acids has an enhanced anti-inflammatory effect on microglia. Neurochemistry International, 99, 206–214.CrossRefPubMedGoogle Scholar
  35. Lee, J. Y., Plakidas, A., Lee, W. H., Heikkinen, A., Chanmugam, P., Bray, G., et al. (2003a). Differential modulation of Toll-like receptors by fatty acids: Preferential inhibition by n-3 polyunsaturated fatty acids. Journal of Lipid Research, 44, 479–486.CrossRefPubMedGoogle Scholar
  36. Lee, A., Sung, S., Kim, Y., & Kim, S. (2003b). Inhibition of lipopolysaccharide-inducible nitric oxide synthase, TNF-α and COX-2 expression by sauchinone effects on I-κBα phosphorylation, C/EBP and AP-1 activation. British Journal of Pharmacology, 139, 11–20.CrossRefPubMedPubMedCentralGoogle Scholar
  37. Libermann, T. A., & Baltimore, D. (1990). Activation of interleukin-6 gene expression through the NF-κ B transcription factor. Molecular and Cellular Biology, 10, 2327–2334.CrossRefPubMedPubMedCentralGoogle Scholar
  38. Lin, P. Y., Chiu, C. C., Huang, S. Y., & Su, K. P. (2012). A meta-analytic review of polyunsaturated fatty acid compositions in dementia. Journal of Clinical Psychiatry, 73, 1245–1254.CrossRefPubMedGoogle Scholar
  39. Lin, H. Y., Huang, B. R., Yeh, W. L., Lee, C. H., Huang, S. S., Lai, C. H., et al. (2014). Antineuroinflammatory effects of lycopene via activation of adenosine monophosphate-activated protein kinase-α1/heme oxygenase-1 pathways. Neurobiology of Aging, 35, 191–202.CrossRefPubMedGoogle Scholar
  40. Lobo-Silva, D., Carriche, G. M., Castro, A. G., Roque, S., & Saraiva, M. (2016). Balancing the immune response in the brain: IL-10 and its regulation. Journal of Neuroinflammation, 13, 297–307.CrossRefPubMedPubMedCentralGoogle Scholar
  41. Luo, X. G., Ding, J. Q., & Chen, S. D. (2010). Microglia in the aging brain: Relevance to neurodegeneration. Molecular Neurodegeneration, 5, 12–21.CrossRefPubMedPubMedCentralGoogle Scholar
  42. Malada-Edelstein, Y. F., Hadad, N., & Levy, R. (2017). Regulatory role of cytosolic phospholipase A2 alpha in the induction of CD40 in microglia. Journal of Neuroinflammation, 14, 33–49.CrossRefPubMedPubMedCentralGoogle Scholar
  43. Mascio, P. D., Kaiser, S., & Sies, H. (1989). Lycopene as the most efficient biological carotenoid singlet oxygen quencher. Archives of Biochemistry and Biophysics, 274, 532–538.CrossRefPubMedGoogle Scholar
  44. Mazereeuw, G., Lanctot, K. L., Chau, S. A., Swardfager, W., & Herrmann, N. (2012). Effects of omega-3 fatty acids on cognitive performance: A meta-analysis. Neurobiology of Aging, 33(1482), e17–e1429.Google Scholar
  45. Mengoni, E., Vichera, G., Rigano, L., Rodriguez-Puebla, M., Galliano, S., Cafferata, E., et al. (2010). Suppression of COX-2, IL-1β and TNF-α expression and leukocyte infiltration in inflamed skin by bioactive compounds from Rosmarinus officinalis L. Fitoterapia, 82, 414–421.CrossRefPubMedGoogle Scholar
  46. Moon, D. O., Kim, K. C., Jin, C. Y., Han, M. H., Park, C., Lee, K. J., et al. (2007). Inhibitory effects of eicosapentaenoic acid on lipopolysaccharide-induced activation in BV2 microglia. International Immunopharmacology, 7, 222–229.CrossRefPubMedGoogle Scholar
  47. Nakanishi, A., & Tsukamoto, I. (2015). n-3 polyunsaturated fatty acids stimulate osteoclastogenesis through PPARγ-mediated enhancement of c-Fos expression, and suppress osteoclastogenesis through PPARγ-dependent inhibition of NFkB activation. Journal of Nutritional Biochemistry, 26, 1317–1327.CrossRefPubMedGoogle Scholar
  48. Nguyen, V. T., & Benveniste, E. N. (2002). Critical role of tumor necrosis factor-α and NF-κ B in interferon-γ-induced CD40 expression in microglia/macrophages. Journal of Biological Chemistry, 277, 13796–13803.CrossRefPubMedGoogle Scholar
  49. Offord, E., Mace, K., Ruffieux, C., Malnoe, A., & Pfeifer, A. (1995). Rosemary components inhibit benzo[a]pyrene-induced genotoxicity in human bronchial cells. Carcinogenesis, 16, 2057–2062.CrossRefPubMedGoogle Scholar
  50. Pantano, C., Reynaert, N., Vliet, A. V. D., & Janssen-Heininger, Y. (2006). Redox-sensitive kinases of the nuclear factor-κB signaling pathway. Antioxidants & Redox Signaling, 8, 1791–1806.CrossRefGoogle Scholar
  51. Parker, G., Gibson, N. A., Brotchie, H., Heruc, G., Rees, A. M., & Hadzi-Pavlovic, D. (2006). Omega-3 fatty acids and mood disorders. American Journal of Psychiatry, 163, 969–978.CrossRefPubMedGoogle Scholar
  52. Perry, V. H., Nicoll, J. A., & Holmes, C. (2010). Microglia in neurodegenerative disease. Nature Reviews Neurology, 6(4), 193–201.CrossRefPubMedGoogle Scholar
  53. Rafi, M., Yadav, P., & Reyes, M. (2007). Lycopene inhibits LPS-induced proinflammatory mediator inducible nitric oxide synthase in mouse macrophage cells. Journal of Food Science, 72, S069–S074.CrossRefPubMedGoogle Scholar
  54. Rice-Evans, C. A., Miller, N. J., & Paganga, G. (1996). Structure-antioxidant activity relationships of flavonoids and phenolic acids. Free Radical Biology and Medicine, 20(7), 933–956.CrossRefPubMedGoogle Scholar
  55. Romo Vaquero, M., Garcia Villalba, R., Larrosa, M., Yanez-Gascon, M. J., Fromentin, E., Flanagan, J., et al. (2013). Bioavailability of the major bioactive diterpenoids in a rosemary extract: Metabolic profile in the intestine, liver, plasma, and brain of Zucker rats. Molecular Nutrition & Food Research, 57(10), 1834–1846.Google Scholar
  56. Sachdeva, A. K., & Chopra, K. (2015). Lycopene abrogates Aβ(1-42)-mediated neuroinflammatory cascade in an experimental model of Alzheimer’s disease. Journal of Nutritional Biochemistry, 26, 736–744.CrossRefPubMedGoogle Scholar
  57. Sagy-Bross, C., Hadad, N., & Levy, R. (2013). Cytosolic phospholipase A2α upregulation mediates apoptotic neuronal death induced by aggregated amyloid-β peptide1-42. Neurochemistry International, 63, 541–550.CrossRefPubMedGoogle Scholar
  58. Samieri, C., Feart, C., Letenneur, L., Dartigues, J. F., Peres, K., Auriacombe, S., et al. (2008). Low plasma eicosapentaenoic acid and depressive symptomatology are independent predictors of dementia risk. American Journal of Clinical Nutrition, 88(3), 714–721.PubMedGoogle Scholar
  59. Samieri, C., Feart, C., Proust-Lima, C., Peuchant, E., Dartigues, J. F., Amieva, H., et al. (2011). Omega-3 fatty acids and cognitive decline: Modulation by ApoEε4 allele and depression. Neurobiology of Aging, 32(2317), e2313–e2322.Google Scholar
  60. Samieri, C., Maillard, P., Crivello, F., Proust-Lima, C., Peuchant, E., Helmer, C., et al. (2012). Plasma long-chain omega-3 fatty acids and atrophy of the medial temporal lobe. Neurology, 79(7), 642–650.CrossRefPubMedGoogle Scholar
  61. Saraiva, M., & O’Garra, A. (2010). The regulation of IL-10 production by immune cells. Nature Reviews Immunology, 10(3), 170.CrossRefPubMedGoogle Scholar
  62. Serhan, C. N. (2007). Resolution phase of inflammation: Novel endogenous anti-inflammatory and proresolving lipid mediators and pathways. Annual Review of Immunology, 25, 101–137.CrossRefPubMedGoogle Scholar
  63. Serhan, C. N., Arita, M., Hong, S., & Gotlinger, K. (2004). Resolvins, docosatrienes, and neuroprotectins, novel omega-3-derived mediators, and their endogenous aspirin-triggered epimers. Lipids, 39, 1125–1132.CrossRefPubMedGoogle Scholar
  64. Soderberg, M., Edlund, C., Kristensson, K., & Dallner, G. (1991). Fatty acid composition of brain phospholipids in aging and in Alzheimer’s disease. Lipids, 26, 421–425.CrossRefPubMedGoogle Scholar
  65. Solomonov, Y., Hadad, N., & Levy, R. (2016). Reduction of cytosolic phospholipase A2α upregulation delays the onset of symptoms in SOD1G93A mouse model of amyotrophic lateral sclerosis. Journal of Neuroinflammation, 13, 134–146.CrossRefPubMedPubMedCentralGoogle Scholar
  66. Stoll, A. L., Severus, W. E., Freeman, M. P., Rueter, S., Zboyan, H. A., Diamond, E., et al. (1999). Omega 3 fatty acids in bipolar disorder: A preliminary double-blind, placebo-controlled trial. Archives of General Psychiatry, 56, 407–412.CrossRefPubMedGoogle Scholar
  67. Superko, H. R., Superko, S. M., Nasir, K., Agatston, A., & Garrett, B. C. (2013). Omega-3 fatty acid blood levels: Clinical significance and controversy. Circulation, 128, 2154–2161.CrossRefPubMedGoogle Scholar
  68. Surette, M. E. (2008). The science behind dietary omega-3 fatty acids. Canadian Medical Association Journal, 178, 177–180.CrossRefPubMedPubMedCentralGoogle Scholar
  69. Szaingurten-Solodkin, I., Hadad, N., & Levy, R. (2009). Regulatory role of cytosolic phospholipase A2α in NADPH oxidase activity and in inducible nitric oxide synthase induction by aggregated Aβ1–42 in microglia. Glia, 57, 1727–1740.CrossRefPubMedGoogle Scholar
  70. Tak, P., & Firestein, G. (2001). NF-κB: A key role in inflammatory diseases. Journal of Clinical Investigation, 107, 7–11.CrossRefPubMedPubMedCentralGoogle Scholar
  71. Tan, C., Xue, J., Lou, X., Abbas, S., Guan, Y., Feng, B., et al. (2014). Liposomes as delivery systems for carotenoids: Comparative studies of loading ability, storage stability and in vitro release. Food Function, 5, 1232–1240.CrossRefPubMedGoogle Scholar
  72. Tarahovsky, Y. S., Muzafarov, E. N., & Kim, Y. A. (2008). Rafts making and rafts braking: How plant flavonoids may control membrane heterogeneity. Molecular and Cellular Biochemistry, 314, 65–71.CrossRefPubMedGoogle Scholar
  73. Thomas, J., Thomas, C. J., Radcliffe, J., & Itsiopoulos, C. (2015). Omega-3 fatty acids in early prevention of inflammatory neurodegenerative disease: A focus on Alzheimer’s disease. BioMed Research International, 2015, 172801–172814.PubMedPubMedCentralGoogle Scholar
  74. Walfisch, Y., Walfisch, S., Agbaria, R., Levy, J., & Sharoni, Y. (2003). Lycopene in serum, skin and adipose tissues after tomato-oleoresin supplementation in patients undergoing haemorrhoidectomy or peri-anal fistulotomy. British Journal of Nutrition, 90, 759–766.CrossRefPubMedGoogle Scholar
  75. Wu, W., Li, Y., Wu, Y., Zhang, Y., Wang, Z., & Liu, X. (2015). Lutein suppresses inflammatory responses through Nrf2 activation and NF-κB inactivation in lipopolysaccharide-stimulated BV-2 microglia. Molecular Nutrition & Food Research, 59(9), 1663–1673.CrossRefGoogle Scholar
  76. Yanagitai, M., Itoh, S., Kitagawa, T., Takenouchi, T., Kitani, H., & Satoh, T. (2012). Carnosic acid, a pro-electrophilic compound, inhibits LPS-induced activation of microglia. Biochemical and Biophysical Research Communications, 418, 22–26.CrossRefPubMedGoogle Scholar
  77. Yeum, K., Booth, S., Sadowski, J., Liu, C., Tang, G., Krinsky, N., et al. (1996). Human plasma carotenoid response to the ingestion of controlled diets high in fruits and vegetables. American Journal of Clinical Nutrition, 64, 594–602.PubMedGoogle Scholar

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Authors and Affiliations

  1. 1.Infectious Diseases Laboratory, Department of Clinical Biochemistry and Pharmacology, Faculty of Health SciencesSoroka University Medical Center and Ben-Gurion University of the NegevBeer-ShevaIsrael

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