A Very Promising Molecule: Resveratrol, Induced Synthesis, and Health Benefits

  • Liliana Martínez
  • Martín Durán
  • Emiliano Malovini
  • María Inés De Rosas
  • Leonor Deis
  • Juan Bruno Cavagnaro


Resveratrol (trans-3,4′,5-trihydroxystilbene) is an abundant stilbene compound that can be found in a large number of plant products, including the skins and seeds of grapes and wines. Many scientific evidence has demonstrated that resveratrol exerts a plethora of biological function, especially cardiovascular protective, antiplatelet, antioxidant, anti-inflammatory, blood glucose-lowering, anticancer, antiaging, and anti-obesity activities. Recently, published data have shown that resveratrol protects also against some neurodegenerative diseases, such as Alzheimer’s disease and obesity, as well as is effective in the management of osteoporosis in postmenopausal woman without an increased risk of breast cancer. Its anti-inflammatory properties are thought to be responsible for anxiolytic properties, as well as its demonstrated antidepressant efficacy. Because of the important activities of resveratrol, there is an increasing interest in producing grapes or wines with higher contents of this compound and a higher nutritional value. Many biotic like fungi or abiotic elicitors, UV-C irradiation, jasmonic acid, salicylic acid, H2O2, O3, and CaCl2 can trigger the resveratrol synthesis in grape berries. Under the same elicitation pressure, viticultural and enological factors can substantially affect resveratrol concentration in the wine. However, one major concern is its poor solubility and absorption when it is given orally, which may lower its biological effectiveness and which has been attributed to its extensive hepatic glucuronidation and sulfation. Recent studies showed that the methoxylation on the free hydroxyl groups of resveratrol could reduce its metabolization and increase its plasma exposure. Different strategies have been assessed to improve trans-resveratrol bioavailability. Many biological mechanisms of action have been proposed for the observed benefits of light to moderate wine consumption on cognitive function in later life. Other stilbenoid compounds such as pterostilbene and 3′-hydroxypterostilbene have promising application for the management and treatment of chronic disorders. However, human studies of stilbenoid compounds are still lacking. Future clinical research for these compounds in chronic diseases is necessary to investigate their physiological and pharmacological effects and safety.


Resveratrol Grapes Vitis vinifera Health benefits 


  1. 1.
    OIV. World vitiviniculture situation. International organization for vine and wine. Statistical report on world viniviticulture situation. 2015;1–15.Google Scholar
  2. 2.
    Samoticha J, Wojdylo A, Golis T. Phenolic composition, physicochemical properties and antioxidant activity of interspecific hybrids of grapes growing in Poland. Food Chem. 2017;245:263–73.CrossRefGoogle Scholar
  3. 3.
    Rapp A, Pretorius PJ. Flavours and off-flavours. In: Charalambous G, editor. Proceedings of the 6th International Flavour Conference, Rethymnon, Crete, Greece. 5–7 July 1989. Amsterdan: Elsevier Science Publishers BV; 1989. p. 1–21.Google Scholar
  4. 4.
    Schreier P. Flavor composition of wines: a review. CRC Crit REV Food Sci Nutr. 1979;12:59–111.CrossRefGoogle Scholar
  5. 5.
    Waterhouse AL. Wine Phenolics. Annal NY Acad S. 2002;957:21–36.CrossRefGoogle Scholar
  6. 6.
    Bavaresco L, Fregoni C. Physiological role and molecular aspects of grapevine stilbene compounds. In: Roubelakis-Angelakis KA, editor. Molecular biology & biotechnology of the grapevine. Netherlands: Kluwer Academic Publishers; 2001. p. 153–82.CrossRefGoogle Scholar
  7. 7.
    Vitrac X, Bornet A, Vanderlinde R, Valls J, Richard T, Delaunay JC, Mérillon JM, Teissédre PL. Determination of stilbenes (delta-viniferin, trans-astringin, trans-piceid, cis- and trans-resveratrol, epsilon-viniferin) in Brazilian wines. J Agric Food Chem. 2005;53(14):5664–9.CrossRefGoogle Scholar
  8. 8.
    Kursvietiene L, Staneviciene I, Mongirdiene A, Bernatoniene J. Multiplicity of effects and health benefits of resveratrol. Med. 2016;52:148–55.Google Scholar
  9. 9.
    Hu Y, Wang S, Wu X, Zhang J, Chen R, Chen M, et al. Chinese herbal medicine-derived compounds for cancer therapy: a focus on hepatocellular carcinoma. J Ethnopharmacol. 2013;149(3):601–12.CrossRefGoogle Scholar
  10. 10.
    Juan ME, Alfaras I, Planas JM. Colorectal cancer chemoprevention by trans-resveratrol. Pharmacol Res. 2012;65:584–91.CrossRefGoogle Scholar
  11. 11.
    Bartolacci C, Andreani C, Amici A, Marchini C. Walking a tightrope: a perspective of resveratrol effects on breast cancer. Current Prot Pep Sci. 2017;18:1.Google Scholar
  12. 12.
    Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003;425:191–6.CrossRefGoogle Scholar
  13. 13.
    Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006;444:337–42.CrossRefGoogle Scholar
  14. 14.
    Lamuela-Raventos RM, Romero-Perez AI, Waterhouse AL, de la Torre-Boronat MC, Romero-Perez, Waterhouse, de la Torre-Boronat. Direct HPLC analysis of cis- and trans-resveratrol and piceid isomers in Spanish red Vitis vinifera wines. J Agric Food Chem. 1995;43(2):281–28.CrossRefGoogle Scholar
  15. 15.
    Bernard E, Britz-McKibbin P, Gernigon N. Resveratrol photoisomerization: an integrative guided-inquiry experiment. J Chem Educ. 2007;84(7):1159.CrossRefGoogle Scholar
  16. 16.
    Mattivi F, Reniero F, Korhammer S. Isolation, characterization, and evolution in red wine vinification of resveratrol monomers. J Agric Food Chem. 1995;43(7):1820–3.CrossRefGoogle Scholar
  17. 17.
    Mohidul Hasan M, Bae H. An overview of stress-induced resveratrol synthesis in grapes: perspectives for resveratrol-enriched grape products. Molecules. 2017;22:294–312.CrossRefGoogle Scholar
  18. 18.
    Donnez D, Jeandet P, Clement C, Courot E. Bioproduction of resveratrol and stilbene derivatives by plant cells and microorganisms. Trends Biotechnol. 2009;27:706–13.CrossRefGoogle Scholar
  19. 19.
    Lanz T, Tropf S, Marner FJ, Schroder J, Schroder G. The role of cysteines in polyketide synthases. Site-directed mutagenesis of resveratrol and chalcone synthases, two key enzymes in different plant-specific pathways. J Biol Chem. 1991;266:9971–6.PubMedGoogle Scholar
  20. 20.
    Vannozzi A, Dry IB, Fasoli M, Zenomi S, Lucchin M. Genome –wide analysis of the grapevine stilbene synthase multigenic family: genomic organization and expression profiles upon biotic and abiotic stresses. BMC Plant Biol. 2012;12:130.CrossRefGoogle Scholar
  21. 21.
    Holl J, Vannozi A, Czemmel S, D’Onofrio C, Walker A. Rausch T. The R2-R3 MYB transcription factors MYB14 and MYB15 regulate stilbene biosynthesis in Vitis vinífera. Plant Cell. 2013;25:4135–49.CrossRefGoogle Scholar
  22. 22.
    Duran MF, de Rosas MI, Garrido F, Martinez L. Expression analysis of the stilbene synthase multigenic family in berry skin from Vitis vinífera L. cv. Malbec elicited with methyl jasmonic acid. Proceedings of the 19th International Meeting of Viticulture GiESCO, Pech Rouge- Montpellier, France. 2015;1:312.Google Scholar
  23. 23.
    Li XD, Wu BH, Wang LJ, Li SH. Extractable amounts of trans-resveratrol in seed and berry skin in Vitis evaluated at the germplasm level. J Agric Food Chem. 2006;54:8804–11.CrossRefGoogle Scholar
  24. 24.
    Wang W, Tang K, Yang HR, Wen PF, Zhang P, Wang HL, Huang WD. Distribution of resveratrol and stilbene synthase in young grape plants (Vitis vinifera L. cv. Cabernet Sauvignon) and the effect of UV-C on its accumulation. Plant Physiol Biochem. 2010;48:142–52.CrossRefGoogle Scholar
  25. 25.
    Mukherjee S, Dudley JI, Das DK. Dose-dependency of resveratrol in providing health benefits. Dose-Response. 2010;8(4):478–500.CrossRefGoogle Scholar
  26. 26.
    Signorelli P, Ghidoni R. Resveratrol as an anticancer nutrient: molecular basis, and promises. J Nutr Biochem. 2005;16(8):449–66.CrossRefGoogle Scholar
  27. 27.
    Wang JF, Maa L, Xi HF, Wang LJ, Li SH. Resveratrol synthesis under natural conditions and after UV-C irradiation in berry skin is associated with berry development stages in “Beihong” (V. vinífera x V. amurensis). Food Chem. 2015;168:430–8.CrossRefGoogle Scholar
  28. 28.
    Cesari C. Caracterización morfológica y molecular de aislamientos de Botryosphareacea de Argentina y estudios de tolerancia de Vitis spp. 2015. Doctoral Thesis.Google Scholar
  29. 29.
    Langcake P. Disease resistance of Vitis spp. and the production of the stress metabolites resveratrol, E-viniferin, alpha-viniferin, and pterostilbene. Physiol Plant Pathol. 1981;18:213–26.CrossRefGoogle Scholar
  30. 30.
    Feys BJ, Parker JE. Interplay of signaling pathways in plant disease resistance. Trends Genet. 2000;16:449–55.CrossRefGoogle Scholar
  31. 31.
    Vuonga TV, Francoa C, Zhang W. Treatment strategies for high resveratrol induction in Vitis vinífera L. cell suspensión culture. Biotechnol Rep. 2014;1–2:15–21.CrossRefGoogle Scholar
  32. 32.
    Wang LJ, Ma L, Xi HF, Duan W, Wang JF, Li SH. Individual and combined effects of CaCl2 and UV-C on the biosynthesis of resveratrol in grape leaves and berry skins. J Agric Food Chem. 2013;61:7135–41.CrossRefGoogle Scholar
  33. 33.
    Bavaresco L, Lucini L, Busconi M, Flamini R, De Rosso M. Wine resveratrol: from the ground up. Nutrients. 2016;8(222):1–8.Google Scholar
  34. 34.
    Atanockovic M, Petrovic A, Jovic S, Cvejic J. Influence of winemaking techniques on the resveratrol content, total phenolic content and antioxidant potential of red wines. Food Chem. 2012;131(2):513–8.CrossRefGoogle Scholar
  35. 35.
    Clare SS, Skurray G, Shalliker RA. Effect of pomace-contacting method on the concentration of cis- and trans-resveratrol and resveratrol glucoside isomers in wine. Am J Enol Vitic. 2004;55:401–6.Google Scholar
  36. 36.
    Trela BC, Waterhouse AL. Resveratrol: isomeric molar absorptivities and stability. J Agric Food Chem. 1996;44:1253–7.CrossRefGoogle Scholar
  37. 37.
    Wightman JD, Price SF, Watson BT, Wrolstad RE. Some effects of processing enzymes on anthocyanins and phenolics in Pinot noir and Cabernet Sauvignon wines. Am J Enol Vitic. 1997;48:39–48.Google Scholar
  38. 38.
    Threlfall RT, Morris JR, Mauromoustakis A. Effect of variety, ultraviolet light exposure, and enological methods on the trans-resveratrol level of wine. Am J Enol Vitic. 1999;50:57–64.Google Scholar
  39. 39.
    Mattivi F, Nicolini G. Influence of the winemaking technique on the resveratrol content of wines. L’Enotecnico. 1993;29:81–8.Google Scholar
  40. 40.
    Roldan A, Palacios V, Caro I, Perez L. Evolution of resveratrol and piceid contents during industrial winemaking process of sherry wine. J Agric Food Chem. 2010;58:4268–73.CrossRefGoogle Scholar
  41. 41.
    Cantos E, Espín JC, Tomás Barberán FA. Postharvest induction modelling method using UV irradiation pulses for obtaining resveratrol-enriched table grapes: a new ¨functional fruit¨? J Agric Food Chem. 2001;49:5052–8.CrossRefGoogle Scholar
  42. 42.
    Hung LM, Chen JK, Huang SS, Lee RS, Su MJ. Cardioprotective effect of resveratrol, a natural antioxidant derived from grapes. Cardiovasc Res. 2000;47(3):549–55.CrossRefGoogle Scholar
  43. 43.
    Kirk RI, Deitch JA, Wu JM, Lerea KM. Resveratrol decreases early signaling events in washed platelets but has little effect on platelet in whole blood. Blood Cell Mol Dis. 2000;26(2):144–50.CrossRefGoogle Scholar
  44. 44.
    Valdecantos MP, Perez-Mature P, Quinter P, Martinez JA, Vitamin C. Resveratrol and lipoic acid actions on isolated rat liver mitochondria: all antioxidants but different. Redox Rep. 2010;15(5):207–16.CrossRefGoogle Scholar
  45. 45.
    de la Lastra CA, Villegas I. Resveratrol as an antioxidant and pro-oxidant agent mechanism and clinical implications. Biochem Soc T. 2007;35(5):1156–60.Google Scholar
  46. 46.
    Sadi G, Bozan D, Yildiz HB. Redox regulation of antioxidant enzymes: post-translational modulation of catalase and glutathione peroxidase activity by resveratrol in diabetic rat liver. Mol Cell Biochem. 2014;393(1):111–22.CrossRefGoogle Scholar
  47. 47.
    Vanamala J, Reddivari L, Radhakrishnan S, Tarver C. Resveratrol suppresses IGF-1 induced human colon cancer cell proliferation and elevates apoptosis via suppression of IGF-1R/Wnt and activation of p53 signaling pathways. BMC Cancer. 2010;10:238.CrossRefGoogle Scholar
  48. 48.
    Tsai HJ, Ho CT, Chen YK. Biological actions and molecular effects of resveratrol, pterostilbene, and 3′-hydroxypterostilbene. J Food Drug Anal. 2017;25:134–47.CrossRefGoogle Scholar
  49. 49.
    Alberdi G, Rodriguez VM, Miranda J, Maccarrulla MT, Arias N, Andrés-Lacueva C, Portillo M. Changes in white adipose tissue metabolism induced by resveratrol in rats. Nutr Metab. 2011;8(1):29–35.CrossRefGoogle Scholar
  50. 50.
    Cucciola V, Borriello L, Oliva A, Galletti P, Zappia V, Della Ragione F. Resveratrol from basic science to the clinic. Cell Cycle. 2007;6(20):2495–510.CrossRefGoogle Scholar
  51. 51.
    Sun AY, Wang Q, Simonyi A, Sun GY. Resveratrol as a therapeutic agent for neurodegenerative diseases. Mol Neurobiol. 2010;41(2–3):375–83.CrossRefGoogle Scholar
  52. 52.
    Su JL, Yang CY, Zhao M, Kuo ML, Yen ML. Forkhead proteins are critical for bone morphogenesis protein-2-regulation and anti-tumor activity of resveratrol. J Biol Chem. 2007;282(27):19385–98.CrossRefGoogle Scholar
  53. 53.
    Pirola L, Projdo S. Resveratrol: one molecule, many targets. IUBMB Life. 2008;60(5):323–32.CrossRefGoogle Scholar
  54. 54.
    Coussens LM, Werb Z. Inflammation and cancer. Nature. 2000;420:860–7.CrossRefGoogle Scholar
  55. 55.
    Lee JA, Ha SK, Gho E, Choi I. Resveratrol as a bioenhancer to improve anti-inflammatory activities of apigenin. Nutrients. 2015;38:9650–61.CrossRefGoogle Scholar
  56. 56.
    Bhatt JK, Thomas S, Nanjan MJ. Resveratrol supplementation improves glycemic control in type 2 diabetes mellitus. Nutr Res. 2012;32:537–41.CrossRefGoogle Scholar
  57. 57.
    Kim S, Jin Y, Choi Y, Park T. Resveratrol exerts anti-obesity effects via mechanisms involving down-regulation of adipogenic and inflammatory processes in mice. Biochem Pharmacol. 2011;81:1343–51.CrossRefGoogle Scholar
  58. 58.
    Konings E, Timmers S, Boekschoten M, Goossens G, Jocken L, Afman L, Muller M, Schrauwen P, Mariman E, Blaak E. The effects of 30 days resveratrol supplementation on adipose tissue morphology and gene expression patterns in obese men. Int J Obes. 2014;38:470–3.CrossRefGoogle Scholar
  59. 59.
    Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Ghung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003;425:191–6.CrossRefGoogle Scholar
  60. 60.
    Lui T, Qi H, Ma L, Liu Z, Fu H, Zhu W, Song T, Yang B, Li G. Resveratrol attenuates oxidative stress and extends life span in the annual fish Nothobranchius guentheri. Rejuvenation Res. 2015;18:225–33.CrossRefGoogle Scholar
  61. 61.
    Rodriguez-Bonilla P, Lopez-Nicolas JM, Mendez-Cazorla L, Garcia-Carmona F. Development of a reversed phase high performance liquid chromatography method based on the use of cyclodextrins as mobile phase additives to determine pterostilbene in blueberries. J Chromatogr B Anal Technol Biomed Life Sci. 2011;879:1091–7.CrossRefGoogle Scholar
  62. 62.
    Shao X, Chen X, Badmaev V, Ho CT, Sang S. Structural identification of mouse urinary metabolites of pterostilbene using liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Sp. 2010;24:1770–8.CrossRefGoogle Scholar
  63. 63.
    Ma ZJ, Li X, Li N, Wang JH. Stilbenes form Sphaerophysa salsula. Fitoterapia. 2002;73:313–5.CrossRefGoogle Scholar
  64. 64.
    Takemoto JK, Remsberg CM, Davies NM. Pharmacologic activities of 3′-hydroxypterostilbene cytotoxic, anti-oxidant, anti-adipogenic, anti-inflammatory, histone deacetylase and sirtuin 1 inhibitory activity. J Pharm Sci. 2015;18:713–27.Google Scholar
  65. 65.
    Gambini J, Inglés M, Olaso O, Lopez-Grueso R, Bonet-Costa W, Gimeno-Mallench L, et al. Properties of resveratrol in vitro and in vivo studies about metabolism, bioavailability, and biological effects in animal models and humans. Oxidative Med Cell Longev. 2015;2015:837042.CrossRefGoogle Scholar
  66. 66.
    Jannin B, Menzel M, Berlot JP, Delmas D, Lancon A, Latruffe N. Transport of resveratrol, a cancer chemopreventive agent, to cellular targets: plasmatic protein binding and cell uptake. Biochem Pharmacol. 2004;68(6):1113–8.CrossRefGoogle Scholar
  67. 67.
    Walle T, Hsieh F, DeLegge MH, Oatis JE Jr, Walle UK. High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab Dispos. 2004;32(12):1377–82.CrossRefGoogle Scholar
  68. 68.
    Nguyen C, Savouret JF, WIderak M, Corvol MT, Rannou F. Resveratrol, potential therapeutic interest in joint disorders: a critical narrative review. Nutrients. 2017;9:45–56.CrossRefGoogle Scholar
  69. 69.
    Ortuño JE, Kontoxakis G, Rubio JL, Guerra P, Santos A. Efficient methodologies for system matrix modelling in iterative image reconstruction for rotating high-resolution PET. Phys Med Biol. 2010;55(7):1833–61.CrossRefGoogle Scholar
  70. 70.
    Ferruzzi MG, Lobo JK, Janle EM, Cooper B, Simon JE, Wu QL, Welch C, Ho L, Weaver C, Pasinetti GM. Bioavailability of gallic acid and catechins from grape seed polyphenol extract is improved by repeated dosing in rats: implications for treatment in Alzheimer’ s disease. J Alzheimers Dis. 2009;18:113–24.CrossRefGoogle Scholar
  71. 71.
    Passamonti S, Vrhovsek U, Vanzo A, Mattivi F. Fast access of some grape pigments to the brain. J Agric Food Chem. 2005;53:7029–34.CrossRefGoogle Scholar
  72. 72.
    Hamaguchi T, Ono K, Murase A, Yamada M. Phenolic compounds prevent Alzheimer’s pathology through different effects on the amyloid-beta aggregation pathway. Am J Pathol. 2009;175:2257–65.CrossRefGoogle Scholar
  73. 73.
    Ho L, Chen LH, Wang J, Zhao W, Talcott ST, Ono K, Teplow D, Humala N, Cheng A, Percival SS, et al. Heterogeneity in red wine polyphenolic contents differentially influences Alzheimer’s disease-type neuropathology and cognitive deterioration. J Alzheimers Dis. 2009;16:59–72.CrossRefGoogle Scholar
  74. 74.
    Scholey A, Benson S, Stough C, Stockey C. Effects of resveratrol and alcohol on mood and cognitive function in older individuals. Nutr Aging. 2014;2:133–8.Google Scholar
  75. 75.
    Stockley C. Wine consumption, cognitive function and dementias- a relationship? Nutr Aging. 2015:125–37.CrossRefGoogle Scholar
  76. 76.
    Chong J, Poutaraud A, Hugueney A. Metabolism and roles of stilbenes in plants. Plant Sci. 2009;177:143–55.CrossRefGoogle Scholar
  77. 77.
    Donnelly LE, Newton R, Kennedy GE, Fenwick PS, Leung RH, Ito K, Russell RE, Barnes PJ. Anti-inflammatory effects of resveratrol in lung epithelial cells: molecular mechanisms. Am J Phys Lung Cell Mol Phys. 2004;287(4):774–83.Google Scholar
  78. 78.
    Fordham JB, Naqvi AR, Nares S. Leukocyte production of inflammatory mediators is Inhibited by the antioxidants phloretin, silymarin, hesperetin, and resveratrol. Mediat Inflamm. 2014;2014:938712. 11 p.CrossRefGoogle Scholar
  79. 79.
    de la Lastra CA, Villegas I. Resveratrol as an anti-inflammatory and anti-aging agent: mechanisms and clinical implications. Mol Nutr Food Res. 2005;49(5):405–30.Google Scholar
  80. 80.
    Patki G, Allan FH, Atrooz F, Dao AT, Solanki N, Chugh G, Asghar M, Jafri F, Bohat R, Alkadhi KA, Salim S. Grape powder intake prevents ovariectomy-induced anxiety-like behavior, memory impairment and high blood pressure in female Wistar rats. PLoS One. 2013;8:e74522.CrossRefGoogle Scholar
  81. 81.
    Finnel JE, Lombard CM, Melson MN, Singh NP, Nagarkatii M, Nagarkatti P, Fadel J, Wood CS, Wood SK. The protective effects of resveratrol on social stress-induced cytokine release and depressive-like behavior. Brain Behav Inmun. 2017;59:147–57.CrossRefGoogle Scholar
  82. 82.
    Ge JF, Xu YY, Qin G, Cheng JQ, Chen FH. Resveratrol ameliorates the anxiety- and depression-like behavior of subclinical hypothyroidism rat: possible involvement of the HPT axis, HPA axis, and Wnt/β-catenin pathway. Front Endocrinol. 2016;7(44):1–11.Google Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Liliana Martínez
    • 1
    • 2
  • Martín Durán
    • 1
  • Emiliano Malovini
    • 1
  • María Inés De Rosas
    • 1
  • Leonor Deis
    • 1
  • Juan Bruno Cavagnaro
    • 3
  1. 1.Facultad de Ciencias AgrariasUniversidad Nacional de CuyoMendozaArgentina
  2. 2.Instituto de Biología Agrícola: IBAM-CONICET-UNCUYOCátedra de Fisiología Vegetal, Facultad de Ciencias Agrarias, Universidad Nacional de CuyoMendozaArgentina
  3. 3.Institute for Agricultural Biology MendozaNational Scientific and Technical Research Council and National University of CuyoMendozaArgentina

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