Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Resveratrol: Twenty Years of Growth, Development and Controversy

  • Pezzuto, John M. (Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University)
  • Received : 2018.09.11
  • Accepted : 2018.09.27
  • Published : 2019.01.01
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Abstract

Resveratrol was first isolated in 1939 by Takaoka from Veratrum grandiflorum O. Loes. Following this discovery, sporadic descriptive reports appeared in the literature. However, spurred by our seminal paper published nearly 60 years later, resveratrol became a household word and the subject of extensive investigation. Now, in addition to appearing in over 20,000 research papers, resveratrol has inspired monographs, conferences, symposia, patents, chemical derivatives, etc. In addition, dietary supplements are marketed under various tradenames. Once resveratrol was brought to the limelight, early research tended to focus on pharmacological activities related to the cardiovascular system, inflammation, and cancer but, over the years, the horizon greatly expanded. Around 130 human clinical trials have been (or are being) conducted with varying results. This may be due to factors such as disparate doses (ca. 5 to 5,000 mg/day) and variable experimental settings. Further, molecular targets are numerous and a dominant mechanism is elusive or nonexistent. In this context, the compound is overtly promiscuous. Nonetheless, since the safety profile is pristine, and use as a dietary supplement is prevalent, these features are not viewed as detrimental. Given the ongoing history of resveratrol, it is reasonable to advocate for additional development and further clinical investigation. Topical preparations seem especially promising, as do conditions that can respond to anti-inflammatory action and/or direct exposure, such as colon cancer prevention. Although the ultimate fate of resveratrol remains an open question, thus far, the compound has inspired innovative scientific concepts and enhanced public awareness of preventative health care.

Keywords

References

  1. Afaq, F., Adhami, V. M. and Ahmad, N. (2003) Prevention of short-term ultraviolet B radiation-mediated damages by resveratrol in SKH-1 hairless mice. Toxicol. Appl. Pharmacol. 186, 28-37. https://doi.org/10.1016/S0041-008X(02)00014-5
  2. Aggarwal, B. B. and S. Shishodia, S. (2006) Resveratrol in Health and Disease, Marcel Dekker, Inc., New York.
  3. Asensi, M., Medina, I., Ortega, A., Carretero, J., Bano, M. C., Obrador, E. and Estrela, J. M. (2002) Inhibition of cancer growth by resveratrol is related to its low bioavailability. Free Radic. Biol. Med. 33, 387-398. https://doi.org/10.1016/S0891-5849(02)00911-5
  4. Ayala, F. (2011) Resveratrol-containing gel for the treatment of acne vulgaris: a single-blind, vehicle-controlled, pilot study. Am. J. Clin. Dermatol. 12, 133-141. https://doi.org/10.2165/11530630-000000000-00000
  5. Aziz, M. H., Reagan-Shaw, S., Wu, J., Longley, B. J. and Ahmad, N. (2005) Chemoprevention of skin cancer by grape constituent resveratrol: relevance to human disease? FASEB J. 19, 1193-1195. https://doi.org/10.1096/fj.04-3582fje
  6. Back, J. H., Zhu, Y., Calabro, A., Queenan, C., Kim, A. S., Arbesman, J. and Kim, A. L. (2012) Resveratrol-mediated downregulation of Rictor attenuates autophagic process and suppresses UV-induced skin carcinogenesis. Photochem. Photobiol. 88, 1165-1172. https://doi.org/10.1111/j.1751-1097.2012.01097.x
  7. Bashmakov, Y. K., Assaad-Khalil, S. H., Seif, M. A., Udumyan, R., Megallaa, M., Rohoma, K. H., Zeitoun, M. and Petyaev, I. M. (2014) Resveratrol promotes foot ulcer size reduction in type 2 diabetes patients. ISRN Endocrinol. 2014, 816307.
  8. Baxter, R. A. (2008) Anti-aging properties of resveratrol: review and report of a potent new antioxidant skin care formulation. J. Cosmet. Dermatol. 7, 2-7. https://doi.org/10.1111/j.1473-2165.2008.00354.x
  9. Berman, H. M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T. N., Weissig, H., Shindyalov, I. N. and Bourne, P. E. (2000) The protein data bank. Nucleic Acids Res. 28, 235-242. https://doi.org/10.1093/nar/28.1.235
  10. Bhat, K. P. L., Lantvit, D., Christov, K., Mehta, R. G., Moon, R. C. and Pezzuto, J. M. (2001) Estrogenic and antiestrogenic properties of resveratrol in mammary tumor models. Cancer Res. 61, 7456-7463.
  11. Bhat, K. P. and Pezzuto, J. M. (2002) Cancer chemopreventive activity of resveratrol. Ann. N.Y. Acad. Sci. 957, 210-229. https://doi.org/10.1111/j.1749-6632.2002.tb02918.x
  12. Bhatt, J. K., Thomas, S. and Nanjan, M. J. (2012) Resveratrol supplementation improves glycemic control in type 2 diabetes mellitus. Nutr. Res. 32, 537-541. https://doi.org/10.1016/j.nutres.2012.06.003
  13. Bhattacharya, S., Darjatmoko, S. R. and Polans, A. S. (2011) Resveratrol modulates the malignant properties of cutaneous melanoma through changes in the activation and attenuation of the antiapoptotic protooncogenic protein Akt/PKB. Melanoma Res. 21, 180-187. https://doi.org/10.1097/CMR.0b013e3283456dfc
  14. Boily, G., He, X. H., Pearce, B., Jardine, K. and McBurney, M. W. (2009) Sirt1-nullmice develop tumors at normal rates but are poorly protected by resveratrol. Oncogene 28, 2882-2893. https://doi.org/10.1038/onc.2009.147
  15. Bomgardner, M. M. (2017) Reviving resveratrol. Chem. Eng. News 95, 38-39.
  16. Brown, V. A., Patel, K. R., Viskaduraki, M., Crowell, J. A., Perloff, M., Booth, T. D., Vasilinin, G., Sen, A., Schinas, A. M., Piccirilli, G., Brown, K., Steward, W. P., Gescher. A. J. and Brenner, D. E. (2010) Repeat dose study of the cancer chemopreventive agent resveratrol in healthy volunteers: safety, pharmacokinetics, and effect on the insulin-like growth factor axis. Cancer Res. 70, 9003-9011. https://doi.org/10.1158/0008-5472.CAN-10-2364
  17. Buhrmann, C., Shayan, P., Popper, B., Goel, A. and Shakibaei, M. (2016) Sirt1 is required for resveratrol-mediated chemopreventive effects in colorectal cancer cells. Nutrients 8, 145. https://doi.org/10.3390/nu8030145
  18. Calabrese, E. J., Mattson, M. P. and Calabrese, V. (2010) Resveratrol commonly displays hormesis: occurrence and biomedical significance. Hum. Exp. Toxicol. 29, 980-1015. https://doi.org/10.1177/0960327110383625
  19. Cao, C., Lu, S., Kivlin, R., Wallin, B., Card, E., Bagdasarian, A., Tamakloe, T., Wang, W. J., Song, X., Chu, W. M., Kouttab, N., Xu, A. and Wan, Y. (2009) SIRT1 confers protection against UVB- and $H_2O_2$-induced cell death via modulation of p53 and JNK in cultured skin keratinocytes. J. Cell. Mol. Med. 13, 3632-3643. https://doi.org/10.1111/j.1582-4934.2008.00453.x
  20. Cao, D., Wang, M., Qiu, X., Liu, D., Jiang, H., Yang, N. and Xu, R. M. (2015) Structural basis for allosteric, substrate-dependent stimulation of SIRT1 activity by resveratrol. Genes Dev. 29, 1316-1325. https://doi.org/10.1101/gad.265462.115
  21. Canto, C., Gerhart-Hines, Z., Feige, J. N., Lagouge, M., Noriega, L., Milne, J. C., Elliott, P. J., Puigserver, P. and Auwerx, J. (2009) AMPK regulates energy expenditure by modulating $NAD^+$ metabolism and SIRT1 activity. Nature 458, 1056-1060. https://doi.org/10.1038/nature07813
  22. Carboni, L. (2013) Peripheral biomarkers in animal models of major depressive disorder. Dis. Markers 35, 33-41. https://doi.org/10.1155/2013/284543
  23. Cho, K. S., Lee, E. J., Kwon, K. J., Gonzales, E. L., Kim, Y. B., Cheong, J. H., Bahn, G. H., Lee, J., Han, S. H., Kim, Y. T. and Shin, C. Y. (2014) Resveratrol down-regulates a glutamate-induced tissue plasminogen activator via Erk and AMPK/mTOR pathways in rat primary cortical neurons. Food Funct. 5, 951-960. https://doi.org/10.1039/c3fo60397k
  24. Chowdhury, S. K. R., Smith, D. R., Saleh, A., Schapansky, J., Marquez, A., Gomes, S., Akude, E., Morrow, D., Calcutt, N. A. and Fernyhough, P. (2012) Impaired adenosine monophosphate-activated protein kinase signaling in dorsal root ganglia neurons is linked to mitochondrial dysfunction and peripheral neuropathy in diabetes. Brain 135, 1751-1766. https://doi.org/10.1093/brain/aws097
  25. ClinicalTrials.gov (2018a) Available from: https://clinicaltrials.gov/ct2/results/map?term=resveratrol&map=) [accessed 2018 Sep 4].
  26. ClinicalTrials.gov (2018b) Available from: https://clinicaltrials.gov/ct2/results?cond=colon+cancer&term=resveratrol&cntry=&state=&city=&dist=) [accessed 2018 Oct 3].
  27. Cichocki, M., Paluszczak, J., Szaefer, H., Piechowiak, A., Rimando, A. M. and Baer-Dubowska, W. (2008) Pterostilbene is equally potent as resveratrol in inhibiting 12-O-tetradecanoylphorbol-13-acetate activated NFkappaB, AP-1, COX-2, and iNOS in mouse epidermis. Mol. Nutr. Food Res. 52, S62-S70. https://doi.org/10.1002/mnfr.200700395
  28. Cragg, G. M. and Pezzuto, J. M. (2016) Natural products as a vital source for the discovery of cancer chemotherapeutic and chemopreventive agents. Med. Princ. Pract. 25 Suppl 2, 41-59. https://doi.org/10.1159/000443404
  29. Csiszar, A., Labinskyy, N., Pinto, J. T., Ballabh, P., Zhang, H., Losonczy, G., Pearson, K., de Cabo, R., Pacher, P., Zhang, C. and Ungvari, Z. (2009) Resveratrol induces mitochondrial biogenesis in endothelial cells. Am. J. Physiol. Heart Circ. Physiol. 297, H13-H20. https://doi.org/10.1152/ajpheart.00368.2009
  30. Damian, J. P., Acosta, V., Da Cuna, M., Ramirez, I., Oddone, N., Zambrana, A., Bervejillo, V. and J. C. Benech, J. C. (2014) Effect of resveratrol on behavioral performance of streptozotocin-induced diabetic mice in anxiety tests. Exp. Anim. 63, 277-287. https://doi.org/10.1538/expanim.63.277
  31. Das, S., Alagappan, V. K., Bagchi, D., Sharma, H. S., Maulik, N. and Das, D. K. (2005) Coordinated induction of iNOS-VEGF-KDR-eNOS after resveratrol consumption: a potential mechanism for resveratrol preconditioning of the heart. Vascul. Pharmacol. 42, 281-289. https://doi.org/10.1016/j.vph.2005.02.013
  32. Das, S., Tosaki, A., Bagchi, D., Maulik, N. and Das, D. K. (2006) Potentiation of a survival signal in the ischemic heart by resveratrol through p38 mitogen-activated protein kinase/mitogen- and stress-activated protein kinase 1/cAMP response element-binding protein signaling. J. Pharmacol. Exp. Ther. 317, 980-988. https://doi.org/10.1124/jpet.105.095133
  33. Do, G. M., Jung, U. J., Park, H. J., Kwon, E. Y., Jeon, S. M., McGregor, R. A. and Choi, M. S. (2012) Resveratrol ameliorates diabetes-related metabolic changes via activation of AMP-activated protein kinase and its downstream targets in db/db mice. Mol. Nutr. Food Res. 56, 1282-1291. https://doi.org/10.1002/mnfr.201200067
  34. El-Mowafy, A. M., Alkhalaf, M. and Nassar, N. N. (2009) Resveratrol reverses ET-1-evoked mitogenic effects in human coronary arterial cells by activating the kinase-G to inhibit ERK-enzymes. Int. J. Cardiol. 136, 263-269. https://doi.org/10.1016/j.ijcard.2008.04.094
  35. Escote, X., Miranda, M., Menoyo, S., Rodriguez-Porrata, B., Carmona-Gutierrez, D., Jungwirth, H., Madeo, F., Cordero, R. R., Mas, A., Tinahones, F., Clotet, J. and Vendrell, J. (2012) Resveratrol induces antioxidant defence via transcription factor Yap1p. Yeast 29, 251-263. https://doi.org/10.1002/yea.2903
  36. Evans, H. M., Howe, P. R. C. and Wong, R. H. X. (2017) Effects of resveratrol on cognitive performance, mood and cerebrovascular function in post-menopausal women; a 14-week randomised placebo-controlled intervention trial. Nutrients 9, E27. https://doi.org/10.3390/nu9010027
  37. Fabbrocini, G., Staibano, S., De Rosa, G., Battimiello, V., Fardella, N., Ilardi, G., La Rotonda, M. I., Longobardi, A., Mazzella, M., Siano, M., Pastore, F., De Vita, V., Vecchione, M. L. and Ayala, F. (2011) Resveratrol-containing gel for the treatment of acne vulgaris: a single-blind, vehicle-controlled, pilot study. Am. J. Clin. Dermatol. 12, 133-141. https://doi.org/10.2165/11530630-000000000-00000
  38. Fu, Z. D., Cao, Y., Wang, K. F., Xu, S. F and Han, R. (2004) Chemopreventive effect of resveratrol to cancer. Ai Zheng 23, 869-873.
  39. Gehm, B. D., McAndrews, J. M., Chien, P. Y and Jameson, J. L. (1997) Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor. Proc. Natl. Acad. Sci. U.S.A. 94, 14138-14143. https://doi.org/10.1073/pnas.94.25.14138
  40. Goh, S. S., Woodman, O. L., Pepe, S., Cao, A. H., Qin, C. and Ritchie, R. H. (2007) The red wine antioxidant resveratrol prevents cardiomyocyte injury following ischemia-reperfusion via multiple sites and mechanisms. Antioxid. Redox. Signal 9, 101-113. https://doi.org/10.1089/ars.2007.9.101
  41. Gracia-Sancho, J., Villarreal, G., Jr., Zhang, Y. and Garcia-Cardena, G. (2010) Activation of SIRT1 by resveratrol induces KLF2 expression conferring an endothelial vasoprotective phenotype. Cardiovasc. Res.85, 514-519. https://doi.org/10.1093/cvr/cvp337
  42. Guilford, J. M. and Pezzuto, J. M. (2011) Wine and health: a review. Am. J. Enol. Vitic. 62, 471-486. https://doi.org/10.5344/ajev.2011.11013
  43. Guo, D., Xie, J., Zhao, J., Huang, T., Guo, X. and Song, J. (2018) Resveratrol protects early brain injury after subarachnoid hemorrhage by activating autophagy and inhibiting apoptosis mediated by the Akt/mTOR pathway. Neuroreport 29, 368-379. https://doi.org/10.1097/WNR.0000000000000975
  44. Hao, Y., Huang, W., Liao, M., Zhu, Y., Liu, H., Hao, C., Liu, G., Zhang, G., Feng, H., Ning, X., Li, H. and Li, Z. (2013a) The inhibition of resveratrol to human skin squamous cell carcinoma A431 xenografts in nude mice. Fitoterapia 86, 84-91. https://doi.org/10.1016/j.fitote.2013.02.005
  45. Hao, Y. Q., Huang, W. X., Feng, H. X., Zhang, G. H., Ning, X. H., Li, H. G., Hao, C. G. and Li, Z. H. (2013b) Study of apoptosis related factors regulatory mechanism of resveratrol to human skin squamous cell carcinoma A431 xenograft in nude mice. Zhonghua Yi Xue Za Zhi 93, 464-468.
  46. Hoshino, J., Park, E. J., Kondratyuk, T. P., Marler, L., Pezzuto, J. M., van Breemen, R. B., Mo, S., Li ,Y. and Cushman, M. (2010) Selective synthesis and biological evaluation of sulfate-conjugated resveratrol metabolites. J. Med. Chem. 53, 5033-5043. https://doi.org/10.1021/jm100274c
  47. Howitz, K. T., Bitterman, K. J., Cohen, H. Y., Lamming, D. W., Lavu, S., Wood, J. G., Zipkin, R. E., Chung, P., Kisielewski, A., Zhang, L. L., Scherer, B. and Sinclair, D. A. (2003) Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425, 191-196. https://doi.org/10.1038/nature01960
  48. Huang, W., Chen, Z., Wang, O., Lin, M., Wu, S., Yan, Q., Wu, F., Yu, X., Xie, X., Li, G., Xu, Y. and Pan, J. (2013) Piperine potentiates the antidepressant-like effect of trans-resveratrol: involvement of monoaminergic system. Metab. Brain Dis. 28, 585-595. https://doi.org/10.1007/s11011-013-9426-y
  49. Hunter, P. (2012) The inflammation theory of disease. EMBO Rep. 13, 968-970. https://doi.org/10.1038/embor.2012.142
  50. Hurley, L. L., Akinfiresoye, L., Kalejaiye, O. and Tizabi, Y. (2014) Antidepressant effects of resveratrol in an animal model of depression. Behav. Brain Res. 268, 1-7. https://doi.org/10.1016/j.bbr.2014.03.052
  51. Jang, M., Cai, L., Udeani, G. O., Slowing, K. V., Thomas, C. F., Beecher, C. W., Fong, H. H., Farnsworth, N. R., Kinghorn, A. D., Mehta, R. G., Moon, R. C., and Pezzuto, J. M. (1997) Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275, 218-220. https://doi.org/10.1126/science.275.5297.218
  52. Jang, M. and Pezzuto, J. M. (1998) Effects of resveratrol on 12-O-tetradecanoylphorbol- 13-acetate-induced oxidative events and gene expression in mouse skin. Cancer Lett. 134, 81-89. https://doi.org/10.1016/S0304-3835(98)00250-X
  53. Jing, Y. H., Chen, K. H., Kuo, P. C., Pao, C. C. and Chen, J. K. (2013) Neurodegeneration in streptozotocin-induced diabetic rats is attenuated by treatment with resveratrol. Neuroendocrinology 98, 116-127. https://doi.org/10.1159/000350435
  54. Johnson, J. M., Nihal, M., Siddiqui, I. A., Scarlett, C. O., Bailey, H. H., Mukhtar, H. and Ahmad, H. (2011a) Enhancing the bioavailability of resveratrol by combining it with piperine. Mol. Nutr. Food Res. 55, 1169-1176. https://doi.org/10.1002/mnfr.201100117
  55. Johnson, W. D., Morrissey, R. L. Usborne, A. L., Kapetanovic, I., Crowell, J. A., Muzzio, M. and McCormick, D. L. (2011b) Subchronic oral toxicity and cardiovascular safety pharmacology studies of resveratrol, a naturally occurring polyphenol with cancer preventive activity. Food Chem. Toxicol. 49, 3319-3327. https://doi.org/10.1016/j.fct.2011.08.023
  56. Juhasz, B., Mukherjee, S. and Das, D. K. (2010) Hormetic response of resveratrol against cardioprotection. Exp. Clin. Cardiol. 15, e134-e138.
  57. Kalra, N., Roy, P., Prasad, S. and Shukla, Y. (2008) Resveratrol induces apoptosis involving mitochondrial pathways in mouse skin tumorigenesis. Life Sci. 82, 348-358. https://doi.org/10.1016/j.lfs.2007.11.006
  58. Kapadia, G. J., Azuine, M. A., Tokuda, H., Takasaki, M., Mukainaka, T., Konoshima, T. and Nishino, H. (2002) Chemopreventive effect of resveratrol, sesamol, sesame oil and sunflower oil in the Epstein-Barr virus early antigen activation assay and the mouse skin two-stage carcinogenesis. Pharmacol. Res. 45, 499-505. https://doi.org/10.1006/phrs.2002.0992
  59. Kennedy, D. O., Wightman, E. L., Reay, J. L., Lietz, G., Okello, E. J., Wilde, A. and Haskell, C. F. (2010) Effects of resveratrol on cerebral blood flow variables and cognitive performance in humans: a double-blind, placebo-controlled, crossover investigation. Am. J. Clin. Nutr. 91, 1590-1597. https://doi.org/10.3945/ajcn.2009.28641
  60. Kim, K. H., Back, J. H., Zhu, Y., Arbesman, J., Athar, M., Kopelovich, L., Kim, A. L. and Bickers, D. R. (2011) Resveratrol targets transforming growth factor-${\beta}2$ signaling to block UV-induced tumor progression. J. Invest. Dermatol. 131, 195-202. https://doi.org/10.1038/jid.2010.250
  61. Kjaer, T. N., Ornstrup, M. J., Poulsen, M. M., Stodkilde-Jorgensen, H., Jessen, N., Jorgensen, J. O. L., Richelsen, B. and Pedersen, S. B. (2017) No beneficial effects of resveratrol on the metabolic syndrome: a randomized placebo-controlled clinical trial. J. Clin. Endocrinol. Metab. 102, 1642-1651. https://doi.org/10.1210/jc.2016-2160
  62. Kowalczyk, M. C., Kowalczyk, P., Tolstykh, O., Hanausek, M., Walaszek, Z. and Slaga, T. J. (2010) Synergistic effects of combined phytochemicals and skin cancer prevention in SENCAR mice. Cancer Prev. Res. 3, 170-178. https://doi.org/10.1158/1940-6207.CAPR-09-0196
  63. Kowalczyk, M. C., Junco, J. J., Kowalczyk, P., Tolstykh, O., Hanausek, M., Slaga, T. J. and Walaszek, Z. (2013) Effects of combined phytochemicals on skin tumorigenesis in SENCAR mice. Int. J. Oncol. 43, 911-918. https://doi.org/10.3892/ijo.2013.2005
  64. Krishnan, V. and Nestler, E. J. (2011) Animal models of depression: molecular perspectives. Curr. Top. Behav. Neurosci. 7, 121-147. https://doi.org/10.1007/7854_2010_108
  65. Kumar, A., Kaundal, R. K., Iyer, S. and Sharma, S. S. (2007) Effects of resveratrol on nerve functions, oxidative stress and DNA fragmentation in experimental diabetic neuropathy. Life Sci. 80, 1236-1244. https://doi.org/10.1016/j.lfs.2006.12.036
  66. Kumar, A., Park, E.-J. and Pezzuto, J. M. (2018) Chapter 3. Resveratrol as an activator or inhibitor of enzymes and proteins. In Resveratrol: State-of-the-Art Science and Health Applications (J. M. Wu and T.-C. Hsieh, Eds.), pp. 55-113. World Scientific Publishing, Singapore.
  67. Kundu, J. K., Chun, K. S., Kim, S. O. and Surh, Y. J. (2004) Resveratrol inhibits phorbol ester-induced cyclooxygenase-2 expression in mouse skin: MAPKs and AP-1 as potential molecular targets. Biofactors 21, 33-39. https://doi.org/10.1002/biof.552210108
  68. Lee, H., Zhang, P., Herrmann, A., Yang, C., Xin, H., Wang, Z., Hoon, D. S., Forman, S. J., Jove, R., Riggs, A. D. and Yu, H. (2012) Acetylated STAT3 is crucial for methylation of tumor suppressor gene promoters and inhibition by resveratrol results in demethylation. Proc. Natl. Acad. Sci. U.S.A. 109, 7765-7769. https://doi.org/10.1073/pnas.1205132109
  69. Lee, T. H., Seo, J. O., Baek, S. H. and Kim, S. Y. (2014) Inhibitory effects of resveratrol on melanin synthesis in ultraviolet B-induced pigmentation in Guinea pig skin. Biomol. Ther. (Seoul) 22, 35-40. https://doi.org/10.4062/biomolther.2013.081
  70. Ma, S. C., Zhang, H. P., Jiao, Y., Wang, Y. H., Zhang, H., Yang, X. L., Yang, A. N. and Jiang, Y. D. (2018) Homocysteine-induced proliferation of vascular smooth muscle cells occurs via PTEN hypermethylation and is mitigated by resveratrol. Mol. Med. Rep. 17, 5312-5319.
  71. Maroon, J. (2009) The Longevity Factor: How Resveratrol and Red Wine Activate Genes for a Longer and Healthier Life. Atria Paperback, New York.
  72. Miller, R. A., Harrison, D. E., Astle, C. M., Baur, J. A., Boyd, A. R., de Cabo, R., Fernandez, E., Flurkey, K., Javors, M. A., Nelson, J. F., Orihuela, C. J., Pletcher, S., Sharp, Z. D., Sinclair, D., Starnes, J. W., Wilkinson, J. E., Nadon, N. L. and Strong, R. (2011) Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. J. Gerontol. A Biol. Sci. Med. Sci. 66, 191-201.
  73. Movahed, A., Nabipour, I., Louis, X. L., Thandapilly, S. J., Yu, L., Kalantarhormozi, M., Rekabpour, S. J. and Netticadan, T. (2013) Antihyperglycemic effects of short term resveratrol supplementation in type 2 diabetic patients. Evid. Based Complement. Alternat. Med. 2013, 851267.
  74. Moyano-Mendez, J. R., Fabbrocini, G., De Stefano, D., Mazzella, C., Mayol, L., Scognamiglio, I., Carnuccio, R., Ayala, F., La Rotonda, M. I. and De Rosa, G. (2014) Enhanced antioxidant effect of transresveratrol: potential of binary systems with polyethylene glycol and cyclodextrin. Drug Deve. Ind. Pharm. 40, 1300-1307. https://doi.org/10.3109/03639045.2013.817416
  75. Mukhopadhyay, P., Mukherjee, S., Ahsan, K., Bagchi, A., Pacher, P. and Das, D. K. (2010) Restoration of altered microRNA expression in the ischemic heart with resveratrol. PLoS One 5, e15705. https://doi.org/10.1371/journal.pone.0015705
  76. Mukhopadhyay, P., Das, S., Ahsan, M. K., Otani, H. and Das, D. K. (2012) Modulation of microRNA 20b with resveratrol and longevinex is linked with their potent anti-angiogenic action in the ischaemic myocardium and synergistic effects of resveratrol and gamma-tocotrienol. J. Cell. Mol. Med. 16, 2504-2517. https://doi.org/10.1111/j.1582-4934.2011.01480.x
  77. Ndiaye, M., Philippe, C., Mukhtar, H. and Nihal Ahmad, N. (2011) The grape antioxidant resveratrol for skin disorders: promise, prospects, and challenges. Arch. Biochem. Biophys. 508, 164-170. https://doi.org/10.1016/j.abb.2010.12.030
  78. Niles, R. M., Cook, C. P., Meadows, G. G., Fu, Y. M., McLaughlin, J. L. and Rankin, G. O. (2006) Resveratrol is rapidly metabolized in athymic (nu/nu) mice and does not inhibit human melanoma xenograft tumor growth. J. Nutr. 136, 2542-2546. https://doi.org/10.1093/jn/136.10.2542
  79. Osmond, G. W., Masko, E. M., Tyler, D. S., Freedland, S. J. and Pizzo, S. (2013) In vitro and in vivo evaluation of resveratrol and 3,5-dihydroxy-4'-acetoxy-trans-stilbene in the treatment of human prostate carcinoma and melanoma. J. Surg. Res. 179, e141-e148. https://doi.org/10.1016/j.jss.2012.02.057
  80. Pacholec, M., Bleasdale, J. E., Chrunyk, B., Cunningham, D., Flynn, D., Garofalo, R. S., Griffith, D., Griffor, M., Loulakis, P., Pabst, B., Qiu, X., Stockman, B., Thanabal, V., Varghese, A., Ward, J., Withka, J. and Ahn, K. (2010) SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. J. Biol. Chem. 285, 8340-8351. https://doi.org/10.1074/jbc.M109.088682
  81. Palomera-Avalos, V., Grinan-Ferre, C., Puigoriol-Ilamola, D., Camins, A., Sanfeliu, C., Canudas, A. M. and Pallas, M. (2017) Resveratrol protects SAMP8 brain under metabolic stress: focus on mitochondrial function and Wnt pathway. Mol. Neurobiol. 54, 1661-1676. https://doi.org/10.1007/s12035-016-9770-0
  82. Pan, Y., Zhang, H., Zheng, Y., Zhou, J., Yuan, J., Yu, Y. and Wang, J. (2017) Resveratrol exerts antioxidant effects by activating SIRT2 to deacetylate Prx1. Biochemistry 56, 6325-6328. https://doi.org/10.1021/acs.biochem.7b00859
  83. Park, D. W., Baek, K., Kim, J. R., Lee, J. J., Ryu, S. H., Chin, B. R. and Baek, S. H. (2009) Resveratrol inhibits foam cell formation via NADPH oxidase 1- mediated reactive oxygen species and monocyte chemotactic protein-1. Exp. Mol. Med. 41, 171-179. https://doi.org/10.3858/emm.2009.41.3.020
  84. Park, E. J. and Pezzuto, J. M. (2015) The pharmacology of resveratrol in animals and humans. Biochim. Biophys. Acta 1852, 1071-1113. https://doi.org/10.1016/j.bbadis.2015.01.014
  85. Patel, K. R., Brown, V. A., Jones, D. J. L., Britton, R. G., Hemingway, D., Miller, A. S., West, K. P., Booth, T. D., Perloff, M., Crowell, J. A., Brenner, D. E., Steward, W. P., Gescher, A. J. and Brown, K. (2010) Clinical pharmacology of resveratrol and its metabolites in colorectal cancer patients. Cancer Res. 70, 7392-7399. https://doi.org/10.1158/0008-5472.CAN-10-2027
  86. Patel, K. R., Andreadi, C., Britton, R. G., Horner-Glister, E., Karmokar, A., Sale, S., Brown, V. A., Brenner, D. E., Singh, R., Steward, W. P., Gescher, A. J. and Brown, K. (2013) Sulfate metabolites provide an intracellular pool for resveratrol generation and induce autophagy with senescence. Sci. Trans. Med. 5, 205ra133. https://doi.org/10.1126/scitranslmed.3005870
  87. Penumathsa, S. V., Koneru, S., Samuel, S. M., Maulik, G., Bagchi, D., Yet, S. F., Menon, V. P. and Maulik, N. (2008) Strategic targets to induce neovascularization by resveratrol in hypercholesterolemic rat myocardium: role of caveolin-1, endothelial nitric oxide synthase, hemeoxygenase-1, and vascular endothelial growth factor. Free Radic. Biol. Med. 45, 1027-1034. https://doi.org/10.1016/j.freeradbiomed.2008.07.012
  88. Pezzuto, J. M. (1997) Plant-derived anticancer agents. Biochem. Pharmacol. 53, 121-133. https://doi.org/10.1016/S0006-2952(96)00654-5
  89. Pezzuto, J. M., Kosmeder, J.W., II, Park, E. J., Lee, S. K., Cuendet, M., Gills, J., Bhat, K., Grubjesic, S., Park, H.-S., Mata-Greenwood, E., Tan, Y. M., Yu, R., Lantvit, D. D. and Kinghorn, A. D. (2005) Characterization of natural product chemopreventive agents. In Cancer Chemoprevention, Volume 2: Strategies for Cancer Chemoprevention (G.J. Kelloff, E.T. Hawk, and C.C. Sigman, Eds.), pp. 3-37. Humana Press Inc., Totowa, New Jersey.
  90. Pezzuto, J. M. (2011) The phenomenon of resveratrol: redefining the virtues of promiscuity. Ann. N.Y. Acad. Sci. 1215, 123-130. https://doi.org/10.1111/j.1749-6632.2010.05849.x
  91. Pezzuto, J. M., Kondratyuk, T. P. and Olgas, T. (2013) Resveratrol derivatives: a patent review (2009-2012). Expert Opin. Ther. Pat. 23, 1529-1546. https://doi.org/10.1517/13543776.2013.834888
  92. Pollack, A. Glaxo says compound in wine may fight aging (https://www.nytimes.com/2008/04/23/business/23wine.html) accessed October 3, 2018.
  93. Popat, R., Plesner, T., Davies, F., Cook, G., Cook, M., Elliott, P., Jacobson, E., Gumbleton, T., Oakervee, H., and Cavenagh, J. (2013) A phase 2 study of SRT501 (resveratrol) with bortezomib for patients with relapsed and or refractory multiple myeloma. Br. J. Haematol. 160, 714-717. https://doi.org/10.1111/bjh.12154
  94. Prabhakar, O. (2013) Cerebroprotective effect of resveratrol through antioxidant and anti-inflammatory effects in diabetic rats. Naunyn Schmiedebergs Arch. Pharmacol. 386, 705-710. https://doi.org/10.1007/s00210-013-0871-2
  95. Price, D. D., Finniss, D. G. and Benedetti, F. (2008) A comprehensive review of the placebo effect: recent advances and current thought. Ann. Rev. Psychol. 59, 565-590. https://doi.org/10.1146/annurev.psych.59.113006.095941
  96. Ratz-Lyko, A. and Arct, J. (2018) Resveratrol as an active ingredient for cosmetic and dermatological applications: a review. J. Cosmet. Laser Ther. doi: 10.1080/14764172.2018.1469767.
  97. Reagan-Shaw, S., Afaq, F., Aziz, M. H. and Ahmad, N. (2004) Modulations of critical cell cycle regulatory events during chemoprevention of ultraviolet B-mediated responses by resveratrol in SKH-1 hairless mouse skin. Oncogene 23, 5151-5160. https://doi.org/10.1038/sj.onc.1207666
  98. Rogers, R. G. and Otis, J. S. (2017) Resveratrol-mediated expression of KLF15 in the ischemic myocardium is associated with an improved cardiac phenotype. Cardiovasc. Drugs Ther. 31, 29-38. https://doi.org/10.1007/s10557-016-6707-9
  99. Roy, P., Kalra, N., Prasad, S., George, J. and Shukla, Y. (2009) Chemopreventive potential of resveratrol in mouse skin tumors through regulation of mitochondrial and PI3K/AKT signaling pathways. Pharm. Res. 26, 211-217. https://doi.org/10.1007/s11095-008-9723-z
  100. Ruderman, N. B., Xu, X. J., Nelson, L., Cacicedo, J. M., Saha, A. K., Lan, F. and Ido, Y. (2010) AMPK and SIRT1: a long-standing partnership? Am. J. Physiol. Endocrinol. Metab. 298, E751-E760. https://doi.org/10.1152/ajpendo.00745.2009
  101. Ruggeri, B. A., Camp, F. and Miknyoczki, S. (2014) Animal models of disease: pre-clinical animal models of cancer and their applications and utility in drug discovery. Biochem. Pharmacol. 87, 150-161. https://doi.org/10.1016/j.bcp.2013.06.020
  102. Sardi, B. (2004) The Anti-Aging Pill. Here and Now Books, San Dimas, CA.
  103. Sawda, C., Moussa, C. and Turner, R. S. (2017) Resveratrol for Alzheimer's disease. Ann. N.Y. Acad. Sci. 1403, 142-149. https://doi.org/10.1111/nyas.13431
  104. Schilder, Y. D., Heiss, E. H., Schachner, D., Ziegler, J., Reznicek, G., Sorescu, D. and Dirsch, V. M. (2009) NADPH oxidases 1 and 4 mediate cellular senescence induced by resveratrol in human endothelial cells. Free Radic. Biol. Med. 46, 1598-1606. https://doi.org/10.1016/j.freeradbiomed.2009.03.013
  105. Schmatz, R., Mazzanti, C. M., Spanevello, R., Stefanello, N., Gutierres, J., Correa, M., da Rosa, M. M., Rubin, M. A., Chitolina Schetinger, M. R. and Morsch, V. M. (2009) Resveratrol prevents memory deficits and the increase in acetylcholinesterase activity in streptozotocin-induced diabetic rats. Eur. J. Pharmacol. 610, 42-48. https://doi.org/10.1016/j.ejphar.2009.03.032
  106. Seyyedebrahimi, S., Khodabandehloo, H., Esfahani, E. N. and Meshkani, R. (2018) The effects of resveratrol on markers of oxidative stress in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled clinical trial. Acta Diabetologica 55, 341-353. https://doi.org/10.1007/s00592-017-1098-3
  107. Sharma, S., Kulkarni, S. K. and Chopra, K. (2006) Resveratrol, a polyphenolic phytoalexin attenuates thermal hyperalgesia and cold allodynia in STZ-induced diabetic rats. Indian J. Exp. Biol. 44, 566-569.
  108. Sharma, S., Kulkarni, S. K. and Chopra, K. (2007) Effect of resveratrol, a polyphenolic phytoalexin, on thermal hyperalgesia in a mouse model of diabetic neuropathic pain. Fundam. Clin. Pharmacol. 21, 89-94. https://doi.org/10.1111/j.1472-8206.2006.00455.x
  109. Shrotriya, S., Tyagi, A., Deep, G., Orlicky, D. J., Wisell, J., Wang, X. J., Sclafani, R. A., Agarwal, R. and Agarwal, C. (2015) Grape seed extract and resveratrol prevent 4-nitroquinoline 1-oxide induced oral tumorigenesis in mice by modulating AMPK activation and associated biological responses. Mol. Carcinog. 54, 291-300. https://doi.org/10.1002/mc.22099
  110. Smoliga, J. M., Baur, J. A. and Hausenblas, H. A. (2011) Resveratrol and health-a comprehensive review of human clinical trials. Mol. Nutr. Food Res. 55, 1129-1141. https://doi.org/10.1002/mnfr.201100143
  111. Soleas, G. J., Grass, L., Josephy, P. D., Goldberg, D. M. and Diamandis, E. P. (2002) A comparison of the anticarcinogenic properties of four red wine polyphenols. Clin. Biochem. 35, 119-124. https://doi.org/10.1016/S0009-9120(02)00275-8
  112. Steele, V. E., Lubet, R. A. and Moon, R. C. (2005) Preclinical Animal Models for the Development of Cancer Chemoprevention Drugs. Humana Press Inc., Totowa, NJ.
  113. Szaefer, H., Krajka-Kuzniak, V. and Baer-Dubowska, W. (2008) The effect of initiating doses of benzo[a]pyrene and 7,12-dimethylbenz[a] anthracene on the expression of PAH activating enzymes and its modulation by plant phenols. Toxicology 251, 28-34. https://doi.org/10.1016/j.tox.2008.07.047
  114. Szklarczyk, D., Morris, J. H., Cook, H., Kuhn, M., Wyder, S., Simonovic, M., Santos, A., Doncheva, N. T., Roth, A., Bork, P., Jensen, L. J. and von Mering, C. (2017) The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res. 45, D362-D68. https://doi.org/10.1093/nar/gkw937
  115. Takaoka, M. (1939) Resveratrol, a new phenolic compound, from Veratrum grandiflorum. J. Chem. Soc. Jpn. 60, 1090-1100.
  116. Tameda, M., Sugimoto, K., Shiraki, K., Inagaki, Y., Ogura, S., Kasai, C., Yoneda, M., Okamoto, R., Yamamoto, N., Takei, Y., Ito, M. and Nobori, T. (2014) Resveratrol sensitizes HepG2 cells to TRAIL-induced apoptosis. Anticancer Drugs 25, 1028-1034. https://doi.org/10.1097/CAD.0000000000000128
  117. Vang, O., Ahmad, N., Baile, C. A., Baur, J. A., Brown, K., Csiszar, A., Das, D. K., Delmas, D., Gottfried, C., Lin, H. Y., Ma, Q. Y., Mukhopadhyay, P., Nalini, N., Pezzuto, J. M., Richard, T., Shukla, Y., Surh, Y. J., Szekeres, T., Szkudelski, T., Walle, T. and Wu, J. M. (2011) What is new for an old molecule? Systematic review and recommendations on the use of resveratrol. PLoS ONE 6, e19881. https://doi.org/10.1371/journal.pone.0019881
  118. Villa-Cuesta, E., Boylan, J. M., Tatar, M. and Gruppuso, P. A. (2011) Resveratrol inhibits protein translation in hepatic cells. PLoS ONE 6, e29513. https://doi.org/10.1371/journal.pone.0029513
  119. Wan, D., Zhou, Y., Wang, K., Hou, Y., Hou, R. and Ye, X. (2016) Resveratrol provides neuroprotection by inhibiting phosphodiesterases and regulating the cAMP/AMPK/SIRT1 pathway after stroke in rats. Brain Res. Bull. 121, 255-262. https://doi.org/10.1016/j.brainresbull.2016.02.011
  120. Wightman, E. L., Reay, J. L., Haskell, C. F., Williamson, G., Dew, T. P. and Kennedy, D. O. (2014) Effects of resveratrol alone or in combinationwith piperine on cerebral blood flow parameters and cognitive performance in human subjects: a randomised, double-blind, placebo-controlled, cross-over investigation. Br. J. Nutr. 112, 203-213. https://doi.org/10.1017/S0007114514000737
  121. Wu, J. M. and Hsieh, T.-C. (2018) Resveratrol: State-of-the-Art Science and Health Applications. World Scientific Publishing, Singapore.
  122. Xia, N., Strand, S., Schlufter, F., Siuda, D., Reifenberg, G., Kleinert, H., Forstermann, U. and Li, H. (2013) Role of SIRT1 and FOXO factors in eNOS transcriptional activation by resveratrol. Nitric Oxide 32, 29-35. https://doi.org/10.1016/j.niox.2013.04.001
  123. Yusuf, Y., Nasti, T. H., Meleth, S. and Elmets, C. A. (2009) Resveratrol enhances cell-mediated immune response to DMBA through TLR4 and prevents DMBA induced cutaneous carcinogenesis. Mol. Carcinog. 48, 713-723. https://doi.org/10.1002/mc.20517

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