The molecular targets of resveratrol
Open accessAbstract
Resveratrol has emerged in recent years as a compound conferring strong protection against metabolic, cardiovascular and other age-related complications, including neurodegeneration and cancer. This has generated the notion that resveratrol treatment acts as a calorie-restriction mimetic, based on the many overlapping health benefits observed upon both interventions in diverse organisms, including yeast, worms, flies and rodents. Though studied for over a decade, the molecular mechanisms governing the therapeutic properties of resveratrol still remain elusive. Elucidating how resveratrol exerts its effects would provide not only new insights in its fundamental biological actions but also new avenues for the design and development of more potent drugs to efficiently manage metabolic disorders. In this review we will cover the most recent advances in the field, with special focus on the metabolic actions of resveratrol and the potential role of SIRT1 and AMPK. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clinical findings to improved patient outcomes.
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RSV improved hepatic steatosis partially by inducing autophagy via the SIRT1 signaling pathway in vitro and in vivo.
“Moreover, RSV is a well-known activator of SIRT1 and our previous study also found that RSV improved hepatic steatosis partially by inducing autophagy via the SIRT1 signaling pathway in vitro and in vivo (36–38).”
RSV is a well-known activator of SIRT1.
“Moreover, RSV is a well-known activator of SIRT1 and our previous study also found that RSV improved hepatic steatosis partially by inducing autophagy via the SIRT1 signaling pathway in vitro and in vivo (36–38).”
Resveratrol produces an ex vivo increase in mitochondrial respiration that may depend on its ability to increase AMPK activity.
“However, despite producing an ex vivo increase in mitochondrial respiration that may be dependent of its ability to increase AMPK activity (Kulkarni and Cantó, 2015)”
From Mitochondrial (Dys)function and Insulin Resistance: From Pathophysiological Molecular Mechanisms to the Impact of Diet (2019) · cites this paper as Kulkarni and Cantó, 2015
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“The deacetylation reaction catalyzed by Sir2 is coordinated with the cleavage of NAD into nicotinamide and 1-O-acetyl-ADP-ribose [23,24].”
BackgroundFibroblast growth factor 21 regulates energy metabolism by activating the AMPK–SIRT1–PGC-1α pathway
Chau, M. D. L., Gao, J., Yang, Q., Wu, Z., & Gromada, J. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1006962107 · Cited by 548 · see citing works
Age-Associated Changes In Oxidative Stress and NAD+ Metabolism In Human Tissue
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“tent declines to the levels thatmight compromise SIRT1 activity [37,38].”
BackgroundDeficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction
Sakamoto, K., McCarthy, A., Smith, D. P., Green, K. A., Hardie, D. G., Ashworth, A., & Alessi, D. R. (2005) · The EMBO Journal · doi:10.1038/sj.emboj.7600667 · Cited by 544 · cited 2× · see citing works
“It was, hence, exciting to see that the Liver Kinase B1 (LKB1), the main upstream kinase for AMPK activation [89,90], was a target for SIRT1 deacetylation in cultured cells and rodent tissues [85].”
BackgroundRapalogs and mTOR inhibitors as anti-aging therapeutics
Lamming, D. W., Ye, L., Sabatini, D. M., & Baur, J. A. (2013) · Journal of Clinical Investigation · doi:10.1172/jci64099 · Cited by 531 · cited 3× · see citing works
“mTOR complexes 1 and 2 (mTORC1 and mTORC2), the mTOR kinase plays a key role in several pathways involved in cancer and metabolic diseases [121].”
BackgroundInfluentialResveratrol Acts as a Mixed Agonist/Antagonist for Estrogen Receptors α and β*
Bowers, J. L., Tyulmenkov, V. V., Jernigan, S. C., & Klinge, C. M. (2000) · Endocrinology · doi:10.1210/endo.141.10.7721 · Cited by 527 · see citing works
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“Initial hypothesis suggested that Rsv might either reduce NF-κB nuclear presence [111] or interfere with the transcriptional activity [112].”
BackgroundMultiple molecular targets of resveratrol: Anti-carcinogenic mechanisms
Athar, M., Back, J. H., Kopelovich, L., Bickers, D. R., & Kim, A. L. (2009) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2009.01.018 · Cited by 462 · see citing works
Inhibition of mitochondrial proton F0F1‐ATPase/ATP synthase by polyphenolic phytochemicals
Zheng, J., & Ramirez, V. D. (2000) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0703397 · Cited by 453 · cited 1× · see citing works
“Themost likely mechanism bywhich Rsv could activate AMPK relies on the ability of Rsv and related polyphenols (such as piceatannol and quercetin) to directly bind and inhibit the mitochondrial F1F0-ATPase/ATP synthase (Complex V), thus impairing ATP production [72,73].”
BackgroundSirT1 Regulates Energy Metabolism and Response to Caloric Restriction in Mice
Boily, G., Seifert, E. L., Bevilacqua, L., He, X. H., Sabourin, G., Estey, C., Moffat, C., Crawford, S., Saliba, S., Jardine, K., et al. (2008) · PLoS ONE · doi:10.1371/journal.pone.0001759 · Cited by 444 · cited 1× · see citing works
“adaptations, including the effect of CR on longevity [41,42].”
BackgroundTargeting Sirtuin 1 to Improve Metabolism: All You Need Is NAD+?
Cantó, C., & Auwerx, J. (2012) · Pharmacological Reviews · doi:10.1124/pr.110.003905 · Cited by 433 · cited 5× · see citing works
“time frames (several hours) in order to drive SIRT1 activation (discussed in [25]).”
BackgroundInfluentialSelf-citationAlmeida, L., Vaz‐da‐Silva, M., Falcão, A. C., Soares, E., Costa, R., Loureiro, A. I., Fernandes‐Lopes, C., Rocha, J., Nunes, T., Wright, L. C., et al. (2009) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.200800177 · Cited by 427 · cited 1× · see citing works
“plasma are either not detectable or clearly below the micromolar range [19,20], as used in vitro.”
MethodAMP-activated protein kinase and its downstream transcriptional pathways
Cantó, C., & Auwerx, J. (2010) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-010-0454-z · Cited by 421 · cited 2× · see citing works
“For example, PGC-1α is one well-established target of SIRT1 that acts as a master orchestrator of mitochondrial biogenesis [47].”
BackgroundSelf-citationResveratrol: Its Biologic Targets and Functional Activity
Pervaiz, S., & Holme, A. L. (2009) · Antioxidants and Redox Signaling · doi:10.1089/ars.2008.2412 · Cited by 411 · cited 1× · see citing works
“in a number of cell lines following Rsv treatment (see [95] and [98]), also supporting the Rsv chemopreventive activity.”
BackgroundA Role for SIR-2.1 Regulation of ER Stress Response Genes in Determining C. elegans Life Span
Viswanathan, M., Kim, S. K., Berdichevsky, A., & Guarente, L. (2005) · Developmental Cell · doi:10.1016/j.devcel.2005.09.017 · Cited by 409 · see citing works
Caloric restriction, SIRT1 and longevity
Cantó, C., & Auwerx, J. (2009) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2009.03.008 · Cited by 395 · see citing works
Self-citationAnti-Inflammatory Responses of Resveratrol
Das, S., & Das, D. K. (2007) · Inflammation & Allergy - Drug Targets · doi:10.2174/187152807781696464 · Cited by 383 · cited 1× · see citing works
“This way, Rsv has been shown to dramatically reduce COX-2 transcription by the combined downregulation of the Akt, MAPK and NF-κB pathways [100,101].”
BackgroundMechanism of inhibition of bovine F 1 -ATPase by resveratrol and related polyphenols
Gledhill, J. R., Montgomery, M. G., Leslie, A. G. W., & Walker, J. E. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0706290104 · Cited by 379 · cited 1× · see citing works
“Themost likely mechanism bywhich Rsv could activate AMPK relies on the ability of Rsv and related polyphenols (such as piceatannol and quercetin) to directly bind and inhibit the mitochondrial F1F0-ATPase/ATP synthase (Complex V), thus impairing ATP production [72,73].”
BackgroundCalorie restriction and cancer prevention: metabolic and molecular mechanisms
Longo, V. D., & Fontana, L. (2010) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2009.11.004 · Cited by 378 · cited 1× · see citing works
“Importantly, CR is an intervention that heavily protects against cancer development in rodents [8].”
BackgroundMagyar, K., Halmosi, R., Pálfi, A., Fehér, G., Czopf, L., Fulop, A., Battyány, I., Sümegi, B., Tóth, K., & Szabados, E. (2012) · Clinical Hemorheology and Microcirculation · doi:10.3233/ch-2011-1424 · Cited by 364 · see citing works
Chemoprevention by resveratrol: molecular mechanisms and therapeutic potential
Shankar, S. (2007) · Frontiers in bioscience · doi:10.2741/2432 · Cited by 340 · cited 1× · see citing works
“in a number of cell lines following Rsv treatment (see [95] and [98]), also supporting the Rsv chemopreventive activity.”
BackgroundGerhart‐Hines, Z., Dominy, J. E., Blättler, S. M., Jedrychowski, M. P., Banks, A. S., Lim, J.-H., Chim, H., Gygi, S. P., & Puigserver, P. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.12.005 · Cited by 323 · see citing works
Calorie Restriction: Is AMPK a Key Sensor and Effector
Cantó, C., & Auwerx, J. (2011) · Physiology · doi:10.1152/physiol.00010.2011 · Cited by 282 · see citing works
Self-citationPKA phosphorylates and inactivates AMPKα to promote efficient lipolysis
Djouder, N., Tuerk, R. D., Suter, M., Chiabotti, P. S., Thali, R. F., Scholz, R., Vaahtomeri, K., Auchli, Y., Rechsteiner, H., Brunisholz, R., et al. (2009) · The EMBO Journal · doi:10.1038/emboj.2009.339 · Cited by 277 · cited 1× · see citing works
“might trigger AMPK activation [106–108], PKA has also been reported to directly phosphorylate and negatively influence AMPK activity [109].”
BackgroundWong, R. H. X., Howe, P. R. C., Buckley, J. D., Coates, A. M., Kunz, I., & Berry, N. M. (2011) · Nutrition, Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2010.03.003 · Cited by 277 · cited 1× · see citing works
“dose-dependently improve endothelium-dependent vasodilatation [15].”
Kundu, J. K., Shin, Y. K., Kim, S. H., & Surh, Y. (2006) · Carcinogenesis · doi:10.1093/carcin/bgi349 · Cited by 272 · cited 1× · see citing works
“This way, Rsv has been shown to dramatically reduce COX-2 transcription by the combined downregulation of the Akt, MAPK and NF-κB pathways [100,101].”
Ashikawa, K., Majumdar, S., Banerjee, S., Bharti, A. C., Shishodia, S., & Aggarwal, B. B. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.11.6490 · Cited by 238 · see citing works
Phytoestrogens and Breast Cancer Prevention: Possible Mechanisms of Action
Mense, S. M., Hei, T. K., Ganju, R. K., & Bhat, H. K. (2008) · Environmental Health Perspectives · doi:10.1289/ehp.10538 · Cited by 229 · cited 3× · see citing works
“phytoestrogenic action of Rsv could support a chemoprotective role in breast cancer, there is also evidence suggesting possible adverse effects [132], likely depending on the distinctive patterns of ERα and ERβ expressions in different cell types.”
BackgroundStimulation of muscle cell glucose uptake by resveratrol through sirtuins and AMPK
Breen, D. M., Sanli, T., Giacca, A., & Tsiani, E. (2008) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2008.06.104 · Cited by 213 · cited 3× · see citing works
“Similarly Rsv triggered skeletal muscle glucose transport in an AMPKdependent manner [62].”
BackgroundMattison, J. A., Wang, M., Bernier, M., Zhang, J., Park, S. S., Maudsley, S. R., An, S. S., Santhanam, L., Martin, B., Faulkner, S., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.04.018 · Cited by 206 · see citing works
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Boocock, D. J., Patel, K. R., Faust, G. E. S., Normolle, D. P., Marczylo, T. H., Crowell, J. A., Brenner, D. E., Booth, T. D., Gescher, A. J., & Steward, W. P. (2006) · Journal of Chromatography B · doi:10.1016/j.jchromb.2006.10.017 · Cited by 199 · cited 1× · see citing works
“plasma are either not detectable or clearly below the micromolar range [19,20], as used in vitro.”
MethodSirt1 enhances skeletal muscle insulin sensitivity in mice during caloric restriction
Schenk, S., McCurdy, C. E., Philp, A., Chen, M. Z., Holliday, M. J., Bandyopadhyay, G. K., Osborn, O., Baar, K., & Olefsky, J. M. (2011) · Journal of Clinical Investigation · doi:10.1172/jci58554 · Cited by 197 · cited 1× · see citing works
“Similarly, basal AMPK activity in the skeletal muscle seems unaffected by SIRT1 deletion [49,87,88].”
BackgroundResveratrol prevents apoptosis in K562 cells by inhibiting lipoxygenase and cyclooxygenase activity
Maccarrone, M., Lorenzon, T., Guerrieri, P., & Finazzi‐Agrò, A. (1999) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.1999.00630.x · Cited by 194 · cited 1× · see citing works
“In addition, Rsv has also been described to inhibit lipooxygenases (LOX) activity [102,103],”
BackgroundRegulation of Caenorhabditis elegans lifespan by sir-2.1 transgenes
Viswanathan, M., & Guarente, L. (2011) · Nature · doi:10.1038/nature10440 · Cited by 191 · see citing works
Garcia-Roves, P. M., Osler, M. E., Holmström, M. H., & Zierath, J. R. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m805078200 · Cited by 190 · cited 1× · see citing works
“Finally, the significant effects of Rsv onmitochondrial biogenesis in the skeletal muscle closely mimic those observed by treatment with AMPK agonists [80] or AMPK gain-of-function models [81], but were not observed in models where SIRT1 was moderately overexpressed [56,82,83].”
BackgroundPatel, 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., et al. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3005870 · Cited by 190 · cited 1× · see citing works
“human colorectal cells into stable sulfate-conjugated forms, which would then gradually regenerate into the parental compound, providing the beneficial effects in vivo [21].”
BackgroundPhilp, A., Chen, A., Lan, D., Meyer, G. A., Murphy, A. N., Knapp, A. E., Olfert, I. M., McCurdy, C. E., Marcotte, G. R., Hogan, M. C., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.261685 · Cited by 184 · cited 1× · see citing works
“Similarly, basal AMPK activity in the skeletal muscle seems unaffected by SIRT1 deletion [49,87,88].”
BackgroundResveratrol Inhibits mTOR Signaling by Promoting the Interaction between mTOR and DEPTOR
Liu, M., Wilk, S. A., Wang, A., Zhou, L., Wang, R.-H., Ogawa, W., Deng, C., Dong, L., & Liu, F. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.169284 · Cited by 177 · cited 4× · see citing works
“Recent studies have also demonstrated that Rsv inhibits mTOR signaling via a SIRT1-independent mechanism [122] and that it represses protein synthesis [123].”
BackgroundInfluentialResveratrol: From Basic Science to the Clinic
Cucciolla, V., Borriello, A., Oliva, A., Galletti, P., Zappia, V., & Ragione, F. D. (2007) · Cell Cycle · doi:10.4161/cc.6.20.4815 · Cited by 174 · see citing works
Concurrent regulation of AMP-activated protein kinase and SIRT1 in mammalian cells
Suchankova, G., Nelson, L. E., Gerhart-Hines, Z., Kelly, M., Gauthier, M.-S., Saha, A. K., Ido, Y., Puigserver, P., & Ruderman, N. B. (2009) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2008.11.130 · Cited by 162 · cited 2× · see citing works
“Surprisingly, Rsv led to AMPK activation within minutes inmost cell lines tested, including hepatic and cultured skeletal muscle cell models [45,62,69,70] much faster than generally required for SIRT1 activation.”
BackgroundLi, L., Pan, R., Li, R., Niemann, B., Aurich, A.-C., Chen, Y., & Rohrbach, S. (2010) · Diabetes · doi:10.2337/db10-0331 · Cited by 159 · see citing works
Inhibition of mammalian S6 kinase by resveratrol suppresses autophagy
Armour, S. M., Baur, J. A., Hsieh, S. N., Land-Bracha, A., Thomas, S. Μ., & Sinclair, D. A. (2009) · Aging · doi:10.18632/aging.100056 · Cited by 156 · cited 1× · see citing works
“Interestingly, Rsv has also been found through an in vitro screen to act as a direct inhibitor of p70S6K [126], a key downstream target of the mTOR pathway regulating autophagy and protein translation rates, albeit at an IC50 of 25 μM[126], which is higher than the lowmicromolar concentrations at which Rsv enhances AM…”
BackgroundResveratrol is a class IA phosphoinositide 3-kinase inhibitor
Fröjdö, S., Cozzone, D., Vidal, H., & Pirola, L. (2007) · Biochemical Journal · doi:10.1042/bj20070236 · Cited by 156 · cited 3× · see citing works
“and colleagues unveiled that Rsv could inhibit PI3K signaling independently of SIRT1 [118].”
BackgroundInfluentialWang, Z., Zou, J., Cao, K., Hsieh, T., Huang, Y., & WU, J. M. (2005) · PubMed · Cited by 152 · see citing works
Distinct roles of IκB proteins in regulating constitutive NF-κB activity
Tergaonkar, V., Correa, R. G., Ikawa, M., & Verma, I. M. (2005) · Nature Cell Biology · doi:10.1038/ncb1296 · Cited by 148 · see citing works
Deng, J.-Y., Hsieh, P., Huang, J., Lu, L., & Hung, L. (2008) · Diabetes · doi:10.2337/db07-1750 · Cited by 147 · cited 1× · see citing works
“In fact, while most data suggests that Rsv increases skeletal muscle glucose uptake [44,59,60], even in an acute fashion [61,62], SIRT1 transgenesis in the muscle does not affect insulin action [63].”
BackgroundActivation of AMP-Activated Protein Kinase by Interleukin-6 in Rat Skeletal Muscle
Kelly, M., Gauthier, M., Saha, A. K., & Ruderman, N. B. (2009) · Diabetes · doi:10.2337/db08-1293 · Cited by 144 · see citing works
Omar, B. A., Zmuda‐Trzebiatowska, E., Manganiello, V. C., Göransson, O., & Degerman, E. (2009) · Cellular Signalling · doi:10.1016/j.cellsig.2009.01.015 · Cited by 141 · see citing works
Resveratrol inhibits NF-kB signaling through suppression of p65 and IkappaB kinase activities.
Ren, Z., Wang, L., Cui, J., Huoc, Z., Xue, J., Hao, C., Mao, Q., & Yang, R. (2013) · PubMed · Cited by 138 · see citing works
Does calorie restriction induce mitochondrial biogenesis? A reevaluation
Hancock, C. R., Han, D., Higashida, K., Kim, S. H., & Holloszy, J. O. (2011) · The FASEB Journal · doi:10.1096/fj.10-170415 · Cited by 131 · cited 1× · see citing works
“Similarly, Rsv, but not SIRT1 overexpression or CR, leads to a dramatic increase in skeletal muscle mitochondrial content [44,56,58].”
BackgroundSIRT1 metabolic actions: Integrating recent advances from mouse models
Boutant, M., & Cantó, C. (2013) · Molecular Metabolism · doi:10.1016/j.molmet.2013.10.006 · Cited by 121 · cited 2× · see citing works
“However, as discussed in a recent review [83], this mechanism might need further clarification given that previous reports failed to detect such phosphorylation event.”
BackgroundSelf-citationNin, V., Escande, C., Chini, C. C. S., Giri, S., Camacho-Pereira, J., Matalonga, J., Lou, Z., & Chini, E. N. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.365874 · Cited by 119 · cited 2× · see citing works
“According to it, AMPK would directly phosphorylate SIRT1 [84].”
BackgroundSirt1 activation by resveratrol is substrate sequence-selective
Lakshminarasimhan, M., Rauh, D., Schutkowski, M., & Steegborn, C. (2013) · Aging · doi:10.18632/aging.100542 · Cited by 117 · cited 1× · see citing works
“with this, efforts from the Steegborn lab illustrated how Rsv action only triggers SIRT1-mediated deacetylation in a substrate specific fashion, and even led to a paradoxical inhibition of SIRT1 actions on certain substrates [51].”
BackgroundMinakawa, M., Miura, Y., & Yagasaki, K. (2012) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2012.05.017 · Cited by 114 · see citing works
Resveratrol inhibits insulin responses in a SirT1-independent pathway
Zhang, J. (2006) · Biochemical Journal · doi:10.1042/bj20050977 · Cited by 114 · cited 1× · see citing works
“IRS-1 and Grb2, which drives MAPK activation [119], although the genuine molecular mechanism was not identified in that case.”
BackgroundMercken, E. M., Hu, J. H., Krzysik-Walker, S. M., Wei, M., Li, Y., McBurney, M. W., de Cabo, R., & Longo, V. D. (2013) · Aging Cell · doi:10.1111/acel.12151 · Cited by 112 · see citing works
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Increased expression of Drosophila Sir 2 extends life span in a dose-dependent manner
Whitaker, R., Faulkner, S., Miyokawa, R., Burhenn, L., Henriksen, M., Wood, J. G., & Helfand, S. L. (2013) · Aging · doi:10.18632/aging.100599 · Cited by 103 · cited 1× · see citing works
“Genetic manipulation of Sir2 orthologs was later demonstrated to affect lifespan in higher eukaryotes, such as nematodes [28, 29] and insects [30,31], even though the consistency and amplitude of this effect has been a matter of debate [32–34].”
BackgroundMiloso, M., Bertelli, A. A. E., Nicolini, G., & Tredici, G. (1999) · Neuroscience Letters · doi:10.1016/s0304-3940(99)00194-9 · Cited by 101 · cited 1× · see citing works
“For example, doses up to the lowmicromolar range might increase ERK signaling, whereas Rsv is inhibitory at the most commonly used, higher, doses (N50 μM) [133].”
BackgroundResveratrol Is a Potent Inhibitor of the Dioxygenase Activity of Lipoxygenase
Pinto, M. C., García-Barrado, J. A., & Macı́as, P. (1999) · Journal of Agricultural and Food Chemistry · doi:10.1021/jf990448n · Cited by 97 · cited 1× · see citing works
“In addition, Rsv has also been described to inhibit lipooxygenases (LOX) activity [102,103],”
BackgroundAdrenergic Regulation of AMP-activated Protein Kinase in Brown Adipose Tissue in Vivo
Pulinilkunnil, T., He, H., Kong, D., Asakura, K., Peroni, O. D., Lee, A. D., & Kahn, B. B. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.218719 · Cited by 84 · see citing works
Fukao, H., Ijiri, Y., Miura, M., Hashimoto, M., Yamashita, T., Fukunaga, C., Oiwa, K., Kawai, Y., Suwa, M., & Yamamoto, J. (2004) · Blood Coagulation & Fibrinolysis · doi:10.1097/00001721-200408000-00001 · Cited by 68 · cited 1× · see citing works
“Rsv effectively protected against plaque development in different animal models of atherogenesis [9,10].”
BackgroundTan, Z., Zhou, L., Mu, P., Liu, S., Chen, S., Fu, X., & Wang, T. (2012) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2011.12.003 · Cited by 66 · cited 1× · see citing works
“In fact, while most data suggests that Rsv increases skeletal muscle glucose uptake [44,59,60], even in an acute fashion [61,62], SIRT1 transgenesis in the muscle does not affect insulin action [63].”
BackgroundLombard, D. B., Pletcher, S. D., Cantó, C., & Auwerx, J. H. (2011) · Nature · doi:10.1038/477410a · Cited by 47 · see citing works
Self-citationWhite, A. T., McCurdy, C. E., Philp, A., Hamilton, D. L., Johnson, C. D., & Schenk, S. (2013) · Diabetologia · doi:10.1007/s00125-013-2912-2 · Cited by 44 · cited 1× · see citing works
“In fact, while most data suggests that Rsv increases skeletal muscle glucose uptake [44,59,60], even in an acute fashion [61,62], SIRT1 transgenesis in the muscle does not affect insulin action [63].”
BackgroundSirt1-Independent Mechanisms of the Putative Sirtuin Enzyme Activators SRT1720 and SRT2183
Huber, J. L., McBurney, M. W., DiStefano, P. S., & McDonagh, T. (2010) · Future Medicinal Chemistry · doi:10.4155/fmc.10.257 · Cited by 41 · see citing works
The pig as a valuable model for testing the effect of resveratrol to prevent cardiovascular disease
Elmadhun, N. Y., Sabe, A. A., Robich, M. P., Chu, L. M., Lassaletta, A. D., & Sellke, F. W. (2013) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.12216 · Cited by 36 · cited 1× · see citing works
“In porcine models, Rsv improved myocardial perfusion, and regional contractility while decreasing oxidative stress [13].”
BackgroundBertelli, A., Falchi, M., Dib, B., Pini, E., Mukherjee, S., & Das, D. K. (2007) · Antioxidants and Redox Signaling · doi:10.1089/ars.2007.1926 · Cited by 25 · see citing works
Resveratrol Inhibits Protein Translation in Hepatic Cells
Villa-Cuesta, E., Boylan, J. M., Tatar, M., & Gruppuso, P. A. (2011) · PLoS ONE · doi:10.1371/journal.pone.0029513 · Cited by 21 · cited 1× · see citing works
“Recent studies have also demonstrated that Rsv inhibits mTOR signaling via a SIRT1-independent mechanism [122] and that it represses protein synthesis [123].”
Background
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The therapeutic potential of resveratrol: a review of clinical trials
Berman, A. Y., Motechin, R. A., Wiesenfeld, M. Y., & Holz, M. K. (2017) · npj Precision Oncology · doi:10.1038/s41698-017-0038-6 · Cited by 895 · see citing works
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A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease
Turner, R. S., Thomas, R. G., Craft, S., van Dyck, C. H., Mintzer, J. E., Reynolds, B., Brewer, J. B., Rissman, R. A., Raman, R., Aisen, P. S. S., et al. (2015) · Neurology · doi:10.1212/wnl.0000000000002035 · Cited by 752 · see citing works
“Resveratrol has many targets, with some engaged at uM concentrations.(4) These findings suggest that a central molecular target may be engaged at nM concentrations.”
InfluentialTargeting cellular senescence with senotherapeutics: senolytics and senomorphics
Zhang, L. J., Pitcher, L. E., Prahalad, V., Niedernhofer, L. J., & Robbins, P. D. (2022) · FEBS Journal · doi:10.1111/febs.16350 · Cited by 648 · see citing works
Resveratrol (RV): A pharmacological review and call for further research
Zhang, L., Li, C., Kakar, M. U., Khan, M. S., Wu, P.-F., Amir, R. M., Dai, D., Naveed, M., Li, Q., Saeed, M., et al. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.112164 · Cited by 552 · see citing works
Health benefits of resveratrol: Evidence from clinical studies
Singh, A. P., Singh, R., Verma, S. S., Rai, V., Kaschula, C. H., Maiti, P., & Gupta, S. C. (2019) · Medicinal Research Reviews · doi:10.1002/med.21565 · Cited by 523 · see citing works
“Both clinical and preclinical data has shown that resveratrol has many targets and that it can modulate numerous signaling molecules including Wnt, nuclear factor‐κB (NF‐κB), cytokines, caspases, Notch, matrix metalloproteinases (MMPs), 5′‐AMP‐activated protein kinase (AMPK), intercellular adhesion molecule (ICAM), va…”
BackgroundIschemia/Reperfusion Injury Revisited: An Overview of the Latest Pharmacological Strategies
Soares, R. O. D. S., Losada, D. M., Jordani, M. C., Évora, P. R. B., & Castro-e-Silva, O. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20205034 · Cited by 415 · see citing works
Sergi, D., Naumovski, N., Heilbronn, L. K., Abeywardena, M., O’Callaghan, N., Lionetti, L., & Luscombe-Marsh, N. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00532 · Cited by 347 · see citing works
Targeting mitochondrial metabolism for precision medicine in cancer
Sainero‐Alcolado, L., Liaño-Pons, J., Ruiz-Pérez, M. V., & Arsenian‐Henriksson, M. (2022) · Cell Death and Differentiation · doi:10.1038/s41418-022-01022-y · Cited by 330 · see citing works
“Complex III Resveratrol Lack of specificity [141]”
Physiological geroscience: targeting function to increase healthspan and achieve optimal longevity
Seals, D. R., Justice, J. N., & LaRocca, T. J. (2015) · The Journal of Physiology · doi:10.1113/jphysiol.2014.282665 · Cited by 312 · see citing works
“…through a variety of SIRT-1-dependent or -independent mechanisms, including antioxidant, anti-inflammatory and/or nitric oxide-enhancing actions, as well as cytoprotective effects mediated via stimulation of cellular stress resistance pathways (Knutson & Leeuwenburgh, 2008; Kulkarni & Canto, 2014).”
BackgroundResveratrol and Its Human Metabolites—Effects on Metabolic Health and Obesity
Springer, M., & Moco, S. (2019) · Nutrients · doi:10.3390/nu11010143 · Cited by 293 · see citing works
“Activation of Akt reduces the activity of AMPK through direct phosphorylation [79].”
BackgroundInfluentialTreatment Options for Motor and Non-Motor Symptoms of Parkinson’s Disease
Church, F. (2021) · Biomolecules · doi:10.3390/biom11040612 · Cited by 303 · see citing works
“Trans-resveratrol is a potent antioxidant capable of reducing free radicals in the environment of the brain [141,142].”
BackgroundResveratrol for Alzheimer's disease
Sawda, C. N., Moussa, C., & Turner, R. S. (2017) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.13431 · Cited by 281 · see citing works
Role of AMPK mediated pathways in autophagy and aging
Ge, Y., Zhou, M., Chen, C., Wu, X., & Wang, X. (2021) · Biochimie · doi:10.1016/j.biochi.2021.11.008 · Cited by 253 · see citing works
Zheng, Z., Bian, Y., Zhang, Y., Ren, G., & Li, G. (2020) · Cell Cycle · doi:10.1080/15384101.2020.1743911 · Cited by 248 · see citing works
Resveratrol supplementation: Where are we now and where should we go?
Novelle, M. G., Wahl, D., Diéguez, C., Bernier, M., & de Cabo, R. (2015) · Ageing Research Reviews · doi:10.1016/j.arr.2015.01.002 · Cited by 247 · see citing works
“The identification and validation of the cellular targets of RSV is key for understanding its health benefits (for a recent review about this topic see (Kulkarni and Canto, 2014)).”
Long non-coding RNAs are emerging targets of phytochemicals for cancer and other chronic diseases
Mishra, S., Verma, S. S., Rai, V., Awasthee, N., Chava, S. P., Hui, K. M., Kumar, A. P., Challagundla, K. B., Sethi, G., & Gupta, S. C. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03053-0 · Cited by 226 · see citing works
Redox Signaling and Advanced Glycation Endproducts (AGEs) in Diet-Related Diseases
Cepas, V., Collino, M., Mayo, J. C., & Sainz, R. M. (2020) · Antioxidants · doi:10.3390/antiox9020142 · Cited by 206 · see citing works
de Oliveira, M. R., Nabavi, S. F., Manayi, A., Daglia, M., Hajheydari, Z., & Nabavi, S. M. (2016) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2016.01.017 · Cited by 192 · see citing works
Therapeutic Versatility of Resveratrol Derivatives
Nawaz, W., Zhou, Z.-Q., Deng, S., Ma, X., Ma, X., Li, C., & Shu, X. H. (2017) · Nutrients · doi:10.3390/nu9111188 · Cited by 175 · see citing works
“The chemical structure of resveratrol is composed of two aromatic rings allied by a methylene bridge, and presents in both trans- and cis-isomeric forms naturally (Figure 1), however, the majority of the recorded medical advantages are attributed to trans-resveratrol but not its cis-form, so the structure activity rel…”
BackgroundUnravelling the mechanisms regulating muscle mitochondrial biogenesis
Hood, D. A., Tryon, L. D., Carter, H. N., Kim, Y., & Chen, C. C. W. (2016) · Biochemical Journal · doi:10.1042/bcj20160009 · Cited by 159 · see citing works
Epigenetic Regulatory Mechanisms Induced by Resveratrol
Fernandes, G., Silva, G., Pavan, A. R., Chiba, D. E., Chin, C. M., & dos Santos, J. L. (2017) · Nutrients · doi:10.3390/nu9111201 · Cited by 162 · see citing works
Kerkhofs, M., Bittremieux, M., Morciano, G., Giorgi, C., Pinton, P., Parys, J. B., & Bultynck, G. (2018) · Cell Death and Disease · doi:10.1038/s41419-017-0179-0 · Cited by 160 · see citing works
Buhrmann, C., Shayan, P., Kraehe, P., Popper, B., Goel, A., & Shakibaei, M. (2015) · Biochemical Pharmacology · doi:10.1016/j.bcp.2015.08.105 · Cited by 148 · see citing works
“Ultrathin sections were contrasted with 2% uranyl acetate/lead citrate and examined under FEI Tecnai12 transmission electron microscope operated at 120 kV. Digital images were taken with an OSIS Megaview III CCD camera or Carl Zeiss Microscopy TEM 902, operated at 80kV, images were digitized using a slow-scan charge-c…”
InfluentialRole of Hedgehog Signaling in Breast Cancer: Pathogenesis and Therapeutics
Galdo, N. A. R., Montero, Á. L., & Wertheimer, E. V. (2019) · Cells · doi:10.3390/cells8040375 · Cited by 142 · see citing works
An instrumented phantom system for analog computation of treatment plans.
Alderson, S. W., Lanzl, L. H., ROLLINS, M., & SPIRA, J. (1962) · PubMed · Cited by 143 · see citing works
Strategies to Improve Resveratrol Systemic and Topical Bioavailability: An Update
Intagliata, S., Modica, M. N., Santagati, L. M., & Montenegro, L. (2019) · Antioxidants · doi:10.3390/antiox8080244 · Cited by 139 · see citing works
“Conversely, RSV activates various biochemical factors such as adenosine monophosphate (AMP)-activated protein kinase (AMPK) [29–33] and the tumor suppressor p53 [34,35], and also induces nitric oxide synthase (NOS) [36].”
BackgroundEffects of Resveratrol against Lung Cancer: In Vitro and In Vivo Studies
Yousef, M., Vlachogiannis, I. A., & Tsiani, E. (2017) · Nutrients · doi:10.3390/nu9111231 · Cited by 138 · see citing works
“Furthermore, RSV has been established as an activator of SIRT1, a histone deacetylase that plays important role in many fundamental cellular processes [64,65].”
BackgroundThe Effects of Resveratrol in the Treatment of Metabolic Syndrome
Hou, C., Tain, Y., Yu, H., & Huang, L. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20030535 · Cited by 137 · see citing works
“AMPK has emerged as a key nutrient sensor, with the ability to regulate whole-body metabolism [24], coordinating many metabolic reactions [25] to maintain metabolic homeostasis and induce the inflammatory response [26].”
BackgroundInhibition of NF-κB Signaling Pathway by Resveratrol Improves Spinal Cord Injury
Xu, L. K., Botchway, B. O. A., Zhang, S., Zhou, J., & Liu, X. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00690 · Cited by 137 · see citing works
“…(Lai et al., 2017), antiapoptosis (Huang et al., 2014), anti-nociception (Pan et al., 2016), anti-depression (Finnell et al., 2016), anti-cancer activities (Chin et al., 2015; Kumar et al., 2015), neuronal protection (Nalagoni and Karnati, 2016) and regulation of metabolism (Luo et al., 2017).”
The Role of Resveratrol in Liver Disease: A Comprehensive Review from In Vitro to Clinical Trials
Izzo, C., Annunziata, M., Melara, G., Sciorio, R., Dallio, M., Masarone, M., Federico, A., & Persico, M. (2021) · Nutrients · doi:10.3390/nu13030933 · Cited by 134 · see citing works
“500 mg od for six months AMPK/SIRT1/Nrf2, ERK/p38, MAPK and PTEN/Akt signaling pathways, inducing autophagy through an mTOR-dependent or TFEB-dependent pathway Synthesis of antioxidant molecules and the expression of related genes involved in the biogenesis of mitochondrial energy [36,37]”
BackgroundSirtuins and FoxOs in osteoporosis and osteoarthritis
Almeida, M., & Porter, R. M. (2019) · Bone · doi:10.1016/j.bone.2019.01.018 · Cited by 129 · see citing works
Valenti, D., Lidia de, B. A. R. I., Rasmo, D. D., Signorile, A., Henrion‐Caude, A., Contestabile, A., & Vacca, R. A. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2016.03.003 · Cited by 128 · see citing works
Natural Compounds as Regulators of NLRP3 Inflammasome-Mediated IL-1 β Production
Tőzsér, J., & Benkő, S. (2016) · Mediators of Inflammation · doi:10.1155/2016/5460302 · Cited by 129 · see citing works
“At high doses, resveratrol has been shown to activate AMPK; which is involved in the negative regulation of the NLRP3-inflammasome [113].”
BackgroundInfluentialTargeting senescent cells: approaches, opportunities, challenges
von Kobbe, C. (2019) · Aging · doi:10.18632/aging.102557 · Cited by 129 · see citing works
Patra, S., Mishra, S. R., Behera, B. P., Mahapatra, K. K., Panigrahi, D. P., Bhol, C. S., Praharaj, P. P., Sethi, G., Patra, S. K., & Bhutia, S. K. (2020) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2020.05.008 · Cited by 126 · see citing works
Zhu, C. W., Grossman, H. T., Neugroschl, J. A., Parker, S., Burden, A. R., Luo, X., & Sano, M. C. (2018) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1016/j.trci.2018.09.009 · Cited by 125 · see citing works
“Finally, neuroprotection has been proposed based on reducing cell death via activation of sirtuins (including SIRT1), resulting in protection against peptide aggregate [9].”
BackgroundZhang, E., Guo, Q., Gao, H., Xu, R., Teng, S., & Wu, Y. (2015) · PLoS ONE · doi:10.1371/journal.pone.0143814 · Cited by 125 · see citing works
Wan, D., Zhou, Y., Wang, K., Hou, Y., Hou, R., & Ye, X. (2016) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2016.02.011 · Cited by 124 · see citing works
Vega-García, C. C., Reyes‐Castro, L. A., Rodríguez-González, G. L., Bautista, C. J., Vázquez‐Martínez, M., Larrea, F., Chamorro‐Cevallos, G. A., Nathanielsz, P. W., & Zambrano, E. (2015) · The Journal of Physiology · doi:10.1113/jp271543 · Cited by 123 · see citing works
“Using transgenic mouse models, it was shown that AMPK and SIRT1 are key mediators of the metabolic health actions driven by resveratrol (Kulkarni & Canto, 2015).”
BackgroundSaunier, E. F., Antonio, S., Regazzetti, A., Auzeil, N., Laprévôte, O., Shay, J. W., Coumoul, X., Barouki, R., Benelli, C., Laurence Therese, H. U. C., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-07006-0 · Cited by 120 · see citing works
Lysosomes: Signaling Hubs for Metabolic Sensing and Longevity
Savini, M., Zhao, Q., & Wang, M. C. (2019) · Trends in Cell Biology · doi:10.1016/j.tcb.2019.08.008 · Cited by 115 · see citing works
“and mice [91,113,114], which is at least partially attributed to lysosomal activation of AMPK [115,116].”
BackgroundThe road ahead for health and lifespan interventions
Gonzalez-Freire, M., Diaz-Ruiz, A., Hauser, D., Martinez-Romero, J., Ferrucci, L., Bernier, M., & de Cabo, R. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101037 · Cited by 118 · see citing works
“The molecular mechanisms of action of resveratrol remain elusive; however, AMPK and the NAD-dependent deacetylase SIRT1 have been proposed to mediate the anti-aging response and disease protection of resveratrol, reminiscent of CR signaling (Baur et al., 2006; Park et al., 2012; Kulkarni and Canto, 2015).”
BackgroundDemaré, S., Kothari, A., Calcutt, N. A., & Fernyhough, P. (2020) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2021.1847645 · Cited by 115 · see citing works
Resveratrol promotes hUC-MSCs engraftment and neural repair in a mouse model of Alzheimer’s disease
Wang, X., Ma, S., Yang, B., Huang, T., Meng, N., Xu, L., Xing, Q., Zhang, Y.-T. Y., Zhang, K., Li, Q., et al. (2017) · Behavioural Brain Research · doi:10.1016/j.bbr.2017.10.032 · Cited by 112 · see citing works
“Studies have shown that resveratrol can mimic certain aspects of caloric restriction and it exerts a wide range of biological effects that can protect against age-related diseases including cardiovascular and neurodegenerative diseases [6].”
Early-Life Origins of Metabolic Syndrome: Mechanisms and Preventive Aspects
Hsu, C., Hou, C., Hsu, W.-H., & Tain, Y. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222111872 · Cited by 111 · see citing works
Lejri, I., Agapouda, A., Grimm, A., & Eckert, A. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/9695412 · Cited by 107 · see citing works
“In fact, the essential neuroprotective effect of resveratrol is based on the action of SIRT1 and AMPK and on the phosphorylation/acetylation status of PGC-1α that consequently activates the mitochondrial biogenesis leading to the improvement of the mitochondrial activity [103] (Figure 3).”
BackgroundSirtuins, resveratrol and the intertwining cellular pathways connecting them
Ungurianu, A., Zanfirescu, A., & Margina, D. M. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.101936 · Cited by 113 · see citing works
The “Yin and Yang” of Natural Compounds in Anticancer Therapy of Triple-Negative Breast Cancers
Varghese, E., Samuel, S. M., Abotaleb, M., Cheema, S., Mamtani, R., & Büsselberg, D. (2018) · Cancers · doi:10.3390/cancers10100346 · Cited by 107 · see citing works
“Resveratrol exerts its anticancer effects in different cancers by reducing ROS, COX, and cytokine expression (antioxidant and anti-inflammatory effect); by decreasing the activity of transcription factors such as NF-κB and AP-1 (anti-proliferative and anti-survival effect); by decreasing cyclins and CDKs (anti-prolife…”
BackgroundResveratrol in Cancer Patients: From Bench to Bedside
Berretta, M., Bignucolo, A., Francia, R. D., Comello, F., Facchini, G., Ceccarelli, M., Iaffaioli, R. V., Quagliariello, V., & Maurea, N. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21082945 · Cited by 107 · see citing works
Iakovou, E., & Kourti, M. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.827900 · Cited by 113 · see citing works
Polyphenol compounds and PKC signaling
Das, J., Ramani, R., & Suraju, M. O. (2016) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2016.06.022 · Cited by 107 · see citing works
Significance of Resveratrol in Clinical Management of Chronic Diseases
Wahab, A., Gao, K., Jia, C., Zhang, F., Tian, G., Murtaza, G., & Chen, J. (2017) · Molecules · doi:10.3390/molecules22081329 · Cited by 107 · see citing works
“Health outcomes of RSV could be better understood if its cellular targets were identified and validated [135].”
BackgroundAntidiabetic Effects of Resveratrol: The Way Forward in Its Clinical Utility
Oyenihi, O. R., Oyenihi, A. B., Adeyanju, A. A., & Oguntibeju, O. O. (2016) · Journal of Diabetes Research · doi:10.1155/2016/9737483 · Cited by 103 · see citing works
“The alleviation of diabetic complications upon the activation of AMPK by RSV has been confirmed in animal models [15, 19, 59, 89].”
BackgroundInfluentialAnti-Cancer Properties of Resveratrol: A Focus on Its Impact on Mitochondrial Functions
Kuršvietienė, L., Kopustinskienė, D. M., Stanevičienė, I., Mongirdienė, A., Kubová, K., Masteiková, R., & Bernatonienė, J. (2023) · Antioxidants · doi:10.3390/antiox12122056 · Cited by 102 · see citing works
“Resveratrol exerts anti-cancer activity through various molecular mechanisms, including the PI3K/Akt, STAT3/5, MAPK, AMPK/mTOR, SIRT1/NF-κ B, and PGC-1 α signaling pathways [46–48].”
BackgroundCHUNG, S. S., Dutta, P., Austin, D., Wang, P., Awad, A., & Vadgama, J. V. (2018) · Oncotarget · doi:10.18632/oncotarget.25993 · Cited by 99 · see citing works
“Resveratrol interacts with various molecular targets associated with inflammation and immunity [13].”
BackgroundLi, W., Ma, X., Li, N., Liu, H., Dong, Q., Zhang, J., Yang, C., Liu, Y., Liang, Q., Zhang, S., et al. (2016) · Experimental Cell Research · doi:10.1016/j.yexcr.2016.11.002 · Cited by 98 · see citing works
Hühn, S., Beyer, F., Zhang, R., Lampe, L., Grothe, J., Kratzsch, J., Willenberg, A., Breitfeld, J., Kovacs, P. L., Stümvoll, M., et al. (2018) · NeuroImage · doi:10.1016/j.neuroimage.2018.03.023 · Cited by 96 · see citing works
“In vitro as well as in vivo rodent and primate studies provided evidence for antioxidative, anti-inflammatory and calorie-restriction mimicking characteristics of resveratrol (Baur, 2010; Bastianetto et al., 2015; Kulkarni and Canto, 2015).”
BackgroundSUGIYAMA, M., Kawahara‐Miki, R., KAWANA, H., Shirasuna, K., Kuwayama, T., & Iwata, H. (2015) · Journal of Reproduction and Development · doi:10.1262/jrd.2015-001 · Cited by 94 · see citing works
Neuroprotective effects of plant polysaccharides: A review of the mechanisms
Gao, Q., Fu, X., Zhang, R., Wang, Z., & Guo, M. (2017) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2017.08.075 · Cited by 93 · see citing works
“By enhancing the degradation of IκB, NF-κB can then migrate into the nuclear compartment, where these transcription factors act as heterodimers that bind the DNA promoters of many inflammatory and immune response genes [28,29].”
BackgroundCurrent nutritional and pharmacological anti-aging interventions
Ros, M., & Carrascosa, J. M. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2019.165612 · Cited by 95 · see citing works
Research Progress on Alzheimer's Disease and Resveratrol
Yan, Y., Yang, H., Xie, Y., Ding, Y., Kong, D., & Yu, H. (2020) · Neurochemical Research · doi:10.1007/s11064-020-03007-0 · Cited by 91 · see citing works
Ramakrishnan, P., Loh, W. M., Gopinath, S. C. B., Bonam, S. R., Fareez, I. M., Guad, R. M., Sim, M. S., & Wu, Y. S. (2019) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2019.11.008 · Cited by 90 · see citing works
Moderate Wine Consumption and Health: A Narrative Review
Hrelia, S., Renzo, L. D., Bavaresco, L., Bernardi, E., Malaguti, M., & Giacosa, A. (2022) · Nutrients · doi:10.3390/nu15010175 · Cited by 89 · see citing works
Resveratrol regulates muscle fiber type conversion via miR-22-3p and AMPK/SIRT1/PGC-1α pathway
Wen, W., Chen, X., Huang, Z., Chen, D., Chen, H., Luo, Y., He, J., Zheng, P., Yu, J., & Yu, B. (2019) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2019.108297 · Cited by 88 · see citing works
Gupta, P., Bala, M., Gupta, S. K., Dua, A., Dabur, R., Injeti, E. R., & Mittal, A. (2016) · Pharmacological Research · doi:10.1016/j.phrs.2016.09.029 · Cited by 90 · see citing works
Nutrition and longevity—From mechanisms to uncertainties
Ekmekcioglu, C. (2020) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2019.1676698 · Cited by 87 · see citing works
Resveratrol distinctively modulates the inflammatory profiles of immune and endothelial cells
Schwager, J., Richard, N., Widmer, F., & Raederstorff, D. (2017) · BMC Complementary and Alternative Medicine · doi:10.1186/s12906-017-1823-z · Cited by 90 · see citing works
“Not unexpectedly, many controversies have grown [6], since the effects of RES were pleiotropic and relied on diverse mode of actions in different cells, tissue, metabolic states and species [21].”
BackgroundResveratrol’s Anti-Cancer Effects through the Modulation of Tumor Glucose Metabolism
Brockmueller, A., Sameri, S., Líšková, A., Zhai, K., Varghese, E., Samuel, S. M., Büsselberg, D., Kubatka, P., & Shakibaei, M. (2021) · Cancers · doi:10.3390/cancers13020188 · Cited by 88 · see citing works
Resveratrol As A Natural Regulator Of Autophagy For Prevention And Treatment Of Cancer
Tian, Y., Song, W., Li, D., Cai, L., & Zhao, Y. (2019) · OncoTargets and Therapy · doi:10.2147/ott.s213043 · Cited by 87 · see citing works
“eral cancers by targeting some molecules that play important roles in tumourigenesis.(3,4) Studies have shown that resveratrol can induce autophagy in cancer cells.”
BackgroundResveratrol and Other Natural Oligomeric Stilbenoid Compounds and Their Therapeutic Applications
Duta-Bratu, C.-G., Nițulescu, G. M., Mihai, D. P., & Olaru, O. T. (2023) · Plants · doi:10.3390/plants12162935 · Cited by 85 · see citing works
“association domain family 1 isoform A (RASSF-1α), pAkt, vascular endothelial growth factor (VEGF), cyclooxygenase 2 (COX-2), nuclear factor erythroid 2-like 2 (Nrf 2), and Kelch-like ECH-associated protein 1 [57,58].”
BackgroundFeng, Y., Liu, T., Dong, S., Guo, Y., Jankovic, J. J., Xu, H., & Wu, Y. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.13172 · Cited by 85 · see citing works
Zhang, D., Yan, Y., Tian, H., Jiang, G., Li, X., & Liu, W. (2017) · Fish Physiology and Biochemistry · doi:10.1007/s10695-017-0421-9 · Cited by 85 · see citing works
Thongchot, S., Ferraresi, A., Vidoni, C., Loilome, W., Yongvanit, P., Namwat, N., & Isidoro, C. (2018) · Cancer Letters · doi:10.1016/j.canlet.2018.05.031 · Cited by 84 · see citing works
de Oliveira, M. T. P., Coutinho, D. D. S., de Souza, É. T., Guterres, S. S., Pohlmann, A. R., Silva, P., Martins, M. A., & Bernardi, A. (2019) · International Journal of Nanomedicine · doi:10.2147/ijn.s200666 · Cited by 83 · see citing works
“RSV effects have been related to the PI3K/Akt and mitogen-activated protein kinase (MAPK) pathways, among others, including the extracellular signal regulated kinases 1 and 2 (ERK1/2).(77) Both the PI3K/Akt and MAPK intracellular cascades can be initiated by LPSTRL4 receptor activation,(78) leading to gene transcripti…”
BackgroundWen, W., Chen, X., Huang, Z., Chen, D., Yu, B., He, J., Luo, Y., Yan, H., Chen, H., Zheng, P., et al. (2021) · Animal nutrition · doi:10.1016/j.aninu.2021.06.012 · Cited by 83 · see citing works
“Sirt1 and PGC-1a, downstream regulators of AMPK are directly activated by AMPK and drive the transformation of fast glycolytic fiber to slow oxidative fiber (Kulkarni and Cant o, 2015; Li et al., 2002).”
BackgroundImplications of Resveratrol in Obesity and Insulin Resistance: A State-of-the-Art Review
Barber, T. M., Kabisch, S., Randeva, H. S., Pfeiffer, A. F. H., & Weickert, M. O. (2022) · Nutrients · doi:10.3390/nu14142870 · Cited by 83 · see citing works
“Other potential mechanisms of resveratrol action include the inhibition of ATP production through the activation of 5′ Adenosine Monophosphate-activated Protein Kinase (AMPK, a key regulator of energy homeostasis), that in turn inhibits mammalian Target of Rapamycin (mTOR) signaling, with possible anti-ageing effects…”
BackgroundResveratrol Regulates Colorectal Cancer Cell Invasion by Modulation of Focal Adhesion Molecules
Buhrmann, C., Shayan, P., Goel, A., & Shakibaei, M. (2017) · Nutrients · doi:10.3390/nu9101073 · Cited by 84 · see citing works
Song, Z., Shi, Y., Han, Q., & Dai, G. (2018) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2018.05.095 · Cited by 82 · see citing works
de Ligt, M., Bruls, Y. M. H., Hansen, J., Habets, M.-F., Havekes, B., Nascimento, E. B. M., Moonen-Kornips, E., Schaart, G., Schrauwen-Hinderling, V. B., van Marken Lichtenbelt, W., et al. (2018) · Molecular Metabolism · doi:10.1016/j.molmet.2018.04.004 · Cited by 79 · see citing works
“Abbreviations: AMPK, AMP-activated protein kinase; BAT, brown adipose tissue; DHR glucose; FDR, first-degree relatives; IHL, intrahepatic lipid; IMCL, intramyocellular lipid malate þ octanoyl-carnitine; MOG, malate þ octanoyl-carnitine þ glutamate; MOG, spectroscopy; NE, norepinephrine; OGTT, oral glucose tolerance te…”
BackgroundInfluentialChatterjee, B., Ghosh, K. K., & Kanade, S. R. (2019) · BioFactors · doi:10.1002/biof.1544 · Cited by 79 · see citing works
The Role of Antioxidants in the Therapy of Cardiovascular Diseases—A Literature Review
Młynarska, E., Hajdys, J., Czarnik, W., Fularski, P., Leszto, K., Majchrowicz, G., Lisińska, W., Rysz, J., & Franczyk, B. (2024) · Nutrients · doi:10.3390/nu16162587 · Cited by 85 · see citing works
“Furthermore, resveratrol enhances vasculoprotective nitric oxide (NO) synthesis through eNOS activation, which is mediated by estrogen receptors, MAPK signaling, and SIRT1 activation.”
BackgroundGuthrie, A. R., Chow, H. ‐. S., & Martinez, J. A. (2017) · Pharmacology Research & Perspectives · doi:10.1002/prp2.294 · Cited by 78 · see citing works
Epigenetic regulation of bone remodeling by natural compounds
Raut, N. A., Wicks, S. M., Lawal, T. O., & Mahady, G. B. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.104350 · Cited by 77 · see citing works
Resveratrol suppresses human hepatocellular carcinoma via targeting HGF-c-Met signaling pathway
Gao, F., Deng, G., Liu, W., Zhou, K., & Li, M. (2017) · Oncology Reports · doi:10.3892/or.2017.5347 · Cited by 76 · see citing works
“Previous studies have demonstrated that resveratrol displayed potent antitumor effect in various types of tumors, including lung, breast, prostate and colon cancer (23,26).”
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“Its bioactivity com es from direct interactions of resveratrol with multip e molecular targets involved on inflammation, cell cycle arrest, cell signaling, metabolism and posttranslat ion l modification [18, 19].”
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Gellan Gum/Pectin Beads Are Safe and Efficient for the Targeted Colonic Delivery of Resveratrol
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“Resveratrol (RES), a class II in the Biopharmaceutical Classification System, is a natural polyphenol with recognized antioxidant properties found in grapes, red wine, peanuts, mulberries, and some medicinal plants [26], and is potentially useful as a dietary supplement or for use in natural medicine [22,23].”
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“These findings emphasize the need for advanced formulations, such as resveratrol analogs or nano-delivery systems, to maximize therapeutic benefits in ongoing trials targeting breast, colon, and prostate cancers [206].”
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Resveratrol promotes oxidative stress to drive DLC1 mediated cellular senescence in cancer cells
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“Resveratrol exhibits chemopreventive(5) and therapeutic effects against several cancers(6) by targeting some molecules that play important roles in tumourigenesis.(7) Indeed, other red”
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“It then dissociates from keap1 and translocates to the cell nucleus, causing the acetylation of DNA, binding to the elements of the antioxidant response in the promoter region of the genes that are involved in the transcription of the already mentioned antioxidant enzymes [58].”
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“Resveratrol also inhibits phosphodiesterases and the NF- B family of transcription factors (45).”
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“Recently, it was reported that SIRT1 activation by Res could deacetylate and activate downstream substrates such as FOXOs or peroxisome proliferator-activated receptor gamma coactivator-1 a (PGC-1 a) under oxidative stress, thereby inducing SOD2 expression, leading to suppression of oxidant-induced cell death [37-39].”
Background
- Authors
- Kulkarni, S. S., & Cantó, C.
- Corresponding author
- Cantó, Carles
- ORCID
- Cantó, Carles
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
- Publisher
- Elsevier BV
- Published
- 2015-06
- Volume
- 1852
- Issue
- 6
- Pages
- 1114-1123
- ISSN
- 0925-4439 (ISSN-L)
- OpenAlex
- W2053510668
- Cited by
- 477
- References
- 135
- Citations by year
- 2026: 15 · 2025: 27 · 2024: 32 · 2023: 23 · 2022: 50 · 2021: 40 · 2020: 56 · 2019: 63 · 2018: 55 · 2017: 39 · 2016: 38 · 2015: 37
- FWCI
- 3.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- resveratrol, molecular targets, caloric restriction mimetics, SIRT1, AMPK, metabolic disorders, neuroprotection, cancer, cardioprotection, aging, drug development
- MeSH terms
- Resveratrol, Animals, Humans, Mitochondria, Stilbenes, Signal Transduction, Transcriptional Activation, NF-kappa B, Sirtuins, AMP-Activated Protein Kinases
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