Resveratrol--pills to replace a healthy diet?

Abstract

Nutrapharmacology, or the use of bioactive food compounds at pharmacological doses is emerging as a therapeutic approach to target the complex metabolic dysregulations in ageing and obesity-related chronic disease. Resveratrol, a polyphenol found in the skin of grapes, and other edible plants and related food products, has received extensive attention through the link with the French paradox, and later with its chemopreventive activity demonstrated in vitro and in animal cancer models. A plethora of laboratory investigations has provided evidence for the multi-faceted properties of resveratrol and suggests that resveratrol may target ageing and obesity-related chronic disease by regulating inflammation and oxidative stress. A number of obstacles stand in the path to clinical usage however, not least the lack of clinical evidence to date, and the myriad of doses and formulations available. Further, data on the effects of resveratrol consumption in a capsule vs. food form is conflicting, and there are uncertain effects of long term dosing. The review will summarize the human pharmacokinetic and pharmacodynamic published data, and the topics for research if resveratrol is to become a multi-target therapeutic agent addressing chronic disease.

Figure 1

Structure of resveratrol. Genes and products affected by exposure to the compound [7, 17, 25, 56]. CDK – 1/2/4/7, cyclin-dependant kinase 1/2 /4/7; HDAC-2, histone deacetylase 2; P53, tumour protein 53; Rb, retinoblastoma tumour suppressor gene; c-Myc, gene myelocytomatosis; PTEN, phosphatase and tensin homolog; p21^Waf1/Cip1, cyclin-dependent kinase inhibitor 1A; P27, cyclin dependant kinase inhibitor 27; Rbf-E2F/DP pathway, Retinoblastoma-family protein/ E2F transcription factor/ DP transcription factor; P300/CBP, CREB binding protein; PARP, poly(ADP)-ribose polymerase; EGF, endothelial growth factor; HGF, human growth factor; GAD45, DNA damage inducible gene 45; FOXO-1/3a/4, forkhead transcription factor 1/3a/4; NFκB, nuclear factor kappa B; AP-1, activating protein-1;NRF-2, nuclear respiratory factor-2; STAT3, signal transducer and activator of transcription 3; PPARγ, peroxisome proliferator activated receptor gamma; HIF-1α, hypoxia inducible factor 1-alpha; Erg-1, ets-related gene; E2F, transcription factor E2F; SP-1, Sp1 transcription factor; CREB, cyclic-AMP response element binding proteins; NF1B, neurofibromin 1b; PI3K, phosphoinositide 3 kinases; ERK1/2, extracellular signal regulated kinase 1 /2; PKC, protein kinase C; PKD, protein kinase D; PKA, protein kinase A; MAPK, mitogen activated protein kinase; JNK-1, c-Jun N-terminal kinases; Akt, serine/threonine protein kinase; IKKβ, IkB kinase beta; JAK, Janus kinase; Src, sarcoma pro-oncogenic tyrosine kinase; syk, spleen tyrosine kinase gene; CKII, casein kinase 2; Cu-Zn-Mn SOD, copper-zinc-manganese superoxide dismustase; Trx1, cytosolic thioredoxin; p47 ^phox, enzyme for production of superoxide; ROS, reactive oxygen species; AMPK, adenosine monophosphate activated protein kinase; GLUT4, glucose transporter 4; UCP-1, uncoupling protein 1; PGC-1α, PPARgamma coactivator 1 proliferator-activated receptor-gamma; PTB1B, protein tyrosine phosphatase 1 B; ER, eostrogen receptor; AR, andogen receptor; CYP isoforms, cytochrome P450 isoforms; NQO2, NADPH dehydrogease quinone 2; hTERT, human telomerase reverse transcriptase; IGF-1, insulin like growth factor-1; IRS-1, insulin receptor substrate 1; IGFBP-3, Insulin-like growth factor-binding protein 3; TNFα, tumour necrosis factor alpha; COX-2, cyclo-oxygenase 2; iNOS, inducible nitric oxide synthase, eNOS, endothelial nitric oxide synthase; NO, nitric oxide; CRP, C- reactive protein; 5-LOX, 5-lipoxygenase- activating protein; NAG-1, nonsteroidal anti-inflammatory drug-activated gene; IFNγ, interferon gamma; ILs, interleukins; MPO, myeloperoxidase; GM-CSF, granulocyte-macrophage colony stimulating factor; TBARS, thiobarbituric acid reactive substances; SOCS3, Suppressor of cytokine signaling 3; MCP-1, monocyte chemotactic protein-1; TGFβ, transforming growth factor beta; Bcl-2, B-cell lymphoma 2; Bcl-XL, BCL2-like 1; TRAF2, TNF receptor-associated factor 2; AP-2α, activating protein 2; XIAP, X-linked Inhibitor of apoptosis protein; mTOR, mammalian target of rapamycin; PUMA, BCL2 binding component 3; noxA, nitrate reductase, NADH oxidase subunit; Bim, BCL2-like 11 apoptosis facilitator; Cyt. C, cytochrome C; DIABLO, diablo homolog; AIF, apoptosis inducing factor; mi/Htra2, HtrA serine peptidase 2; cIAPs, inhibitor of apoptosis proteins; ASK-1, Apoptosis signal-regulating kinase 1; Bid, BH3 interacting domain death agonist; TRAIL, TNF-related apoptosis-inducing ligand; Bak, BCL2-antagonist/killer 1; Bax, Bcl-2 associated protein; Fasl, Fas antigen ligand; MMP-2/9, matrix metalloproteinases 2/9; NQO1, human NAD(P)H quinone 1; VEGF, vascular endothelial growth factor; bFGF, basic fibroblast growth factor; ICAM-1, inter-cellular adhesion molecule 1; VCAM-1, vascular cell adhesion molecule 1; ELAM-1, endothelium leukocyte adhesion molecule 1; Wnt, wingless-type MMTV integration site family, member; PSA, prostate-specific antigen; DR4/5, tumour necrosis factor receptor superfamily, member 10a/10b; PIG7, p53-induced gene 7.

Figure 2

The potential clinical applications of resveratrol and main proposed mechanisms of action [6, 7, 24, 56, 70]. NFκB, nuclear factor kappa B; STAT3, signal transducer and activator of transcription 3; COX-1/2, cyclo-oxygenase 1 /2; IL's, interleukins; CRP, C-reactive protein; AMPK, adenosine monophosphate activated protein kinase; TNFα, tumour necrosis factor alpha; TG, triglycerides; HDL, high density lipoproteins; LDL, low density lipoproteins; ICAM, inter-cellular adhesion molecule 1; VCAM, vascular cell adhesion molecule 1; iNOS, inducible nitric oxide synthase; eNOS, endothelial nitric oxide synthase.