Bioactive polyphenols from wine grapes. Jeff Stuart Biological Sciences April 3, 2013

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1 Bioactive polyphenols from wine grapes Jeff Stuart Biological Sciences April 3, 2013

2 Ellen Robb PhD candidate Friday, April 26

3 Stresses, both abiotic and biotic, stimulate phytoalexin synthesis in Vitis vinifera phytoalexins

4 trans-resveratrol synthetic pathway H O N H 2 phenylalanine O p henylalanine ammonia lyase H O cinnamic acid O c innamate 4 - hydroxylase O H H O p- coumaric acid O 4 - coumarate:coa l igase + 3 C H 3 O O S CoA p - coumaroyl - CoA malonyl - CoA stilbene synthase O H O H H O trans - resveratrol

5 trans-resveratrol synthetic pathway H O N H 2 phenylalanine O p henylalanine ammonia lyase H O cinnamic acid O c innamate 4 - hydroxylase O H H O p- coumaric acid O 4 - coumarate:coa l igase + 3 C H 3 O O S CoA p - coumaroyl - CoA malonyl - CoA stilbene synthase O H O H H O trans - resveratrol

6 trans-resveratrol synthetic pathway individual stilbene synthase genes have been identified in Vitis vinifera! (C Parage et al 2012, Plant Physiol)

7 The resveratrol industry

8 Further metabolism of resveratrol in planta O H O H H O Trans - resveratrol O H O H O Glycosylation Methoxylation Oxidative oligomerization H O ƍ - viniferin O H O H O H O H O C H 3 H O H O O O O C H 3 H O O O H Piceid H O O H O H H O Pterostilbene H O O H Ɛ - viniferin

9 Aus J Grape Wine Res 18, 11-19, 2012

10 Resveratrol has received far more attention from researchers than have its derivative molecules 5000 Number of publications (as of April 2, 2013) resveratrol piceid pterostilbene viniferins

11 Do resveratrol s derivatives its biological activities (in people)?

12 Do resveratrol s derivatives share its biological activities? Slows growth of cancer cells?

13 Do resveratrol s derivatives share its biological activities? Slows growth of cancer cells yes

14 Do resveratrol s derivatives share its biological activities? Slows growth of cancer cells yes Cardiovascular effects?

15 Do resveratrol s derivatives share its biological activities? Slows growth of cancer cells Cardiovascular effects yes yes

16 Do resveratrol s derivatives share its biological activities? Slows growth of cancer cells Cardiovascular effects yes yes Neuroprotective?

17 Do resveratrol s derivatives share its biological activities? Slows growth of cancer cells Cardiovascular effects Neuroprotective yes yes yes

18 Do resveratrol s derivatives share its biological activities? Slows growth of cancer cells Cardiovascular effects Neuroprotective yes yes yes Metabolic disease?

19 Do resveratrol s derivatives share its biological activities? Slows growth of cancer cells Cardiovascular effects Neuroprotective Metabolic disease yes yes yes yes

20 Do resveratrol s derivatives share its biological activities? yes

21 Do the resveratrol derivatives share resveratrol s cellular mechanisms?

22 Pterostilbene and piceid have the same effect as resveratrol on cellular antioxidant systems Robb and Stuart, unpublished

23 Pterostilbene and piceid inhibit cell proliferation similarly to resveratrol Robb and Stuart, unpublished

24 Pterostilbene and piceid enhance cellular stress resistance similarly to resveratrol Robb and Stuart, unpublished

25 Pterostilbene and piceid elicit very similar biological activities in people in vivo and have very similar cellular effects ex vivo

26 Pterostilbene and piceid elicit very similar biological activities in vivo and have very similar cellular effects Why and How?

27 Pterostilbene and piceid elicit very similar biological activities in vivo and have very similar cellular effects Do they stimulate the same signal transduction pathway?

28 Resveratrol has similar chemical structure to estrogen 17β-Estradiol trans-resveratrol

29 .and similar biological activities Stuart and Robb, in press

30 Many of estrogen s effects mediated by the classical estrogen receptors ERα and ERβ E 2 ERα ERβ

31 ERα and ERβ regulate transcription of hundreds of genes

32 Drugs are available that specifically bind to and stimulate ERβ (and not to ERα) DPN

33 The cellular (and in vivo) effects of resveratrol, pterostilbene, and piceid can be reproduced using DPN and are reduced or abolished in ERβ knockout cells

34 Induction of the intracellular antioxidant system is reproduced by DPN and blunted in the absence of ERβ Robb and Stuart, unpublished

35 Cell proliferative growth is inhibited also by DPN and the effect is reduced in the absence of ERβ Robb and Stuart, unpublished

36 Cellular stress resistance is stimulated by DPN and abolished in absence of ERβ Robb and Stuart, unpublished

37 Resveratrol, pterostilbene, and piceid appear to work through the same pathway: ERβ

38 Resveratrol, pterostilbene, and piceid are working through the same pathway: ERβ Are pterostilbene and piceid better than resveratrol?

39 Pterostilbene and piceid have better bioavailability in vivo than resveratrol

40 stilbene stilbene An opportunity! stilbene stilbene

41 Summary Phytoalexins are molecules produced by stressed grapevines that are present in grapes and in wines fermented in the presence of grapes

42 Summary Phytoalexins are molecules produced by stressed grapevines that are present in grapes and in wines fermented in the presence of grapes Resveratrol, pterostilbene, and piceid are all phytoalexins

43 Summary Phytoalexins are molecules produced by stressed grapevines that are present in grapes and in wines fermented in the presence of grapes Resveratrol, pterostilbene, and piceid are all phytoalexins Although resveratrol is the best characterized, many of its effects in people and in isolated cells can be replicated using pterostilbene or piceid.

44 Summary Resveratrol, pterostilbene, and piceid stimulate ERβ to generate some of their beneficial effects. Other ERβ agonists being developed to treat postmenopausal symptoms: MF101; phyotestrogen formulations

45 There is very little research data available for some other resveratrol derivatives that we know are also present in grapes do they also stimulate ERβ? Aus J Grape Wine Res 18, 11-19, 2012

46 The way forward

47 The way forward Detailed experimental determination of grapeskin phytoalexins effects both alone and in combination both ex vivo and in vivo

48 The way forward Detailed experimental determination of grapeskin phytoalexins effects both alone and in combination both ex vivo and in vivo Better understanding of how grape growing and storage practices, fermentation methods, affect stilbene levels in grapes (e.g. organic growing methods)

49 The way forward Detailed experimental determination of grapeskin phytoalexins effects both alone and in combination both ex vivo and in vivo Better understanding of how grape growing and storage practices, fermentation methods, affect stilbene levels in grapes (e.g. organic growing methods) Capture the full value of grapeskins, which may currently be considered waste in the process

50 Acknowledgements: Brock University Advancement Fund