Celestino Santos-Buelga is Professor of Food Chemistry, Department of Analytical Chemistry, Nutrition and Food Science, Faculty of Pharmacy, University of Salamanca, Spain Maria Teresa Escribano-Bailon is Lecturer in Food Technology, Technical School of Zamora, University of Salamanca, Spain Vincenzo Lattanzio is Professor of Plant Biochemistry and Physiology, Department of Agro- Environmental Sciences, Chemistry and Plant Protection, Faculty of Agricultural Sciences, University of Foggia, ItalyEdited by Celestino Santos-Buelga, Maria Teresa Escribano-Bailon and Vincenzo Lattanzio

• Contributors xiv Preface xviii1 The Visible Flavonoids or Anthocyanins: From Research to Applications 1Raymond Brouillard, Stefan Chassaing, Géraldine Isorez, Marie Kueny-Stotz, and Paulo Figueiredo1.1 Introduction 11.2 Copigmentation of anthocyanins 51.3 Formation of inclusion complexes 61.4 Ion-pair formation 71.5 Metalloanthocyanins 71.6 Z-Chalcones: unexpected open cavities for the ferriccation 111.7 Anthocyanin biological activity 141.8 Some thoughts on applications 151.9 References 172 Flavonoid Chemistry of the Leguminosae 23Nigel C. Veitch2.1 Introduction 232.1.1 Classification and nomenclature of the Leguminosae: a brief synopsis 242.2 Flavonoid structures in the Leguminosae: trends and distribution 262.2.1 Occurrence of 5-deoxyfl avonoids in the Leguminosae 282.2.2 Isofl avonoids in subfamily Papilionoideae 302.2.2.1 Recent advances in biosynthetic studies 322.2.2.2 Isoflavonoid glycosides 352.2.2.3 Isoflavone glucosyltransferases 352.2.2.4 Acylated isoflavone glycosides 362.2.3 Leguminosae anthocyanins: malonyltransferases of Clitoria ternatea 382.3 Advances in analytical methodology applied to Leguminosae flavonoids 382.3.1 Hyphenated MS techniques 402.3.2 Hyphenated NMR techniques and miniaturization 412.3.3 Chiroptical methods 432.4 Leguminosae flavonoids and chemosystematics 442.4.1 The disputed position of the Swartzieae: subfamily Caesalpinioideae or Papilionoideae? 442.4.2 Generic delimitation in the aldinoid clade of swartzioid legumes: Cordyla and Dupuya 472.4.3 Species-level studies of the isoflavonoid chemistry of Cicer 502.5 Concluding remarks 522.6 Acknowledgments 522.7 References 523 Updating Wine Pigments 59Victor A.P. de Freitas and Nuno Mateus3.1 General overview 593.2 Factors that affect wine color intensity and stability 603.3 Chemical transformations of flavonoids 633.3.1 Condensation between anthocyanins and flavanols mediated by aldehydes 653.3.2 Reaction between flavanols and aldehydes 673.3.3 Direct condensation between flavanols and anthocyanins 683.3.4 Pyranoanthocyanins 693.3.4.1 Reaction between anthocyanins and vinyl compounds 703.3.4.2 Yeast metabolites involved in anthocyanin transformations 723.3.5 Vinylpyranoanthocyanins (portisins) 743.4 Final remarks 753.5 Acknowledgments 763.6 References 764 Ellagitannins – An Underestimated Class of Plant Polyphenols: Chemical Reactivity of C-Glucosidic Ellagitannins in Relation to Wine Chemistry and Biological Activity 81Stéphane Quideau, Michael Jourdes, Dorothée Lefeuvre, Patrick Pardon, Cédric Saucier, Pierre-Louis Teissedre, and Yves Glories4.1 Ellagitannins: an underestimated class of bioactive plant polyphenols 814.2 C-Glucosidic ellagitannins: a special subclass of ellagitannins 954.2.1 Major C-glucosidic ellagitannins in oak and chestnut heartwoods 1004.2.2 Complex C-glucosidic ellagitannins 1024.2.3 Biosynthesis of C-glucosidic ellagitannins 1074.2.4 Chemical reactivity of vescalagin and castalagin 1104.2.5 Diastereofacial differentiation of the vescalagin-derived benzylic cation 1134.3 Implications of C-glucosidic ellagitannins in wine chemistry 1144.3.1 Hemisynthesis of acutissimins and their occurrence in wine 1154.3.2 Condensation reaction between vescalagin and glutathione 1184.3.3 Hemisynthesis of anthocyano-ellagitannins: possible influence on wine color 1194.3.4 Oxidative conversion of acutissimin A into mongolicain A 1204.4 Biological activity of C-glucosidic ellagitannins 1224.4.1 Antiviral activity of C-glucosidic ellagitannins 1234.4.2 Antitumor activity of C-glucosidic ellagitannins 1244.5 Conclusion 1254.6 Acknowledgments 1264.7 References 1265 Strategies to Optimize the Flavonoid Content of Tomato Fruit 138Arnaud G. Bovy, Victoria Gómez-Roldán, and Robert D. Hall5.1 Introduction 1385.2 The metabolic route to flavonoids in tomato fruit 1405.3 The natural biodiversity of flavonoids in tomato 1415.3.1 Flavonoid biodiversity I: commercially available genotypes 1425.3.2 Flavonoid biodiversity II: wild tomato species 1425.3.3 Flavonoid biodiversity III: information from specific tomato mutants 1435.4 Metabolic engineering of the flavonoid pathway 1455.4.1 Exploitation of the transgenic approach using up regulation of structural genes 1455.4.2 Using RNAi to block targeted steps in the flavonoid pathway 1465.4.3 Production of novel tomato flavonoids by introducing new branches of the flavonoid pathway: flavonoid-related stilbenes 1475.4.4 Production of novel tomato flavonoids by introducing new branches of the flavonoid pathway: deoxychalcones 1485.4.5 Production of novel tomato flavonoids by introducing new branches of the flavonoid pathway: flavones, isofl avones, and aurones 1495.4.6 Modifying the flavonoid pathway using regulatory genes 1505.5 Metabolomics-assisted breeding 1545.6 Conclusions and future prospects 1565.7 Acknowledgments 1565.8 References 1566 Biological Activity of Phenolics in Plant Cells 163Luc P.R. Bidel, Marc Coumans, Yves Baissac, Patrick Doumas, and Christian Jay-Allemand6.1 Introduction 1636.2 Synthesis and transports 1646.2.1 Metabolic channeling at the endoplasmic reticulum (ER) level 1646.2.2 Endomembrane carriers 1656.2.3 Vesicle trafficking 1666.2.4 Long-distance transport 1666.3 Phenolics interact with plasmalemma components 1676.3.1 Biophysical interactions with phospholipid bilayers 1676.3.2 Interactions with plasma membrane-associated proteins 1696.3.3 Flavonoids prevent and alleviate oxidative burst 1726.3.4 Phenolics modulate plasma membrane carriers 1726.4 Phenolics in apoplast 1756.4.1 Phenolics as a major player in mechanical tissue rigidification 1756.4.2 Phenolics as major components of apoplastic chemical protection 1756.4.3 Phenolics as apoplastic allelochemical signals 1776.5 Phenolics in hyaloplasm 1776.5.1 Phenolics interact with cytoskeleton 1786.5.2 Phenolics inhibit carbohydrate catabolism 1786.5.3 Many fl avonoids prevent and alleviate oxidative and nitrosative stresses 1786.5.4 Salicylic acid promotes oxidative stress signaling pathway 1796.6 Phenolics in vacuoles 1806.6.1 Sunscreen role for vacuolar phenolics 1806.6.2 Are vacuolar phenolics effective buffers? 1806.6.3 Are vacuolar phenolics effective chelators? 1826.7 Phenolics in mitochondria and chloroplasts 1836.7.1 Inhibitory effects 1836.7.2 Protecting effects 1836.7.3 Putative phenolic photoreceptors 1836.8 Phenolics have many emergent roles within the nucleus 1846.8.1 Presence of phenolics within the nucleus 1846.8.2 Flavonoids prevent DNA damages 1846.8.3 Prooxidative actions of phenolics on DNA 1866.8.4 Flavonoids affect histone acetylation and phosphorylation 1866.8.5 Flavonoids inhibit DNA methylation 1876.8.6 Phenolics affect cell cycle 1876.8.7 Phenolics inhibit replication 1886.8.8 Phenolics promote or repress transcription 1896.9 Conclusion 1906.10 References 1917 Muriel Wheldale Onslow and the Rediscovery of Anthocyanin Function in Plants 206Kevin S. Gould7.1 Introduction 2067.1.1 Muriel Wheldale Onslow: a brief biography 2087.2 Functional hypotheses for anthocyanins in vegetative tissues 2117.3 A modern spin on some old ideas 2137.3.1 Photoprotection revisited 2137.3.2 Anthocyanins, sugars, and autumn leaves 2177.4 Concluding remarks 2187.5 Acknowledgments 2197.6 References 2198 Plant Phenolic Compounds Controlling Leaf Movement 226Minoru Ueda and Yoko Nakamura8.1 Introduction 2268.2 Endogenous bioactive substance controlling nyctinasty 2278.3 The chemical mechanism of the rhythm in nyctinasty 2288.4 Bioorganic studies of nyctinasty using functionalized leaf-movementfactors as molecular probes 2308.4.1 Fluorescence studies on nyctinasty 2308.4.2 Photoaffinity labeling of the target protein for the leaf-movement factor 2318.4.3 Are leaf-movement target proteins common to the same plant genus? 2348.5 References 2359 Red Clover Derived Isoflavones: Metabolism and Physiological Effects in Cattle and Sheep and their Concentration in Milk Produced for Human Consumption 238Juhani Taponen, Eeva A. Mustonen, Lea Kontio, Ilkka Saastamoinen, Aila Vanhatalo, Hannu Saloniemi, and Kristiina Wähälä9.1 Introduction 2389.2 Phytoestrogens in ruminant feeds 2389.3 Red clover as a source of isoflavones 2399.4 Metabolism of isofl avones in ruminants 2419.5 Equol: the most important metabolite 2439.6 Physiological effects and regulatory mechanisms of endogenous estrogens 2459.7 Effects of phytoestrogens in sheep reproduction 2479.7.1 Classical clover disease 2479.7.2 Temporary subfertility 2479.7.3 Permanent infertility 2479.8 Effects of phytoestrogens in cattle reproduction 2489.9 Antioxidant capacity of isoflavones 2499.10 New outlook 2499.11 References 25010 Polyphenols as Biomarkers in Nutrition Research: Resveratrol Metabolome a Useful Nutritional Marker of Moderate Wine Consumption 255Raul Zamora-Ros and Cristina Andrés-Lacueva10.1 Introduction 25510.2 Characteristics of nutritional biomarkers 25610.3 Strengths and limitations of biological biomarkers over dietary estimation 26110.4 Resveratrol: a useful biomarker of wine consumption 26210.5 References 26511 Translation of Chemical Properties of Polyphenols into Biological Activity with Impact on Human Health 269João Laranjinha11.1 Introduction 26911.2 Polyphenols as antioxidants: the earlier notions 27011.2.1 The infl uence of redox potentials 27011.2.2 Redox cycles of polyphenols with vitamins E and C: the influence of solubility 27211.3 Beyond “global” antioxidation: alternate biological activities for polyphenols with impact on human health 27411.3.1 Modulation of redox signaling pathways 27411.3.2 Modulation of nitric oxide metabolism 27611.4 References 27812 Mitigation of Oxidative Stress and Infl ammatory Signaling by Fruit and Walnut Polyphenols: Implications for Cognitive Aging 283James A. Joseph, Barbara Shukitt-Hale, and Lauren M. Willis12.1 Introduction 28312.2 Oxidative stress/infl ammatory interactions 28412.2.1 Oxidative stress 28412.2.2 Inflammation 28412.2.3 Intracellular signaling 28512.2.4 Calcium buffering capacity 28612.2.5 Neurogenesis 28612.2.6 Membrane changes 28712.3 Nutritional interventions 28712.3.1 Fruit polyphenols as neuroprotective agents 28712.3.2 Polyunsaturated fatty acids and cognition: animal studies 28912.4 References 29113 Antiatherosclerotic Effects of Dietary Flavonoids: Insight into their Molecular Action Mechanism at the Target Site 299Junji Terao, Kaeko Murota, and Yoshichika Kawai13.1 Introduction 29913.2 Flavonoids in the diet and their antioxidant/prooxidant activity 30013.3 Absorption and metabolism of dietary flavonoids in the digestive system 30413.4 Oxidative LDL theory and antioxidant activity of fl avonoids in plasma 30713.5 Antioxidant and “beyond” antioxidant activity of flavonoids in the artery 30913.6 Activated macrophages as potential targets of dietary flavonoids as antiatherosclerotic factors 31213.7 Conclusion 31313.8 References 314Index 319

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Celestino Santos-Buelga is Professor of Food Chemistry, Department of Analytical Chemistry, Nutrition and Food Science, Faculty of Pharmacy, University of Salamanca, Spain Maria Teresa Escribano-Bailon is Lecturer in Food Technology, Technical School of Zamora, University of Salamanca, Spain Vincenzo Lattanzio is Professor of Plant Biochemistry and Physiology, Department of Agro- Environmental Sciences, Chemistry and Plant Protection, Faculty of Agricultural Sciences, University of Foggia, ItalyEdited by Celestino Santos-Buelga, Maria Teresa Escribano-Bailon and Vincenzo Lattanzio

• Contributors xiv Preface xviii1 The Visible Flavonoids or Anthocyanins: From Research to Applications 1Raymond Brouillard, Stefan Chassaing, Géraldine Isorez, Marie Kueny-Stotz, and Paulo Figueiredo1.1 Introduction 11.2 Copigmentation of anthocyanins 51.3 Formation of inclusion complexes 61.4 Ion-pair formation 71.5 Metalloanthocyanins 71.6 Z-Chalcones: unexpected open cavities for the ferriccation 111.7 Anthocyanin biological activity 141.8 Some thoughts on applications 151.9 References 172 Flavonoid Chemistry of the Leguminosae 23Nigel C. Veitch2.1 Introduction 232.1.1 Classification and nomenclature of the Leguminosae: a brief synopsis 242.2 Flavonoid structures in the Leguminosae: trends and distribution 262.2.1 Occurrence of 5-deoxyfl avonoids in the Leguminosae 282.2.2 Isofl avonoids in subfamily Papilionoideae 302.2.2.1 Recent advances in biosynthetic studies 322.2.2.2 Isoflavonoid glycosides 352.2.2.3 Isoflavone glucosyltransferases 352.2.2.4 Acylated isoflavone glycosides 362.2.3 Leguminosae anthocyanins: malonyltransferases of Clitoria ternatea 382.3 Advances in analytical methodology applied to Leguminosae flavonoids 382.3.1 Hyphenated MS techniques 402.3.2 Hyphenated NMR techniques and miniaturization 412.3.3 Chiroptical methods 432.4 Leguminosae flavonoids and chemosystematics 442.4.1 The disputed position of the Swartzieae: subfamily Caesalpinioideae or Papilionoideae? 442.4.2 Generic delimitation in the aldinoid clade of swartzioid legumes: Cordyla and Dupuya 472.4.3 Species-level studies of the isoflavonoid chemistry of Cicer 502.5 Concluding remarks 522.6 Acknowledgments 522.7 References 523 Updating Wine Pigments 59Victor A.P. de Freitas and Nuno Mateus3.1 General overview 593.2 Factors that affect wine color intensity and stability 603.3 Chemical transformations of flavonoids 633.3.1 Condensation between anthocyanins and flavanols mediated by aldehydes 653.3.2 Reaction between flavanols and aldehydes 673.3.3 Direct condensation between flavanols and anthocyanins 683.3.4 Pyranoanthocyanins 693.3.4.1 Reaction between anthocyanins and vinyl compounds 703.3.4.2 Yeast metabolites involved in anthocyanin transformations 723.3.5 Vinylpyranoanthocyanins (portisins) 743.4 Final remarks 753.5 Acknowledgments 763.6 References 764 Ellagitannins – An Underestimated Class of Plant Polyphenols: Chemical Reactivity of C-Glucosidic Ellagitannins in Relation to Wine Chemistry and Biological Activity 81Stéphane Quideau, Michael Jourdes, Dorothée Lefeuvre, Patrick Pardon, Cédric Saucier, Pierre-Louis Teissedre, and Yves Glories4.1 Ellagitannins: an underestimated class of bioactive plant polyphenols 814.2 C-Glucosidic ellagitannins: a special subclass of ellagitannins 954.2.1 Major C-glucosidic ellagitannins in oak and chestnut heartwoods 1004.2.2 Complex C-glucosidic ellagitannins 1024.2.3 Biosynthesis of C-glucosidic ellagitannins 1074.2.4 Chemical reactivity of vescalagin and castalagin 1104.2.5 Diastereofacial differentiation of the vescalagin-derived benzylic cation 1134.3 Implications of C-glucosidic ellagitannins in wine chemistry 1144.3.1 Hemisynthesis of acutissimins and their occurrence in wine 1154.3.2 Condensation reaction between vescalagin and glutathione 1184.3.3 Hemisynthesis of anthocyano-ellagitannins: possible influence on wine color 1194.3.4 Oxidative conversion of acutissimin A into mongolicain A 1204.4 Biological activity of C-glucosidic ellagitannins 1224.4.1 Antiviral activity of C-glucosidic ellagitannins 1234.4.2 Antitumor activity of C-glucosidic ellagitannins 1244.5 Conclusion 1254.6 Acknowledgments 1264.7 References 1265 Strategies to Optimize the Flavonoid Content of Tomato Fruit 138Arnaud G. Bovy, Victoria Gómez-Roldán, and Robert D. Hall5.1 Introduction 1385.2 The metabolic route to flavonoids in tomato fruit 1405.3 The natural biodiversity of flavonoids in tomato 1415.3.1 Flavonoid biodiversity I: commercially available genotypes 1425.3.2 Flavonoid biodiversity II: wild tomato species 1425.3.3 Flavonoid biodiversity III: information from specific tomato mutants 1435.4 Metabolic engineering of the flavonoid pathway 1455.4.1 Exploitation of the transgenic approach using up regulation of structural genes 1455.4.2 Using RNAi to block targeted steps in the flavonoid pathway 1465.4.3 Production of novel tomato flavonoids by introducing new branches of the flavonoid pathway: flavonoid-related stilbenes 1475.4.4 Production of novel tomato flavonoids by introducing new branches of the flavonoid pathway: deoxychalcones 1485.4.5 Production of novel tomato flavonoids by introducing new branches of the flavonoid pathway: flavones, isofl avones, and aurones 1495.4.6 Modifying the flavonoid pathway using regulatory genes 1505.5 Metabolomics-assisted breeding 1545.6 Conclusions and future prospects 1565.7 Acknowledgments 1565.8 References 1566 Biological Activity of Phenolics in Plant Cells 163Luc P.R. Bidel, Marc Coumans, Yves Baissac, Patrick Doumas, and Christian Jay-Allemand6.1 Introduction 1636.2 Synthesis and transports 1646.2.1 Metabolic channeling at the endoplasmic reticulum (ER) level 1646.2.2 Endomembrane carriers 1656.2.3 Vesicle trafficking 1666.2.4 Long-distance transport 1666.3 Phenolics interact with plasmalemma components 1676.3.1 Biophysical interactions with phospholipid bilayers 1676.3.2 Interactions with plasma membrane-associated proteins 1696.3.3 Flavonoids prevent and alleviate oxidative burst 1726.3.4 Phenolics modulate plasma membrane carriers 1726.4 Phenolics in apoplast 1756.4.1 Phenolics as a major player in mechanical tissue rigidification 1756.4.2 Phenolics as major components of apoplastic chemical protection 1756.4.3 Phenolics as apoplastic allelochemical signals 1776.5 Phenolics in hyaloplasm 1776.5.1 Phenolics interact with cytoskeleton 1786.5.2 Phenolics inhibit carbohydrate catabolism 1786.5.3 Many fl avonoids prevent and alleviate oxidative and nitrosative stresses 1786.5.4 Salicylic acid promotes oxidative stress signaling pathway 1796.6 Phenolics in vacuoles 1806.6.1 Sunscreen role for vacuolar phenolics 1806.6.2 Are vacuolar phenolics effective buffers? 1806.6.3 Are vacuolar phenolics effective chelators? 1826.7 Phenolics in mitochondria and chloroplasts 1836.7.1 Inhibitory effects 1836.7.2 Protecting effects 1836.7.3 Putative phenolic photoreceptors 1836.8 Phenolics have many emergent roles within the nucleus 1846.8.1 Presence of phenolics within the nucleus 1846.8.2 Flavonoids prevent DNA damages 1846.8.3 Prooxidative actions of phenolics on DNA 1866.8.4 Flavonoids affect histone acetylation and phosphorylation 1866.8.5 Flavonoids inhibit DNA methylation 1876.8.6 Phenolics affect cell cycle 1876.8.7 Phenolics inhibit replication 1886.8.8 Phenolics promote or repress transcription 1896.9 Conclusion 1906.10 References 1917 Muriel Wheldale Onslow and the Rediscovery of Anthocyanin Function in Plants 206Kevin S. Gould7.1 Introduction 2067.1.1 Muriel Wheldale Onslow: a brief biography 2087.2 Functional hypotheses for anthocyanins in vegetative tissues 2117.3 A modern spin on some old ideas 2137.3.1 Photoprotection revisited 2137.3.2 Anthocyanins, sugars, and autumn leaves 2177.4 Concluding remarks 2187.5 Acknowledgments 2197.6 References 2198 Plant Phenolic Compounds Controlling Leaf Movement 226Minoru Ueda and Yoko Nakamura8.1 Introduction 2268.2 Endogenous bioactive substance controlling nyctinasty 2278.3 The chemical mechanism of the rhythm in nyctinasty 2288.4 Bioorganic studies of nyctinasty using functionalized leaf-movementfactors as molecular probes 2308.4.1 Fluorescence studies on nyctinasty 2308.4.2 Photoaffinity labeling of the target protein for the leaf-movement factor 2318.4.3 Are leaf-movement target proteins common to the same plant genus? 2348.5 References 2359 Red Clover Derived Isoflavones: Metabolism and Physiological Effects in Cattle and Sheep and their Concentration in Milk Produced for Human Consumption 238Juhani Taponen, Eeva A. Mustonen, Lea Kontio, Ilkka Saastamoinen, Aila Vanhatalo, Hannu Saloniemi, and Kristiina Wähälä9.1 Introduction 2389.2 Phytoestrogens in ruminant feeds 2389.3 Red clover as a source of isoflavones 2399.4 Metabolism of isofl avones in ruminants 2419.5 Equol: the most important metabolite 2439.6 Physiological effects and regulatory mechanisms of endogenous estrogens 2459.7 Effects of phytoestrogens in sheep reproduction 2479.7.1 Classical clover disease 2479.7.2 Temporary subfertility 2479.7.3 Permanent infertility 2479.8 Effects of phytoestrogens in cattle reproduction 2489.9 Antioxidant capacity of isoflavones 2499.10 New outlook 2499.11 References 25010 Polyphenols as Biomarkers in Nutrition Research: Resveratrol Metabolome a Useful Nutritional Marker of Moderate Wine Consumption 255Raul Zamora-Ros and Cristina Andrés-Lacueva10.1 Introduction 25510.2 Characteristics of nutritional biomarkers 25610.3 Strengths and limitations of biological biomarkers over dietary estimation 26110.4 Resveratrol: a useful biomarker of wine consumption 26210.5 References 26511 Translation of Chemical Properties of Polyphenols into Biological Activity with Impact on Human Health 269João Laranjinha11.1 Introduction 26911.2 Polyphenols as antioxidants: the earlier notions 27011.2.1 The infl uence of redox potentials 27011.2.2 Redox cycles of polyphenols with vitamins E and C: the influence of solubility 27211.3 Beyond “global” antioxidation: alternate biological activities for polyphenols with impact on human health 27411.3.1 Modulation of redox signaling pathways 27411.3.2 Modulation of nitric oxide metabolism 27611.4 References 27812 Mitigation of Oxidative Stress and Infl ammatory Signaling by Fruit and Walnut Polyphenols: Implications for Cognitive Aging 283James A. Joseph, Barbara Shukitt-Hale, and Lauren M. Willis12.1 Introduction 28312.2 Oxidative stress/infl ammatory interactions 28412.2.1 Oxidative stress 28412.2.2 Inflammation 28412.2.3 Intracellular signaling 28512.2.4 Calcium buffering capacity 28612.2.5 Neurogenesis 28612.2.6 Membrane changes 28712.3 Nutritional interventions 28712.3.1 Fruit polyphenols as neuroprotective agents 28712.3.2 Polyunsaturated fatty acids and cognition: animal studies 28912.4 References 29113 Antiatherosclerotic Effects of Dietary Flavonoids: Insight into their Molecular Action Mechanism at the Target Site 299Junji Terao, Kaeko Murota, and Yoshichika Kawai13.1 Introduction 29913.2 Flavonoids in the diet and their antioxidant/prooxidant activity 30013.3 Absorption and metabolism of dietary flavonoids in the digestive system 30413.4 Oxidative LDL theory and antioxidant activity of fl avonoids in plasma 30713.5 Antioxidant and “beyond” antioxidant activity of flavonoids in the artery 30913.6 Activated macrophages as potential targets of dietary flavonoids as antiatherosclerotic factors 31213.7 Conclusion 31313.8 References 314Index 319

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Celestino Santos-Buelga is Professor of Food Chemistry, Department of Analytical Chemistry, Nutrition and Food Science, Faculty of Pharmacy, University of Salamanca, Spain Maria Teresa Escribano-Bailon is Lecturer in Food Technology, Technical School of Zamora, University of Salamanca, Spain Vincenzo Lattanzio is Professor of Plant Biochemistry and Physiology, Department of Agro- Environmental Sciences, Chemistry and Plant Protection, Faculty of Agricultural Sciences, University of Foggia, ItalyEdited by Celestino Santos-Buelga, Maria Teresa Escribano-Bailon and Vincenzo Lattanzio

• Contributors xiv Preface xviii1 The Visible Flavonoids or Anthocyanins: From Research to Applications 1Raymond Brouillard, Stefan Chassaing, Géraldine Isorez, Marie Kueny-Stotz, and Paulo Figueiredo1.1 Introduction 11.2 Copigmentation of anthocyanins 51.3 Formation of inclusion complexes 61.4 Ion-pair formation 71.5 Metalloanthocyanins 71.6 Z-Chalcones: unexpected open cavities for the ferriccation 111.7 Anthocyanin biological activity 141.8 Some thoughts on applications 151.9 References 172 Flavonoid Chemistry of the Leguminosae 23Nigel C. Veitch2.1 Introduction 232.1.1 Classification and nomenclature of the Leguminosae: a brief synopsis 242.2 Flavonoid structures in the Leguminosae: trends and distribution 262.2.1 Occurrence of 5-deoxyfl avonoids in the Leguminosae 282.2.2 Isofl avonoids in subfamily Papilionoideae 302.2.2.1 Recent advances in biosynthetic studies 322.2.2.2 Isoflavonoid glycosides 352.2.2.3 Isoflavone glucosyltransferases 352.2.2.4 Acylated isoflavone glycosides 362.2.3 Leguminosae anthocyanins: malonyltransferases of Clitoria ternatea 382.3 Advances in analytical methodology applied to Leguminosae flavonoids 382.3.1 Hyphenated MS techniques 402.3.2 Hyphenated NMR techniques and miniaturization 412.3.3 Chiroptical methods 432.4 Leguminosae flavonoids and chemosystematics 442.4.1 The disputed position of the Swartzieae: subfamily Caesalpinioideae or Papilionoideae? 442.4.2 Generic delimitation in the aldinoid clade of swartzioid legumes: Cordyla and Dupuya 472.4.3 Species-level studies of the isoflavonoid chemistry of Cicer 502.5 Concluding remarks 522.6 Acknowledgments 522.7 References 523 Updating Wine Pigments 59Victor A.P. de Freitas and Nuno Mateus3.1 General overview 593.2 Factors that affect wine color intensity and stability 603.3 Chemical transformations of flavonoids 633.3.1 Condensation between anthocyanins and flavanols mediated by aldehydes 653.3.2 Reaction between flavanols and aldehydes 673.3.3 Direct condensation between flavanols and anthocyanins 683.3.4 Pyranoanthocyanins 693.3.4.1 Reaction between anthocyanins and vinyl compounds 703.3.4.2 Yeast metabolites involved in anthocyanin transformations 723.3.5 Vinylpyranoanthocyanins (portisins) 743.4 Final remarks 753.5 Acknowledgments 763.6 References 764 Ellagitannins – An Underestimated Class of Plant Polyphenols: Chemical Reactivity of C-Glucosidic Ellagitannins in Relation to Wine Chemistry and Biological Activity 81Stéphane Quideau, Michael Jourdes, Dorothée Lefeuvre, Patrick Pardon, Cédric Saucier, Pierre-Louis Teissedre, and Yves Glories4.1 Ellagitannins: an underestimated class of bioactive plant polyphenols 814.2 C-Glucosidic ellagitannins: a special subclass of ellagitannins 954.2.1 Major C-glucosidic ellagitannins in oak and chestnut heartwoods 1004.2.2 Complex C-glucosidic ellagitannins 1024.2.3 Biosynthesis of C-glucosidic ellagitannins 1074.2.4 Chemical reactivity of vescalagin and castalagin 1104.2.5 Diastereofacial differentiation of the vescalagin-derived benzylic cation 1134.3 Implications of C-glucosidic ellagitannins in wine chemistry 1144.3.1 Hemisynthesis of acutissimins and their occurrence in wine 1154.3.2 Condensation reaction between vescalagin and glutathione 1184.3.3 Hemisynthesis of anthocyano-ellagitannins: possible influence on wine color 1194.3.4 Oxidative conversion of acutissimin A into mongolicain A 1204.4 Biological activity of C-glucosidic ellagitannins 1224.4.1 Antiviral activity of C-glucosidic ellagitannins 1234.4.2 Antitumor activity of C-glucosidic ellagitannins 1244.5 Conclusion 1254.6 Acknowledgments 1264.7 References 1265 Strategies to Optimize the Flavonoid Content of Tomato Fruit 138Arnaud G. Bovy, Victoria Gómez-Roldán, and Robert D. Hall5.1 Introduction 1385.2 The metabolic route to flavonoids in tomato fruit 1405.3 The natural biodiversity of flavonoids in tomato 1415.3.1 Flavonoid biodiversity I: commercially available genotypes 1425.3.2 Flavonoid biodiversity II: wild tomato species 1425.3.3 Flavonoid biodiversity III: information from specific tomato mutants 1435.4 Metabolic engineering of the flavonoid pathway 1455.4.1 Exploitation of the transgenic approach using up regulation of structural genes 1455.4.2 Using RNAi to block targeted steps in the flavonoid pathway 1465.4.3 Production of novel tomato flavonoids by introducing new branches of the flavonoid pathway: flavonoid-related stilbenes 1475.4.4 Production of novel tomato flavonoids by introducing new branches of the flavonoid pathway: deoxychalcones 1485.4.5 Production of novel tomato flavonoids by introducing new branches of the flavonoid pathway: flavones, isofl avones, and aurones 1495.4.6 Modifying the flavonoid pathway using regulatory genes 1505.5 Metabolomics-assisted breeding 1545.6 Conclusions and future prospects 1565.7 Acknowledgments 1565.8 References 1566 Biological Activity of Phenolics in Plant Cells 163Luc P.R. Bidel, Marc Coumans, Yves Baissac, Patrick Doumas, and Christian Jay-Allemand6.1 Introduction 1636.2 Synthesis and transports 1646.2.1 Metabolic channeling at the endoplasmic reticulum (ER) level 1646.2.2 Endomembrane carriers 1656.2.3 Vesicle trafficking 1666.2.4 Long-distance transport 1666.3 Phenolics interact with plasmalemma components 1676.3.1 Biophysical interactions with phospholipid bilayers 1676.3.2 Interactions with plasma membrane-associated proteins 1696.3.3 Flavonoids prevent and alleviate oxidative burst 1726.3.4 Phenolics modulate plasma membrane carriers 1726.4 Phenolics in apoplast 1756.4.1 Phenolics as a major player in mechanical tissue rigidification 1756.4.2 Phenolics as major components of apoplastic chemical protection 1756.4.3 Phenolics as apoplastic allelochemical signals 1776.5 Phenolics in hyaloplasm 1776.5.1 Phenolics interact with cytoskeleton 1786.5.2 Phenolics inhibit carbohydrate catabolism 1786.5.3 Many fl avonoids prevent and alleviate oxidative and nitrosative stresses 1786.5.4 Salicylic acid promotes oxidative stress signaling pathway 1796.6 Phenolics in vacuoles 1806.6.1 Sunscreen role for vacuolar phenolics 1806.6.2 Are vacuolar phenolics effective buffers? 1806.6.3 Are vacuolar phenolics effective chelators? 1826.7 Phenolics in mitochondria and chloroplasts 1836.7.1 Inhibitory effects 1836.7.2 Protecting effects 1836.7.3 Putative phenolic photoreceptors 1836.8 Phenolics have many emergent roles within the nucleus 1846.8.1 Presence of phenolics within the nucleus 1846.8.2 Flavonoids prevent DNA damages 1846.8.3 Prooxidative actions of phenolics on DNA 1866.8.4 Flavonoids affect histone acetylation and phosphorylation 1866.8.5 Flavonoids inhibit DNA methylation 1876.8.6 Phenolics affect cell cycle 1876.8.7 Phenolics inhibit replication 1886.8.8 Phenolics promote or repress transcription 1896.9 Conclusion 1906.10 References 1917 Muriel Wheldale Onslow and the Rediscovery of Anthocyanin Function in Plants 206Kevin S. Gould7.1 Introduction 2067.1.1 Muriel Wheldale Onslow: a brief biography 2087.2 Functional hypotheses for anthocyanins in vegetative tissues 2117.3 A modern spin on some old ideas 2137.3.1 Photoprotection revisited 2137.3.2 Anthocyanins, sugars, and autumn leaves 2177.4 Concluding remarks 2187.5 Acknowledgments 2197.6 References 2198 Plant Phenolic Compounds Controlling Leaf Movement 226Minoru Ueda and Yoko Nakamura8.1 Introduction 2268.2 Endogenous bioactive substance controlling nyctinasty 2278.3 The chemical mechanism of the rhythm in nyctinasty 2288.4 Bioorganic studies of nyctinasty using functionalized leaf-movementfactors as molecular probes 2308.4.1 Fluorescence studies on nyctinasty 2308.4.2 Photoaffinity labeling of the target protein for the leaf-movement factor 2318.4.3 Are leaf-movement target proteins common to the same plant genus? 2348.5 References 2359 Red Clover Derived Isoflavones: Metabolism and Physiological Effects in Cattle and Sheep and their Concentration in Milk Produced for Human Consumption 238Juhani Taponen, Eeva A. Mustonen, Lea Kontio, Ilkka Saastamoinen, Aila Vanhatalo, Hannu Saloniemi, and Kristiina Wähälä9.1 Introduction 2389.2 Phytoestrogens in ruminant feeds 2389.3 Red clover as a source of isoflavones 2399.4 Metabolism of isofl avones in ruminants 2419.5 Equol: the most important metabolite 2439.6 Physiological effects and regulatory mechanisms of endogenous estrogens 2459.7 Effects of phytoestrogens in sheep reproduction 2479.7.1 Classical clover disease 2479.7.2 Temporary subfertility 2479.7.3 Permanent infertility 2479.8 Effects of phytoestrogens in cattle reproduction 2489.9 Antioxidant capacity of isoflavones 2499.10 New outlook 2499.11 References 25010 Polyphenols as Biomarkers in Nutrition Research: Resveratrol Metabolome a Useful Nutritional Marker of Moderate Wine Consumption 255Raul Zamora-Ros and Cristina Andrés-Lacueva10.1 Introduction 25510.2 Characteristics of nutritional biomarkers 25610.3 Strengths and limitations of biological biomarkers over dietary estimation 26110.4 Resveratrol: a useful biomarker of wine consumption 26210.5 References 26511 Translation of Chemical Properties of Polyphenols into Biological Activity with Impact on Human Health 269João Laranjinha11.1 Introduction 26911.2 Polyphenols as antioxidants: the earlier notions 27011.2.1 The infl uence of redox potentials 27011.2.2 Redox cycles of polyphenols with vitamins E and C: the influence of solubility 27211.3 Beyond “global” antioxidation: alternate biological activities for polyphenols with impact on human health 27411.3.1 Modulation of redox signaling pathways 27411.3.2 Modulation of nitric oxide metabolism 27611.4 References 27812 Mitigation of Oxidative Stress and Infl ammatory Signaling by Fruit and Walnut Polyphenols: Implications for Cognitive Aging 283James A. Joseph, Barbara Shukitt-Hale, and Lauren M. Willis12.1 Introduction 28312.2 Oxidative stress/infl ammatory interactions 28412.2.1 Oxidative stress 28412.2.2 Inflammation 28412.2.3 Intracellular signaling 28512.2.4 Calcium buffering capacity 28612.2.5 Neurogenesis 28612.2.6 Membrane changes 28712.3 Nutritional interventions 28712.3.1 Fruit polyphenols as neuroprotective agents 28712.3.2 Polyunsaturated fatty acids and cognition: animal studies 28912.4 References 29113 Antiatherosclerotic Effects of Dietary Flavonoids: Insight into their Molecular Action Mechanism at the Target Site 299Junji Terao, Kaeko Murota, and Yoshichika Kawai13.1 Introduction 29913.2 Flavonoids in the diet and their antioxidant/prooxidant activity 30013.3 Absorption and metabolism of dietary flavonoids in the digestive system 30413.4 Oxidative LDL theory and antioxidant activity of fl avonoids in plasma 30713.5 Antioxidant and “beyond” antioxidant activity of flavonoids in the artery 30913.6 Activated macrophages as potential targets of dietary flavonoids as antiatherosclerotic factors 31213.7 Conclusion 31313.8 References 314Index 319

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