Annalisa Romani, board member of the « Groupe Polyphénols » (2008-2014), is Professor of Food Sciences and Technologies at the University of Florence, Italy. Her research laboratory is specialized in analytical, structural determination and biological activities of plant polyphenols, with a recent focus on food supplement and innovative extraction green technologies for the recovery of purified molecules as bio-phenols. Vincenzo Lattanzio, former President of the « Groupe Polyphénols » (2004-2008), is full Professor of Plant Biochemistry and Physiology at the University of Foggia (Italy). His research interest concerns studies of the role of phenolic compounds in resistance mechanisms of plant tissues against biotic and abiotic stresses, with a recent focus on trade-off mechanism between growth rate and adaptive response of plant tissues under nutritional stress. Stéphane Quideau, former President of the Groupe Polyphénols (2008-2012), is full Professor of Organic and Bioorganic Chemistry at the University of Bordeaux, France. His research laboratory is specialized in plant polyphenol chemistry and chemical biology, with a focus on the studies of ellagitannin chemical reactivity and synthesis, and interactions of bioactive polyphenols with their protein targets.

• Acknowledgments viiContributors xviiPreface xix1 Monolignol Biosynthesis and its Genetic Manipulation: The Good, the Bad, and the Ugly 1Richard A. Dixon, M.S. Srinivasa Reddy, and Lina Gallego-Giraldo1.1 Introduction 21.2 Function and distribution of lignin in plants 21.3 Targets for modification of lignin biosynthesis 51.3.1 Gene targets 1. Biosynthetic enzymes 51.3.1.1 L-phenylalanine ammonia-lyase (PAL) 61.3.1.2 Cinnamate 4-hydroxylase (C4H) 61.3.1.3 4-coumarate: coenzyme-A ligase (4CL) 61.3.1.4 Enzymes of the coumaroyl shikimate shunt 71.3.1.5 Caffeoyl-CoA 3-O-methyltransferase (CCoAOMT) 71.3.1.6 Ferulate 5-hydroxylase (F5H) 81.3.1.7 Caffeic acid 3-O-methyltransferase (COMT) 81.3.1.8 Cinnamoyl-CoA reductase 81.3.1.9 Cinnamyl alcohol dehydrogenase (CAD) 91.3.2 Gene targets 2. Transcription factors 91.4 Impacts of lignin modification through targeting of the monolignol biosynthetic pathway 91.4.1 L-phenylalanine ammonia-lyase (PAL) 101.4.2 Cinnamate 4-hydroxylase (C4H) 101.4.3 4-coumarate: coenzyme-A ligase (4CL) 111.4.4 Hydroxycinnamoyl-CoA: shikimate hydroxycinnamoyl transferase (HCT) 131.4.5 4-coumaroyl shikimate 3′-hydroxylase (C3′H) 141.4.6 Caffeoyl CoA 3-O-methyltransferase (CCoAOMT) 151.4.7 Ferulate 5-hydroxylase (F5H) 171.4.8 Caffeic acid O-methyltransferase (COMT) 181.4.9 Cinnamoyl-CoA reductase (CCR) 201.4.10 Cinnamyl alcohol dehydrogenase (CAD) 221.5 Impacts of lignin modification through targeting of TFs 231.5.1 NAC master switches 241.5.2 MYB repressors of monolignol biosynthesis 241.5.3 WRKY repressors of lignification in pith 241.6 Monolignol pathway modification and plant growth 251.7 Conclusions: it isn’t all that bad! 26References 272 Perturbing Lignin Biosynthesis: Metabolic Changes in Response to Manipulation of the Phenylpropanoid Pathway 39Nickolas A. Anderson and Clint Chapple2.1 Introduction 402.1.1 Cell wall-bound phenylpropanoids 402.1.2 Soluble phenylpropanoids 432.2 Changes in metabolism associated with phenylpropanoid-pathway disruptions 442.2.1 Phenylalanine ammonia-lyase (PAL) 442.2.2 Cinnamate 4-hydroxylase (C4H) 452.2.3 4-coumarate: CoA ligase (4CL) 462.2.4 Hydroxycinnamoyl-coenzyme A: shikimate/quinate hydroxycinnamoyltransferase (HCT)/p-coumaroyl shikimate 3′-hydroxylase (C3′H) 462.2.5 Cinnamoyl CoA reductase (CCR) 472.2.6 Ferulate 5-hydroxylase (F5H) 482.2.7 Caffeic acid/5-hydroxyferulic acid O-methyltransferase (COMT)/caffeoyl CoA 3-O-methyltransferase (CCoAOMT) 492.2.8 Cinnamyl alcohol dehydrogenases (CAD) 502.3 Atypical lignins 502.4 Dwarfism 512.5 Conclusions 52References 523 Function, Structure, and Evolution of Flavonoid Glycosyltransferases in Plants 61Keiko Yonekura-Sakakibara and Kazuki Saito3.1 Introduction 613.2 UDP-dependent glycosyltransferases 633.2.1 Functional identification of flavonoid UGTs 633.2.1.1 Flavonoid 3-O-glycosyltransferases 633.2.1.2 Flavonoid 7-O-glycosyltransferases 633.2.1.3 Flavonoid glycosyltransferases that glycosylate the sugar moiety attached to a flavonoid aglycone 673.2.1.4 Flavonoid 3′-O-glycosyltransferase 693.2.1.5 Flavonoid C-glycosyltransferase 693.2.2 3D structures of flavonoid UGTs 703.2.3 Functional evolution in UGTs 723.2.3.1 Functional evolution in flavonoid UGTs 743.3 Glycoside hydrolase-type glycosyltransferases 753.3.1 Functional identification of flavonoid GH1-type glycosyltransferases 753.3.1.1 Anthocyanin 5/7-O-glycosyltransferases 753.3.1.2 Anthocyanin 3-O-6′′-O-coumaroylglucoside: glucosyltransferase 763.3.2 The reaction mechanism of GH1-type glycosyltransferases 783.4 Conclusions 78References 784 The Chemistry and Chemical Ecology of Ellagitannins in Plant–Insect Interactions: From Underestimated Molecules to Bioactive Plant Constituents 83Juha-Pekka Salminen4.1 Introduction 844.2 Definitions and chemical structures of hydrolyzable tannins 854.3 Biosynthetic pathways of hydrolyzable tannins in plants 874.3.1 Tannin biosynthetic pathways have many branching points that affect the flux of biosynthetic energy towards different tannins 904.3.2 Biosynthesis of gallic acid, galloylglucoses, and gallotannins 914.3.3 Biosynthesis of ellagitannins 924.4 Distributions of different types of tannin in plants 944.5 Tannins in plant–herbivore interactions 984.5.1 General aspects of tannins and plant–herbivore interactions 984.5.2 The tannin oxidation hypothesis and its verification in plant–herbivore interactions 1024.5.3 The ease of oxidation of individual ellagitannins can be predicted by their chemical structures and chromatographic properties 1044.5.4 Other factors that may affect ellagitannin activities against insect herbivores 1074.6 Conclusions 108Acknowledgments 109References 1095 Diverse Ecological Roles of Plant Tannins: Plant Defense and Beyond 115C. Peter Constabel, Kazuko Yoshida, and Vincent Walker5.1 Introduction 1155.2 Overview of tannin structure and function in defense 1165.2.1 Structural diversity and distribution 1165.2.2 In vitro biochemical activities 1195.2.3 Old and new views on tannins in defense 1205.2.4 The antimicrobial nature of tannins 1225.3 Tissue localization and ecological function 1245.3.1 Distribution of tannins in vegetative tissues 1255.3.2 Tannins in seeds and fruit 1265.3.3 Ecology of fruit tannins 1275.4 Tannins in plant–soil–environment interactions 1295.4.1 Tannin distribution and stability in soil 1295.4.2 Impact of tannins on soil nitrogen cycling and microbial activity 1305.4.3 Interaction with community and ecosystem processes 1315.4.4 Tannins and other plant stress adaptations 1335.5 Conclusions 134Acknowledgments 134References 1346 Epigenetics, Plant (Poly)phenolics, and Cancer Prevention 143Clarissa Gerhauser6.1 Introduction 1436.2 Influence of polyphenols on DNA methylation 1456.2.1 DNA methylation in normal and tumor cells 1456.2.2 Inhibition of DNMTs in vitro 1456.2.3 Inhibition of DNA methylation in cellular systems and in vivo 1476.2.3.1 Quercetin 1476.2.3.2 Nordihydroguaiaretic acid (NDGA) 1476.2.3.3 Resveratrol 1586.2.3.4 Apple polyphenols 1596.2.3.5 Black raspberry polyphenols 1596.3 Influence of polyphenols on histone-modifying enzymes 1606.3.1 Acetylation of histones and non-histone proteins 1616.3.1.1 Anacardic acid 1616.3.1.2 Curcumin 1656.3.1.3 Garcinol 1666.3.1.4 Gallic acid 1676.3.1.5 Delphinidin 1676.3.2 Deacetylation by HDACs and sirtuins 1686.3.2.1 Inhibition of HDAC activity 1686.3.2.2 Modulation of sirtuin activity 1686.3.3 Histone methylation marks 1716.3.3.1 Histone lysine methylation 1716.3.3.2 Histone lysine demethylation 1716.4 Influence of noncoding miRNAs on gene expression 1726.5 Chemopreventive polyphenols affecting the epigenome via multiple mechanisms 1736.5.1 (−)-epigallocatechin 3-gallate (EGCG) and green-tea polyphenols (GTPs) 1736.5.1.1 DNA methylation 1746.5.1.2 Histone-modifying enzymes (HATs, HDACs, HMTs) 1786.5.1.3 miRNAs 1816.5.2 Genistein and soy isoflavones 1836.5.2.1 DNA methylation 1836.5.2.2 Influence on histone acetylation and methylation 1896.5.2.3 miRNAs affected by isoflavones 1926.6 Conclusions 1956.6.1 DNA methylation 1956.6.2 Histone-modifying enzymes 1956.6.3 miRNAs 1966.6.4 Summary 196References 1967 Discovery of Polyphenol-Based Drugs for Cancer Prevention and Treatment: The Tumor Proteasome as a Novel Target 209Fathima R. Kona, Min Shen, Di Chen, Tak Hang Chan, and Q. Ping Dou7.1 Introduction 2097.2 Secondary metabolites of plants 2107.3 Plant polyphenols and their analogs 2117.3.1 Classification and bioavailability of plant polyphenols 2117.3.2 Tea and tea polyphenols 2127.3.3 Targeting of the tumor proteasome by tea polyphenols 2167.3.4 EGCG analogs as proteasome inhibitors 2177.3.4.1 Peracetate and other prodrugs of EGCG 2197.3.4.2 Fluoro-substituted EGCG analogs 2227.3.4.3 Para-amino substituent on the D ring 2227.3.4.4 Bis-galloyl derivatives of EGCG 2237.3.4.5 Methylation-resistant (−)-EGCG analogs 2237.3.5 Other molecular targets of tea polyphenols 2247.3.5.1 AMPK activation 2247.3.6 Proteasome inhibitory action of other plant polyphenols 2257.4 Natural polyphenols in reversal of drug resistance 2267.4.1 Mechanisms of tumor drug resistance 2267.4.2 The ubiquitin–proteasome pathway in drug resistance 2267.4.3 EGCG and overcoming drug resistance 2277.4.4 Genistein and overcoming drug resistance 2287.4.5 Curcumin and overcoming drug resistance 2287.4.6 Clinical trials using polyphenols and chemotherapy 2297.5 Conclusions 231Acknowledgments 231References 2318 Flavonoid Occurrence, Bioavailability, Metabolism, and Protective Effects in Humans: Focus on Flavan-3-ols and Flavonols 239Luca Calani, Margherita Dall’Asta, Renato Bruni, and Daniele Del Rio8.1 Introduction 2408.2 Focus on flavan-3-ols and flavonols: chemical structures and dietary sources 2408.2.1 Flavan-3-ols 2408.2.2 Flavonols 2438.3 Metabolism and bioavailability of flavonoids in humans 2448.3.1 Flavan-3-ols 2458.3.2 Flavonols 2518.4 In vitro studies 2558.4.1 Flavan-3-ols 2568.4.1.1 Phase II metabolites 2568.4.1.2 Microbe-derived metabolites 2598.4.2 Flavonols 2608.4.2.1 Phase II metabolites 2608.4.2.2 Microbe-derived metabolites 2658.5 In vivo studies 2668.5.1 Cardiovascular and endothelial protection 2678.5.1.1 Flavan-3-ols 2678.5.1.2 Flavonols 2688.5.2 Neuroprotection 2698.5.2.1 Flavan-3-ols 2698.5.3 Cancer prevention 2698.5.3.1 Flavan-3-ols 2698.5.3.2 Flavonols 2708.6 Conclusions 271References 2729 Inhibition of VEGF Signaling by Polyphenols in Relation to Atherosclerosis and Cardiovascular Disease 281Rebecca L. Edwards and Paul A. Kroon9.1 Introduction 2829.2 VEGF and VEGF signaling 2829.3 VEGF signaling and angiogenesis 2869.4 Angiogenesis and atherosclerosis 2869.5 Polyphenols in foods and diets, and their absorption and metabolism 2899.6 Effects of polyphenols on VEGF signaling, angiogenesis, and atherosclerosis 2909.6.1 VEGF signaling 3149.6.2 Angiogenesis 3159.6.3 Atherosclerosis 3159.7 Relationships between polyphenol consumption and CVD risk 3169.7.1 Epidemiological studies 3169.7.2 Intervention studies 3189.8 Conclusions 319Acknowledgments 320References 32010 Phenolic Compounds from a Sex-Gender Perspective 327Ilaria Campesi, Annalisa Romani, Maria Marino, and Flavia Franconi10.1 Introduction 32810.2 Phenolic compound classification and molecular mechanisms 32910.3 Sex-gender and the xenokinetics of phenolic compounds 33010.4 Sex-gender differences in xenodynamics 33310.5 Conclusions 334References 33411 Thermodynamic and Kinetic Processes of Anthocyanins and Related Compounds and their Bio-Inspired Applications 341Fernando Pina11.1 Introduction 34211.2 Anthocyanins in aqueous solution 34211.2.1 Step-by-step procedure for calculating rate and equilibrium constants 34911.2.1.1 Step 1: determination of the equilibrium constant K′a 34911.2.1.2 Step 2: determination of the equilibrium constant Ka 34911.2.1.3 Step 3: determination of the equilibrium constant Kt and the respective rate constants 35011.2.1.4 Step 4: determination of the hydration rate and equilibrium constants 35011.2.1.5 Step 5: determination of the isomerization rate and equilibrium constants 35011.2.1.6 Step 6: verification of the self-consistency of all the data 35111.3 Influence of anthocyanin self-aggregation on the determination of rate and equilibrium constants 35111.4 Photochromism: applications bio-inspired in anthocyanins 35711.4.1 Systems lacking the cis–trans isomerization barrier 35711.4.2 Systems exhibiting high cis–trans isomerization barriers 36111.4.2.1 The concept of right–lock–read–unlock–erase optical memories 36111.4.3 Styryl-1-benzopyrylium (styryl flavylium) and naphthoflavylium 36211.4.4 Dye-sensitized solar cells based on anthocyanins 36211.5 How to construct an energy-level diagram 36411.6 How to calculate the mole-fraction distribution of a network species 367References 36812 Synthetic Strategies and Tactics for Catechin and Related Polyphenols 371Ken Ohmori and Keisuke Suzuki12.1 Introduction 37112.2 Early synthetic work 37512.3 Stereoselective approaches to flavan-3-ols 38012.3.1 Synthesis of catechin-series (= 2,3-trans) derivatives 38012.3.2 Synthesis of epi-series (= 2,3-cis) catechins 39312.4 Conclusions 407Abbreviations 407Acknowledgments 408References 408Index 411

Annalisa Romani, board member of the « Groupe Polyphénols » (2008-2014), is Professor of Food Sciences and Technologies at the University of Florence, Italy. Her research laboratory is specialized in analytical, structural determination and biological activities of plant polyphenols, with a recent focus on food supplement and innovative extraction green technologies for the recovery of purified molecules as bio-phenols. Vincenzo Lattanzio, former President of the « Groupe Polyphénols » (2004-2008), is full Professor of Plant Biochemistry and Physiology at the University of Foggia (Italy). His research interest concerns studies of the role of phenolic compounds in resistance mechanisms of plant tissues against biotic and abiotic stresses, with a recent focus on trade-off mechanism between growth rate and adaptive response of plant tissues under nutritional stress. Stéphane Quideau, former President of the Groupe Polyphénols (2008-2012), is full Professor of Organic and Bioorganic Chemistry at the University of Bordeaux, France. His research laboratory is specialized in plant polyphenol chemistry and chemical biology, with a focus on the studies of ellagitannin chemical reactivity and synthesis, and interactions of bioactive polyphenols with their protein targets.

• Acknowledgments viiContributors xviiPreface xix1 Monolignol Biosynthesis and its Genetic Manipulation: The Good, the Bad, and the Ugly 1Richard A. Dixon, M.S. Srinivasa Reddy, and Lina Gallego-Giraldo1.1 Introduction 21.2 Function and distribution of lignin in plants 21.3 Targets for modification of lignin biosynthesis 51.3.1 Gene targets 1. Biosynthetic enzymes 51.3.1.1 L-phenylalanine ammonia-lyase (PAL) 61.3.1.2 Cinnamate 4-hydroxylase (C4H) 61.3.1.3 4-coumarate: coenzyme-A ligase (4CL) 61.3.1.4 Enzymes of the coumaroyl shikimate shunt 71.3.1.5 Caffeoyl-CoA 3-O-methyltransferase (CCoAOMT) 71.3.1.6 Ferulate 5-hydroxylase (F5H) 81.3.1.7 Caffeic acid 3-O-methyltransferase (COMT) 81.3.1.8 Cinnamoyl-CoA reductase 81.3.1.9 Cinnamyl alcohol dehydrogenase (CAD) 91.3.2 Gene targets 2. Transcription factors 91.4 Impacts of lignin modification through targeting of the monolignol biosynthetic pathway 91.4.1 L-phenylalanine ammonia-lyase (PAL) 101.4.2 Cinnamate 4-hydroxylase (C4H) 101.4.3 4-coumarate: coenzyme-A ligase (4CL) 111.4.4 Hydroxycinnamoyl-CoA: shikimate hydroxycinnamoyl transferase (HCT) 131.4.5 4-coumaroyl shikimate 3′-hydroxylase (C3′H) 141.4.6 Caffeoyl CoA 3-O-methyltransferase (CCoAOMT) 151.4.7 Ferulate 5-hydroxylase (F5H) 171.4.8 Caffeic acid O-methyltransferase (COMT) 181.4.9 Cinnamoyl-CoA reductase (CCR) 201.4.10 Cinnamyl alcohol dehydrogenase (CAD) 221.5 Impacts of lignin modification through targeting of TFs 231.5.1 NAC master switches 241.5.2 MYB repressors of monolignol biosynthesis 241.5.3 WRKY repressors of lignification in pith 241.6 Monolignol pathway modification and plant growth 251.7 Conclusions: it isn’t all that bad! 26References 272 Perturbing Lignin Biosynthesis: Metabolic Changes in Response to Manipulation of the Phenylpropanoid Pathway 39Nickolas A. Anderson and Clint Chapple2.1 Introduction 402.1.1 Cell wall-bound phenylpropanoids 402.1.2 Soluble phenylpropanoids 432.2 Changes in metabolism associated with phenylpropanoid-pathway disruptions 442.2.1 Phenylalanine ammonia-lyase (PAL) 442.2.2 Cinnamate 4-hydroxylase (C4H) 452.2.3 4-coumarate: CoA ligase (4CL) 462.2.4 Hydroxycinnamoyl-coenzyme A: shikimate/quinate hydroxycinnamoyltransferase (HCT)/p-coumaroyl shikimate 3′-hydroxylase (C3′H) 462.2.5 Cinnamoyl CoA reductase (CCR) 472.2.6 Ferulate 5-hydroxylase (F5H) 482.2.7 Caffeic acid/5-hydroxyferulic acid O-methyltransferase (COMT)/caffeoyl CoA 3-O-methyltransferase (CCoAOMT) 492.2.8 Cinnamyl alcohol dehydrogenases (CAD) 502.3 Atypical lignins 502.4 Dwarfism 512.5 Conclusions 52References 523 Function, Structure, and Evolution of Flavonoid Glycosyltransferases in Plants 61Keiko Yonekura-Sakakibara and Kazuki Saito3.1 Introduction 613.2 UDP-dependent glycosyltransferases 633.2.1 Functional identification of flavonoid UGTs 633.2.1.1 Flavonoid 3-O-glycosyltransferases 633.2.1.2 Flavonoid 7-O-glycosyltransferases 633.2.1.3 Flavonoid glycosyltransferases that glycosylate the sugar moiety attached to a flavonoid aglycone 673.2.1.4 Flavonoid 3′-O-glycosyltransferase 693.2.1.5 Flavonoid C-glycosyltransferase 693.2.2 3D structures of flavonoid UGTs 703.2.3 Functional evolution in UGTs 723.2.3.1 Functional evolution in flavonoid UGTs 743.3 Glycoside hydrolase-type glycosyltransferases 753.3.1 Functional identification of flavonoid GH1-type glycosyltransferases 753.3.1.1 Anthocyanin 5/7-O-glycosyltransferases 753.3.1.2 Anthocyanin 3-O-6′′-O-coumaroylglucoside: glucosyltransferase 763.3.2 The reaction mechanism of GH1-type glycosyltransferases 783.4 Conclusions 78References 784 The Chemistry and Chemical Ecology of Ellagitannins in Plant–Insect Interactions: From Underestimated Molecules to Bioactive Plant Constituents 83Juha-Pekka Salminen4.1 Introduction 844.2 Definitions and chemical structures of hydrolyzable tannins 854.3 Biosynthetic pathways of hydrolyzable tannins in plants 874.3.1 Tannin biosynthetic pathways have many branching points that affect the flux of biosynthetic energy towards different tannins 904.3.2 Biosynthesis of gallic acid, galloylglucoses, and gallotannins 914.3.3 Biosynthesis of ellagitannins 924.4 Distributions of different types of tannin in plants 944.5 Tannins in plant–herbivore interactions 984.5.1 General aspects of tannins and plant–herbivore interactions 984.5.2 The tannin oxidation hypothesis and its verification in plant–herbivore interactions 1024.5.3 The ease of oxidation of individual ellagitannins can be predicted by their chemical structures and chromatographic properties 1044.5.4 Other factors that may affect ellagitannin activities against insect herbivores 1074.6 Conclusions 108Acknowledgments 109References 1095 Diverse Ecological Roles of Plant Tannins: Plant Defense and Beyond 115C. Peter Constabel, Kazuko Yoshida, and Vincent Walker5.1 Introduction 1155.2 Overview of tannin structure and function in defense 1165.2.1 Structural diversity and distribution 1165.2.2 In vitro biochemical activities 1195.2.3 Old and new views on tannins in defense 1205.2.4 The antimicrobial nature of tannins 1225.3 Tissue localization and ecological function 1245.3.1 Distribution of tannins in vegetative tissues 1255.3.2 Tannins in seeds and fruit 1265.3.3 Ecology of fruit tannins 1275.4 Tannins in plant–soil–environment interactions 1295.4.1 Tannin distribution and stability in soil 1295.4.2 Impact of tannins on soil nitrogen cycling and microbial activity 1305.4.3 Interaction with community and ecosystem processes 1315.4.4 Tannins and other plant stress adaptations 1335.5 Conclusions 134Acknowledgments 134References 1346 Epigenetics, Plant (Poly)phenolics, and Cancer Prevention 143Clarissa Gerhauser6.1 Introduction 1436.2 Influence of polyphenols on DNA methylation 1456.2.1 DNA methylation in normal and tumor cells 1456.2.2 Inhibition of DNMTs in vitro 1456.2.3 Inhibition of DNA methylation in cellular systems and in vivo 1476.2.3.1 Quercetin 1476.2.3.2 Nordihydroguaiaretic acid (NDGA) 1476.2.3.3 Resveratrol 1586.2.3.4 Apple polyphenols 1596.2.3.5 Black raspberry polyphenols 1596.3 Influence of polyphenols on histone-modifying enzymes 1606.3.1 Acetylation of histones and non-histone proteins 1616.3.1.1 Anacardic acid 1616.3.1.2 Curcumin 1656.3.1.3 Garcinol 1666.3.1.4 Gallic acid 1676.3.1.5 Delphinidin 1676.3.2 Deacetylation by HDACs and sirtuins 1686.3.2.1 Inhibition of HDAC activity 1686.3.2.2 Modulation of sirtuin activity 1686.3.3 Histone methylation marks 1716.3.3.1 Histone lysine methylation 1716.3.3.2 Histone lysine demethylation 1716.4 Influence of noncoding miRNAs on gene expression 1726.5 Chemopreventive polyphenols affecting the epigenome via multiple mechanisms 1736.5.1 (−)-epigallocatechin 3-gallate (EGCG) and green-tea polyphenols (GTPs) 1736.5.1.1 DNA methylation 1746.5.1.2 Histone-modifying enzymes (HATs, HDACs, HMTs) 1786.5.1.3 miRNAs 1816.5.2 Genistein and soy isoflavones 1836.5.2.1 DNA methylation 1836.5.2.2 Influence on histone acetylation and methylation 1896.5.2.3 miRNAs affected by isoflavones 1926.6 Conclusions 1956.6.1 DNA methylation 1956.6.2 Histone-modifying enzymes 1956.6.3 miRNAs 1966.6.4 Summary 196References 1967 Discovery of Polyphenol-Based Drugs for Cancer Prevention and Treatment: The Tumor Proteasome as a Novel Target 209Fathima R. Kona, Min Shen, Di Chen, Tak Hang Chan, and Q. Ping Dou7.1 Introduction 2097.2 Secondary metabolites of plants 2107.3 Plant polyphenols and their analogs 2117.3.1 Classification and bioavailability of plant polyphenols 2117.3.2 Tea and tea polyphenols 2127.3.3 Targeting of the tumor proteasome by tea polyphenols 2167.3.4 EGCG analogs as proteasome inhibitors 2177.3.4.1 Peracetate and other prodrugs of EGCG 2197.3.4.2 Fluoro-substituted EGCG analogs 2227.3.4.3 Para-amino substituent on the D ring 2227.3.4.4 Bis-galloyl derivatives of EGCG 2237.3.4.5 Methylation-resistant (−)-EGCG analogs 2237.3.5 Other molecular targets of tea polyphenols 2247.3.5.1 AMPK activation 2247.3.6 Proteasome inhibitory action of other plant polyphenols 2257.4 Natural polyphenols in reversal of drug resistance 2267.4.1 Mechanisms of tumor drug resistance 2267.4.2 The ubiquitin–proteasome pathway in drug resistance 2267.4.3 EGCG and overcoming drug resistance 2277.4.4 Genistein and overcoming drug resistance 2287.4.5 Curcumin and overcoming drug resistance 2287.4.6 Clinical trials using polyphenols and chemotherapy 2297.5 Conclusions 231Acknowledgments 231References 2318 Flavonoid Occurrence, Bioavailability, Metabolism, and Protective Effects in Humans: Focus on Flavan-3-ols and Flavonols 239Luca Calani, Margherita Dall’Asta, Renato Bruni, and Daniele Del Rio8.1 Introduction 2408.2 Focus on flavan-3-ols and flavonols: chemical structures and dietary sources 2408.2.1 Flavan-3-ols 2408.2.2 Flavonols 2438.3 Metabolism and bioavailability of flavonoids in humans 2448.3.1 Flavan-3-ols 2458.3.2 Flavonols 2518.4 In vitro studies 2558.4.1 Flavan-3-ols 2568.4.1.1 Phase II metabolites 2568.4.1.2 Microbe-derived metabolites 2598.4.2 Flavonols 2608.4.2.1 Phase II metabolites 2608.4.2.2 Microbe-derived metabolites 2658.5 In vivo studies 2668.5.1 Cardiovascular and endothelial protection 2678.5.1.1 Flavan-3-ols 2678.5.1.2 Flavonols 2688.5.2 Neuroprotection 2698.5.2.1 Flavan-3-ols 2698.5.3 Cancer prevention 2698.5.3.1 Flavan-3-ols 2698.5.3.2 Flavonols 2708.6 Conclusions 271References 2729 Inhibition of VEGF Signaling by Polyphenols in Relation to Atherosclerosis and Cardiovascular Disease 281Rebecca L. Edwards and Paul A. Kroon9.1 Introduction 2829.2 VEGF and VEGF signaling 2829.3 VEGF signaling and angiogenesis 2869.4 Angiogenesis and atherosclerosis 2869.5 Polyphenols in foods and diets, and their absorption and metabolism 2899.6 Effects of polyphenols on VEGF signaling, angiogenesis, and atherosclerosis 2909.6.1 VEGF signaling 3149.6.2 Angiogenesis 3159.6.3 Atherosclerosis 3159.7 Relationships between polyphenol consumption and CVD risk 3169.7.1 Epidemiological studies 3169.7.2 Intervention studies 3189.8 Conclusions 319Acknowledgments 320References 32010 Phenolic Compounds from a Sex-Gender Perspective 327Ilaria Campesi, Annalisa Romani, Maria Marino, and Flavia Franconi10.1 Introduction 32810.2 Phenolic compound classification and molecular mechanisms 32910.3 Sex-gender and the xenokinetics of phenolic compounds 33010.4 Sex-gender differences in xenodynamics 33310.5 Conclusions 334References 33411 Thermodynamic and Kinetic Processes of Anthocyanins and Related Compounds and their Bio-Inspired Applications 341Fernando Pina11.1 Introduction 34211.2 Anthocyanins in aqueous solution 34211.2.1 Step-by-step procedure for calculating rate and equilibrium constants 34911.2.1.1 Step 1: determination of the equilibrium constant K′a 34911.2.1.2 Step 2: determination of the equilibrium constant Ka 34911.2.1.3 Step 3: determination of the equilibrium constant Kt and the respective rate constants 35011.2.1.4 Step 4: determination of the hydration rate and equilibrium constants 35011.2.1.5 Step 5: determination of the isomerization rate and equilibrium constants 35011.2.1.6 Step 6: verification of the self-consistency of all the data 35111.3 Influence of anthocyanin self-aggregation on the determination of rate and equilibrium constants 35111.4 Photochromism: applications bio-inspired in anthocyanins 35711.4.1 Systems lacking the cis–trans isomerization barrier 35711.4.2 Systems exhibiting high cis–trans isomerization barriers 36111.4.2.1 The concept of right–lock–read–unlock–erase optical memories 36111.4.3 Styryl-1-benzopyrylium (styryl flavylium) and naphthoflavylium 36211.4.4 Dye-sensitized solar cells based on anthocyanins 36211.5 How to construct an energy-level diagram 36411.6 How to calculate the mole-fraction distribution of a network species 367References 36812 Synthetic Strategies and Tactics for Catechin and Related Polyphenols 371Ken Ohmori and Keisuke Suzuki12.1 Introduction 37112.2 Early synthetic work 37512.3 Stereoselective approaches to flavan-3-ols 38012.3.1 Synthesis of catechin-series (= 2,3-trans) derivatives 38012.3.2 Synthesis of epi-series (= 2,3-cis) catechins 39312.4 Conclusions 407Abbreviations 407Acknowledgments 408References 408Index 411

Annalisa Romani, board member of the « Groupe Polyphénols » (2008-2014), is Professor of Food Sciences and Technologies at the University of Florence, Italy. Her research laboratory is specialized in analytical, structural determination and biological activities of plant polyphenols, with a recent focus on food supplement and innovative extraction green technologies for the recovery of purified molecules as bio-phenols. Vincenzo Lattanzio, former President of the « Groupe Polyphénols » (2004-2008), is full Professor of Plant Biochemistry and Physiology at the University of Foggia (Italy). His research interest concerns studies of the role of phenolic compounds in resistance mechanisms of plant tissues against biotic and abiotic stresses, with a recent focus on trade-off mechanism between growth rate and adaptive response of plant tissues under nutritional stress. Stéphane Quideau, former President of the Groupe Polyphénols (2008-2012), is full Professor of Organic and Bioorganic Chemistry at the University of Bordeaux, France. His research laboratory is specialized in plant polyphenol chemistry and chemical biology, with a focus on the studies of ellagitannin chemical reactivity and synthesis, and interactions of bioactive polyphenols with their protein targets.

• Acknowledgments viiContributors xviiPreface xix1 Monolignol Biosynthesis and its Genetic Manipulation: The Good, the Bad, and the Ugly 1Richard A. Dixon, M.S. Srinivasa Reddy, and Lina Gallego-Giraldo1.1 Introduction 21.2 Function and distribution of lignin in plants 21.3 Targets for modification of lignin biosynthesis 51.3.1 Gene targets 1. Biosynthetic enzymes 51.3.1.1 L-phenylalanine ammonia-lyase (PAL) 61.3.1.2 Cinnamate 4-hydroxylase (C4H) 61.3.1.3 4-coumarate: coenzyme-A ligase (4CL) 61.3.1.4 Enzymes of the coumaroyl shikimate shunt 71.3.1.5 Caffeoyl-CoA 3-O-methyltransferase (CCoAOMT) 71.3.1.6 Ferulate 5-hydroxylase (F5H) 81.3.1.7 Caffeic acid 3-O-methyltransferase (COMT) 81.3.1.8 Cinnamoyl-CoA reductase 81.3.1.9 Cinnamyl alcohol dehydrogenase (CAD) 91.3.2 Gene targets 2. Transcription factors 91.4 Impacts of lignin modification through targeting of the monolignol biosynthetic pathway 91.4.1 L-phenylalanine ammonia-lyase (PAL) 101.4.2 Cinnamate 4-hydroxylase (C4H) 101.4.3 4-coumarate: coenzyme-A ligase (4CL) 111.4.4 Hydroxycinnamoyl-CoA: shikimate hydroxycinnamoyl transferase (HCT) 131.4.5 4-coumaroyl shikimate 3′-hydroxylase (C3′H) 141.4.6 Caffeoyl CoA 3-O-methyltransferase (CCoAOMT) 151.4.7 Ferulate 5-hydroxylase (F5H) 171.4.8 Caffeic acid O-methyltransferase (COMT) 181.4.9 Cinnamoyl-CoA reductase (CCR) 201.4.10 Cinnamyl alcohol dehydrogenase (CAD) 221.5 Impacts of lignin modification through targeting of TFs 231.5.1 NAC master switches 241.5.2 MYB repressors of monolignol biosynthesis 241.5.3 WRKY repressors of lignification in pith 241.6 Monolignol pathway modification and plant growth 251.7 Conclusions: it isn’t all that bad! 26References 272 Perturbing Lignin Biosynthesis: Metabolic Changes in Response to Manipulation of the Phenylpropanoid Pathway 39Nickolas A. Anderson and Clint Chapple2.1 Introduction 402.1.1 Cell wall-bound phenylpropanoids 402.1.2 Soluble phenylpropanoids 432.2 Changes in metabolism associated with phenylpropanoid-pathway disruptions 442.2.1 Phenylalanine ammonia-lyase (PAL) 442.2.2 Cinnamate 4-hydroxylase (C4H) 452.2.3 4-coumarate: CoA ligase (4CL) 462.2.4 Hydroxycinnamoyl-coenzyme A: shikimate/quinate hydroxycinnamoyltransferase (HCT)/p-coumaroyl shikimate 3′-hydroxylase (C3′H) 462.2.5 Cinnamoyl CoA reductase (CCR) 472.2.6 Ferulate 5-hydroxylase (F5H) 482.2.7 Caffeic acid/5-hydroxyferulic acid O-methyltransferase (COMT)/caffeoyl CoA 3-O-methyltransferase (CCoAOMT) 492.2.8 Cinnamyl alcohol dehydrogenases (CAD) 502.3 Atypical lignins 502.4 Dwarfism 512.5 Conclusions 52References 523 Function, Structure, and Evolution of Flavonoid Glycosyltransferases in Plants 61Keiko Yonekura-Sakakibara and Kazuki Saito3.1 Introduction 613.2 UDP-dependent glycosyltransferases 633.2.1 Functional identification of flavonoid UGTs 633.2.1.1 Flavonoid 3-O-glycosyltransferases 633.2.1.2 Flavonoid 7-O-glycosyltransferases 633.2.1.3 Flavonoid glycosyltransferases that glycosylate the sugar moiety attached to a flavonoid aglycone 673.2.1.4 Flavonoid 3′-O-glycosyltransferase 693.2.1.5 Flavonoid C-glycosyltransferase 693.2.2 3D structures of flavonoid UGTs 703.2.3 Functional evolution in UGTs 723.2.3.1 Functional evolution in flavonoid UGTs 743.3 Glycoside hydrolase-type glycosyltransferases 753.3.1 Functional identification of flavonoid GH1-type glycosyltransferases 753.3.1.1 Anthocyanin 5/7-O-glycosyltransferases 753.3.1.2 Anthocyanin 3-O-6′′-O-coumaroylglucoside: glucosyltransferase 763.3.2 The reaction mechanism of GH1-type glycosyltransferases 783.4 Conclusions 78References 784 The Chemistry and Chemical Ecology of Ellagitannins in Plant–Insect Interactions: From Underestimated Molecules to Bioactive Plant Constituents 83Juha-Pekka Salminen4.1 Introduction 844.2 Definitions and chemical structures of hydrolyzable tannins 854.3 Biosynthetic pathways of hydrolyzable tannins in plants 874.3.1 Tannin biosynthetic pathways have many branching points that affect the flux of biosynthetic energy towards different tannins 904.3.2 Biosynthesis of gallic acid, galloylglucoses, and gallotannins 914.3.3 Biosynthesis of ellagitannins 924.4 Distributions of different types of tannin in plants 944.5 Tannins in plant–herbivore interactions 984.5.1 General aspects of tannins and plant–herbivore interactions 984.5.2 The tannin oxidation hypothesis and its verification in plant–herbivore interactions 1024.5.3 The ease of oxidation of individual ellagitannins can be predicted by their chemical structures and chromatographic properties 1044.5.4 Other factors that may affect ellagitannin activities against insect herbivores 1074.6 Conclusions 108Acknowledgments 109References 1095 Diverse Ecological Roles of Plant Tannins: Plant Defense and Beyond 115C. Peter Constabel, Kazuko Yoshida, and Vincent Walker5.1 Introduction 1155.2 Overview of tannin structure and function in defense 1165.2.1 Structural diversity and distribution 1165.2.2 In vitro biochemical activities 1195.2.3 Old and new views on tannins in defense 1205.2.4 The antimicrobial nature of tannins 1225.3 Tissue localization and ecological function 1245.3.1 Distribution of tannins in vegetative tissues 1255.3.2 Tannins in seeds and fruit 1265.3.3 Ecology of fruit tannins 1275.4 Tannins in plant–soil–environment interactions 1295.4.1 Tannin distribution and stability in soil 1295.4.2 Impact of tannins on soil nitrogen cycling and microbial activity 1305.4.3 Interaction with community and ecosystem processes 1315.4.4 Tannins and other plant stress adaptations 1335.5 Conclusions 134Acknowledgments 134References 1346 Epigenetics, Plant (Poly)phenolics, and Cancer Prevention 143Clarissa Gerhauser6.1 Introduction 1436.2 Influence of polyphenols on DNA methylation 1456.2.1 DNA methylation in normal and tumor cells 1456.2.2 Inhibition of DNMTs in vitro 1456.2.3 Inhibition of DNA methylation in cellular systems and in vivo 1476.2.3.1 Quercetin 1476.2.3.2 Nordihydroguaiaretic acid (NDGA) 1476.2.3.3 Resveratrol 1586.2.3.4 Apple polyphenols 1596.2.3.5 Black raspberry polyphenols 1596.3 Influence of polyphenols on histone-modifying enzymes 1606.3.1 Acetylation of histones and non-histone proteins 1616.3.1.1 Anacardic acid 1616.3.1.2 Curcumin 1656.3.1.3 Garcinol 1666.3.1.4 Gallic acid 1676.3.1.5 Delphinidin 1676.3.2 Deacetylation by HDACs and sirtuins 1686.3.2.1 Inhibition of HDAC activity 1686.3.2.2 Modulation of sirtuin activity 1686.3.3 Histone methylation marks 1716.3.3.1 Histone lysine methylation 1716.3.3.2 Histone lysine demethylation 1716.4 Influence of noncoding miRNAs on gene expression 1726.5 Chemopreventive polyphenols affecting the epigenome via multiple mechanisms 1736.5.1 (−)-epigallocatechin 3-gallate (EGCG) and green-tea polyphenols (GTPs) 1736.5.1.1 DNA methylation 1746.5.1.2 Histone-modifying enzymes (HATs, HDACs, HMTs) 1786.5.1.3 miRNAs 1816.5.2 Genistein and soy isoflavones 1836.5.2.1 DNA methylation 1836.5.2.2 Influence on histone acetylation and methylation 1896.5.2.3 miRNAs affected by isoflavones 1926.6 Conclusions 1956.6.1 DNA methylation 1956.6.2 Histone-modifying enzymes 1956.6.3 miRNAs 1966.6.4 Summary 196References 1967 Discovery of Polyphenol-Based Drugs for Cancer Prevention and Treatment: The Tumor Proteasome as a Novel Target 209Fathima R. Kona, Min Shen, Di Chen, Tak Hang Chan, and Q. Ping Dou7.1 Introduction 2097.2 Secondary metabolites of plants 2107.3 Plant polyphenols and their analogs 2117.3.1 Classification and bioavailability of plant polyphenols 2117.3.2 Tea and tea polyphenols 2127.3.3 Targeting of the tumor proteasome by tea polyphenols 2167.3.4 EGCG analogs as proteasome inhibitors 2177.3.4.1 Peracetate and other prodrugs of EGCG 2197.3.4.2 Fluoro-substituted EGCG analogs 2227.3.4.3 Para-amino substituent on the D ring 2227.3.4.4 Bis-galloyl derivatives of EGCG 2237.3.4.5 Methylation-resistant (−)-EGCG analogs 2237.3.5 Other molecular targets of tea polyphenols 2247.3.5.1 AMPK activation 2247.3.6 Proteasome inhibitory action of other plant polyphenols 2257.4 Natural polyphenols in reversal of drug resistance 2267.4.1 Mechanisms of tumor drug resistance 2267.4.2 The ubiquitin–proteasome pathway in drug resistance 2267.4.3 EGCG and overcoming drug resistance 2277.4.4 Genistein and overcoming drug resistance 2287.4.5 Curcumin and overcoming drug resistance 2287.4.6 Clinical trials using polyphenols and chemotherapy 2297.5 Conclusions 231Acknowledgments 231References 2318 Flavonoid Occurrence, Bioavailability, Metabolism, and Protective Effects in Humans: Focus on Flavan-3-ols and Flavonols 239Luca Calani, Margherita Dall’Asta, Renato Bruni, and Daniele Del Rio8.1 Introduction 2408.2 Focus on flavan-3-ols and flavonols: chemical structures and dietary sources 2408.2.1 Flavan-3-ols 2408.2.2 Flavonols 2438.3 Metabolism and bioavailability of flavonoids in humans 2448.3.1 Flavan-3-ols 2458.3.2 Flavonols 2518.4 In vitro studies 2558.4.1 Flavan-3-ols 2568.4.1.1 Phase II metabolites 2568.4.1.2 Microbe-derived metabolites 2598.4.2 Flavonols 2608.4.2.1 Phase II metabolites 2608.4.2.2 Microbe-derived metabolites 2658.5 In vivo studies 2668.5.1 Cardiovascular and endothelial protection 2678.5.1.1 Flavan-3-ols 2678.5.1.2 Flavonols 2688.5.2 Neuroprotection 2698.5.2.1 Flavan-3-ols 2698.5.3 Cancer prevention 2698.5.3.1 Flavan-3-ols 2698.5.3.2 Flavonols 2708.6 Conclusions 271References 2729 Inhibition of VEGF Signaling by Polyphenols in Relation to Atherosclerosis and Cardiovascular Disease 281Rebecca L. Edwards and Paul A. Kroon9.1 Introduction 2829.2 VEGF and VEGF signaling 2829.3 VEGF signaling and angiogenesis 2869.4 Angiogenesis and atherosclerosis 2869.5 Polyphenols in foods and diets, and their absorption and metabolism 2899.6 Effects of polyphenols on VEGF signaling, angiogenesis, and atherosclerosis 2909.6.1 VEGF signaling 3149.6.2 Angiogenesis 3159.6.3 Atherosclerosis 3159.7 Relationships between polyphenol consumption and CVD risk 3169.7.1 Epidemiological studies 3169.7.2 Intervention studies 3189.8 Conclusions 319Acknowledgments 320References 32010 Phenolic Compounds from a Sex-Gender Perspective 327Ilaria Campesi, Annalisa Romani, Maria Marino, and Flavia Franconi10.1 Introduction 32810.2 Phenolic compound classification and molecular mechanisms 32910.3 Sex-gender and the xenokinetics of phenolic compounds 33010.4 Sex-gender differences in xenodynamics 33310.5 Conclusions 334References 33411 Thermodynamic and Kinetic Processes of Anthocyanins and Related Compounds and their Bio-Inspired Applications 341Fernando Pina11.1 Introduction 34211.2 Anthocyanins in aqueous solution 34211.2.1 Step-by-step procedure for calculating rate and equilibrium constants 34911.2.1.1 Step 1: determination of the equilibrium constant K′a 34911.2.1.2 Step 2: determination of the equilibrium constant Ka 34911.2.1.3 Step 3: determination of the equilibrium constant Kt and the respective rate constants 35011.2.1.4 Step 4: determination of the hydration rate and equilibrium constants 35011.2.1.5 Step 5: determination of the isomerization rate and equilibrium constants 35011.2.1.6 Step 6: verification of the self-consistency of all the data 35111.3 Influence of anthocyanin self-aggregation on the determination of rate and equilibrium constants 35111.4 Photochromism: applications bio-inspired in anthocyanins 35711.4.1 Systems lacking the cis–trans isomerization barrier 35711.4.2 Systems exhibiting high cis–trans isomerization barriers 36111.4.2.1 The concept of right–lock–read–unlock–erase optical memories 36111.4.3 Styryl-1-benzopyrylium (styryl flavylium) and naphthoflavylium 36211.4.4 Dye-sensitized solar cells based on anthocyanins 36211.5 How to construct an energy-level diagram 36411.6 How to calculate the mole-fraction distribution of a network species 367References 36812 Synthetic Strategies and Tactics for Catechin and Related Polyphenols 371Ken Ohmori and Keisuke Suzuki12.1 Introduction 37112.2 Early synthetic work 37512.3 Stereoselective approaches to flavan-3-ols 38012.3.1 Synthesis of catechin-series (= 2,3-trans) derivatives 38012.3.2 Synthesis of epi-series (= 2,3-cis) catechins 39312.4 Conclusions 407Abbreviations 407Acknowledgments 408References 408Index 411