Recent Advances in Polyphenol Research, Volume 5 E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Serie: Recent Advances in Polyphenol Research
• Sprache: Englisch

Seitenzahl: 771

Veröffentlichungsjahr: 2016

Beschreibung

Plant polyphenols are secondary metabolites that constitute one of the most common and widespread groups of natural products. They express a large and diverse panel of biological activities including beneficial effects on both plants and humans. Many polyphenols, from their structurally simplest representatives to their oligo/polymeric versions (also referred to as vegetable tannins), are notably known as phytoestrogens, plant pigments, potent antioxidants, and protein interacting agents.

Sponsored by the scholarly society Groupe Polyphénols, this publication, which is the fifth volume in this highly regarded Recent Advances in Polyphenol Research series, is edited by Kumi Yoshida, Véronique Cheynier and Stéphane Quideau. They have once again, like their predecessors, put together an impressive collection of cutting-edge chapters written by expert scientists, internationally respected in their respective field of polyphenol sciences. This Volume 5 highlights some of the latest information and opinion on the following major research topics about polyphenols:  

• Chemistry, physicochemistry & materials science
• Biosynthesis, genetic & metabolic engineering
• Plant & ecosystem, lignocellulosic biomass
• Food, nutrition & health
• Natural medicine & Kampo
• Tannins & their functions

Chemists, biochemists, plant scientists, pharmacognosists and pharmacologists, biologists, ecologists, food scientists and nutritionists will all find this book an invaluable resource. Libraries in all universities and research institutions where these disciplines are studied and taught should have copies on their bookshelves. 

Leseprobe

Table of Contents

Cover

Title Page

Contributors

Preface

Chapter 1: The Physical Chemistry of Polyphenols

1.1 Introduction

1.2 Molecular complexation of polyphenols

1.3 Polyphenols as electron donors

1.4 Polyphenols as ligands for metal ions

1.5 Conclusions

References

Chapter 2: Polyphenols in Bryophytes

2.1 Introduction

2.2 Distribution of cyclic and acyclic bis‐bibenzyls in Marchantiophyta (liverworts)

2.3 Biosynthesis of bis‐bibenzyls

2.4 The structures of bis‐bibenzyls and their total synthesis

2.5 Biological activity of bis‐bibenzyls

2.6 Conclusions

Acknowledgments

References

Chapter 3: Oxidation Mechanism of Polyphenols and Chemistry of Black Tea

3.1 Introduction

3.2 Catechin oxidation and production of theaflavins

3.3 Theasinensins

3.4 Coupled oxidation mechanism

3.5 Bicyclo[3.2.1]octane intermediates

3.6 Structures of catechin oxidation products

3.7 Oligomeric oxidation products

3.8 Conclusions

Acknowledgments

References

Chapter 4: A Proteomic‐Based Quantitative Analysis of the Relationship Between Monolignol Biosynthetic Protein Abundance and Lignin Content Using Transgenic

Populus trichocarpa

4.1 Introduction

4.2 Results

4.3 Discussion

4.4 Materials and methods

References

Chapter 5: Monolignol Biosynthesis and Regulation in Grasses

5.1 Introduction

5.2 Unique cell walls in grasses

5.3 Lignin deposition in grasses

5.4 Monolignol biosynthesis in grasses

5.5 Regulation of monolignol biosynthesis in grasses

5.6 Remarks

Acknowledgments

References

Chapter 6: Creation of Flower Color Mutants Using Ion Beams and a Comprehensive Analysis of Anthocyanin Composition and Genetic Background

6.1 Introduction

6.2 Induction of flower color mutants by ion beams

6.3 Mutagenic effects and the molecular nature of the mutations

6.4 Comprehensive analyses of flower color, pigments, and associated genes in fragrant cyclamen

6.5 Mutagenesis and screening

6.6 Genetic background and the obtained mutants

6.7 Carnations with peculiar glittering colors

6.8 Conclusions

Acknowledgments

References

Chapter 7: Flavonols Regulate Plant Growth and Development through Regulation of Auxin Transport and Cellular Redox Status

7.1 Introduction

7.2 The flavonoids and their biosynthetic pathway

7.3 Flavonoids affect root elongation and gravitropism through alteration of auxin transport

7.4 Mechanisms by which flavonols regulate IAA transport

7.5 Lateral root formation

7.6 Cotyledon, trichome, and root hair development

7.7 Inflorescence architecture

7.8 Fertility and pollen development

7.9 Flavonols modulate ROS signaling in guard cells to regulate stomatal aperture

7.10 Transcriptional machinery that controls synthesis of flavonoids

7.11 Hormonal controls of flavonoid synthesis

7.12 Flavonoid synthesis is regulated by light

7.13 Conclusions

Acknowledgments

References

Chapter 8: Structure of Polyacylated Anthocyanins and Their UV Protective Effect

8.1 Introduction

8.2 Occurrence and structure of polyacylated anthocyanins in blue flowers

8.3 Molecular associations of polyacylated anthocyanins in blue flower petals

8.4 UV protection of polyacylated anthocyanins from solar radiation

8.5 Conclusions

References

Chapter 9: The Involvement of Anthocyanin‐Rich Foods in Retinal Damage

9.1 Introduction

9.2 Anthocyanin‐rich foods for eye health

9.3 Experimental models to mimic eye diseases and the effect of anthocyanin‐rich foods

9.4 Conclusions

References

Chapter 10: Prevention and Treatment of Diabetes Using Polyphenols via Activation of AMP‐Activated Protein Kinase and Stimulation of Glucagon‐like Peptide‐1 Secretion

10.1 Introduction

10.2 Activation of AMPK and metabolic change

10.3 GLP‐1 action and diabetes prevention/suppression

10.4 Future issues and prospects

References

Chapter 11: Beneficial Vascular Responses to Proanthocyanidins

11.1 Introduction

11.2 Appraisal of test materials

11.3 Endothelial dysfunction

11.4

In vitro

test systems

11.5 Vasorelaxant mechanisms

11.6 Bioavailability and metabolic transformation: the missing link in the evidence to action in the body

11.7 Conclusions

References

Chapter 12: Polyphenols for Brain and Cognitive Health

12.1 Introduction

12.2 Studies of total polyphenols and cognition

12.3 Pine bark

12.4 Discussion and conclusions

References

Chapter 13: Curcumin and Cancer Metastasis

13.1 Introduction

13.2 Effects of curcumin on intra‐hepatic metastasis of liver cancer

13.3 Effects of curcumin on lymp node metastasis of lung cancer

13.4 Effects of curcumin on tumor angiogenesis

13.5 Conclusions

References

Chapter 14: Phytochemical and Pharmacological Overview of

Cistanche

Species

14.1 Introduction

14.2 Chemical constituents of

Cistanche

species

14.3 Bioactivities of the extracts and pure compounds from

Cistanche

species

14.4 Conclusions

References

Index

End User License Agreement

List of Tables

Chapter 02

Table 2.1 Bis‐bibenzyls found in the Marchantiophyta (liverworts) (Asakawa & Ludwiczuk, 2012).

Table 2.2 Biologically active bis‐bibenzyls from liverworts (Asakawa, 1982, 1995, 2008a; Asakawa

et al.

, 2013a, 2013b).

Chapter 04

Table 4.1 Core proteins of monolignol biosynthesis in

Populus trichocarpa

.

Table 4.2 Parameter estimates from segmented regression models predicting lignin content of

Populus trichocarpa

from protein abundance.

Chapter 06

Table 6.1 Frequency of flower mutants induced by gamma rays and carbon ions in the chrysanthemum cultivar “Taihei” (Pink flowers).

Table 6.2 Frequency of flower mutants induced by carbon ions, EMS, gamma rays, and X‐rays in the carnation cultivar “Vital” (cherry pink flowers).

Chapter 07

Table 7.1 Summary of transcription factors that have been demonstrated to control levels of transcripts of genes encoding pathway enzymes of flavonoid biosynthesis and the organism and tissue in which this regulation has been observed.

Chapter 11

Table 11.1 Data on the chemical composition of procyanidin samples.

Table 11.2 Overview of important inhibitors and their targets.

Table 11.3 Vasorelaxant mechanisms studied in procyanidin‐containing plant products.

Chapter 12

Table 12.1 Controlled trials of the cognitive effects of polyphenols/polyphenol rich products.

Chapter 14

Table 14.1 Chemical types and their distribution in

Cistanche

species.

Table 14.2 PhGs from

Cistanche

species (

1–70

).

Table 14.3 Benzyl glycosides from

Cistanche

species (

71–76

).

Table 14.4 Structures of iridoid aglycones (

77

−

87

).

Table 14.5 Structures of iridoid glycosides (

88

−

102

).

Table 14.6 Structures of monoterpenoids (

103

−

109

).

Table 14.7 Structures of ditetrahydrofuran lignans from

Cistanche

species (

110–117

).

Table 14.8 The structural properties of polysaccharides from

C. deserticola

.

Table 14.9 Other type compounds from

Cistanche

species.

List of Illustrations

Chapter 01

Fig. 1.1 A simplified view of polyphenol bioavailability.

Fig. 1.2 Health effects expressed by polyphenols.

Fig. 1.3 Pathways of inflammation and oxidative stress in cells. Kinases, proinflammatory transcription factors, and pro‐oxidant enzymes are possible target proteins for polyphenols and their metabolites.

Fig. 1.4 Snapshots of the location of quercetin (a) and quercetin 3‐

O

‐β‐

D

‐glucuronide (b) in a 1,2‐dioleoyl‐

sn

‐glycero‐3‐phosphatidylcholine lipid bilayer. Spheres represent the phosphatidyl groups.

Fig. 1.5 Schematic description of (a) PCET involving five electrons and (b) HAT.

Fig. 1.6 Various geometries of noncovalent ArOH‐‐‐ROO

•

arrangements. (a)

transoid

H‐bonding, (b)

cisoid

H‐bonding, (c) π–π stacking, and (d) XH–π stacking complexes.

Fig. 1.7 Schematic potential energy surfaces with respect to the reaction coordinate (a) corresponding to the electron transfer and (b) defining the internal reorganization energies.

Fig. 1.8 Activation of heme iron (metmyoglobin) by lipid hydroperoxides and the role of phenolic antioxidants.

Fig. 1.9 Polyphenols and transition metal ions. Acidic conditions: iron binding and subsequent electron transfer. Neutral conditions: binding and autoxidation.

Fig. 1.10 Spin density distribution: (a) [Fe

III

(Cat

1−

)(H

2

O)

5

]

+2

and (b) [Fe

III

(Cat

2−

)(H

2

O)

4

]

+1

.

Fig. 1.11 Electronic structure of the Fe

III

–Catecholate complex in its high spin (sextet) state, showing the two possible electronic configurations.

Fig. 1.12 Proposed mechanism for the Fe

III

‐induced oxidation of catechol (L = H

2

O).

Chapter 02

Fig. 2.1 Marchantia polymorpha.

Fig. 2.2 Marchantia paleacea var. diptera.

Fig. 2.3 Pellia epiphylla.

Fig. 2.4 Structures of bis‐bibenzyls (

1–24

,

27

) found in the Marchantiophyta (liverworts).

Fig. 2.5 Structures of bis‐bibenzyls (

25, 26–43

) found in the Marchantiophyta (liverworts).

Fig. 2.6 Structures of bis‐bibenzyls (

44–67a

) found in the Marchantiophyta (liverworts).

Fig. 2.7 Structures of bis‐bibenzyls (

68–77

) and their dimers (

78–81

) found in the Marchantiophyta (liverworts).

Fig. 2.8 Structures of bis‐bibenzyls (

82–85

) found in the Marchantiophyta (liverworts).

Fig. 2.9 Structures of acyclic bis‐bibenzyl dimers (

82, 85

), bis‐bibenzyls (

83, 84

), and acyclic bis‐bibenzyls (

86, 87

) found in the Marchantiophyta (liverworts).

Fig. 2.10 Biosynthetic pathways for marchantin A (

14

) (Friederich

et al

., 1999a, 1999b).

Fig. 2.11 Stereochemistry of isoplagiochins C (

46

) and D (

47

).

Chapter 03

Fig. 3.1 Reversed‐phase high‐performance liquid chromatography (HPLC) profiles of major tea products (maximum absorbance): (a) green tea (Japan), (b) postfermented tea produced under aerobic conditions (Hunan, China), (c) oolong tea (Fujian, China), and (d) black tea (Assam, India). Caf, caffeine; Cat, catechin; Fl, unidentified flavonol glycoside; GA, gallic acid; GC, gallocatechin; GCg, gallocatechin‐3‐

O

‐gallate; TB, theobromine; TCA, theacitrin A; ThG, theogallin; epigallocatechin (

1

), epicatechin (

2

), epigallocatechin‐3‐

O

‐gallate (

3

), epicatechin‐3‐

O

‐gallate (

4

), theaflavin (

5

), theaflavin‐3‐

O

‐gallate (

6

), theaflavin‐3′‐

O

‐gallate (

7

), theaflavin‐3,3′‐di‐

O

‐gallate (

8

), theasinensin A (

9

), theasinensin B (

10

), and theasinensin C (

11

). HPLC conditions: Cosmosil 5C

18

‐AR II (Nacalai Tesque, Japan) column (4.6 × 250 mm i.d.) with gradient elution from 4 to 30% (39 min) and from 30 to 75% (15 minutes) of CH

3

CN in 50‐mM H

3

PO

4

, flow rate, 0.8 ml/minute; column temperature, 35°C; detection, JASCO photodiode array detector MD‐910.

Fig. 3.2 Structures of major black tea polyphenols

1–14

. The names of structures were the same as described in Fig. 3.1.

Fig. 3.3 Production of theaflavin and oxidation of proanthocyanidins.

Fig. 3.4 Reversed‐phase HPLC profiles of crushed fresh tea leaves (maximum absorbance): (a) 60% ethanol (EtOH) extract of crushed tea leaves, (b) 60% EtOH extract of crushed tea leaves after treatment with

o

‐phenylenediamine–acetic acid/EtOH, and (c) 60% EtOH extract of crushed tea leaves after heating at 80°C. HPLC conditions were the same as described in Fig. 3.1.

Fig. 3.5 Structures of dehydrotheasinensin A (

15

) and phenazine derivatives.

Fig. 3.6 Oxidation of

1

with radical initiator. AMVN: 2,2′‐azobis(2,4‐dimethyl‐valeronitrile).

Fig. 3.7 Degradation of dehydrotheasinensin A (

15

) on heating: (a) before heating and (b) after heating of aqueous solution of

15

at 90°C for 30 minutes. HPLC column: Develosil C30‐UG‐5 (250 × 4.6 mm, Nomura Chemical) with gradient elution 4–30% (39 minutes) and 30–75% (15 minutes) of CH

3

CN in 50‐mM H

3

PO

4

; flow rate, 0.8 ml/minute; column temperature, 35°C; detection, JASCO photodiode array detector MD‐910.

Fig. 3.8 Structures of oxidation products of

15

.

Fig. 3.9 Production and oxidation of theaflavin by coupled oxidation of

1

and

2

.

Fig. 3.10 Production of black tea polyphenols from bicyclo[3.2.1]octane intermediates. EGC, epigallocatechin.

Fig. 3.11 Minor oxidation products obtained by

in vitro

enzymatic oxidation of tea catechins.

Fig. 3.12 Oxidation products of epicatechin and epicatechin‐3‐

O

‐gallate.

Fig. 3.13 Reversed‐phase HPLC profiles of black tea fractions. Aqueous acetone extract of black tea was successively partitioned with ethyl acetate (AcOEt) and

n

‐butanol (

n

‐BuOH) (yields from black tea: AcOEt layer, 9%;

n

‐BuOH layer, 17%; aqueous layer, 21%). The

n

‐BuOH fraction was further fractionated by Sephadex LH‐20 column chromatography into five fractions (yields from

n

‐BuOH layer: Fr. 1 (caffeine), 43%; Fr. 2 (gallic acid and flavonol glycoside), 8.7%; Fr. 3, 8.7%; Fr. 4, 21%; Fr. 5, 16.4%). HPLC conditions were the same as described in Fig. 3.1.

Fig. 3.14

13

C Nuclear magnetic resonance spectra of oligomeric polyphenols and

3

(in DMSO‐

d

6

). (a) Spectrum of oligomeric polyphenol fraction obtained from Assam black tea by size‐exclusion column chromatography (Yanagida

et al

., 2003; Tanaka

et al

., 2009). (b) Spectrum of

3

. A, A‐ring; B, B‐ring; C, C‐ring; G, galloyl group.

Chapter 04

Fig. 4.1 The monolignol biosynthetic pathway in

Populus trichocarpa

. The pathway consists of 20 enzymes (phenylalanine ammonia‐lyases, PtrPAL1‐5; cinnamic acid 4‐hydroxylases, PtrC4H1 and 2; cinnamic acid 3‐hydroxylase, PtrC3H3; hydroxycinnamoyl‐CoA shikimate hydroxycinnamoyl transferases, PtrHCT1 and 6; 4‐coumaric acid:CoA ligases, Ptr4CL3 and 5; caffeoyl‐CoA

O

‐methyltransferases, PtrCCoAOMT1‐3; cinnamoyl‐CoA reductase, PtrCCR2; coniferaldehyde 5‐hydroxylases, PtrCAld5H1 and 2; 5‐hydroxyconiferaldehyde

O

‐methyltransferase, PtrAldOMT2; cinnamyl alcohol dehydrogenase, PtrCAD1) and 24 metabolites (bold numbers) that convert phenylalanine to the monolignols. The cofactors are reduced nicotinamide adenine dinucleotide phosphate (NADPH), oxidized nicotinamide adenine dinucleotide phosphate (NADP+), coenzyme A (CoA), adenosine triphosphate (ATP), adenosine monophosphate (AMP), pyrophosphate (PPi),

S

‐adenosyl methionine (SAM), and

S

‐adenosyl homocysteine (SAH).

Fig. 4.2 Monolignol biosynthetic protein abundance in wild‐type and transgenic

Populus trichocarpa

. The LC–MS/MS‐based absolute protein abundance of (a) PtrPAL1, (b) PtrPAL2, (c) PtrPAL3, (d) PtrPAL4/5, (e) PtrC4H1, (f) PtrC3H3, (g) PtrCCR2, and (h) PtrCAD1 in stem differentiating xylem of the 92 wild‐type and transgenic

P. trichocarpa

trees (6 months old). The

x

‐axis specifies the target gene(s) for downregulation in each transgenic sample. Error bars represent one standard error of biological replicates.

Fig. 4.3 Lignin content of wild‐type and transgenic

Populus trichocarpa

. (a) The absolute lignin content of wild‐type and transgenic

P. trichocarpa

as weight percentage of the extractive‐free wood, determined by the Klason method. (b) The standardized lignin content for wild‐type (dark gray) and transgenic (light gray)

P. trichocarpa

, standardized based on the lignin content of corresponding wild‐type samples of the same batch. Frequency values indicate the number of trees.

Fig. 4.4 The scatter plots show the relationship between the protein abundance and lignin content for monolignol biosynthetic protein families (a) PtrPAL, (b) PtrC4H, (c) PtrC3H, (d) Ptr4CL, (e) PtrHCT, (f) PtrCCoAOMT, (g) PtrCCR, (h) PtrCAD, (i) PtrCAld5H, and (j) PtrAldOMT. (k) The solid circles represent data from the transgenic trees. The triangles represent transgenic trees exhibiting dwarfed phenotype. The squares represent data from wild‐type. The solid lines represent segmented regression models. Protein abundance (nM) was derived from concentration (μg/g of total protein) using the conversion factor of 0.74 ml/g (water content of SDX tissue) (Shuford et al., 2012).

Chapter 05

Fig. 5.1 The monolignol biosynthesis pathway in grasses.

Fig. 5.2 Regulation of monolignol biosynthesis in grasses. Genes in boxes are regulators of monolignol biosynthesis. Dashed lines indicate that gene functions have not been verified in grasses.

Chapter 06

Fig. 6.1 Cyclamen cultivars, wild species, and flower color mutants shown beside the anthocyanin biosynthesis pathway. Flowers are grouped according to their major anthocyanins. (a)

Cyclamen persicum

cultivar “Strauss (St).” (b–d) Deeper color mutants “ion246” (b) and “ion3” (c) obtained from fragrant cyclamen cultivar “Uruwashi‐no‐kaori (UR)” (d). (e)

C. persicum

cultivar “Golden Boy (GB).” (f) A pale yellow‐flowered mutant obtained from a hybrid (GB × 

Cyclamen purpurascens

) “GBCP.” (g)

C. persicum

cultivar “Pure White (Pw).” (h) A white‐flowered mutant obtained from fragrant cyclamen cultivar “Koko‐no‐kaori (KO).” (i–k) Red–purple‐flowered mutants “KMrp” (i), “KMmv3” (j), and “KMmv35” (k) obtained from fragrant cyclamen cultivar “kaori‐no‐mai (KM).” (l) A hybrid “GBCP” derived from GB × 

C. purpurascens

. (m and n) Fragrant cyclamen cultivars KM (m) and KO (n). (o) Scented wild species

C. purpurascens

. Fragrant cyclamen cultivars were created by a cross between

C. persicum

cultivars and

C. purpurascens

. Flower color mutants were obtained from mutagenized populations of fragrant cyclamen cultivars irradiated with ion beams. ANS, anthocyanidin synthase; AOMT, anthocyanin

O‐

methyltransferase; Ch2G, chalcone 2′‐glucoside; CHI, chalcone isomerase; Cy3,5dG, cyanidin 3,5‐diglucoside; DFR, dihydroflavonol 4‐reductase; Dp3,5dG, delphinidin 3,5‐diglucoside; F3H, flavanone 3‐hydroxylase; F3′H, flavonoid 3′‐hydroxylase; F3′5′H, flavonoid 3′5′‐hydroxylase; FLS, flavonol synthase; 2′GT, chalcone 2′‐glucosyltransferase; 3GT, anthocyanidin 3‐glucosyltransferase; 5GT, anthocyanin 5‐glucosyltransferase; Mv3G, malvidin 3‐glucoside; Mv3,5dG, malvidin 3,5‐diglucoside; Pn3Nh, peonidin 3‐neohesperidoside; Pn3,5dG, peonidin 3,5‐diglucoside.

Fig. 6.2 Carnation with peculiar colors that contain nonacylated anthocyanins. (a) Flowers and transverse sections of petal epidermis of carnation cultivar “Beam Cherry (left)” and “Nazareno (right).” (b) The experimental strain “07MC4” and the mutant “07GRP” with peculiar colors obtained by inactivation of AMalT activity with carbon ion irradiation. The genotype for AMalT locus is shown in parenthesis. AMalT and a bar represent the active and inactive AMalT locus, respectively. The major anthocyanins are shown beside each flower. (c) Flowers of all four types of acylated and nonacylated‐type anthocyanin in carnation. The major anthocyanins are shown beside each flower. AMalT, anthocyanin malyltransferase; Cy3,5cMdG, cyanidin 3,5‐cyclic malyl diglucoside; Cy3,5dG, cyanidin 3,5‐diglucoside; Cy3G, cyanidin 3‐glucoside; Cy3MG, cyanidin 3‐malyl glucoside; Pg3,5cMdG, pelargonidin 3,5‐cyclic malyl diglucoside; Pg3,5dG, pelargonidin 3,5‐diglucoside; Pg3G, pelargonidin 3‐glucoside; Pg3MG, pelargonidin 3‐malyl glucoside.

Chapter 07

Fig. 7.1 The flavonol biosynthetic pathway is illustrated, showing enzymatic steps and indicating

Arabidopsis transport testa

(

tt

) and tomato anthocyanin mutant names. Bolded sections of the pathway are specific to tomato and petunia. CHI, chalcone isomerase; CHS, chalcone synthase; F3H, flavanone 3‐hydroxylase; F3′H, flavonoid 3′‐hydroxylase; F3′5′H, flavonoid 3′,5′‐hydroxylase; FLS, flavonol synthase; DFR, dihydroflavonol reductase; OMT1, flavone 3′‐

O

‐methyltransferase 1. Tomato mutants are

anthocyaninless

(

a

),

anthocyanin reduced

(

are

), and

anthocyanin without

(

aw

).

Fig. 7.2 A model illustrates how flavonoids may function during root gravitropism. In vertically oriented seedlings,

tt4

is deficient in flavonols (yellow) and has elevated

PIN2

gene products (green) and shootward auxin transport (black arrows). When roots are reoriented by 90°, flavonol levels increase in the root epidermis, especially in the elongation zone, which may block auxin movement out of the region where differential gravitropic growth occurs. This may concentrate the auxin in the distal elongation zone where root gravitropic bending occurs, enhancing the asymmetric distribution enhancing the rate of gravitropic curvature. In

tt4

, there is both enhanced auxin movement into and out of this region, reducing the asymmetric distribution of auxin.

Fig. 7.3 Lateral root numbers are reduced in the tomato

are

mutant. (a) Image showing 6‐day‐old seedlings of wild‐type (VF36) and

are

displaying differences in lateral rooting and hypocotyl pigmentation. (b) Numbers of emerged lateral roots, unemerged lateral root primordia, and combined totals of emerged and primordial roots. Average and SE are presented. Asterisk indicates difference between genotypes with

p

 ≤ 0.05 (

n

 = 15). (c) Lateral root numbers are reported for untransformed VF36,

are,

and three

F3H

overexpression lines in each background genotype. Asterisk indicates differences from VF36, and number symbols indicate differences from

are,

with

p

 ≤ 0.05 (

n

 = 16). Black bars indicate lines in the

are

background.

Fig. 7.4 Flavonol accumulation is absent in

tt4

leading to increased ROS and more rapid stomatal closure. Flavonols are visualized by diphenylboric acid 2‐aminoethyl ester (DPBA) (yellow), and ROS is visualized by 2′,7′dihydrodichloro‐fluorescein diacetate (DCF) (green), with chlorophyll in blue. Ethylene overproduction in

eto1

leads to enhanced flavonol accumulation and less ROS. Bar = 15 µm. Guard cells of wild‐type and

tt4‐2

were examined by light microscopy immediately before treatment with ABA and 45 minutes after treatment with 20 μM ABA. Bar = 15 µm. Watkins

et al.

(2014). © The fluorescent image is reprinted with permission from American Society of Plant Biologists (www.plantphysiol.org).

Fig. 7.5 A model of controls of flavonol synthesis and their function. This figure illustrates the positive effects of ethylene, auxin, sucrose, and light on flavonol synthesis. The action of flavonols in regulating root growth and other developmental processes are summarized with those shown to be mediated through effects on auxin transport and on levels of reactive oxygen species (ROS) indicated.

Chapter 08

Fig. 8.1 Structure of anthocyanin forms, Flavylium ion‐quinonoidal base‐pseudobase‐(

Z

)‐chalcone‐(

E

)‐chalcone formed at various pH values.

Fig. 8.2 The structures of polyacylated anthocyanins reviewed in this chapter: Phacelianin (

1

), demalonylphacelianin (

2

), tecophilin (

3

), heavenly blue anthocyanin (

4a

), gentiodelphin (

5a

),

cis

‐gentiodelphin (

5b

), alatanin C (

6

), malonylshisonin (

7a

), and

cis

‐malonylshisonin (

7b

).

Fig. 8.3 Long‐range NOEs in the NMR spectrum of phacelianin (

1

) and Vis‐UV spectra and CD spectra of petal of

Phacelia campanularia

.

Fig. 8.4 Long‐range NOEs of tecophilin (

3

), Vis‐UV spectra and CD spectra of petal of

Tecophilaea cyanocrocus

and proposed 3‐D structure of

3

.

Fig. 8.5 The optimized 3‐D structure of gentiodelphin (

5a

) obtained by calculation using NMR data and the comparison of the stability of

5a

and deacylated pigments.

Fig. 8.6 Structure of UVB irradiation products of HBA, and their

1

H NMR spectra (500 MHz) in the low field region recorded in 5% TFA

d

‐CD

3

OD (500 MHZ).

Fig. 8.7 Prevention of DNA lesions induced by broad UV‐B with HBA solution screen (5 mM). ▪: Control; ◽: pH 7.5; ◦: 0.5% TFA aq. ▵: 0.5% TFA‐MeOH. Upper: CPDs; lower: 6‐4PPs.

Chapter 09

Fig. 9.1 Image showing posterior eye diseases and their common causes. (a) Image of eye structure and each posterior eye disease. (b) Mapping common causes of posterior eye diseases.

Fig. 9.2 Anthocyanin‐rich foods used in our experiments.

Fig. 9.3 Effect of bilberry extract (BBE) on

N

‐methyl‐

D

‐aspartate receptor (NMDA)‐induced retinal damage in mice. Hematoxylin and eosin staining of sections (thickness 5 µm) obtained from mice 7 days after intravitreal injection of NMDA. (a) Representative photographs show nontreated control retina, NMDA‐injected vehicle‐treated retina, retina treated with NMDA injection plus BBE at 10 µg/eye, and retina treated with NMDA injection plus BBE at 100 µg/eye. Horizontal bar represents 25 µm. Vertical bar and arrows indicate inner plexiform layer (IPL) and retinal ganglion cells (RGC), respectively. (b and c) Cell numbers in RGC and thickness of IPL. Data are shown as mean ± SEM (

n

 = 6–11). C, control; V, vehicle;

##

p

 < 0.01 versus control;

*

p

 < 0.05 versus vehicle. These results were cited in Matsunaga

et al

. (2009).

Fig. 9.4 Purple rice extract (PRE) inhibited tube formation induced by vascular endothelial growth factor (VEGF) A. (a) Representative photographs of tube formation. Scale bar = 1 mm. Human umbilical vein endothelial cells (HUVECs) were cocultured with human fibroblasts, as described in the section on methods, and incubated for 11 days with or without the indicated concentrations of PRE, with the concomitant addition of VEGF‐A (10 ng/ml). Tube formation was observed in five randomly chosen fields, and tube area (b), length (c), joints (d), and paths (e) were measured using an Angiogenesis Image Analyzer. Data are shown as mean ± SEM (

n

 = 3). C, control; V, vehicle;

##

p

 < 0.01 versus control (Student’s

t

‐test); **

p

 < 0.01 versus vehicle (Dunnett’s multiple‐comparison test). These results were cited in Tanaka

et al

. (2012).

Fig. 9.5 Bilberry extract (BBE) inhibited neovascular tufts on oxygen‐induced retinopathy in mice. Retinal flat mounts were examined by FITC–dextran angiography. Representative photographs of retina from saline‐treated eye (a) and BBE‐treated eye (b). Scale bar = 100 µm. (c) Areas of neovascular tufts in saline‐ and BBE‐treated eyes. Each column and bar represent mean ± SEM (

n

 = 9). *

p

 < 0.05 versus saline (paired

t

‐test). These results were cited in Matsunaga

et al

. (2010a).

Fig. 9.6 Effects of maqui berry extract (MBE) on visible‐light‐induced 661W cell damage. (a) Representative microscopy at 24 hours after light exposure. (b) Representative fluorescence microscopy of Hoechst 33342 (blue color, cell nuclear stained) and propidium iodide (PI; red color, dead cell stained) fluorescence staining at 24 hours after light exposure. Each scale bar represents 250 µm. These results were cited in Tanaka

et al

. (2013).

Fig. 9.7 Effects of purple rice extract (PRE) on retinal damage induced by exposure to light in mice. Hematoxylin and eosin staining of sections (thickness 5 lm) obtained from mice 5 days after light exposure. (a) Representative photographs show nontreated control retina, light‐exposed vehicle‐treated retina, light‐exposed retina treated with PRE at 10 µg/eye. (b) Measurement of the thickness in the outer nuclear layer (ONL) 5 days after light exposure. Data are shown as mean ± SEM (

n

 = 5 or 6).

#

p

 < 0.05 and

##

p

 < 0.01 versus control. *

p

 < 0.05 and **

p

 < 0.01 versus vehicle. The scale bar represents 25 µm. These results were cited in Tanaka

et al

. (2011).

Chapter 10

Fig. 10.1 Activation of AMPK leads to various metabolic changes. AMPKK, AMPK kinase.

Fig. 10.2 Proposed mechanism for amelioration of hyperglycemia and insulin sensitivity by dietary bilberry extract, BBE. ACC, acetyl‐CoA carboxylase; ACO, acyl‐CoA oxidase; CPT1A, carnitine palmitoyltransferase‐1A; G6Pase, glucose‐6‐phosphatase; PEPCK, phosphoenolpyruvate carboxykinase.

Fig. 10.3 Chemical structures of cyanidin 3‐glucoside (C3G) and procyanidins (PCs) contained in dietary black soybean seed coat (BE).

Fig. 10.4 Proposed mechanism for amelioration of hyperglycemia and insulin sensitivity by dietary black soybean seed coat (BE) in mice.

Fig. 10.5 Overview of actions of GLP‐1 and GIP.

Fig. 10.6 Relationship between dietary factors (nutrients, nonnutrients) and incretin action.

Fig. 10.7 Stimulation of GLP‐1 secretion by curcuminoids (25 μM) (a), and the dose response of curcumin (1–50 μM) on GLP‐1 secretion (b) in GLUTag cells. Glutamine (10 mM) was used as a positive control. Values are means ± SEM,

n

 = 3. Values without a common letter significantly differ at

P

 < 0.05.

Fig. 10.8 Structure–activity relationship between curcumin derivatives and stimulation of GLP‐1 secretion (GLUTag cells).

Fig. 10.9 Proposed mechanism for stimulation of GLP‐1 secretion by curcumin.

Fig. 10.10 Proposed mechanism for amelioration of hyperglycemia by dietary sweet potato leaves, Suioh,

in vivo

.

Fig. 10.11 GLP‐1 secretion in the medium of GLUTag cells treated with various anthocyanins (a) and/or varying concentrations of D3R (b). (a) The final concentration of anthocyanins and sugars are 100 μM. Values are expressed as the means ± SEM,

n

 = 3–9. Values without a common letter differ significantly at

P

 < 0.05 (Kato

et al

., 2015). Mal3R, malvidin 3‐rutinoside.

Fig. 10.12 (a) The effect of CaMKII inhibitor (KN‐93, 10 μM) on D3R (100 μM)‐induced GLP‐1 secretion. (b and c) Immunoblot analysis of the phosphorylated CaMKII, total CaMKII, and β‐actin protein treated with D3R duration (b) and dose (c) in GLUTag cells. Values are expressed as the means ± SEM,

n

 = 3. Values without a common letter significantly differ at

P

 < 0.05.

Fig. 10.13 Proposed mechanism for stimulation of GLP‐1 secretion by D3R in GLUTag cells. ER, endoplasmic reticulum.

Chapter 11

Fig. 11.1 Global fatalities and cardiovascular diseases.

Fig. 11.2 Representative structures of 2,3‐

cis

‐ (left) and 2,3‐

trans

‐procyanidins (right).

Fig. 11.3 Simplified illustration of the regulation of vascular tone.

Fig. 11.4 Schematic illustration of the endothelium‐dependent NO‐signaling pathway and its role in the response to procyanidins. Endothelial production of NO is triggered via a redox‐sensitive activation of the phosphaditylinositol‐3‐kinase (PI3K)/Akt pathway promoting eNOS catalysis, that is, conversion of

L

‐arginine to

L

‐citrulline and NO. Stimulation of the NO‐sensitive soluble guanosyl cyclase (sGC) generates cyclic guanosyl monophosphate (cGMP) from guanosine triphosphate (GTP). Relaxation of the smooth muscle cell is due to cyclic GMP‐dependent protein kinases. PIP2, phosphatidylinositol biphosphate; PIP3, phosphatidylinositol triphosphate; ROS, reactive oxygen species.

Fig. 11.5 Schematic illustration of the endothelium‐dependent hyperpolarization factor (EDHF)‐mediated relaxation and modulation of intracellular Ca

2+

concentrations ([Ca

2+

]

i

): current view on responses to procyanidins. Ca

2+

release from intracellular stores and Ca

2+

influx from extracellular sources via store‐operated calcium channels (SOCCs) upon store depletion stimulate the opening of endothelial Ca

2+

‐dependent K

+

channels (K

Ca

). Activation of K

Ca

hyperpolarizes the endothelial cell and the effluxing K

+

can spread the effect to the smooth muscle. Increased endothelial [Ca

2+

]

i

may enhance eNOS activation. A decrease of cytosolic Ca

2+

concentration in the smooth muscle cell involves cGMP‐dependent protein kinases (NO signaling), closure of Ca

2+

channels, and refilling of intracellular stores (SERCA).

Chapter 13

Fig. 13.1 Diagram of the pathogenesis of metastasis.

Fig. 13.2 Chemical structure of curcumin and its biological properties.

Fig. 13.3 Effect of curcumin on intrahepatic metastasis

in vivo

.

Fig. 13.4 Effect of curcumin on the invasion of CBO140C12 cells.

Fig. 13.5 Effect of curcumin on the expression of integrin α and β subunits on cell surface of tumor cells.

Fig. 13.6 Effect of curcumin on the formation of actin stress fiber on fibronectin‐coated substrate.

Fig. 13.7 Tumor growth and lymph node metastasis on day 15 after orthotopic implantation of LLC or LLC‐MLN cells.

Fig. 13.8 Effect of curcumin on the growth of the inoculated tumor and mediastinal lymph node metastasis after the orthotopic implantation of LLC cells.

Fig. 13.9 Life‐prolonging effect of curcumin, CDDP, and combination treatment.

Fig. 13.10 Dual reporter assay for evaluation of anti‐AP‐1 activity of LLC cells treated with curcumin.

Fig. 13.11 Effect of curcumin on the mRNAs expression levels of u‐PA and u‐PAR.

Fig. 13.12 Effect of curcumin on the tube‐like formation lymphatic endothelial TR‐LE cells.*

p

 < 0.05; **

p

 < 0.01.

Fig. 13.13 Inhibition of IkB kinase is independent of antilymphangiogenic effect of curcumin.

Fig. 13.14 Inhibitory effect of curcumin on Akt pathway of lymphatic endothelial cells.

Fig. 13.15 Inhibitory effect of curcumin on MMP‐2 activity of lymphatic endothelial cells.

Chapter 14

Fig. 14.1 Structures of other lignans (

118–125

).

Fig. 14.2 Structures of other type compounds (

139–182

).

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Recent Advances in Polyphenol Research

A series for researchers and graduate students whose work is related to plant phenolics and polyphenols, as well as for individuals representing governments and industries with interest in this field. Each volume in this biennial series focuses on several important research topics in plant phenols and polyphenols, including chemistry, biosynthesis, metabolic engineering, ecology, physiology, food, nutrition, and health.

Volume 5 Editors:

Kumi Yoshida, Véronique Cheynier, and Stéphane Quideau

Series Editor‐in‐Chief:

Stéphane Quideau (University of Bordeaux, France)

Series Editorial Board:

Oyvind Andersen (University of Bergen, Norway)

Luc Bidel (INRA, Montpellier, France)

Véronique Cheynier (INRA, Montpellier, France)

Catherine Chèze (University of Bordeaux, France)

Gilles Comte (University of Lyon, France)

Fouad Daayf (University of Manitoba, Winnipeg, Canada)

Olivier Dangles (University of Avignon, France)

Kevin Davies (Plant & Food Research, Palmerston North, New Zealand)

Maria Teresa Escribano‐Bailon (University of Salamanca, Spain)

Ann E. Hagerman (Miami University, Oxford, OH, USA)

Victor de Freitas (University of Porto, Portugal)

Johanna Lampe (Fred Hutchinson Cancer Research Center, Seattle, WA, USA)

Vincenzo Lattanzio (University of Foggia, Italy)

Virginie Leplanquais (LVMH Research, Christian Dior, France)

Stephan Martens (Fondazione Edmund Mach, IASMA, San Michele all'Adige, Italy)

Nuno Mateus (University of Porto, Portugal)

Annalisa Romani (University of Florence, Italy)

Pascale Sarni‐Manchado (INRA, Montpellier, France)

Celestino Santos‐Buelga (University of Salamanca, Spain)

Katy Schwinn (Plant & Food Research, Palmerston North, New Zealand)

David Vauzour (University of East Anglia, Norwich, UK)

Recent Advances in Polyphenol Research

Volume 5

Edited by

Kumi Yoshida

Professor, Natural Product and Bioorganic ChemistryGraduate School of Information ScienceNagoya University, Japan

Véronique Cheynier

Research Director, Plant and Food chemistryInstitut National de la Recherche AgronomiqueUMR1083 Sciences pour l’ŒnologieMontpellier, France

Stéphane Quideau

Professor, Organic and Bioorganic ChemistryInstitut des Sciences Moléculaires, CNRS‐UMR 5255University of Bordeaux, France

This edition first published 2017 © 2017 by John Wiley & Sons, Ltd.

Registered OfficeJohn Wiley & Sons, Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK

Editorial Offices9600 Garsington Road, Oxford, OX4 2DQ, UKThe Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK111 River Street, Hoboken, NJ 07030‐5774, USA

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Library of Congress Cataloging‐in‐Publication Data

ISBN: 9781118883266

Recent advances in polyphenol research

ISSN 2474‐7696

A catalogue record for this book is available from the British Library.

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Cover image: The ICP2014 Organizing Committee

Dedication

To Michel Bourzeix—one of the founders of Groupe Polyphénols and its secretary from 1972 to 1995—who devoted his career to promoting research on polyphenols and supported GP activities and conferences with dedication and enthusiasm

To Dieter Treutter—a faithful member of the Groupe Polyphénols board for many years and the organiser of ICP2000

in memoriam

The editors wish to thank all of the members of the “Groupe Polyphénols” Board Committee (2012–2014) for their guidance and assistance throughout this project.

Groupe Polyphénols Board 2012–2014

Prof. Oyvind Andersen

Dr. Luc Bidel

Dr. Véronique Cheynier

Dr. Catherine Chèze

Prof. Olivier Dangles

Prof. Ann E. Hagerman

Dr. Johanna Lampe

Prof. Vincenzo Lattanzio

Dr. Virginie Leplanquais

Dr. Nuno Mateus

Dr. Gary Reznik

Prof. Celestino Santos‐Buelga

Dr. Katy Schwinn

Dr. David Vauzour

Prof. Kristiina Wähälä

Prof. Kumi Yoshida

Contributors

Yoshinori Asakawa, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro‐cho, Tokushima, Japan.

Vincent L. Chiang, Forest Biotechnology Group, Department of Forestry and Environmental Resources, North Carolina State University, Raleigh, NC, USA.

Ling Chuang, Forest Biotechnology Group, Department of Forestry and Environmental Resources, North Carolina State University, Raleigh, NC, USA.

Katherine H. M. Cox, Centre for Human Psychopharmacology, School of health Sciences, Swinburne University, Melbourne, Victoria, Australia.

Olivier Dangles, UMR 408 INRA, Sécurité et Qualité des Produits d’Origine Végétale, University of Avignon, Avignon Cedex 9, France.

Joel J. Ducoste, Civil, Construction and Environmental Engineering, North Carolina State University, Raleigh, NC, USA.

Claire Dufour, UMR 408 INRA, Sécurité et Qualité des Produits d’Origine Végétale, Centre de Recherche PACA, University of Avignon, Avignon Cedex 9, France.

Sheena R. Gayomba, Department of Biology and Center for Molecular Signaling, Wake Forest University, Winston‐Salem, NC, USA.

Hideaki Hara, Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.

Yoshihiro Hase, Ion Beam Mutagenesis Research Group, Quantum Beam Science Directorate, Japan Atomic Energy Agency, Takasaki, Gunma, Japan.

Fikret Isik, NCSU Cooperative Tree Improvement Program, Department of Forestry and Environmental Resources, North Carolina State University, Raleigh, NC, USA.

Yong Jiang, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China.

Herbert Kolodziej, Institute of Pharmacy, Pharmaceutical Biology, Freie Universität Berlin, Berlin, Germany.

Tadao Kondo, Graduate School of Information Science, Nagoya University, Chikusa, Nagoya, Japan.

Laigeng Li, National Key Laboratory of Plant Molecular Genetics and CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai, China.

Quanzi Li, State Key Laboratory of Tree Genetics and Breeding, Chinese Academy of Forestry, Beijing, China.

Jie Liu, Forest Biotechnology Group, Department of Forestry and Environmental Resources, North Carolina State University, Raleigh, NC, USA.

Philip L. Loziuk, W.M. Keck Fourier Transform Mass Spectrometry Laboratory, Department of Chemistry, North Carolina State University, Raleigh, NC, USA.

Hai‐Ning Lv, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China.

Yosuke Matsuo, Department of Natural Product Chemistry, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.

Gloria K. Muday, Department of Biology and Center for Molecular Signaling, Wake Forest University, Winston‐Salem, NC, USA.

David C. Muddiman, W.M. Keck Fourier Transform Mass Spectrometry Laboratory, Department of Chemistry, North Carolina State University, Raleigh, NC, USA.

Punith P. Naik, Civil, Construction and Environmental Engineering, North Carolina State University, Raleigh, NC, USA.

Kenjirou Ogawa, Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.

Kin‐ichi Oyama, Research Center for Materials Science, Nagoya University, Chikusa, Nagoya, Japan.

Ikuo Saiki, Division of Pathogenic Biochemistry, Institute of Natural Medicine (INM), University of Toyama, Toyama, Japan.

Andrew Scholey, Centre for Human Psychopharmacology, School of health Sciences, Swinburne University, Melbourne, Victoria, Australia.

Ronald R. Sederoff, Forest Biotechnology Group, Department of Forestry and Environmental Resources, North Carolina State University, Raleigh, NC, USA.

Rui Shi, Forest Biotechnology Group, Department of Forestry and Environmental Resources, North Carolina State University, Raleigh, NC, USA.

Yue‐Lin Song, Modern Research Center for Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.

Takashi Tanaka, Department of Natural Product Chemistry, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.

Claire Tonnelé, Chimie des Matériaux Nouveaux, University of Mons, Mons, Belgium.

Patrick Trouillas, UMR 850 INSERM, Faculté de Pharmacie, University of Limoges, Limoges Cedex, France.

Takanori Tsuda, College of Bioscience and Biotechnology, Chubu University, Kasugai, Aichi, Japan.

Peng‐Fei Tu, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China.

Sermsawat Tunlaya‐Anukit, Forest Biotechnology Group, Department of Forestry and Environmental Resources, North Carolina State University, Raleigh, NC, USA.

Jack P. Wang, Forest Biotechnology Group, Department of Forestry and Environmental Resources, North Carolina State University, Raleigh, NC, USA.

Justin M. Watkins, Department of Biology and Center for Molecular Signaling, Wake Forest University, Winston‐Salem, NC, USA.

Cranos M. Williams, Electrical and Computer Engineering, North Carolina State University, Raleigh, NC, USA.

Peng Xu, National Key Laboratory of Plant Molecular Genetics and Key Laboratory of Synthetic Biology, Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai, China.

Chenmin Yang, Forest Biotechnology Group, Department of Forestry and Environmental Resources, North Carolina State University, Raleigh, NC, USA.

Ting‐Feng Yeh, Forestry and Resource Conservation, National Taiwan University, Taipei, Taiwan.

Kumi Yoshida, Natural Product and Bioorganic Chemistry, Graduate School of Information Science, Nagoya University, Chikusa, Nagoya, Japan.

Ke‐Wu Zeng, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China.

Preface

Polyphenols are secondary metabolites that are variously distributed in the plant kingdom and characterized by a wide diversity of chemical structures. On behalf of the international scholarly society “Groupe Polyphénols,” which organizes the biennial conference, “International Conference on Polyphenols” (ICP), we define the term “polyphenol” as related to plant products exclusively derived from the shikimate/phenylpropanoid and/or the polyketide pathway, featuring more than one phenolic unit and deprived of nitrogen‐based functions (http://www.groupepolyphenols.com/the‐society/why‐bother‐with‐polyphenols/). The number of known plant polyphenols is quite large, from structurally simple compounds such as the stilbenoid resveratrol or the flavonoid quercetin to complex macromolecules such as the proanthocyanidin oligomers or the lignin polymer. It is thus not surprising that their functions in plant and physicochemical properties are also quite varied. In the early 20th century, investigations on polyphenols were mainly dedicated to the determination of their structures and their roles in traditional medicines, as well as in vegetable tanning. Nowadays, research on plant polyphenols concerns a much wider area of science with novel and multidisciplinary efforts made toward the understanding of their properties and exploitation thereof in inter alia the development of new materials, the innovation in agriculture and food products, including the development of new crops and flowers, the higher fixation of carbon dioxide, and the formulation of functional foods with human health benefits, as well as the discovery of new pharmaceutical medicines.

This book series “Recent Advances in Polyphenol Research” began its publication in 2008 on the occasion of the 24th ICP in Salamanca, Spain. The content of this first volume was already mostly based on review articles written by plenary lecturers of the previous ICP, which had taken place in Winnipeg, Canada. Since then, this flagship publication of the Groupe Polyphénols has been released without any discontinuity every 2 years to provide the reader with authoritative updates on various topics of polyphenol research written by ICP plenary lecturers and by invited expert contributors.

This book, the fifth volume of the series, is concerned with the topics that were covered during the 27th ICP, which was organized jointly with the 8th edition of the Tannin Conference in September 2014 in Nagoya, Japan. In more than 40 years of the history of the Groupe Polyphénols, it was the first time that the International Conference on Polyphenols took place in Asia. Six different main topics of the polyphenol science were selected for the scientific program of this memorable ICP2014 edition:

Chemistry, Physicochemistry, and Materials Science

, covering structures, reactivity, organic synthesis, molecular modeling, fundamental aspects, chemical analysis, spectroscopy, molecular associations, and interactions of polyphenols.

Biosynthesis, Genetics, and Metabolic Engineering

, covering molecular biology, genetics, enzymology, gene expression and regulation, trafficking, biotechnology, horticultural science, and molecular breeding related to polyphenols.

Plants and Ecosystems, Lignocellulose Biomass

, covering plant growth and development, biotic and abiotic stress, resistance, ecophysiology, sustainable development, valorization, plant environmental system, forest chemistry, and lignin and lignan.

Food, Nutrition, and Health

, covering food ingredients, nutrient components, functional food, mode of action, bioavailability and metabolism, food processing, influence on food and beverages properties, cosmetics, and antioxidant activity of polphenols.

Natural Medicine and Kampo

, a special session for this first conference held in Asia covering oriental traditional medicine, herbal medicine, Chinese herbal medicine, folklore, mode of action, metabolism, natural products chemistry, and drug discovery.

Tannins and Their Functions

, another special session on the occasion of this joint meeting with the

Tannin Conference

covering research topics related to condensed tannins, hydrolyzable tannins, tea, wine, persimmon, seed‐coat color, mode of action, and enzymatic reactions.

More than 500 scientists from 35 countries attended the conference, with 321 paper contributions that comprised 61 oral communications and 260 poster presentations. The fifth volume of “Recent Advances in Polyphenol Research” contains chapters from 14 guest speakers of the conference. The support and assistance of the Groupe Polyphénols, the Tannin Conference Group, several Japanese academic associations and foundations, notably the Nagoya University, the City of Nagoya and the Nagoya Convention & Visitors Bureau, and numerous private sponsors are gratefully acknowledged, as the great success of these joint editions of the International Conference on Polyphenols and the Tannin Conference would not have been possible without their contributions. As a final note, we would also like to deeply thank all of the plenary, communication, and poster presenters for the quality of their contributions, from basic science to more applied fields, and all of the attendees, with a special thank to the numerous Asian researchers for their first participation in the ICP and for expressing their eagerness to attend the next ICP meetings.

Kumi Yoshida

Véronique Cheynier

Stéphane Quideau

Chapter 1The Physical Chemistry of Polyphenols: Insights into the Activity of Polyphenols in Humans at the Molecular Level

Olivier Dangles, Claire Dufour, Claire Tonnelé and Patrick Trouillas

Abstract: This chapter reviews the following versatile physicochemical properties of polyphenols in relation with their potential activity in humans:

Interactions with proteins and lipid–water interfaces. These interactions must be qualified with respect to the current knowledge on polyphenol bioavailability and metabolism. They are expected to mediate most of the cell signaling activity of polyphenols.

A general reducing capacity that may be expressed in the gastrointestinal tract submitted to postprandial oxidative stress and also in cells, for example, by direct scavenging of reactive oxygen species, especially if preliminary deconjugation of metabolites takes place

The complex relationships with transition metal ions involving binding and/or electron transfer in close connection with the antioxidant versus pro‐oxidant activity of polyphenols

Keywords: polyphenol, flavonoid, Health effectsbiological activity, mechanism, antioxidant, protein, membrane, metal ion, gastrointestinal tract, DFT methods.

1.1 Introduction

The activity, functions, and structural diversity of polyphenols in plants, food, and humans reflect the remarkable diversity of their physicochemical properties: UV–visible absorption, electron donation, affinity for metal ions, propensity to develop molecular interactions (van der Waals, hydrogen bonding) with proteins and lipid–water interfaces, and nucleophilicity. This chapter aims to exemplify how polyphenols act to promote health in humans at the molecular level. It rests on two common assumptions based on epidemiological evidence and food analysis (Manach et al., 2005; Crozier et al., 2010; Del Rio et al., 2013):

The consumption of fruit and vegetables helps prevent chronic diseases and, in particular, favors cardiovascular health.

Phenolic compounds, from the simple hydroxybenzoic and hydroxycinnamic acids to the complex condensed and hydrolyzable tannins, constitute the most abundant class of plant secondary metabolites in our diet and take part in this protection.

By contributing to the sensorial properties of food, for example, color and astringency, native polyphenols and their derivatives obtained after technological and domestic processing can directly influence the consumer’s choice. Moreover, polyphenols undergo only minimal enzymatic conversion in the oral cavity and in the gastric compartment although their release from the food matrix (bioaccessibility) is an important issue. Thus, intact food polyphenols may directly promote health benefits in the upper digestive tract, in particular by fighting postprandial oxidative stress resulting from an unbalanced diet (Sies et al., 2005; Kanner et al., 2012). Beyond the gastric compartment, polyphenol bioavailability1 (Fig. 1.1) must be considered as a priority to tackle any biological effects (Manach et al., 2005; Crozier et al., 2010; Del Rio et al., 2013). Indeed, even for polyphenols that can be partially absorbed in the upper intestinal tract (aglycones, glucosides), most of the dietary intake reaches the colon where extensive catabolism by the microbiota takes place: hydrolysis of glycosidic and ester bonds, release of flavanol monomers from proanthocyanidins, hydrogenation of the C═C double bond of hydroxycinnamic acids, deoxygenation of aromatic rings, cleavage of the central heterocycle of flavonoids, and so on. Conjugation of polyphenols and their bacterial metabolites in intestinal and liver cells eventually results in a complex mixture of circulating polyphenol O‐β‐D‐glucuronides and O‐sulfo forms (less rigorously called sulfates). When present, catechol groups are also partially methylated.

Fig. 1.1 A simplified view of polyphenol bioavailability.

The concentration of circulating polyphenols is usually evaluated after treatment by a mixture of glucuronidases and sulfatases that release the aglycones and their O‐methyl ethers. This concentration is usually quite low (barely higher than 0.1 μM) and much lower than that of typical plasma antioxidants such as ascorbate (> 30 μM). At first sight, this does not argue in favor of nonspecific biological effects, such as the antioxidant activity by radical scavenging or chelation of transition metal ions to form inert complexes. This seems all the more true that the catechol group, displayed by many common dietary polyphenols and which is a critical determinant of the electron‐donating and metal‐binding capacities, is generally either absent in the circulating metabolites (bacterial deoxygenation) or at least partially conjugated. However, the claim that in vivo polyphenol concentrations are low should be nuanced for the following reasons:

The complete assessment of polyphenol bioavailability must include the bacterial catabolites and their conjugates, some being much more abundant in the circulation than the parent phenol. A spectacular example can be found in the case of anthocyanins. Indeed, after consumption of blood orange juice, the total amount of native cyanidin 3‐

O

‐β‐

D

‐glucoside (C3G) in plasma is 0.02% of the ingested dose versus 44% for (unconjugated) protocatechuic acid (PCA), its main catabolite (Vitaglione

et al

., 2007). When the fecal content is also taken into account, PCA eventually represents ca. 73% of the metabolic fate of ingested C3G. Its absence in urine (unlike C3G) also suggests that it takes part in the antioxidant protection and is thus oxidized in tissues.

The circulating concentration and its time dependence say nothing concerning either the possibility of polyphenol metabolites accumulation at a much higher local concentration at specific sites of inflammation and oxidative stress or their deconjugation into more active forms.

For instance, when quercetin is continuously perfused through the vascular wall of arteries, it rapidly undergoes oxidative degradation into PCA, whereas the fraction retained in the wall is much more stable and partially methylated (Menendez et al., 2011). By contrast, quercetin 3‐O‐β‐D‐glucuronide (Q3G), the main circulating metabolite, is not oxidized upon perfusion but slowly converted into quercetin. The kinetics of quercetin release parallels the inhibition in the contractile response of the artery. Thus, the biological effect can be ascribed to quercetin released from its glucuronide, which basically appears as a stable storage form. A schematic view for the bioactivity of polyphenols is summed up in Fig. 1.2.

Fig. 1.2 Health effects expressed by polyphenols.

1.2 Molecular complexation of polyphenols

The phenolic nucleus can be regarded as a benchmark chemical group for molecular interactions as it combines an acidic OH group liable to develop hydrogen bonds (both as a donor and as an acceptor) and an aromatic nucleus for dispersion interactions (the stabilizing component of van der Waals interactions).

1.2.1 Polyphenol–protein binding

Polyphenol–protein binding of nutritional relevance can be classified as follows:

Binding processes within the gastrointestinal (GI) tract, that is, with food proteins, mucins, and the digestive enzymes, with an impact on the bioaccessibility of polyphenols and the digestibility of macronutrients

Interactions with plasma proteins, with an impact on transport and the rate of clearance from the general circulation

Interactions with specific cell proteins (enzymes, receptors, transcription factors, etc.) that would mediate the nonredox health effects of polyphenols

As the last two situations lie downstream the intestinal absorption and passage through the liver, they concern the circulating polyphenol metabolites. However, some exceptions may be found. For instance, epigallocatechin 3‐O‐gallate (EGCG), the major green tea flavanol, is a rare example of a polyphenol entering the blood circulation mostly in its initial (nonconjugated) form (Manach et al., 2005). No less remarkable, EGCG is also one of the rare polyphenols for which a specific receptor has been identified, namely the 67‐kDa laminin receptor (67LR) that is expressed on the surface of various tumor cells (Umeda et al., 2008). EGCG‐67LR binding leads to myosin phosphatase activation and actin cytoskeleton rearrangement, thus inhibiting cell growth. It provides a strong basis for interpreting the in vivo anticancer activity of EGCG and its anti‐inflammatory activity in endothelial cells (Byun et al., 2014).

It is not the authors’ purpose to provide the reader with an exhaustive updated report on polyphenol–protein binding processes (see Dangles and Dufour (2008) for a specific review on this topic). Only a few recent important examples will be discussed with an emphasis on works dealing with polyphenol metabolites.

1.2.1.1 Interactions in the digestive tract

In the postprandial phase, black tea drinking leads to vasorelaxation as evidenced by flow‐mediated dilation experiments in humans and a strong increase in the activity of endothelial nitric oxide synthase (eNOS) (Lorenz et al., 2007). However, these effects are completely abolished when 10% milk is added to black tea. Experiments with isolated fractions of milk proteins show that caseins are actually responsible for this inhibition. It can thus be proposed that caseins bind and probably precipitate black tea polyphenols in the GI tract, thereby preventing their intestinal absorption. This is a spectacular example of how food proteins may sequester oligomeric polyphenols and cancel their bioaccessibility and downstream biological effects.

The binding between dietary polyphenols and the digestive enzymes is best evidenced with large polyphenols such as oligomeric proanthocyanidins (OPAs). For instance, OPAs inhibit pancreatic elastase, a serine protease, proportionally to their mean degree of polymerization (Bras et al., 2010). A Ki value of ca. 0.5 mM was estimated for a catechin tetramer. However, a mixture of n‐mers (n = 2–6) rich in 3‐O‐galloyl flavanol units binds much more tightly (Ki ≈ 14 μM). Similar data were obtained with trypsin (Goncalves et al., 2007). By slowing down the digestion, such interactions could prolong the sensation of satiety and help fight weight gain and obesity. By contrast, simple phenols were shown to mildly enhance pepsin activity at pH 2 in the following order: resveratrol ≥ quercetin > EGCG > catechin (Tagliazucchi et al., 2005). Tannins are known to inhibit pancreatic lipase (McDougall et al., 2009), thereby possibly contributing to lowering fat intake. Polyphenol‐rich berry extracts also inhibit pancreatic α‐amylase (thus decreasing starch digestibility) and intestinal α‐glucosidase, with tannins and anthocyanins being, respectively, the main contributors to the observed inhibition (McDougall et al., 2005). These mild inhibitory effects could help regulate the circulating D‐glucose concentration.

1.2.1.2 Interactions beyond intestinal absorption

In the circulating blood, polyphenol metabolites likely travel in association with serum albumin, the most abundant plasma protein, which displays several binding sites for the transport of drugs, free fatty acids, and other nutrients. Our recent work (Khan et al., 2011) has shown that flavanone glucuronides (conjugation at the A‐ or B‐ring) are moderate serum albumin ligands (Kb = 3–6 × 104 M−1) that bind site 2 (subdomain IIIA), in contrast to the more planar flavones and flavonols, which bind site 1 (subdomain IIA).

Once delivered to tissues, polyphenol metabolites are expected to bind specific cell proteins to express their biological effects, in particular their well‐documented anti‐inflammatory activity (Pan et al., 2010; Spencer et al., 2012; Wu & Schauss, 2012). Inflammation is an adaptive response to deleterious stimuli, activating the immune system. What is at stake with dietary polyphenols is the inhibition of chronic low‐grade inflammation (in contrast to acute inflammation following microbial infection) associated with the development of degenerative diseases, such as type 2 diabetes and cardiovascular disease. Indeed, this pathological state is deeply influenced by lifestyle and environmental factors, especially dietary habits.

At the cell level, inflammation involves complex signaling pathways and cascades (Fig. 1.3). In particular, mitogen‐activated protein kinases (MAPKs, e.g., ERK, JNK, and p38) are important in the transduction of extracellular signals into cellular responses. When activated by oxidative stress or proinflammatory eicosanoids (prostaglandins, leukotrienes) and cytokines (e.g., TNFα, interleukins, and C‐reactive protein), MAPKs phosphorylate both cytosolic and nuclear target proteins resulting in the assembly and translocation of transcription factors such as NF‐κB, STAT1, and AP1. By upregulating the expression of inducible NO synthase (iNOS), cycloxygenase‐2 (COX2), NADPH oxidase (NOX), cell adhesion molecules, cytokines, and cytokine receptors, these transcription factors trigger cell damage, inflammation, or apoptosis. MAPKs and the subsequently activated transcription factors (or their cytosolic components) are all potential targets of polyphenols and their metabolites, which rationalize their anti‐inflammatory action. However, such mechanisms are subtle and not easy to track down to the highest level of resolution, that is, polyphenols interacting with specific proteins.

Fig. 1.3 Pathways of inflammation and oxidative stress in cells. Kinases, proinflammatory transcription factors, and pro‐oxidant enzymes are possible target proteins for polyphenols and their metabolites.

An additional difficulty also stems from the complex interplay between inflammation and oxidative stress. For instance, activated leucocytes (macrophages) produce reactive oxygen species (ROS) via the activity of NOX and iNOS. Conversely, NF‐κB can be directly activated by ROS (Gloire et al., 2006). Indeed, H2O2