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Genomics, Proteomics and Metabolomics in Nutraceuticals and Functional Foods, 2nd Edition

Genomics, Proteomics and Metabolomics in Nutraceuticals and Functional Foods, 2nd Edition

Debasis Bagchi (Editor), Anand Swaroop (Editor), Manashi Bagchi (Editor)

ISBN: 978-1-118-93043-4

Aug 2015

688 pages

$204.99

Description

Functional foods and nutraceuticals have received considerable interest in the past decade largely due to increasing consumer awareness of the health benefits associated with food. Diet in human health is no longer a matter of simple nutrition: consumers are more proactive and increasingly interested in the health benefits of functional foods and their role in the prevention of illness and chronic conditions. This, combined with an aging population that focuses not only on longevity but also quality of life, has created a market for functional foods and nutraceuticals.

A fully updated and revised second edition, Genomics, Proteomics and Metabolomics in Nutraceuticals and Functional Foods reflects the recent upsurge in "omics" technologies and features 48 chapters that cover topics including genomics, proteomics, metabolomics, epigenetics, peptidomics, nutrigenomics and human health, transcriptomics, nutriethics and nanotechnology. This cutting-edge volume, written by a panel of experts from around the globe reviews the latest developments in the field with an emphasis on the application of these novel technologies to functional foods and nutraceuticals.

Contributors xxiv

Preface xxxi

Part I Introduction 1

1 Novel Omics Technologies in Food Nutrition 3
Xuewu Zhang, Lijun You, Wei Wang, and Kaijun Xiao

1.1 Introduction 3

1.2 Transcriptomics in Nutritional Research 4

1.3 Proteomics in Nutritional Research 5

1.4 Metabolomics in Nutritional Research 7

1.5 Systems Biology in Nutritional Research 9

1.6 Conclusions 9

2 Seafood Authentication using Foodomics: Proteomics, Metabolomics, and Genomics 14
Karola Böhme, Jorge Barros-Velázquez, Pilar Calo-Mata, José M. Gallardo, and Ignacio Ortea

2.1 Introduction 14

2.2 Proteomic Approaches 15

2.3 Metabolomic Approaches 19

2.4 Genomic Approaches 20

2.5 Conclusions 25

3 A Foodomics Approach Reveals Hypocholesterolemic Activity of Red Microalgae 31
Irit Dvir, Aliza H. Stark, and Shoshana (Malis) Arad

3.1 Introduction 31

3.2 Marine Functional Foods and Supplements 32

3.3 Microalgae 33

3.4 Summary 37

Part II Genomics 41

4 Gene]Diet Interaction and Weight Management 43
Lu Qi

4.1 Introduction 43

4.2 Diet and Lifestyle Modifications in Weight Management 44

4.3 The Role of Genetic Factors in Determining Body Weight and Weight Loss 44

4.4 Gene-Diet Interactions on Body Weight and Risk of Obesity 46

4.5 Gene-Diet Interactions on Weight Loss in Randomized Clinical Trials 47

4.6 Gene]Diet Interactions on Weight Maintenance 48

4.7 Personalized Weight Management through Diet and Lifestyle Modifications 49

4.8 Summary and Concluding Remarks 50

5 NutrimiRomics: The Promise of a New Discipline in Nutrigenomics 53
Amitava Das and Chandan K. Sen

5.1 Introduction 53

5.2 miRomics: A New Cornerstone 56

5.3 Nutrigenomics and miR 57

6 Genomics as a Tool to Characterize Anti]inflammatory Nutraceuticals 61
Amitava Das, Scott Chaffee, and Sashwati Roy

6.1 Chronic Inflammation in Disease 61

6.2 Nutraceuticals in the Management of Chronic Inflammation 64

6.3 GeneChipTM as a Tool to Characterize the Anti]Inflammatory Properties of Nutraceuticals 65

7 Nutrigenomics, Inflammaging, and Osteoarthritis: A Review 71
Ali Mobasheri, Richard Barrett-Jolley, Caroline A. Staunton, Chris Ford, and Yves Henrotin

7.1 Introduction 71

7.2 Osteoarthritis (OA) 72

7.3 Antioxidants and the Inflammatory Microenvironment 73

7.4 Inflammaging 75

7.5 Nutrigenomics 76

7.6 Muscle Inflammation in OA 77

7.7 Conclusions 80

8 Genetic Basis of Anti-Inflammatory Properties of Boswellia Extracts 85
Golakoti Trimurtulu, Chandan K. Sen, Alluri V. Krishnaraju, Kiran Bhupathiraju, and Krishanu Sengupta

8.1 Introduction 85

8.2 Boswellia serrata 86

8.3 Mechanism of Action 87

8.4 Development of 5-LOXIN (BE-30) 87

8.5 Gene Chip Probe Array Analysis 88

8.6 Proteomics 89

8.7 Molecular Basis of Anti-Inflammatory Properties of 5-LOXIN 95

8.8 In vivo Studies 96

8.9 Safety of 5-LOXIN 96

8.10 Clinical Efficacy of 5-LOXIN in the Management of Osteoarthritis 97

8.11 An Advanced 5-LOXIN: Aflapin 99

8.12 Conclusion 100

9 Cancer Chemopreventive Phytochemicals Targeting NF-κB and Nrf2 Signaling Pathways 102
Hye-Kyung Na and Young-Joon Surh

9.1 Introduction 102

9.2 Molecular-Based Cancer Chemoprevention 104

9.3 Nuclear Factor-Kappa B (NF-κB) 105

9.4 Nrf2 108

9.5 Interplay/Crosstalk between Nrf2 and NF]κB Signaling Pathways 114

9.6 Conclusion 115

10 The Beneficial Health Effects of Fucoxanthin 122
Kazuo Miyashita and Masashi Hosokawa

10.1 Introduction 122

10.2 The Beneficial Health Effects of Carotenoids as Antioxidants 124

10.3 Anticancer Activity of Fucoxanthin 124

10.4 Anti-Obesity Effects of Fucoxanthin 126

10.5 Anti-Diabetic Effects of Fucoxanthin 127

10.6 Conclusion 130

11 Nutrition, Genomics, and Human Health: A Complex Mechanism for Wellness 135
Okezie I. Aruoma

11.1 Introduction 135

11.2 Nutrition Sciences and Clinical Applications in Nutritional Genomics 136

12 Application of Genomics and Bioinformatics Analysis in Exploratory Study of Functional Foods 140
Kohsuke Hayamizu and Aiko Manji

12.1 Introduction 140

12.2 Analysis Tools 141

12.3 Interpretation Tools 142

12.4 Application Example of Kale (Brassica oleracea L. Var Acephala DC) 143

12.5 Conclusion 148

13 Omics Analysis and Databases for Plant Science 150
Masaaki Kobayashi, Hajime Ohyanagi, and Kentaro Yano

13.1 Introduction 150

13.2 NGS Technologies and Data Processing 151

13.3 De novo Plant Genome Assembly by NGS 151

13.4 Plant Genome Resequencing by NGS 153

13.5 Plant Transcriptome Analysis by NGS 154

13.6 Plant Genome and Annotation Databases 154

13.7 Plant Omics Databases 155

13.8 Conclusion 156

14 Synergistic Plant Genomics and Molecular Breeding Approaches for Ensuring Food Security 160
Shouvik Das and Swarup K. Parida

14.1 Introduction 160

14.2 Plant Genomics, Transcriptomics, Proteomics, and Metabolomics Resources 161

14.3 Molecular Markers in Plant Genome Analysis 163

14.4 Identification of Functionally Relevant Molecular Tags Governing Agronomic Traits 167

14.5 Genomics]Assisted Crop Improvement 170

15 Combinatorial Approaches Utilizing Nutraceuticals in Cancer Chemoprevention and Therapy: A Complementary Shift with Promising Acuity 185
Madhulika Singh and Yogeshwer Shukla

15.1 Introduction 185

15.2 Nutraceuticals 187

15.3 Nutraceuticals and Key Events in Cancer Development 189

15.4 Nutraceuticals in Combinatorial Therapy of Human Cancer: A Pledge of the Future 191

15.5 Curcumin: Potential for Combination Therapy 195

15.6 Resveratrol: Potential for Combination Therapy 199

15.7 Lycopene (a Carotenoid): Potential for Combinations Therapy 202

15.8 Soy Nutraceuticals: Potential for Combination Therapy 203

15.9 Tea Polyphenols Potential for Combinatorial Therapy 204

15.10 D-Limonene: Potential for Combination Therapy 207

15.12 Conclusion 208

16 Nutrigenomic Approaches to Understanding the Transcriptional and Metabolic Responses of Phytochemicals to Diet-Induced Obesity and its Complications 218
Myung-Sook Choi and Eun-Young Kwon

16.1 Introduction 218

16.2 Nutrigenomics 219

16.3 Obesity and Cardiometabolic Syndrome 222

16.4 Anti-Obesity Action of Luteolin 225

16.5 Conclusion 226

17 Going Beyond the Current Native Nutritional Food Through the Integration of the Omic Data in the Post]Genomic Era: A Study in (Resistant) Starch Systems Biology 230
Treenut Saithong and Saowalak Kalapanulak

17.1 Introduction 230

17.2 Starch and its Yield Improvement in Plants 231

17.3 An Extension of the (Resistant) Starch Yield Improvement Research on the Systems Biology Regime: Integration of the Omic Data from the Post-Genomic Technology 233

Part III Proteomics 243

18 Proteomics and Nutrition Research: An Overview 245
Arun K. Tewari, Sudhasri Mohanty, and Sashwati Roy

18.1 Introduction 245

18.2 Proteomics 245

18.3 Nutrition and Proteins 246

18.4 Nutritional Biomarkers 248

18.5 Nutritional Bioactives 248

18.6 Diet-Based Proteomics Application to Animal Products (Livestock Applications) 249

18.7 Proteomics and Food Safety 249

18.8 Conclusion 249

18.9 Significance 250

19 Proteomics Analysis for the Functionality of Toona sinensis 253
Sue-Joan Chang and Chun-Yung Huang

19.1 Introduction 253

19.2 Toona sinensis 253

19.3 TSLs Regulate Functions of Testes/Spermatozoa 254

19.4 TSLs Regulate Liver Metabolism 257

19.5 TSL as a Novel Antioxidant 261

19.6 Possible Active Compounds in TSL Extracts 261

19.7 Conclusion 261

20 Proteomic Approaches to Identify Novel Therapeutics and Nutraceuticals from Filamentous Fungi: Prospects and Challenges 265
Samudra Prosad Banik, Suman Khowala, Chiranjib Pal, and Soumya Mukherjee

20.1 Introduction 265

20.2 Mushroom Derived Immunomodulators and their Target Cells in the Immune System 266

20.3 Mushroom Derived Metabolites in Treating Cancer 271

20.4 Mushroom Derived Metabolites in Infectious Diseases 271

20.5 Fungal Enzymes as Therapeutics and Dietary Supplements 274

20.6 Identification and Characterization of Mushroom Derived Bioactive Therapeutics 275

20.7 Challenges in Intracellular Proteome Preparation 279

20.8 Challenges in Extracellular Proteome Preparation 279

20.9 New Generation MS Technologies to Track the Dynamic Proteome 280

20.10 Glycoproteomics: A New Arsenal in the Proteomic Toolbox 280

20.11 Glycoproteomics of Filamentous Fungi 281

20.12 High]Throughput Approaches to Decipher Fungal Glycan Structures 282

20.13 Challenges in MS Studies of Glycans/Glycopeptides 284

20.14 Optimized MS Instrumentation for Glycan Analysis 284

20.15 Tandem Mass Spectrometry 285

20.16 Bioinformatics for Glycoproteomics: Hitting Databases with MS Peaks 285

20.17 Predicting Glycan Structures with Computational Tools 286

20.18 Concluding Remarks: The Road Ahead 287

21 Proteomics and Metaproteomics for Studying Probiotic Activity 296
Rosa Anna Siciliano and Maria Fiorella Mazzeo

21.1 Introduction 296

21.2 Molecular Mechanisms of Probiotic Action as Studied by Proteomics 297

21.3 Probiotics and Prebiotics 299

21.4 Investigation on Human Microbiota Dynamics by Proteomics 300

21.5 Concluding Remarks and Future Directions 301

22 Proteomics Approach to Assess the Potency of Dietary Grape Seed Proanthocyanidins and Dimeric Procyanidin B2 304
Hai-qing Gao, Bao-ying Li, Mei Cheng, Xiao-li Li, Fei Yu, and Zhen Zhang

22.1 Chemoprotective Properties of GSPs 305

22.2 Proteomic Platform 309

22.3 Proteomics Analysis of the Actions of GSPs 311

22.4 Functional Confirmation of Proteins 317

22.5 Future Perspectives 317

23 Genomic and Proteomic Approaches to Lung Transplantation: Identifying Relevant Biomarkers to Improve Surgical Outcome 321
John Noel, Ronald Carnemola, and Shampa Chatterjee

23.1 Introduction 321

23.2 Lung Transplantation 322

23.3 Challenges of Lung Transplantation 323

23.4 Inflammatory Biomarkers with Lung Rejection: Markers of Inflammation Signaling such as CAMs, Chemokines, and Cytokines and their Status with Transplants 324

23.5 Microarray Technology to Identify Transplant Rejection Biomarkers 324

23.6 Challenges and Future Directions 325

24 Proteomics in Understanding the Molecular Basis of Phytochemicals for Health 328
Jung Yeon Kwon, Sanguine Byun, and Ki Won Lee

24.1 Introduction 328

24.2 Proteomics in Phytochemical Research in Cancer Prevention 329

24.3 Perspectives 331

24.4 Proteomics in Phytochemical Research for Metabolic Diseases 333

24.5 Proteomics for Neuroprotective Phytochemicals 333

24.6 Proteomics for Phytochemicals with Other Functions for Health Benefits 334

24.7 Conclusions 334

25 Genomics/Proteomics of NEXT-II, a Novel Water]Soluble, Undenatured Type II Collagen in Joint Health Care 338
Orie Yoshinari, Hiroyoshi Moriyama, Manashi Bagchi, and Debasis Bagchi

25.1 Introduction 338

25.2 Mechanism of RA 339

25.3 About NEXT-II 340

25.4 Hypothesized Mechanism of NEXT-II 342

25.5 Future Perspectives 343

25.6 Conclusion 343

Part IV Metabolomics 347

26 Harnessing Metabolic Diversity for Nutraceutical Plant Breeding 349
Ashish Saxena and Vicki L. Schlegel

26.1 What is Metabolomics? 349

26.2 Nutraceuticals 350

26.3 Importance of Secondary Metabolites 350

26.4 Complementing Plant Breeding with "Omics" 351

26.5 Nutraceutical Breeding 352

26.6 Crop Quality 353

26.7 Metabolomics and Plant Stresses 353

26.8 Food Safety 354

26.9 Future 354

27 Metabolomics and Fetal-Neonatal Nutrition: An Overview 357
Angelica Dessì, Flaminia Cesare Marincola, and Vassilios Fanos

27.1 Introduction 357

27.2 IUGR and LGA: Fetal Programming 358

27.3 Metabolomics in Nutritional Research 358

27.4 Nutrimetabolomics in Animal Models 360

27.5 Nutrimetabolomics in Human Models 361

27.6 Conclusions 362

28 Metabolomics, Bioactives, and Cancer 365
Shannon R. Sweeney, John DiGiovanni, and Stefano Tiziani

28.1 Introduction 365

28.2 Nuclear Magnetic Resonance Spectroscopy 366

28.3 Mass Spectrometry 367

28.4 Application of Scientific Computing and Data Analysis 368

28.5 Metabolomics, Bioactive Food Components, and Cancer 369

28.6 Future Perspectives 373

29 NMR]Based Metabolomics of Foods 379
Takuya Miyakawa, Tingfu Liang, and Masaru Tanokura

29.1 Introduction 379

29.2 Principal Aspects of NMR in Food Analyses 380

29.3 NMR Techniques Applied to Food Metabolomics 380

29.4 Monitoring of Metabolic Changes in Food Processing Using Quantitative NMR 381

29.5 NMR Profiling Based on Multivariate Analyses 382

29.6 Conclusion 386

30 Cancer Chemopreventive Effect of Curcumin through Suppressing Metabolic Crosstalk between Components in the Tumor Microenvironment 388
Dong Hoon Suh and Yong-Sang Song

30.1 Introduction 388

30.2 Cancer Metabolism 389

30.3 Metabolic Onco-Targets of Curcumin in the Tumor Microenvironment 391

30.4 Clinical Trials of Curcumin as Metabolic Modulators in Cancer 393

30.5 Conclusions and Future Perspectives 393

31 Metabolomics of Green Tea 397
Yoshinori Fujimura and Hirofumi Tachibana

31.1 Introduction 397

31.2 Metabolic Profiling 398

31.3 Tea Chemical Composition 401

31.4 Metabolic Responses to Tea Consumption 402

31.5 Biotransformation of Dietary Tea Components 403

31.6 Conclusion 404

Part V Epigenetics 407

32 The Potential Epigenetic Modulation of Diabetes Influenced by Nutritional Exposures In Utero 409
Jie Yan and Huixia Yang

32.1 Introduction 409

32.2 Insulin Resistance 409

32.3 Skeletal Muscle 410

32.4 Type 2 Diabetes 410

32.5 Influence of High]Fat Diet 410

32.6 Obesity 410

32.7 Intrauterine Growth Restriction (IUGR) 411

32.8 Environmental Factors and Epigenetic Modifications 411

32.9 Mitochondria and Energy Homeostasis 413

32.10 Diabetes Progression 413

32.11 Conclusion 414

33 The Time has Come (and the Tools are Available) for Nutriepigenomics Studies 418
Pearlly S. Yan

33.1 Introduction: Great Strides in Deciphering Methylomes 418

33.2 Recent Findings in Methylome Research and their Implications for Future Nutriepigenomic Research 419

33.3 Strategies for Identifying and Optimizing a Small Number of Promising Methylation Markers 419

33.4 Validation of Methylation Markers Performance in Large Cohorts using Highly Targeted Assays 421

33.5 Summaries 422

34 Natural Phytochemicals as Epigenetic Modulators 424
Gauri Deb and Sanjay Gupta

34.1 Introduction 424

34.2 Epigenetic Mechanisms in Mammals 425

34.3 Natural Phytochemicals and Epigenetic Mechanisms 427

34.4 Conclusion and Future Perspectives 433

Part VI Peptidomics 441

35 Detection and Identification of Food-Derived Peptides in Human Blood: Food-Derived Short Chain Peptidomes in Human Blood 443
Kenji Sato and Daisuke Urado

35.1 Introduction 443

35.2 Detection of Apparent Bioactive Peptides in Human Blood 444

35.3 Identification of Food]Derived Peptides in Human Blood 444

35.4 Future Prospects 448

Part VII Nutrigenomics and Human Health 453

36 Use of Omics Approaches for Developing Immune-Modulatory and Anti-Inflammatory Phytomedicines 455
Shu-Yi Yin, Pradeep M. S., and Ning-Sun Yang

36.1 Introduction 455

36.2 Transcriptomics Study in Medicinal Plant Research 458

36.3 Proteomics Studies on Research into Medicinal Plants 462

36.4 Metabolomics Study on the Research of Medicinal Plants 463

36.5 Lipidomics Study on the Research of Medicinal Plants 466

36.6 Comparative and Bioinformatics Tools for Omics Studies 466

36.7 Challenges and Perspectives 469

37 The Application of Algae for Cosmeceuticals in the Omics Age 476
Nyuk Ling Ma, Su Shiung Lam, and Rahman Zaidah

37.1 Introduction 476

37.2 Metabolomics 477

37.3 Genomics 477

37.4 Proteomics 481

37.5 Conclusion 483

38 Gut Microbiome and Functional Foods: Health Benefits and Safety Challenges 489
Abhai Kumar, Smita Singh, and Anil Kumar Chauhan

38.1 Introduction 489

38.2 Microbiome Symbiosis 490

38.3 Functional Food Intervention of Gut Microbiota 492

38.4 Types of Functional Foods and Their Effects 493

38.5 Regulations and Safety of Functional Food 497

38.6 Safety Challenges of Functional Food 499

38.7 Functional Foods and Nutrigenomics 499

38.8 Conclusions 500

39 An Overview on Germinated Brown Rice and its Nutrigenomic Implications 504
Mustapha Umar Imam and Maznah Ismail

39.1 Diet and Health: The Role of Staple Foods and Nutrigenomic Implications 504

39.2 Health Implications of White Rice and Brown Rice Consumption 506

39.3 Germinated Brown Rice: Bioactives, Functional Effects, and Mechanistic Insights 506

39.4 Conclusions 513

39.5 Future Considerations 513

40 Novel Chromium (III) Supplements and Nutrigenomics Exploration: A Review 518
Sreejayan Nair, Anand Swaroop, and Debasis Bagchi

40.1 Introduction 518

40.2 Trivalent Chromium, Insulin Regulation, and Signaling 519

40.3 Regulatory Pathways 519

40.4 MicroRNAs 522

40.5 Summary and Conclusions 522

Part VIII Transcriptomics 525

41 Transcriptomics of Plants Interacting with Pathogens and Beneficial Microbes 527
Hooman Mirzaee, Louise Shuey, and Peer M. Schenk

41.1 Introduction 527

41.2 Plant Defense Responses against Pathogens 528

41.3 Transcriptomics during Plant]Pathogen Interactions 529

41.4 Plant Responses during Interactions with Beneficial Microbes 530

41.5 Transcriptomics during Beneficial Plant]Microbe Interactions 531

41.6 Knowledge on Modulation of Host Immunity by Pathogens and Beneficial Microbes May Lead to New Resistance Strategies 532

42 Transcriptomic and Metabolomic Profiling of Chicken Adipose Tissue: An Overview 537
Brynn H. Voy, Stephen Dearth, and Shawn R. Campagna

42.1 Introduction 537

42.2 Chicken as a Model Organism 537

42.3 Chicken Genome and Genetic Diversity 538

42.4 Chicken as a Model for Studies of Adipose Biology and Obesity 538

42.5 Natural and Selected Models of Differential Fatness 538

42.6 Transcriptomics and Metabolomics as Tools for the Studies of Adipose Biology in Chicken 539

42.7 Insight into Control of Adipose Tissue Growth and Metabolism in Chickens from Transcriptomics and Metabolomics 541

42.8 Conclusions and Future Directions 543

43 Nutritional Transcriptomics: An Overview 545
M. R. Noori]Daloii and A. Nejatizadeh

43.1 Introduction 545

43.2 Molecular Nutrition 546

43.3 From Nutrients to Genes Expression Profiling 547

43.4 Biological Actions of Nutrients 548

43.5 Nutritional Transcriptomics 548

43.6 Transcriptomic Technologies 549

43.7 Transcriptomics and Development of New Nutritional Biomarkers 552

43.8 The Micronutrient Genomics Project 553

43.9 Transcriptomics in Nutrition Research 553

43.10 Perspectives 554

44 Dissecting Transcriptomes of Cyanobacteria for Novel Metabolite Production 557
Sucheta Tripathy, Deeksha Singh, Mathumalar C., and Abhishek Das

44.1 Introduction 557

44.2 Phylogenetic Relationships in Cyanobacteria 558

44.3 Genomic Studies of Cyanobacteria 560

44.4 Plasmids in Cyanobacteria 562

44.5 Dissecting Transcriptomes of Cyanobacteria 563

44.6 Conclusion 571

45 Inflammation, Nutrition, and Transcriptomics 573
Gareth Marlow and Lynnette R. Ferguson

45.1 Introduction 573

45.2 Inflammation 573

45.3 Nutrition 575

45.4 Nutrigenomics 575

45.5 Dietary Factors and Inflammation 576

45.6 Transcriptomics 577

45.7 Conclusions 578

46 Transcriptomics and Nutrition in Mammalians 581
Carmen Arnal, Jose M. Lou-Bonafonte, María V. Martínez]Gracia, María J. Rodríguez-Yoldi, and Jesús Osada

46.1 Introduction 581

46.2 Adipocyte Transcriptome 584

46.3 Intestinal Transcriptome 587

46.4 Hepatic Transcriptome 590

46.5 Muscular Transcriptome 599

46.6 Conclusion 601

Part IX Nutriethics 609

47 Nutritional Sciences at the Intersection of Omics Disciplines and Ethics: A Focus on Nutritional Doping 611
Nicola Luigi Bragazzi

47.1 Introduction 611

47.2 Nutrigenomics and Nutriproteomics 612

47.3 Sports Nutriproteogenomics 614

47.4 Nutritional and Sports Ethics 615

47.5 Conclusions 617

Part X Nanotechnology 623

48 Current Relevant Nanotechnologies for the Food Industry 625
Kelvii Wei Guo

48.1 Introduction 625

48.2 Nanotechnology in Food Industry 626

48.3 Natural Biopolymers 630

48.4 Nanotechnology for Food Packaging 630

48.5 Outstanding State-of-the-Art Issues 633

48.6 Conclusion 633

References 634

Index 637