Antioxidant Polymers E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 695

Veröffentlichungsjahr: 2012

Beschreibung

Antioxidant Polymers is an exhaustive overview of the recent developments in the field of polymeric materials showing antioxidant properties. This research area has grown rapidly in the last decade because antioxidant polymers have wide industry applications ranging from materials science to biomedical, pharmaceuticals and cosmetics.

Leseprobe

Contents

Cover

Half Title page

Title page

Copyright page

Preface

List of Contributors

Chapter 1: Antioxidants: Introduction

1.1 The Meaning of Antioxidant

1.2 The Category of Antioxidants and Introduction of often Used Antioxidants

1.3 Antioxidant Evaluation Methods

1.4 Antioxidant and its Mechanisms

1.5 Adverse Effects of Antioxidants

References

Chapter 2: Natural Polyphenol and Flavonoid Polymers

2.1 Introduction

2.2 Structural Classification of Polyphenols

2.3 Polyphenol Biosynthesis and Function in Plants

2.4 Tannins in Human Nutrition

2.5 Antioxidant Activity of Tannins

2.6 Protective Effects of Proanthocyanidins in Human Health

2.7 Conclusion

Acknowledgements

References

Chapter 3: Synthesis and Applications of Polymeric Flavonoids

3.1 Introduction

3.2 Polycondensates of Catechin with Aldehydes

3.3 Enzymatically Polymerized Flavonoids

3.4 Biopolymer-flavonoid Conjugates

3.5 Conclusion

References

Chapter 4: Antioxidant Polymers: Metal Chelating Agents

4.1 Introduction

4.2 Chitin and Chitosan

4.3 Alginates

4.4 Chelation Studies

4.5 Conclusions

References

Chapter 5: Antioxidant Polymers by Chitosan Modification

5.1 Introduction

5.2 Chitosan Characteristics

5.3 Reactive Oxygen Species and Chitosan as Antioxidant

5.4 Structure Modifications

5.5 Conclusion

References

Chapter 6: Cellulose and Dextran Antioxidant Polymers for Biomedical Applications

6.1 Introduction

6.2 Antioxidant Polymers Cellulose-based

6.3 Antioxidant Polymers Dextran-based

References

Chapter 7: Antioxidant Polymers by Free Radical Grafting on Natural Polymers

7.1 Introduction

7.2 Grafting of Antioxidant Molecules on Natural Polymers

7.3 Proteins-based Antioxidant Polymers

7.4 Polysaccharides-based Antioxidant Polymers

7.5 Conclusions

Acknowledgements

References

Chapter 8: Natural Polymers with Antioxidant Properties: Poly-/oligosaccharides of Marine Origin

8.1 Introduction to Polysaccharides from Marine Sources

8.2 Antioxidant Activities of Marine Polysaccharides and their Derivatives

8.3 Applications of Marine Antioxidant Polysaccharides and their Derivatives

8.4 Structure-antioxidant Relationships of Marine Poly-/oligosaccharides

8.5 Conclusions

Acknowledgements

References

Chapter 9: Antioxidant Peptides from Marine Origin: Sources, Properties and Potential Applications

9.1 Introduction

9.2 Whole Fish Hydrolysates

9.3 Marine Invertebrate Hydrolysates

9.4 Fish Frames Hydrolysates

9.5 Viscera Hydrolysates

9.6 Muscle Hydrolysates

9.7 Collagen and Gelatin Hydrolysates

9.8 Seaweeds Hydrolysates

9.9 Potential Applications

9.10 Conclusions

Acknowledgements

References

Chapter 10: Synthetic Antioxidant Polymers: Enzyme Mimics

10.1 Introduction

10.2 Organo-selenium/tellurium Compound Mimics

10.3 Metal Complex Mimics

10.4 Selenoprotein Mimics

10.5 Supramolecular Nanoenzyme Mimics

10.6 Conclusion

References

Chapter 11: Synthetic Polymers with Antioxidant Properties

11.1 Introduction

11.2 Intrinsically Conducting Polymers

11.3 Intrinsically Conducting Polymers with Antioxidant Properties

11.4 Synthesis of Antioxidant Intrinsically Conducting Polymers

11.5 Polymer Morphologies

11.6 Mechanism of Radical Scavenging

11.7 Assessment of Free Radical Scavenging Capacity

11.8 Factors Affecting the Radical Scavenging Activity

11.9 Polymer Blends and Practical Applications

References

Chapter 12: Synthesis of Antioxidant Monomers Based on Sterically Hindered Phenols, α-Tocopherols, Phosphites and Hindered Amine Light Stabilizers (HALS) and their Copolymerization with Ethylene, Propylene or Styrene

12.1 Introduction

12.2 Synthesis of Antioxidant Monomers to Enhance Physical Persistence and Performance of Stabilizers

12.3 Phenolic Antioxidant Monomers and their Copolymerization with Coordination Catalysts

12.4 Copolymerization of Antioxidant Monomers with Ethylene, Propylene, Styrene and Carbon Monoxide Using Single Site Catalysts

12.5 Conclusions

Acknowledgements

References

Chapter 13: Novel Polymeric Antioxidants for Materials

13.1 Industrial Antioxidants

13.2 Antioxidants Used in Plastics (Polymer) Industry

13.3 Antioxidants Used in Lubricant Industry

13.4 Antioxidants Used in Elastomer (Rubber) Industry

13.5 Antioxidants Used in Fuel Industry

13.6 Antioxidants Used in Food Industry

13.7 Limitations of Conventional Antioxidants

13.8 Trends towards High Molecular Weight Antioxidants

13.9 Motivation, Design and Methodology for Synthesis of Polymeric Antioxidants

13.10 Biocatalytic Synthesis of Polymeric Antioxidants

13.11 General Procedure for Enzymatic Polymerization

13.12 Conclusions

Acknowledgement

References

Chapter 14: Biopolymeric Colloidal Particles Loaded with Polyphenolic Antioxidants

14.1 Introduction

14.2 Polyphenols: Antioxidant Properties and Health Benefits

14.3 Polyphenols: Formulation and Delivery Challenges

14.4 Polyphenols Loaded Biopolymeric Colloidal Particles

14.5 Conclusion

References

Chapter 15: Antioxidant Polymers for Tuning Biomaterial Biocompatibility: From Drug Delivery to Tissue Engineering

15.1 Introduction

15.2 Oxidative Stress in Relation to Biocompatibility

15.3 Antioxidant Polymers in Drug Delivery

15.4 Antioxidant Polymers in Anti-cancer Therapies

15.5 Antioxidant Polymers in Wound Healing and Tissue Engineering

15.6 Conclusions and Perspectives

References

Index

Antioxidant Polymers

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Library of Congress Cataloging-in-Publication Data:

ISBN 978-1-118-20854-0

Preface

This book is a complete and detailed overview on the recent development in the field of polymeric materials showing antioxidant properties. The research area has grown rapidly in the last decade because antioxidant polymers combine the advantageous properties of both polymeric materials and antioxidants components.

The importance of antioxidant materials in biomedicine, bio-pharmaceutics, cosmetic and nutrition has been highlighted by various scientific reports including research articles, review articles, as well as book chapters, proving the link between oxidative stress and the development of several human pathologies such as cancer, cardiovascular and neurodegenerative diseases, atherosclerosis, and so on. On the other hand, advancements in synthesis techniques and processing technologies have transformed both natural and synthetic polymers into an integral part of everyday life, with importance from both production and application points of view in innovative technological and engineering processes.

Antioxidant polymers are a topic of great interest for researchers in many industrials fields: a large number of research groups have helped to develop various industrial divisions such as pharmaceutical, cosmetic and food industry, plastic materials industries and nano-engineering technology. Furthermore, the strong interest in these materials has stimulated the activity of botanic and marine researchers that have broadened the expertise in this context.

In materials science, antioxidant polymers are studied in terms of innovative and unique physical-chemical properties with particular emphasis to the stability behaviour as well as to the mechanical strength and long-time stability. Recent years have, indeed, witnessed significant progress in the development of efficient and tailor-made stabilizer compounds for various plastics, rubbers, elastomers and coatings to meet the needs of the multiple industrial sectors.

In the biomedical area, antioxidant conjugates of various polymers were synthesized in consideration of extension and amplification of the physiological properties. In particular, novel drugs (e.g. anticancer, synthetic enzymes) or pro-drugs, in which the active ingredient is a molecule showing antioxidant ability, were proposed; furthermore, new polymeric drug delivery systems and tissue scaffolds have been prepared by covalent and/or non-covalent incorporation of antioxidant molecules with the aim to increase the bio-compatibility and to reduce the living tissue side-effects. In the last cases, the antioxidant is required to overcome the side-effects recorded after the topic or systemic administration of the device.

Regarding the pharmaceutical and cosmetic industry, the interest in antioxidant polymers is related not only to their biological activity, but also to their ability to protect the whole formulation and its components from degradation. A considerable limitation in the use of some promising pharmaceutical and cosmetic formulation is often ascribed to the short-term stability of their components which leads to the reduction of their efficiency and, even worse, to the development of toxic side-effects.

Last but not least, it should also be mentioned that food science and technology show this to be an important breakthrough area. Antioxidant polymers are studied from both a nutritional and an industrial points of view with respect to new functional foods or materials for food packaging. The growing evidence about specific health benefits of natural polymeric products, coupled with the recent popularity of functional foods, has led to an increased interest among food scientists to characterize and incorporate them in food products. The presence of antioxidant compounds in food has a strong impact on human health and nutritional value, contributing to the preservation quality of foods while in storage conditions. During storage, the nutritional behaviour of a food could be altered as a consequence of the interaction with atmospheric agents or packaging materials. To overcome these problems, an emerging field is the so-called “intelligent packaging”, in which the materials employed for the production of the package are based on antioxidant polymers.

The whole of the above-mentioned application fields of antioxidant polymers are highlighted in this book. The contributors are researchers from top universities and research and development laboratories (from Europe, USA, Asia and Oceania) and their chapters give an exhaustive overview of the synthesis, characterization, and practical applicability of these materials. In the choice of the chapter contributions and related authors, particular attention has been devoted to cover all the aspects of polymeric antioxidant materials.

After the first chapter which deals with a complete overview of the antioxidant compounds, the book goes in detail with the description of the natural and synthetic polymeric antioxidants, with particular attention to both their chemical and biological properties. The naturally occurring polymeric antioxidant (e.g. polyphenols and flavonoids) are subsequently treated, and the principal synthetic approach based on enzymatic catalysis for their synthesis explored. After this introductory section, polysaccharide biopolymers produced by different organisms are analyzed in terms of antioxidant properties and the most significant chemical approaches for their modification with the aim to improve their antioxidant activity are highlighted. The overview on natural polymers concludes with the treatment of particular kinds of antioxidant polymers (polysaccharides and proteins) from marine origin and to their extraction methodologies.

The section about synthetic antioxidant polymers starts with the description of enzyme mimics and follows with an overview on conducting polymers. Subsequently, a more chemical approach is present in the description of functionalized side-chain polymer with polyphenol moieties.

The final chapters of the book are mainly focused on applications. After an overview of the possible industrial application of the antioxidants in which particular attention is devoted to the differences between the applicability of low- and high-molecular weight antioxidants, as well as to some synthetic approaches for their preparation, the book elucidates the applicability of polymers and antioxidants in pharmaceutical and biomedical fields for the preparation of innovative drug delivery devices and tissue scaffolds.

Finally, the editors would like to thank all the contributing authors for their high quality cooperation which is the primary intent of this edited volume.

Giuseppe CirilloFrancesca Iemma

March 23, 2012

List of Contributors

David Cochran is a PhD candidate under Dr. Thomas Dziubla in Chemical Engineering at the University of Kentucky, Lexington KY. He is also a participant in the Integrative Graduate Education and Research Traineeship (IGERT) program. His research is focused on the development of actively targeted antioxidant polymers for the treatment of inflammation mediated events such as metal particulate inhalation, ischemia/reperfusion injury, and cancer metastasis.

Manuela Curcio was born in Rossano, Italy and received a degree in Chemistry and Pharmaceutical Technology cum laude from the University of Calabria in 2006. She continued her graduate studies at the University of Calabria and completed her PhD in 2009. Since 2006 she has been engaged in teaching activities as a tutor, and from 2010–2011 as a contract professor. In 2011 she became CEO of Macrofarm s.r.l., a spin-off of the University of Calabria, and received a post-doctoral fellowship.

Thomas Dziubla is an Assistant Professor of Chemical Engineering at the University of Kentucky, Lexington KY. He has authored over 30 publications and 4 patents in the field of drug delivery, antioxidant therapy and biomaterials. He has recently been awarded the Kentucky Commercialization Fund Award for his work with degradable antioxidant polymers.

H. Stephen Ewart completed his PhD in Biochemistry from Memorial University of Newfoundland and post-doctoral studies at Toronto’s Hospital for Sick Children and at the University of Calgary. He has focused on the discovery and commercialization of marine-based nutraceuticals and functional food ingredients at Ocean Nutrition Canada Limited and at National Research Council of Canada. Currently he is an independent research consultant.

M. Carmen Gómez-Guillén is a Doctor of Veterinary Sciences at the Complutense University of Madrid and is a Senior Research Scientist.

Begoña Giménez Castillo is a Doctor of Veterinary Sciences at the University of Zaragoza and is a Research Scientist.

M. Elvira López-Caballero is a Doctor of Veterinary Sciences at the Complutense University of Madrid and is a Research Scientist.

M. Pilar Montero García is a Doctor in Biological Sciences at the Complutense University of Madrid and is a Professor of Research.

These 4 authors are affiliated with the Spanish National Research Council (CSIC) at the Institute of Food Science, Technology and Nutrition (ICTAN) in Madrid (Spain), in the Development, Valorisation and Innovation of Fish Products Group. The main research lines are focused on the science and technology of fish products, especially on quality, minimal processing technologies, protein functionality, design and development of functional products and valorisation of protein wastes.

Chunhuan He is originally from Guangxi Province, China. He received a BS and MS degree in Organic Chemistry from Guangxi Normal University. He began his independent research career in 2010 as an Assistant Researcher at Guangxi Institute of Chinese Medicine and Pharmaceutical Science. His research interests include the separation and investigation of the biological activity of Chinese medicines.

Xiaowen Ji is originally from Guangxi Zhuang Autonomous Region, China. She received a BS and MS degree in Analytical Chemistry from Guangxi Normal University. She began her independent research career in 2010 as an Assistant Researcher at Guangxi Botanical Garden of Medicinal Plants, the Chinese Academy of Sciences. Her research interests include the investigation of the biological activity of herbs and pharmaceutical analysis.

Guangling Jiao obtained a Bachelor’s degree in Pharmacy from Yantai University (China). She has three years’ visiting work experience at the Institute for Marine Biosciences-National Research Council of Canada. Currently a PhD candidate at the Ocean University of China, her field of interest is marine polysaccharides-based drugs and functional food studies.

Paul Kilmartin is an Associate Professor in the School of Chemical Sciences at the University of Auckland, New Zealand. He obtained his PhD from the same department in 1997 in the field of conducting polymer electrochemistry, and has continued to undertake research in applications of conducting polymers and in the electrochemistry of beverage polyphenols.

Young-Jin Kim received his BS degree in 1996 and MS degree in 1998 from Kyungpook National University. In 2004, he received his PhD from Kyoto University. He joined Nano Practical Application Center as Team Leader in 2005. He moved to the Department of Biomedical Engineering, Catholic University of Daegu as Assistant Professor in 2007. His main interests are biopolymers and biomimetic materials.

Gui-min Luo graduated from the Chemistry Department of Jilin University in 1966. He has proposed a new strategy for generating abzymes and successfully prepared the first selenium-containing abzyme in the world. He has frequently visited the University of Southern California and Columbia University for cooperative research. So far, he has published more than 98 papers collected by SCI.

Mohammad S. Mubarak received his BS and MS degrees in chemistry from the University of Jordan in 1976 and 1978, respectively and obtained his PhD degree from Indiana University, Bloomington, USA in 1982. His research program is broadly based on synthetic organic chemistry, especially the synthesis of compounds with expected biological activity, in addition to work that involves synthesis and sorption properties of chelating polymers. He is the author and coauthor of more than 100 research papers.

Ashveen V. Nand obtained his BS and MS degrees in Chemistry from the University of the South Pacific, Fiji Islands. Currently, he is working on his PhD thesis at the University of Auckland under the supervision of Prof. Paul Kilmartin. He is investigating the application of intrinsically conducting polymers as antioxidant materials.

Yingming Pan is originally from Jiangxi Province, China. He received a BS degree in Organic Chemistry from Gannan Normal University, a MS degree from Guangxi University, and his PhD from Xiamen University. In 2009, he became full Professor in Organic Chemistry in Guangxi Normal University. His research interests include the separation, synthesis, and investigation of the biological activity of natural compounds.

Ashok Patel is a former Marie Curie International Incoming Fellow and is currently working as a Research Scientist (under NanoNextNL consortium) at Unilever R&D Vlaardingen, the Netherlands.

Sonia Trombino graduated in Pharmacy at the University of Calabria (Italy), where in 2003 she also specialized in Clinical Pathology. Since 2006 she has been a researcher at the Faculty of Pharmacy of the same university. Her research activity involves the synthesis of hydrogels made from natural polymers such as proteins and polysaccharides; the preparation and characterization of micro- and nanoparticles for drug delivery; the chemical modification of natural fibers, and; the evaluation of antioxidant activity of natural and synthetic polymers.

Hiroshi Uyama received his BS degree in 1985 and MS degree in 1987 from Kyoto University. In 1988, he joined the Department of Applied Chemistry, Tohoku University, as Assistant Professor. In 1997 he moved to the Department of Materials Chemistry, Kyoto University. In 2004, he was appointed as a full Professor at Osaka University. His main interests are biomass plastics and functional biopolymers.

Krassimir Velikov is an Expertise Team Leader/Science Leader at Unilever R&D, the Netherlands and Adjunct Assistant Professor at Debye Institute for Nanomaterials Science, Utrecht University, the Netherlands.

Jarmila Vinšová, Prof. RNDr. and PhD, works at the Department of Organic and Inorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University in Prague (the Czech Republic). Her research area is the design and synthesis of new compounds with antimicrobial activities, especially antimycobacterial and antifungal activity and prodrug modelling. She is a Vice-Chairman of The Czech Chemical Society.

Cheng Wang received his MS in Biochemistry in 2006 from the Inner Mongolia University of Science and Technology and is currently pursuing his PhD at the Key Laboratory of Molecular Enzymology and Engineering of the Ministry of Education in Jilin University. His current research interests include selenium-containing abzyme with antioxidant activity.

Hengshan Wang was born in Beijing, China in 1965. He received a MS degree in Phytochemistry in 1990 and a PhD in Biochemistry from Lanzhou University in 2000. In 2001, he became full Professor in Organic Chemistry at Guangxi Normal University. His research interests involve the fields of bioactive natural products in regard to new synthetic methods and some aspects of medicinal chemistry.

Carl-Eric Wilén is currently Professor of Polymer Technology at Åbo Akademi University, Finland. He is also a partner of the Finnish Center of Excellence for Functional Materials (FUNMAT). His main research interests are functional polymers, plastic additives and printable electronics. He has published more than 60 peer-reviewed papers and is an inventor in over 15 issued or pending patent applications.

Gang-lin Yan received his BS in Chemistry in 1977 from Jilin University. After graduation, he joined the faculty of the Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education in Jilin University. His main research interests include chemical synthesis and biosynthesis of antioxidant enzyme mimics.

Guangli Yu completed his PhD in Medicinal Chemistry from Ocean University of China. His focus is the study of marine carbohydrate-based drugs and functional foods at the school of Medicine and Pharmacy, Ocean University of China. He is currently a Professor and Vice-Director of Key Laboratory of Marine Drugs, Ministry of Education of China.

Hiba Zalloum is a researcher at Hamdi Mango Center for Scientific Research at the University of Jordan and holds a Master degree in Chemistry. Her practical research dealt with the synthesis, chelation and sorption properties of chelating polymers. Recently, her research interest is turning to molecular modeling and the drug discovery field.

Junzeng Zhang obtained a PhD in Natural Products Chemistry from the Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, and a MBA from Saint Mary’s University. His post-doctoral research experience was at Peking University, Rutgers University and Institut Armand-Frappier (Quebec). He then joined Ocean Nutrition Canada Limited to work on the discovery and commercialization of marine-based nutraceuticals and functional food ingredients. He is currently a research officer at the Institute for Nutrisciences and Health, National Research Council of Canada.

Xiaoliang Zhao obtained a Bachelor’s degree in Biotechnology from Northwest Normal University (China). He then worked at Tarim University (China) on bioactive polysaccharides research. Currently a graduate student of Ocean University of China, he is studying the structure-activities of marine poly-/oligosaccharides using glycoarray technology.

Chapter 1

Antioxidants: Introduction

Chunhuan He1,2, Yingming Pan1, Xiaowen Ji1, Hengshan Wang1

1 Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), School of Chemistry & Chemical Engineering of Guangxi Normal University, Guilin, P. R. China

2 Guangxi Institute of Chinese Medicine & Pharmaceutical Science, Nanning, P. R. China

Abstract

It is well known that reactive oxygen species (ROS) are involved in a variety of physiological and pathological processes. ROS are continuously balanced by antioxidative defense systems in healthy individuals. However, when the physiological balance between pro-oxidants and antioxidants is disrupted in favor of the former, oxidative stress occurs ensuing in potential damage for the organism. Therefore in recent years, the role and beneficial effects of antioxidants against various disorders and diseases induced by oxidative stress have received much attention. An antioxidant is a substance which when present at low concentrations compared to those of oxidizable substrates, significantly delays or inhibits oxidation of that substrate. The main content of this chapter includes the meaning of antioxidant, categories of antioxidants, antioxidant evaluation methods, and their functional mechanisms and adverse effects.

Keywords: Antioxidant, category, evaluation methods, mechanisms, adverse effect

1.1 The Meaning of Antioxidant

Lipid oxidation in food and biological systems is responsible for a multitude of adverse effects and implications in the food industry as well as in human health. Oxidation may occur in foods during harvesting, processing, and storage. It is responsible for rancid odors and flavors of foods, with a consequent decrease in nutritional quality and safety caused by the formation of secondary, potentially toxic compounds, thus making the lipid or lipid-containing foods unsuitable for consumption [1]. It has also been reported that oxidation in vivo is associated with pathophysiology of human health problems such as carcinogenesis, inflammation, atherosclerosis, and aging [2–5]. Among the methods employed for preventing lipid oxidation, the addition of antioxidants is the most effective, convenient, and economical strategy for stabilizing food and non-food commodities [6]. The common definition of an antioxidant is any substance that significantly delays or prevents oxidation of that substrate when present at low concentrations compared with those of an oxidizable substrate [7]. In the field of foods, antioxidants are classified as compounds that are able to delay, retard or prevent autooxidation processes [8, 9]. In terms of the effects in the human body, an antioxidant is a substance in foods that significantly decreases the adverse effects of reactive species, such as reactive oxygen and nitrogen, on normal physiological functions, as defined by the Institute of Medicine [10]. Antioxidants such as butylated hydroxyanisole (BHA), butylated hydroxutoluene (BHT), and propyl gallate (PG) have been used by food manufacturers worldwide to retard food lipid oxidation and thus prevent quality deterioration and improve the shelf-life of products [11].

1.2 The Category of Antioxidants and Introduction of often Used Antioxidants

According to the pathways of antioxidant production, there are natural antioxidants, synthetic antioxidants and nature-identical antioxidants [12]. The most widely encountered way of antioxidant formation is natural antioxidant, which is synthesized by various microorganisms, fungi, and even animals, but most often by plants. Synthetic antioxidants are produced by human experts by way of synthesis or biosynthesis in the industry. And nature-identical antioxidants are found in foods, but synthesized in the industry.

Lipid oxidation is one of the major reasons for deterioration of food products during processing and storage. Its mechanism is shown in Figure 1.1 [13, 14]. A large number of synthetic and natural antioxidants have been shown to induce beneficial effects on food storage. The most frequently encountered antioxidants are listed in Figure 1.2. According to the mechanism of lipid oxidation, several types of inhibitors of lipid oxidation are available: inhibitors of free-radical oxidation reactions (also called preventive antioxidants), inhibitors interrupting the propagation of the autoxidation chain reaction (called chain-breaking antioxidants), singlet oxygen quenchers, synergists of proper antioxidants, reducing agents, metal chelators, and inhibitors of pro-oxidative enzymes [12].

Figure 1.1 Mechanism of lipid oxidation [13, 14].

Figure 1.2 The frequently encountered antioxidants.

There is a growing interest in natural antioxidants found in plants from a safety point of view. Polyphenols comprise a large class of antioxidants and include flavonoids, anthocyanins, phenolic acids, lignans, and stilbenes. They have been receiving increasing interest from consumers and manufacturers in the past few decades because of numerous health benefits such as their antibacterial, anti-inflammatory, antiallergic, hepatoprotective, antithrombotic, antiviral, anticarcinogenic, and vasodilatory actions [15, 16]. We will present a brief introduction of some frequently encountered phenolic antioxidants including synthetic antioxidants and natural antioxidants in the following part.

1.2.1 BHT

Butylated hydroxytoluene (BHT), namely 2,6-bis(1,l-dimethylethyl)-4-methylphenol or 3,5-di-tert-butylhydroxy-toluene, is a synthetic, highly lipid-soluble antioxidant, which is commonly used in the manufacture of plastics, elastomers, oils, lubricants, vitamins and fragrances, as well as in the field of preservation of human foods, cosmetics and other lipid-containing products [17–19]. BHT is allocated an acceptable daily intake (ADI) of 0–0.3 mg/kg body weight. It is able to terminate lipid peroxidation chain reactions before the spoilage of food by donating hydrogen-atoms of phenol hydroxyl groups and stabilizing the peroxyl radicals [20]. It was reported that administration of BHT to animals can not only prevent sugar-induced cataract and inhibit cholesterol-induced atherosclerosis, but also diminished tumor development in rats exposed to cancerogenic compounds [18]. Considering the increased usage of BHT in our foods, concern over the safety of BHT has been growing and its biological activities have been investigated in the past few decades. BHT exacerbates a chronic urticaria in an early clinical study [21]. Lung inflammation is induced in mice by BHT administration and hepatic toxicity in rats has been found when administered orally [22–24]. Moreover, BHT acts as a tumor promoter in animals treated with tumor initiators such as urethane and 3-methylcholanthrene [19]. In humans, the intake of BHT can result in health problems for oversensitive individuals, evaluated as allergic reactions [25].

1.2.2 Quercetin

In recent years, quercetin, one of the most important members in the flavonoid family, has become the focus of medical researchers. It has been found to have many pharmacological uses such as an antioxidant and for scavenging oxygen free radicals [26, 27]. It is anti-aggregatory [28] and has anticancer [29–31] and vasodilating effects [32], is anti-virus [33] and anti-inflammatory [34, 35], reverses multidrug resistance [36], and so on. The antioxidant activities of quercetin, rutin, catechin, epicatechin and resveratrol in red grape have been tested by Iacopini et al., using 2, 2-diphenyl-1-picrylhydrazyl (DPPH) free radical and peroxynitrite scavenging assay, and the results showed that quercetin had the lowest IC50 value towards both kinds of free radicals [37]. Quercetin suppressed the viability of human cervical cancer (HeLa) cells in a dose-dependent manner by inducing G2/M phase cell cycle arrest and mitochondrial apoptosis through a p53-dependent mechanism [38]. Recently, the experimental study of quercetin-treatment with rats bearing Walker 256 carcinosarcoma strongly supported the anticancer function of this flavonoid [39]. Moreover, quercetin can inhibit the invasion and proliferation of U87 glioma cells [40].

1.2.3 BHA

BHA is produced by the chemical reaction between p-methoxyphenol and isobutene. Commercial preparations of BHA, referred to as 2(3)-tert-butyl-4-hydroxy anisole, are a mixture of 85% or more 3-tert-butyl-4-hydroxya-nisole (3-BHA, see Figure 1.2) and 15% or less 2-tert-butyl-4-hydroxyanisole (2-BHA) [41]. It is soluble in fats, oils, alcohol and ether, but insoluble in water [42]. It has been widely used to suppress the formation of free radicals and prevent lipid oxidation and food spoilage. Considering its safety, BHA is limited by a total antioxidant content of not more than 0.02% of the oil or fat content of the food, and its ADI is between 0 and 0.5 mg/kg body weight per day [42, 43].

1.2.4 2-tert-Butylhydroquinone (TBHQ)

Like BHA, TBHQ is also a derivative of hydroquinone, substituted with a tert-butyl group, and it is lipid-soluble. TBHQ is often used in vegetable oils, animal fats, and meat products. And its ADI allocated by the joint FAO/WHO Expert Committee on Food Additives is 0–0.7 mg/kg body weight. Metabolically, TBHQ is formed from BHA by O-demethylation, and it is further oxidized to 2-tert-butyl-1, 4-benzoquinone [44].

1.2.5 Gallic Acid

Gallic acid (GA, 3, 4, 5-trihydroxibenzoic acid), a natural plant triphenol that constitutes tannin, is present in many fruits, vegetables and derivative products (tea, wines, etc.). It is a well-known antioxidant, and some alkylesters including ethyl-, propyl-, butyl-, octyl-, and laurylgallates are known to act as antioxidants. They are widely used as food additives for scavenging reactive oxygen species that are responsible for the rancidity of different foodstuffs [45]. GA could prove beneficial to numerous disease states, such as cardiovascular disease, due to its antioxidant effect. However, another report highlighted that GA had cytotoxic activity: cytotoxicity in vascular smooth muscle cells and hepatocytes, and antitumoral effects via apoptosis in certain tumor cell lines [46].

1.2.6 Resveratrol

Resveratrol (RES; 3,5,4’-tri-hydroxystilbene), a phytoalexin made naturally by plants such as red grapes, raspberries, mulberries, plums, peanuts, bilberries, blueberries, cranberries, Scots pine, and Japanese knotweed, has been produced by chemical synthesis because of its potential anticancer, anti-inflammatory, blood-sugar-lowering, and other beneficial cardiovascular effects [47–49]. RES exists in two isoforms, that is trans-resveratrol and cis-resveratrol, and the trans-isomer (see Figure 1.2) is the steadier one which plays a role in nearly all biological actions of RES [50]. RES is rapidly and efficiently absorbed following oral administration, though its bioavailability is low due to its metabolism to sulfated and glucoronidated derivates during first pass metabolism by the liver [51].

1.2.7 Luteolin

Luteolin (LUT) is a polyphenolic compound, found in a variety of fruits, vegetables, and seeds, which has a variety of pharmacological properties including antioxidant, anticancer, antimutagenic, and anti-allergic effects, as well as anti-inflammatory, antibacterial, and vasorelaxant effects [52–54]. LUT is able to protect against cell death by the induction of heme oxygenase-1 expression in auditory cells and a calcium/mitochondrion/caspase-dependent pathway in endothelial cells [55].

1.2.8 Caffeic Acid

Caffeic acid (CAF, 3,4-dihydroxycinnamic acid), is a widespread phenolic compound which is derived biosynthetically from phenylalanine in plants, and it has been employed as a natural antioxidant for inhibiting oxidation of fish lipids present in different food matrices [56]. CAF occurs naturally in many agricultural products such as coffee, wine, olive oil, fruits, and vegetables [57]. In the last decade, CAF has attracted considerable attention due to its various biological and pharmacological activities, including antioxidative activities [58–60], anticancer [61, 62] and anti-inflammatory activities [63, 64], and its immunomodulatory effect [65].

1.2.9 Catechin

Green tea contains characteristic polyphenol constituents, generally known as catechins, which consists of eight polyphenolic flavonoid-type compounds, namely, (+)-catechin (Figure 1.2), (-)-epicatechin, (+)-gallocatechin, (-)-epigallocatechin (Figure 1.2), (+)-catechin gallate, (-)-epigallocatechin-3-gallate, (+)-gallocatechin gallate, and (-)-epicatechin gallate [66]. Among these catechins, (-)-epigallocatechin-3-gallate is the most abundant and the most biologically active compound. Catechin intake has been associated with a wide variety of beneficial health effects such as being anti-inflammatory [67], antioxidant [68, 69], anticarcinogenic [70, 71], antiobesity [72, 73], antitumorigenic [74], antihypertensive [75], antidiabetic [76], chemopreventative [77], and antiallergic [78].

1.3 Antioxidant Evaluation Methods

The antioxidant capacities of samples might be influenced by several factors, such as working mechanism and test system, and could not be fully described by one single method. A wide range of assays are currently used to assess antioxidant capacity of plants and antioxidant components [10, 79, 80]. Some often used assays are stated in detail below.

1.3.1 DPPH Radical Scavenging Assay

DPPH can make a stable free radical in aqueous or ethanol solution and has a UV-vis absorption maximum at 515 nm. Upon receiving proton from any hydrogen donor, mainly from phenolics, it loses its chromophore and became yellow. This method is technically simple and is used first as a screen for antioxidant components within the primary extracts [81, 82].

The DPPH assay involves the following procedures [83]: DPPH solution (3.9 mL, 0.004 g/mL) in ethanol or methanol is mixed with sample solution (0.1 mL). The absorbance of the mixture is monitored at 515 nm for 30 min or until the absorbance is stable. DPPH radical scavenging activity (%) of sample is calculated using the formula: (1-[Asample/Acontrol,t=0] × 100).

1.3.2 ABTS Radical Scavenging Activity

ABTS assay was first reported by Miller and coworkers in 1993 [84]. There are different improved versions later. It is an excellent tool for determining the antioxidant activity of hydrogen-donating antioxidants (scavengers of aqueous phase radicals), and of chain-breaking antioxidants (scavenger of lipid peroxyl radicals) [85]. In improved assay, ABT·+ is generated by reacting 2, 2’-azinobis [3-ethylbenzothiazoline-6-sulfonate] (ABTS) with potassium persulfate. ABTS·+ has a relatively stable blue-green color, which has a UV-vis absorption maximum at 734 nm. Antioxidants reduce intensity of this color to a degree that is in proportion to their antioxidant concentration or activity.

The ABTS assay is typically run by the following procedure [86]. In brief, the ABTS·+ stock solution was prepared from 7 mM ABTS and 2.45 mM potassium persulphate in a volume ratio of 1:1, then incubated in the dark for 12–16 h at room temperature. This solution was diluted with ethanol buffer (pH 7.4) to an absorbance of 0.70 ± 0.05 at 734 nm. One hundred microliters of tested sample were mixed with 3.8 mL ABTS·+ diluted solution. The absorbance of the mixture was measured at 734 nm after 6 min of incubation at room temperature, and the percent of inhibition of absorbance was calculated.

1.3.3 Phosphomolybdenum Assay

This method is based on reduction of Mo (VI) to Mo (V) in the presence of reductants (antioxidants). In this assay, a green phosphate/Mo (V) complex will be formed in the condition of acid pH and could be monitored at 695 nm with a spectrophotometer [87].

The phosphomolybdenum assay is typically run by the following procedure: 0.4 ml of sample (1 mg/mL) was mixed with 4 mL of reagent solution (0.6 M sulphuric acid, 4 mM ammonium molybdate and 28 mM sodium phosphate). The mixture was incubated in water bath at 95°C for 90 min. The absorbance of the green phosphomolybdenum complex was measured at 695 nm when the sample had cooled to room temperature. The antioxidant activity was determined using a standard curve with ascorbic acid solutions as the standard.

1.3.4 Reducing Power Assay

In this assay, the presence of reductants (antioxidants) in the samples would result in the reduction of the Fe3+/ferricyanide complex to its ferrous form. The amount of Fe2+ complex can then be monitored by measuring the formation of Perl’s Prussian blue at 700 nm [88].

The reducing power assay is typically run by the following procedure [89, 90]: One millilitre of sample solution with different concentrations was mixed with phosphate buffer (2.5 mL, 0.2 M, pH 6.6) and potassium ferricyanide (2.5 mL, 1%). After the mixture was incubated at 50°C for 20 min, trichloroacetic acid (2.5 mL, 10%) was added, and the mixture was centrifuged at 3000 rpm for 10 min. The upper layer of solution (2.5 mL) was mixed with distilled water (2.5 mL) and ferric chloride (0.5 mL, 0.1%), and then the absorbance was measured at 700 nm against a blank.

1.3.5 Total Phenols Assay by Folin-Ciocalteu Reagent

The total phenols assay by Folin-Ciocalteu Reagent is very convenient, simple and reproducible, and thus has become a routine assay in studying plants that contain phenolic compounds.

The process of making Folin-Ciocalteu Reagent is: mix sodium tungstate (Na2WO4·2H2O, 100 g), sodium molybdate (Na2MoO4·2H2O, 25 g), concentrated hydrochloric acid (100 mL), 85% phosphoric acid (50 mL) and water (700 mL), then boil for 10 h; after that lithium sulfate (Li2SO4·4H2O, 150 g) is added to the mixture [10]. The molybdenum is easier to be reduced in the complex and electron-transfer reaction occurs between reductants and Mo (VI).

Total phenols are often estimated as gallic acid equivalents, per gram of extract [93]. Experimentally, this assay was carried out by first transferring 6.0 mL H2O and 100 μL sample (conc. 4 mg/mL), then adding 500 μL undiluted Folin–Ciocalteu reagent. After 1 min, 1.5 mL 20% (w/v) Na2CO3 were added and the volume was made up to 10.0 mL with H2O. After 2 h incubation at 25°C, the absorbance was measured at 760 nm and compared to a gallic acid calibration curve.

1.3.6 Hydroxyl Radical Scavenging Assay

The deoxyribose method for scavenging of the hydroxyl radical (OH·) was first described by Halliwell and coworkers in 1987 [94]. In this assay, OH· is generated by a mixture of ascorbic acid, Fe3+-EDTA and H2O2. It attacks deoxyribose, degrading it into fragments that give a chromogen upon heating with thiobarbituric acid at low pH. If an antioxidant (OH· scavenger) is added, it competes with deoxyribose for OH· and inhibits chromogen formation.

The deoxyribose assay involves the following procedures [95]: One hundred microliters of sample (pH 7.4) was added to 690 μL of 10 mM phosphate buffer at pH 7.4 containing 2.5 mM 2-deoxyribose. Then 100 μL of 1.0 mM iron ammonium sulfate premixed with 1.04 mM EDTA was added. The mixture was kept in a water bath at 37°C, and the reaction was started by adding 100 μL of 1.0 mM ascorbic acid and 10 μL of 0.1 M H2O2. Samples were maintained at 37°C for 10 min, and then 1.0 mL of cold 2.8% trichloroacetic acid was added followed by 0.5 mL of 1% thiobarbituric acid. Samples were boiled for 8 min and cooled, and the absorbance was measured at 532 nm.

1.3.7 β-carotene–linoleic Acid Assay

In this assay, the oxidation of linoleic acid generates peroxyl free radicals [96]. The free radical will oxidize the unsaturated β-carotene, and antioxidants in the tested sample will minimize the oxidation of β-carotene, so the degradation rate of β-carotene indicates the antioxidant activity of the tested sample [97].

The detailed procedures of the β-carotene–linoleic acid assay are described by Amarowicz and coworkers [98]. In general, 0.4 mg β-carotene, 40 mg of purified linoleic acid, 400 mg of Tween 40 as an emulsifier, and 100 ml of distilled water were added to the flask with vigorous shaking. Aliquots (4.8 ml) of this emulsion were transferred into a series of tubes containing 200 μl of the sample in methanol. As soon as the emulsion was added, the zero time absorbance was measured at 470 nm with an UV-spectrophotometer. Subsequent absorbance was recorded over a 2 h period at 20 min intervals by keeping the samples in a water bath at 50°C. Blank samples, devoid of β-carotene, were prepared for background subtraction

1.3.8 Superoxide Radical Scavenging Assay

Superoxide radical, which is a highly toxic species, is generated in numerous biological reactions. It is very important to study the scavenging of superoxide radical because these radical anions are potential precursors of highly reactive species, such as hydroxyl radical [99].

One of superoxide radical scavenging assays is dependent on the reducing activity of test compound by an O2·− dependent reaction, which releases chromphoric products [100]. In general, pyrogallol solution (3 mM) was added into a tube containing sample (2.0 mg/mL) previously dissolved in Tris–HCl–EDTA buffer (0.1 M, pH 8.0). The optical density was measured in triplicate at 320 nm using a spectrophotometer. The antioxidant activity was determined as the percentage of inhibiting pyrogallol autoxidation, which was calculated from optical density in the presence or absence of pyrogallol and test compound.

1.3.9 Metal Ion Chelating Assay

1.3.10 Determination of Total Flavonoid Content

Total flavonoid content is determined by a colorimetric method [103]. In brief, 1mL of appropriate dilution of sample was added to volumetric flask containing 1 mL of 5% (w/v) NaNO2 and placed for 6 min, followed by adding 1 mL of 10% (w/v) Al(NO3)3 to form a flavonoid–aluminum complex. After 6 min, 10 mL of 4.3% (w/v) NaOH was added and the total was made up to 25 mL with distilled water. The final solution was mixed well and placed for 15 min at room temperature, and then the absorbance was measured against a blank at 510 nm with a spectrophotometer. The total flavonoid content of sample was expressed as a catechin equivalent (g catechin/g sample).

1.4 Antioxidant and its Mechanisms

Many types of antioxidants with different functions play their role in the defense network in vivo. They may act as free radical scavengers, singlet oxygen quenchers, inactivators of peroxides and other ROS, metal ion chelators, quenchers of secondary oxidation products and inhibitors of pro-oxidative enzymes [104]. It is very important to know their functional mechanisms. Much attention has been paid to the mechanisms of phenolic antioxidants, thus significant gains have been made in understanding the molecular mechanisms underpinning the chemopreventive effects of polyphenols. In this part, we will mainly talk about the mechanisms of polyphenols, including scavenging free radicals, metal chelating properties.

1.4.1 Mechanism of Scavenging Free Radicals

The reactive oxygen species (ROS) family includes superoxide anion (O2·−), hydroperoxyl radical (HOO·), peroxyl radical (ROO·), hydroxyl radical (OH·), hydrogen peroxide (H2O2) and hydrochlorous acid (HOCl), while reactive nitrogen species (RNS) includes free radicals such as nitric oxide (NO·) and nitrogen dioxide (NO2) and peroxynitrite (ONOO−) [105, 106]. The production of these free radicals is a natural process that can occur with or without the aid of enzymes and only becomes a health concern when defense mechanisms are not able to neutralize [107]. Many phenolic compounds and aromatic amines act as a free radical-scavenging antioxidant. The free radical-scavenging potential of polyphenolic compounds appears to depend on the pattern (both number and location) of free OH groups on the flavonoid skeleton [108]. Polyphenols function by scavenging active free radicals before they attack biologically essential molecules by donating hydrogen atom (Reaction 1) or electron followed by proton transfer (Reaction 2) to give a stable compound and antioxidant-derived radical [109, 110]. In reaction 1, the antioxidant ArOH transferred a hydrogen atom to the free radical R· and gained less reactive products RH and ArO· and the antioxidant action depends on the bond dissociation enthalpy of the ArO–H bond. The lower the bond dissociation enthalpy value, the easier the reaction with the free radicals. In reaction 2, an electron of antioxidant was donated to the R· and got stable products. In this step, the lower the ionisation potential value, the easier the reaction with free radicals.

(1.1)

(1.2)

1.4.2 Mechanism of Metal Chelating Properties

Bivalent transition metal ions, Fe2+ in particular can catalyze oxidative processes, leading to the formation of hydroxyl radicals, and can decompose hydroperoxides via Fenton reactions [15, 109, 111, 112] (see Reaction 3). Among the ROS family, hydroxyl radical exhibits the strongest oxidative activity and induces severe damage to biomolecules including lipids, proteins, and nucleic acids at virtually diffusion-limited rates, thus giving rise to many diseases, including arthritis, atherosclerosis, cirrhosis, diabetes, cancer, Alzheimer’s disease, emphysema, and ageing [113]. Together with scavenging free radicals, polyphenols may entrap metals and avoid them to take part in the reactions generating free radicals; chelating these metals can effectively reduce oxidation [94, 114].

(1.3)

For example, it is proven that quercetin chelates intracellular transition metal iron, thereby avoiding its catalyzing effect on the formation of ROS [115]. There are three potential sites for the metal to bind in quercetin (see Figure 1.3) [109], and the number of OH group and its position on the ring of molecule determine the antioxidant capacity of flavonols [116].

Figure 1.3 Mechanism for transition metals chelation [109].

1.5 Adverse Effects of Antioxidants

Synthetic antioxidants such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate (PG), tocopherol, and tertiary-butylhydroquinone (TBHQ) are the most commonly used antioxidants in the food industry and are included in the human diet. However, recent reports reveal that these compounds may be implicated in many health risks such as cancer and carcinogenesis. In this part we will mainly focus on the adverse effects of synthetic antioxidants.

Propyl gallate (3,4,5-trihydroxybenzoic acid propyl ester) is widely used as a synthetic antioxidant in foods and its potential toxicity has been investigated in vivo and in vitro to assess various toxicological properties. A previous study carried out by the National Toxicology Program Technical Report showed that PG induced preputial gland tumors, islet-cell tumors of the pancreas and pheochromocytomas of the adrenal glands [117]. It was reported by Wargovich et al. that PG increased the number of aberrant crypt foci after benzo (a) pyrene induction in the F344 rat colon [118]. Another study indicated that PG was cytotoxic to isolated rat hepatocytes by impairing mitochondria and leading to ATP depletion [119]. Reseachers also found that PG exerted pro-oxidant properties [120–122]. PG inhibits growth of microorganisms by inhibiting respiration and nucleic acid synthesis [123]. Recently, the toxic effects of PG to aquatic organisms were investigated by using five model systems from four trophic levels and it was found that PG cytotoxicity was dependent on glutathione levels, and general antioxidants or calcium chelators did not modify the toxicity of PG, and PG should be classified as toxic to aquatic organisms [124].

BHA has been reported to act as a tumor initiator or a tumor promoter in some animal tissues. For example, dietary administration of BHA at concentrations between 0.5 and 2% significantly enhanced forestomach carcinogenesis of rats when using N-methyl-N’-nitro-N-nitrosoguanidine, N-methylnitrosourea or N-dibutylnitrosamine as initiators [125]. A previous report showed that chronic dietary administration of BHA enhanced the development of preneoplastic and neoplastic lesions in the rat kidney and urinary bladder [126]. What is more, BHA induced proliferative effects in the esophagus of pigs and primates [127].

It was demonstrated that TBHQ caused DNA cleavage in vitro and the formation of 8-hydroxydeoxyguanosine in calf thymus DNA due to the generation of ROS such as superoxide anion and hydrogen peroxide [128, 129]. Although TBHQ was not considered to be carcinogenic in rats or mice, a high dose (400 mmol/kg body weight, i.v.) of glutathione conjugates of TBHQ, a metabolite of the urinary tract, were found to be toxic to kidney and bladder [44].

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