Nutraceuticals and Natural Product Derivatives: Disease Prevention & Drug Discovery

By Mohammad Fahad Ullah and Aamir Ahmad

Introduces readers to the growing applications of nutraceuticals and other natural product derivatives

This comprehensive book presents a prophylactic and therapeutic approach to chronic disease prevention strategy by highlighting the translational potential of plant-derived dietary and non-dietary factors from epidemiological, laboratory, and clinical studies. It also shares the experiences of highly reputed experts working in the area of phytomedicine and nutraceutical agents in chemoprevention, to promote the significance of natural products and dietary factors as an elite priority for containing chronic diseases in the human population.

Nutraceuticals and Natural Product Derivatives: Disease Prevention & Drug Discovery starts by examining natural food sources for the control of glycemia and the prevention of diabetic complications. It then looks at the anti-aging effects of sulfur-containing amino acids and nutraceuticals, and the potential of garcinia fruits to combat metabolic syndrome. Other topics covered include honey- and propolis-mediated regulation of protein networks in cancer cells; recent trends in drug discovery against Alzheimer’s disease; the therapeutic potential of metalloherbal nanoceuticals; and much more.

• Offers an alternative, natural approach to the prevention of chronic diseases
• Emphasizes the potential of plant-derived dietary and non-dietary factors from epidemiological, laboratory, and clinical studies
• Features contributions from world-renowned experts in the field of phytomedicine and nutraceutical agents in chemoprevention
• Includes prevention strategies in normal/risk populations through routine inclusion of specific dietary regimens and as therapeutic strategy for better management through adjuvant interventions with conventional treatment protocols

Nutraceuticals and Natural Product Derivatives: Disease Prevention & Drug Discovery will appeal to graduate students and professionals in cell and molecular biology, translational research, pharmacology/drug discovery, medicinal chemistry, and clinical nutrition.

• Language: English
• Publisher: Wiley
• Release date: Dec 11, 2018
• ISBN: 9781119436737

Book preview

Editor Biographies

Mohammad Fahad Ullah, PhD, is an Assistant Professor of Biochemistry in the Department of Medical Laboratory Technology (FAMS) and a research scientist at Prince Fahd Research Chair, University of Tabuk, Tabuk, Saudi Arabia. He received his academic degrees along with a gold medal in MSc (biochemistry) from Aligarh Muslim University, Aligarh, India. Furthermore, he worked as a research associate at the Experimental Oncology Laboratory, Department of Biomedical & Diagnostic Sciences, University of Tennessee, Knoxville, TN, USA. His research interests include assessing novel plant‐ or diet‐derived bioactive compounds for their mechanism of action and translational potential against chronic diseases, including cancer and diabetes. He is an active member of the American Association for Cancer Research (AACR, USA) and the Royal Society of Chemistry (UK), and a member of the editorial/reviewer board of a number of scientific journals. Dr. Ullah has more than eight years of experience in teaching biochemistry to the students of health sciences. His academic works include close to 50 publications in reputed journals and two books entitled Critical Dietary Factors in Cancer Chemoprevention (Springer, Switzerland) and Illustrated Notes on Biomolecules (Partridge, Singapore).

Aamir Ahmad, PhD, is an Assistant Professor of Oncologic Sciences at University of South Alabama's Mitchell Cancer Institute, Mobile, AL, USA. He received his academic degrees from Aligarh Muslim University, Aligarh, India, and received university gold medals for the highest marks in his department as well as all the faculties combined. He completed postdoctoral training at the National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. His research interests include understanding the mechanisms of cancer drug resistance and metastasis in different cancers, with emphasis on the roles of microRNAs, noncoding RNAs, epigenetics, exosomes, and cancer stem cells. He has authored more than 140 scientific research or review articles, authored more than 20 book chapters, and edited or coedited 6 books. He is the Founding Editor‐in‐Chief of the journal Non‐coding RNA Research and serves as a Section Editor for the journal PLoS ONE. He is also the Editor‐in‐Chief of the Elsevier Cancer Metastasis series.

List of Contributors

Faisel M. Abu‐Duhier

Laboratory of Phytomedicine and Therapeutics

Prince Fahd Research Chair

Department of Medical Laboratory Technology

Faculty of Applied Medical Sciences

University of Tabuk

Tabuk, Saudi Arabia

Zeliha S. Akdemir

Department of Pharmacognosy

Faculty of Pharmacy

Hacettepe University

Ankara, Turkey

Amparo Alegría

Nutrition and Food Science Area

Faculty of Pharmacy

University of Valencia

Burjassot, Valencia, Spain

Aliye Aras

Department of Botany

Faculty of Science

Istanbul University

Istanbul, Turkey

Muhammad Arif

Faculty of Pharmacy

Integral University

Lucknow, Uttar Pradesh, India

Reyes Barberá

Nutrition and Food Science Area

Faculty of Pharmacy

University of Valencia

Burjassot, Valencia, Spain

Showket Hussain Bhat

Laboratory of Phytomedicine and Therapeutics

Prince Fahd Research Chair

Department of Medical Laboratory Technology

Faculty of Applied Medical Sciences

University of Tabuk

Tabuk, Saudi Arabia

Adelar Bracht

Post Graduate Program of Food Science

Universidade Estadual de Maringá

Maringá, Paraná, Brazil

Lindsay Brown

School of Health and Wellbeing and

Functional Foods Research Group

Institute for Agriculture and the Environment

University of Southern Queensland

Toowoomba, Queensland, Australia

Antonio Cilla

Nutrition and Food Science Area

Faculty of Pharmacy

University of Valencia

Burjassot, Valencia, Spain

Rúbia Carvalho Gomes Corrêa

Post Graduate Program of Food Science

Universidade Estadual de Maringá

Maringá, Paraná, Brazil

Vanesa Gesser Correa

Post Graduate Program of Food Science

Universidade Estadual de Maringá

Maringá, Paraná, Brazil

Abhijit Dey

Department of Life Sciences

Presidency University

Kolkata, India

Ammad Ahmad Farooqi

Institute of Biomedical and Genetic Engineering

Islamabad, Pakistan

Mohd Farhan

Department of Biochemistry

Faculty of Life Sciences

Aligarh Muslim University

Aligarh, Uttar Pradesh, India

Geetika Garg

Department of Biochemistry

University of Allahabad

Allahabad, Uttar Pradesh, India

S.M. Hadi

Department of Biochemistry

Faculty of Life Sciences

Aligarh Muslim University

Aligarh, Uttar Pradesh, India

Syed Misbah Hasan

Faculty of Pharmacy

Integral University

Lucknow, Uttar Pradesh, India

Carla Iacobini

Dipartimento di Medicina Clinica Molecolare

Università La Sapienza

Roma, Italy

Fyaz M.D. Ismail

Pharmacy and Biomolecular Sciences

Faculty of Science

Liverpool John Moores University

Liverpool, UK

Oliver John

School of Health and Wellbeing and

Functional Foods Research Group

Institute for Agriculture and the Environment

University of Southern Queensland

Toowoomba, Queensland, Australia

Cigdem Kahraman

Department of Pharmacognosy

Faculty of Pharmacy

Hacettepe University

Ankara, Turkey

Eloá Angélica Koehnlein

Department of Nutrition

Federal University of Southern Border

Campus Realeza‐PR

Realeza, Paraná, Brazil

Gabriel López‐García

Nutrition and Food Science Area

Faculty of Pharmacy

University of Valencia

Burjassot, Valencia, Spain

Jingyi Ma

Department of Clinical Pharmacology

Aerospace Center Hospital

Beijing, China

Sudatta Maity

Department of Life Sciences

Presidency University

Kolkata, India

Stefano Menini

Dipartimento di Medicina Clinica Molecolare

Università La Sapienza

Roma, Italy

Syed Mudassar

Department of Clinical Biochemistry

Sher‐I‐Kashmir Institute of Medical Sciences (SKIMS)

Srinagar, Jammu and Kashmir, India

Samapika Nandy

Department of Life Sciences

Presidency University

Kolkata, India

Sunil K. Panchal

Functional Foods Research Group

Institute for Agriculture and the Environment

University of Southern Queensland

Toowoomba, Queensland, Australia

Rosane Marina Peralta

Post Graduate Program of Food Science

Universidade Estadual de Maringá

Maringá, Paraná, Brazil

Carlo Pesce

Dipartimento di Neuroscienze, riabilitazione, oftalmologia, genetica e scienze materno‐infantili (DINOGMI)

Università di Genova

Genova, Italy

Muhammad Zahid Qureshi

Department of Chemistry

Government College University

Lahore, Pakistan

Syed Ibrahim Rizvi

Department of Biochemistry

University of Allahabad

Allahabad, Uttar Pradesh, India

Mirna Azalea Romero

Laboratorio de Investigación Clínica

Unidad Académica de Medicina

Universidad Autónoma de Guerrero

Acapulco, Guerrero, México

Aaliya Shah

Department of Clinical Biochemistry

Sher‐I‐Kashmir Institute of Medical Sciences (SKIMS)

Srinagar, Jammu and Kashmir, India

Uzma Shamim

Department of Biochemistry

Faculty of Life Sciences

Aligarh Muslim University

Aligarh, Uttar Pradesh, India

Abhishek Kumar Singh

Department of Biochemistry

University of Allahabad

Allahabad, Uttar Pradesh, India

Sandeep Singh

Department of Biochemistry

University of Allahabad

Allahabad, Uttar Pradesh, India

I. Irem Tatli

Department of Pharmaceutical Botany

Faculty of Pharmacy

Hacettepe University

Ankara, Turkey

Mohammad Fahad Ullah

Laboratory of Phytomedicine and Therapeutics

Prince Fahd Research Chair

Department of Medical Laboratory Technology

Faculty of Applied Medical Sciences

University of Tabuk

Tabuk, Saudi Arabia

Shazia Usmani

Faculty of Pharmacy

Integral University

Lucknow, Uttar Pradesh, India

Tatiane Francielli Vieira

Post Graduate Program of Food Science

Universidade Estadual de Maringá

Maringá, Paraná, Brazil

Lara Hanna Wakim

Faculty of Agricultural and Food Sciences

Holy Spirit University of Kaslik

Jounieh, Mount Lebanon, Lebanon

Xuelin Zhou

Department of Pharmacy

302 Military Hospital of China

Beijing, China

Foreword

Photo of professor Dr. Jan Frederik Stevens in an office sitting in front of a table.

This book contains a collection of review articles highlighting the potential and demonstrated health‐promoting effects of foods, natural products in foods, and their derivatives. While the research community has established that a diet rich in fruits and vegetables helps maintain health, large gaps in our knowledge still exist regarding the biological effects of individual food components. We know even less about the effects of their metabolites and derivatives. In the past, the focus has been primarily on the antioxidant effects of components naturally present in plant‐derived foods. In recent years, it has become increasingly clear that food components (in common with pharmaceuticals) can interact with molecular targets to regulate cell signaling, such as inflammation, and metabolism. While beneficial to the host to fight off infections, inflammation can be detrimental to human health when it persists chronically. Many basic science and clinical researchers are interested in mitigating chronic inflammation and dysregulated metabolism by dietary means, with the goal to prevent the early stages of a pathological condition from progressing into disease. Other investigators focus their research on developing naturally occurring chemicals as drugs to treat disease. The reader will find excellent examples, in 14 chapters, of either approach in this book.

In Chapter 1, researchers from the Universities of Genoa and Rome, Italy, discuss nutraceuticals and phytochemicals used in folk medicine for management of diabetes and metabolic syndrome. As a specific example, researchers from the University of Southern Queensland, Australia, review in Chapter 3 the broad‐spectrum effects of active principles in Garcinia fruit for mitigating metabolic syndrome. Diabetes and metabolic syndrome are also the focus of Chapter 8, specifically how phenolic acids, catechins, and methylxanthines from yerba mate can influence dysregulated metabolism in these abnormal physiological conditions.

Whey protein–derived sulfur‐containing amino acids and a cellular antioxidant, glutathione, are the topic of Chapter 2, in which researchers from the University of Allahabad, India, make a case that intake of sulfur‐containing proteins might offer protection against metabolic and neurodegenerative diseases. In Chapter 9, pharmaceutical scientists from the University of Hacettepe, Ankara, Turkey, review the redox properties of secondary metabolites from Verbascum, Scrophularia, and Buddleja species and how they may retard or halt the initiation and progression of neurodegenerative diseases. Alzheimer's disease, with its various pathologies and potential targets for treatment with plant secondary metabolites, is discussed in the following Chapter 10, contributed by researchers from Presidency University, India.

Angiogenesis, or the formation of new blood vessels, has long been recognized as a target for therapies aimed against tumorigenesis and metastasis. In Chapter 4, Beijing hospital researchers summarize the effects of naturally occurring polyphenols, alkaloids, and terpenoids in cell culture and animal models of angiogenesis.

In Chapter 5, investigators from the University of Tabuk, Saudi Arabia, argue that nature's enormous chemical diversity offers endless opportunities for discovery and development of natural products that can prevent, ameliorate, or treat cancer, diabetes, and neurodegenerative diseases. Honeybees take nature's chemical diversity home to their beehives in the form of honey, propolis, pollen, and wax. In Chapter 6, an international group of researchers describes the pharmacological effects of honey and propolis on the regulation of protein networks in cancer cells. In Chapter 7, researchers from the University of Valencia review the antiproliferative and apoptotic effects of phytosterols, an understudied group of natural products, in cultured breast, prostate, and colon cancer cells. The cancer‐related properties of green tea polyphenols, specifically those of the catechin type, are discussed in Chapter 12. The authors of this chapter propose that the cancer‐related properties of these flavanols can be attributed to a copper‐dependent pro‐oxidant effect, resulting in death of the cancer cell. In Chapter 14, researchers from SKIMS (Sher‐i‐Kashmir Institute of Medical Sciences), Srinagar, India, outline the studies that relate the benefits of fruits and vegetables in hepatopathological conditions.

In Chapter 11, Shazia Usmani from Integral University, India, discusses the use and formulation of metals in Ayurvedic medicine from a therapeutic and toxicological perspective. Extending the significance of natural products to the realm of infectious diseases, in Chapter 13, Fyaz Ismail from Liverpool John Moores University, UK, describes several natural and semisynthetic drug candidates for malarial infections, focusing on different geographical regions worldwide.

The collection of chapters spans a wide range of highly complementary topics with minimal overlap. This book will be a useful resource for researchers interested in herbal medicine and pharmacognosy at all career stages. I congratulate the editors, Drs. Ullah and Ahmad, for recruiting a group of diverse contributors, all experts in their chosen subjects, from all over the world.

March 2018

Dr. Jan Frederik Stevens, Professor

Linus Pauling Institute & College of Pharmacy,

Oregon State University, Corvallis, Oregon, USA

Preface

The burden of chronic diseases in the human population has increased exponentially ever since the beginning of recorded history. Despite advancements in modern diagnostic and therapeutic paradigms, the projected global rates of incidence of these diseases, including cancer, diabetes, and neurodegenerative disorders, and the associated mortality for future decades display many challenges and poor outcomes. Rejuvenated interest in the natural product pharmacology in the last two decades has been partially based on the fact that some of the most effective drugs in clinical practice are derivatives of natural products. It is known that over the centuries, human civilizations have acquired sophisticated knowledge of disease cures from sources derived from their environment, and this perhaps represents natural product–based traditional and complementary medicine worldwide. The advent of synthetic chemistry and combinatorial approaches has indeed revolutionized the drug development premises. However, this has also impeded interest in the natural products that have in the past served as an enormous repository of bioactive compounds. The huge diversity in chemical structures of natural products provides inexhaustible potential as leads in drug discovery. This book, Nutraceuticals and Natural Product Derivatives: Disease Prevention and Drug Discovery, is an attempt to archive a few such ideas in the scientific and public domains. We commend John Wiley & Sons for providing the platform for this endeavor and entrusting us with the task of managing, compiling, and editing the current volume that we present before the audience.

Precisely, the volume contains an expert commentary that is followed by 14 chapters, each focusing on the significance of natural products in disease prevention. The expert commentary provides an excellent presentation of the concept that is important to understanding the relevance of natural products. Chapter 1, Natural Food Sources for the Control of Glycemia and the Prevention of Diabetic Complications, deals with the vast literature that has appeared in the last decade on specific food nutrients with purported beneficial effects to prevent type 2 diabetes and its microvascular and macrovascular complications. Chapter 2, Anti‐Aging Effect of Sulfur‐Containing Amino Acids and Nutraceuticals, focuses on proteins rich in L‐cysteine as redox modulators during age‐associated diseases and the possibility of future strategies employing sulfur‐containing amino acids in intervention to treat multiple metabolic and neuronal diseases. Chapter 3, "Garcinia Fruits: Their Potential to Combat Metabolic Syndrome," discusses the potential of the bioactive compounds found in Garcinia species as therapeutic candidates for metabolic syndrome. Chapter 4, Pro‐Angiogenic and Anti‐Angiogenic Effects of Small Molecules from Natural Products, describes recent research findings on pro‐ and anti‐angiogenic effects of small molecules from nutraceuticals and natural products by modulating key factors in cell proliferation, migration, invasion, and assembly. Chapter 5, Nutraceuticals and Natural Product Derivatives in the Premises of Disease Prevention, presents an overview of the therapeutic significance of natural products in chronic diseases, including cancer, diabetes, gout, and neurodegenerative disorders. Chapter 6, Honey and Propolis‐Mediated Regulation of Protein Networks in Cancer Cells, summarizes most recent evidence related to anticancer activities of honey and propolis and how these amazingly effective products modulate different proteins in cancer cells to inhibit or prevent cancer. Chapter 7, Antiproliferative Effects and Mechanism of Action of Phytosterols Derived from Bioactive Plant Extracts, reviews the activity of plant extracts containing phytosterols, or isolated phytosterols obtained from plant extracts, upon breast, prostate, and colon cancer. Chapter 8, "Yerba Mate ( Ilex paraguariensis A. St. Hil.): A Promising Adjuvant in the Treatment of Diabetes, Obesity, and Metabolic Syndrome, reports on the beneficial actions of yerba mate, known to be rich in phenolic acids and used in different kinds of beverages, as an adjuvant in the treatment of diabetes, obesity, and metabolic syndrome. Chapter 9, Role of Natural Antioxidants from Selected Plants Belonging to the Scrophulariaceae and Buddlejaceae Families in the Prevention and Treatment of Neurodegenerative Diseases," describes Verbascum, Scrophularia, and Buddleja species used in traditional medicines and relates their significance in oxidative stress and neurodegenerative disorders. Chapter 10, Recent Trends in Drug Discovery against Alzheimer's Disease: Use of Natural Products and Nutraceuticals from Botanicals, discusses the underlying mechanism of disease onset along with therapeutic effects of different phytochemicals and traditional herbal formulations in both crude and synergistic forms. Chapter 11, Therapeutic Potential of Metallo‐Herbal Nanoceuticals: Current Status and Future Perspectives, describes the metallo‐herbal formulations of ancient Indian Ayurvedic medicine and their implications in alternative therapies. Chapter 12, Green Tea Polyphenols: A Putative Mechanism for Cytotoxic Action against Cancer Cells, discusses a copper‐dependent pro‐oxidant mechanism of action of green tea polyphenols that accounts for their observed chemopreventive properties. Chapter 13, Nature's Armamentarium against Malaria: Antimalarials and Their Semisynthetic Derivatives, focuses on the putative sources of new drugs or prototypes from plant sources with antiplasmodial activity. Chapter 14, Nutraceutical‐Based Pharmacological Intervention in the Management of Liver Diseases, describes dietary natural products as key elements for prevention and treatment of liver diseases.

We express our gratitude to all the authors for valuable contributions from around the globe. It is indeed their willingness to share their onerous experiences that has facilitated this piece of scientific literature. We appreciate the support of Ms. Mindy Okura‐Marszycki (Senior Acquisitions Editor) for working out the procedural framework of our book proposal. Fortunately, we had Ms. Kshitija Iyer and Mr. Antony Sami (Project Editors), Priya Subbrayal (Production editor), who were instrumental in ensuring the required basics of attractive and meaningful academic production. We are indeed honored to have Professor Fred Stevens introducing the substance of the book in the foreword.

Lastly, we wish that the audience will like the content of this book and that this book will, as desired, serve as a promising literature for inspiring researchers who intend to explore the vast armamentarium of natural products for disease prevention and drug discovery.

Mohammad Fahad Ullah, Saudi Arabia

Aamir Ahmad, USA

About the Book

An impressive collection of preclinical and clinical data, along with epidemiological and dietary intervention studies in literature, has accumulated over the years showing the therapeutic potential of natural products and dietary nutraceuticals against a number of chronic diseases, including cancer, diabetes, neurodegenerative disorders, and a multitude of metabolic diseases. A number of action mechanisms have been reported for these naturally derived agents to retard, block, or reverse the diseased states. The current global burden of most of these chronic diseases serves as a major socioeconomic challenge for nations worldwide. It has been observed that the rates of both incidence and mortality associated with these diseases will increase manifold in the coming decades, thus further impeding the efforts to improve public health and its socioeconomic impact on the human population globally.

Natural products refer to chemical substances found in nature and represent an armamentarium of pharmacologically active agents with distinctive abilities to serve as novel lead compounds or pharmacophores in drug discovery. Nutraceuticals are constituents of the human diet with observed health benefits in humans. An assessment of all US Food and Drug Administration (FDA)‐approved new molecular entities (NMEs) reveals that natural products and their derivatives represent over one‐third of all NMEs. According to an analysis, of all the 175 small molecules approved for cancer therapy from the 1940s to the year 2014, 85 (49%) were natural products or directly derived therefrom. Therefore, natural products and nutraceuticals appear to hold a significant place in the domain of drug discovery and design. Furthermore, the clinical potential of these agents might also be exploited as adjuvant therapy in the management of chronic diseases along with conventional treatment to enhance the clinical outcome.

This book presents a prophylactic and therapeutic approach to primary prevention of chronic diseases by highlighting the translational potential of natural products and nutraceuticals from epidemiological, laboratory, and clinical studies. The volume shares the experiences of highly reputed experts working in the area of natural products and disease prevention, to promote the significance of natural product derivatives and nutraceuticals in containing the chronic diseases in the human population.

Expert Commentary: Dietary Factors and Natural Product Derivatives in Cancer Therapy

Summary

Several natural dietary factors possess potent anticancer activity. Since cancer remains a leading cause of death in the USA, these factors have been a subject of intense investigational interest for many years. They are generally nontoxic, inexpensive, and pleiotropic. However, they are also less bioavailable. Current research involving natural dietary anticancer compounds and their derivatives strives to strike a balance between their beneficial properties and the shortcomings, and this remains the focus of this commentary.

Introduction

Natural products have traditionally played a significant role in the drug discovery process [1]. This is particularly true for anticancer drugs, for which it is estimated that over a period of approximately 74 years (from the 1940s to 2014), 49% of all US Food and Drug Administration (FDA)‐approved drugs were either direct natural products or their derivatives [1]. This clearly underlines the importance of natural products in our fight against cancer. These natural anticancer agents afford multiple advantages, the foremost being that many natural agents are part of the normal human diet and are therefore well tolerated. This brings us to an important point of recognition that a number of anticancer agents that are part of the human diet, and hence termed dietary factors, have a natural origin (i.e. they are found in fruits, vegetables, spices, etc.). However, it is important to recognize that many natural anticancer compounds are not part of normal human diets; rather, they are just found in nature. Such nondietary anticancer compounds also fit into the class of natural anticancer agents [2, 3]. For the purpose of discussion here, we will limit ourselves to just those anticancer compounds that are natural as well as part of the human diet (i.e. dietary anticancer compounds).

Screening for Novel Anticancer Drugs of Natural Origin

Nature happens to be an excellent source of drugs, including those helping us fight cancer [4, 5]. Therefore, there has been a visible interest in screening the enormous number of natural compounds and chemical structures with putative anticancer activity. A number of approaches for the screening of natural anticancer compounds are available; these include in silico modeling [4], mathematical modeling [6], and so on. Such screening has resulted in testing of several natural agents in clinical trials [2]. However, despite all the screening and the often encouraging preclinical data, a majority of anticancer drugs fail in clinical trials [7, 8]. On an optimistic note, though, it is recognized that only a small fraction of natural resources (mostly plants) has been explored for bioactive compounds that can serve as anticancer agents [9], and thus there is scope for so much more to be done.

Dietary Anticancer Drugs: Promises and Challenges

As mentioned, dietary anticancer compounds are well tolerated, as supported by evidence from clinical trials involving several dietary anticancer compounds that were documented to be well tolerated at the doses administered [9]. This is critical, given the known toxicity associated with most anticancer regimens that do not have a natural origin [10]. While the nontoxic nature of dietary anticancer compounds is desirable, it comes at its own price. These compounds have lower bioavailability [11]. They are usually cleared by the body very efficiently, and this is often blamed for the poor outcomes in clinical trials [12].

A number of strategies have been proposed to overcome the issue of bioavailability associated with natural anticancer compounds, with primary focus on novel formulations to sustain systemic circulation and decrease turnover [13–16]. Synthesis of chemical derivatives or analogs is one such strategy that has been shown to significantly improve the bioavailability of natural anticancer compounds [17–19]. Interestingly, of the natural compounds used as anticancer drugs, it is estimated that half of them are direct natural compounds while the rest are their derivatives [9]. Clearly, the derivatives of natural anticancer compounds have their own unique place in cancer therapy. They not only improve the bioavailability but also are often reported to be significantly more active than their parent compounds [17, 19].

Another unique feature of natural compounds and their derivatives as anticancer agents is their ability to act on multiple targets (i.e. their pleiotropic nature) [15]. Molecularly targeted therapies that act against uniquely defined oncotargets are effective initially as they inhibit their molecular target, often leading to tumor remission. However, in a majority of cancer patients, tumor cells shift their dependency from the targeted molecule to an alternate signaling molecule or pathway [20]. In the face of adverse conditions, cancer cells reprogram their metabolism [21]. All this results in activation of parallel and/or alternative pathways of survival and proliferation, thus rendering the targeted therapy ineffective. In such a scenario, pleiotropic natural compounds can still be effective anticancer drugs by virtue of their simultaneous targeting of multiple, and often several, major oncogenic pathways.

The past several years have witnessed a shift toward personalized or precision medicine because of the realization that tumors, and probably cancer patients, are extremely heterogeneous [22, 23]. This calls for molecular characterization of cancer patients to develop tailored therapies that individual patients are most likely to benefit from. Interestingly, a role of natural anticancer compounds in such personalized cancer therapy has been advocated [24, 25]. In modern‐day cancer research, cancer stem cells, noncoding RNAs, and epigenetic alterations are being investigated as novel targets for therapy. Natural products, which were initially investigated as anticancer drugs because of their antioxidant and anti‐inflammatory properties and their ability to modulate cellular signaling, have evolved with time to now being investigated as agents that can inhibit cancer stem cells [15, 17, 26] and modulate noncoding RNAs as well as epigenetic events [15, 27].

Conclusions

Anticancer drugs of natural origin have been a focus of numerous investigations for several decades. Despite setbacks, such as low bioavailability and disappointing outcomes in several clinical trials, the interest in them has never faded. They keep coming back as modulators of key physiological phenomena that emerge as hot topics in cancer research. The pleiotropic ability of natural anticancer drugs to simultaneously affect multiple molecules and pathways is one key reason for their success. Additionally, derivatives and analogs of natural compounds have shown promise in their collective ability to fight cancer. Even though a great deal of information has been made available, our knowledge of precise mechanistic insights into the detailed anticancer activity of natural agents remains far from complete. It is important that the success witnessed in preclinical studies is translated to benefit scores of cancer patients.

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27 Yang, A.Y., Kim, H., Li, W. et al. (2016). Natural compound‐derived epigenetic regulators targeting epigenetic readers, writers and erasers. Curr. Top. Med. Chem. 16: 697–713.

1

Natural Food Sources for the Control of Glycemia and the Prevention of Diabetic Complications

Carlo Pesce¹Carla Iacobini² and Stefano Menini²

¹ Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno‐Infantili (DINOGMI), Università di Genova, Genova, Italy

² Dipartimento di Medicina Clinica Molecolare, Università La Sapienza, Roma, Italy

1.1 Introduction: Obesity, Metabolic Syndrome, and Type 2 Diabetes Epidemics: The Role of Nutrition

Over the last 50 years, people have experienced drastic changes in their living environment, behavior, and lifestyle. These changes have led to an alarming increase in the incidence of type 2 diabetes, overweight, and frank obesity [1]. The replacement of human labor with automation, increased consumption of empty calories, globalization of technology, and improvement in transportation are some of the factors that have led to this sad state of affairs [2]. A study on the prevalence of obesity, carried out by the World Health Organization (WHO) and the International Obesity Task Force, found that the worldwide prevalence of overweight individuals, after adjusting for ethnic differences, was 1700 million, of which 312 million were obese [1, 3]. Data from successive cohorts of the National Health and Nutrition Examination Survey [4] show that the average waist circumference of adults in the USA increased progressively from 95.5 cm in 1999–2000 to 98.5 cm in 2011–2012. The same study reported that prevalence of abdominal obesity increased significantly from 46.4% in 1999–2000 to 54.2% in the same period of observation. Of note, over the past 20 years, prevalence rates for obesity have tripled in those developing countries that have adopted western lifestyles [1], including reduced physical activity and overconsumption of high‐calorie meals. Accordingly, obesity is now considered one of the greatest health threats in the world, for it is the major risk factor of a wide range of noncommunicable disease and, particularly, type 2 diabetes [1, 3].

Today, the extent of the type 2 diabetes epidemic is growing worldwide, in both developed and emerging countries. WHO reports that the number of people with diabetes has almost quadrupled in a quarter of a century, from 108 million in 1980 to 422 million in 2014, that is, from 4.7% to 8.5% of the general population. Prevalence of diabetes has risen even more rapidly in middle‐ and low‐income countries (http://www.who.int/mediacentre/factsheets/fs312/en), an alarming trend that represents a major burden for public health systems worldwide. WHO estimated that 1.6 million deaths worldwide were directly linked to diabetes in 2015 (http://www.who.int/mediacentre/factsheets/fs312/en). The control of diabetes, a major risk factor for vascular diseases, is crucial for the prevention of debilitating and life‐threatening conditions such as kidney failure, blindness, stroke, heart attacks, and lower limb complications [5]. Vascular complications are among the most serious manifestations of type 2 diabetes. Atherosclerosis is the main factor limiting life expectancy; retinopathy and diabetic nephropathy (DN) cause blindness and end‐stage renal disease [5]. The most efficacious approach to prevent vascular complications of diabetes includes strict blood glucose control with antidiabetic drugs and/or insulin, antihypertensive treatment, and statin administration to decrease cholesterol levels. Despite current therapeutic advances, diabetes complications are a persistent concern because keeping blood glucose in check, which is effective to delay the onset of nephropathy and retinopathy, is less effective at reducing diabetes‐associated cardiovascular disease [6]. Therefore, identification of novel therapeutic approaches for diabetes, obesity, metabolic syndrome, and their vascular complications is an enthusiastic area of research.

Lifestyle adjustment is a key point for treatment of type 2 diabetes, metabolic syndrome, and obesity [7], which result from a predisposing genetic background exacerbated by an unhealthy lifestyle, namely sedentary behavior and poor diet quality. The crucial step is weight loss, which is associated with numerous beneficial effects, including lipid profile improvement, reduction of glucose and inflammation marker levels, and normalization of blood pressure and left ventricular mass. The combined long‐term gain of these changes is abatement of the diabetes‐associated death risk and, in obese subjects and in patients with metabolic syndrome, delayed progression to type 2 diabetes [8, 9]. Both exercise and diet correction contribute to reduction and maintenance of body weight [10], which is associated with improvement of all manifestations of metabolic syndrome and reduction of incidence of vascular complications [11]. In particular, diet interventions can help prevent the onset and progression of cardiometabolic disorders and DN [12].

The diet composition can also affect vascular health through the protective effects provided by specific food components. Besides well‐established general recommendations, such as restricting intake of fat of animal origin; increasing servings of fruits, vegetables, and fiber‐rich cereals; avoiding industrially processed foods; and increasing the protein fraction of white meat and fish, a major area of discussion today is supplementing the diet with functional foods. These sources provide nutraceuticals with antiglycemic, anti‐inflammatory, antioxidant, and additional protective effects for metabolic disorders and diabetic vascular complications [13]. Our chapter deals with the vast literature that has appeared in the last decade on specific food nutrients with purported beneficial effects to prevent diabetes and its microvascular and macrovascular complications, including nephropathy, retinopathy, ischemic heart disease, and cerebrovascular disease.

1.2 Phytochemicals of Nutraceutical Importance and Functional Foods of Plant Origin

1.2.1 Dietary Oils

Considerable attention has been paid in recent decades to the possible beneficial effects of olive oil, especially that of extra‐virgin grade – one of the three pillars, with cereals and grapes, of the Mediterranean diet. In an experimental setting with mice fed a high‐fat (lard) diet, extra‐virgin olive oil substitution for lard improved plasma lipid profile, and it reduced body weight; plasma and epidydimal‐fat interferon‐γ (INFγ), interleukin‐6 (IL6), and leptin levels; and macrophage infiltration [14]. The positive effects of extra‐virgin olive oil are ascribed to its polyphenol compounds content, which has antioxidant properties. A possible confirmation of the popularity of the Mediterranean diet is the steady rise in olive oil consumption in Central and Northern Europe.

Olive oil supplement administered to healthy volunteers from Scotland led to a significant improvement in the proteomic coronary artery disease score change; both normal and extra‐virgin olive oils were related to positive changes in the urinary proteomic biomarkers and other indicators such as triacylglycerols, oxidized low‐density lipoprotein (LDL), and LDL cholesterol [15]. In the clinical setting, the effects of a polyphenol‐rich extra‐virgin olive oil on the metabolic control and the production of specific pro‐ and anti‐inflammatory adipokines were evaluated in overweight patients with type 2 diabetes mellitus. This diet reduced fasting plasma glucose levels, body mass index (BMI), and body weight, and it lowered serum levels of aspartate aminotransferase and alanine aminotransferase [16].

Non‐olive vegetable oils have also been investigated. Canola oil was administered as a food supplement to diabetic Sprague–Dawley rats, which were less hyperphagic and retained more adipose tissue than diabetic rats on an unsupplemented diet. The canola oil–supplemented diet decreased plasmatic concentrations of free fatty acids, triglycerides, and cholesterol, and it showed improved osmolarity, water clearances, and creatinine depuration [17]. Another study on canola oil and rice bran oil was performed clinically with 75 postmenopausal women with type 2 diabetes. Patients with canola oil and rice bran oil supplementation showed decreases in triglyceride, total cholesterol, and LDL cholesterol concentration in comparison with the control patient group [18].

1.2.2 Vegetables and Fruits

Ellagic acid, the dilactone of hexa‐hydroxy‐diphenic acid, is a natural phenol antioxidant found in oak species and in several edible fruits such as berries, pomegranates, walnuts, and pecan nuts. In diabetic rats administered ellagic acid supplement for 16 weeks, activation of renal nuclear factor‐κB (NFκB), a major mediator of the inflammation associated with diabetes, was significantly inhibited. Kidney lesions were reduced; tissue with transforming growth factor‐β (TGFβ) and fibronectin expression was suppressed. In tubular cell cultures, ellagic acid also inhibited high‐glucose‐induced activation of NFκB and proinflammatory cytokine synthesis. In summary, ellagic acid exhibits renal‐protective effects in the experimental setting through anti‐hyperglycemic activity and attenuation of inflammation [19].

Several fruits have been hypothesized to exert positive properties against diabetes, often – again – as indicated by folk medicine and local traditions. The role of commonly used spices, such as cinnamon, for prevention and management of diabetes and associated complications is a booming area of investigation. Cinnamic acid is common in plants and can be found with its derivatives in numerous plant‐based foods. These substances show a positive effect on diabetes and its complications on account of different mechanisms of action, including stimulation of insulin secretion, improvement of pancreatic β‐cell functionality, inhibition of hepatic gluconeogenesis, enhanced glucose uptake, increased insulin signaling pathway, delay of carbohydrate digestion and glucose absorption, and inhibition of protein glycation and insulin fibrillation. Diabetic rats were fed either 3% cinnamon (Cinnamomum zeylanicum) or 0.002% procyanidin‐B2, the active component of cinnamon that inhibits advanced glycation end‐products (AGEs) formation in vitro. Both types of supplementation prevented glycation‐mediated erythrocyte–immunoglobulin G (IgG) crosslinks, as well as accumulation of hemoglobin A1c (HbA1c) and iN‐carboxy methyl lysine. Loss of expression of the glomerular podocyte proteins, podocin and nephrin, was also prevented [20].

Cyanidin is a natural anthocyanidin present in fruits (especially berries) and vegetables, which shows antidiabetic properties including stimulation of insulin secretion. Stimulation of pancreatic β cells with cyanidin, which diffuses across the plasma membrane, activates insulin secretion, for it leads to activation of nimodipine, an l‐type voltage‐dependent Ca² channel blocker. The increase in intracellular Ca² stimulated insulin secretion and the expression of genes involved in this process [21]. Red raspberries have been fed to obese diabetic mice, with improved antioxidant status and lessened plasma IL6. However, plasma levels of total cholesterol, LDL cholesterol, and resistin increased. The authors hypothesize that the enhanced detoxifying cell defenses exerted by raspberry intake might be due to its polyphenolics and fiber [22].

A standardized delphinidin‐rich extract from maqui berry as a supplement was evaluated in prediabetic humans based on glycemia and insulinemia curves obtained from an oral glucose tolerance test. Glycemia peaks were dose‐dependently lowered, while insulinemia peaks were higher for the lowest dose and lower for other doses [23]. The effects of pomegranate juice and seed powder on the levels of plasma glucose and insulin, inflammatory biomarkers, lipid profiles, and health of the islets of Langerhans were studied in streptozotocin‐induced diabetes in Sprague–Dawley rats. Active constituents with high antioxidant properties present in pomegranate are responsible for its anti‐hyperlipidemic and anti‐inflammatory effects, and for restoration of the damaged islets of Langerhans [24]. The alkekengi calyx includes polysaccharides that have shown the potential to prevent loss of body weight in diabetic mice and decrease of fasting blood glucose and glycated serum protein, with increase of fasting serum insulin in a dose‐dependent manner. These polysaccharides can protect and reverse β cells of the pancreas from necrosis following alloxan administration in mice [25, 26].

The properties of safranal, an organic compound isolated from the stigmas (saffron) of crocus flowers (Crocus sativus), were investigated in diabetic rats. After four weeks of diet supplementation, safranal‐receiving diabetic rats had reduced blood urea nitrogen (BUN) and creatinine levels in comparison with controls. In the renal tissue, safranal exhibited both anti‐inflammatory and antioxidative properties, which were confirmed by significant changes in total antioxidant capacity, total oxidant capacity, oxidative stress index, and tumor necrosis factor‐α (TNFα), IL1β, IL18, and interferon‐γ (IFNγ) levels [27]. Berberine, a traditional dye and a remedy in Chinese folk medicine, is a salt of the protoberberine group of isoquinoline alkaloids, which is found in Berberis plants, such as tree turmeric, Oregon grape, and barberry. Diabetic rats undergoing berberine administration by gavage for 20 weeks showed significant reduction of glucose and lipids, reduced albuminuria, and milder DN microscopic lesions. Berberine‐induced inactivation of NFκB was related to blockage of pro‐inflammatory cytokines; also, its inactivation of the TGFβ/Smad3 signaling pathway reduced expression of fibrosis determinants, such as fibronectin, collagen I, and collagen IV [28]. Aged garlic extract reduced blood glucose and the plasma levels of glycated albumin in Tsumura Suzuki obese diabetes (TSOD) mice. Treatment also suppressed the messenger RNA (mRNA) expression of fatty acid synthase and monocyte chemoattractant protein‐1 [29].

Purple corn, which is rich in anthocyanins, decreased expression of endothelial vascular cell adhesion molecule‐1, E‐selectin, and monocyte integrin‐ß1 and ‐ß2 through blocking the mesangial Tyk2 pathway in human endothelial cells and THP1 monocytes cultured in conditioned media exposed to 33 mM glucose. In the glomeruli of diabetic kidneys, purple corn extract attenuated induction of intracellular cell adhesion molecule‐1 and CD11b. It also decreased monocyte chemoattractant protein‐1 expression and macrophage inflammatory protein‐2 transcription in the kidney [30]. Grape seed pro‐anthocyanidin extracts were administered to rats with a high‐carbohydrate, high‐fat diet and streptozotocin. Inflammation in the aortic intima and media, as well as receptor of AGE expression, assessed through histology and immunohistochemistry, were lower in the animals treated with grape seed extract. These results were corroborated by in vitro evaluation of intercellular adhesion molecule‐1 (ICAM1) and vascular cell adhesion molecule‐1 activity [31]. Another experimental study showed that grape powder reduced blood glucose levels following oral glucose gavage after glucagon‐like peptide‐1 (GLP1) receptor antagonism by exendin‐3 [32].

Yam (Dioscorea cayenensis) or dasheen (Colocassia esculenta), two dietary staples in the Caribbean, a region where diabetes and DN show high prevalence, were added to the normal diet of diabetic rats. Either vegetable raised malic enzyme activity, which decreased in diabetic controls, to almost normal values; alanine transaminase levels in the kidneys of diabetic rats fed yam extract were significantly higher than in healthy controls. Since dasheen extract lowered nicotinamide adenine dinucleotide phosphate (NADP+) isocitrate dehydrogenase activity, yam and dasheen supplementation has been postulated to aggravate diabetes [33]. Rats fed a standard American Institute of Nutrition (AIN)‐76 diet with a 5% supplement of banana flower or pseudostem had reduced synthesis of extracellular mesangial components, such as laminin, fibronectin, and collagen IV, as well as the glucose transporters protein kinase C‐α (PKCα) and TGFß in the kidney tissue [34]. The positive effects on diabetes of Stevia rebaudiana, an herb used for centuries in traditional medicine in Brazil, were studied experimentally in different groups of diabetic rats using the whole plant as a diet supplement, or the extracted polyphenols or the herb fibers. Not only did the whole plant and its extracted polyphenols induce reduction in blood glucose and increments of insulin levels, but they also improved progression of glomerulosclerosis [35]. Kidney function in diabetic rats improved with supplementation of green tea catechin because of its antithrombotic action. Two groups of diabetic rats fed catechin (0.25% and 0.5%, respectively) for four weeks were injected with streptozotocin. Catechin administration induced a decrease in thromboxane A2 and an increase in prostacyclin synthesis, the amount of which was related to the dosage. Furthermore, the glomerular filtration rate (GFR) was maintained with diabetes, and ß2‐microglobulin content increased significantly less than in controls [36].

Monascus purporeus (red yeast rice) is a mold used in China in the preparation of different fermented foods and in traditional medicine. When Monascus‐fermented rice was administered to diabetic rats as a diet supplement, it decreased glycemia and HbA1c. In addition, there was a significant increase in antioxidant levels in the kidney [37]. Abelmoschus esculentus (okra), a common vegetable reported to possess many important biological properties, has been administered as extract for 35 days to male Wistar