Preview PDF

Handbook of Nutraceuticals
and Functional Foods

Third Edition
Handbook of Nutraceuticals
Third Edition
Edited by
Robert E.C. Wildman
Richard S. Bruno
CRC Press
Taylor & Francis Group
6000 Broken Sound Parkway NW, Suite 300
Boca Raton, FL 33487-2742
© 2020 by Taylor & Francis Group, LLC

CRC Press is an imprint of Taylor & Francis Group, an Informa business
No claim to original U.S. Government works
Printed on acid-free paper
International Standard Book Number-13: 978-1-4987-0372-7 (Hardback)
This book contains information obtained from authentic and highly regarded sources. Reasonable efforts have been
made to publish reliable data and information, but the author and publisher cannot assume responsibility for the
validity of all materials or the consequences of their use. The authors and publishers have attempted to trace the
copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to
publish in this form has not been obtained. If any copyright material has not been acknowledged please write and let
us know so we may rectify in any future reprint.
Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or
utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including pho-
tocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission
from the publishers.
For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://
www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA
01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users.
For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been
arranged.
Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for
identification and explanation without intent to infringe.
Visit the Taylor & Francis Web site at
http://www.taylorandfrancis.com
and the CRC Press Web site at
http://www.crcpress.com
To Amber, Gage, & Bryn for your daily support and love as well as
Carol, Dave, & David for eternal inspiration! – Rob
To Jenny, William, and Olivia – their support and
love inspire me each and every day. – Rich
Additional Support
The editors would like to thank Brett Hanna for his contribution.
Contents
Preface...............................................................................................................................................ix
Editors................................................................................................................................................xi
Contributors.................................................................................................................................... xiii
Unit I Overview of Nutraceuticals and Functional Foods
Chapter 1 Nutraceuticals and Functional Foods............................................................................3

Robert E.C. Wildman
Chapter 2 Regulation of Nutraceuticals and Functional Foods................................................... 23

Rick Collins, Esq., Jay Manfre, Esq., and Robert E.C. Wildman
Unit II Plant-Derived Nutraceuticals
Chapter 3 Lycopene: Food Sources, Properties, and Effects on Human Health......................... 37

Jessica L. Cooperstone
Chapter 4 Lutein in Neural Health and Disease.......................................................................... 55

Amy C. Long and Amy D. Mackey
Chapter 5 Garlic: Chemistry, Function, and Implications for Health and Disease..................... 75
Sharon A. Ross and Craig S. Charron
Chapter 6 The Role of Tocopherols in Health........................................................................... 105

Richard S. Bruno
Chapter 7 Health Benefits of Green Tea.................................................................................... 127

Priyankar Dey, Geoffrey Y. Sasaki, and Richard S. Bruno
Chapter 8 Scientific, Legal, and Regulatory Considerations for Cannabidiol........................... 147

Jay Manfre, Esq., Rick Collins, Esq., Marielle Kahn Weintraub,
and Robert E.C. Wildman
Chapter 9 Coffee as a Functional Beverage............................................................................... 159

Victoria Burgess, Lem Taylor, and Jose Antonio
vii
viii Contents
Chapter 10 Dietary Fiber and Coronary Heart Disease.............................................................. 173

Thunder Jalili, Eunice Mah, Denis M. Medeiros, and Robert E.C. Wildman
Chapter 11 Anthocyanins and Their Health Benefits.................................................................. 189

Justin G. Martin, Gary D. Stoner, and Jairam K.P. Vanamala
Chapter 12 Olive Oil and Health Benefits................................................................................... 211

Denis M. Medeiros and Meghan Hampton
Chapter 13 Nutraceutical Herbs and Insulin Resistance............................................................. 223

Giuseppe Derosa and Pamela Maffioli
Unit III Food Nutraceuticals from Animals
Chapter 14 Protein as a Functional Food Ingredient for Optimizing Weight Loss

and Body Composition.............................................................................................. 245
Paul J. Arciero, Michael J. Ormsbee, Robert E.C. Wildman,
and Donald K. Layman
Chapter 15 Nutraceutical Application of Creatine....................................................................... 267

Richard B. Kreider, Douglas S. Kalman, Jose Antonio, Tim N. Ziegenfuss,
Robert E.C. Wildman, Darren G. Candow, and Chad M. Kerksick
Chapter 16 Chicken Eggs and Human Health............................................................................. 295

Jonathan Merkle, Christopher Bailey, and Kevin Ruff
Chapter 17 Dairy Milk: A Functional Beverage for Human Health...........................................307

Joshua D. McDonald and Richard S. Bruno
Index............................................................................................................................................... 325
Preface
The field of functional foods, and by association their bioactive food components, is a booming
area of nutrition. This area was relatively unknown in the second half of the twentieth century, with
only a few thousand total publications during this period, but then experienced exponential growth
around the turn of the twenty-first century and now continues to flourish, with nearly 5000 scientific
publications on an annual basis. It is difficult to imagine a more exciting field of nutrition research,
education, and general health promotion.
Investigative opportunities are clearly endless. Large-scale epidemiological studies routinely

identify health-promoting relationships with intakes of specific functional foods and the bioactive
food components. These works have provided the foundational support for hypothesis-driven
research at the cellular level, in animal models, and even controlled interventions in humans. Not
only does the complement of these studies appear in the peer-reviewed literature, but knowledge is
also disseminated rapidly across the globe through consumer publications and the entirety of the
Internet. While the advent of many investigative techniques occurred in the latter half of the twentieth
century to support the study of other critical areas of the nutrition field, the field of functional foods
has not only prospered by these tools but also advances in experimental tools that permit detailed
scientific inquiry. These advances have allowed scientists to objectively investigate some of the
most ancient concepts in the application of foods as well as epidemiological relationships related to
optimizing health and performance and the prevention and/or treatment of diseases.
Throughout the twentieth century, nutrition recommendations often had a connotation of
focusing on “what not to eat” and obtaining adequate dietary intakes of nutrients to prevent
nutrition deficiency. For example, many recommendations focused on reducing intakes of sodium,
saturated fat, cholesterol, and in some cases avoiding certain foods such as eggs. Today, there has
been continued shift in focus to “what to eat” as the basis of many nutrition messages of public
health importance. What remains clear over the past few decades is that those who eat a diet rich
in more natural foods, such as fruits, vegetables, nuts, whole grains, and fish, tend to be protected
from various chronic diseases. The incidences of certain cancers and heart disease are markedly
lower than in populations that eat considerably lower amounts of these foods. For a while, many
nutritionists believed that this observation was more of an association rather than cause and effect.
This is to say that the higher incidence of disease was more the result of excess energy intake, fat
and processed foods in conjunction with lower physical activity typically associated with the lower
consumption of fruits, vegetables, and so on rather than the lack of these health-promoting foods.
Thus, recommendations focused on limiting many of the “bad” food items by substituting them with
foods that were not associated with the degenerative diseases, deemed “good” foods somewhat by
ix
x Preface
default. With time scientists were able to better understand the composition and bioactivities of the
“good” foods. Evidence quickly mounted as portrayed in the figure to support earlier beliefs that
many natural foods are seemingly prophylactic and medicinal.
Today we find ourselves at a critical crossroads to understand humanity’s relationship with nature.
While the incorporation of various functional foods is health beneficial, the concept of nutraceuticals
reminds us that other nonessential dietary constituents may also be critical for lowering the risk of
chronic disorders and improving healthspan. For it is many functional foods that provide us with
nutraceuticals that yield protection against the environment in which we exist and the potentially
pathological events we internally create. Food was an environmental tool used in the sculpting of
the human genome. It is only logical to think, then, that eating more natural foods such as fruits and
vegetables would lead to a healthier existence.
Advancement of scientific techniques, including various “omics” approaches, has not only allowed
us to better understand the diet we are supposed to eat, but it has also opened the door to one of the
most interesting events in commerce. Food companies are now able to market foods with approved
health claims touting the nutraceutical or functional properties of the food. Food companies are
also able to fortify existing foods with nutraceutical substances and/or create new foods designed
to include one or more nutraceutical substances in their recipes. The opportunity afforded to food
companies involved in functional foods appears without limitations at this time.
Even though this book reviews numerous nutraceuticals and functional foods, the field is still
relatively young and surely there is much more to be learned and applied to a healthier existence. It
is hard to imagine that nutrition science would ever be more exciting than this. But perhaps some
scientist wrote that very same thought less than a century ago during the vitamin and mineral boom.
We truly hope you enjoy this book and welcome your comments and thoughts for future editions.
Editors
Robert E.C. Wildman, PhD, is a native of Philadelphia, Pennsylvania,
and attended the University of Pittsburgh (BS), Florida State
University (MS), and Ohio State University (PhD). He is currently
faculty at Texas Woman’s University in Denton, Texas. Dr. Wildman is
author of The Nutritionist: Food, Nutrition, and Optimal Health and
co-author of the textbooks Advanced Human Nutrition and Exercise
and Sport Nutrition as well as creator of TheNutritionDr.com and
founder of the International Protein Board. Dr. Wildman’s research
focuses primarily on the impact of exercise and protein and amino
acids on body weight, composition, and health and he presents around
the world to educate and activate people to achieve better fitness and
health.
Richard S. Bruno, PhD, is a professor of human nutrition at The

Ohio State University. He earned his doctorate in human nutrition
from The Ohio State University (Columbus, Ohio), and both his MS
and BS degrees in nutrition from the University of Delaware (Newark,
Delaware). He also completed his postdoctoral training at the Linus
Pauling Institute at Oregon State University (Corvallis, Oregon).
Dr. Bruno is a bionutritionist and registered dietitian with expertise
in the areas of phytochemical function and metabolism in relation
to oxidative and inflammatory distress. His research program at The
Ohio State University focuses on the bioavailability and metabolism
of polyphenols and vitamin E, and their health-promoting functions
to manage cardiometabolic disorders. Complementary areas of research also include the study of
functional foods and their bioactive components to establish evidence-based dietary recommendations
that enhance vascular endothelial function.
xi
Contributors
Jose Antonio Jessica L. Cooperstone
Department of Health and Human Food Science and Technology
Performance The Ohio State University
Nova Southeastern University Columbus, Ohio
Davie, Florida
Giuseppe Derosa
Paul J. Arciero Centre of Diabetes and Metabolic Diseases
Department of Health and Human Fondazione IRCCS Policlinico San Matteo
Physiological Sciences University of Pavia
Skidmore College Pavia, Italy
Saratoga Springs, New York
Priyankar Dey
Christopher Bailey Department of Human Sciences
Nutrition Sciences The Ohio State University
Stratum Nutrition Columbus, Ohio
Carthage, Missouri
Thunder Jalili
Meghan Hampton Division of Nutrition
Naval Health Clinic Quantico University of Utah
Quantico, Virginia Salt Lake City, Utah
Richard S. Bruno Douglas S. Kalman

Department of Human Sciences Nutrition Research Unit
The Ohio State University Miami Research Associates
Columbus, Ohio Miami, Florida
Victoria Burgess Chad M. Kerksick

Department of Health and Human School of Health Sciences
Performance Lindenwood University
Nova Southeastern University St. Charles, Missouri
Davie, Florida
Richard B. Kreider
Darren G. Candow Department of Health & Kinesiology
Faculty of Kinesiology and Health Studies Texas A&M University
University of Regina College Station, Texas
Regina, Canada
Donald K. Layman
Craig S. Charron Department of Food Science & Human
Food Components and Health Laboratory Nutrition
Agricultural Research Service University of Illinois
United States Department of Agriculture Urbana, Illinois
Beltsville, Maryland
Amy C. Long
Rick Collins, Esq. Human Nutrition
Collins Gann McCloskey & Barry PLLC Abbott Nutrition
Mineola, New York Columbus, Ohio
xiii
xiv Contributors
Amy D. Mackey Sharon A. Ross

Human Nutrition Nutritional Science Research Group
Abbott Nutrition Division of Cancer Prevention
Columbus, Ohio National Cancer Institute
National Institute Health
Pamela Maffioli Rockville, Maryland
Centre of Diabetes and Metabolic Diseases
Fondazione IRCCS Policlinico San Matteo Kevin Ruff
University of Pavia Human Nutrition Sciences
Pavia, Italy Stratum Nutrition
Carthage, Missouri
Eunice Mah
Biofortis Merieux NutriSciences Geoffrey Y. Sasaki
Addison, Illinois Department of Human Sciences
The Ohio State University
Jay Manfre, Esq. Columbus, Ohio
Collins Gann McCloskey & Barry PLLC
Mineola, New York
Gary D. Stoner
Medical College of Wisconsin
Justin G. Martin
Wauwatosa, Wisconsin
Department of Chemical Engineering
Pennsylvania State University
University Park, Pennsylvania Lem Taylor
School of Exercise & Sport Science
Joshua D. McDonald University of Mary Hardin-Baylor
Department of Human Nutrition Belton, Texas
Winthrop University
Rock Hill, South Carolina Jairam K.P. Vanamala
Department of Food Science
Denis M. Medeiros Pennsylvania State University
Department of Molecular Biology and University Park, Pennsylvania
Biochemistry
University of Missouri-Kansas City Marielle Kahn Weintraub
Kansas City, Missouri President-Board of Directors
US Hemp Authority
Jonathan Merkle Lexington, Kentucky
Nutrition Sciences
Michael Foods Robert E.C. Wildman
Minneapolis, Minnesota Department of Food & Nutrition Sciences
Texas Woman’s University
Michael J. Ormsbee Denton, Texas
Institute of Sports Sciences & Medicine
Nutrition, Food & Exercise Sciences Tim N. Ziegenfuss
Florida State University The Center for Applied Health Sciences
Tallahassee, Florida Stow, Ohio
Unit I
Overview of Nutraceuticals
1 Nutraceuticals and
Functional Foods
Robert E.C. Wildman
CONTENTS
1.1 Introduction...............................................................................................................................3
1.2 Defining Nutraceuticals and Functional Foods.........................................................................4
1.3 Classifying Nutraceutical Factors.............................................................................................. 5
1.4 Food and Nonfood Sources of Nutraceutical Factors................................................................ 6
1.5 Nutraceutical Factors in Specific Foods.................................................................................... 6
1.6 Mechanism of Action................................................................................................................8
1.7 Classifying Nutraceutical Factors Based on Chemical Nature............................................... 10
1.7.1 Isoprenoid Derivatives (Terpenoids)............................................................................ 11
1.7.2 Phenolic Compounds................................................................................................... 15
1.7.3 Carbohydrates and Derivatives.................................................................................... 17
1.7.4 Fatty Acids and Structural Lipids................................................................................20
1.7.5 Amino Acid–Based..................................................................................................... 21
1.7.6 Microbes (Probiotics).................................................................................................. 21
1.7.7 Minerals....................................................................................................................... 22
References......................................................................................................................................... 22
1.1 INTRODUCTION
Interest in nutraceuticals and functional foods continues to grow, powered by progressive research
efforts to identify properties and potential applications of nutraceutical substances, and coupled
with public interest and consumer demand. Estimates vary; global market size for functional food
ingredients is projected to exceed 250 billion by 2025. Among the principal reasons for the growth
of the functional food market are current population and health trends. Across the globe, populations
are aging. For instance, in 2015, the average projected life expectancy globally for those born that
year was 71.4 years. Moreover, about 30 countries recorded average life expectancy at 80 years or
above, including Japan, Singapore, and Switzerland, all above 83 years.1
Meanwhile, obesity is now recognized as a global epidemic as its incidence continues to climb in
countries throughout the world. According to reports of the World Health Organization (WHO) in
2016, more than 1.9 billion adults aged 18 years and older were overweight, with over 650 million
adults obese. In 2016, 39% of adults aged 18 years and over were overweight. Overall, about 13%
of the world’s adult population (11% of men and 15% of women) were obese in 2016.2 In the United
States of America in 2017, nearly 38% of adults were obese. Nearly 8% are extremely obese.3 Global
trends show stability or favor an increased incidence of obesity versus a reduction. Meanwhile, heart
disease continues to be a primary cause of death, responsible for one out of every four deaths in the
U.S., and cancer, osteoporosis, and arthritis remain highly prevalent.
Although genetics play a major role in the development of the diseases mentioned above, by
and large most are considered preventable or could be minimized by a health-promoting diet and
physical activity, weight management, and a healthier lifestyle, including environment. Additionally,
3
4 Handbook of Nutraceuticals and Functional Foods
people can optimize the health-promoting capabilities of their diet by way of supplementation and by
consuming foods that have been formulated or fortified to include health-promoting factors.
Another reason for the growing trend in functional foods is public education. People today are
more nutrition savvy than ever before, the interest in health-related information being met by many
informational resources. Every day people are exposed to media articles, blogs, and social media
posts devoted to the relationship between diet and health. Numerous websites have been developed
by government agencies such as the U.S. Department of Agriculture (USDA; www.nal.usda.gov) and
organizations such as the American Heart Association (www.americanheart.org) and the American
Cancer Society (www.cancer.org). Last, information-based entities abound on the Internet, including
WebMD.com and TheNutritionDr.com.
1.2 DEFINING NUTRACEUTICALS AND FUNCTIONAL FOODS

The term nutraceutical is a hybrid or contraction of nutrition and pharmaceutical. Reportedly, it was
coined in 1989 by DeFelice and the Foundation for Innovation in Medicine.4 Restated and clarified in a
press release in 1994, its definition was “any substance that may be considered a food or part of a food
and provides medical or health benefits, including the prevention and treatment of disease. Such products
may range from isolated nutrients, dietary supplements and diets to genetically engineered ‘designer’
foods, herbal products, and processed foods such as cereals, soups, and beverages.”5 At present there
are no universally accepted definitions for nutraceuticals and functional foods, although commonality
exists between the definitions offered by different health-oriented professional organizations.
According to the International Food Information Council (IFIC), functional foods are foods or
dietary components that may provide a health benefit beyond basic nutrition.6 The International
Life Sciences Institute of North America (ILSI) has defined functional foods as “foods that by
virtue of physiologically active food components provide health benefits beyond basic nutrition.”7
Meanwhile, Health Canada defines functional foods as “similar in appearance to a conventional
food, consumed as part of the usual diet, with demonstrated physiological benefits, and/or to reduce
the risk of chronic disease beyond basic nutritional functions.”8 The Nutrition Business Journal
classified functional food as “food fortified with added or concentrated ingredients to functional
levels, which improves health or performance. Functional foods include enriched cereals, breads,
sport drinks, bars, fortified snack foods, baby foods, prepared meals, and more.”9
In the 2013 Academy of Nutrition and Dietetics (AND) position paper on nutraceuticals and
functional foods, the authors state: “It is the position of the Academy of Nutrition and Dietetics to
recognize that although all foods provide some level of physiological function, the term functional
foods is defined as whole foods along with fortified, enriched, or enhanced foods that have a potentially
beneficial effect on health when consumed as part of a varied diet on a regular basis at effective levels
based on significant standards of evidence. The Academy supports Food and Drug Administration
(FDA)-approved health claims on food labels when based on rigorous scientific substantiation.”10
Based on these statements, one can surmise that functional foods include everything from natural
foods, such as fruits and vegetables endowed with antioxidants and fiber, to fortified and enriched
foods, such as orange juice with added calcium or additional carotenoids, to formulated ready-
to-drink beverages containing protein, amino acids, vitamins, minerals, antioxidants, immune-
supporting factors, etc.
Regarding the term “nutraceutical,” the Nutrition Business Journal states that it uses the term
nutraceutical for anything that is consumed primarily or particularly for health reasons. Based on
that definition, a functional food would be a kind of nutraceutical.9 On the other hand, Health Canada
states that nutraceuticals are a product that is “prepared from foods but sold in the form of pills or
powders (potions), or in other medicinal forms not usually associated with foods. A nutraceutical is
demonstrated to have a physiological benefit or provide protection against chronic disease.”8 Based
on this definition and how functional foods are characterized, as noted previously, nutraceuticals
would be distinct from functional foods.
Nutraceuticals and Functional Foods 5
TABLE 1.1
Food Label Claim Guidelines
Claim Purpose Example
Nutrient content claim Describe content of certain nutrients. “Fat-free,” “low sodium.”
Qualified health claim Describe the relationship between food, food “Some scientific evidence suggests that
component, or dietary supplement and consumption of antioxidant vitamins
reduced risk of a disease or health related may reduce the risk of certain forms
condition. This claim uses qualifying of cancer. However, FDA has
language because the evidence for this determined that this evidence is
relationship is emerging and is not yet strong limited and not conclusive.”
enough to meet the standard of significant
scientific advancement set by the FDA.
NLEA authorized health claims Characterize a relationship between a food, a “Diets high in calcium may reduce the
food component, dietary ingredient, or risk of osteoporosis.”
dietary supplement and risk of a disease.
Structure/function claim Describes role of nutrient or ingredient “Calcium builds strong bones.”
intended to affect normal structure or
function in humans.
May characterize the means by which the
nutrient or ingredient affects the structure or
function.
May describe a benefit related to a deficiency.
Must be accompanied by a disclaimer stating
that FDA has not reviewed the claim and
that the product is not intended to “diagnose,
treat, cure, or prevent any disease.”
Source: Adapted from International Life Sciences Institute of North America Web site, http://www.ilsi.org/, 2006.
The potential functions of nutraceutical/functional food ingredients are so often related to the
maintenance or improvement of health that it is necessary to distinguish between a food ingredient
that has function and a drug. The core definition of a drug is any article that is “intended for use
in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals”
(21 U.S.C. 321(g)(1)(B)). At the same time, certain health claims can be made for foods and
ingredients that are associated with health conditions.11 In the U.S., such health claims are defined
and regulated by the U.S. Food and Drug Administration (FDA). Health claims related to foods
and ingredients include an implied or explicit statement about the relationship of a food substance
to a disease or health-related condition (21 U.S.C.343(r)(1)(B) and 21 C.F.R.101.14(a)(1)). The major
categories of health claims are listed in Table 1.1 with examples of each.
1.3 CLASSIFYING NUTRACEUTICAL FACTORS

The number of purported nutraceutical substances is in the hundreds, and some of the more
recognizable substances include isoflavones, tocotrienols, allyl sulfur compounds, fiber, and
carotenoids. Considering a long and growing list of nutraceutical substances, organization systems
are needed to allow for easier understanding and application. This is particularly true for academic
instruction, as well as product formulation by food companies.
Depending upon one’s interest and/or background, the appropriate organizational scheme for
nutraceuticals can vary. For example, cardiologists may be most interested in those nutraceutical
substances that are associated with reducing the risk factors of heart disease. Specifically, their
interest may lie in substances purported to positively influence hypertension and hypercholesterolemia
and to reduce free radical or platelet-dependent thrombotic activity. Accordingly, nutraceutical

factors such as certain fibers, omega-3 fatty acids, phytosterols, quercetin, and grape flavonoids
would be of interest. Meanwhile, oncologists may be more interested in those substances that target
anticarcinogenic activities. These substances may be associated with augmentations of microsomal
detoxification systems and antioxidant defenses, or they may slow the progression of existing cancer.
Thus, their interest may lie in both chemoprevention or potential adjunctive therapy.
On the other hand, the nutraceutical interest of food scientists working on the development of a
functional food product will not only include physiological properties, but also stability and sensory
properties, as well as issues of cost efficiency. To demonstrate this point, the anticarcinogenic
triterpene limonin is lipid-soluble and intensely bitter, somewhat limiting its commercial use as a
functional food ingredient.12 However, the glucoside derivative of limonin, which shares some of
the potential anticarcinogenic activity of limonin, is water soluble and virtually tasteless, thereby
enhancing its potential use as an ingredient.13
Whether it is for academic instruction, clinical trial design, functional food development, or dietary
recommendations, nutraceutical factors can be organized in several ways. Cited below are a few ways
of organizing nutraceuticals based upon food source, mechanism of action, and chemical nature.
1.4 FOOD AND NONFOOD SOURCES OF NUTRACEUTICAL FACTORS

One of the broader models of organization for nutraceuticals is based upon their potential as a food
source to humans. Here nutraceuticals may be separated into plant, animal, and microbial (i.e.,
bacteria and yeast) groups. Grouping nutraceutical factors in this manner has numerous merits and
can be a valuable tool for diet planning, as well as classroom and seminar instruction.
One interesting consideration with this organization system is that the food source may not
necessarily be the point of origin for one or more substances. An obvious example is conjugated linoleic
acid (CLA), which is part of the human diet, mostly as a component of beef and dairy foods. However,
it is made by bacteria in the rumen of the cow. Therefore, issues involving the food chain or symbiotic
relationships may have to be considered for some individuals working with this organization scheme.
Because of conserved biochemical aspects across species, many nutraceutical substances are
found in both plants and animals, and sometimes in microbes. For example, microbes, plants, and
animals contain choline and phosphotidylcholine. This is also true for sphingolipids; however, plants
and animals are better sources. Also, linolenic acid (18:3ω-3 fatty acid) can be found in a variety of
food resources, including animal flesh, even though it is primarily synthesized in plants and other
lower members of the food chain. Table 1.2 presents some of the more recognizable nutraceutical
substances grouped according to food-source providers.
Nonfood sources of nutraceutical factors have been sourced by the development of modern
fermentation methods. For example, amino acids and their derivatives have been produced by bacteria
grown in fermentation systems. The emergence of recombinant-genetic techniques has enabled new
avenues for obtaining nutraceutical compounds. These techniques and their products are being
evaluated in the arenas of the marketplace and regulatory concerns around the world. An example
is the production of eicosapentaenoic acid (EPA) by bacteria, which is normally produced by some
algae and bacteria. The EPA derived from salmon are produced by algae and are later incorporated
in the salmon that consume the algae. Meanwhile, there is the potential to produce EPA by non–EPA-
producing bacteria by importing the appropriate DNA through recombinant methods.14 The ability to
transfer the production of nutraceutical molecules into organisms that allows for economically feasible
production is cause for both optimism and discussion concerning regulatory and popular acceptance.
1.5 NUTRACEUTICAL FACTORS IN SPECIFIC FOODS

In an organization model related to the one above, nutraceuticals can be grouped based upon
relatively concentrated foods. This model is more appropriate when there is interest in a nutraceutical
TABLE 1.2
Examples of Nutraceutical Substances Grouped by Food Source
Plants Animal Microbial
β-Glucan Conjugated Linoleic Acid (CLA) Saccharomyces boulardii (yeast)

Ascorbic acid Eicosapentaenoic acid (EPA) Bifidobacterium bifidum
γ-Tocotrienol Docosahexenoic acid (DHA) B. longum
Quercetin Spingolipids B. infantis
Luteolin Choline Lactobacillus acidophilus (LC1)
Cellulose Lecithin L. acidophilus (NCFB 1748)
Lutein Calcium Streptococcus salvarius (subs. Thermophilus)
Gallic acid Coenzyme Q10
Perillyl alcohol Selenium
Indole-3-carbonol Zinc
Pectin Creatine
Daidzein Minerals
Glutathione
Potassium
Allicin
δ-Limonene
Genestein
Lycopene
Hemicellulose
Lignin
Capsaicin
Geraniol
β-Ionone
α-Tocopherol
β-Carotene
Nordihydrocapsaicin
Selenium
Zeaxanthin
Minerals
MUFA
Note: The substances listed in this table include those that are either accepted or purported nutraceutical substances.
compound or related compounds, or when there is interest in a specific food for agricultural/
geographic reasons or functional food-development purposes. For example, the interest may be in
the nutraceutical qualities of a local crop or a traditionally consumed food in a geographic region,
such as pepper fruits in the southwestern United States, olive oil in Mediterranean regions, and red
wine in western Europe and Northern California.
There are several nutraceutical substances that are found in higher concentrations in specific
foods or food families. These include capsaicinoids, which are found primarily in pepper fruit, and
allyl sulfur (organosulfur) compounds, which are particularly concentrated in onions and garlic.
Table 1.3 provides a listing of certain nutraceuticals that are considered unique to certain foods
or food families. One consideration for this model is that for several substances, such as those just
named, there is a relatively short list of foods that are concentrated sources. However, the list of food
sources for other nutraceutical substances can be much longer and can include numerous seemingly
unrelated foods. For instance, citrus fruit contain the isoflavone quercetin, as do onions, a plant food
seemingly unrelated. Citrus fruit grow on trees, whereas the edible bulb of the onion plant (an herb)
TABLE 1.3
Examples of Foods with Higher Content of Specific Nutraceutical Substances
Nutraceutical Substance/Family Foods of Remarkably High Content
Allyl sulfur compounds Onions, garlic
Isoflavones (e.g., genestein, daidzein) Soybeans and other legumes, apios
Quercetin Onion, red grapes, citrus fruit, broccoli, Italian yellow squash
Capsaicinoids Pepper fruit
EPA and DHA Fish oils
Lycopene Tomatoes and tomato products
Isothiocyanates Cruciferous vegetables
β-Glucan Oat bran
CLA Beef and dairy
Resveratrol Grapes (skin), red wine
β-Carotene Citrus fruit, carrots, squash, pumpkin
Carnosol Rosemary
Catechins Teas, berries
Adenosine Garlic, onion
Indoles Cabbage, broccoli, cauliflower, kale, brussels sprouts
Curcumin Tumeric
Ellagic acid Grapes, strawberries, raspberries, walnuts
Anthocyanates Red wine
3-n-Butyl phthalide Celery
Cellulose Most plants (component of cell walls)
Lutein, zeaxanthin Kale, collards, spinach, corn, eggs, citrus
Psyllium Psyllium husk
Monounsaturated fatty acids Tree nuts, olive oil
Inulin, Fructooligosaccharides (FOS) Whole grains, onions, garlic
Lactobacilli, Bifidobacteria Yogurt and other dairy
Catechins Tea, cocoa, apples, grapes
Lignans Flax, rye
Note: The substances listed in this table include those that are either accepted or purported nutraceutical
substances.
develops at ground level. Other plant foods with higher quercetin content are red grapes—but not
white grapes—broccoli (which is a cruciferous vegetable), and the Italian yellow squash. Again,
these foods appear to bear very little resemblance to citrus fruit, or onions for that matter. On the
other hand, there are no guarantees that closely related or seemingly similar foods contain the same
nutraceutical compounds. For example, both the onion plant and the garlic plant are perennial herbs
arising from a rooted bulb and are also cousins in the lily family. However, although onions are
loaded with quercetin, with some varieties containing up to 10% of their dry weight of this flavonoid,
garlic is quercetin void.
1.6 MECHANISM OF ACTION

Another means of classifying nutraceuticals is by their mechanism of action. This system groups
nutraceutical factors together, regardless of food source, based upon their proven or purported
physiological properties. Among the classes would be antioxidant, antibacterial, antihypertensive,
anti-hypercholesterolemic, anti-aggregate, anti-inflammatory, anti-carcinogenic, osteoprotective,
and so on. Like the scheme just discussed, credible Internet resources may prove invaluable to this
TABLE 1.4
Examples of Nutraceuticals Grouped by Mechanisms of Action
Positive Influence on Antioxidant Osteogenetic or Bone
Anticancer Blood Lipid Profile Activity Antiinflammatory Protective
Capsaicin β-Glucan CLA Linolenic acid CLA
Genestein γ-Tocotrienol Ascorbic acid EPA Soy protein
Daidzein δ-Tocotrienol β-Carotene DHA Genestein
α-Tocotrienol MUFA Polyphenolics GLA Daidzein
γ-Tocotrienol Quercetin Tocopherols (gamma-linolenic Calcium
CLA ω-3 PUFAs Tocotrienols acid) Casein phosphopeptides
Lactobacillus acidophilus Resveratrol Indole-3-carbonol Capsaicin FOS
Sphingolipids Tannins α-Tocopherol Quercetin (fructooligosaccharides)
Limonene β-Sitosterol Ellagic acid Curcumin Inulin
Diallyl sulfide Saponins Lycopene
Ajoene Guar Lutein
α-Tocopherol Pectin Glutathione
Enterolactone Hydroxytyrosol
Glycyrrhizin Luteolin
Equol Oleuropein
Curcumin Catechins
Ellagic acid Gingerol
Lutein Chlorogenic acid
Carnosol Tannins
L. bulgaricus
Note: The substances listed in this table include those that are either accepted or purported nutraceutical substances.
approach. Examples are presented in Table 1.4. This model would also be helpful to an individual
who is genetically predisposed to a medical condition or to scientists trying to develop powerful
functional foods for just such a person.
The information in this model would then be helpful in diet planning in conjunction with the
organization scheme just discussed and presented in Table 1.3. It would also be helpful to a product
developer trying to develop a new functional food, perhaps for heart health. This developer might
consider the ingredients listed in several categories to develop a product that would reduce blood
pressure, total and LDL-cholesterol levels, and inflammation.
Some nutraceutical ingredients or mixtures are marketed on the basis that they have been used for
many years in the practice of traditional or cultural medicine, that is, treatments for medical illness
that have developed in cultural tradition because of trial and error. This rationale for use can be both
compelling and a cause for concern. The plant and animal kingdoms contain many compounds that
offer therapeutic benefit or danger; often the same compound offers both, with the difference being
dependent upon the dose.15 While traditional medicines are assumed low risk for the most part, one
5-year study that followed over 1000 cases reported a possible or confirmed association between use
and toxicity in nearly 61% of the cases.16 Thus, whereas a statement regarding traditional use seems
to offer a sense of safety by virtue of use by many individuals over time, there always need to be
systematic regulatory efforts to determine and document safety over time.
What may be of interest is that there are several nutraceuticals that can be listed as having more
than one mechanism of action. One of the seemingly most versatile nutraceutical families is the
omega-3 polyunsaturated fatty acids (PUFAs). Their nutraceutical properties can be related to direct
effects as well as to some indirect effects. For example, these fatty acids are used as precursors
for eicosanoid substances that locally vasodilate, bronchodilate, and deter platelet aggregation and
clot formation. These roles can be prophylactic for asthma and heart disease. Omega-3 PUFA may
also reduce the activities of protein kinase C and tyrosine kinase, both of which are involved in a
cell-growth-signaling mechanism. Here, the direct effects of these fatty acids may reduce cardiac
hypertrophy and cancer-cell proliferation. Omega-3 PUFA also appears to inhibit the synthesis
of fatty acid synthase (FAS), which is a principal enzyme complex involved in de novo fatty acid
synthesis. Here the nutraceutical effect may be considered indirect, as chronic consumption of
these PUFAs may theoretically lead to decreased quantities of body fat over time and slow the
development of obesity. The obesity might then lead to the development of hyperinsulinemia and
related physiological aberrations such as hypertension and hyperlipidemia.
1.7 CLASSIFYING NUTRACEUTICAL FACTORS BASED ON CHEMICAL NATURE

Another method of grouping nutraceuticals is based upon their chemical nature. This approach
allows nutraceuticals to be categorized under molecular/elemental groups. This preliminary model
includes several large groups, which then provide a basis for subclassification or subgroups, and so
on. One way to group nutraceuticals grossly is as follows:
• Isoprenoid derivatives
• Phenolic substances
• Fatty acids and structural lipids
• Carbohydrates and derivatives
• Amino acid–based substances
• Microbes
• Minerals
As scientific investigation continues, several hundred substances will probably be deemed

nutraceuticals. As many of these nutraceutical compounds appear to be related in synthetic origin or
molecular nature, there is the potential to broadly group many of the substances together (Figure 1.1).
This scheme is by no means perfect, and it is offered “in pencil,” as opposed to being “etched in
stone.” It is expected that scientists will ponder this organization system, find flaws, and suggest
ways to evolve the scheme, or disregard it completely in favor of a better concept. Even at this point,
FIGURE 1.1 Organizational scheme for nutraceuticals.

several “gray” areas are apparent. For instance, mixtures of different classes can exist, such as
mixed isoprenoids, prenylated coumarins, and flavonoids. Also, phenolic compounds could arguably
be grouped under a very large “amino acid and derivatives” category. Although most phenolic
molecules arise from phenylalanine as part of the shikimic acid metabolic pathway, other phenolic
compounds are formed via the malonic acid pathway, thereby circumventing phenylalanine as an
intermediate. Thus, phenolics stand alone in their own group, whose most salient characteristic is
chemical structure, not necessarily synthetic pathway.
1.7.1 Isoprenoid Derivatives (Terpenoids)

Isoprenoids and terpenoids are terms used to refer to the same class of molecules. These substances
are without question one of the largest groups of plant secondary metabolites. In accordance with
this ranking, they are also the basis of many plant-derived nutraceuticals. Under this large umbrella
are many popular nutraceutical families such as carotenoids, tocopherols, tocotrienols, and saponins.
This group is also referred to as isoprenoid derivatives because the principal building block molecule
is isoprene (Figure 1.2). Isoprene itself is synthesized from acetyl coenzyme A (CoA), in the well-
researched mevalonic acid pathway (Figure 1.3), and the glycolysis-associated molecules pyruvate
and 3-phosphoglycerate in a less-understood metabolic pathway.17 In both pathways, the product is
isopentenyl phosphate (IPP), and IPP is often regarded as the pivotal molecule in the formation of
larger isoprenoid structures.
Once IPP is formed, it can reversibly isomerize to dimethylallyl pyrophosphate (DMAPP) as
presented in Figure 1.4. Both five-carbon structures are then used to form geranyl pyrophosphate
(GPP), which can give rise to monoterpenes. Among the monoterpenes are limonene and perillyl
alcohol. GPP can also react with IPP to form the 15-carbon structure farnesyl pyrophosphate (FPP),
which then can give rise to the sesquiterpenes. FPP can react with IPP or another FPP to produce
either the 20-carbon geranylgeranyl pyrophosphate (GGPP) or the 30-carbon squalene molecule,
respectively. GGPP can give rise to diterpenes, while squalene can give rise to triterpenes and
steroids. Lastly, GGPP and GPP can condense to form the 40-carbon phytoene structure, which then
can give rise to tetraterpenes.
Most plants contain so-called essential oils, which contain a mixture of volatile monterpenes and
sesquiterpenes. Limonene is found in the essential oils of citrus peels, whereas menthol is the chief
monoterpene in peppermint essential oil (Figure 1.5). Two potentially nutraceutical diterpenes in
coffee beans are kahweol and cafestol.18 Both of these diterpenes contain a furan ring. As discussed
by Miller and colleagues, the furan-ring component might be very important in yielding some of the
potential antineoplastic activity of these compounds.19
Several triterpenes (examples in Figure 1.6) have been reported to have nutraceutical properties.
These compounds include plant sterols; however, some of these structures may have been modified
to contain fewer than 30 carbons. One of the most recognizable triterpene families is the limonoids.
These triterpenes are found in citrus fruit and impart most of their bitter flavor. Limonin and nomilin
are two triterpenoids that may have nutraceutical application, limonin more so than nomilin.20 Both
of these molecules contain a furan component. In citrus fruit, limonoids can also be found with an
attached glucose, forming a limonoid glycoside.21 As discussed above, the addition of the sugar group
reduces the bitter taste tremendously and makes the molecule more water soluble. These properties
FIGURE 1.2 Isoprene.

FIGURE 1.3 The mevalonic acid pathway.

FIGURE 1.4 Formation of terpene structures. In addition: (1) FPP + FPP produces squalene (30 carbons)
which yields triterpenes and steroids, and (2) GGPP + GGPP produces phytoene (40 carbons) which yields
tetraterpenes.
may make it more attractive as a functional food ingredient. Saponins are also triterpene derivatives,
and their nutraceutical potential is attracting interest.22,23
The carotenoids (carotenes and xanthrophils), whose name is derived from carrots (Daucus
carota), are perhaps the most recognizable form of coloring pigment within the isoprenoid class.
Carotenes and xanthrophils differ only slightly, in that true carotenes are purely hydrocarbon
molecules (i.e., lycopene, α-carotene, β-carotene, γ-carotene); the xanthrophils (i.e., lutein,
capsanthin, cryptoxanthin, zeaxanthin, astaxanthin) contain oxygen in the form of hydroxyl,
methoxyl, carboxyl, keto, and epoxy groups. With the exception of crocetin and bixin, naturally
occurring carotenoids are tetraterpenoids, and thus have a basic structure of 40 carbons with unique
CH3 CH3 CH2
CH2
OH
H3C CH2 H3 C H3C

CH3 CH3
Limonene Menthol Myrcene
FIGURE 1.5 Structure of select monoterpenes.
FIGURE 1.6 Examples of triterpenes.
modifications. The carotenoids are pigments that generally produce colors of yellow, orange, and
red. Carotenoids are also very important in photosynthesis and photoprotection.
Different foods have different kinds and relative amounts of carotenoids. Also, the carotenoid content
can vary seasonally and during the ripening process. For example, peaches contain violaxanthin,
cryptoxanthin, β-carotene, persicaxanthin, neoxanthin, and as many as 25 other carotenoids; apricots
contain mostly α-carotene, β-carotene, and lycopene; and carrots contain about 50–55 parts per
million of carotene in total, mostly α-carotene, β-carotene, and γ-carotene, as well as lycopene.
Many vegetable oils also contain carotenoids, with palm oil containing the most. For example, crude
palm oil contains up to 0.2% carotenoids. Meanwhile, there are a few synthetic carotenoids, including
β-apo-8′-carotenal (apocarotenal), and canthaxanthin. Beta-Apo-8′-carotenal (apocarotenal) imparts
a light reddish-orange color, and canthaxanthin imparts an orange-red to red color.
1.7.2 Phenolic Compounds
Like the terpenoids, phenolic compounds are also considered secondary metabolites. The base
for this very diverse family of molecules is a phenol structure, which is a hydroxyl group on an
aromatic ring. From this structure, larger and interesting molecules are formed such as anthocyanins,
coumarins, phenylpropamides, flavonoids, tannins, and lignin. Phenolic compounds perform a
variety of functions for plants, including defending against herbivores and pathogens, absorbing
light, attracting pollinators, reducing the growth of competitive plants, and promoting symbiotic
relationships with nitrogen-fixing bacteria.
There are a couple of biosynthetic pathways that form phenolic compounds. The predominant
pathways are the shikimic acid pathway and the malonic acid pathway. The shikimic pathway is more
significant in higher plants, although the malonic acid pathway is also present.17 Actually, the malonic
pathway is the predominant source of secondary metabolites in lower plants, fungi, and bacteria. The
shikimic pathway is so named because an intermediate of the pathway is shikimic acid. Inhibition
of this pathway is the purpose of a commercially available herbicide (Roundup).
The malonic acid pathway begins with acetyl CoA. Meanwhile, in the shikimic pathway, simple
carbohydrate intermediates of glycolysis and the pentose phosphate pathway (PPP) are used to form
the aromatic amino acids phenylalanine and tyrosine. A third aromatic amino acid, tryptophan, is
also a derivative of this pathway. As animals do not possess the shikimic acid pathway, these aromatic
amino acids are diet essentials. Obviously, these amino acids are considered primary metabolites
or products. Thus, it is the reactions beyond the formation of these amino acids that are of greater
importance to the production of secondary metabolites. Once formed, phenylalanine can be used to
generate flavonoids (Figure 1.7). The reaction that generates cinnamic acid from phenylalanine is
catalyzed by one of the most-studied enzymes associated with secondary metabolites, phenylalanine
ammonia lyase (PAL). The expression of PAL is increased during fungal infestation and other
stimuli, which may be critical to the plant.
From trans-cinnamic acid, several simple phenolic compounds can be made. These include the
benzoic acid derivatives vanillin and salicylic acid (Figure 1.8). Also, trans-cinnamic acid can be
converted to para-coumaric acid. Simple phenolic derivatives of para-coumaric acid include caffeic
acid and ferulic acid. CoA can be attached to para-coumaric acid to form para-coumaryl CoA. Both
para-coumaric acid and para-coumaryl CoA can also be used to form lignin-building blocks, para-
coumaryl alcohol, coniferyl alcohol, and sinapyl alcohol. After cellulose, lignin is the most abundant
organic molecule in plants. To continue the formation of other phenolic classes, para-coumaryl CoA
can undergo further enzymatic modification, involving three malonyl CoA molecules, to create
polyphenolic molecules such as chalcones and then flavonones. The basic flavonone structure is
then the precursor for the flavones, isoflavones, and flavonols. Also, flavonones can be used to make
anthocyanins and tannins via dihydroflavonols (Figures 1.7, 1.9, and 1.10).
The flavonoids are one of the largest classes of phenolic compounds in plants. The basic carbon
structure of flavonoids contains 15 carbons and is endowed with two aromatic rings linked by
a 3-carbon bridge (Figure 1.11).17 The rings are labeled A and B. Whereas the simpler phenolic
compounds and lignin-building blocks result from the shikimic pathway and are phenylalanine
derivatives, formation of the flavonoids requires some assistance from both the shikimic pathway
and the malonic acid pathway. Ring A is derived from acetic acid (acetyl CoA) and the malonic acid
pathway (see the use of 3 malonyl CoA to form chalcones in Figure 1.7). Meanwhile, ring B and the
FIGURE 1.7 Production of plant phenolic molecules via phenylalanine.

FIGURE 1.8 Select coumarins (first row) and two benzoic-acid-derived phenolic molecules (second row).
3-carbon bridge are derived from the shikimic acid pathway.17 The flavonoids are subclassified based
primarily on the degree of oxidation of the 3-carbon bridge. Also, hydroxyl groups are typically
found at carbon positions 4, 5, and 7, as well as other locations.
The majority of naturally occurring flavonoids are actually glycosides, meaning a sugar moiety is
attached. The attachment of hydroxyl groups and sugars will increase the hydrophilic properties of
the flavonoid molecule, while attachment of methyl esters or modified isopentyl units will increase the
lipophilic character. Anthocyanins and anthocyanidins (Figure 1.9) are produced by plants and function
largely as coloring pigments. Basically, anthocyanins are anthocyanidins with sugar moieties attached
at position 3 of the 3-carbon bridge between rings A and B.17 These molecules help attract animals for
pollination and seed dispersal. They are responsible for the red, pink, blue, and violet coloring of many
fruits and vegetables, including blueberries, apples, red cabbage, cherries, grapes, oranges, peaches,
plums, radishes, raspberries, and strawberries. Only about 16 anthocyanidins have been identified in
plants and include pelargonidin, cyanidin, delphinidin, peonidin, malvidin, and petunidin.
Although the flavonols and flavones are structurally like their close cousin anthocyanidins and
the anthocyanidin-glycoside derivatives anthocynanins, they absorb light at shorter wavelengths
and thus are not perceived as color to the human eye. However, they may be detected by insects
and help direct them to areas of pollination. Because flavones and flavonols do absorb UV–B light
energy (280–320 nm), they are believed to serve a protective role in plants. Also, certain flavonoids
promote the formation of a symbiotic relationship between plant roots and nitrogen-fixing bacteria.
The primary structural feature that separates the isoflavones from the other flavonoids is a shift in
the position of the B ring. Perhaps the most ubiquitous flavonoid is quercetin. Hesperidin is also a
common flavonoid, especially in citrus fruit.
1.7.3 Carbohydrates and Derivatives

The glucose derivative ascorbic acid (vitamin C) is perhaps one of the most recognizable nutraceutical
substances and is a very popular supplement. Ascorbic acid functions as a nutraceutical compound,
primarily as an antioxidant. Meanwhile, plants produce some oligosaccharides that appear to
function as prebiotic substances.
FIGURE 1.9 Anthocyanidin (A) and molecular derivatives including anthocyanin (B).
Several plant polysaccharide families are not readily available energy sources for humans, as
they are resistant to secreted digestive enzymes. These polysaccharides are grouped together along
with the phenolic polymer compound lignin to form one of the most recognizable nutraceutical
families—fibers. By and large the role of fibers is structural for plants. For example, cellulose and
hemicellulose are major structural polysaccharides found within plant cell walls. Beyond providing
structural characteristics to plant tissue, another interesting role of certain fibers is in tissue repair
after trauma, somewhat analogous to scar tissue in animals.
The non-starch polysaccharides can be divided into homogeneous and heterogeneous
polysaccharides, as well as into soluble and insoluble substances. Cellulose is a homogeneous non-
starch polysaccharide, as it consists of repeating units of glucose monomers. The links between
the glucose monomers are β1-4 in nature. These polysaccharides are found in plant cell walls as
microfibril bundles. Hemicellulose is found in association with cellulose within plant-cell walls and
is composed of a mixture of both straight-chain and highly branched polysaccharides containing
pentoses, hexoses, and uronic acids. Pentoses such as xylans, mannans, galactans, and arabicans are
found in relatively higher abundance. Hemicelluloses are somewhat different from cellulose in that
they are not limited to glucose, and they are also vulnerable to hydrolysis by bacterial degradation.
Another homopolysaccharide is pectin, where the repeating subunits are largely methylgalacturonic
acid units. It is a jelly-like material that acts as a cellular cement in plants. The linkage between
the subunits is also β1-4 bonds. The carboxyl groups become methylated in a seemingly random
FIGURE 1.10 Basic tannin structure formed from phenolic units.
FIGURE 1.11 (A) Basic flavonoid carbon structure and (B) flavonoid structure production: Carbons 5 to 8
are derived from the malonate pathway and 2 to 4 and 1′ to 6′ are derived from the shikimic acid pathway via
the amino acid phenylalanine. Carbons 2 to 4 comprise the 3-carbon bridge.
manner as fruit ripen. Chemically related to pectin is chitin. Chitin is not a plant polysaccharide but
is found within the animal kingdom, although not necessarily in humans. It is a β1-4 homopolymer
of N-acetyl-glucosamine found in shells or exoskeletons of insects and crustacea. Chitin has been
positioned as a dietary ingredient for weight loss.
Another family of polysaccharides that is worthy of discussion is glycosaminoglycans (GAGs).
While these compounds are found in animal connective tissue, they are important to this discussion,
as they are potential components of functional foods. At present, GAG and chondroitin sulfate are
popular nutrition supplements being used by individuals recovering from joint injuries and suffering
joint inflammatory disorders. Glycosaminoglycans are often referred to as mucopolysaccharides.
They are characterized by their content of amino sugars and uronic acids, which occur in combination
with proteins in secretions and structures.
GAGs are responsible for the viscosity of body-mucus secretions and are components of extracellular
amorphous ground substances surrounding collagen and elastin fibers, and cells of connective tissues and
bone. Some examples of glycosaminoglycans are hyaluronic acid and chondroitin sulfate. Hyaluronic
acid is a component of the ground substance found in most connective tissue, including the synovial
fluid of joints. It is a jelly-like substance composed of repeating disaccharides of β-glucuronic acid and
N-acetyl-d-glucosamine. Hyaluronic acid can contain several thousand disaccharide residues and is
unique from the other glycosaminoglycans in that it will not interact with proteins to form proteoglycans.
Chondroitin sulfate is composed of β-glucuronic acid and N-acetylgalactosamine sulfate.
This molecule has a relatively high viscosity and ability to bind water. It is the major organic
component of the ground substance of cartilage and bone. Both polysaccharides have β1-3 linkage
between uronic acid and acetylated amino sugars but are linked by β1-4 covalent bonds to other
polysaccharide units. Unlike hyaluronic acid, chondroitin sulfate will bind to proteins to form
proteoglycans.
1.7.4 Fatty Acids and Structural Lipids

At present, there are several fatty acids and/or their derivatives that have piqued the interests of
researchers for their functional potential. These include the omega-3 PUFA found in higher
concentrations in plants, fish, and other marine animals, and conjugated linoleic acid(CLA) produced
by bacteria in the rumen of grazing animals such as cattle. The formation of CLA probably serves
to help control the vitality of the released bacterial population in the rumen, whereas plants and fish
use omega-3 fatty acids for their properties in membranes. Some plants also use omega-3 PUFA in
a second messenger system to form jasmonic acid when plant tissue is under attack (i.e., by insect
feeding). The CLA precursor, linoleic acid, and omega-3 PUFA are produced largely in plants. In
processes very similar to those found in humans, plants construct fatty acids using two-carbon units
derived from acetyl CoA. In humans and other animals, the reactions involved in fatty acid synthesis
occur in the cytosol, whereas in plants they occur in the plastids. In both situations, FAS, acetyl CoA
carboxylase enzymes, and acyl carrier protein (ACP) are major players. Plants primarily produce
fatty acids to become components of triglycerides in energy stores (oils), as well as components
of cell membrane glycerophospholipids and glyceroglycolipids, which serve roles similar to the
phospholipids in humans. In fact, several of the plant glycerophospholipids are generally the same
as phospholipids. Some of the major fatty acids produced include palmitic acid (16:0), oleic acid
(18:1ω-9), linoleic acid (18:2ω-6), and linolenic acid (18:3ω-3). Grazing animals ingest linoleic acid,
which is then metabolized to CLA by rumen bacteria. Herbivorous fish also ingest these fatty acids
when they consume algae and other seaweeds and phytoplankton. Carnivorous fish and marine
animals then acquire these PUFA and derivatives from the tissue of other fish and marine life.
Fish will further metabolize the PUFA to produce longer and more unsaturated fatty acids such as
DHA (docosahexaenoic acid, 22:6ω-3) and EPA (eicosapentaenoic acid, 20:5ω-3). The elongation
and further unsaturation yield cell-membrane fatty acids more appropriately suited for colder
temperatures and higher hydrostatic pressures, usually associated with deeper water environments.
CLA is distinct from typical linoleic acid in that CLA is not necessarily a single structure. There seem
to be as many as nine different isomers of CLA. However, the primary forms are mainly 9-cis, 11-trans,
and 10-trans, 12-cis. From these positions, it is clear that the locations of the double bonds are unique.
The double bonds are conjugated and not interrupted by methylene. Said another way, the double bonds
are not separated by a saturated carbon but are adjacent. CLA is found mostly in the fat and milk of
ruminant animals, which indicates that beef, dairy foods, and lamb are major dietary sources.
Two other types of lipids in food products are structured lipids and diglycerides. Structured
lipids are triglycerides that have undergone hydrolysis and re-esterification under conditions that
resulted in triglycerides with new combinations of fatty acids. For example, a mixture of medium-
chain triglycerides and fish oil taken through this process results in triglycerides that can contain
medium-chain fatty acids and EPA, and DHA. The basic process results in the free fatty acids being
randomly re-esterified to the glycerol backbones. However, the process can be manipulated to place
specific fatty acids in preferred positions on the glycerol molecule. This option is quite expensive and
thus has not been adopted by the food industry to any degree. However, the random re-esterification
process has been used to produce structured triglycerides designed to facilitate the absorption of
both medium-chain and long-chain omega-3 fatty acids.
Diglycerides have been used as emulsifying agents in manufactured food products for many years.
More recently, more specialized diglycerides, termed diacylglycerols (DAGs), have been produced
by limited hydrolysis of triglycerides. This process results in a mixture of 1,2-diglycerides and
1,3-diglycerides. These diglycerides have absorption and metabolism characteristics like those of
medium-chain triglycerides; that is, some of the fatty acids escape re-esterification within the cells
of the small intestine and subsequent delivery to adipose tissue via the lymphatic system. Instead,
they are delivered to the liver, where they are oxidized to produce energy and possibly to produce
ketones. The result is an apparent caloric content that is somewhat less than the 9 kcal/g associated
with most fats.
1.7.5 Amino Acid –Based

This group has the potential to include intact protein (i.e., soy protein), polypeptides, amino acids, and
nitrogenous and sulfur amino acid derivatives. Today, a few amino acids are also being investigated
for their nutraceutical potential. Among these amino acids are arginine, ornithine, taurine, and
aspartic acid. Arginine has been speculated to be cardioprotective in that it is a precursor molecule
for the vasodilating substance nitric oxide (NO). Also, arginine may reduce atherogenesis.
The non-proteogenic amino acid taurine may have blood pressure–lowering properties as well
as antioxidant roles. However, the research in these areas is still inconclusive, and the effects of
supplementation of these amino acids on other aspects of human physiology is unclear. Several plant
molecules are formed via amino acids. A few of the most striking examples are isothiocyanates, indole-
3-carbinol, allyl sulfur compounds, and capsaicinoids. Another nutraceutical amino acid–derived
molecule is folic acid, which is believed to be cardioprotective in its role of minimizing homocysteine
levels. Other members of this group would include the tripeptide glutathione and choline.
Several amino acid–derived molecules have nutraceutical potential as well. These include
creatine, which is derived from three amino acids and found in meats. Creatine is an important
short-term anaerobic energy reserve in muscle tissue, brain, kidneys, and other tissue. Higher intakes
via supplementation can support gains and/or retention of strength and power and provide cellular
protection during transient anoxia. In addition, carnitine might have application in supporting
healthier blood glucose and lipid levels.
1.7.6 Microbes (Probiotics)
Where the other groupings of nutraceuticals involve molecules or elements, probiotics involve intact
microorganisms. This group largely includes bacteria, and its criteria are that a microbe must be
resistant to: Acid conditions of the stomach, bile, and digestive enzymes normally found in the
human gastrointestinal tract; able to colonize the human intestine; be safe for human consumption;
and, lastly, have scientifically proven efficacy. Among the bacterial species recognized as having
functional food potential are Lactobacillus acidophilus, L. plantarum, L. casei, Bifidobacterium
bifidum, B. infantis, and Streptococcus salvarius subspecies thermophilus. Some yeasts have been
noted as well, including Saccharomyces boulardii.
1.7.7 Minerals
Several minerals have been recognized for their nutraceutical potential and thus become candidates
for functional food recipes. Among the most obvious is calcium with relation to bone health, colon
cancer, and perhaps hypertension and cardiovascular disease. Potassium has also been purported
to reduce hypertension and thus improve cardiovascular health. A couple of trace minerals have
also been found to have nutraceutical potential. These include copper, selenium, manganese, and
zinc. Their nutraceutical potential is usually discussed in relation to antioxidation. Copper, zinc,
and manganese are components of superoxide dismutase (SOD) enzymes, whereas selenium is a
component of glutathione peroxidase. Certainly, more investigation is required in trace elements
considering their metabolic relationships to other nutrients and the potential for toxicity.
REFERENCES
1. World Health Organization Life Expectancy. http://www.who.int/gho/mortality_burden_disease/
life_tables/situation_trends/en/
2. WHO | Obesity and overweight—World Health Organization—www.who.int/mediacentre/factsheets/
fs311/en/
3. #stateofobesity http://stateofobesity.org/adult-obesity/
4. Kalra, E.K. Nutraceutical—Definition and Introduction. AAPS PharmSci., 2003; 5: Article 25 (found at
http://www.aapsj.org/).
5. DeFelice, S.L. What Is a True Nutraceutical? And What Is the Nature and Size of the U.S. Market? 1994,
http://www.fimdefelice.org/archives/arc.whatisnut.html.
6. International Food Information Council Web site, http://ific.org/nutrition/functional/index.cfm, 2006.
7. International Life Sciences Institute of North America Web site, http://www.ilsi.org/, 2006.
8. Health Canada, http://www.hc-sc.gc.ca, 2006.
9. Sports Nutrition and Weight Management Report © 2018 Informa. https://www.nutritionbusinessjournal.
com/reports/2018-sports-nutrition-and-weight-management-report/
10. Academy of Nutrition & Dietetics. Position of the Academy of Nutrition and Dietetics: Functional Foods.
J Acad. Nutr. Diet, 113: 1096–1103, 2013.
11. U.S. Food and Drug Administration. Center for Food Safety and Applied Nutrition, A Food Labeling
Guide, http://www.cfsan.fda.gov.
12. Miller, E.G., Gonzales-Sanders, A.P., Couvillon, A.M., Binnie, W.H., Hasegawa, S., and Lam, L.K.T.
Citrus liminoids as inhibitors of oral carcinogenesis. Food Technol., 48: 110–114, 1994.
13. Fong, C.H., Hasegawa, S., Herman, Z., and Ou, P. Liminoid glucosides in commercial citrus juices,
J. Food Sci., 54: 1505–1506, 1990.
14. Yu, R., Yamada, A., Watanabe, K., Yazawa, K., Takeyama, H., Matsunaga, T., and Kurane, R., Production
of eicosapentaenoic acid by a recombinant marine cyanobacterium, Synechococcus sp. Lipids, 35(10):
1061–4, 2000.
15. Duan L., Guo L., Wang L., Yin Q., Zhang C.M., Zheng Y.G., and Liu E.H. Application of metabolomics in
toxicity evaluation of traditional Chinese medicines. Chin. Med., 13: 60, 2018 Dec 4.
16. Shaw, D., Leon, C., Kolev, S., and Murray, V., Traditional remedies and food supplements: A 5-year
toxicological study (1991–1995), Drug Saf., 17: 342–56, 1997.
17. Taiz, L. and Zeiger, E., Plant defenses, in Plant Physiology, 2nd ed., Sinauer Associates, Sunderland, MA, 1998.
18. Wattenberg, L.W. and Lam, L.K.T., Protective effects of coffee constituents on carcinogenesis in
experimental animals, Banbury Rep., 17: 137–145, 1984.
19. Miller, E.G., McWhorter, K., Rivera-Hidalgo, F., Wright, J.M., Hirsbrunner, P., and Sunahara, G.I.,
Kahweol and cafestol: Inhibitors of hamster buccal pouch carcinogenesis, Nutr. Cancer, 15: 41–46, 1991.
20. Miller, E.G., Gonzalez-Sanders, A.P., Couvillon, A.M., Binnie, W.H., Hasegawa, S., and Lam, L.K.T.,
Citrus limonoids as inhibitors of oral carcinogenesis, Food Technol., 110–114, 1994.
21. Hasegawa, S., Bennet, R.D., Herman, Z., Fong, C.H., and Ou, P., Limonoids glucosides in citrus,
Phytochemistry, 28: 1717–1720, 1989.
22. Chang, M.S., Lee, S.G., and Rho, H.M., Transcriptional activation of Cu/Zn superoxide dismutase and catalase
genes by panaxadiol ginsenosides extracted from Panax ginseng, Phytother. Res., 13(8): 641–644, 1999.
23. Lee, S.J., Sung, J.H., Lee, S.J., Moon, C.K., and Lee, B.H., Antitumor activity of a novel ginseng saponin
metabolite in human pulmonary adenocarcinoma cells resistant to cisplatin, Cancer Lett., 144(1): 39–43, 1999.
1. https://www.fda.gov/AboutFDA/WhatWeDo/History/FOrgsHistory/EvolvingPowers/ucm124403.htm
2. https://www.fda.gov/AboutFDA/Transparency/Basics/ucm214416.htm
4. https://www.fda.gov/AboutFDA/Transparency/Basics/ucm214416.htm
5. A Practical Guide to FDA’s Food and Drug Law and Regulation, Fifth Edition, Chapter 12—Page 352.
7. https://www.fda.gov/downloads/aboutfda/whatwedo/history/productregulation/ucm593507.pdf
8. https://www.fda.gov/downloads/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/
UCM515733.pdf
9. http://media.ca11.uscourts.gov/opinions/pub/files/201713376.pdf
10. https://www.fda.gov/Food/DietarySupplements/UsingDietarySupplements/ucm480069.htm
11. https://www.gpo.gov/fdsys/pkg/STATUTE-108/pdf/STATUTE-108-Pg4325.pdf
12. https://newdrugapprovals.org/tag/lovaza/
13. https://www.gpo.gov/fdsys/pkg/STATUTE-108/pdf/STATUTE-108-Pg4325.pdf
14. https://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/
DietarySupplements/ucm2006823.htm
20. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=101.5
22. Brown, A.C. An overview of herb and dietary supplement efficacy, safety and government regulations
in the United States with suggested improvements. Part 1 of 5 series. Food. Chem. Toxicol. 2017, 107,
449–471, doi:10.1016/j.fct.2016.11.001.
23. http://www.ahpa.org/Portals/0/PDFs/AHPA_Report_Aug_2019--Recall%20Excerpt.pdf
1. Aune D, Giovannucci E, Boffetta P, Fadnes LT, Keum NN, Norat T, Greenwood DC, Riboli E, Vatten LJ,
Tonstad S. Fruit and vegetable intake and the risk of cardiovascular disease, total cancer and all-cause
mortality—A systematic review and dose-response meta-analysis of prospective studies. Int J Epidemiol.
2017;46:1029–56.
2. Heber D. Vegetables, fruits and phytoestrogens in the prevention of diseases. J Postgrad Med.
2004;50:145–9.
3. Britton G, Liaaen-Jensen S, Pfander H, editors. Carotenoids Handbook. Basel, Switzerland: Birkhauser
Verlag; 2004.
4. Khachik F, Spangler C, Smith J, Canfield L, Steck A, Pfander H. Identification, quantification, and
relative concentrations of carotenoids and their metabolites in human milk and serum. Anal Chem.
1997;69:1873–81.
5. Britton G. Structure and properties of carotenoids in relation to function. FASEB J. 1995;9:1551–8.
6. Hartsen F. Beiträge zur organischen chemie, ueber den einfluss der jahreszeiten auf die chemie der
pflanzen. Chem Zentr. 1873;4:205.
7. Millardet A. Note sur une substance colorante nouvelle (solanorubine) decouverte dans la tomate. Bull
Soc Sci Nancy. 1875;2:21–32.
8. Burrows TL, Williams R, Rollo M, Wood L, Garg ML, Jensen M, Collins CE. Plasma carotenoid levels
as biomarkers of dietary carotenoid consumption: A systematic review of the validation studies. J Nutr
Intermed Metab. 2015;2:15–64.
9. Clinton SK, Emenhiser C, Schwartz SJ, Bostwick DG, Williams AW, More BJ, Erdman Jr. JW. cis-trans
lycopene isomers, carotenoids, and retinol in the human prostate. Cancer Epidemiol Biomarkers Prev.
1996;5:823–33.
10. Cooperstone JL, Schwartz SJ. Recent insights into health benefits of carotenoids. In: Carle R, Schweiggert
R, editors. Handbook on Natural Pigments in Food and Beverages: Industrial Applications for Improving
Food Color. Woodhead Publishing; 2016, pp. 473–97.
11. Story EN, Kopec RE, Schwartz SJ, Harris GK. An update on the health effects of tomato lycopene. Annu
Rev Food Sci Technol. 2010;1:189–210.
12. Clinton SK. Lycopene: Chemistry, biology, and implications for human health and disease. Nutr Rev.
1998;56:35–51.
13. U.S. Department of Agriculture ARS, U.S. Department of Agriculture Agricultural Research Service
NDL. USDA National Nutrient Database for Standard Reference, Release 2. 2016.
14. Moran NE, Cichon MJ, Riedl KM, Grainger EM, Schwartz SJ, Novotny JA, Erdman Jr. JW, Clinton
SK. Compartmental and noncompartmental modeling of 13C-lycopene absorption, isomerization, and
distribution kinetics in healthy adults. Am J Clin Nutr. 2015;102:1436–49.
15. Harris WM, Spurr AR. Chromoplasts of tomato fruits. II. The red tomato. Am J Bot. 1969;56:380–9.
16. Fray RG, Grierson D. Identification and genetic analysis of normal and mutant phytoene synthase genes
of tomato by sequencing, complementation and co-suppression. Plant Mol Biol. 1993;22:589–602.
17. Levin I, de Vos C, Tadmor Y, Bovy A, Lieberman M, Oren-Shamir M, Segev O, Kolotilin I, Keller M,
Ovadia R et al. High pigment tomato mutants—More than just lycopene (a review). Isr J Plant Sci.
2006;54:179–90.
18. Cooperstone JL, Ralston RA, Riedl KM, Haufe TC, Schweiggert RM, King SA, Timmers CD, Francis
DM, Lesinski GB, Clinton SK, et al. Enhanced bioavailability of lycopene in humans when consumed
as cis-isomers from tangerine tomatoes compared to red tomato juices, a randomized, cross-over clinical
trial. Mol Nutr Food Res. 2015;59:658–69.
19. Shi J, Le Maguer M. Lycopene in tomatoes: Chemical and physical properties affected by food processing.
Crit Rev Biotechnol. 2000;20:293–334.
20. Nguyen ML, Schwartz SJ. Lycopene stability during food processing. Proc Soc Exp Biol Med.
1998;218:101–5.
21. Nguyen ML, Francis DM, Schwartz SJ. Thermal isomerisation susceptibility of carotenoids in different
tomato varieties. J Sci Food Agric. 2001;81:910–7.
22. Unlu NZ, Bohn T, Francis DM, Nagaraja HN, Clinton SK, Schwartz SJ. Lycopene from heat-induced cis-
isomer-rich tomato sauce is more bioavailable than from all-trans-rich tomato sauce in human subjects.
Br J Nutr. 2007;98:140–6.
23. Simpson KL, Chichester CO. Metabolism and nutritional significance of carotenoids. Annu Rev Nutr.
1981;1:351–74.
24. Cooperstone JL, Francis DM, Schwartz SJ. Thermal processing differentially affects lycopene and other
carotenoids in cis-lycopene containing, tangerine tomatoes. Food Chem. 2016;210:466–72.
25. Itsch ROB, Tto KOO, Seybold C, Fröhlich K, Bitsch R, Otto K, Böhm V, Fröhlich K, Bitsch R, Otto K
et al. Changes in contents of carotenoids and vitamin E during tomato processing. J Agric Food Chem.
2004;52:7005–10.
26. Schierle J, Bretzel W, Bühler I, Faccin N, Hess D, Steiner K, Schüep W. Content and isomeric ratio of
lycopene in food and human blood plasma. Food Chem. 1997;59:459–65.
27. Gartner C, Stahl W, Sies HH. Lycopene is more bioavailable from fresh tomatoes from tomato paste
than. Am J Clin Nutr. 1997;66:116–22.
28. Stahl W, Sies H. Uptake of lycopene and its geometrical isomers is greater from heat-processed than
from unprocessed tomato juice in humans. J Nutr. 1992;122:2161–6.
29. van het Hof KH, de Boer BC, Tijburg LBM, Lucius BRHM, Zijp I, West CE, Hautvast JGAJ, Weststrate
JA, Hof KH Van, Boer BCJ De et al. Carotenoid bioavailability in humans from tomatoes processed in
different ways determined from the carotenoid response in the triglyceride-rich lipoprotein fraction of
plasma after a single consumption and in plasma after four days of consumption. J Nutr. 2000;130:1189–96.
30. During A, Harrison EH. Intestinal absorption and metabolism of carotenoids: Insights from cell culture.
Arch Biochem Biophys. 2004;430:77–88.
31. Yonekura L, Nagao A. Intestinal absorption of dietary carotenoids. Mol Nutr Food Res. 2007;51:107–15.
32. van Vliet T, Schreurs WH, van den Berg H. Intestinal β-carotene absorption and cleavage in men:
Response of β-carotene and retinyl esters in the triglyceride-rich lipoprotein fraction after a single oral
dose of β-carotene. Am J Clin Nutr. 1995;62:110–6.
33. Kopec RE, Failla ML. Recent advances in the bioaccessibility and bioavailability of carotenoids and
effects of other dietary lipophiles. J Food Compos Anal. 2017;68:16–30.
34. Harrison EH, Kopec RE. Digestion and intestinal absorption of dietary carotenoids and vitamin A. In:
Physiology of the Gastrointestinal Tract. 6 edn. Elsevier Inc.; 2018, pp. 1133–51.
35. Moran NE, Mohn ES, Hason N, Erdman JW, Johnson EJ. Intrinsic and extrinsic factors impacting
absorption, metabolism, and health effects of dietary carotenoids. Adv Nutr. 2018;9:465–92.
36. Bohn T, Desmarchelier C, Dragsted LO, Nielsen CS, Stahl W, Rühl R, Keijer J, Borel P. Host-related
factors explaining interindividual variability of carotenoid bioavailability and tissue concentrations in
humans. Mol Nutr Food Res. 2017;61:1600685.
37. Castenmiller JJ, West CE, Castenmiller. Bioavailability of carotenoids. Pure Appl Chem.
1997;69:2145.
38. Castenmiller JJM, West CE. Bioavailability and bioconversion of carotenoids. Annu Rev Nutr.
1998;18:19–38.
39. Moran NE, Erdman JW, Clinton SK. Complex interactions between dietary and genetic factors impact
lycopene metabolism and distribution. In: Arch Biochem Biophys. Elsevier Inc.; 2013;539:171–80.
40. Harrison EH. Mechanisms involved in the intestinal absorption of dietary vitamin A and provitamin A
carotenoids. Biochim Biophys Acta. 2012;1821:70–7.
41. Ross AC, Harrison EH. Vitamin A nutrition aspects of retinoids and carotenoids. In: Zempleni J, Suttie
JW, Gregory III JF, Stover PJ, editors. Handbook of Vitamins. 5th edn. Boca Raton, FL: CRC Press;
2014, pp. 1–50.
42. van het Hof KH, West CE, Weststrate JA, Hautvast JG. Recent advances in nutritional sciences dietary
factors that affect the bioavailability of carotenoids 1. J Nutr. 2000;503–6.
43. Unlu NZ, Bohn T, Francis D, Clinton SK, Schwartz SJ. Carotenoid absorption in humans consuming
tomato sauces obtained from tangerine or high-beta-carotene varieties of tomatoes. J Agric Food Chem.
2007;55:1597–603.
44. Diwadkar-Navsariwala V, Novotny JA, Gustin DM, Sosman JA, Rodvold KA, Crowell JA, Stacewicz-
Sapuntzakis M, Bowen PE. A physiological pharmacokinetic model describing the disposition of
lycopene in healthy men. J Lipid Res. 2003;44:1927–39.
45. Gustin DM, Rodvold KA, Sosman JA, Diwadkar-Navsariwala V, Stacewicz-Sapuntzakis M, Viana M,
Crowell JA, Murray J, Tiller P, Bowen PE. Single-Dose pharmacokinetic study of lycopene delivered
in a well-defined food-based lycopene delivery system (tomato paste-oil mixture) in healthy adult male
subjects. Cancer Epidemiol Biomarkers Prev. 2004;13:850–60.
46. Zhou J, Gugger E, Erdman Jr. JW. The crystalline form of carotenes and the food matrix in carrot root
decrease the relative bioavailability of beta- and alpha-carotene in the ferret model. J Am Coll Nutr.
1996;15:84–91.
47. Schweiggert RM, Kopec RE, Villalobos-Gutierrez MG, Högel J, Quesada S, Esquivel P, Schwartz SJ,
Carle R. Carotenoids are more bioavailable from papaya than from tomato and carrot in humans: A
randomised cross-over study. Br J Nutr. 2014;111:490–8.
48. Schweiggert RM, Carle R. Carotenoid deposition in plant and animal foods and its impact on
bioavailability. Crit Rev Food Sci Nutr. 2017;57:1807–30.
49. Roodenburg AJC, Leenen R, Hof KH Van, Weststrate JA, Tijburg LBM. Amount of fat in the diet affects
bioavailability of lutein esters but not alpha-carotene, beta-carotene and vitamin E in humans. Am J Clin
Nutr. 2000;71:1187–93.
50. Kopec RE, Cooperstone JL, Schweiggert RM, Young GS, Harrison EH, Francis DM, Clinton SKS,
Schwartz SJ. Avocado consumption enhances human postprandial provitamin A absorption and
conversion from a novel high-β-carotene tomato sauce and from carrots. J Nutr. 2014;144:1158–66.
51. Unlu NZ, Bohn T, Clinton SK, Schwartz SJ. Carotenoid absorption from salad and salsa by humans is
enhanced by the addition of avocado or avocado oil. J Nutr. 2005;135:431–6.
52. Brown MJ, Ferruzzi MG, Nguyen ML, Cooper DA, Eldridge AL, Schwartz SJ, White WS. Carotenoid
bioavailability is higher from salads ingested with full-fat than with fat-reduced salad dressings as
measured with electrochemical detection. Am J Clin Nutr. 2004;80:396–403.
53. Goltz SR, Sapper TN, Failla ML, Campbell WW, Ferruzzi MG. Carotenoid bioavailability from raw
vegetables and a moderate amount of oil in human subjects is greatest when the majority of daily
vegetables are consumed at one meal. Nutr Res. 2013;33:358–66.
54. Goulinet S, Chapman M. Plasma LDL and HDL subspecies are heterogeneous in particle content
of tocopherols and oxygenated and hydrocarbon carotenoids. Relevance to oxidative resistance and
atherogenesis. Arterioscler Thromb Vasc Biol. 1997;17:786–96.
55. Goltz SR, Ferruzzi MG. Carotenoid bioavailability: Influence of dietary lipid and fiber. In: Tanumihardjo
SA, editor. Carotenoids and Human Health. New York, NY: Springer Science+Business Media; 2013,
pp. 111–28.
56. Floreani A, Baragiotta A, Martines D, Naccarato R, D’odorico A. Plasma antioxidant levels in chronic
cholestatic liver diseases. Aliment Pharmacol Ther. 2000;14:353–8.
57. Borel P, Desmarchelier C, Nowicki M, Bott R. Lycopene bioavailability is associated with a combination
of genetic variants. Free Radic Biol Med. 2015;83:238–44.
58. Ferrucci L, Perry JRBB, Matteini A, Perola M, Tanaka T, Silander K, Rice N, Melzer D, Murray A,
Cluett C et al. Common variation in the β-carotene 15,15′-monooxygenase 1 gene affects circulating
levels of carotenoids: A genome-wide association study. Am J Hum Genet. 2009;84:123–33.
59. Wang TT, Edwards AJ, Clevidence BA. Strong and weak plasma response to dietary carotenoids
identified by cluster analysis and linked to beta-carotene 15,15’-monooxygenase 1 single nucleotide
polymorphisms. J Nutr Biochem. 2013;24:1538–46.
60. Borel P. Genetic variations involved in interindividual variability in carotenoid status. Mol Nutr Food
Res. 2012;56:228–40.
61. Zubair N, Kooperberg C, Liu J, Di C, Peters U, Neuhouser ML. Genetic variation predicts serum lycopene
concentrations in a multiethnic population of postmenopausal women. J Nutr. 2015;145:187–92.
62. Desmarchelier C, Landrier J-F, Borel P. Genetic factors involved in the bioavailability of tomato
carotenoids. Curr Opin Clin Nutr Metab Care. 2018;21:489–97.
63. Casso D, White E, Patterson R, Agurs-Collins T, Kooperberg C, Haines P. Correlates of serum lycopene
in older women. Nutr Cancer. 2000;36:163–9.
64. Brady WE, Mares-Perlman JA, Bowen P, Stacewicz-Sapuntzakis M. Human serum carotenoid
concentrations are related to physiologic and lifestyle factors. J Nutr. 1996;126:129–37.
65. Walmsley CM, Bates CJ, Prentice A, Cole TJ. Relationship between alcohol and nutrient intakes and
blood status indices of older people living in the UK: Further analysis of data from the National Diet
and Nutrition Survey of people aged 65 years and over, 1994/5. Public Health Nutr. 1998;1:157–67.
66. Van Breemen RB, Sharifi R, Viana M, Pajkovic N, Zhu D, Yuan L, Yang Y, Bowen PE, Stacewicz-
Sapuntzakis M. Antioxidant effects of lycopene in African American men with prostate cancer or benign
prostate hyperplasia: A randomized, controlled trial. Cancer Prev Res. 2011;4:711–8.
67. Yeum K-J, Ahn S-H, de Paiva SAR, Lee-Kim YC, Krinsky NI, Russell RM. Correlation between
carotenoid concentrations in serum and normal breast adipose tissue of women with benign breast tumor
or breast cancer. J Nutr. 1998;128:1920–6.
68. Walfisch Y, Walfisch S, Agbaria R, Levy J, Sharoni Y. Lycopene in serum, skin and adipose tissues after
tomato-oleoresin supplementation in patients undergoing haemorrhoidectomy or peri-anal fistulotomy.
Br J Nutr. 2003;90:759–66.
69. Chen L, Stacewicz-Sapuntzakis M, Duncan C, Sharifi R, Ghosh L, van Breemen R, Ashton D, Bowen
PE. Oxidative DNA damage in prostate cancer patients consuming tomato sauce-based entrees as a
whole-food intervention. J Natl Cancer Inst. 2001;93:1872–9.
70. Schwarz S, Obermüller-Jevic UC, Hellmis E, Koch W, Jacobi G, Biesalski H-K. Lycopene inhibits
disease progression in patients with benign prostate hyperplasia. J Nutr. 2008;138:49–53.
71. Shim E, Yeum K-J, Tang G, Ahn SH, Hwang J, Lee-Kim YC. Retinoids, carotenoids, and tocopherols
in breast adipose tissue and serum of benign breast disease and breast cancer patients. Nutr Cancer.
2012;64:956–63.
72. Peng YM, Peng YS, Lin Y, Moon T, Baier M. Micronutrient concentrations in paired skin and plasma
of patients with actinic keratoses: Effect of prolonged retinol supplementation. Cancer Epidemiol
Biomarkers Prev. 1993;2:145–50.
73. Bowen P, Chen L, Stacewicz-Sapuntzakis M, Duncan C, Sharifi R, Ghosh L, Kim H-S,
Christov-Tzelkov K, van Breemen R. Tomato sauce supplementation and prostate cancer: Lycopene
accumulation and modulation of biomarkers of carcinogenesis. Exp Biol Med. 2002;227:886–93.
74. Freeman VL, Meydani M, Yong S, Pyle J, Wan Y, Arvizu-Durazo R, Liao Y. Prostatic levels of
tocopherols, carotenoids, and retinol in relation to plasma levels and self-reported usual dietary intake.
Am J Epidemiol. 2000;151:109–18.
75. Kaplan LA, Lau JM, Stein EA. Carotenoid composition, concentrations, and relationships in various
human organs. Clin Physiol Biochem. 1990;8:1–10.
76. Stahl W, Schwarz W, Sundquist AR, Sies H. cis-trans isomers of lycopene and beta-carotene in human
serum and tissues. Arch Biochem Biophys. 1992;294:173–7.
77. Khachik F, Carvalho L, Bernstein PS, Muir GJ, Zhao D-Y, Katz NB. Chemistry, distribution, and
metabolism of tomato carotenoids and their impact on human health. Exp Biol Med. 2002;227:845–51.
78. Schmitz HH, Poor CL, Wellman RB, Erdman Jr. JW. Concentrations of selected carotenoids and vitamin
A in human liver, kidney and lung tissue. J Nutr. 1991;121:1613–21.
79. Parker RS. Carotenoid and tocopherol composition of human adipose tissue. Am J Clin Nutr. 1988;47:33–6.
80. Nierenberg DW, Stukel TA, Baron JA, Dain BJ, Greenberg ER, Group TSCPS. Determinants of increase
in plasma concentration of ß-carotene after chronic oral supplementation. Am J Clin Nutr. 1991;53:1443–9.
81. Peng Y-M, Peng Y-S, Lin Y, Moon T, Roe DJ, Ritenbaugh C. Concentrations and plasma-tissue-diet
relationships of carotenoids, retinoids, and tocopherols in humans. Nutr Cancer. 1995;23:233–46.
82. Craft N, Haitema T, Garnett K, Fitch K, Dorey C. Carotenoid, tocopherol, and retinol concentrations in
elderly human brain. J Nutr Heal Aging. 2004;8:156–62.
83. Grainger EM, Hadley CW, Moran NE, Riedl KM, Gong MC, Pohar K, Schwartz SJ, Clinton SK. A
comparison of plasma and prostate lycopene in response to typical servings of tomato soup, sauce or
juice in men before prostatectomy. Br J Nutr. 2015;114:596–607.
84. Lipkie TE, Morrow AL, Jouni ZE, McMahon RJ, Ferruzzi MG. Longitudinal survey of carotenoids in
human milk from urban cohorts in China, Mexico, and the USA. PLOS ONE. 2015;10:1–14.
85. Boileau TW-MM, Boileau AC, Erdman Jr JW. Bioavailability of all-trans and cis-isomers of lycopene.
Exp Biol Med. 2002;227:914–9.
86. Lindshield BL, Canene-Adams K, Erdman Jr. JW. Lycopenoids: Are lycopene metabolites bioactive?
Arch Biochem Biophys. 2007;458:136–40.
87. Wyss A, Wirtz G, Woggon W-D, Brugger R, Wyss M, Friedlein A, Bachmann H, Hunziker W. Cloning
and expression of β,β-carotene 15,15′-dioxygenase. Biochem Biophys Res Commun. 2000;271:334–6.
88. von Lintig J, Vogt K. Filling the gap in vitamin A research. J Biol Chem. 2000;275:11915–20.
89. dela Seña C, Narayanasamy S, Riedl KM, Curley RW, Schwartz SJ, Harrison EH. Substrate specificity
of purified recombinant human β-carotene 15,15′-oxygenase (BCO1). J Biol Chem. 2013;288:37094–103.
90. Kiefer C, Hessel S, Lampert JM, Vogt K, Lederer MO, Breithaupt DE, von Lintig J. Identification and
characterization of a mammalian enzyme catalyzing the asymmetric oxidative cleavage of provitamin A.
J Biol Chem. 2001;276:14110–6.
91. dela Seña C, Sun J, Narayanasamy S, Riedl KM, Yuan Y, Curley RW, Schwartz SJ, Harrison EH.
Substrate specificity of purified recombinant chicken β-carotene 9′,10′-oxygenase (BCO2). J Biol Chem.
2016;291:14609–19.
92. Kopec RE, Riedl KM, Harrison EH, Curley RW, Hruszkewycz DP, Clinton SK, Schwartz SJ. Identification and
quantification of apo-lycopenals in fruits, vegetables, and human plasma. J Agric Food Chem. 2010;58:3290–6.
93. Tan H-L, Moran NE, Cichon MJ, Riedl KM, Schwartz SJ, Erdman JW, Pearl DK, Thomas-Ahner JM,
Clinton SK. β-carotene-9′,10′-oxygenase status modulates the impact of dietary tomato and lycopene on
hepatic nuclear receptor-, stress-, and metabolism-related gene expression in mice. J Nutr. 2014;144:431–9.
94. Cichon MJ, Moran NE, Riedl KM, Schwartz SJ, Clinton SK. Identification of an epoxide metabolite of
lycopene in human plasma using13C-labeling and QTOF-MS. Metabolites. 2018;8.
95. Cooperstone JL, Novotny JA, Riedl KM, Cichon MJ, Francis DM, Curley RW, Schwartz SJ, Harrison
EH. Limited appearance of apocarotenoids is observed in plasma after consumption of tomato juices: A
randomized human clinical trial. Am J Clin Nutr. 2018;108:1–8.
96. Ross AB, Vuong LT, Ruckle J, Synal HA, Schulze-ko T, Wertz K, Ru R, Liberman RG, Skipper PL,
Tannenbaum SR et al. Lycopene bioavailability and metabolism in humans: An accelerator mass
spectrometry study. Am J Clin Nutr. 2011;93:1263–73.
97. Giovannucci E, Ascherio A, Rimm EB, Stampfer MJ, Colditz GA, Willett WC. Intake of carotenoids
and retinol in relation to risk of prostate cancer. J Natl Cancer Inst. 1995;87:1767–76.
98. Gann PH, Ma J, Giovannucci E, Willett W, Sacks FM, Hennekens CH, Stampfer MJ. Lower prostate cancer risk
in men with elevated plasma lycopene levels: Results of a prospective analysis. Cancer Res. 1999;59:1225–30.
99. Rowles JL, Katherine III, Catherine MR, Sookyoung CA, Ruopeng J, Jr. JWE. Processed and raw tomato
consumption and risk of prostate cancer: A systematic review and dose–response meta-analysis. In:
Prostate Cancer Prostatic Dis. US: Springer; 2017.
100. Chen J, Song Y, Zhang L. Lycopene/tomato consumption and the risk of prostate cancer: A systematic
review and meta-analysis of prospective studies. J Nutr Sci Vitaminol. 2013;59:213–23.
101. Xu X, Li J, Wang X, Wang S, Meng S, Zhu Y, Liang Z, Zheng X, Xie L. Tomato consumption and
prostate cancer risk: A systematic review and meta-analysis. Sci Rep. 2016;6:1–8.
102. Etminan M, Takkouche B, Caamano-Isorna F. The role of tomato products and lycopene in the prevention
of prostate cancer: A meta-analysis of observational studies. Cancer Epidemiol Biomarkers Prev.
2004;13:340–5.
103. Wang Y, Cui R, Xiao Y, Fang J, Xu Q. Effect of carotene and lycopene on the risk of prostate cancer: A
systematic review and dose-response meta-analysis of observational studies. PLOS ONE. 2015;10:1–20.
104. Chen P, Zhang W, Wang X, Zhao K, Negi DS, Zhuo L, Qi M, Wang X, Zhang X. Lycopene and risk of
prostate cancer: A systematic review and meta-analysis. Med. 2015;94:e1260.
105. Kucuk O, Sarkar FH, Sakr W, Khachik F, Djuric Z, Banerjee M, Pollak MN, Bertram JS, Wood Jr. DP.
Lycopene in the treatment of prostate cancer. Pure Appl Chem. 2002;74:1443.
106. Kucuk O, Sarkar FH, Sakr W, Djuric Z, Pollak MN, Khachik F, Li Y-W, Banerjee M, Grignon D, Bertram
JS et al. Phase II randomized clinical trial of lycopene supplementation before radical prostatectomy.
Cancer Epidemiol Biomarkers Prev. 2001;10:861–8.
107. Kucuk O, Sarkar FH, Djuric Z, Sakr W, Pollak MN, Khachik F, Banerjee M, Bertram JS, Wood DP,
Wood Jr DP. Effects of lycopene supplementation in patients with localized prostate cancer. Exp Biol
Med. 2002;227:881–5.
108. Bunker CH, McDonald AC, Evans RW, de la Rosa N, Boumosleh JM, Patrick AL. A randomized trial of
lycopene supplementation in Tobago men with high prostate cancer risk. Nutr Cancer. 2007;57:130–7.
109. Gann PH, Deaton RJ, Rueter EE, van Breemen RB, Nonn L, Macias V, Han M, Ananthanarayanan V.
A phase II randomized trial of lycopene-rich tomato extract among men with high-grade prostatic
intraepithelial neoplasia. Nutr Cancer. 2015;67:1104–12.
110. Ansari MS, Gupta NP. A comparison of lycopene and orchidectomy vs orchidectomy alone in the
management of advanced prostate cancer. BJU Int. 2003;92:375–8.
111. Vaishampayan U, Hussain M, Banerjee M, Seren S, Sarkar FH, Fontana J, Forman JD, Cher ML,
Powell I, Pontes JD, et al. Lycopene and soy isoflavones in the treatment of prostate cancer. Nutr
Cancer. 2007;59:1–7.
112. Barber NJ, Zhang X, Zhu G, Pramanik R, Barber JA, Martin FL, Morris JDH, Muir GH. Lycopene
inhibits DNA synthesis in primary prostate epithelial cells in vitro and its administration is associated
with a reduced prostate-specific antigen velocity in a phase II clinical study. Prostate Cancer Prostatic
Dis. 2006;9:407–13.
113. Kumar NB, Besterman-Dahan K, Kang L, Pow-Sang J, Xu P, Allen K, Riccardi D, Krischer JP. Results
of a randomized clinical trial of the action of several doses of lycopene in localized prostate cancer:
Administration prior to radical prostatectomy. Clin Med Urol. 2008;1:1–14.
114. Jatoi A, Burch P, Hillman D, Vanyo JM, Dakhil S, Nikcevich D, Rowland K, Morton R, Flynn PJ,
Young C et al. A tomato-based, lycopene-containing intervention for androgen-independent prostate
cancer: Results of a phase II study from The North Central Cancer Treatment Group. Urology.
2007;69:289–94.
115. Clark PE, Hall MC, Borden LS, Miller AA, Hu JJ, Lee WR, Stindt D, D’Agostino R, Lovato J, Harmon M
et al. Phase I-II prospective dose-escalating trial of lycopene in patients with biochemical relapse of
prostate cancer after definitive local therapy. Urology. 2006;67:1257–61.
116. Walfisch S, Walfisch Y, Kirilov E, Linde N, Mnitentag H, Agbaria R, Sharoni Y, Levy J. Tomato
lycopene extract supplementation decreases insulin-like growth factor-I levels in colon cancer patients.
Eur J Cancer Prev. 2007;16:298–303.
117. Vrieling A, Voskuil DW, Bonfrer JM, Korse CM, Van Doorn J, Cats A, Depla AC, Timmer R, Witteman
BJ, Van Leeuwen FE et al. Lycopene supplementation elevates circulating insulin-like growth factor-
binding protein-1 and -2 concentrations in persons at greater risk of colorectal cancer. Am J Clin Nutr.
2007;86:1456–62.
118. Mannisto S, Yaun S-S, Hunter DJ, Spiegelman D, Adami H-O, Albanes D, Van Den Brandt PA, Buring
JE, Cerhan JR, Colditz GA et al. Dietary carotenoids and risk of colorectal cancer in a pool analysis of
11 cohort studies. Am J Epidemiol. 2007;165:246–55.
119. Eliassen AH, Liao X, Rosner B, Tamimi RM, Tworoger SS, Hankinson SE. Plasma carotenoids and risk
of breast cancer over 20 y of follow-up. Am J Clin Nutr. 2015;101:1197–205.
120. Eliassen AH, Hendrickson SJ, Brinton LA, Buring JE, Campos H, Dai Q, Dorgan JF, Franke AA,
Gao Y, Goodman MT et al. Circulating carotenoids and risk of breast cancer: Pooled analysis of eight
prospective studies. J Natl Cancer Inst. 2012;104:1905–16.
121. Aune D, Chan DSM, Vieira AR, Rosenblatt DAN, Vieira R, Greenwood DC, Norat T. Dietary compared
with blood concentrations of carotenoids and breast cancer risk: A systematic review and meta-analysis
of prospective. Am J Clin Nutr. 2012;96:356–73.
122. Hu F, Wang Yi B, Zhang W, Liang J, Lin C, Li D, Wang F, Pang D, Zhao Y. Carotenoids and breast
cancer risk: A meta-analysis and meta-regression. Breast Cancer Res Treat. 2012;131:239–53.
123. Yang T, Yang X, Wang X, Wang Y, Song Z. The role of tomato products and lycopene in the prevention
of gastric cancer: A meta-analysis of epidemiologic studies. Med Hypotheses. 2013;80:383–8.
124. Dauchet L, Amouyel P, Hercberg S, Dallongeville J. Fruit and vegetable consumption and risk of coronary
heart disease: A meta-analysis of cohort studies. J Nutr. 2006;136:2588–93.
125. He F, Nowson C, Lucas M, MacGregor G. Increased consumption of fruit and vegetables is related
to a reduced risk of coronary heart disease: Meta-analysis of cohort studies. J Hum Hypertens.
2007;21:717–28.
126. Oyebode O, Gordon-Dseagu V, Walker A, Mindell JS. Fruit and vegetable consumption and all-cause,
cancer and CVD mortality: Analysis of Health Survey for England data. J Epidemiol Community Health.
2014;68:856–62.
127. Sesso HD, Gaziano JM. Heart and vascular diseases. In: Krinsky NI, Mayne ST, Sies H, editors:
Carotenoids in Health and Disease. New York, NY: Marcel Dekker; 2004, pp. 473–90.
128. Böhm V. Lycopene and heart health. Mol Nutr Food Res. 2012;56:296–303.
129. Mordente A, Guantario B, Meucci E, Silvestrini A, Lombardi E, Martorana GE, Giardina B, Bohm V,
Böhm V. Lycopene and cardiovascular diseases: An update. Curr Med Chem. 2011;18:1146–63.
130. Burton-Freeman BM, Sesso HD. Whole food versus supplement : Comparing the clinical evidence of
tomato intake and lycopene supplementation on cardiovascular risk factors. Adv Nutr. 2014;5:457–85.
131. Ried K, Fakler P. Protective effect of lycopene on serum cholesterol and blood pressure: Meta-analyses
of intervention trials. Maturitas. 2011;68:299–310.
132. Cheng HM, Koutsidis G, Lodge JK, Ashor A, Siervo M, Lara J. Tomato and lycopene supplementation
and cardiovascular risk factors: A systematic review and meta-analysis. Atherosclerosis. 2017;257:100–8.
133. Johnson EJ, Krinsky NI. Carotenoids and coronary heart disease. In: Britton G, Liaaen-Jensen S, Pfander
H, editors. Carotenoids Volume 5: Nutrition and Health. Birkhauser Verkag Basek; 2009, pp. 288–300.
134. Agarwal S, Rao AV. Tomato lycopene and low density lipoprotein oxidation: A human dietary intervention
study. Lipids. 1998;33:981–4.
135. Bub A, Watzl B, Abrahamse L, Delincée H, Adam S, Wever J, Müller H, Rechkemmer G. Moderate
intervention with carotenoid-rich vegetable products reduces lipid peroxidation in men. J Nutr.
2000;130:2200–6.
136. Chopra M, O’Neill ME, Keogh N, Wortley G, Southon S, Thurnham DI. Influence of increased fruit and
vegetable intake on plasma and lipoprotein carotenoids and LDL oxidation in smokers and nonsmokers.
Clin Chem. 2000;46:1818–29.
137. Upritchard JE, Sutherland WH, Mann JI. Effect of supplementation with tomato juice, vitamin E, and
vitamin C on LDL oxidation and products of inflammatory activity in type 2 diabetes. Diabetes Care.
2000;23:733–8.
138. Hadley CW, Clinton SK, Schwartz SJ. The consumption of processed tomato products enhances plasma
lycopene concentrations in association with a reduced lipoprotein sensitivity to oxidative damage. J Nutr.
2003;133:727–32.
139. Briviba K, Kulling SE, Moseneder J, Watzl B, Rechkemmer G, Bub A. Effects of supplementing a low-
carotenoid diet with a tomato extract for 2 weeks on endogenous levels of DNA single strand breaks and
immune functions in healthy non-smokers and smokers. Carcinogenesis. 2004;25:2373–8.
140. Burton-Freeman B, Talbot J, Park E, Krishnankutty S, Edirisinghe I. Protective activity of processed
tomato products on postprandial oxidation and inflammation: A clinical trial in healthy weight men and
women. Mol Nutr Food Res. 2012;56:622–31.
141. Visioli F, Riso P, Grande S, Galli C, Porrini M. Protective activity of tomato products on in vivo markers
of lipid oxidation. Eur J Nutr. 2003;42:201–6.
142. Silaste ML, Alfthan G, Aro A, Kesäniemi YA, Hörkkö S. Tomato juice decreases LDL cholesterol levels
and increases LDL resistance to oxidation. Br J Nutr. 2007;98:1251–8.
143. Ghavipour M, Saedisomeolia A, Djalali M, Sotoudeh G, Eshraghyan MR, Malekshahi Moghadam A,
Wood LG, Moghadam AM, Wood LG. Tomato juice consumption reduces systemic inflammation in
overweight and obese females. Br J Nutr. 2013;109:1–5.
144. McEneny J, Wade L, Young IS, Masson L, Duthie G, McGinty A, McMaster C, Thies F. Lycopene
intervention reduces inflammation and improves HDL functionality in moderately overweight middle-
aged individuals. J Nutr Biochem. 2012;1:1–6.
145. Gajendragadkar PR, Hubsch A, Mäki-Petäjä KM, Serg M, Wilkinson IB, Cheriyan J. Effects of oral
lycopene supplementation on vascular function in patients with cardiovascular disease and healthy
volunteers: A randomised controlled trial. PLOS ONE. 2014;9:e99070.
146. Steinberg FM, Chait A. Antioxidant vitamin supplementation and lipid peroxidation in smokers. Am J
Clin Nutr. 1998;68:319–27.
147. Dugas TR, Morel DW, Harrison EH. Dietary supplementation with β-carotene, but not with lycopene,
inhibits endothelial cell-mediated oxidation of low-density lipoprotein. Free Radic Biol Med.
1999;26:1238–44.
148. Sutherland WH, Walker RJ, De Jong SA, Upritchard JE. Supplementation with tomato juice increases
plasma lycopene but does not alter susceptibility to oxidation of low-density lipoproteins from renal
transplant recipients. Clin Nephrol. 1999;52:30–36.
149. Bub A, Barth SW, Watzl B, Briviba K, Rechkemmer G. Paraoxonase 1 Q192R (PON1-192) polymorphism
is associated with reduced lipid peroxidation in healthy young men on a low-carotenoid diet supplemented
with tomato juice. Br J Nutr. 2005;93:291.
150. Rao AV. Processed tomato products as a source of dietary lycopene: Bioavailability and antioxidant
properties. Can J Diet Pract Res. 2004;65:161–5.
151. Shidfar F, Froghifar N, Vafa M, Rajab A, Hosseini S, Shidfar S, Gohari M. The effects of tomato
consumption on serum glucose, apolipoprotein B, apolipoprotein A-I, homocysteine and blood pressure
in type 2 diabetic patients. Int J Food Sci Nutr. 2011;62:289–94.
152. Thies F, Masson LF, Rudd A, Vaughan N, Tsang C, Brittenden J, Simpson WG, Duthie S, Horgan
GW, Duthie G. Effect of a tomato-rich diet on markers of cardiovascular disease risk in moderately
overweight, disease-free, middle-aged adults: A randomized controlled trial. Am J Clin Nutr.
2012;95:1013–22.
153. Wu X, Schauss AG. Mitigation of inflammation with foods. J Agric Food Chem. 2012;60:6703–17.
154. Arnson Y, Shoenfeld Y, Amital H. Effects of tobacco smoke on immunity, inflammation and
autoimmunity. J Autoimmun. 2010;34:J258–65.
155. Aravindaram K, Yang NS. Anti-inflammatory plant natural products for cancer therapy. Planta Med.
2010;76:1103–17.
156. Li Y-F, Chang Y-Y, Huang H-C, Wu Y-C, Yang M-D, Chao P-M. Tomato juice supplementation in
young women reduces inflammatory adipokine levels independently of body fat reduction. Nutrition.
2015;31:691–6.
157. Watzl B, Kulling SE, Moseneder J, Barth SW, Bub A. A 4-wk intervention with high intake of carotenoid-
rich vegetables and fruit reduces plasma C-reactive protein in healthy, nonsmoking men. Am J Clin Nutr.
2005;82:1052–8.
158. Jacob K, Periago MJ, Böhm V, Berruezo GR, Bohm V, Berruezo GR. Influence of lycopene and vitamin
C from tomato juice on biomarkers of oxidative stress and inflammation. Br J Nutr. 2008;99:137–46.
159. Sies H, Stahl W. Nutritional protection against skin damage from sunlight. Annu Rev Nutr.
2004;24:173–200.
160. Riso P, Visioli F, Grande S, Guarnieri S, Gardana C, Simonetti P, Porrini M. Effect of a tomato-based
drink on markers of inflammation, immunomodulation, and oxidative stress. J Agric Food Chem.
2006;54:2563–6.
161. Biddle MJ, Lennie TA, Bricker G V, Kopec RE, Schwartz SJ, Moser DK. Lycopene dietary intervention,
a pilot study in patients with heart failure. J Cardiovasc Nurs. 2015;30:205–12.
162. Sánchez-Moreno C, Cano MP, de Ancos B, Plaza L, Olmedilla B, Granado F, Martín A. Consumption
of high-pressurized vegetable soup increases plasma vitamin C and decreases oxidative stress and
inflammatory biomarkers in healthy humans. J Nutr. 2004;134:3021–5.
163. Watzl B, Bub A, Briviba K, Rechkemmer G. Supplementation of a low-carotenoid diet with tomato or
carrot juice modulates immune functions in healthy men. Ann Nutr Metab. 2003;47:255–61.
164. Kim H. Inhibitory mechanism of lycopene on cytokine expression in experimental pancreatitis. Ann N
Y Acad Sci. 2011;1229:99–102.
165. Blum A, Monir M, Khazim K, Peleg A, Blum N. Tomato-rich (Mediterranean) diet does not modify
inflammatory markers. Clin Invest Med. 2007;30:E70–4.
166. Denniss SG, Haffner TD, Kroetsch JT, Davidson SR, Rush JWE, Hughson RL. Effect of short-term
lycopene supplementation and postprandial dyslipidemia on plasma antioxidants and biomarkers of
endothelial health in young, healthy individuals. Vasc Health Risk Manag. 2008;4:213–22.
167. Markovits N, Amotz AB, Levy Y. The effect of tomato-derived lycopene on low carotenoids and
enhanced systemic inflammation and oxidation in severe obesity. Isr Med Assoc J. 2009;11:598–601.
168. Di Mascio P, Kaiser S, Sies H. Lycopene as the most efficient biological carotenoid singlet oxygen
quencher. Arch Biochem Biophys. 1989;274:532–8.
169. Mathews-Roth MM, Pathak MA, Fitzpatrick TB, Harber LC, Kass EH. Beta-carotene as a photoprotective
agents in erythropoetic protoporphyria. N Engl J Med. 1970;282:1231–1234.
170. Mathews-Roth MM. Carotenoids in erythropoetic protoporphyria and other photosensitivity diseases.
Ann N Y Acad Sci. 1993;691:127–38.
171. Mathews-Roth MM, Pathak MA, Fitzpatrick TB, Harber LC, Kass EH. Beta-carotene as an oral
photoprotective agent in erythropoetic protoporphyria. J Am Med Assoc. 1974;228:1004–8.
172. Mathews-Roth MM, Pathak MA, Fitzpatrick TB, Harber LH, Kass EH. Beta carotene therapy for
erythropoietic protoporphyria and other photosensitivity diseases. Arch Dermatol. 1977;113:1229–32.
173. Epstein JH. Effects of beta-carotene on ultraviolet induced cancer formation in the hairless mouse skin.
Photochem Photobiol. 1977;25:211–3.
174. Mathews-Roth MM, Krinsky NI. Carotenoids affect development of UV-B induced skin cancer.
Photochem Photobiol. 1987;46:507–9.
175. Wingerath T, Sies H, Stahl W. Xanthophyll esters in human skin. Arch Biochem Biophys [Internet].
1998;355:271–4.
176. Stahl W, Sies H. Beta-carotene and other carotenoids in protection from sunlight. Am J Clin Nutr.
2012;96:1179–84.
177. Aust O, Stahl W, Sies H, Tronnier H, Heinrich U. Supplementation with tomato-based products increases
lycopene, phytofluene, and phytoene levels in human serum and protects against UV-light-induced
erythema. Int J Vitam Nutr Res. 2005;75:54–60.
178. Stahl W, Heinrich U, Wiseman S, Eichler O, Sies H, Tronnier H. Dietary tomato paste protects against
ultraviolet light-induced erythema in humans. J Nutr. 2001;1311449–51.
179. Rizwan M, Rodriguez-Blanco I, Harbottle A, Birch-Machin MA, Watson REB, Rhodes LE. Tomato paste
rich in lycopene protects against cutaneous photodamage in humans in vivo: A randomized controlled
trial. Br J Dermatol. 2011;164:154–62.
180. Heinrich U, Gärtner C, Wiebusch M, Eichler O, Sies H, Tronnier H, Stahl W, Gartner C, Wiebusch M,
Eichler O et al. Supplementation with beta-carotene or a similar amount of mixed carotenoids protects
humans from UV-induced erythema. J Nutr. 2003;133:98–101.
181. Césarini JP, Michel L, Maurette JM, Adhoute H, Béjot M. Immediate effects of UV radiation on the
skin: Modification by an antioxidant complex containing carotenoids. Photodermatol Photoimmunol
Photomed. 2003;19:182–9.
1. Namitha KK, Negi PS. Chemistry and biotechnology of carotenoids. Crit Rev Food Sci Nutr. 2010;
50:728–60.
2. Nisar N, Li L, Lu S, Khin NC, Pogson BJ. Carotenoid metabolism in plants. Mol Plant. 2015; 8:68–82.
3. Hashimoto H, Uragami C, Cogdell RJ. Carotenoids and Photosynthesis. Subcell Biochem. 2016;
79:111–39.
4. Widomska J, Subczynski WK. Why has nature chosen lutein and zeaxanthin to protect the retina? J Clin
Exp Ophthalmol. 2014; 5(1):326.
5. Vishwanathan R, Iannaccone A, Scott TM et al. Macular pigment optical density is related to cognitive
function in older people. Age Ageing. 2014; 43:271–5.
6. Ojima F, Sakamoto H, Ishiguro Y, Terao J. Consumption of carotenoids in photosensitized oxidation of
human plasma and plasma low density lipoprotein. Free Rad Biol Med. 1993; 15:377–84.
7. Gruszecki WI, Strzałka K. Carotenoids as modulators of lipid membrane physical properties. Biochim
Biophys Acta. 2005; 1740:108–15.
8. Mangels A, Holden J, Beecher G, Forman M, Lanza E. Carotenoid content of fruits and vegetables: An
evaluation of analytic data. J Am Diet Assoc. 1993; 93:284–96.
9. Perry A, Rasmussen H, Johnson EJ. Xanthophyll (lutein, zeaxanthin) content in fruits, vegetables and
corn and egg products. J Food Comp Anal. 2009; 22:9–15.
10. van het Hof KH, Brouwer IA, West CE, Haddeman E, Steegers-Theunissen RP, Van Dusseldorp M,
Weststrate JA, Eskes TK, Hautvast JG. Bioavailability of lutein from vegetables is five times higher than
that of beta-carotene. Am J Clin Nutr. 1999; 70:261–8.
11. van Het Hof K, West C, Weststrate J, Hautvast J. Dietary factors that affect the bioavailability of
carotenoids. J Nutr. 2000; 130:503–6.
12. Handelman G, Nightingale Z, Lichtenstein A, Schaefer E, Blumberg J. Lutein and zeaxanthin
concentrations in plasma after dietary supplementation with egg yolk. Am J Clin Nutr. 1999; 70:247–51.
13. Thürmann PA, Schalch W, Aebischer JC, Tenter U, Cohn W. Plasma kinetics of lutein, zeaxanthin, and
3-dehydro-lutein after multiple oral doses of a lutein supplement. Am J Clin Nutr. 2005; 82(1):88–97.
14. Burri BJ, Neidlinger TR, Clifford AJ. Serum carotenoid depletion follows first-order kinetics in healthy
adult women fed naturally low carotenoid diets. J Nutr. 2001; 131:2096–100.
15. Rock CL, Swendseid ME, Jacob RA, McKee RW. Plasma carotenoid levels in human subjects fed a low
carotenoid diet. J Nutr. 1992; 122(1):96–100.
16. Khachik F, de Moura FF, Zhao DY, Aebischer CP, Bernstein PS. Transformations of selected carotenoids
in plasma, liver, and ocular tissues of humans and in nonprimate animal models. Invest Ophthalmol Vis
Sci. 2002; 43:3383–92.
17. Yeum K, Taylor A, Tang G, Russell R. Measurement of carotenoids, retinoids, and tocopherols in human
lenses. Invest Ophthalmol Vis Sci. 1995; 36:2756–61.
18. Sommerburg O, Siems WG, van Kuijk FJ. Localization of carotenoids in different eye tissues. Biofactors.
2000; 11:3–6.
19. Landrum JT, Bone RA, Moore LL, Gomez CM. Analysis of zeaxanthin distribution within individual
human retinas. Methods Enzymol. 1999; 299:457–67.
20. Smith JW, Rogers RB, Jeon S, Rubakhin SS, Wang L, Sweedler JV, Neuringer M, Kuchan MJ, Erdman
JW Jr. Carrot solution culture bioproduction of uniformly labeled (13)C-lutein and in vivo dosing in non-
human primates. Exp Biol Med (Maywood). 2017; 242:305–15.
21. Malinow MR, Feeney-Burns L, Peterson LH, Klien ML, Neuringer M. Diet-related macular abnormalities
in monkeys. IOVS. 1980; 19:857–63.
22. Neuringer M, Sandstrom M, Johnson E, Snodderly D. Nutritional manipulation of primate retinas, I:
Effects of lutein or zeaxanthin supplements on serum and macular pigment in xanthophyll-free rhesus
monkeys. Invest Ophthalmol Vis Sci. 2004; 45:3234–43.
23. Leung IY, Sandstrom MM, Zucker CL, Neuringer M, Snodderly DM. Nutritional manipulation of
primate retinas, II: Effects of age, n-3 fatty acids, lutein, and zeaxanthin on retinal pigment epithelium.
Invest Ophthalmol Vis Sci. 2004; 45:3244–56.
24. Johnson EJ, Neuringer M, Russell RM, Schalch W, Snodderly DM. Nutritional manipulation of primate
retinas, III: Effects of lutein or zeaxanthin supplementation on adipose tissue and retina of xanthophyll-
free monkeys. Invest Ophthalmol Vis Sci. 2005; 46:692–702.
25. Barker FM 2nd, Snodderly DM, Johnson EJ, Schalch W, Koepcke W, Gerss J, Neuringer M. Nutritional
manipulation of primate retinas, V: Effects of lutein, zeaxanthin, and n-3 fatty acids on retinal sensitivity
to blue-light-induced damage. Invest Ophthalmol Vis Sci. 2011; 52:3934–42.
26. McGill TJ, Renner LM, Neuringer M. Elevated fundus autofluorescence in monkeys deficient in lutein,
zeaxanthin, and omega-3 fatty acids. Invest Ophthalmol Vis Sci. 2016; 57:1361–9.
27. Castenmiller JJM, West EE, Linssen JPH, van het Hof KH, Voragen AGJ. The food matrix of spinach
is a limiting factor in determining the bioavailability of beta-carotene and to a lesser extent of lutein in
humans. J Nutr. 1999; 129:349–55.
28. Bone RA, Landrum JT, Guerra LH, Ruiz CA. Lutein and zeaxanthin dietary supplements raise macular
pigment density and serum concentrations of these carotenoids in humans. J Nutr. 2003; 133:992–8.
29. Marriage BJ, Williams JA, Chose YS, Maki KC, Vurma M, DeMichele S. Mono- and diglycerides
improve lutein absorption in healthy adults: A randomized, double-blind, cross-over, single dose study.
Br J Nutr. 2017; 118:813–21.
30. Campbell DR, Gross MD, Martini MC, Grandits GA, Slavin JL, Potter JD. Plasma carotenoids as
biomarkers of vegetable and fruit intake. Cancer Epidemiol Biomarkers Prev. 1994; 3:493–500.
31. McEligot AJ, Rock CL, Flatt SW, Newman V, Faerber S, Pierce JP. Plasma carotenoids are biomarkers
of long-term high vegetable intake in women with breast cancer. J Nutr. 1999; 129:2258–63.
32. Johnson EJ, Hammond BR, Yeum KJ, Qin J, Wang XD, Castaneda C, Snodderly DM, Russell RM.
Relation among serum and tissue concentrations of lutein and zeaxanthin and macular pigment density.
Am J Clin Nutr. 2000; 71:1555–62.
33. Olmedilla B, Granado F, Blanco I, Vaquero M. Lutein, but not alpha-tocopherol, supplementation
improves visual function in patients with age-related cataracts: A 2-y double-blind, placebo-controlled
pilot study. Nutrition. 2003; 19:21–4.
34. Olson JA. Absorption, transport, and metabolism of carotenoids in humans. Pure Appl Chem. 1994;
66:1011–6.
35. Omaye ST, Krinsky NI, Kagan VE, Mayne ST, Liebler DC, Bidlack WR. β-Carotene: Friend or foe.
Fundam Appl Toxicol. 1997; 40:163–74.
36. Institute of Medicine (IOM). β-Carotene and other carotenoids. In: Dietary Reference Intakes for Vitamin
C, Vitamin E, Selenium, and Carotenoids. Panel on Dietary Antioxidants and Related Compounds,
Subcommittees on Upper Reference Levels of Nutrients and Interpretation and Uses of DRIs, Standing
Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board,
Institute of Medicine (IOM). Washington (DC): National Academy Press (NAP), 2000; pp. 325–82.
37. Yates AA, Erdman JW, Shao A, Dolan LC, Griffiths JC. Bioactive nutrients—Time for tolerable upper
intake levels to address safety. Reg Toxicol Pharmacol. 2017; 84:94–101.
38. Biesalski HK, Erdman JW, Hathcock J et al. Nutrient reference values for bioactives: New approaches
needed? A conference report. Eur J Nutr. 2013; 52:1–9.
39. Yetley EA, MacFarlane AJ, Greene-Finestone LS et al. Options for basing Dietary Reference Intakes
(DRIs) on chronic disease endpoint: Report for a joint US-/Canadian-sponsored working group. Am J
Clin Nutr. 2017; 105:249S–85S.
40. Ranard KM, Jeon S, Mohn ES, Griffiths JC, Johnson EJ, Erdman JW. Dietary guidance for lutein:
Consideration for intake recommendations is scientifically supported. Eur J Nutr. 2017; S37–42.
41. Alves-Rodrigues A, Shao A. The science behind lutein. Toxicol Lett. 2004; 150(1):57–83.
42. Shao A, Hathcock JN. Risk assessment for the carotenoids lutein and lycopene. Reg Toxicol Pharmacol.
2006; 45:289–98.
43. United States Food and Drug Administration. GRN No. 110. Lutein esters, 2002.
44. United States Food and Drug Administration. GRN No. 140. Crystalline lutein, 2004.
45. United States Food and Drug Administration. GRN No. 221. Suspended lutein, 2007.
46. European Food Safety Authority (EFSA). Scientific opinion of the Panel on Dietetic Products, Nutrition
and Allergies [on a request from the European Commission on the] “Safety, bioavailability, and suitability
of lutein for the particular nutritional use by infants and young children.” EFSA J. 2008; 823:1–24.
47. European Food Safety Authority (EFSA). Scientific opinion on the re-evaluation of lutein (E 161b) as a
food additive. EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS). EFSA J. 2010;
8(7):1678.
48. Food Standards Australia New Zealand (FSANZ). First Review Report. Application A594: Addition of
Lutein as a Nutritive Substance to Infant Formula Products. (4-09). 2009.
49. Food Standards Australia New Zealand (FSANZ). Final Assessment Report. Application A597: Addition
of lutein to formulated supplementary foods for young children. (4-09). 2009.
50. Joint Expert Committee on Food Additives (JECFA). Lutein from Tagetes erecta L. In: Safety Evaluation
of Certain Food Additives. Sixty-third Meeting of the Joint FAO/WHO Expert Committee on Food
Additives, June 8–17, 2004, Geneva, Switz. (WHO Food Additives Series, no 54). Geneva, Switz.: World
Health Organization (WHO), International Programme on Chemical Safety (IPCS), 2006; pp. 49–86,
637–638.
51. Nebeling LC, Forman MR, Graubard BI, Snyder RA. Changes in carotenoid intake in the United States:
The 1987 and 1992 National Health Interview Surveys. J Am Diet Assoc 1997; 97:991–6.
52. Kruger C, Murphy M, DeFreitas Z, Pfannkuch F, Heimbach J. An innovative approach to the determination
of safety for a dietary ingredient derived from a new source: Case study using a crystalline lutein product.
Food Chem Toxicol 2002; 40:1535–49.
53. Johnson EJ, Maras JE, Rasmussen HM, Tucker KL. Intake of lutein and zeaxanthin differ with age, sex,
and ethnicity. J Am Diet Assoc. 2010; 110:1357–62.
54. Brown MJ, Ferruzzi MG, Nguyen ML, Cooper DA, Eldridge AL, Schwartz SJ, White WS. Carotenoid
bioavailability is higher from salads ingested with full-fat than with fat-reduced salad dressings as
measured with electrochemical detection. Am J Clin Nutr. 2004; 80:396–403.
55. Unlu NZ, Bohn T, Clinton SK, Schwartz SJ. Carotenoid absorption from salad and salsa by humans is
enhanced by the addition of avocado or avocado oil. J Nutr. 2005; 135(3):431–6.
56. Goltz SR, Campbell WW, Chitchumroonchokchai C, Failla ML, Ferruzzi MG. Meal triacylglycerol
profile modulates postprandial absorption of carotenoids in humans. Mol Nutr Food Res. 2012; 56:866–77.
57. Reboul E. Absorption of vitamin A and carotenoids by the enterocyte: Focus on transport proteins.
Nutrients. 2013 Sep 12; 5:3563–81.
58. Yonekura L, Nagao A. Intestinal absorption of dietary carotenoids. Mol Nutr Food Res. 2007;
51(1):107–15.
59. Sugawara T, Kushiro M, Zhang H, Nara E, Ono H, Nagao A. Lysophosphatidylcholine enhances
carotenoid uptake from mixed micelles by Caco-2 human intestinal cells. J Nutr. 2001; 131:2921–7.
60. Borel P. Genetic variations involved in interindividual variability in carotenoid status. Mol Nutr Food
Res. 2012; 56:228–40.
61. Herron KL, McGrane MM, Waters D, Lofgren IE, Clark RM, Ordovas JM, Fernandez ML. The ABCG5
polymorphism contributes to individual responses to dietary cholesterol and carotenoids in eggs. J Nutr.
2006; 136:1161–5.
62. Parker RS. Absorption, metabolism, and transport of carotenoids. FASEB J. 1996 Apr; 10(5):542–51.
63. Connor WE, Duell PB, Kean R, Wang Y. The prime role of HDL to transport lutein into the retina:
Evidence from HDL-deficient WHAM chicks having a mutant ABCA1 transporter. Invest Ophthalmol
Visual Sci. 2007; 48:4226–31.
64. Rigotti A, Miettinen HE, Krieger M. The role of the high-density lipoprotein receptor SR-BI in the lipid
metabolism of endocrine and other tissues. Endocr Rev. 2003; 24(3):357–87.
65. During A, Dawson HD, Harrison EH. Carotenoid transport is decreased and expression of the lipid
transporters SR-BI, NPC1L1, and ABCA1 is downregulated in Caco-2 cells treated with ezetimibe.
J Nutr. 2005; 135:2305–12.
66. During A, Doraiswamy S, Harrison EH. Xanthophylls are preferentially taken up compared with beta-
carotene by retinal cells via a SRBI-dependent mechanism. J Lipid Res. 2008; 49:1715–24.
67. Thomas SE, Harrison EH. Mechanisms of selective delivery of xanthophylls to retinal pigment epithelial
cells by human lipoproteins. J Lipid Res. 2016; 57:1865–78.
68. Shyam R, Vachali P, Gorusupudi A, Nelson K, Bernstein PS. All three human scavenger receptor class
B proteins can bind and transport all three macular xanthophyll carotenoids. Arch Biochem Biophys.
2017; 634:21–8.
69. Sakudoh T, Iizuka T, Narukawa J et al. A CD36-related transmembrane protein is coordinated with an
intracellular lipid binding protein in selective carotenoid transport for cocoon coloration. J Biol Chem.
2010; 285:7739–51.
70. Bhosale P, Bernstein P. Vertebrate and invertebrate carotenoid binding proteins. Arch Biochem Biophys.
2007; 458:121–7.
71. Li B, Vachali P, Bernstein PS. Human ocular carotenoid-binding proteins. Photochem Photobiol Sci.
2010; 9:1418–25.
72. Ribaya-Mercado J, Blumberg J. Lutein and zeaxanthin and their potential roles in disease prevention.
J Am Coll Nutr. 2004; 23:567S–87S.
73. Bates C, Chen S, Macdonald A, Holden R. Quantitation of vitamin E and a carotenoid pigment in
cataractous human lenses, and the effect of a dietary supplement. Int J Vitam Nutr Res. 1996; 66:316–21.
74. Bernstein P, Khachik F, Carvalho L, Muir G, Zhao D, Katz N. Identification and quantitation of
carotenoids and their metabolites in the tissues of the human eye. Exp Eye Res. 2001; 72:215–23.
75. Krinsky NI, Landrum JT, Bone RA. Biologic mechanisms of the protective role of lutein and zeaxanthin
in the eye. Annu Rev Nutr. 2003; 23:171–201.
76. Landrum JT, Bone RA. Lutein, zeaxanthin, and the macular pigment. Arch Biochem Biophys. 2001;
385:28–40.
77. Woodall A, Britton G, Jackson M. Carotenoids and protection of phospholipids in solution or in liposomes
against oxidation by peroxyl radicals: Relationship between carotenoid structure and protective ability.
Biochim Biophys Acta. 1997; 1336:575–86.
78. Wisniewska A, Subczynski W. Effects of polar carotenoids on the shape of the hydrophobic barrier of
phospholipid bilayers. Biochim Biophys Acta. 1998; 1368:235–46.
79. Nolan J, Stack J, O’connell E, Beatty S. The relationships between macular pigment optical density and
its constituent carotenoids in diet and serum. Invest Ophthalmol Vis Sci. 2007; 48:571–82.
80. Bhosale P, Zhao da Y, Bernstein P. HPLC measurement of ocular carotenoid levels in human donor eyes
in the lutein supplementation era. Invest Ophthalmol Vis Sci. 2007; 48:543–9.
81. Hammond BR, Curran-Celentano J, Judd S et al. Sex differences in macular pigment optical density:
Relation to plasma carotenoid concentrations and dietary patterns. Vision Res. 1996; 36:2001–12.
82. Bone RA, Landrum JT, Dixon Z, Chen Y, Llerena CM. Lutein and zeaxanthin in the eyes, serum and
diet of human subjects. Exp Eye Res. 2000; 71:239–45.
83. Curran-Celentano J, Hammond BR, Ciulla TA, Cooper DA, Pratt LM, Danis RB. Relation between
dietary intake, serum concentrations, and retinal concentrations of lutein and zeaxanthin in adults in a
Midwest population. Am J Clin Nutr. 2001; 74:796–802.
84. Chucair AJ, Rotstein NP, Sangiovanni JP, During A, Chew EY, Politi LE. Lutein and zeaxanthin protect
photoreceptors from apoptosis induced by oxidative stress: Relation with docosahexaenoic acid. Invest
Ophthalmol Vis Sci. 2007; 48:5168–77.
85. Perrone S, Longini M, Marzocchi B, Picardi A, Bellieni CV, Proietti F, Rodriguez A, Turrisi G,
Buonocore G. Effects of lutein on oxidative stress in the term newborn: A pilot study. Neonatology.
2010; 97:36–40.
86. Mukherjee PK. Pediatric Ophthalmology. Delhi, India: New Age International Pvt Ltd., 2005.
87. Bone RA, Landrum JT, Fernandez L, Tarsis SL. Analysis of the macular pigment by HPLC: Retinal
distribution and age study. Invest Ophthalmol Vis Sci. 1988; 29:843–9.
88. Handelman GJ, Dratz EA, Reay CC, van Kuijk JG. Carotenoids in the human macula and whole retina.
Invest Ophthalmol Vis Sci. 1988; 29:850–5.
89. Hardy P, Dumont I, Bhattacharya M, Hou X, Lachapelle P, Varma DR, Chemtob S. Oxidants, nitric oxide
and prostanoids in the developing ocular vasculature: A basis for ischemic retinopathy. Cardiovasc Res.
2000; 47:489–509.
90. Zimmer JP, Hammond BR Jr. Possible influences of lutein and zeaxanthin on the developing retina.
Clin Ophthalmol. 2007; 1:25–35.
91. Dillon J, Zheng L, Merriam JC, Gaillard ER. Transmission of light to the aging human retina: Possible
implications for age related macular degeneration. Exp Eye Res. 2004; 79:753–9.
92. Wing GL, Blanchard GC, Weiter JJ. The topography and age relationship of lipofuscin concentration in
the retinal pigment epithelium. IOVS. 1978; 17:601–7.
93. Feeney-Burns L, Hilderbrand ES, Eldridge S. Aging human RPE: Morphometric analysis of macular,
equatorial, and peripheral cells. IOVS. 1984; 25:195–200.
94. Craft NE, Haitema TB, Garnett KM, Fitch KA, Dorey CK. Carotenoid, tocopherol, and retinol
concentrations in elderly human brain. J Nutr Health Aging. 2004; 8:156–62.
95. Jeon S, Neuringer M, Johnson EE, Kuchan MJ, Pereira SL, Johnson EJ, Erdman JW. Effect of carotenoid
supplemented formula on carotenoid bioaccumulation in tissues of infant rhesus macaques: A pilot study
focused on lutein. Nutrients. 2017; 9.
96. Renzi LM, Dengler MJ, Puente A, Miller LS, Hammond BR Jr. Relationships between macular pigment
optical density and cognitive function in unimpaired and mildly cognitively impaired older adults.
Neurobiol Aging. 2014; 35:1695–9.
97. Vazhappilly R, Lai C-S, Kuchan M. Natural vitamin E and lutein protects DHA from peroxidation in
neurons. Abstract presented at: American College of Nutrition 54th Annual Conference; November
13–16, 2013; San Diego, CA.
98. Mohn ES, Erdman JW Jr, Neuringer M, Kuchan MJ, Johnson EJ. Brain xanthophyll content and
exploratory gene expression analysis: Subspecies differences in rhesus macaque. Genes Nutr. 2017; 12:9.
99. Walter MH, Floss DS, Strack D. Apocarotenoids: Hormones, mycorrhizal metabolites and aroma
volatiles. Planta. 2010; 232:1–7.
100. Cazzonelli CI, Pogson BJ. Source to sink: Regulation of carotenoid biosynthesis in plants. Trends Plant
Sci. 2010; 15:266–74.
101. Eroglu A, Harrison EH. Carotenoid metabolism in mammals, including man: Formation, occurrence,
and function of apocarotenoids. J Lipid Res. 2013; 54:1719–30.
102. Stahl W, Ale-Agha N, Polidori CM. Non-antioxidant properties of carotenoids. Biol Chem. 2002;
383:553–8.
103. Zhang LX, Cooney RV, Bertram JS. Carotenoids up-regulate connexin-43 gene expression independent
of their provitamin A or antioxidant properties. Cancer Res. 1992; 52:5707–12.
104. Stahl W, Sies H. Antioxidant activity of carotenoids. Mol Asp Med. 2003; 24:345–51.
105. Teicher V, Kucharski N, Martin H, van der Saag P, Sies H, Stahl W. Biological activities of apo-
canthaxanthinoic acids related to gap junctional communication. Arch Biochem Biophys. 1999; 365:150–5.
106. Bernstein PS, Sharifzadeh M, Liu A, Ermakov I, Nelson K, Sheng X, Panish C, Carlstrom B, Hoffman
RO, Gellermann W. Blue-light reflectance imaging of macular pigment in infants and children. Invest
Ophthalmol Vis Sci. 2013; 54:4034–40.
107. Schweigert FJ, Bathe K, Chen F, Büscher U, Dudenhausen JW. Effect of the stage of lactation in
humans on carotenoid levels in milk, blood plasma and plasma lipoprotein fractions. Eur J Nutr. 2004;
43(1):39–44.
108. Canfield LM, Clandinin MT, Davies DP et al. Multinational study of major breast milk carotenoids of
healthy mothers. Eur J Nutr. 2003; 42:133–41.
109. Song BJ, Jouni ZE, Ferruzzi MG. Assessment of phytochemical content in human milk during different
stages of lactation. Nutrition. 2013; 29:195–202.
110. Lipkie TE, Morrow AL, Jouni ZE, McMahon RJ, Ferruzzi MG. Longitudinal survey of carotenoids in
human milk from urban cohorts in China, Mexico, and the USA. PLOS ONE. 2015; 10:e0127729.
111. Allen LH, Haskell M. Estimating the potential for vitamin A toxicity in women and young children.
J Nutr. 2002; 132:2907S–19S.
112. Canfield LM, Giuliano AR, Neilson EM, Yap HH, Graver EJ, Cui HA, Blashill BM. Beta-carotene in
breast milk and serum is increased after a single beta-carotene dose. Am J Clin Nutr. 1997; 66:52–61.
113. Mackey AD, Albrecht D, Oliver J, Williams T, Long AC, Price PT. Plasma carotenoid concentrations of
infants are increased by feeding a milk-based infant formula supplemented with carotenoids. J Sci Food
Agric. 2013; 93:1945–52.
114. Bettler J, Zimmer JP, Neuringer M, DeRusso PA. Serum lutein concentrations in healthy term infants
fed human milk or infant formula with lutein. Eur J Nutr. 2010; 49:45–51.
115. Price P, Mackey A, Oliver J, Albrecht D, Kuchan M. Infant plasma response to lutein in formula and
human milk. Acta Biologica Cracoviensia 2011; 1.15 (abstract).
116. The Vision Council. Digital Eye Strain. Available at: https://www.thevisioncouncil.org/content/digital-
eye-strain. Accessed 12 Feb 2018).
117. American Optometric Association. Survey Reveals Parents Drastically Underestimate the Time
Kids Spend on Electronic Devices. Children’s Omnibus survey, 2014. Available at: http://www.aoa.
org/newsroom/survey-reveals-parents-drastically-underestimate-the-time-kids-spend-on-electronic-
devices?sso=y. Accessed 12 Feb 2018.
118. Hassevoort KM, Khazoum SE, Walker JA et al. Macular carotenoids, aerobic fitness, and central
adiposity are associated differentially with hippocampal-dependent relational memory in preadolescent
children. J Pediatr. 2017; 183:108–14.e1.
119. Walk AM, Khan NA, Barnett SM, Raine LB, Kramer AF, Cohen NJ, Moulton CJ, Renzi-Hammond
LM, Hammond BR, Hillman CH. From neuro-pigments to neural efficiency: The relationship between
retinal carotenoids and behavioral and neuroelectric indices of cognitive control in childhood. Int J
Psycholphysiol. 2017; 118:1–8.
120. Johnson EJ, Vishwanathan R, Johnson MA et al. Relationship between serum and brain carotenoids,
α-tocopherol, and retinol concentrations and cognitive performance in the oldest old from the Georgia
Centenarian Study. J Aging Res. 2013; 2013:951786
121. Vishwanathan R, Kuchan MJ, Sen S, Johnson EJ. Lutein and preterm infants with decreased concentrations
of brain carotenoids. J Pediatr Gastroenterol Nutr. 2014; 59:659–65.
122. Feeney J, Finucane C, Savva GM, Cronin H, Beatty S, Nolan JM, Kenny RA. Low macular pigment
optical density is associated with lower cognitive performance in a large, population-based sample of
older adults. Neurobiol Aging. 2013; 34:2449–56.
123. Johnson EJ, McDonald K, Caldarella SM, Chung HY, Troen AM, Snodderly DM. Cognitive findings of
an exploratory trial of docosahexaenoic acid and lutein supplementation in older women. Nutr Neurosci.
2008; 11:75–83.
124. Lindbergh CA, Mewborn CM, Hammond BR, Renzi-Hammond LM, Curran-Celentano JM, Miller
LS. Relationship of lutein and zeaxanthin levels to neurocognitive functioning: An fMRI study of older
adults. J Int Neuropsychol Soc. 2017; 23:11–22.
125. Renzi-Hammond LM, Bovier ER, Fletcher LM, Miller LS, Mewborn CM, Lindbergh CA, Baxter JH,
Hammond BR. Effects of a lutein and zeaxanthin intervention on cognitive function: A randomized,
double-masked, placebo-controlled trial of younger healthy adults. Nutrients. 2017; 9:pii: E1246.
126. Mewborn CM, Terry DP, Renzi-Hammond LM, Hammond BR, Miller LS. Relation of retinal and
serum lutein and zeaxanthin to white matter integrity in older adults: A diffusion tensor imaging study.
Arch Clin Neuropsychol. 2017; 17:1–4.
127. Tacca MC. Commonalities between perception and cognition. Front Psychol. 2011; 302:358.
128. Chen SP, Bhattacharya J, Pershing S. Association of vision loss with cognition in older adults. JAMA
Ophthalmol. 2017; 135:963–70.
129. Renzi LM, Hammond BR Jr. The relation between the macular carotenoids, lutein and zeaxanthin, and
temporal vision. Ophthalmic Physiol Opt. 2010 Jul; 30(4):351–7.
130. Stringham JM, Hammond BR. Macular pigment and visual performance under glare conditions. Opt Vis
Sci. 2008; 85:82–8.
131. Hammond BR Jr, Wooten BR, Engles M, Wong JC. The influence of filtering by the macular carotenoids
on contrast sensitivity measured under simulated blue haze conditions. Vision Res. 2012; 15; 63:58–62.
132. Mecocci P, Polidori MC, Cherubini A, Ingegni T, Mattioli P, Catani M, Rinaldi P, Cecchetti R, Stahl W,
Senin U, Beal MF. Lymphocyte oxidative DNA damage and plasma antioxidants in Alzheimer disease.
Arch Neurol. 2002; 59(5):794–8.
133. Nakagawa K, Kiko T, Miyazawa T, Sookwong P, Tsuduki T, Satoh A, Miyazawa T. Amyloid β-induced
erythrocytic damage and its attenuation by carotenoids. FEBS Lett. 2011; 585(8):1249–54.
134. Liu T, Liu WH, Zhao JS, Meng FZ, Wang H. Lutein protects against β-amyloid peptide-induced oxidative
stress in cerebrovascular endothelial cells through modulation of Nrf-2 and NF-κb. Cell Biol Toxicol.
2017; 33:57–67.
135. Stringham JM, Garcia PV, Smith PA, Hiers PL, McLin LN, Kuyk TK, Foutch BK. Macular pigment and
visual performance in low-light conditions. Invest Ophthalmol Vis Sci. 2015; 56:2459–68.
136. Min JY, Min KB. Serum lycopene, lutein and zeaxanthin, and the risk of Alzheimer’s disease mortality
in older adults. Dement Geriatr Cogn Disord. 2014; 37:246–56.
137. Friedman DS, O’Colmain BJ, Muñoz B, Tomany SC, McCarty C, de Jong PT, Nemesure B, Mitchell P,
Kempen J; Eye Diseases Prevalence Research Group. Prevalence of age-related macular degeneration
in the United States. Arch Ophthalmol 2004; 122:564–72.
138. Huang GH, Klein R, Klein BE, Tomany SC. Birth cohort effect on prevalence of age-related maculopathy
in the Beaver Dam Eye Study. Am J Epidemiol. 2003; 157(8):721–9.
139. Mares J. Lutein and zeaxanthin isomers in eye health and disease. Ann Rev Nutr. 2016; 36:571–602.
140. Bernestein PS, Li B, Vachali PP, Gorusupudi A, Shyam R, Henriksen BS, Nolan JM. Lutein, zeaxanthin,
and meso-zeaxanthin: The basic and clinical science underlying carotenoid-based nutritional interventions
against ocular disease. Prog Ret Eye Res. 2016; 50:24–66.
141. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of
high-dose supplementation with vitamin C and E, beta-carotene, and zinc for age-related macular
degeneration and vision loss: AREDS report no. 8. Arch. Ophthalmol. 2001; 119:1417–36.
142. Age-Related Eye Disease Study 2 Research Group. Lutein + zeaxanthin and omega-3 fatty acids for
age-related macular degeneration: The Age-Related Eye Disease Study2 (AREDS2) randomized clinical
trial. JAMA. 2013; 309:2005–15.
143. Age-Related Eye Disease Study 2 Research Group. Secondary analyses of the effects of lutein/zeaxanthin
on age-related macular degeneration progression AREDS2 report no. 3. JAMA Ophthalmol. 2014;
132:142–9.
144. Mares J. Food antioxidants to prevent cataract. JAMA 2015; 313:1048–9.
145. Hayashi R, Hayashi S, Sakai M, Arai K, Chikuda M, Machida S. Gender difference in mRNA expression
of aquaporin 8 and glutathione peroxidase in cataractous lens following intake of an antioxidant
supplement. Exp Eye Res 2018; 168:28–32.
146. Jackson JG, Zimmer PJ. Lutein and zeaxanthin in human milk independently and significantly differ
among women from Japan, Mexico, and the United Kingdom. Nutrition Research 2007; 27:449–53.
147. Gossage CP, Deyhim M, Yamini S, Douglass LW, Moser-Veillon PB. Carotenoid composition of human
milk during the first month postpartum and the response to beta-carotene supplementation. Am J Clin
Nutr. 2002 Jul; 76(1):193–7.
148. Cena H, Castellazzi AM, Pietri A, Roggi C, Turconi G. Lutein concentration in human milk during early
lactation and its relationship with dietary lutein intake. Public Health Nutr. 2009 Oct; 12(10):1878–84.
149. Jewell VC, Mayes CB, Tubman TR, Northrop-Clewes CA, Thurnham DI. A comparison of lutein and
zeaxanthin concentrations in formula and human milk samples from Northern Ireland mothers. Eur J
Clin Nutr. 2004; 58:90–7.
150. Meneses F, Torres AG, Trugo NM. Influence of recent dietary intake on plasma and human milk levels
of carotenoids and retinol in Brazilian nursing women. Adv Exp Med Biol. 2004; 554:351–4.
151. Tacken KJ, Vogelsang A, van Lingen RA, Slootstra J, Dikkeschei BD, van Zoeren-Grobben D. Loss of
triglycerides and carotenoids in human milk after processing. Arch Dis Child Fetal Neonatal Ed. 2009;
94:F447–50.
152. Macias C, Schweigert FJ. Changes in the concentration of carotenoids, vitamin A, alpha-tocopherol and
total lipids in human milk throughout early lactation. Ann Nutr Metab. 2001; 45(2):82–5.
153. Jackson JG, Lien EL, White SJ, Bruns NJ, Kuhlman CF. Major carotenoids in mature human milk:
Longitudinal and diurnal patterns. Nutr Biochem. 1998; 9:2–7.
154. Hanson C, Lyden E, Furtado J, Van Ormer M, Anderson-Berry A. A comparison of nutritional antioxidant
content in breast milk, donor milk, and infant formulas. Nutrients. 2016; 8:pii: E681.
155. Kim H, Yi H, Jung JA, Chang N. Association between lutein intake and lutein concentrations in human
milk samples from lactating mothers in South Korea. Eur J Nutr. 2018; 57:417–421.
156. Sherry CL, Oliver JS, Renzi LM, Marriage BJ. Lutein supplementation increases breast milk and plasma
lutein concentrations in lactating women and infant plasma concentrations but does not affect other
carotenoids. J Nutr. 2014; 144:1256–63.
157. Costa S, Giannantonio C, Romagnoli C, Barone, G, Gervasoni J, Perri A, Zecca E. Lutein and zeaxanthin
concentrations in formula and human milk samples from Italian mothers. Eur J Clin Nutr. 2015; 69,
531–2.
1. Zeng, T., Zhang, C.L., Zhao, X.L., and Xie, K.Q., The roles of garlic on the lipid parameters: A systematic
review of the literature, Crit Rev Food Sci Nutr, 53(3): 215–230, 2013.
2. Bahadoran, Z., Mirmiran, P., Momenan, A.A., and Azizi, F., Allium vegetable intakes and the incidence
of cardiovascular disease, hypertension, chronic kidney disease, and type 2 diabetes in adults: A
longitudinal follow-up study, J Hypertens, 35(9): 1909–1916, 2017.
3. Guercio, V., Galeone, C., Turati, F., and La Vecchia, C., Gastric cancer and allium vegetable intake: A
critical review of the experimental and epidemiologic evidence, Nutr Cancer, 66(5): 757–773, 2014.
4. Ngo, S.N.T., Williams, D.B., Cobiac, L., and Head, R.J., Does garlic reduce risk of colorectal cancer? A
systematic review, J. Nutr, 137: 2264–2269, 2007.
5. Banerjee, S.K., Mukherjee, P.K., and Maulik, S.K., Garlic as an antioxidant: The good, the bad and the
ugly, Phytother Res, 17(2): 97–106, 2003.
6. Kyo, E., Uda, N., Kasuga, S., and Itakura, Y., Immunomodulatory effects of aged garlic extract, J Nutr,
131(3s): 1075S–1079S, 2001.
7. Mathew, B.C. and Biju, R.S., Neuroprotective effects of garlic: A review, Libyan J Med, 3(1): 23–33,
2008.
8. United States Department of Agriculture, N.A.S.S., Vegetables: 2015 Summary. 2016.
9. United States Department of Agriculture, E.R.S. Vegetable and Pulses Yearbook 2017, 2017, Last
Updated: 4/6/2017, Date Accessed: 2/27/2018, Available from: https://www.ers.usda.gov/webdocs/
DataFiles/83086/Section%202_SandU%20Fresh.pdf?v=42831.
10. Fleischauer, A.T., Poole, C., and Arab, L., Garlic consumption and cancer prevention: Meta-analyses of
colorectal and stomach cancers, Am J Clin Nutr, 72(4): 1047–1052, 2000.
11. Jappe, U., Bonnekoh, B., Hausen, B.M., and Gollnick, H., Garlic-related dermatoses: Case report and
review of the literature, Am J Contact Dermat, 10(1): 37–39, 1999.
12. Lee, T.Y. and Lam, T.H., Contact dermatitis due to topical treatment with garlic in Hong Kong, Contact
Dermatitis, 24(3): 193–196, 1991.
13. Burden, A.D., Wilkinson, S.M., Beck, M.H., and Chalmers, R.J., Garlic-induced systemic contact
dermatitis, Contact Dermatitis, 30(5): 299–300, 1994.
14. Moyle, M., Frowen, K., and Nixon, R., Use of gloves in protection from diallyl disulphide allergy,
Australas J Dermatol, 45(4): 223–225, 2004.
15. Umar, I.A., Arjinoma, Z.G., Gidado, A., and Hamza, H.H., Prevention of garlic (Allium sativum Linn)-
induced anaemia in rats by supplementation with ascorbic acid and vitamin E, Nig J Biochem Mol Biol,
13: 31–40, 1998.
16. Yamato, O., Sugiyama, Y., Matsuura, H., Lee, K.W., Goto, K., Hossain, M.A., Maede, Y., and
Yoshihara, T., Isolation and identification of sodium 2-propenyl thiosulfate from boiled garlic (Allium
sativum) that oxidizes canine erythrocytes, Biosci Biotechnol Biochem, 67(7): 1594–1596, 2003.
17. Borrelli, F., Capasso, R., and Izzo, A.A., Garlic (Allium sativum L.): Adverse effects and drug interactions
in humans, Mol Nutr Food Res, 51(11): 1386–1397, 2007.
18. Fenwick, G.R. and Hanley, A.B., The genus Allium. Part 2, Crit Rev Food Sci Nutr, 22(4): 273–377, 1985.
19. Block, E., Garlic and Other Alliums. 2010, Cambridge: The Royal Society of Chemistry.
20. Kubec, R., Svobodova, M., and Velisek, J., Gas chromatographic determination of S-alk(en)ylcysteine
sulfoxides, J Chromatogr A, 862(1): 85–94, 1999.
21. Freeman, G.G. and Mossadeghi, N., Studies on the effect of sulphate nutrition on the flavour components
of onion (Allium cepa), Biochem J, 118(2): 24P, 1970.
22. Sugii, M., Suzuki, T., Nagasawa, S., and Kawashima, K., Isolation of gamma-1-glutamyl-s-allylmercapto-
l-cysteine and s-allylmercapto-l-cysteine from garlic, Chem Pharm Bull (Tokyo), 12: 1114–1115, 1964.
23. Block, E., The chemistry of garlic and onions, Sci Am, 252(3): 114–119, 1985.
24. Lawson, L.D., Wang, Z.-Y.J., and Hughes, B.G., Identification and HPLC quantitation of the sulfides and
dialk(en)yl thiosulfinates in commercial garlic products, Planta Med, 57(4): 363–370, 1991.
25. Tamaki, T. and Sonoki, S., Volatile sulfur compounds in human expiration after eating raw or heat-
treated garlic, J Nutr Sci Vitaminol, 45(2): 213–222, 1999.
26. Borek, C., Antioxidant health effects of aged garlic extract, J Nutr, 131(3 Suppl.): 1010S–1015S, 2001.
27. Lawson, L.D., The composition and chemistry of garlic cloves and processed garlic, in Garlic: The
Science and Therapeutic Application of Allium Sativum L. and Related Species, H.P. Koch and L.D.
Lawson, Editors. 1996, Williams & Waverly: Baltimore. p. 37–107.
28. Lawson, L.D. and Gardner, C.D., Composition, stability, and bioavailability of garlic products used in a
clinical trial, J Agric Food Chem, 53(16): 6254–6261, 2005.
29. Staba, E.J., Lash, L., and Staba, J.E., A commentary on the effects of garlic extraction and formulation
on product composition, J Nutr, 131(3): 1118S–1119, 2001.
30. Lachmann, G., Lorenz, D., Radeck, W., and Steiper, M., [The pharmacokinetics of the S35 labeled garlic
constituents alliin, allicin and vinyldithiine], Arzneimittelforschung, 44(6): 734–743, 1994.
31. Lawson, L.D. and Wang, Z.J., Allicin and allicin-derived garlic compounds increase breath acetone through
allyl methyl sulfide: Use in measuring allicin bioavailability, J Agric Food Chem, 53(6): 1974–1983, 2005.
32. Egen-Schwind, C., Eckard, R., and Kemper, F.H., Metabolism of garlic constituents in the isolated
perfused rat liver, Planta Med, 58(4): 301–305, 1992.
33. Freeman, F. and Kodera, Y., Garlic chemistry: Stability of S-(2-propenyl) 2-propene-1-sulfinothioate
(allicin) in blood, solvents, and simulated physiological fluids, J Agric Food Chem, 43: 2332–2338, 1995.
34. Germain, E., Auger, J., Ginies, C., Siess, M.H., and Teyssier, C., In vivo metabolism of diallyl disulphide
in the rat: Identification of two new metabolites, Xenobiotica, 32(12): 1127–1138, 2002.
35. Teyssier, C., Guenot, L., Suschetet, M., and Siess, M.H., Metabolism of diallyl disulfide by human liver
microsomal cytochromes P-450 and flavin-containing monooxygenases, Drug Metab Dispos, 27(7):
835–841, 1999.
36. Krause, R.J., Glocke, S.C., and Elfarra, A.A., Sulfoxides as urinary metabolites of S-allyl-L-cysteine in
rats: Evidence for the involvement of flavin-containing monooxygenases, Drug Metab Dispos, 30(10):
1137–1142, 2002.
37. Modem, S., DiCarlo, S.E., and Reddy, T.R., Fresh garlic extract induces growth arrest and morphological
differentiation of MCF7 breast cancer cells, Genes and Cancer, 3(2): 177–186, 2012.
38. Yan, J.Y., Tian, F.M., Hu, W.N., Zhang, J.H., Cai, H.F., and Li, N., Apoptosis of human gastric cancer
cells line SGC 7901 induced by garlic-derived compound S-allylmercaptocysteine (SAMC), Eur Rev
Med Pharmaco, 17(6): 745–751, 2013.
39. Kim, H.J., Han, M.H., Kim, G.Y., Choi, Y.W., and Choi, Y.H., Hexane extracts of garlic cloves induce
apoptosis through the generation of reactive oxygen species in Hep3B human hepatocarcinoma cells,
Oncology Reports, 28(5): 1757–1763, 2012.
40. Chiang, E.P.I., Chiu, S.C., Pai, M.H., Wang, Y.C., Wang, F.Y., Kuo, Y.H., and Tang, F.Y., Organosulfur
garlic compounds induce neovasculogenesis in human endothelial progenitor cells through a modulation
of microRNA 221 and the PI3-K/Akt signaling pathways, J Agric Food Chem, 61(20): 4839–4849, 2013.
41. Tang, F.-Y., Chiang, E.-P.I., Chung, J.-G., Lee, H.-Z., and Hsu, C.-Y., S-allylcysteine modulates the
expression of E-cadherin and inhibits the malignant progression of human oral cancer, J Nutr Biochem,
20(12):1013–1020, 2009.
42. Sakamoto, K., Lawson, L.D., and Milner, J.A., Allyl sulfides from garlic suppress the in vitro proliferation
of human A549 lung tumor cells, Nutr Cancer, 29(2): 152–156, 1997.
43. Sundaram, S.G. and Milner, J.A., Diallyl disulfide induces apoptosis of human colon tumor cells,
Carcinogenesis, 17(4): 669–673, 1996.
44. Hu, X., Benson, P.J., Srivastava, S.K., Xia, H., Bleicher, R.J., Zaren, H.A., Awasthi, S., Awasthi, Y.C.,
and Singh, S.V., Induction of glutathione S-transferase π as a bioassay for the evaluation of potency of
inhibitors of benzo(a)pyrene-induced cancer in a murine model, Int J Cancer, 73(6): 897–902, 1997.
45. Charron, C.S., Milner, J.A., and Novotny, J.A., Garlic, in Encyclopedia of Food and Health, B. Caballero,
P. Finglas, and F. Toldra, Editors. 2016, Academic Press: Oxford. p. 184–190.
46. Adetumbi, M.A. and Lau, B.H., Allium sativum (garlic)—A natural antibiotic, Med Hypotheses, 12(3):
227–237, 1983.
47. Verma, S., Kaur, S., Singh, J., and Garg, A., Anti-bacterial effect of garlic (Allium sativum L) extract on
different pathogenic and non-pathogenic bacteria, Res J Pharm Biol Chem Sci, 6(3): 1103–1107, 2015.
48. Lai, P.K. and Roy, J., Antimicrobial and chemopreventive properties of herbs and spices, Curr Med
Chem, 11(11): 1451–1460, 2004.
49. Davis, S.R., An overview of the antifungal properties of allicin and its breakdown products—The
possibility of a safe and effective antifungal prophylactic, Mycoses, 48(2): 95–100, 2005.
50. Ruddock, P.S., Liao, M., Foster, B.C., Lawson, L., Arnason, J.T., and Dillon, J.A., Garlic natural health
products exhibit variable constituent levels and antimicrobial activity against Neisseria gonorrhoeae,
Staphylococcus aureus and Enterococcus faecalis, Phytother Res, 19(4): 327–334, 2005.
51. Siao, D. and Somsouk, M., Helicobacter pylori: Evidence-based review with a focus on immigrant
populations, J Gen Intern Med, 29(3): 520–528, 2014.
52. Webb, P.M., Law, M., Varghese, C., and Forman, D., Gastric cancer and Helicobacter pylori: A combined
analysis of 12 case control studies nested within prospective cohorts, Gut, 49(3): 347–353, 2001.
53. Cellini, L., Di Campli, E., Masulli, M., Di Bartolomeo, S., and Allocati, N., Inhibition of Helicobacter
pylori by garlic extract (Allium sativum), FEMS Immunol Med Microbiol, 13(4): 273–277, 1996.
54. Chung, J.G., Chen, G.W., Wu, L.T., Chang, H.L., Lin, J.G., Yeh, C.C., and Wang, T.F., Effects of garlic
compounds diallyl sulfide and diallyl disulfide on arylamine N-acetyltransferase activity in strains of
Helicobacter pylori from peptic ulcer patients, Am J Chin Med, 26(3–4): 353–364, 1998.
55. Jonkers, D., van den Broek, E., van Dooren, I., Thijs, C., Dorant, E., Hageman, G., and Stobberingh, E.,
Antibacterial effect of garlic and omeprazole on Helicobacter pylori, J Antimicrob Chemother, 43(6):
837–839, 1999.
56. You, W.C. et al., Helicobacter pylori infection, garlic intake and precancerous lesions in a Chinese
population at low risk of gastric cancer, Int J Epidemiol, 27(6): 941–944, 1998.
57. Aydin, A., Ersoz, G., Tekesin, O., Akcicek, E., and Tuncyurek, M., Garlic oil and Helicobacter pylori
infection, Am J Gastroenterol, 95(2): 563–564, 2000.
58. McNulty, C.A.M., Wilson, M.P., Havinga, W., Johnston, B., O’Gara, E.A., and Maslin, D.J., A pilot
study to determine the effectiveness of garlic oil capsules in the treatment of dyspeptic patients with
Helicobacter pylori, Helicobacter, 6(3): 249–253, 2001.
59. Graham, D.Y., Anderson, S.Y., and Lang, T., Garlic or jalapeno peppers for treatment of Helicobacter
pylori infection, Am J Gastroenterol, 94(5): 1200–1202, 1999.
60. Hekmatdoost, A., Ghobeh, M., Shaker-Hosseini, R., MirSattari, D., Rastmanesh, R., Rashidkhani, B.,
and Navai, L., The effect of garlic consumption on Helicobacter pylori treatment using urea breath test:
A randomized clinical trial, J Nutr Sci Diet, 1(1): 21–27, 2015.
61. Zardast, M., Namakin, K., Esmaelian Kaho, J., and Hashemi, S.S., Assessment of antibacterial effect of
garlic in patients infected with Helicobacter pylori using urease breath test, Avicenna J Phytomed, 6(5):
495–501, 2016.
62. Arora, D.S. and Kaur, J., Antimicrobial activity of spices, Int J Antimicrob Agents, 12(3): 257–262, 1999.
63. Ledezma, E., Marcano, K., Jorquera, A., De Sousa, L., Padilla, M., Pulgar, M., and Apitz-Castro, R.,
Efficacy of ajoene in the treatment of tinea pedis: A double-blind and comparative study with terbinafine,
J Am Acad Dermatol, 43(5 Pt 1): 829–832, 2000.
64. Rabinkov, A., Miron, T., Mirelman, D., Wilchek, M., Glozman, S., Yavin, E., and Weiner, L.,
S-allylmercaptoglutathione: The reaction product of allicin with glutathione possesses SH-modifying
and antioxidant properties, Biochimica et Biophysica Acta – Molecular Cell Research, 1499(1–2): 144–
153, 2000.
65. Gupta, N. and Porter, T.D., Garlic and garlic-derived compounds inhibit human squalene monooxygenase,
J Nutr, 131(6): 1662–1667, 2001.
66. Balkis, M.M., Leidich, S.D., Mukherjee, P.K., and Ghannoum, M.A., Mechanisms of fungal resistance:
An overview, Drugs, 62(7): 1025–1040, 2002.
67. Sonnenburg, J.L. and Bäckhed, F., Diet-microbiota interactions as moderators of human metabolism,
Nature, 535(7610): 56–64, 2016.
68. Filocamo, A., Nueno-Palop, C., Bisignano, C., Mandalari, G., and Narbad, A., Effect of garlic powder
on the growth of commensal bacteria from the gastrointestinal tract, Phytomedicine, 19(8–9): 707–711,
2012.
69. Milner, J.A., Molecular targets for bioactive food components, J Nutr, 134(9): 2492S–2498S, 2004.
70. Sikand, G., Kris-Etherton, P., and Boulos, N.M., Impact of functional foods on prevention of cardiovascular
disease and diabetes, Curr Cardiol Rep, 17(6): 39, 2015.
71. Mayne, S.T., Playdon, M.C., and Rock, C.L., Diet, nutrition, and cancer: Past, present and future, Nat
Rev Clin Oncol, 13(8): 504–515, 2016.
72. American Institute for Cancer Research, Food, Nutrition, Physical Activity, and the Prevention of
Cancer: A Global Perspective. 2007, World Cancer Research Fund/American Institute for Cancer
Research: Washington, D.C. p. 1–16.
73. Kodali, R.T. and Eslick, G.D., Meta-analysis: Does garlic intake reduce risk of gastric cancer? Nutr
Cancer, 67(1): 1–11, 2015.
74. Hu, J.Y., Hu, Y.W., Zhou, J.J., Zhang, M.W., Li, D., and Zheng, S., Consumption of garlic and risk
of colorectal cancer: An updated meta-analysis of prospective studies, World J Gastroenterol, 20(41):
15413–15422, 2014.
75. Zhou, Y., Zhuang, W., Hu, W., Liu, G.J., Wu, T.X., and Wu, X.T., Consumption of large amounts of allium
vegetables reduces risk for gastric cancer in a meta-analysis, Gastroenterology, 141(1): 80–89, 2011.
76. Zhou, X.F., Ding, Z.S., and Liu, N.B., Allium vegetables and risk of prostate cancer: Evidence from
132,192 subjects, Asian Pac J Cancer Prev, 14(7): 4131–4134, 2013.
77. World Cancer Research Fund/American Institute for Cancer Research, Diet, Nutrition, Physical Activity
and Cancer: A Global Perspective. Continuous Update Project Expert Report 2018., 2018.
78. Steinmetz, K.A., Kushi, L.H., Bostick, R.M., Folsom, A.R., and Potter, J.D., Vegetables, fruit, and colon
cancer in the Iowa women’s health study, Am J Epidemiol, 139: 1–15, 1994.
79. Kim, H., Keum, N., Giovannucci, E.L., Fuchs, C.S., and Bao, Y., Garlic intake and gastric cancer risk:
Results from two large prospective US cohort studies, Int J Cancer, 143(5):1047–1053, 2018.
80. Myneni, A.A. et al., Raw garlic consumption and lung cancer in a Chinese population, Cancer Epidem
Biomar Prev, 25(4): 624–633, 2016.
81. Tanaka, S. et al., Effects of aged garlic extract (AGE) on colorectal adenomas: A double-blinded study,
Hiroshima J Med Sci, 53(3–4): 39–45, 2004.
82. You, W.C., Blot, W.J., Chang, Y.S., Ershow, A., Yang, Z.T., An, Q., Henderson, B.E., Fraumeni, J.F.,
Jr., and Wang, T.G., Allium vegetables and reduced risk of stomach cancer, J Natl Cancer Inst, 81(2):
162–164, 1989.
83. Gail, M.H. et al., Factorial trial of three interventions to reduce the progression of precancerous gastric
lesions in Shandong, China: Design issues and initial data, Control Clin Trials, 19(4): 352–369, 1998.
84. Ma, J.L. et al., Fifteen-year effects of Helicobacter pylori, garlic, and vitamin treatments on gastric
cancer incidence and mortality, J Natl Cancer Inst, 104(6): 488–492, 2012.
85. Li, H., Li, H.-Q., Wang, Y., Xu, H.-X., Fan, W.-T., Wang, M.-L., Sun, P.-H., and Xie, X.-Y., An intervention
study to prevent gastric cancer by micro-selenium and large dose of allitridum, Chinese Med J Peking,
117(8): 1155–1160, 2004.
86. Singh, A. and Shukla, Y., Antitumour activity of diallyl sulfide on polycyclic aromatic hydrocarbon-
induced mouse skin carcinogenesis, Cancer Lett, 131(2): 209–214, 1998.
87. Ip, C., Lisk, D.J., and Stoewsand, G.S., Mammary cancer prevention by regular garlic and selenium-
enriched garlic, Nutr Cancer, 17(3): 279–286, 1992.
88. Wargovich, M.J., Diallyl sulfide, a flavor component of garlic (Allium sativum), inhibits dimethylhydrazine-
induced colon cancer, Carcinogenesis, 8(3): 487–489, 1987.
89. Hussain, S.P., Jannu, L.N., and Rao, A.R., Chemopreventive action of garlic on methylcholanthrene-
induced carcinogenesis in the uterine cervix of mice, Cancer Lett, 49(2): 175–180, 1990.
90. Wargovich, M.J., Woods, C., Eng, V.W., Stephens, L.C., and Gray, K., Chemoprevention of
N-nitrosomethylbenzylamine-induced esophageal cancer in rats by the naturally occurring thioether,
diallyl sulfide, Cancer Res, 48(23): 6872–6875, 1988.
91. Hong, J.Y., Wang, Z.Y., Smith, T.J., Zhou, S., Shi, S., Pan, J., and Yang, C.S., Inhibitory effects of diallyl
sulfide on the metabolism and tumorigenicity of the tobacco-specific carcinogen 4-(methylnitrosamino)-
1-(3-pyridyl)-1-butanone (NNK) in A/J mouse lung, Carcinogenesis, 13(5): 901–904, 1992.
92. Takahashi, S., Hakoi, K., Yada, H., Hirose, M., Ito, N., and Fukushima, S., Enhancing effects of diallyl
sulfide on hepatocarcinogenesis and inhibitory actions of the related diallyl disulfide on colon and renal
carcinogenesis in rats, Carcinogenesis, 13(9): 1513–1518, 1992.
93. Nagabhushan, M., Line, D., Polverini, P.J., and Solt, D.B., Anticarcinogenic action of diallyl sulfide in
hamster buccal pouch and forestomach, Cancer Lett, 66(3): 207–216, 1992.
94. Park, K.A., Kweon, S., and Choi, H., Anticarcinogenic effect and modification of cytochrome P450 2E1
by dietary garlic powder in diethylnitrosamine-initiated rat hepatocarcinogenesis, J Biochem Mol Biol,
35(6): 615–622, 2002.
95. Ross, S.A., Finley, J.W., and Milner, J.A., Allyl sulfur compounds from garlic modulate aberrant crypt
formation, J Nutr, 136(3): 852S–854, 2006.
96. Wargovich, M.J., Chen, C.D., Jimenez, A., Steele, V.E., Velasco, M., Stephens, L.C., Price, R.,
Gray, K., and Kelloff, G.J., Aberrant crypts as a biomarker for colon cancer: Evaluation of potential
chemopreventive agents in the rat, Cancer Epidem Biomar Prev, 5(5): 355–360, 1996.
97. Wargovich, M.J., Jimenez, A., McKee, K., Steele, V.E., Velasco, M., Woods, J., Price, R., Gray, K., and
Kelloff, G.J., Efficacy of potential chemopreventive agents on rat colon aberrant crypt formation and
progression, Carcinogenesis, 21(6): 1149–1155, 2000.
98. Jakszyn, P., Agudo, A., Ibanez, R., Garcia-Closas, R., Pera, G., Amiano, P., and Gonzalez, C.A.,
Development of a food database of nitrosamines, heterocyclic amines, and polycyclic aromatic
hydrocarbons, J Nutr, 134(8): 2011–2014, 2004.
99. Lijinsky, W., N-nitroso compounds in the diet, Mutat Res, 443(1–2): 129–138, 1999.
100. Shenoy, N.R. and Choughuley, A.S., Inhibitory effect of diet related sulphydryl compounds on the
formation of carcinogenic nitrosamines, Cancer Lett, 65(3): 227–232, 1992.
101. Milner, J.A., Mechanisms by which garlic and allyl sulfur compounds suppress carcinogen bioactivation.
Garlic and carcinogenesis, Adv Exp Med Biol, 492: 69–81, 2001.
102. Dion, M.E., Agler, M., and Milner, J.A., S-allyl cysteine inhibits nitrosomorpholine formation and
bioactivation, Nutr Cancer, 28(1): 1–6, 1997.
103. Mei, X., Lin, X., Liu, J., Lin, X.Y., Song, P.J., Hu, J.F., and Liang, X.J., The blocking effect of garlic on
the formation of N-nitrosoproline in humans, Acta Nutrimenta Sinica, 11: 141–145, 1989.
104. Ohshima, H. and Bartsch, H., Quantitative estimation of endogenous N-nitrosation in humans by
monitoring N-nitrosoproline in urine, Methods Enzymol, 301: 40–49, 1999.
105. Cope, K., Seifried, H., Seifried, R., Milner, J., Kris-Etherton, P., and Harrison, E.H., A gas
chromatography-mass spectrometry method for the quantitation of N-nitrosoproline and N-acetyl-S-
allylcysteine in human urine: Application to a study of the effects of garlic consumption on nitrosation,
Anal Biochem, 394(2): 243–248, 2009.
106. Haber-Mignard, D., Suschetet, M., Berges, R., Astorg, P., and Siess, M.H., Inhibition of aflatoxin B1- and
N-nitrosodiethylamine-induced liver preneoplastic foci in rats fed naturally occurring allyl sulfides, Nutr
Cancer, 25(1): 61–70, 1996.
107. Knasmuller, S., de Martin, R., Domjan, G., and Szakmary, A., Studies on the antimutagenic activities of
garlic extract, Environ Mol Mutagen, 13(4): 357–365, 1989.
108. Wargovich, M.J., Diallylsulfide and allylmethylsulfide are uniquely effective among organosulfur
compounds in inhibiting CYP2E1 protein in animal models, J Nutr, 136(3): 832S–834S, 2006.
109. Yang, C.S., Chhabra, S.K., Hong, J.Y., and Smith, T.J., Mechanisms of inhibition of chemical toxicity and
carcinogenesis by diallyl sulfide (DAS) and related compounds from garlic, J Nutr, 131(3s): 1041s–1045s,
2001.
110. Jin, L. and Baillie, T.A., Metabolism of the chemoprotective agent diallyl sulfide to glutathione conjugates
in rats, Chem Res Toxicol, 10(3): 318–327, 1997.
111. Rounds, L., Havens, C.M., Feinstein, Y., Friedman, M., and Ravishankar, S., Plant extracts, spices, and
essential oils inactivate Escherichia coli O157:H7 and reduce formation of potentially carcinogenic
heterocyclic amines in cooked beef patties, J Agric Food Chem, 60(14): 3792–3799, 2012.
112. Gibis, M., Effect of oil marinades with garlic, onion, and lemon juice on the formation of heterocyclic
aromatic amines in fried beef patties, J Agric Food Chem, 55(25): 10240–10247, 2007.
113. Davenport, D.M. and Wargovich, M.J., Modulation of cytochrome P450 enzymes by organosulfur
compounds from garlic, Food Chem Toxicol, 43(12): 1753–1762, 2005.
114. Yu, F.S., Yu, C.S., Lin, J.P., Chen, S.C., Lai, W.W., and Chung, J.G., Diallyl disulfide inhibits
N-acetyltransferase activity and gene expression in human esophagus epidermoid carcinoma CE 81 T/
VGH cells, Food Chem Toxicol, 43(7): 1029–1036, 2005.
115. Lin, X.Y., Liu, J.Z., and Milner, J.A., Dietary garlic suppresses DNA adducts caused by N-nitroso
compounds, Carcinogenesis, 15(2): 349–352, 1994.
116. Schaffer, E.M., Liu, J.Z., Green, J., Dangler, C.A., and Milner, J.A., Garlic and associated allyl sulfur
components inhibit N-methyl-N-nitrosourea induced rat mammary carcinogenesis, Cancer Lett, 102(1–
2): 199–204, 1996.
117. Cohen, L.A., Zhao, Z., Pittman, B., and Lubet, R., S-allylcysteine, a garlic constituent, fails to inhibit
N-methylnitrosourea-induced rat mammary tumorigenesis, Nutr Cancer, 35(1): 58–63, 1999.
118. Ludeke, B.I., Domine, F., Ohgaki, H., and Kleihues, P., Modulation of N-nitrosomethylbenzylamine
bioactivation by diallyl sulfide in vivo, Carcinogenesis, 13(12): 2467–2470, 1992.
119. Zhang, Y.J., Chen, Y., Ahsan, H., Lunn, R.M., Chen, S.Y., Lee, P.H., Chen, C.J., and Santella, R.M.,
Silencing of glutathione S-transferase P1 by promoter hypermethylation and its relationship to
environmental chemical carcinogens in hepatocellular carcinoma, Cancer Lett, 221(2): 135–143, 2005.
120. Le Bon, A.M., Vernevaut, M.F., Guenot, L., Kahane, R., Auger, J., Arnault, I., Haffner, T., and Siess,
M.H., Effects of garlic powders with varying alliin contents on hepatic drug metabolizing enzymes in
rats, J Agric Food Chem, 51(26): 7617–7623, 2003.
121. Wu, C.-C., Sheen, L.-Y., Chen, H.-W., Kuo, W.-W., Tsai, S.-J., and Lii, C.-K., Differential effects of garlic
oil and its three major organosulfur components on the hepatic detoxification system in rats, J Agric Food
Chem, 50(2): 378–383, 2002.
122. Foster, B.C., Foster, M.S., Vandenhoek, S., Krantis, A., Budzinski, J.W., Arnason, J.T., Gallicano, K.D.,
and Choudri, S., An in vitro evaluation of human cytochrome P450 3A4 and P-glycoprotein inhibition
by garlic, J Pharm Pharm Sci, 4(2): 176–184, 2001.
123. Brady, J.F., Ishizaki, H., Fukuto, J.M., Lin, M.C., Fadel, A., Gapac, J.M., and Yang, C.S., Inhibition of
cytochrome P-450 2E1 by diallyl sulfide and its metabolites, Chem Res Toxicol, 4(6): 642–647, 1991.
124. Amano, H., Kazamori, D., and Itoh, K., Evaluation of the effects of S-allyl-L-cysteine, S-methyl-L-
cysteine, trans-S-1-propenyl-L-cysteine, and their N-acetylated and S-oxidized metabolites on human
CYP activities, Biol Pharm Bull, 39(10): 1701–1707, 2016.
125. Uno, S., Dalton, T.P., Derkenne, S., Curran, C.P., Miller, M.L., Shertzer, H.G., and Nebert, D.W., Oral
exposure to benzo[a]pyrene in the mouse: Detoxication by inducible cytochrome P450 is more important
than metabolic activation, Mol Pharmacol, 65(5): 1225–1237, 2004.
126. Singh, S.V., Pan, S.S., Srivastava, S.K., Xia, H., Hu, X., Zaren, H.A., and Orchard, J.L., Differential
induction of NAD(P)H:quinone oxidoreductase by anti-carcinogenic organosulfides from garlic,
Biochem Biophys Res Commun, 244(3): 917–920, 1998.
127. Chen, C., Pung, D., Leong, V., Hebbar, V., Shen, G., Nair, S., Li, W., and Kong, A.N., Induction of
detoxifying enzymes by garlic organosulfur compounds through transcription factor Nrf2: Effect of
chemical structure and stress signals, Free Radic Biol Med, 37(10): 1578–1590, 2004.
128. Kim, S., Lee, H.G., Park, S.A., Kundu, J.K., Keum, Y.S., Cha, Y.N., Na, H.K., and Surh, Y.J., Keap1 cysteine
288 as a potential target for diallyl trisulfide-induced Nrf2 activation, PLOS ONE, 9(1): e85984, 2014.
129. Munday, R. and Munday, C.M., Relative activities of organosulfur compounds derived from onions and
garlic in increasing tissue activities of quinone reductase and glutathione transferase in rat tissues, Nutr
Cancer, 40(2): 205–210, 2001.
130. Charron, C.S., Dawson, H.D., and Novotny, J.A., Garlic influences gene expression in vivo and in vitro,
J Nutr, 146(2): 444s–449s, 2016.
131. Berges, R., Siess, M.H., Arnault, I., Auger, J., Kahane, R., Pinnert, M.F., Vernevaut, M.F., and le Bon,
A.M., Comparison of the chemopreventive efficacies of garlic powders with different alliin contents
against aflatoxin B1 carcinogenicity in rats, Carcinogenesis, 25(10): 1953–1959, 2004.
132. Surh, Y.J., Lee, R.C., Park, K.K., Mayne, S.T., Liem, A., and Miller, J.A., Chemoprotective effects
of capsaicin and diallyl sulfide against mutagenesis or tumorigenesis by vinyl carbamate and
N-nitrosodimethylamine, Carcinogenesis, 16(10): 2467–2471, 1995.
133. Zhang, C.L., Zeng, T., Zhao, X.L., and Xie, K.Q., Garlic oil attenuated nitrosodiethylamine-induced
hepatocarcinogenesis by modulating the metabolic activation and detoxification enzymes, Int J Biol Sci,
9(3): 237–245, 2013.
134. Herman-Antosiewicz, A. and Singh, S.V., Signal transduction pathways leading to cell cycle arrest and
apoptosis induction in cancer cells by allium vegetable-derived organosulfur compounds: A review,
Mutat Res, 555(1–2): 121–131, 2004.
135. Wu, X., Kassie, F., and Mersch-Sundermann, V., Induction of apoptosis in tumor cells by naturally
occurring sulfur-containing compounds, Mutat Res, 589(2): 81–102, 2005.
136. Wu, X.J., Kassie, F., and Mersch-Sundermann, V., The role of reactive oxygen species (ROS) production
on diallyl disulfide (DADS) induced apoptosis and cell cycle arrest in human A549 lung carcinoma cells,
Mutat Res, 579(1–2): 115–124, 2005.
137. Knowles, L.M. and Milner, J.A., Possible mechanism by which allyl sulfides suppress neoplastic cell
proliferation, J Nutr, 131(3): 1061S–1066, 2001.
138. Ling, H., Lu, L.F., He, J., Xiao, G.H., Jiang, H., and Su, Q., Diallyl disulfide selectively causes checkpoint
kinase-1 mediated G2/M arrest in human MGC803 gastric cancer cell line, Oncol Rep, 32(5): 2274–2282,
2014.
139. Knowles, L.M. and Milner, J.A., Diallyl disulfide inhibits p34(cdc2) kinase activity through changes in
complex formation and phosphorylation, Carcinogenesis, 21(6): 1129–1134, 2000.
140. Knowles, L.M. and Milner, J.A., Diallyl disulfide induces ERK phosphorylation and alters gene
expression profiles in human colon tumor cells, J Nutr, 133(9): 2901–2906, 2003.
141. Filomeni, G., Rotilio, G., and Ciriolo, M.R., Molecular transduction mechanisms of the redox network
underlying the antiproliferative effects of allyl compounds from garlic, J Nutr, 138(11): 2053–2057, 2008.
142. Puccinelli, M.T. and Stan, S.D., Dietary bioactive diallyl trisulfide in cancer prevention and treatment,
Int J Mol Sci, 18(8), 2017.
143. Iciek, M., Kwiecien, I., Chwatko, G., Sokolowska-Jezewicz, M., Kowalczyk-Pachel, D., and Rokita,
H., The effects of garlic-derived sulfur compounds on cell proliferation, caspase 3 activity, thiol levels
and anaerobic sulfur metabolism in human hepatoblastoma HepG2 cells, Cell Biochem Funct, 30(3):
198–204, 2012.
144. L’Vova G, N. and Zasukhina, G.D., [Modification of repair DNA synthesis in mutagen-treated human
fibroblasts during adaptive response and the antimutagenic effect of garlic extract], Genetika, 38(3):
306–309, 2002.
145. Konkimalla, V.S., Wang, G., Kaina, B., and Efferth, T., Microarray-based expression of DNA repair genes
does not correlate with growth inhibition of cancer cells by natural products derived from traditional
Chinese medicine, Cancer Genom Proteom, 5(2): 79–84, 2008.
146. Ross, S.A., Diet and DNA methylation interactions in cancer prevention, Ann NY Acad Sci, 983: 197–207,
2003.
147. Xu, Y., Su, D., Zhu, L., Zhang, S., Ma, S., Wu, K., Yuan, Q., and Lin, N., S-allylcysteine suppresses
ovarian cancer cell proliferation by DNA methylation through DNMT1, J Ovarian Res, 11(1): 39, 2018.
148. Lea, M.A., Randolph, V.M., and Patel, M., Increased acetylation of histones induced by diallyl disulfide
and structurally related molecules, Int J Oncol, 15(2): 347–352, 1999.
149. Lea, M.A., Rasheed, M., Randolph, V.M., Khan, F., Shareef, A., and desBordes, C., Induction of histone
acetylation and inhibition of growth of mouse erythroleukemia cells by S-allylmercaptocysteine, Nutr
Cancer, 43(1): 90–102, 2002.
150. Druesne, N., Pagniez, A., Mayeur, C., Thomas, M., Cherbuy, C., Duee, P.H., Martel, P., and Chaumontet,
C., Diallyl disulfide (DADS) increases histone acetylation and p21(waf1/cip1) expression in human colon
tumor cell lines, Carcinogenesis, 25(7): 1227–1236, 2004.
151. Zhao, J., Huang, W.G., He, J., Tan, H., Liao, Q.J., and Su, Q., Diallyl disulfide suppresses growth of
HL-60 cell through increasing histone acetylation and p21WAF1 expression in vivo and in vitro, Acta
Pharmacol Sin, 27(11): 1459–1466, 2006.
152. Druesne-Pecollo, N. and Latino-Martel, P., Modulation of histone acetylation by garlic sulfur compounds,
Anti-Cancer Agents Med Chem, 11(3): 254–259, 2011.
153. Nian, H., Delage, B., Pinto, J.T., and Dashwood, R.H., Allyl mercaptan, a garlic-derived organosulfur
compound, inhibits histone deacetylase and enhances Sp3 binding on the P21WAF1 promoter,
Carcinogenesis, 29(9): 1816–1824, 2008.
154. Arora, A. and Shukla, Y., Induction of apoptosis by diallyl sulfide in DMBA-induced mouse skin tumors,
Nutr Cancer, 44(1): 89–94, 2002.
155. Myzak, M.C., Ho, E., and Dashwood, R.H., Dietary agents as histone deacetylase inhibitors, Mol
Carcinog, 45(6): 443–446, 2006.
156. Bartel, D.P., microRNAs: Target recognition and regulatory functions, Cell, 136(2): 215–233, 2009.
157. Zhang, B., Pan, X., Cobb, G.P., and Anderson, T.A., microRNAs as oncogenes and tumor suppressors,
Dev Biol, 302(1): 1–12, 2007.
158. Xiao, X., Chen, B., Liu, X., Liu, P., Zheng, G., Ye, F., Tang, H., and Xie, X., Diallyl disulfide suppresses
SRC/Ras/ERK signaling-mediated proliferation and metastasis in human breast cancer by up-regulating
miR-34a, PLOS ONE, 9(11): e112720, 2014.
159. Rabinkov, A., Miron, T., Konstantinovski, L., Wilchek, M., Mirelman, D., and Weiner, L., The mode of
action of allicin: Trapping of radicals and interaction with thiol containing proteins, Biochim Biophys
Acta, 1379(2): 233–244, 1998.
160. Rahman, K., Garlic and aging: New insights into an old remedy, Ageing Res Rev, 2(1): 39–56, 2003.
161. Dwivedi, C., John, L.M., Schmidt, D.S., and Engineer, F.N., Effects of oil-soluble organosulfur
compounds from garlic on doxorubicin-induced lipid peroxidation, Anticancer Drugs, 9(3): 291–294,
1998.
162. Atmaca, G., Antioxidant effects of sulfur-containing amino acids, Yonsei Med J, 45(5): 776–788, 2004.
163. Okada, Y., Tanaka, K., Fujita, I., Sato, E., and Okajima, H., Antioxidant activity of thiosulfinates derived
from garlic, Redox Rep, 10(2): 96–102, 2005.
164. Petropoulos, S., Fernandes, A., Barros, L., Ciric, A., Sokovic, M., and Ferreira, I., Antimicrobial and
antioxidant properties of various Greek garlic genotypes, Food Chem, 245: 7–12, 2018.
165. Nencini, C., Menchiari, A., Franchi, G.G., and Micheli, L., In vitro antioxidant activity of aged extracts
of some Italian allium species, Plant Foods Hum Nutr (Dordrecht, Netherlands), 66(1): 11–16, 2011.
166. Gorinstein, S. et al., Comparison of the bioactive compounds and antioxidant potentials of fresh and
cooked Polish, Ukrainian, and Israeli garlic, J Agric Food Chem, 53(7): 2726–2732, 2005.
167. Schafer, G. and Kaschula, C.H., The immunomodulation and anti-inflammatory effects of garlic
organosulfur compounds in cancer chemoprevention, Anti-Cancer Agents Med Chem, 14(2): 233–240,
2014.
168. Arreola, R., Quintero-Fabian, S., Lopez-Roa, R.I., Flores-Gutierrez, E.O., Reyes-Grajeda, J.P., Carrera-
Quintanar, L., and Ortuno-Sahagun, D., Immunomodulation and anti-inflammatory effects of garlic
compounds, J Immunol Res, 2015: 401630, 2015.
169. Lamm, D.L. and Riggs, D.R., Enhanced immunocompetence by garlic: Role in bladder cancer and other
malignancies, J Nutr, 131(3): 1067S–1070, 2001.
170. Colic, M. and Savic, M., Garlic extracts stimulate proliferation of rat lymphocytes in vitro by increasing
IL-2 and IL-4 production, Immunopharm Immunot, 22(1): 163–181, 2000.
171. Colic, M., Vucevic, D., Kilibarda, V., Radicevic, N., and Savic, M., Modulatory effects of garlic extracts
on proliferation of T-lymphocytes in vitro stimulated with concanavalin A, Phytomedicine, 9(2): 117–124,
2002.
172. Jeong, H.G. and Lee, Y.W., Protective effects of diallyl sulfide on N-nitrosodimethylamine-induced
immunosuppression in mice, Cancer Lett, 134(1): 73–79, 1998.
173. Ishikawa, H., Saeki, T., Otani, T., Suzuki, T., Shimozuma, K., Nishino, H., Fukuda, S., and Morimoto, K.,
Aged garlic extract prevents a decline of NK cell number and activity in patients with advanced cancer,
J Nutr, 136(3 Suppl): 816s–820s, 2006.
174. Morioka, N., Sze, L.L., Morton, D.L., and Irie, R.F., A protein fraction from aged garlic extract enhances
cytotoxicity and proliferation of human lymphocytes mediated by interleukin-2 and concanavalin A,
Cancer Immunol Immunother, 37(5): 316–322, 1993.
175. Charron, C.S., Dawson, H.D., Albaugh, G.P., Solverson, P.M., Vinyard, B.T., Solano-Aguilar, G.I.,
Molokin, A., and Novotny, J.A., A single meal containing raw, crushed garlic influences expression of
immunity- and cancer-related genes in whole blood of humans, J Nutr, 145(11): 2448–2455, 2015.
176. Chang, H.P., Huang, S.Y., and Chen, Y.H., Modulation of cytokine secretion by garlic oil derivatives
is associated with suppressed nitric oxide production in stimulated macrophages, J Agric Food Chem,
53(7): 2530–2534, 2005.
177. Dirsch, V.M., Kiemer, A.K., Wagner, H., and Vollmar, A.M., Effect of allicin and ajoene, two compounds
of garlic, on inducible nitric oxide synthase, Atherosclerosis, 139(2): 333–339, 1998.
178. Chang, H.P. and Chen, Y.H., Differential effects of organosulfur compounds from garlic oil on nitric
oxide and prostaglandin E2 in stimulated macrophages, Nutrition, 21(4): 530–536, 2005.
179. Saud, S.M., Li, W., Gray, Z., Matter, M.S., Colburn, N.H., Young, M.R., and Kim, Y.S., Diallyl disulfide
(DADS), a constituent of garlic, inactivates NF-kappaB and prevents colitis-induced colorectal cancer
by inhibiting GSK-3beta, Cancer Prev Res (Philadelphia, Pa.), 9(7): 607–615, 2016.
180. Smith, B.J., Curtis, J.F., and Eling, T.E., Bioactivation of xenobiotics by prostaglandin H synthase, Chem
Biol Interact, 79(3): 245–264, 1991.
181. Li, N., Sood, S., Wang, S., Fang, M., Wang, P., Sun, Z., Yang, C.S., and Chen, X., Overexpression of
5-lipoxygenase and cyclooxygenase 2 in hamster and human oral cancer and chemopreventive effects of
zileuton and celecoxib, Clin Cancer Res, 11(5): 2089–2096, 2005.
182. Song, K. and Milner, J.A., Heating garlic inhibits its ability to suppress 7, 12-dimethylbenz(a)anthracene-
induced DNA adduct formation in rat mammary tissue, J Nutr, 129(3): 657–661, 1999.
183. Ali, M., Mechanism by which garlic (Allium sativum) inhibits cyclooxygenase activity. Effect of raw
versus boiled garlic extract on the synthesis of prostanoids, Prostaglandins Leukot Essent Fatty Acids,
53(6): 397–400, 1995.
184. Belman, S., Solomon, J., Segal, A., Block, E., and Barany, G., Inhibition of soybean lipoxygenase and
mouse skin tumor promotion by onion and garlic components, J Biochem Toxicol, 4(3): 151–160, 1989.
185. Dirsch, V.M. and Vollmar, A.M., Ajoene, a natural product with non-steroidal anti-inflammatory drug
(NSAID)-like properties? Biochem Pharmacol, 61(5): 587–593, 2001.
186. Velmurugan, B., Bhuvaneswari, V., Abraham, S.K., and Nagini, S., Protective effect of tomato against
N-methyl-N’-nitro-N-nitrosoguanidine-induced in vivo clastogenicity and oxidative stress, Nutrition,
20(9): 812–816, 2004.
187. Bhuvaneswari, V., Abraham, S.K., and Nagini, S., Combinatorial antigenotoxic and anticarcinogenic
effects of tomato and garlic through modulation of xenobiotic-metabolizing enzymes during hamster
buccal pouch carcinogenesis, Nutrition, 21(6): 726–731, 2005.
188. Kumaraguruparan, R., Chandra Mohan, K.V., Abraham, S.K., and Nagini, S., Attenuation of N-methyl-
N’-nitro-N-nitrosoguanidine induced genotoxicity and oxidative stress by tomato and garlic combination,
Life Sci, 76(19): 2247–2255, 2005.
189. Schaffer, E.M., Liu, J.Z., and Milner, J.A., Garlic powder and allyl sulfur compounds enhance the ability
of dietary selenite to inhibit 7,12-dimethylbenz[a]anthracene-induced mammary DNA adducts, Nutr
Cancer, 27(2): 162–168, 1997.
190. Amagase, H., Schaffer, E.M., and Milner, J.A., Dietary components modify the ability of garlic to
suppress 7,12-dimethylbenz(a)anthracene-induced mammary DNA adducts, J Nutr, 126(4): 817–824,
1996.
191. Ip, C., Lisk, D.J., and Thompson, H.J., Selenium-enriched garlic inhibits the early stage but not the late
stage of mammary carcinogenesis, Carcinogenesis, 17(9): 1979–1982, 1996.
192. Ganther, H.E., Selenium metabolism, selenoproteins and mechanisms of cancer prevention: Complexities
with thioredoxin reductase, Carcinogenesis, 20(9): 1657–1666, 1999.
193. Sundaram, S.G. and Milner, J.A., Diallyl disulfide inhibits the proliferation of human tumor cells in
culture, Biochim Biophys Acta, 1315(1): 15–20, 1996.
194. Knowles, L.M. and Milner, J.A., Depressed p34cdc2 kinase activity and G2/M phase arrest induced by
diallyl disulfide in HCT-15 cells, Nutr Cancer, 30(3): 169–174, 1998.
195. Schaffer, E.M. and Milner, J.A., Impact of dietary fatty acids on 7,12-dimethylbenz[a]anthracene-induced
mammary DNA adducts, Cancer Lett, 106(2): 177–183, 1996.
196. Tang, F., Zhou, J., and Gu, L., [In vivo and in vitro effects of selenium-enriched garlic on growth of human
gastric carcinoma cells], Zhonghua Zhong Liu Za Zhi, 23(6): 461–464, 2001.
197. Seki, T., Tsuji, K., Hayato, Y., Moritomo, T., and Ariga, T., Garlic and onion oils inhibit proliferation and
induce differentiation of HL-60 cells, Cancer Lett, 160(1): 29–35, 2000.
198. Talib, W.H., Consumption of garlic and lemon aqueous extracts combination reduces tumor burden by
angiogenesis inhibition, apoptosis induction, and immune system modulation, Nutrition, 43–44: 89–97,
2017.
199. Reinhart, K.M., Talati, R., White, C.M., and Coleman, C.I., The impact of garlic on lipid parameters: A
systematic review and meta-analysis, Nutr Res Rev, 22(1): 39–48, 2009.
200. Varshney, R. and Budoff, M.J., Garlic and heart disease, J Nutr, 146(2): 416S–421S, 2016.
201. Gardner, C.D., Lawson, L.D., Block, E., Chatterjee, L.M., Kiazand, A., Balise, R.R., and Kraemer, H.C.,
Effect of raw garlic vs commercial garlic supplements on plasma lipid concentrations in adults with
moderate hypercholesterolemia: A randomized clinical trial, Arch Intern Med, 167: 346–353, 2007.
202. Sobenin, I.A., Pryanishnikov, V.V., Kunnova, L.M., Rabinovich, Y.A., Martirosyan, D.M., and Orekhov,
A.N., The effects of time-released garlic powder tablets on multifunctional cardiovascular risk in patients
with coronary artery disease, Lipids Health Dis, 9, 119, 2010.
203. Ried, K., Toben, C., and Fakler, P., Effect of garlic on serum lipids: An updated meta-analysis, Nutr Rev,
71(5): 282–299, 2013.
204. Sahebkar, A., Serban, C., Ursoniu, S., and Banach, M., Effect of garlic on plasma lipoprotein(a)
concentrations: A systematic review and meta-analysis of randomized controlled clinical trials, Nutrition,
32(1): 33–40, 2016.
205. Jabbari, A., Argani, H., Ghorbanihaghjo, A., and Mahdavi, R., Comparison between swallowing and
chewing of garlic on levels of serum lipids, cyclosporine, creatinine and lipid peroxidation in renal
transplant recipients, Lipids Health Dis, 4, 11, 2005.
206. Song, K. and Milner, J.A., The influence of heating on the anticancer properties of garlic, J Nutr, 131(3):
1054S–1057, 2001.
207. Maiolino, G., Rossitto, G., Caielli, P., Bisogni, V., Rossi, G.P., and Calò, L.A., The role of oxidized low-
density lipoproteins in atherosclerosis: The myths and the facts, Mediat Inflamm, 2013, 714653, 2013.
208. Lau, B.H.S., Suppression of LDL oxidation by garlic, J Nutr, 131(3 Suppl.): 985S–988S, 2001.
209. Munday, J.S., James, K.A., Fray, L.M., Kirkwood, S.W., and Thompson, K.G., Daily supplementation
with aged garlic extract, but not raw garlic, protects low density lipoprotein against in vitro oxidation,
Atherosclerosis, 143(2): 399–404, 1999.
210. Lau, B.H.S., Suppression of LDL oxidation by garlic compounds is a possible mechanism of cardiovascular
health benefit, J Nutr, 136(3): 765S–768S, 2006.
211. Byrne, D.J., Neil, H.A., Vallance, D.T., and Winder, A.F., A pilot study of garlic consumption shows
no significant effect on markers of oxidation or sub-fraction composition of low-density lipoprotein
including lipoprotein(a) after allowance for non-compliance and the placebo effect, Clin Chim Acta,
285(1–2): 21–33, 1999.
212. Ou, C.C., Tsao, S.M., Lin, M.C., and Yin, M.C., Protective action on human LDL against oxidation and
glycation by four organosulfur compounds derived from garlic, Lipids, 38(3): 219–224, 2003.
213. Huang, C.N., Horng, J.S., and Yin, M.C., Antioxidative and antiglycative effects of six organosulfur
compounds in low-density lipoprotein and plasma, J Agric Food Chem, 52(11): 3674–3678, 2004.
214. Law, M.R., Morris, J.K., and Wald, N.J., Use of blood pressure lowering drugs in the prevention of
cardiovascular disease: Meta-analysis of 147 randomised trials in the context of expectations from
prospective epidemiological studies, BMJ, 338(7705): 1245, 2009.
215. Ried, K., Garlic lowers blood pressure in hypertensive individuals, regulates serum cholesterol, and
stimulates immunity: An updated meta-analysis and review, J Nutr, 146(2): 389S–396S, 2016.
216. Li, L., Sun, T., Tian, J., Yang, K., Yi, K., and Zhang, P., Garlic in clinical practice: An evidence-based
overview, Crit Rev Food Sci Nutr, 53(7): 670–681, 2013.
217. Fallon, M.B., Abrams, G.A., Abdel-Razek, T.T., Dai, J., Chen, S.J., Chen, Y.F., Luo, B., Oparil, S., and
Ku, D.D., Garlic prevents hypoxic pulmonary hypertension in rats, Am J Physiol, 275(2 Pt 1): L283–287,
1998.
218. Maslin, D.J., Brown, C.A., Das, I., and Zhang, X.H., Nitric oxide—a mediator of the effects of garlic?
Biochem Soc Trans, 25(3): 408S, 1997.
219. Lei, Y.P., Liu, C.T., Sheen, L.Y., Chen, H.W., and Lii, C.K., Diallyl disulfide and diallyl trisulfide protect
endothelial nitric oxide synthase against damage by oxidized lowdensity lipoprotein, Mol Nutr Food Res,
54(Suppl. 1): S42–S52, 2010.
220. Aqel, M.B., Gharaibah, M.N., and Salhab, A.S., Direct relaxant effects of garlic juice on smooth and
cardiac muscles, J Ethnopharmacol, 33(1–2): 13–19, 1991.
221. Ashraf, M.Z., Hussain, M.E., and Fahim, M., Endothelium mediated vasorelaxant response of garlic in
isolated rat aorta: Role of nitric oxide, J Ethnopharmacol, 90(1): 5–9, 2004.
222. Benavides, G.A., Squadrito, G.L., Mills, R.W., Patel, H.D., Isbell, T.S., Patel, R.P., Darley-Usmar, V.M.,
Doeller, J.E., and Kraus, D.W., Hydrogen sulfide mediates the vasoactivity of garlic, P Natl Acad Sci
USA, 104(46): 17977–17982, 2007.
223. Jiang, B., Tang, G., Cao, K., Wu, L., and Wang, R., Molecular mechanism for H2S-induced activation of
K ATP channels, Antioxid Redox Signal, 12(10): 1167–1178, 2010.
224. Patel, V.B. and Topol, E.J., The pathogenesis and spectrum of acute coronary syndromes: From plaque
formation to thrombosis, Cleve Clin J Med, 66(9): 561–571, 1999.
225. Budoff, M.J., Takasu, J., Flores, F.R., Niihara, Y., Lu, B., Lau, B.H., Rosen, R.T., and Amagase, H.,
Inhibiting progression of coronary calcification using aged garlic extract in patients receiving statin
therapy: A preliminary study, Prev Med, 39(5): 985–991, 2004.
226. Budoff, M.J., Ahmadi, N., Gul, K.M., Liu, S.T., Flores, F.R., Tiano, J., Takasu, J., Miller, E., and Tsimikas,
S., Aged garlic extract supplemented with B vitamins, folic acid and l-arginine retards the progression
of subclinical atherosclerosis: A randomized clinical trial, Prev Med, 49(2–3): 101–107, 2009.
227. Matsumoto, S. et al., Aged garlic extract reduces low attenuation plaque in coronary arteries of patients
with metabolic syndrome in a prospective randomized double-blind study, J Nutr, 146(2): 427S–432S,
2016.
228. Versteylen, M.O. et al., Additive value of semiautomated quantification of coronary artery disease using
cardiac computed tomographic angiography to predict future acute coronary syndrome, J Am Coll
Cardiol, 61(22): 2296–2305, 2013.
229. Koscielny, J., Klussendorf, D., Latza, R., Schmitt, R., Radtke, H., Siegel, G., and Kiesewetter, H., The
antiatherosclerotic effect of Allium sativum, Atherosclerosis, 144(1): 237–249, 1999.
230. Mahdavi-Roshan, M., Zahedmehr, A., Mohammad-Zadeh, A., Sanati, H.R., Shakerian, F., Firouzi, A.,
Kiani, R., and Nasrollahzadeh, J., Effect of garlic powder tablet on carotid intima-media thickness in
patients with coronary artery disease: A preliminary randomized controlled trial, Nutr Health, 22(2):
143–155, 2013.
231. Sobenin, I.A., Korneev, N.V., Romanov, I.V., Shutikhina, I.V., Kuntsevich, G.I., Romanenko, E.B.,
Myasoedova, V.A., Revin, V.V., and Orekhov, A.N., The effects of garlic powder tablets in subclinical
carotid atherosclerosis, Exp Clin Cardiol, 20(1): 629–638, 2014.
232. Zahid Ashraf, M., Hussain, M.E., and Fahim, M., Antiatherosclerotic effects of dietary supplementations
of garlic and turmeric: Restoration of endothelial function in rats, Life Sci, 77(8): 837–857, 2005.
233. Ali, M., Bordia, T., and Mustafa, T., Effect of raw versus boiled aqueous extract of garlic and onion on
platelet aggregation, Prostaglandins Leukot Essent Fatty Acids, 60(1): 43–47, 1999.
234. Rahman, K., Lowe, G.M., and Smith, S., Aged garlic extract inhibits human platelet aggregation by
altering intracellular signaling and platelet shape change, J Nutr, 146(2): 410S–415S, 2016.
235. Steiner, M. and Lin, R.S., Changes in platelet function and susceptibility of lipoproteins to oxidation
associated with administration of aged garlic extract, J Cardiovasc Pharmacol, 31(6): 904–908, 1998.
236. Rahman, K. and Billington, D., Dietary supplementation with aged garlic extract inhibits ADP-induced
platelet aggregation in humans, J Nutr, 130(11): 2662–2665, 2000.
237. Kumar, A., Nirmala, K., Prasad, M.P.R., Panpatil, V.V., Prasanna Krishna, T., Sesikeran, B., and Polasa,
K., Reduction in platelet aggregation (in vitro) by diallyl sulphide in female participants with type 2
diabetes mellitus, J Pharmacol Toxicol, 6(4): 381–390, 2011.
238. Ross, S.A. and Milner, J.A., Garlic, the mystical food in health promotion, in Handbook of Nutraceuticals
and Functional Foods, Second Edition, R.E.C. Wildman, Editor. 2006, CRC Press: Boca Raton, FL. p.
73–99.
239. Marks, H.S., Anderson, J.L., and Stoewsand, G.S., Inhibition of benzo[a]pyrene-induced bone marrow
micronuclei formation by diallyl thioethers in mice, J Toxicol Environ Health, 37(1): 1–9, 1992.
240. Balasenthil, S., Arivazhagan, S., Ramachandran, C.R., and Nagini, S., Effects of garlic on
7,12-dimethylbenz[a]anthracene-induced hamster buccal pouch carcinogenesis, Cancer Detect Prev,
23(6): 534–538, 1999.
241. Hatono, S., Jimenez, A., and Wargovich, M.J., Chemopreventive effect of S-allylcysteine and its
relationship to the detoxification enzyme glutathione S-transferase, Carcinogenesis, 17(5): 1041–1044,
1996.
242. Sengupta, A., Ghosh, S., and Das, S., Tomato and garlic can modulate azoxymethane-induced colon
carcinogenesis in rats, Eur J Cancer Prev, 12(3): 195–200, 2003.
243. Sparnins, V.L., Barany, G., and Wattenberg, L.W., Effects of organosulfur compounds from garlic
and onions on benzo[a]pyrene-induced neoplasia and glutathione S-transferase activity in the mouse,
Carcinogenesis, 9(1): 131–134, 1988.
244. Wattenberg, L.W., Sparnins, V.L., and Barany, G., Inhibition of N-nitrosodiethylamine carcinogenesis
in mice by naturally occurring organosulfur compounds and monoterpenes, Cancer Res, 49(10): 2689–
2692, 1989.
245. Hu, P.J. and Wargovich, M.J., Effect of diallyl sulfide on MNNG-induced nuclear aberrations and
ornithine decarboxylase activity in the glandular stomach mucosa of the Wistar rat, Cancer Lett, 47(1–2):
153–158, 1989.
246. el-Mofty, M.M., Sakr, S.A., Essawy, A., and Abdel Gawad, H.S., Preventive action of garlic on aflatoxin
B1-induced carcinogenesis in the toad Bufo regularis, Nutr Cancer, 21(1): 95–100, 1994.
247. Guyonnet, D., Belloir, C., Suschetet, M., Siess, M.H., and Le Bon, A.M., Mechanisms of protection against
aflatoxin B(1) genotoxicity in rats treated by organosulfur compounds from garlic, Carcinogenesis, 23(8):
1335–1341, 2002.
248. Samaranayake, M.D., Wickramasinghe, S.M., Angunawela, P., Jayasekera, S., Iwai, S., and Fukushima,
S., Inhibition of chemically induced liver carcinogenesis in Wistar rats by garlic (Allium sativum),
Phytother Res, 14(7): 564–567, 2000.
249. Suzui, N., Sugie, S., Rahman, K.M., Ohnishi, M., Yoshimi, N., Wakabayashi, K., and Mori, H., Inhibitory
effects of diallyl disulfide or aspirin on 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-induced
mammary carcinogenesis in rats, Jpn J Cancer Res, 88(8): 705–711, 1997.
250. Hong, J.Y., Smith, T., Lee, M.J., Li, W.S., Ma, B.L., Ning, S.M., Brady, J.F., Thomas, P.E., and Yang, C.S.,
Metabolism of carcinogenic nitrosamines by rat nasal mucosa and the effect of diallyl sulfide, Cancer
Res, 51(5): 1509–1514, 1991.
251. Dwivedi, C., Rohlfs, S., Jarvis, D., and Engineer, F.N., Chemoprevention of chemically induced skin
tumor development by diallyl sulfide and diallyl disulfide, Pharm Res, 9(12): 1668–1670, 1992.
252. Shrotriya, S., Kundu, J.K., Na, H.K., and Surh, Y.J., Diallyl trisulfide inhibits phorbol ester-induced
tumor promotion, activation of AP-1, and expression of COX-2 in mouse skin by blocking JNK and Akt
signaling, Cancer Res, 70(5): 1932–1940, 2010.
1. Institute of Medicine (U.S.). Panel on Dietary Antioxidants and Related Compounds. Dietary Reference
Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids: A Report of the Panel on Dietary
Antioxidants and Related Compounds, Subcommittees on Upper Reference Levels of Nutrients and
of Interpretation and Use of Dietary Reference Intakes, and the Standing Committee on the Scientific
Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine. Washington,
D.C.: National Academy Press; 2000.
2. Bruno RS, Traber MG. Cigarette smoke alters human vitamin E requirements. J Nutr. 2005;135:671–4.
3. Evans HM, Bishop KS. On the existence of a hitherto unrecognized dietary factor essential for
reproduction. Science. 1922;56:650–1.
4. Sure B. Dietary requirements for reproduction. II. The existence of a specific vitamin for reproduction.
J Biol Chem. 1924;58:693–709.
5. Evans HM, Emerson OH, Emerson GA. The isolation from wheat germ oil of an alcohol, α-tocopherol,
having the properties of vitamin. J Biol Chem. 1936;113:319–32.
6. Emerson OH, Emerson GA, Mohammad A, Evans HM. The chemistry of vitamin E. Tocopherols from
various sources. J Biol Chem. 1937;122:99–107.
7. Machlin LJ. Handbook of Vitamins. 2nd, rev. and expand ed. New York: M. Dekker; 1991.
8. Horwitt MK. Erythrocyte survival time and reticulocyte levels after tocopherol depletion in man. Am J
Clin Nutr. 1963;12:99–106.
9. Horwitt MK, Harvey CC, Duncan GD, Wilson WC. Effects of limited tocopherol intake in man with
relationships to erythrocyte hemolysis and lipid oxidations. Am J Clin Nutr. 1956;4:408–19.
10. Horwitt MK. Vitamin E and lipid metabolism in man. Am J Clin Nutr. 1960;8:451–61.
11. Sokol RJ, Heubi JE, Iannaccone ST, Bove KE, Balistreri WF. Vitamin E deficiency with normal serum
vitamin E concentrations in children with chronic cholestasis. N Engl J Med. 1984;310:1209–12.
12. Rader DJ, Brewer HB, Jr. Abetalipoproteinemia. New insights into lipoprotein assembly and vitamin E
metabolism from a rare genetic disease. JAMA. 1993;270:865–9.
13. Kalra V, Grover J, Ahuja GK, Rathi S, Khurana DS. Vitamin E deficiency and associated neurological
deficits in children with protein-energy malnutrition. J Trop Pediatr. 1998;44:291–5.
14. Cavalier L, Ouahchi K, Kayden HJ, Di Donato S, Reutenauer L, Mandel JL, Koenig M. Ataxia with
isolated vitamin E deficiency: Heterogeneity of mutations and phenotypic variability in a large number
of families. Am J Hum Genet. 1998;62:301–10.
15. Terasawa Y, Ladha Z, Leonard SW, Morrow JD, Newland D, Sanan D, Packer L, Traber MG, Farese RV, Jr.
Increased atherosclerosis in hyperlipidemic mice deficient in alpha -tocopherol transfer protein and
vitamin E. Proc Natl Acad Sci U S A. 2000;97:13830–4.
16. Burton GW, Ingold KU. Vitamin E as an in vitro and in vivo antioxidant. Ann N Y Acad Sci. 1989;570:7–22.
17. Burton GW, Cheeseman KH, Doba T, Ingold KU, Slater TF. Vitamin E as an antioxidant in vitro and in
vivo. Ciba Found Symp. 1983;101:4–18.
18. Buettner GR. The pecking order of free radicals and antioxidants: Lipid peroxidation, alpha-tocopherol,
and ascorbate. Arch Biochem Biophys. 1993;300:535–43.
19. Terentis AC, Thomas SR, Burr JA, Liebler DC, Stocker R. Vitamin E oxidation in human atherosclerotic
lesions. Circ Res. 2002;90:333–9.
20. Upston JM, Terentis AC, Stocker R. Tocopherol-mediated peroxidation of lipoproteins: Implications for
vitamin E as a potential antiatherogenic supplement. Faseb J. 1999;13:977–94.
21. Burton GW, Doba T, Gabe EJ, Hughes L, Lee FL, Prasad L, Ingold KU. Autoxidation of biological
molecules. 4. Maximizing the antioxidant activity of phenols. J Am Chem Soc. 1985;107:7053–65.
22. Handelman GJ, Packer L, Cross CE. Destruction of tocopherols, carotenoids, and retinol in human
plasma by cigarette smoke. Am J Clin Nutr. 1996;63:559–65.
23. Leonard SW, Bruno RS, Paterson E, Schock BC, Atkinson J, Bray TM, Cross CE, Traber MG. 5-nitro-
gamma-tocopherol increases in human plasma exposed to cigarette smoke in vitro and in vivo. Free
Radic Biol Med. 2003;35:1560–7.
24. Frei B, England L, Ames BN. Ascorbate is an outstanding antioxidant in human blood plasma. Proc Natl
Acad Sci U S A. 1989;86:6377–81.
25. Botti H, Batthyany C, Trostchansky A, Radi R, Freeman BA, Rubbo H. Peroxynitrite-mediated
alpha-tocopherol oxidation in low-density lipoprotein: A mechanistic approach. Free Radic Biol Med.
2004;36:152–62.
26. Sacheck JM, Blumberg JB. Role of vitamin E and oxidative stress in exercise. Nutrition. 2001;17:809–14.
27. Traber MG, Buettner GR, Bruno RS. The relationship between vitamin C status, the gut-liver axis, and
metabolic syndrome. Redox Biol. 2018;21:101091.
28. Mastaloudis A, Leonard SW, Traber MG. Oxidative stress in athletes during extreme endurance exercise.
Free Radic Biol Med. 2001;31:911–22.
29. Mah E, Sapper TN, Chitchumroonchokchai C, Failla ML, Schill KE, Clinton SK, Bobe G, Traber MG,
Bruno RS. alpha-tocopherol bioavailability is lower in adults with metabolic syndrome regardless of
dairy fat co-ingestion: A randomized, double-blind, crossover trial. Am J Clin Nutr. 2015;102:1070–80.
30. Bruno RS, Ramakrishnan R, Montine TJ, Bray TM, Traber MG. {alpha}-tocopherol disappearance
is faster in cigarette smokers and is inversely related to their ascorbic acid status. Am J Clin Nutr.
2005;81:95–103.
31. Basu S, Helmersson J. Factors regulating isoprostane formation in vivo. Antioxid Redox Signal.
2005;7:221–35.
32. Bruno RS, Leonard SW, Atkinson J, Montine TJ, Ramakrishnan R, Bray TM, Traber MG. Faster plasma
vitamin E disappearance in smokers is normalized by vitamin C supplementation. Free Radic Biol Med.
2006;40:689–97.
33. Roberts LJ, 2nd, Oates JA, Linton MF, Fazio S, Meador BP, Gross MD, Shyr Y, Morrow JD. The
relationship between dose of vitamin E and suppression of oxidative stress in humans. Free Radic Biol
Med. 2007;43:1388–93.
34. Boscoboinik D, Szewczyk A, Azzi A. Alpha-tocopherol (vitamin E) regulates vascular smooth muscle
cell proliferation and protein kinase C activity. Arch Biochem Biophys. 1991;286:264–9.
35. Chatelain E, Boscoboinik DO, Bartoli GM, Kagan VE, Gey FK, Packer L, Azzi A. Inhibition of smooth
muscle cell proliferation and protein kinase C activity by tocopherols and tocotrienols. Biochim Biophys
Acta. 1993;1176:83–9.
36. Devaraj S, Li D, Jialal I. The effects of alpha tocopherol supplementation on monocyte function.
Decreased lipid oxidation, interleukin 1 beta secretion, and monocyte adhesion to endothelium. J Clin
Invest. 1996;98:756–63.
37. Freedman JE, Farhat JH, Loscalzo J, Keaney JFJ. Alpha-tocopherol inhibits aggregation of human
platelets by a protein kinase C-dependent mechanism. Circulation. 1996;94:2434–40.
38. Cominacini L, Garbin U, Pasini AF, Davoli A, Campagnola M, Contessi GB, Pastorino AM, Lo Cascio
V. Antioxidants inhibit the expression of intercellular cell adhesion molecule-1 and vascular cell adhesion
molecule-1 induced by oxidized LDL on human umbilical vein endothelial cells. Free Radic Biol Med.
1997;22:117–27.
39. Chan AC, Wagner M, Kennedy C, Mroske C, Proulx P, Laneuville O, Tran K, Choy PC. Vitamin E
up-regulates phospholipase A2, arachidonic acid release and cyclooxygenase in endothelial cells. Akt
Ernahr-Med. 1998;23:1–8.
40. Chan AC, Wagner M, Kennedy C, Chen E, Lanuville O, Mezl VA, Tran K, Choy PC. Vitamin E
up-regulates arachidonic acid release and phospholipase A2 in megakaryocytes. Mol Cell Biochem.
1998;189:153–9.
41. Wu D, Liu L, Meydani M, Meydani SN. Vitamin E increases production of vasodilator prostanoids in
human aortic endothelial cells through opposing effects on cyclooxygenase-2 and phospholipase A2.
J Nutr. 2005;135:1847–53.
42. Devaraj S, Jialal I. Alpha tocopherol supplementation decreases serum C-reactive protein and
monocyte interleukin-6 levels in normal volunteers and type 2 diabetic patients. Free Rad Biol Med.
2000;29:790–2.
43. Devaraj S, Jialal I. Alpha-tocopherol decreases tumor necrosis factor-alpha mRNA and protein from
activated human monocytes by inhibition of 5-lipoxygenase. Free Radic Biol Med. 2005;38:1212–20.
44. Suzuki YJ, Packer L. Inhibition of NF-kappa B DNA binding activity by alpha-tocopheryl succinate.
Biochem Mol Biol Int. 1993;31:693–700.
45. Calfee-Mason KG, Spear BT, Glauert HP. Vitamin E inhibits hepatic NF-kappaB activation in rats
administered the hepatic tumor promoter, phenobarbital. J Nutr. 2002;132:3178–85.
46. Jiang Q, Elson-Schwab I, Courtemanche C, Ames BN. Gamma-tocopherol and its major metabolite,
in contrast to alpha-tocopherol, inhibit cyclooxygenase activity in macrophages and epithelial cells.
Proc Natl Acad Sci U S A. 2000;97:11494–9.
47. Jiang Q, Ames BN. Gamma-tocopherol, but not alpha-tocopherol, decreases proinflammatory eicosanoids
and inflammation damage in rats. Faseb J. 2003;17:816–22.
48. Christen S, Jiang Q, Shigenaga MK, Ames BN. Analysis of plasma tocopherols alpha, gamma, and
5-nitro-gamma in rats with inflammation by HPLC coulometric detection. J Lipid Res. 2002;43:1978–85.
49. Christen S, Woodall AA, Shigenaga MK, Southwell-Keely PT, Duncan MW, Ames BN. Gamma-
tocopherol traps mutagenic electrophiles such as NO(X) and complements alpha-tocopherol: Physiological
implications. Proc Natl Acad Sci U S A. 1997;94:3217–22.
50. Hoglen NC, Waller SC, Sipes IG, Liebler DC. Reactions of peroxynitrite with gamma-tocopherol.
Chem Res Toxicol. 1997;10:401–7.
51. Morton LW, Ward NC, Croft KD, Puddey IB. Evidence for the nitration of gamma-tocopherol in vivo:
5-nitro-gamma-tocopherol is elevated in the plasma of subjects with coronary heart disease. Biochem J.
2002;364:625–8.
52. Williamson KS, Gabbita SP, Mou S, West M, Pye QN, Markesbery WR, Cooney RV, Grammas P,
Reimann-Philipp U et al. The nitration product 5-nitro-gamma-tocopherol is increased in the Alzheimer
brain. Nitric Oxide. 2002;6:221–7.
53. Church DF, Pryor WA. Free-radical chemistry of cigarette smoke and its toxicological implications.
Environ Health Perspect. 1985;64:111–26.
54. Dial S, Eitenmiller RR. Tocopherols and tocotrienols in key foods in the U.S. diet. In: Ong ASH,
Niki E, Packer L, editors. Nutrition, Lipids, Health, and Disease. Champaign, IL: AOCS Press; 1995.
pp. 327–42.
55. Maras JE, Bermudez OI, Qiao N, Bakun PJ, Boody-Alter EL, Tucker KL. Intake of alpha-tocopherol is
limited among US adults. J Am Diet Assoc. 2004;104:567–75.
56. McLaughlin PJ, Weihrauch JL. Vitamin E content of foods. J Am Diet Assoc. 1979;75:647–65.
57. Bieri JG, Evarts RP. Gamma tocopherol: Metabolism, biological activity and significance in human
vitamin E nutrition. Am J Clin Nutr. 1974;27:980–6.
58. Muller PY, Netscher T, Frank J, Stoecklin E, Rimbach G, Barella L. Comparative quantification of
pharmacodynamic parameters of chiral compounds (RRR- vs. all-rac-alpha tocopherol) by global gene
expression profiling. J Plant Physiol. 2005;162:811–7.
59. Traber MG, Burton GW, Ingold KU, Kayden HJ. RRR- and SRR-alpha-tocopherols are secreted without
discrimination in human chylomicrons, but RRR-alpha-tocopherol is preferentially secreted in very low
density lipoproteins. J Lipid Res. 1990;31:675–85.
60. Burton GW, Traber MG, Acuff RV, Walters DN, Kayden H, Hughes L, Ingold KU. Human plasma
and tissue alpha-tocopherol concentrations in response to supplementation with deuterated natural and
synthetic vitamin E. Am J Clin Nutr. 1998;67:669–84.
61. Traber MG, Rader D, Acuff RV, Brewer HB, Jr., Kayden HJ. Discrimination between RRR- and all-
racemic-alpha-tocopherols labeled with deuterium by patients with abetalipoproteinemia. Atherosclerosis.
1994;108:27–37.
62. Bruno RS, Leonard SW, Li J, Bray TM, Traber MG. Lower plasma alpha-carboxyethyl-hydroxychroman
after deuterium-labeled alpha-tocopherol supplementation suggests decreased vitamin E metabolism in
smokers. Am J Clin Nutr. 2005;81:1052–9.
63. Valk EE, Hornstra G. Relationship between vitamin E requirement and polyunsaturated fatty acid intake
in man: A review. Int J Vitam Nutr Res. 2000;70:31–42.
64. Mertz W, Tsui JC, Judd JT, Reiser S, Hallfrisch J, Morris ER, Steele PD, Lashley E. What are people
really eating? The relation between energy intake derived from estimated diet records and intake
determined to maintain body weight. Am J Clin Nutr. 1991;54:291–5.
65. Briefel RR, Sempos CT, McDowell MA, Chien S, Alaimo K. Dietary methods research in the third
National Health and Nutrition Examination Survey: Underreporting of energy intake. Am J Clin Nutr.
1997;65:1203S–9S.
66. McBurney MI, Yu EA, Ciappio ED, Bird JK, Eggersdorfer M, Mehta S. Suboptimal serum alpha-
tocopherol concentrations observed among younger adults and those depending exclusively upon food
sources, NHANES 2003–2006. PLOS ONE. 2015;10:e0135510.
67. Michels AJ, Leonard SW, Uesugi SL, Bobe G, Frei B, Traber MG. Daily consumption of Oregon
hazelnuts affects alpha tocopherol status in healthy older adults: A pre-post intervention study. J Nutr.
2018;148:1924–30.
68. Traber MG. Vitamin E. In: Shils ME, Olson JA, Shike M, Ross AC, editors. Modern Nutrition in Health
and Disease. Baltimore, MD: Williams & Wilkins; 1999. pp. 347–62.
69. Sokol RJ. Vitamin E deficiency and neurological disorders. In: Packer L, Fuchs J, editors. Vitamin E in
Health and Disease. New York, NY: Marcel Dekker, Inc.; 1993. pp. 815–49.
70. Cohn JS, McNamara JR, Cohn SD, Ordovas JM, Schaefer EJ. Plasma apolipoprotein changes in the
triglyceride-rich lipoprotein fraction of human subjects fed a fat-rich meal. J Lipid Res. 1988;29:925–36.
71. Blomstrand R, Forsgren L. Labelled tocopherols in man. Intestinal absorption and thoracic-duct lymph
transport of dl-alpha-tocopheryl-3,4-14C2 acetate dl-alpha-tocopheramine-3,4-14C2 dl-alpha-tocopherol-
(5-methyl-3H) and N-(methyl-3H)-dl-gamma-tocopheramine. Int Z Vitaminforsch. 1968;38:328–44.
72. Traber MG, Kayden HJ, Green JB, Green MH. Absorption of water-miscible forms of vitamin E in a
patient with cholestasis and in thoracic duct-cannulated rats. Am J Clin Nutr. 1986;44:914–23.
73. Bruno RS, Leonard SW, Park S, Zhao YY, Traber MG. Human vitamin E requirements assessed with the
use of apples fortified with deuterium-labeled alpha-tocopheryl acetate. Am J Clin Nutr. 2006;83:299–304.
74. Traber MG, Burton GW, Hughes L, Ingold KU, Hidaka H, Malloy M, Kane J, Hyams J, Kayden HJ.
Discrimination between forms of vitamin E by humans with and without genetic abnormalities of
lipoprotein metabolism. J Lipid Res. 1992;33:1171–82.
75. Traber MG, Rudel LL, Burton GW, Hughes L, Ingold KU, Kayden HJ. Nascent VLDL from liver
perfusions of cynomolgus monkeys are preferentially enriched in RRR- compared with SRR-alpha-
tocopherol: Studies using deuterated tocopherols. J Lipid Res. 1990;31:687–94.
76. Kayden HJ, Traber MG. Absorption, lipoprotein transport, and regulation of plasma concentrations of
vitamin E in humans. J Lipid Res. 1993;34:343–58.
77. Catignani GL, Bieri JG. Rat liver alpha-tocopherol binding protein. Biochim Biophys Acta.
1977;497:349–57.
78. Sato Y, Hagiwara K, Arai H, Inoue K. Purification and characterization of the alpha-tocopherol transfer
protein from rat liver. FEBS Lett. 1991;288:41–5.
79. Yoshida H, Yusin M, Ren I, Kuhlenkamp J, Hirano T, Stolz A, Kaplowitz N. Identification, purification,
and immunochemical characterization of a tocopherol-binding protein in rat liver cytosol. J Lipid Res.
1992;33:343–50.
80. Min KC, Kovall RA, Hendrickson WA. Crystal structure of human alpha-tocopherol transfer protein
bound to its ligand: Implications for ataxia with vitamin E deficiency. Proc Natl Acad Sci U S A.
2003;100:14713–8.
81. Arita M, Sato Y, Miyata A, Tanabe T, Takahashi E, Kayden HJ, Arai H, Inoue K. Human alpha-
tocopherol transfer protein: cDNA cloning, expression and chromosomal localization. Biochem J.
1995;306(Pt 2):437–43.
82. Traber MG. Vitamin E, nuclear receptors and xenobiotic metabolism. Arch Biochem Biophys.
2004;423:6–11.
83. Hosomi A, Arita M, Sato Y, Kiyose C, Ueda T, Igarashi O, Arai H, Inoue K. Affinity for alpha-
tocopherol transfer protein as a determinant of the biological activities of vitamin E analogs. FEBS Lett.
1997;409:105–8.
84. Schock BC, Van der Vliet A, Corbacho AM, Leonard SW, Finkelstein E, Valacchi G, Obermueller-Jevic
U, Cross CE, Traber MG. Enhanced inflammatory responses in alpha-tocopherol transfer protein null
mice. Arch Biochem Biophys. 2004;423:162–9.
85. Cellini E, Piacentini S, Nacmias B, Forleo P, Tedde A, Bagnoli S, Ciantelli M, Sorbi S. A family with
spinocerebellar ataxia type 8 expansion and vitamin E deficiency ataxia. Archiv Neurol. 2002;59:1952–3.
86. Birringer M, Drogan D, Brigelius-Flohe R. Tocopherols are metabolized in HepG2 cells by side chain
omega-oxidation and consecutive beta-oxidation. Free Radic Biol Med. 2001;31:226–32.
87. Parker RS, Sontag TJ, Swanson JE. Cytochrome P4503A-dependent metabolism of tocopherols and
inhibition by sesamin. Biochem Biophys Res Commun. 2000;277:531–4.
88. Sontag TJ, Parker RS. Cytochrome P450 omega-hydroxylase pathway of tocopherol catabolism. Novel
mechanism of regulation of vitamin E status. J Biol Chem. 2002;277:25290–6.
89. Kluth D, Landes N, Pfluger P, Muller-Schmehl K, Weiss K, Bumke-Vogt C, Ristow M, Brigelius-Flohe
R. Modulation of Cyp3a11 mRNA expression by alpha-tocopherol but not gamma-tocotrienol in mice.
Free Radic Biol Med. 2005;38:507–14.
90. Traber MG, Siddens LK, Leonard SW, Schock B, Gohil K, Krueger SK, Cross CE, Williams DE.
alpha-Tocopherol modulates Cyp3a expression, increases gamma-CEHC production, and limits tissue
gamma-tocopherol accumulation in mice fed high gamma-tocopherol diets. Free Radic Biol Med.
2005;38:773–85.
91. Farley SM, Leonard SW, Taylor AW, Birringer M, Edson KZ, Rettie AE, Traber MG. Omega-
hydroxylation of phylloquinone by CYP4F2 is not increased by alpha-tocopherol. Mol Nutr Food Res.
2013;57:1785–93.
92. Bardowell SA, Stec DE, Parker RS. Common variants of cytochrome P450 4F2 exhibit altered vitamin
E-{omega}-hydroxylase specific activity. J Nutr. 2010;140:1901–6.
93. Leonard SW, Paterson E, Atkinson JK, Ramakrishnan R, Cross CE, Traber MG. Studies in humans
using deuterium-labeled alpha- and gamma-tocopherols demonstrate faster plasma gamma-tocopherol
disappearance and greater gamma-metabolite production. Free Radic Biol Med. 2005;38:857–66.
94. Schultz M, Leist M, Petrzika M, Gassmann B, Brigelius-Flohe R. Novel urinary metabolite of alpha-
tocopherol, 2,5,7,8-tetramethyl-2(2’-carboxyethyl)-6-hydroxychroman, as an indicator of an adequate
vitamin E supply? Am J Clin Nutr. 1995;62:1527S–34S.
95. Lebold KM, Ang A, Traber MG, Arab L. Urinary alpha-carboxyethyl hydroxychroman can be used
as a predictor of alpha-tocopherol adequacy, as demonstrated in the Energetics Study. Am J Clin Nutr.
2012;96:801–9.
96. Betancor-Fernandez A, Sies H, Stahl W, Polidori MC. In vitro antioxidant activity of 2,5,7,8-tetramethyl-
2-(2’-carboxyethyl)-6-hydroxychroman (alpha-CEHC), a vitamin E metabolite. Free Radic Res.
2002;36:915–21.
97. Ouahchi K, Arita M, Kayden H, Hentati F, Ben Hamida M, Sokol R, Arai H, Inoue K, Mandel JL, Koenig
M. Ataxia with isolated vitamin E deficiency is caused by mutations in the alpha-tocopherol transfer
protein. Nat Genet. 1995;9:141–5.
98. Ban R, Takitani K, Kim HS, Murata T, Morinobu T, Ogihara T, Tamai H. Alpha-tocopherol transfer
protein expression in rat liver exposed to hyperoxia. Free Radic Res. 2002;36:933–8.
99. Kim ES, Noh SK, Koo SI. Marginal zinc deficiency lowers the lymphatic absorption of alpha-tocopherol
in rats. J Nutr. 1998;128:265–70.
100. Shaw HM, Huang C. Liver alpha-tocopherol transfer protein and its mRNA are differentially altered by
dietary vitamin E deficiency and protein insufficiency in rats. J Nutr. 1998;128:2348–54.
101. Hathcock JN, Azzi A, Blumberg J, Bray T, Dickinson A, Frei B, Jialal I, Johnston CS, Kelly FJ et al.
Vitamins E and C are safe across a broad range of intakes. Am J Clin Nutr. 2005;81:736–45.
102. Kappus H, Diplock AT. Tolerance and safety of vitamin E: A toxicological position report. Free Radic
Biol Med. 1992;13:55–74.
103. Miller ER, 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: High-
dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005;142:37–46.
104. Gerss J, Kopcke W. The questionable association of vitamin E supplementation and mortality—Inconsistent
results of different meta-analytic approaches. Cell Mol Biol (Noisy-le-grand). 2009;55(Suppl):OL1111–20.
105. Abner EL, Schmitt FA, Mendiondo MS, Marcum JL, Kryscio RJ. Vitamin E and all-cause mortality: A
meta-analysis. Curr Aging Sci. 2011;4:158–70.
106. Eidelman RS, Hollar D, Hebert PR, Lamas GA, Hennekens CH. Randomized trials of vitamin E in the
treatment and prevention of cardiovascular disease. Arch Intern Med. 2004;164:1552–6.
107. Shekelle PG, Morton SC, Jungvig LK, Udani J, Spar M, Tu W, M JS, Coulter I, Newberry SJ, Hardy
M. Effect of supplemental vitamin E for the prevention and treatment of cardiovascular disease. J Gen
Intern Med. 2004;19:380–9.
108. Vivekananthan DP, Penn MS, Sapp SK, Hsu A, Topol EJ. Use of antioxidant vitamins for the prevention
of cardiovascular disease: Meta-analysis of randomised trials. Lancet. 2003;361:2017–23.
109. Ashor AW, Siervo M, Lara J, Oggioni C, Afshar S, Mathers JC. Effect of vitamin C and vitamin E
supplementation on endothelial function: A systematic review and meta-analysis of randomised
controlled trials. Br J Nutr. 2015;113:1182–94.
110. Afri M, Ehrenberg B, Talmon Y, Schmidt J, Cohen Y, Frimer AA. Active oxygen chemistry within the
liposomal bilayer. Part III: Locating vitamin E, ubiquinol and ubiquinone and their derivatives in the
lipid bilayer. Chem Phys Lipids. 2004;131:107–21.
111. Huang J, May JM. Ascorbic acid spares alpha-tocopherol and prevents lipid peroxidation in cultured
H4IIE liver cells. Mol Cell Biochem. 2003;247:171–6.
112. May JM, Qu ZC, Mendiratta S. Protection and recycling of alpha-tocopherol in human erythrocytes by
intracellular ascorbic acid. Arch Biochem Biophys. 1998;349:281–9.
113. Bisby RH, Parker AW. Reaction of ascorbate with the alpha-tocopheroxyl radical in micellar and bilayer
membrane systems. Arch Biochem Biophys. 1995;317:170–8.
114. Burton GW, Wronska U, Stone L, Foster DO, Ingold KU. Biokinetics of dietary RRR-alpha-tocopherol
in the male guinea pig at three dietary levels of vitamin C and two levels of vitamin E. Evidence that
vitamin C does not “spare” vitamin E in vivo. Lipids. 1990;25:199–210.
115. Salonen JT, Nyyssonen K, Salonen R, Lakka HM, Kaikkonen J, Porkkala-Sarataho E, Voutilainen S,
Lakka TA, Rissanen T et al. Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study:
A randomized trial of the effect of vitamins E and C on 3-year progression of carotid atherosclerosis.
J Intern Med. 2000;248:377–86.
116. Salonen RM, Nyyssonen K, Kaikkonen J, Porkkala-Sarataho E, Voutilainen S, Rissanen TH, Tuomainen
TP, Valkonen VP, Ristonmaa U et al. Six-year effect of combined vitamin C and E supplementation on
atherosclerotic progression: The Antioxidant Supplementation in Atherosclerosis Prevention (ASAP)
Study. Circulation. 2003;107:947–53.
117. Buettner GR. Commentary on “Faster plasma vitamin E disappearance in smokers is normalized by
vitamin C supplementation.” Free Radic Biol Med. 2006;40:555.
118. Betteridge DJ. What is oxidative stress? Metabolism. 2000;49:3–8.
119. Heron M. Deaths: Leading causes for 2016. Natl Vital Stat Rep. 2018;67:1–76.
120. Stocker R, Keaney JF, Jr. Role of oxidative modifications in atherosclerosis. Physiol Rev. 2004;84:1381–478.
121. Harris A, Devaraj S, Jialal I. Oxidative stress, alpha-tocopherol therapy, and atherosclerosis.
Curr Atheroscler Rep. 2002;4:373–80.
122. Jialal I, Devaraj S. Scientific evidence to support a vitamin E and heart disease health claim: Research
needs. J Nutr. 2005;135:348–53.
123. Miwa K, Okinaga S, Fujita M. Low serum alpha-tocopherol concentrations in subjects with various
coronary risk factors. Circ J. 2004;68:542–6.
124. Fuller CJ, Chandalia M, Garg A, Grundy SM, Jialal I. RRR-alpha-tocopheryl acetate supplementation at
pharmacologic doses decreases low-density-lipoprotein oxidative susceptibility but not protein glycation
in patients with diabetes mellitus. Am J Clin Nutr. 1996;63:753–9.
125. Devaraj S, Adams-Huet B, Fuller CJ, Jialal I. Dose-response comparison of RRR-alpha-tocopherol and
all-racemic alpha-tocopherol on LDL oxidation. Arterioscler Thromb Vasc Biol. 1997;17:2273–9.
126. Devaraj S, Jialal I. The effects of alpha-tocopherol on critical cells in atherogenesis. Curr Opin Lipidol.
1998;9:11–5.
127. Stephens NG, Parsons A, Schofield PM, Kelly F, Cheeseman K, Mitchinson MJ. Randomised controlled
trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS).
Lancet. 1996;347:781–6.
128. Boaz M, Smetana S, Weinstein T, Matas Z, Gafter U, Iaina A, Knecht A, Weissgarten Y, Brunner D et al.
Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE):
Randomised placebo-controlled trial. Lancet. 2000;356:1213–8.
129. Fang JC, Kinlay S, Beltrame J, Hikiti H, Wainstein M, Behrendt D, Suh J, Frei B, Mudge GH et al. Effect
of vitamins C and E on progression of transplant-associated arteriosclerosis: A randomised trial. Lancet.
2002;359:1108–13.
130. Lee IM, Cook NR, Gaziano JM, Gordon D, Ridker PM, Manson JE, Hennekens CH, Buring JE.
Vitamin E in the primary prevention of cardiovascular disease and cancer: The Women’s Health Study:
A randomized controlled trial. JAMA. 2005;294:56–65.
131. Palmer AM, Burns MA. Selective increase in lipid peroxidation in the inferior temporal cortex in
Alzheimer’s disease. Brain Res. 1994;645:338–42.
132. Behl C, Davis JB, Lesley R, Schubert D. Hydrogen peroxide mediates amyloid beta protein toxicity. Cell.
1994;77:817–27.
133. Behl C, Davis J, Cole GM, Schubert D. Vitamin E protects nerve cells from amyloid beta protein toxicity.
Biochem Biophys Res Commun. 1992;186:944–50.
134. Behl C. Vitamin E protects neurons against oxidative cell death in vitro more effectively than 17-beta estradiol
and induces the activity of the transcription factor NF-kappaB. J Neural Transm. 2000;107:393–407.
135. Leonard SW, Terasawa Y, Farese RV, Jr., Traber MG. Incorporation of deuterated RRR- or all-rac-
alpha-tocopherol in plasma and tissues of alpha-tocopherol transfer protein—Null mice. Am J Clin Nutr.
2002;75:555–60.
136. Pillai SR, Traber MG, Steiss JE, Kayden HJ, Cox NR. Alpha-tocopherol concentrations of the nervous
system and selected tissues of adult dogs fed three levels of vitamin E. Lipids. 1993;28:1101–5.
137. Socci DJ, Crandall BM, Arendash GW. Chronic antioxidant treatment improves the cognitive performance
of aged rats. Brain Res. 1995;693:88–94.
138. Wortwein G, Stackman RW, Walsh TJ. Vitamin E prevents the place learning deficit and the cholinergic
hypofunction induced by AF64A. Exp Neurol. 1994;125:15–21.
139. Monji A, Morimoto N, Okuyama I, Yamashita N, Tashiro N. Effect of dietary vitamin E on lipofuscin
accumulation with age in the rat brain. Brain Res. 1994;634:62–8.
140. Hara H, Kato H, Kogure K. Protective effect of alpha-tocopherol on ischemic neuronal damage in the
gerbil hippocampus. Brain Res. 1990;510:335–8.
141. Morris MC, Beckett LA, Scherr PA, Hebert LE, Bennett DA, Field TS, Evans DA. Vitamin E and vitamin
C supplement use and risk of incident Alzheimer disease. Alzheimer Dis Assoc Disord. 1998;12:121–6.
142. Morris MC, Evans DA, Bienias JL, Tangney CC, Bennett DA, Aggarwal N, Wilson RS, Scherr PA.
Dietary intake of antioxidant nutrients and the risk of incident Alzheimer disease in a biracial community
study. JAMA. 2002;287:3230–7.
143. Morris MC, Evans DA, Tangney CC, Bienias JL, Wilson RS, Aggarwal NT, Scherr PA. Relation of the
tocopherol forms to incident Alzheimer disease and to cognitive change. Am J Clin Nutr. 2005;81:508–14.
144. Kryscio RJ, Abner EL, Caban-Holt A, Lovell M, Goodman P, Darke AK, Yee M, Crowley J, Schmitt
FA. Association of antioxidant supplement use and dementia in the Prevention of Alzheimer’s Disease
by Vitamin E and Selenium Trial (PREADViSE). JAMA neurology. 2017;74:567–73.
145. Dysken MW, Sano M, Asthana S, Vertrees JE, Pallaki M, Llorente M, Love S, Schellenberg GD,
McCarten JR et al. Effect of vitamin E and memantine on functional decline in Alzheimer disease: The
TEAM-AD VA cooperative randomized trial. JAMA. 2014;311:33–44.
146. Petersen RC, Thomas RG, Grundman M, Bennett D, Doody R, Ferris S, Galasko D, Jin S, Kaye J et al.
Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med. 2005;352:2379–88.
147. Lloret A, Badia MC, Mora NJ, Pallardo FV, Alonso MD, Vina J. Vitamin E paradox in Alzheimer’s disease:
It does not prevent loss of cognition and may even be detrimental. J Alzheimers Dis. 2009;17:143–9.
148. Block G, Patterson B, Subar A. Fruit, vegetables, and cancer prevention: A review of the epidemiological
evidence. Nutr Cancer. 1992;18:1–29.
149. Bjelakovic G, Nikolova D, Simonetti RG, Gluud C. Antioxidant supplements for preventing gastrointestinal
cancers. Cochrane Database Syst Rev. 2004:CD004183.
150. Wagner KH, Kamal-Eldin A, Elmadfa I. Gamma-tocopherol—An underestimated vitamin? Ann Nutr
Metab. 2004;48:169–88.
151. Albanes D, Heinonen OP, Huttunen JK, Taylor PR, Virtamo J, Edwards BK, Haapakoski J, Rautalahti
M, Hartman AM et al. Effects of alpha-tocopherol and beta-carotene supplements on cancer incidence
in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study. Am J Clin Nutr. 1995;62:1427S–30S.
152. Virtamo J, Pietinen P, Huttunen JK, Korhonen P, Malila N, Virtanen MJ, Albanes D, Taylor PR, Albert
P. Incidence of cancer and mortality following alpha-tocopherol and beta-carotene supplementation: A
postintervention follow-up. JAMA. 2003;290:476–85.
153. Goodman GE, Schaffer S, Omenn GS, Chen C, King I. The association between lung and prostate cancer
risk, and serum micronutrients: Results and lessons learned from beta-carotene and retinol efficacy trial.
Cancer Epidemiol Biomarkers Prev. 2003;12:518–26.
154. Lippman SM, Klein EA, Goodman PJ, Lucia MS, Thompson IM, Ford LG, Parnes HL, Minasian LM,
Gaziano JM et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: The
Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2009;301:39–51.
155. Klein EA, Thompson IM, Jr., Tangen CM, Crowley JJ, Lucia MS, Goodman PJ, Minasian LM, Ford
LG, Parnes HL et al. Vitamin E and the risk of prostate cancer: The Selenium and Vitamin E Cancer
Prevention Trial (SELECT). JAMA. 2011;306:1549–56.
156. Ni J, Chen M, Zhang Y, Li R, Huang J, Yeh S. Vitamin E succinate inhibits human prostate cancer cell
growth via modulating cell cycle regulatory machinery. Biochem Biophys Res Commun. 2003;300:357–63.
157. Sigounas G, Anagnostou A, Steiner M. dl-alpha-tocopherol induces apoptosis in erythroleukemia,
prostate, and breast cancer cells. Nutr Cancer. 1997;28:30–5.
158. Hartman TJ, Dorgan JF, Virtamo J, Tangrea JA, Taylor PR, Albanes D. Association between serum
alpha-tocopherol and serum androgens and estrogens in older men. Nutr Cancer. 1999;35:10–5.
159. Moyad MA, Brumfield SK, Pienta KJ. Vitamin E, alpha- and gamma-tocopherol, and prostate cancer.
Semin Urol Oncol. 1999;17:85–90.
160. Jiang Q, Wong J, Ames BN. Gamma-tocopherol induces apoptosis in androgen-responsive LNCaP
prostate cancer cells via caspase-dependent and independent mechanisms. Ann N Y Acad Sci.
2004;1031:399–400.
161. Bjelakovic G, Nikolova D, Simonetti RG, Gluud C. Antioxidant supplements for prevention of
gastrointestinal cancers: A systematic review and meta-analysis. Lancet. 2004;364:1219–28.
162. Campbell S, Stone W, Whaley S, Krishnan K. Development of gamma (gamma)-tocopherol as a

colorectal cancer chemopreventive agent. Crit Rev Oncol Hematol. 2003;47:249–59.
163. Stone WL, Krishnan K, Campbell SE, Qui M, Whaley SG, Yang H. Tocopherols and the treatment of
colon cancer. Ann N Y Acad Sci. 2004;1031:223–33.
164. Yang CS, Suh N. Cancer prevention by different forms of tocopherols. Top Curr Chem. 2013;329:21–33.
165. Burton GW, Traber MG. Vitamin E: Antioxidant activity, biokinetics, and bioavailability. Annu Rev Nutr.
1990;10:357–82.
1. McKay DL, Blumberg JB. The role of tea in human health: An update. J Am Coll Nutr. 2002;21(1):1–13.
2. Hayat K, Iqbal H, Malik U, Bilal U, Mushtaq S. Tea and its consumption: Benefits and risks. Crit Rev
Food Sci Nutr. 2015;55(7):939–54.
3. Zhang C, Qin YY, Wei X, Yu FF, Zhou YH, He J. Tea consumption and risk of cardiovascular outcomes
and total mortality: A systematic review and meta-analysis of prospective observational studies. Eur J
Epidemiol. 2015;30(2):103–13.
4. Kuriyama S. The relation between green tea consumption and cardiovascular disease as evidenced by
epidemiological studies. J Nutr. 2008;138(8):1548S–53S.
5. Saito E, Inoue M, Sawada N, Shimazu T, Yamaji T, Iwasaki M, Sasazuki S et al. Association of green tea
consumption with mortality due to all causes and major causes of death in a Japanese population: The
Japan Public Health Center-based Prospective Study (JPHC Study). Ann Epidemiol. 2015;25(7):512–8 e3.
6. Kokubo Y, Iso H, Saito I, Yamagishi K, Yatsuya H, Ishihara J, Inoue M, Tsugane S. The impact of green
tea and coffee consumption on the reduced risk of stroke incidence in Japanese population: The Japan
public health center-based study cohort. Stroke. 2013;44(5):1369–74.
7. Kuriyama S, Shimazu T, Ohmori K, Kikuchi N, Nakaya N, Nishino Y, Tsubono Y, Tsuji I. Green tea
consumption and mortality due to cardiovascular disease, cancer, and all causes in Japan: The Ohsaki
study. JAMA. 2006;296(10):1255–65.
8. Tang J, Zheng JS, Fang L, Jin Y, Cai W, Li D. Tea consumption and mortality of all cancers, CVD and
all causes: A meta-analysis of eighteen prospective cohort studies. Br J Nutr. 2015;114(5):673–83.
9. Yuan JM. Cancer prevention by green tea: Evidence from epidemiologic studies. Am J Clin Nutr.
2013;98(6 Suppl):1676S–81S.
10. Tang N, Wu Y, Zhou B, Wang B, Yu R. Green tea, black tea consumption and risk of lung cancer: A
meta-analysis. Lung Cancer. 2009;65(3):274–83.
11. Kurahashi N, Sasazuki S, Iwasaki M, Inoue M, Tsugane S. Green tea consumption and prostate cancer
risk in Japanese men: A prospective study. Am J Epidemiol. 2008;167(1):71–7.
12. Yang G, Zheng W, Xiang YB, Gao J, Li HL, Zhang X, Gao YT, Shu XO. Green tea consumption
and colorectal cancer risk: A report from the Shanghai Men’s Health Study. Carcinogenesis.
2011;32(11):1684–8.
13. Ui A, Kuriyama S, Kakizaki M, Sone T, Nakaya N, Ohmori-Matsuda K, Hozawa A, Nishino Y, Tsuji I.
Green tea consumption and the risk of liver cancer in Japan: The Ohsaki Cohort study. Cancer Causes
Control. 2009;20(10):1939–45.
14. Marventano S, Salomone F, Godos J, Pluchinotta F, Del Rio D, Mistretta A, Grosso G. Coffee and tea
consumption in relation with non-alcoholic fatty liver and metabolic syndrome: A systematic review and
meta-analysis of observational studies. Clin Nutr. 2016;35(6):1269–81.
15. Vernarelli JA, Lambert JD. Tea consumption is inversely associated with weight status and other markers
for metabolic syndrome in US adults. Eur J Nutr. 2013;52(3):1039–48.
16. Sharangi AB. Medicinal and therapeutic potentialities of tea (Camellia sinensis L.)—A review.
Food Res Int. 2009;42(5):529–35.
17. Weisburger JH. Tea and health: A historical perspective. Cancer Lett. 1997;114(1–2):315–7.
18. Harbowy ME, Balentine DA. Tea chemistry. Crit Rev Plant Sci. 1997;16(5):415–80.
19. Yang CS, Wang X, Lu G, Picinich SC. Cancer prevention by tea: Animal studies, molecular mechanisms
and human relevance. Nat Rev Cancer. 2009;9(6):429–39.
20. Chang K. World tea production and trade: Current and future development: Food and Agriculture
Organization of the United Nations; 2015.
21. Cabrera C, Artacho R, Gimenez R. Beneficial effects of green tea—A review. J Am Coll Nutr.
2006;25(2):79–99.
22. Sarma DN, Barrett ML, Chavez ML, Gardiner P, Ko R, Mahady GB, Marles RJ, Pellicore LS, Giancaspro
GI, Low Dog T. Safety of green tea extracts: A systematic review by the US Pharmacopeia. Drug Saf.
2008;31(6):469–84.
23. Feng WY. Metabolism of green tea catechins: An overview. Curr Drug Metab. 2006;7(7):755–809.
24. Wang Y, Ho CT. Polyphenolic chemistry of tea and coffee: A century of progress. J Agric Food Chem.
2009;57(18):8109–14.
25. Graham HN. Green tea composition, consumption, and polyphenol chemistry. Prev Med.
1992;21(3):334–50.
26. Dai W, Qi D, Yang T, Lv H, Guo L, Zhang Y, Zhu Y et al. Nontargeted analysis using ultraperformance
liquid chromatography-quadrupole time-of-flight mass spectrometry uncovers the effects of harvest
season on the metabolites and taste quality of tea (Camellia sinensis L.). J Agric Food Chem.
2015;63(44):9869–78.
27. Balentine DA, Wiseman SA, Bouwens LC. The chemistry of tea flavonoids. Crit Rev Food Sci Nutr.
1997;37(8):693–704.
28. Manach C, Scalbert A, Morand C, Remesy C, Jimenez L. Polyphenols: Food sources and bioavailability.
Am J Clin Nutr. 2004;79(5):727–47.
29. Sang S, Lambert JD, Ho CT, Yang CS. The chemistry and biotransformation of tea constituents.
Pharmacol Res. 2011;64(2):87–99.
30. Masterjohn C, Bruno RS. Therapeutic potential of green tea in nonalcoholic fatty liver disease. Nutr Rev.
2012;70(1):41–56.
31. Khan N, Mukhtar H. Tea polyphenols for health promotion. Life Sci. 2007;81(7):519–33.
32. Neilson AP, Green RJ, Wood KV, Ferruzzi MG. High-throughput analysis of catechins and
theaflavins by high performance liquid chromatography with diode array detection. J Chromatogr A.
2006;1132(1–2):132–40.
33. Lin LZ, Chen P, Harnly JM. New phenolic components and chromatographic profiles of green and
fermented teas. J Agric Food Chem. 2008;56(17):8130–40.
34. Dai W, Tan J, Lu M, Xie D, Li P, Lv H, Zhu Y et al. Nontargeted modification-specific metabolomics
investigation of glycosylated secondary metabolites in tea (Camellia sinensis L.) based on liquid
chromatography-high-resolution mass spectrometry. J Agric Food Chem. 2016;64(35):6783–90.
35. Yang CS, Chen L, Lee MJ, Balentine D, Kuo MC, Schantz SP. Blood and urine levels of tea catechins
after ingestion of different amounts of green tea by human volunteers. Cancer Epidemiol Biomarkers
Prev. 1998;7(4):351–4.
36. Lee MJ, Maliakal P, Chen L, Meng X, Bondoc FY, Prabhu S, Lambert G, Mohr S, Yang CS.
Pharmacokinetics of tea catechins after ingestion of green tea and (-)-epigallocatechin-3-gallate by
humans: Formation of different metabolites and individual variability. Cancer Epidemiol Biomarkers
Prev. 2002;11(10 Pt 1):1025–32.
37. Lee MJ, Wang ZY, Li H, Chen L, Sun Y, Gobbo S, Balentine DA, Yang CS. Analysis of plasma and
urinary tea polyphenols in human subjects. Cancer Epidemiol Biomarkers Prev. 1995;4(4):393–9.
38. Chow HH, Cai Y, Alberts DS, Hakim I, Dorr R, Shahi F, Crowell JA, Yang CS, Hara Y. Phase I
pharmacokinetic study of tea polyphenols following single-dose administration of epigallocatechin
gallate and polyphenon E. Cancer Epidemiol Biomarkers Prev. 2001;10(1):53–8.
39. Renouf M, Marmet C, Guy PA, Beaumont M, Lepage M, Williamson G, Dionisi F. Dose-response plasma
appearance of green tea catechins in adults. Mol Nutr Food Res. 2013;57(5):833–9.
40. Fung ST, Ho CK, Choi SW, Chung WY, Benzie IF. Comparison of catechin profiles in human
plasma and urine after single dosing and regular intake of green tea (Camellia sinensis). Br J Nutr.
2013;109(12):2199–207.
41. Clifford MN, van der Hooft JJ, Crozier A. Human studies on the absorption, distribution, metabolism,
and excretion of tea polyphenols. Am J Clin Nutr. 2013;98(6 Suppl):1619S–30S.
42. Chen L, Lee MJ, Li H, Yang CS. Absorption, distribution, elimination of tea polyphenols in rats.
Drug Metab Dispos. 1997;25(9):1045–50.
43. Zhu M, Chen Y, Li RC. Pharmacokinetics and system linearity of tea catechins in rat. Xenobiotica.
2001;31(1):51–60.
44. Kim S, Lee MJ, Hong J, Li C, Smith TJ, Yang GY, Seril DN, Yang CS. Plasma and tissue levels of tea catechins
in rats and mice during chronic consumption of green tea polyphenols. Nutr Cancer. 2000;37(1):41–8.
45. Neilson AP, Ferruzzi MG. Influence of formulation and processing on absorption and metabolism of
flavan-3-ols from tea and cocoa. Annu Rev Food Sci Technol. 2011;2:125–51.
46. Zhang L, Zheng Y, Chow MS, Zuo Z. Investigation of intestinal absorption and disposition of green tea
catechins by Caco-2 monolayer model. Int J Pharm. 2004;287(1–2):1–12.
47. Nakagawa K, Okuda S, Miyazawa T. Dose-dependent incorporation of tea catechins, (-)-epigallocatechin-
3-gallate and (-)-epigallocatechin, into human plasma. Biosci Biotechnol Biochem. 1997;61(12):1981–5.
48. Neilson AP, Hopf AS, Cooper BR, Pereira MA, Bomser JA, Ferruzzi MG. Catechin degradation with
concurrent formation of homo- and heterocatechin dimers during in vitro digestion. J Agric Food Chem.
2007;55(22):8941–9.
49. Lambert JD, Sang S, Yang CS. Biotransformation of green tea polyphenols and the biological activities
of those metabolites. Mol Pharm. 2007;4(6):819–25.
50. Yang CS, Sang S, Lambert JD, Lee MJ. Bioavailability issues in studying the health effects of plant
polyphenolic compounds. Mol Nutr Food Res. 2008;52(Suppl 1):S139–51.
51. Del Rio D, Calani L, Cordero C, Salvatore S, Pellegrini N, Brighenti F. Bioavailability and catabolism
of green tea flavan-3-ols in humans. Nutrition. 2010;26(11–12):1110–6.
52. Kohri T, Suzuki M, Nanjo F. Identification of metabolites of (-)-epicatechin gallate and their metabolic
fate in the rat. J Agric Food Chem. 2003;51(18):5561–6.
53. Sang S, Lee MJ, Yang I, Buckley B, Yang CS. Human urinary metabolite profile of tea polyphenols
analyzed by liquid chromatography/electrospray ionization tandem mass spectrometry with data-
dependent acquisition. Rapid Commun Mass Spectrom. 2008;22(10):1567–78.
54. Li C, Meng X, Winnik B, Lee MJ, Lu H, Sheng S, Buckley B, Yang CS. Analysis of urinary metabolites
of tea catechins by liquid chromatography/electrospray ionization mass spectrometry. Chem Res Toxicol.
2001;14(6):702–7.
55. Monagas M, Urpi-Sarda M, Sánchez-Patán F, Llorach R, Garrido I, Gómez-Cordovés C, Andres-Lacueva
C, Bartolomé B. Insights into the metabolism and microbial biotransformation of dietary flavan-3-ols
and the bioactivity of their metabolites. Food Funct. 2010;1(3):233–53.
56. Lu H, Meng X, Li C, Sang S, Patten C, Sheng S, Hong J et al. Glucuronides of tea catechins: Enzymology
of biosynthesis and biological activities. Drug Metab Dispos. 2003;31(4):452–61.
57. Takano M, Yumoto R, Murakami T. Expression and function of efflux drug transporters in the intestine.
Pharmacol Ther. 2006;109(1–2):137–61.
58. Vaidyanathan JB, Walle T. Glucuronidation and sulfation of the tea flavonoid (-)-epicatechin by the
human and rat enzymes. Drug Metab Dispos. 2002;30(8):897–903.
59. Lu H, Meng X, Yang CS. Enzymology of methylation of tea catechins and inhibition of catechol-O-
methyltransferase by (-)-epigallocatechin gallate. Drug Metab Dispos. 2003;31(5):572–9.
60. Sang S, Yang CS. Structural identification of novel glucoside and glucuronide metabolites of
(-)-epigallocatechin-3-gallate in mouse urine using liquid chromatography/electrospray ionization
tandem mass spectrometry. Rapid Commun Mass Spectrom. 2008;22(22):3693–9.
61. Sang S, Lambert JD, Hong J, Tian S, Lee MJ, Stark RE, Ho CT, Yang CS. Synthesis and structure
identification of thiol conjugates of (-)-epigallocatechin gallate and their urinary levels in mice. Chem Res
Toxicol. 2005;18(11):1762–9.
62. Schantz M, Erk T, Richling E. Metabolism of green tea catechins by the human small intestine.
Biotechnol J. 2010;5(10):1050–9.
63. Auger C, Mullen W, Hara Y, Crozier A. Bioavailability of polyphenon E flavan-3-ols in humans with an
ileostomy. J Nutr. 2008;138(8):1535S–42S.
64. Stalmach A, Mullen W, Steiling H, Williamson G, Lean ME, Crozier A. Absorption, metabolism, and
excretion of green tea flavan-3-ols in humans with an ileostomy. Mol Nutr Food Res. 2010;54(3):323–34.
65. Meng X, Sang S, Zhu N, Lu H, Sheng S, Lee MJ, Ho CT, Yang CS. Identification and characterization
of methylated and ring-fission metabolites of tea catechins formed in humans, mice, and rats. Chem Res
Toxicol. 2002;15(8):1042–50.
66. Roowi S, Stalmach A, Mullen W, Lean ME, Edwards CA, Crozier A. Green tea flavan-3-ols: Colonic
degradation and urinary excretion of catabolites by humans. J Agric Food Chem. 2010;58(2):1296–304.
67. Li C, Lee MJ, Sheng S, Meng X, Prabhu S, Winnik B, Huang B, Chung JY, Yan S, Ho CT, Yang CS.
Structural identification of two metabolites of catechins and their kinetics in human urine and blood
after tea ingestion. Chem Res Toxicol. 2000;13(3):177–84.
68. Calani L, Del Rio D, Luisa Callegari M, Morelli L, Brighenti F. Updated bioavailability and 48 h
excretion profile of flavan-3-ols from green tea in humans. Int J Food Sci Nutr. 2012;63(5):513–21.
69. Mazzanti G, Di Sotto A, Vitalone A. Hepatotoxicity of green tea: An update. Arch Toxicol.
2015;89(8):1175–91.
70. Mazzanti G, Menniti-Ippolito F, Moro PA, Cassetti F, Raschetti R, Santuccio C, Mastrangelo S.
Hepatotoxicity from green tea: A review of the literature and two unpublished cases. Eur J Clin
Pharmacol. 2009;65(4):331–41.
71. Isomura T, Suzuki S, Origasa H, Hosono A, Suzuki M, Sawada T, Terao S, Muto Y, Koga T. Liver-related
safety assessment of green tea extracts in humans: A systematic review of randomized controlled trials.
Eur J Clin Nutr. 2016;70(11):1340.
72. Lambert JD, Kennett MJ, Sang S, Reuhl KR, Ju J, Yang CS. Hepatotoxicity of high oral dose
(-)-epigallocatechin-3-gallate in mice. Food Chem Toxicol. 2010;48(1):409–16.
73. Wang D, Wang Y, Wan X, Yang CS, Zhang J. Green tea polyphenol (-)-epigallocatechin-3-gallate
triggered hepatotoxicity in mice: Responses of major antioxidant enzymes and the Nrf2 rescue pathway.
Toxicol Appl Pharmacol. 2015;283(1):65–74.
74. James KD, Kennett MJ, Lambert JD. Potential role of the mitochondria as a target for the hepatotoxic
effects of (-)-epigallocatechin-3-gallate in mice. Food Chem Toxicol. 2017;111:302–9.
75. Chow HH, Hakim IA, Vining DR, Crowell JA, Ranger-Moore J, Chew WM, Celaya CA, Rodney
SR, Hara Y, Alberts DS. Effects of dosing condition on the oral bioavailability of green tea
catechins after single-dose administration of Polyphenon E in healthy individuals. Clin Cancer Res.
2005;11(12):4627–33.
76. Yang CS, Pan E. The effects of green tea polyphenols on drug metabolism. Expert Opin Drug Metab
Toxicol. 2012;8(6):677–89.
77. Salminen WF, Yang X, Shi Q, Greenhaw J, Davis K, Ali AA. Green tea extract can potentiate
acetaminophen-induced hepatotoxicity in mice. Food Chem Toxicol. 2012;50(5):1439–46.
78. Chow HH, Cai Y, Hakim IA, Crowell JA, Shahi F, Brooks CA, Dorr RT, Hara Y, Alberts DS.
Pharmacokinetics and safety of green tea polyphenols after multiple-dose administration of
epigallocatechin gallate and polyphenon E in healthy individuals. Clin Cancer Res. 2003;9(9):3312–9.
79. Frank J, George TW, Lodge JK, Rodriguez-Mateos AM, Spencer JP, Minihane AM, Rimbach G.
Daily consumption of an aqueous green tea extract supplement does not impair liver function or alter
cardiovascular disease risk biomarkers in healthy men. J Nutr. 2009;139(1):58–62.
80. Dostal AM, Samavat H, Bedell S, Torkelson C, Wang R, Swenson K, Le C et al. The safety of green tea
extract supplementation in postmenopausal women at risk for breast cancer: Results of the Minnesota
Green Tea Trial. Food Chem Toxicol. 2015;83:26–35.
81. Liu CY, Huang CJ, Huang LH, Chen IJ, Chiu JP, Hsu CH. Effects of green tea extract on insulin resistance
and glucagon-like peptide 1 in patients with type 2 diabetes and lipid abnormalities: A randomized,
double-blinded, and placebo-controlled trial. PLOS ONE. 2014;9(3):e91163.
82. Sang S, Hou Z, Lambert JD, Yang CS. Redox properties of tea polyphenols and related biological
activities. Antioxid Redox Signal. 2005;7(11–12):1704–14.
83. Valcic S, Burr JA, Timmermann BN, Liebler DC. Antioxidant chemistry of green tea catechins. New
oxidation products of (-)-epigallocatechin gallate and (-)-epigallocatechin from their reactions with
peroxyl radicals. Chem Res Toxicol. 2000;13(9):801–10.
84. Higdon JV, Frei B. Tea catechins and polyphenols: Health effects, metabolism, and antioxidant functions.
Crit Rev Food Sci Nutr. 2003;43(1):89–143.
85. Park HJ, DiNatale DA, Chung M-Y, Park Y-K, Lee J-Y, Koo SI, O’Connor M, Manautou JE, Bruno RS.
Green tea extract attenuates hepatic steatosis by decreasing adipose lipogenesis and enhancing hepatic
antioxidant defenses in ob/ob mice. J Nutr Biochem. 2011;22(4):393–400.
86. Li J, Sapper TN, Mah E, Rudraiah S, Schill KE, Chitchumroonchokchai C, Moller MV, McDonald JD,
Rohrer PR, Manautou JE. Green tea extract provides extensive Nrf2-independent protection against lipid
accumulation and NFκB pro-inflammatory responses during nonalcoholic steatohepatitis in mice fed a
high-fat diet. Mol Nutr Food Res. 2016;60(4):858–70.
87. Lambert JD, Elias RJ. The antioxidant and pro-oxidant activities of green tea polyphenols: A role in
cancer prevention. Arch Biochem Biophys. 2010;501(1):65–72.
88. Nomura M, Ma W, Chen N, Bode AM, Dong Z. Inhibition of 12-O-tetradecanoylphorbol-13-acetate-
induced NF-kappaB activation by tea polyphenols, (-)-epigallocatechin gallate and theaflavins.
Carcinogenesis. 2000;21(10):1885–90.
89. Yang F, de Villiers WJ, McClain CJ, Varilek GW. Green tea polyphenols block endotoxin-induced tumor
necrosis factor-production and lethality in a murine model. J Nutr. 1998;128(12):2334–40.
90. Chung JY, Huang C, Meng X, Dong Z, Yang CS. Inhibition of activator protein 1 activity and cell growth
by purified green tea and black tea polyphenols in H-ras-transformed cells: Structure-activity relationship
and mechanisms involved. Cancer Res. 1999;59(18):4610–7.
91. Basu A, Du M, Sanchez K, Leyva MJ, Betts NM, Blevins S, Wu M, Aston CE, Lyons TJ. Green tea
minimally affects biomarkers of inflammation in obese subjects with metabolic syndrome. Nutrition.
2011;27(2):206–13.
92. de Maat MP, Pijl H, Kluft C, Princen HM. Consumption of black and green tea had no effect on
inflammation, haemostasis and endothelial markers in smoking healthy individuals. Eur J Clin Nutr.
2000;54(10):757–63.
93. Ryu OH, Lee J, Lee KW, Kim HY, Seo JA, Kim SG, Kim NH, Baik SH, Choi DS, Choi KM. Effects of
green tea consumption on inflammation, insulin resistance and pulse wave velocity in type 2 diabetes
patients. Diabetes Res Clin Pract. 2006;71(3):356–8.
94. Nantz MP, Rowe CA, Bukowski JF, Percival SS. Standardized capsule of Camellia sinensis lowers
cardiovascular risk factors in a randomized, double-blind, placebo-controlled study. Nutrition.
2009;25(2):147–54.
95. Finkelstein EA, Khavjou OA, Thompson H, Trogdon JG, Pan L, Sherry B, Dietz W. Obesity and severe
obesity forecasts through 2030. Amer J Prev Med. 2012;42(6):563–70.
96. Huang J, Wang Y, Xie Z, Zhou Y, Zhang Y, Wan X. The anti-obesity effects of green tea in human
intervention and basic molecular studies. Eur J Clin Nutr. 2014;68(10):1075–87.
97. Maki KC, Reeves MS, Farmer M, Yasunaga K, Matsuo N, Katsuragi Y, Komikado M et al. Green tea
catechin consumption enhances exercise-induced abdominal fat loss in overweight and obese adults.
J Nutr. 2009;139(2):264–70.
98. Shimotoyodome A, Haramizu S, Inaba M, Murase T, Tokimitsu I. Exercise and green tea extract
stimulate fat oxidation and prevent obesity in mice. Med Sci Sports Exerc. 2005;37(11):1884–92.
99. Dulloo AG, Duret C, Rohrer D, Girardier L, Mensi N, Fathi M, Chantre P, Vandermander J. Efficacy of
a green tea extract rich in catechin polyphenols and caffeine in increasing 24-h energy expenditure and
fat oxidation in humans. Am J Clin Nutr. 1999;70(6):1040–5.
100. Dulloo A, Seydoux J, Girardier L, Chantre P, Vandermander J. Green tea and thermogenesis: Interactions
between catechin-polyphenols, caffeine and sympathetic activity. Int J Obes. 2000;24(2):252.
101. Shixian Q, VanCrey B, Shi J, Kakuda Y, Jiang Y. Green tea extract thermogenesis-induced weight loss
by epigallocatechin gallate inhibition of catechol-O-methyltransferase. J Med Food. 2006;9(4):451–8.
102. Auvichayapat P, Prapochanung M, Tunkamnerdthai O, Sripanidkulchai BO, Auvichayapat N,
Thinkhamrop B, Kunhasura S, Wongpratoom S, Sinawat S, Hongprapas P. Effectiveness of green tea
on weight reduction in obese Thais: A randomized, controlled trial. Physiol Behav. 2008;93(3):486–91.
103. Cunha CA, Lira FS, Rosa Neto JC, Pimentel GD, Souza GI, da Silva CMG, de Souza CT, Ribeiro
EB, Sawaya ACHF, Oller do Nascimento CM. Green tea extract supplementation induces the lipolytic
pathway, attenuates obesity, and reduces low-grade inflammation in mice fed a high-fat diet. Mediators
Inflamm. 2013;2013.
104. Oba S, Nagata C, Nakamura K, Fujii K, Kawachi T, Takatsuka N, Shimizu H. Consumption of coffee,
green tea, oolong tea, black tea, chocolate snacks and the caffeine content in relation to risk of diabetes
in Japanese men and women. Br J Nutr. 2010;103(3):453–9.
105. Toolsee NA, Aruoma OI, Gunness TK, Kowlessur S, Dambala V, Murad F, Googoolye K et al.
Effectiveness of green tea in a randomized human cohort: Relevance to diabetes and its complications.
Biomed Res Int. 2013;2013:412379.
106. Ortsater H, Grankvist N, Wolfram S, Kuehn N, Sjoholm A. Diet supplementation with green tea extract
epigallocatechin gallate prevents progression to glucose intolerance in db/db mice. Nutr Metab (Lond).
2012;9:11.
107. Tsuneki H, Murata S, Anzawa Y, Soeda Y, Tokai E, Wada T, Kimura I, Yanagisawa M, Sakurai T,
Sasaoka T. Age-related insulin resistance in hypothalamus and peripheral tissues of orexin knockout
mice. Diabetologia. 2008;51(4):657–67.
108. Liu K, Zhou R, Wang B, Chen K, Shi LY, Zhu JD, Mi MT. Effect of green tea on glucose control and
insulin sensitivity: A meta-analysis of 17 randomized controlled trials. Am J Clin Nutr. 2013;98(2):340–8.
109. Park JH, Jin JY, Baek WK, Park SH, Sung HY, Kim YK, Lee J, Song DK. Ambivalent role of gallated
catechins in glucose tolerance in humans: A novel insight into non-absorbable gallated catechin-derived
inhibitors of glucose absorption. J Physiol Pharmacol. 2009;60(4):101–9.
110. Kobayashi Y, Suzuki M, Satsu H, Arai S, Hara Y, Suzuki K, Miyamoto Y, Shimizu M. Green tea
polyphenols inhibit the sodium-dependent glucose transporter of intestinal epithelial cells by a
competitive mechanism. J Agric Food Chem. 2000;48(11):5618–23.
111. Lochocka K, Bajerska J, Glapa A, Fidler-Witon E, Nowak JK, Szczapa T, Grebowiec P, Lisowska A,
Walkowiak J. Green tea extract decreases starch digestion and absorption from a test meal in humans:
A randomized, placebo-controlled crossover study. Sci Rep. 2015;5:12015.
112. Miao M, Jiang B, Jiang H, Zhang T, Li X. Interaction mechanism between green tea extract and human
alpha-amylase for reducing starch digestion. Food Chem. 2015;186:20–5.
113. Yilmazer-Musa M, Griffith AM, Michels AJ, Schneider E, Frei B. Grape seed and tea extracts and
catechin 3-gallates are potent inhibitors of alpha-amylase and alpha-glucosidase activity. J Agric Food
Chem. 2012;60(36):8924–9.
114. Borges CM, Papadimitriou A, Duarte DA, Lopes de Faria JM, Lopes de Faria JB. The use of green
tea polyphenols for treating residual albuminuria in diabetic nephropathy: A double-blind randomised
clinical trial. Sci Rep. 2016;6:28282.
115. Mohan T, Velusamy P, Chakrapani LN, Srinivasan AK, Singh A, Johnson T, Periandavan K. Impact of
EGCG supplementation on the progression of diabetic nephropathy in rats: An insight into fibrosis and
apoptosis. J Agric Food Chem. 2017;65(36):8028–36.
116. Neuschwander-Tetri BA. Non-alcoholic fatty liver disease. BMC Med. 2017;15(1):45.
117. Imai K, Nakachi K. Cross sectional study of effects of drinking green tea on cardiovascular and liver
diseases. BMJ. 1995;310(6981):693–6.
118. Pezeshki A, Safi S, Feizi A, Askari G, Karami F. The effect of green tea extract supplementation on liver
enzymes in patients with nonalcoholic fatty liver disease. Int J Prev Med. 2016;7.
119. Sakata R, Nakamura T, Torimura T, Ueno T, Sata M. Green tea with high-density catechins improves
liver function and fat infiltration in non-alcoholic fatty liver disease (NAFLD) patients: A double-blind
placebo-controlled study. Int J Mol Med. 2013;32(5):989–94.
120. Bruno RS, Dugan CE, Smyth JA, DiNatale DA, Koo SI. Green tea extract protects leptin-deficient,
spontaneously obese mice from hepatic steatosis and injury. J Nutr. 2008;138(2):323–31.
121. Park HJ, Lee JY, Chung MY, Park YK, Bower AM, Koo SI, Giardina C, Bruno RS. Green tea extract
suppresses NFkappaB activation and inflammatory responses in diet-induced obese rats with nonalcoholic
steatohepatitis. J Nutr. 2012;142(1):57–63.
122. Li J, Sapper TN, Mah E, Moller MV, Kim JB, Chitchumroonchokchai C, McDonald JD, Bruno RS. Green
tea extract treatment reduces NFκB activation in mice with diet-induced nonalcoholic steatohepatitis by
lowering TNFR1 and TLR4 expression and ligand availability. J Nutr Biochem. 2017;41:34–41.
123. Li J, Sasaki GY, Dey P, Chitchumroonchokchai C, Labyk AN, McDonald JD, Kim JB, Bruno RS.
Green tea extract protects against hepatic NFkappaB activation along the gut-liver axis in diet-induced
obese mice with nonalcoholic steatohepatitis by reducing endotoxin and TLR4/MyD88 signaling. J Nutr
Biochem. 2017;53:58–65.
124. Dey P, Sasaki GY, Wei P, Li J, Wang L, Zhu J, McTigue D, Yu Z, Bruno RS. Green tea extract prevents
obesity in male mice by alleviating gut dysbiosis in association with improved intestinal barrier function
that limits endotoxin translocation and adipose inflammation. J Nutr Biochem. 2019;67:78–89.
125. Pang J, Zhang Z, Zheng TZ, Bassig BA, Mao C, Liu X, Zhu Y et al. Green tea consumption and risk of
cardiovascular and ischemic related diseases: A meta-analysis. Int J Cardiol. 2016;202:967–74.
126. Nakachi K, Matsuyama S, Miyake S, Suganuma M, Imai K. Preventive effects of drinking green tea
on cancer and cardiovascular disease: Epidemiological evidence for multiple targeting prevention.
Biofactors. 2000;13(1–4):49–54.
127. Widlansky ME, Hamburg NM, Anter E, Holbrook M, Kahn DF, Elliott JG, Keaney JF, Jr., Vita JA. Acute
EGCG supplementation reverses endothelial dysfunction in patients with coronary artery disease. J Am
Coll Nutr. 2007;26(2):95–102.
128. Schroeter H, Heiss C, Balzer J, Kleinbongard P, Keen CL, Hollenberg NK, Sies H, Kwik-Uribe C,
Schmitz HH, Kelm M. (-)-Epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular
function in humans. Proc Natl Acad Sci U S A. 2006;103(4):1024–9.
129. Lee W, Min WK, Chun S, Lee YW, Park H, Lee DH, Lee YK, Son JE. Long-term effects of green tea
ingestion on atherosclerotic biological markers in smokers. Clin Biochem. 2005;38(1):84–7.
130. Lorenz M, Wessler S, Follmann E, Michaelis W, Dusterhoft T, Baumann G, Stangl K, Stangl V. A
constituent of green tea, epigallocatechin-3-gallate, activates endothelial nitric oxide synthase by a
phosphatidylinositol-3-OH-kinase-, cAMP-dependent protein kinase-, and Akt-dependent pathway and
leads to endothelial-dependent vasorelaxation. J Biol Chem. 2004;279(7):6190–5.
131. Ludwig A, Lorenz M, Grimbo N, Steinle F, Meiners S, Bartsch C, Stangl K, Baumann G, Stangl V. The
tea flavonoid epigallocatechin-3-gallate reduces cytokine-induced VCAM-1 expression and monocyte
adhesion to endothelial cells. Biochem Biophys Res Commun. 2004;316(3):659–65.
132. Hong MH, Kim MH, Chang HJ, Kim NH, Shin BA, Ahn BW, Jung YD. (-)-Epigallocatechin-3-gallate
inhibits monocyte chemotactic protein-1 expression in endothelial cells via blocking NF-kappaB
signaling. Life Sci. 2007;80(21):1957–65.
133. El Bedoui J, Oak MH, Anglard P, Schini-Kerth VB. Catechins prevent vascular smooth muscle cell
invasion by inhibiting MT1-MMP activity and MMP-2 expression. Cardiovasc Res. 2005;67(2):317–25.
134. Mizugaki M, Ishizawa F, Yamazaki T, Hishinuma T. Epigallocatechin gallate increase the prostacyclin
production of bovine aortic endothelial cells. Prostaglandins Other Lipid Mediat. 2000;62(2):157–64.
135. Chyu KY, Babbidge SM, Zhao X, Dandillaya R, Rietveld AG, Yano J, Dimayuga P, Cercek B, Shah PK.
Differential effects of green tea-derived catechin on developing versus established atherosclerosis in
apolipoprotein E-null mice. Circulation. 2004;109(20):2448–53.
136. Miura S, Watanabe J, Tomita T, Sano M, Tomita I. The inhibitory effects of tea polyphenols (flavan-
3-ol derivatives) on Cu2+ mediated oxidative modification of low density lipoprotein. Biol Pharm Bull.
1994;17(12):1567–72.
137. Forester SC, Lambert JD. Antioxidant effects of green tea. Mol Nutr Food Res. 2011;55(6):844–54.
138. Yuan F, Dong H, Fang K, Gong J, Lu F. Effects of green tea on lipid metabolism in overweight or obese
people: A meta-analysis of randomized controlled trials. Mol Nutr Food Res. 2018;62(1).
139. Velayutham P, Babu A, Liu D. Green tea catechins and cardiovascular health: An update. Curr Med
Chem. 2008;15(18):1840–50.
140. Koo SI, Noh SK. Green tea as inhibitor of the intestinal absorption of lipids: Potential mechanism for its
lipid-lowering effect. J Nutr Biochem. 2007;18(3):179–83.
141. Shrestha S, Ehlers SJ, Lee JY, Fernandez ML, Koo SI. Dietary green tea extract lowers plasma and
hepatic triglycerides and decreases the expression of sterol regulatory element-binding protein-1c mRNA
and its responsive genes in fructose-fed, ovariectomized rats. J Nutr. 2009;139(4):640–5.
142. Johnson J, Bailey H, Mukhtar H. Green tea polyphenols for prostate cancer chemoprevention: A
translational perspective. Phytomedicine. 2010;17(1):3–13.
143. Jian L, Xie LP, Lee AH, Binns CW. Protective effect of green tea against prostate cancer: A case-control
study in southeast China. Int J Cancer. 2004;108(1):130–5.
144. Gupta S, Hastak K, Ahmad N, Lewin JS, Mukhtar H. Inhibition of prostate carcinogenesis in TRAMP
mice by oral infusion of green tea polyphenols. Proc Natl Acad Sci U S A. 2001;98(18):10350–5.
145. Gupta S, Ahmad N, Nieminen AL, Mukhtar H. Growth inhibition, cell-cycle dysregulation, and induction
of apoptosis by green tea constituent (-)-epigallocatechin-3-gallate in androgen-sensitive and androgen-
insensitive human prostate carcinoma cells. Toxicol Appl Pharmacol. 2000;164(1):82–90.
146. Chung LY, Cheung TC, Kong SK, Fung KP, Choy YM, Chan ZY, Kwok TT. Induction of apoptosis by
green tea catechins in human prostate cancer DU145 cells. Life Sci. 2001;68(10):1207–14.
147. Ogunleye AA, Xue F, Michels KB. Green tea consumption and breast cancer risk or recurrence: A meta-
analysis. Breast Cancer Res Treat. 2010;119(2):477–84.
148. Wu AH, Arakawa K, Stanczyk FZ, Van Den Berg D, Koh WP, Yu MC. Tea and circulating estrogen
levels in postmenopausal Chinese women in Singapore. Carcinogenesis. 2005;26(5):976–80.
149. Sen T, Moulik S, Dutta A, Choudhury PR, Banerji A, Das S, Roy M, Chatterjee A. Multifunctional effect
of epigallocatechin-3-gallate (EGCG) in downregulation of gelatinase-A (MMP-2) in human breast
cancer cell line MCF-7. Life Sci. 2009;84(7–8):194–204.
150. Farabegoli F, Papi A, Orlandi M. (-)-Epigallocatechin-3-gallate down-regulates EGFR, MMP-2,
MMP-9 and EMMPRIN and inhibits the invasion of MCF-7 tamoxifen-resistant cells. Biosci Rep.
2011;31(2):99–108.
151. Li Y, Chang S-C, Goldstein BY, Scheider WL, Cai L, You N-CY, Tarleton HP, Ding B, Zhao J, Wu M.
Green tea consumption, inflammation and the risk of primary hepatocellular carcinoma in a Chinese
population. Cancer Epidemiol. 2011;35(4):362–8.
152. Shimizu M, Shirakami Y, Sakai H, Kubota M, Kochi T, Ideta T, Miyazaki T, Moriwaki H. Chemopreventive
potential of green tea catechins in hepatocellular carcinoma. Int J Mol Sci. 2015;16(3):6124–39.
153. Shimizu M, Shirakami Y, Sakai H, Tatebe H, Nakagawa T, Hara Y, Weinstein IB, Moriwaki H. EGCG
inhibits activation of the insulin-like growth factor (IGF)/IGF-1 receptor axis in human hepatocellular
carcinoma cells. Cancer Lett. 2008;262(1):10–8.
154. Shirakami Y, Shimizu M, Adachi S, Sakai H, Nakagawa T, Yasuda Y, Tsurumi H, Hara Y, Moriwaki H.
(-)-Epigallocatechin gallate suppresses the growth of human hepatocellular carcinoma cells by inhibiting
activation of the vascular endothelial growth factor-vascular endothelial growth factor receptor axis.
Cancer Sci. 2009;100(10):1957–62.
155. Sakata R, Ueno T, Nakamura T, Sakamoto M, Torimura T, Sata M. Green tea polyphenol epigallocatechin-
3-gallate inhibits platelet-derived growth factor-induced proliferation of human hepatic stellate cell line
LI90. J Hepatol. 2004;40(1):52–9.
156. Myung SK, Bae WK, Oh SM, Kim Y, Ju W, Sung J, Lee YJ, Ko JA, Song JI, Choi HJ. Green tea
consumption and risk of stomach cancer: A meta-analysis of epidemiologic studies. Int J Cancer.
2009;124(3):670–7.
157. Gao YT, McLaughlin JK, Blot WJ, Ji BT, Dai Q, Fraumeni JF, Jr. Reduced risk of esophageal cancer
associated with green tea consumption. J Natl Cancer Inst. 1994;86(11):855–8.
158. Yang G, Shu XO, Li H, Chow WH, Ji BT, Zhang X, Gao YT, Zheng W. Prospective cohort study
of green tea consumption and colorectal cancer risk in women. Cancer Epidemiol Biomarkers Prev.
2007;16(6):1219–23.
159. Ji BT, Chow WH, Hsing AW, McLaughlin JK, Dai Q, Gao YT, Blot WJ, Fraumeni JF, Jr. Green tea
consumption and the risk of pancreatic and colorectal cancers. Int J Cancer. 1997;70(3):255–8.
160. Luo J, Inoue M, Iwasaki M, Sasazuki S, Otani T, Ye W, Tsugane S. Green tea and coffee intake and risk
of pancreatic cancer in a large-scale, population-based cohort study in Japan (JPHC study). Eur J Cancer
Prev. 2007;16(6):542–8.
161. Yin X, Yang J, Li T, Song L, Han T, Yang M, Liao H, He J, Zhong X. The effect of green tea intake on
risk of liver disease: A meta analysis. Int J Clin Exp Med. 2015;8(6):8339–46.
162. Peng X, Zhou R, Wang B, Yu X, Yang X, Liu K, Mi M. Effect of green tea consumption on blood
pressure: A meta-analysis of 13 randomized controlled trials. Sci Rep. 2014;4:6251.
163. Huang YQ, Lu X, Min H, Wu QQ, Shi XT, Bian KQ, Zou XP. Green tea and liver cancer risk: A meta-
analysis of prospective cohort studies in Asian populations. Nutrition. 2016;32(1):3–8.
164. Guo Y, Zhi F, Chen P, Zhao K, Xiang H, Mao Q, Wang X, Zhang X. Green tea and the risk of prostate
cancer: A systematic review and meta-analysis. Medicine. 2017;96(13).
1. National Conference of State Legislatures (Last updated 2019, Nov. 1) State Industrial Hemp Statutes.
http://www.ncsl.org/research/agriculture-and-rural-development/state-industrial-hemp-statutes.aspx
2. WHO Expert Committee on Drug Dependence: Thirty-ninth report. Geneva: World Health Organization;
2017 (WHO Pre-Review Report; Agenda Item 5.2). http://www.who.int/medicines/access/controlled-
substances/5.2_CBD.pdf
3. Gaoni, Y. and Mechoulam, R. 1964. Isolation, structure, and partial synthesis of an active constituent of
hashish. J Am Chem Soc, 86, 1646–1647.
4. Mechoulam, R. and Shvo, Y. 1963. Hashish-I: The structure of cannabidiol. Tetrahedron, 19, 2073–2078.
5. Devane, W.A., Dysarz, F.A., Johnson, M.R., Melvin, L.S., and Howlett, A.C. 1988. Determination and
characterization of a cannabinoid receptor in rat brain. Mol Pharmacol, 34, 605–613.
6. Matsuda, L.A., Lolait, S.J., Brownstein, M.J., Young, A.C., and Bonner, T.I. 1990. Structure of a
cannabinoid receptor and functional expression of the clones cDNA. Nature, 346, 561–564.
7. Devane, W.A., Hanus, L., Breuer, A. et al. 1992. Isolation and structure of a brain constituent that bind
to the cannabinoid receptor. Science, 258, 1946–1949.
8. Mechoulam, R., Ben-Shabat, S., Hanus, L. et al. 1995. Identification of an endogenous 2-monoglyceride,
present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol, 50, 83–90.
9. Sugiura, T., Kondo, S., Sukagawa, A. et al. 1995. 2-Arachidonoylglycerol: A possible endogenous
cannabinoid receptor ligand in brain. Biochem Biophys Res Commun, 215, 89–97.
10. Fine, P.G. and Rosenfeld, M.J. 2013. The endocannabinoid system, cannabinoids, and pain. Rambam
Maimonides Med J, 4, e0022.
11. Alvarez, F.J., Lafuente, H., Rey-Santano, M.C. et al. 2008. Neuroprotective effects of the nonpsychoactive
cannabinoid cannabidiol in hypoxic-ischemic newborn piglets. Pediatr Res, 64, 653–658.
12. Lu, H. and Mackie, K. 2016. An introduction to the endogenous cannabinoid system. Biol Psychiatry,
79, 516–525.
13. Alger, B.E. 2002. Retrograde signaling in the regulation of synaptic transmission: Focus on
endocannabinoids. Prog Neurobiol, 68, 247–286.
14. Hanuš, L., Breuer, A., Tchilibon, S. et al. 1999. HU-308: A specific agonist for CB2, a peripheral
cannabinoid receptor. Proc Natl Acad Sci, 96, 14228–14233.
15. Pertwee, R.G. 1997. Pharmacology of cannabinoid CB1 and CBD2 receptors. Pharmacol Ther, 74,
129–180.
16. Munro, S., Thomas, K.L., and Abu-Shaar, M. 1993. Molecular characterization of a peripheral receptor
for cannabinoids. Nature, 365, 61–65.
17. Hulsebosch, C.E. 2012. Special issue on microglia and chronic pain. Exp Neurol, 234, 253–254.
18. Dietrich, A. and McDaniel, W.F. 2004. Endocannabinoids and exercise. Br J Sports Med, 38, 536–541.
19. Donvito, G., Nass, S.R., Wilkerson, J.L. et al. 2018. The endogenous cannabinoid system: A budding
source of targets for treating inflammation and neuropathic pain. Neuropsychopharmacology, 43, 52–79.
20. Woodhams, S.G., Chapman, V., Finn, D.P., Hohmann, A.G., and Neugebauer, V. 2017. The cannabinoid
system and pain. Neuropharmacology, 124, 105–120.
21. Basu, S. and Dittel, B. 2011. Unraveling the complexities of cannabinoid receptor 2 (CB2) immune
regulation in health and disease. Immunol Res, 51, 26–38.
22. Johnson, J.R., Burnell-Nugent, M., Lossignol, D., Ganae-Motan, E.D., Potts, R., and Fallon, M.T. 2010.
Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety,
and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain.
J Pain Symptom Manage, 39, 167–179.
23. Richardson, D., Pearson, R.G., Kurian, N. et al. 2008 Characterization of the cannabinoid receptor
system in synovial tissue and fluid in patients with osteoarthritis and rheumatoid arthritis. Arthritis Res
Ther, 10, R43.
24. Valastro, C., Campanile, D., Marinaro, M. et al. 2017. Characterization of endocannabinoids and related
acylethanolamides in the synovial fluid of dogs with osteoarthritis: A pilot study. BMC Vet Res, 6, 309.
25. Dietrich, A. and McDaniel, W.F. 2004. Endocannabinoids and exercise. Br J Sports Med, 28, 526–541.
26. Calignano, I., Katona, F., Desarnaud, A. et al. 2000. Bidirectional control of airway responsiveness by
endogenous cannabinoids. Nature, 408, 96–101.
27. Lopez, H. 2018, September 5. Potential Role of Hemp-Derived Full-Spectrum CBD Oil in Rehabilitation
and Physical Therapy. http://rehab-insider.advanceweb.com/potential-role-of-hemp-derived-
full-spectrum-cbd-oil-in-rehabilitation-and-physical-therapy/
28. Miller, J.S. and Jackson, N.M. 2017. The evolving law and regulation of industrial hemp in the United
States. Louis D. Brandeis School of Law University of Louisville, 8, 12–37.
29. Mez, J., Daneshvar, DH., Kiernan, PT. et al. 2017. Clinicopathological Evaluation of Chronic Traumatic
Encephalopathy in Players of American Football. JAMA, 318(4):360–370. doi:10.1001/jama.2017.8334
30. Public Law 113–79: Agricultural Act of 2014. https://docs.wixstatic.com/ugd/89d621_884253959e9541
6aa5973114084f10b0.pdf
31. Wallace, A. 2017, July 5. In the DEA’s words: Agency Stance on CBD, Hemp Products and the
Farm Bill. The Cannabist. https://www.thecannabist.co/2017/07/05/dea-statement-cbd-hemp-farm-
bill-controlled-substances-act/83100/
32. Public Law 115-334: Agriculture Improvement Act of 2018. https://www.agriculture.senate.gov/imo/
media/doc/Agriculture%20Improvement%20Act%20of%202018.pdf
33. Angell, T. 2018, June 28. U.S. Senate Votes to Legalize Hemp after Decades-Long Ban Under Marijuana
Prohibition. Forbes. https://www.forbes.com/sites/tomangell/2018/06/28/u-s-senate-votes-to-legalize-
hemp-after-decades-long-ban-under-marijuana-prohibition/#1ec754b5418a
34. Controlled Substances Act, 21 U.S.C. 812(c).
35. Dietary Supplement Health and Education Act, 21 U.S.C.A. Ch. 9.
36. U.S. Food & Drug Administration. 2018, Dec. 20. FDA Responds to Three GRAS Notices for
Hemp Seed-Derived Ingredients for Use in Human Food. https://www.fda.gov/Food/NewsEvents/
ConstituentUpdates/ucm628910.htm
37. U.S. Food & Drug Administration. 2018, June 25. FDA Approves First Drug Comprised of an Active
Ingredient Derived from Marijuana to Treat Rare, Severe Forms of Epilepsy. https://www.fda.gov/
NewsEvents/Newsroom/PressAnnouncements/ucm611046.htm
38. U.S. Food & Drug Administration (Last updated 2018, Dec. 20) FDA and Marijuana: Questions and
Answers. https://www.fda.gov/NewsEvents/PublicHealthFocus/ucm421168.htm#dietary_supplements
39. U.S. Food & Drug Administration. 2018, Dec. 20. Statement from FDA Commissioner Scott Gottlieb,
M.D., on Signing of the Agriculture Improvement Act and the Agency’s Regulation of Products
Containing Cannabis and Cannabis-Derived Compounds. https://www.fda.gov/NewsEvents/Newsroom/
PressAnnouncements/ucm628988.htm
40. Senate Democrats. 2018, June 27. Schumer Introduces Marijuana Freedom and Opportunity Act—
New Legislation Would Decriminalize Marijuana at Federal Level. https://www.democrats.senate.
gov/newsroom/press-releases/schumer-introduces-marijuana-freedom-and-opportunity-act_-new-
legislation-would-decriminalize-marijuana-at-federal-level
1. Graham, T.E. Caffeine and exercise: Metabolism, endurance and performance. Sports Med. 2001; 31, 785–807.
2. Kruk, B., Chmura, J., Krzeminski, K. et al. Influence of caffeine, cold and exercise on multiple choice
reaction time. Psychopharmacology (Berl). 2001; 157, 197–201.
3. Tarnopolsky, M., Cupido, C. Caffeine potentiates low frequency skeletal muscle force in habitual and
nonhabitual caffeine consumers. J Appl Physiol. 2000; 89, 1719–1724.
4. Bruce, C.R., Anderson, M.E., Fraser, S.F. et al. Enhancement of 2000 meter rowing performance after
caffeine ingestion. Med Sci Sports Exerc. 2000; 32, 1958–1963.
5. Anderson, M.E., Bruce, C.R., Fraser, S.F. et al. Improved 2000 meter rowing performance in competitive
oarswomen after caffeine ingestion. Int J Sport Nutr Exerc Metab. 2000; 10, 464–475.
6. Talanian, J.L., Spriet, L.L. Low and moderate doses of caffeine late in exercise improve performance in
trained cyclists. Appl Physiol Nutr Metab. 2016; 41(8), 850–855.
7. Graham, T.E., Spriet, L.L. Metabolic, catecholamine, and exercise performance responses to various
doses of caffeine. J Appl Physiol. 1995; 78, 867–874.
8. Kovacs, E.M., Stegen, J.H.C.H., Brouns, F. Effect of caffeinated drinks on substrate metabolism, caffeine
excretion, and performance. J Appl Physiol. 1998; 85, 709–715.
9. Pasman, W.J., van Baak, M.A., Jeukendrup, A.E., de Haan, A. The effect of different dosages of caffeine
on endurance performance time. Int J Sports Med. 1995; 16, 225–230.
10. Spriet, L.L. Exercise and sport performance with low doses of caffeine. Sports Med, 2014;
44(Suppl 2):S175–184. doi, 10.1007/s40279-014-0257-8
11. Doherty, M., Smith, P.M. Effects of caffeine ingestion on rating of perceived exertion during and after
exercise: A meta-analysis. Scand J Med Sci Sports. 2005; 15(2), 69–78.
12. Graham, T.E., Spriet, L.L. Performance and metabolic responses to a high caffeine dose during prolonged
exercise. J Appl Physiol. 1991; 71, 2292–2298.
13. Acheson, K.J., Gremaud, G., Meirim, I. et al. Metabolic effects of caffeine in humans: Lipid oxidation
or futile cycling? Am J Clin Nutr. 2004; 79, 40–46.
14. Perkins, K.A., Sexton, J.E., Epstein, L.H., DiMarco, A., Fonte, C., Stiller, R.L., Jacob, R.G. Acute
thermogenic effects of nicotine combined with caffeine during light physical activity in male and female
smokers. Am J Clin Nutr. 1994; 60(3), 312–319. doi, 10.1093/ajcn/60.3.312
15. Bracco, D., Ferrarra, J.M., Arnaud, M.J., Jequier, E., Schutz, Y. Effects of caffeine on energy
metabolism, heart rate, and methylxanthine metabolism in lean and obese women. Am J Physiol. 1995;
269(4 Pt 1):E671–678.
16. Collins, L.C., Cornelius, M.F., Vogel, R.L., Walker, J.F., Stamford, B.A. Effect of caffeine and/or
cigarette smoking on resting energy expenditure. Int J Obes Relat Metab Disord. 1994; 18, 551–556.
17. Dulloo, A.G., Geissler, C.A., Horton, T., Collins, A., Miller, D.S. Normal caffeine consumption: Influence
on thermogenesis and daily energy expenditure in lean and post obese human volunteers. Am J Clin Nutr.
1989; 49, 44–50.
18. Poehlman, E.T., LaChance, P., Tremblay, A. et al. The effect of prior exercise and caffeine ingestion on
metabolic rate and hormones in young adult males. Can J Physiol Pharmacol. 1989; 67, 10–16.
19. Koot, P., Deurenberg, P. Comparison of changes in energy expenditure and body temperatures after
caffeine consumption. Ann Nutr Metab. 1995; 39, 135–142.
20. Belza, A., Jessen, A.B. Bioactive food stimulants of sympathetic activity: Effect on 24-h energy
expenditure and fat oxidation. Eur J Clin Nutr. 2005; 59, 733–741.
21. de Mendonca, A., Cunha, R.A. Therapeutic opportunities for caffeine in Alzheimer’s disease and other
neurodegenerative disorders. J Alzheimers Dis. 2010; 20(Suppl 1):S1–S2.
22. Paluska, S.A. Caffeine and exercise. Curr Sports Med Rep. 2003; 2, 213–219.
23. Graham, T.E. Caffeine, coffee and ephedrine: Impact on exercise performance and metabolism. Can J
Appl Physiol. 2001; 26(Suppl.):S103–S119.
24. Motl, R.W., O’Connor, P.J., Dishman, R.K. Effect of caffeine on perceptions of leg muscle pain during
moderate intensity cycling exercise. J Pain. 2003; 4, 316–321.
25. Hogervorst, E., Riedel, W.J., Kovacs, E., Brouns, F., Jolles, J. Caffeine improves cognitive performance
after strenuous physical exercise. Int J Sports Med. 1999; 20, 354–361.
26. Applegate, E. Effective nutritional ergogenic aids. Int J Sport Nutr. 1999; 9, 229–239.
27. Costill, D.L., Dalsky, G.P., Fink, W.J. Effects of caffeine ingestion on metabolism and exercise
performance. Med Sci Sports. 1978; 10, 155–158.
28. McLellan, T.M., Bell, D.G. The impact of prior coffee consumption on the subsequent ergogenic effect
of anhydrous caffeine. Int J Sport Nutr Exerc Metab. 2004; 14, 698–708.
29. Higgins, S., Straight, C.R., Lewis, R.D. The effects of preexercise caffeinated coffee ingestion on
endurance performance: An evidence-based review. Int J Sport Nutr Exerc Metab. 2016; 26(3), 221–239.
doi, 10.1123/ijsnem.2015-0147
30. Fiala, K.A., Casa, D.J., Roti, M.W. Rehydration with a caffeinated beverage during the nonexercise
periods of three consecutive days of twice-a-day practices. Int J Sport Nutr Exerc Metab. 2004; 14,
419–429.
31. Armstrong, L.E. Caffeine, body fluid -electrolyte balance, and exercise performance. Int J Sport Nutr
Exerc Metab. 2002; 12, 189–206.
32. Goldstein, E.R., Ziegenfuss, T., Kalman, D., Kreider, R., Campbell, B., Wilborn, C., Antonio, J. International
society of sports nutrition position stand: Caffeine and performance. J Int Soc Sports Nutr. 2010; 7(1), 5.
33. Ryu, S., Choi, S.K., Joung, S.S. et al. Caffeine as a lipolytic food component increases endurance
performance in rats and athletes. J Nutr Sci Vitaminol (Tokyo). 2001; 47, 139–146.
34. Erickson, M.A., Schwarzkopf, R.J., McKenzie, R.D. Effects of caffeine, fructose, and glucose ingestion
on muscle glycogen utilization during exercise. Med Sci Sports Exerc. 1987; 19, 579–583.
35. Spriet, L.L., MacLean, D.A., Dyck, D.J., Hultman, E., Cederblad, G., Graham, T.E. Caffeine ingestion
and muscle metabolism during prolonged exercise in humans. Am J Physiol. 1992; 262:E891–E898.
36. Holtzman, S.G., Mante, S., Minneman, K.P. Role of adenosine receptors in caffeine tolerance.
J Pharmacol Exp Ther. 1991; 256, 62–68.
37. Mohr, T., Van Soeren, M., Graham, T.E., Kjaer, M. Caffeine ingestion and metabolic responses of
tetraplegic humans during electrical cycling. J Appl Physiol. 1998; 85, 979–985.
38. Bell, D.G., Jacobs, I., Ellerington, K. Effect of caffeine and ephedrine ingestion on anaerobic exercise
performance. Med Sci Sports Exerc. 2001; 33, 1399–1403.
39. Davis, J.K., Green, J.M. Caffeine and anaerobic performance: Ergogenic value and mechanisms of
action. Sports Med. 2009; 39(10), 813–832.
40. Penner, R., Neher, E., Takeshima, H., Nishimura, S., Numa, S. Functional expression of the calcium
release channel from skeletal muscle ryanodine receptor cDNA. FEBS Lett. 1989; 259, 217–221.
41. Fryer, M.W., Neering, I.R. Actions of caffeine on fast- and slow-twitch muscles of the rat. J Physiol. 1989;
416, 435–454.
42. Lopes, J.M., Aubier, M., Jardim, J., Aranda, J.V., Macklem, P.T. Effect of caffeine on skeletal muscle
function before and after fatigue. J Appl Physiol. 1983; 54, 1303–1305.
43. Weber, A., Herz, R. The relationship between caffeine contracture of intact muscle and the effect of
caffeine on reticulum. J Gen Physiol. 1968; 52(5), 750–759.
44. Tallis, J., James, R.S., Cox, V.M., Duncan, M.J. The effect of physiological concentrations of caffeine on
the power output of maximally and submaximally stimulated mouse EDL (fast) and soleus (slow) muscle.
J Appl Physiol. 2012; 112(1), 64–71.
45. Moore, T.M., Mortensen, X.M., Ashby, C.K., Harris, A.M., Kump, K.J., Laird, D.W., Thomson, D.M.
The effect of caffeine on skeletal muscle anabolic signaling and hypertrophy. Appl Physiol Nutr Metab.
2017; 42(6), 621–629.
46. Doherty, M., Smith, P., Hughes, M., Davison, R. Caffeine lowers perceptual response and increases
power output during high-intensity cycling. J Sports Sci. 2004; 22, 637–643.
47. Mack, W.J., Preston-Martin, S., Dal Maso, L. et al. A pooled analysis of case-control studies of thyroid cancer:
Cigarette smoking and consumption of alcohol, coffee, and tea. Cancer Causes Control. 2003; 14, 773–785.
48. Killen, L.G., Green, J.M., O’Neal, E.K., McIntosh, J.R., Hornsby, J., Coates, T.E. Effects of caffeine on
session ratings of perceived exertion. Eur J Appl Physiol. 2013; 113(3), 721–727.
49. Cox, G.R., Desbrow, B., Montgomery, P.G., Anderson, M.E., Bruce, C.R., Macrides, T.A., Burke, L.M.
Effect of different protocols of caffeine intake on metabolism and endurance performance. J Appl
Physiol. 2002; 93(3), 990–999.
50. Liguori, A., Hughes, J.R., Grass, J.A. Absorption and subjective effects of caffeine from coffee, cola and
capsules. Pharmacol Biochem Behav. 1997; 58(3), 721–726.
51. Wakabayashi, K., Kono, S., Shinchi, K. et al. Habitual coffee consumption and blood pressure: A study
of self-defense officials in Japan. Eur J Epidemiol. 1998; 14, 669–673.
52. Mesas, A.E., Leon-Munoz, L.M., Rodriguez-Artalejo, F., Lopez-Garcia, E. The effect of coffee on blood
pressure and cardiovascular disease in hypertensive individuals: A systematic review and meta-analysis.
Am J Clin Nutr. 2011; 94(4), 1113–1126. doi, 10.3945/ajcn.111.016667
53. Lancaster, T., Muir, J., Silagy, C. The effects of coffee on serum lipids and blood pressure in a U.K.
population. J R Soc Med. 1994; 87, 506–507.
54. Geleijnse, J.M. Habitual coffee consumption and blood pressure: An epidemiological perspective.
Vasc Health Risk Manag. 2008; 4(5), 963–970.
55. Rakic, V., Burke, V., Beilin, L.J. Effects of coffee on ambulatory blood pressure in older men and women:
A randomized controlled trial. Hypertension. 1999; 33, 869–873.
56. Hakim, A.A., Ross, G.W., Curb, J.D. et al. Coffee consumption in hypertensive men in older middle- age
and the risk of stroke: The Honolulu heart program. J Clin Epidemiol. 1998; 51, 487–494.
57. Rodriguez-Artalejo, F., Lopez-Garcia, E. Coffee consumption and cardiovascular disease: A condensed
review of epidemiological evidence and mechanisms. J Agric Food Chem. 2018; 66(21), 5257–5263.
58. Willett, W.C., Stampfer, M.J., Manson, J.E. et al. Coffee consumption and coronary heart disease in
women: A ten-year followup. JAMA. 1996; 275, 458–462.
59. Mukamal, K.J., Maclure, M., Muller, J.E., Sherwood, J.B., Mittleman, M.A. Caffeinated coffee
consumption and mortality after acute myocardial infarction. Am Heart J. 2004; 147, 999–1004.
60. Jazbec, A., Simic, D., Corovic, N., Durakovic, Z., Pavlovic, M. Impact of coffee and other selected factors
on general mortality and mortality due to cardiovascular disease in Croatia. J Health Popul Nutr. 2003;
21, 332–340.
61. Kleemola, P., Jousilahti, P., Pietinen, P., Vartiainen, E., Tuomilehto, J. Coffee consumption and the risk
of coronary heart disease and death. Arch Intern Med. 2000; 160, 3393–3400.
62. Park, S.Y., Freedman, N.D., Haiman, C.A., Le Marchand, L., Wilkens, L.R., Setiawan, V.W. Association
of coffee consumption with total and cause-specific mortality among nonwhite populations. Ann Intern
Med. 2017; 167(4), 228–235.
63. Muley, A., Muley, P., Shah, M. Coffee to reduce risk of type 2 diabetes?: A systematic review.
Curr Diabetes Rev. 2012; 8(3), 162–168.
64. Carlsson, S., Hammar, N., Grill, V., Kaprio, J. Coffee consumption and risk of type 2 diabetes in Finnish
twins. Int J Epidemiol. 2004; 33, 616–617.
65. Gerber, D.A. Coffee consumption and type 2 diabetes mellitus. Ann Intern Med. 2004; 141, 323; author
reply 323–4.
66. Glaser, J.H., Glaser, S.K. Coffee consumption and type 2 diabetes mellitus. Ann Intern Med. 2004; 141,
323; author reply 323–4.
67. Louria, D.B. Coffee consumption and type 2 diabetes mellitus. Ann Intern Med. 2004; 141, 321; author
reply 323–4.
68. Rosengren, A., Dotevall, A., Wilhelmsen, L., Thelle, D., Johansson, S. Coffee and incidence of diabetes
in Swedish women: A prospective 18-year follow-up study. J Intern Med. 2004; 255, 89–95.
69. Ranheim, T., Halvorsen, B. Coffee consumption and human health—Beneficial or detrimental?
Mechanisms for effects of coffee consumption on different risk factors for cardiovascular disease and
type 2 diabetes mellitus. Mol Nutr Food Res. 2005; 49, 274–284.
70. Salazar-Martinez, E., Willett, W.C., Ascherio, A. et al. Coffee consumption and risk for type 2 diabetes
mellitus. Ann Intern Med. 2004; 140, 1–8.
71. Lee, J.H., Oh, M.K., Lim, J.T., Kim, H.G., Lee, W.J. Effect of coffee consumption on the progression of
type 2 diabetes mellitus among prediabetic individuals. Korean J Fam Med. 2016; 37(1), 7–13.
72. American Diabetes Association. Statistics about diabetes. 2018. Available from http://www.diabetes.org/
diabetes-basics/statistics/
73. Boyle, J.P., Thompson, T.J., Gregg, E.W., Barker, L.E., Williamson, D.F. Projection of the year 2050
burden of diabetes in the US adult population: Dynamic modeling of incidence, mortality, and prediabetes
prevalence. Popul Health Metr. 2010; 8, 29.
74. Wang, A., Wang, S., Zhu, C., Huang, H., Wu, L., Wan, X., Zhao, H. Coffee and cancer risk: A meta-
analysis of prospective observational studies. Sci Rep. 2016; 6, 33711. doi, 10.1038/srep33711
75. Oh, J.K., Sandin, S., Strom, P., Lof, M., Adami, H.O., Weiderpass, E. Prospective study of breast cancer
in relation to coffee, tea and caffeine in Sweden. Int J Cancer. 2015; 137(8), 1979–1989.
76. Zhang, Y., Wang, X., Cui, D. Association between coffee consumption and the risk of oral cancer:
A meta-analysis of observational studies. Int J Clin Exp Med. 2015; 8(7), 11657–11665.
77. Schmit, S.L., Rennert, H.S., Rennert, G., Gruber, S.B. Coffee consumption and the risk of colorectal
cancer. Cancer Epidemiol Biomarkers Prev. 2016; 25(4), 634–639.
78. Chrysant, S.G. The impact of coffee consumption on blood pressure, cardiovascular disease and diabetes
mellitus. Expert Rev Cardiovasc Ther. 2017; 15(3), 151–156.
79. Soriguer, F., Rojo-Martinez, G., de Antonio, I.E. Coffee consumption and type 2 diabetes mellitus.
Ann Intern Med. 2004; 141, 321–323; author reply 323–4
80. Tuomilehto, J., Hu, G., Bidel, S., Lindstrom, J., Jousilahti, P. Coffee consumption and risk of type 2
diabetes mellitus among middle-aged Finnish men and women. JAMA. 2004; 291, 1213–1219.
81. Van Dam, R.M., Pasman, W.J., Verhoef, P. Effects of coffee consumption on fasting blood glucose and insulin
concentrations: Randomized controlled trials in healthy volunteers. Diabetes Care. 2004; 27, 2990–2992.
82. Wadhawan, M., Anand, A.C. Coffee and Liver Disease. J Clin Exp Hepatol. 2016; 6(1), 40–46.
doi:10.1016/j.jceh.2016.02.003
83. Poole, R., Kennedy, O.J., Roderick, P., Fallowfield, J. A., Hayes, P.C., Parkes, J. Coffee consumption
and health: Umbrella review of meta-analyses of multiple health outcomes. BMJ. 2017; 359, j5024.
doi:10.1136/bmj.j5024
84. Lee, J., Lee, J. E., Kim, Y. Relationship between coffee consumption and stroke risk in Korean population:
The Health Examinees (HEXA) Study. Nutr J. 2017; 16(1), 7. doi:10.1186/s12937-017-0232-y
85. Antwi, S.O., Eckel-Passow, J.E., Diehl, N.D., Serie, D.J., Custer, K.M., Arnold, M.L., Parker, A.S. Coffee
consumption and risk of renal cell carcinoma. Cancer Causes Control. 2017; 28(8), 857–866. doi:10.1007/
s10552-017-0913-z
86. Je, Y., Giovannucci, E. Coffee consumption and total mortality: A meta-analysis of twenty prospective
cohort studies. Br J Nutr. 2014; 111(7), 1162–1173. doi:10.1017/S0007114513003814
87. Wijarnpreecha, K., Thongprayoon, C., Ungprasert, P. Coffee consumption and risk of nonalcoholic fatty
liver disease: A systematic review and meta-analysis. Eur J Gastroenterol Hepatol. 2017; 29(2), e8–e12.
doi:10.1097/MEG.0000000000000776
88. Miranda, A.M., Steluti, J., Fisberg, R.M., Marchioni, D.M. Association between Coffee Consumption
and Its Polyphenols with Cardiovascular Risk Factors: A Population-Based Study. Nutrients. 2017; 9(3).
doi:10.3390/nu9030276
89. Rhee, J.J., Qin, F., Hedlin, H.K., Chang, T.I., Bird, C.E., Zaslavsky, O., Winkelmayer, W.C. Coffee and
caffeine consumption and the risk of hypertension in postmenopausal women. Am J Clin Nutr. 2016;
103(1), 210–217. doi:10.3945/ajcn.115.120147
90. Lukic, M., Licaj, I., Lund, E., Skeie, G., Weiderpass, E., Braaten, T. Coffee consumption and the risk of
cancer in the Norwegian Women and Cancer (NOWAC) Study. Eur J Epidemiol. 2016; 31(9), 905–916.
doi:10.1007/s10654-016-0142-x
91. Larsson, S.C., Giovannucci, E.L., Wolk, A. Coffee Consumption and Risk of Gallbladder Cancer in a
Prospective Study. J Natl Cancer Inst. 2017; 109(3), 1–3. doi:10.1093/jnci/djw237
92. Qi, H., Li, S. Dose-response meta-analysis on coffee, tea and caffeine consumption with risk of
Parkinson’s disease. Geriatr Gerontol Int. 2014; 14(2), 430–439. doi:10.1111/ggi.12123
93. Suliga, E., Koziel, D., Ciesla, E., Rebak, D., Gluszek, S. Coffee consumption and the occurrence and
intensity of metabolic syndrome: A cross-sectional study. Int J Food Sci Nutr. 080/09637486.2016.1256381
1. Dietary Reference Intakes: Energy, Carbohydrates, Fiber, Fat, Fatty Acids, Cholesterol, Protein and
Amino Acids. Washington D.C.: Institute of Medicine: Food and Nutrition Board. National Academies
Press; 2005.
2. Food and Drug Administration. The Declaration of Certain Isolated or Synthetic Non-Digestible
Carbohydrates as Dietary Fiber on Nutrition and Supplement Facts Labels: Guidance for Industry. 2018.
3. Dietary Reference Intakes: Proposed Definition of Dietary Fiber. Washington, D.C.: Institute of
Medicine, Food and Nutrition Board. National Academies Press; 2001:1–64.
4. Englyst HN, Wiggins HS, Cummings JH. Determination of the non-starch polysaccharides in plant foods
by gas-liquid chromatography of constituent sugars as alditol acetates. Analyst. 1982;107:307–318.
5. Makki K, Deehan EC, Walter J and Backhed F. The impact of dietary fiber on gut microbiota in host
health and disease. Cell Host Microbe. 2018;23:705–715.
6. Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, de Ferranti SD et al. American Heart
Association Statistics C and Stroke Statistics S. Heart disease and stroke statistics—2017 update: A
report from the American Heart Association. Circulation. 2017;135:e146–e603.
7. Leading Causes of Death in Females, 2015 current listing. Centers for Disease Control and Prevention.
2018.
8. Kannel WB, Gordon T and Castelli WP. Role of lipids and lipoprotein fractions in atherogenesis: The
Framingham study. Prog Lipid Res. 1981;20:339–348.
9. Martin MJ, Hulley SB, Browner WS, Kuller LH and Wentworth D. Serum cholesterol, blood pressure,
and mortality: implications from a cohort of 361,662 men. Lancet. 1986;2:933–936.
10. Simons LA. Interrelations of lipids and lipoproteins with coronary artery disease mortality in 19
countries. Am J Cardiol. 1986;57:5G–10G.
11. Stamler J, Wentworth D and Neaton JD. Is relationship between serum cholesterol and risk of premature
death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the
Multiple Risk Factor Intervention Trial (MRFIT). JAMA. 1986;256:2823–2828.
12. Anderson JW and Hanna TJ. Impact of nondigestible carbohydrates on serum lipoproteins and risk for
cardiovascular disease. J Nutr. 1999;129:1457S–1466S.
13. Todd S, Woodward M, Tunstall-Pedoe H and Bolton-Smith C. Dietary antioxidant vitamins and fiber in
the etiology of cardiovascular disease and all-causes mortality: results from the Scottish Heart Health
Study [In Process Citation]. Am J Epidemiol. 1999;150:1073–1080.
14. Wolk A, Manson JE, Stampfer MJ, Colditz GA, Hu FB, Speizer FE, Hennekens CH and Willett WC.
Long-term intake of dietary fiber and decreased risk of coronary heart disease among women. JAMA.
1999;281:1998–2004.
15. Brown L, Rosner B, Willett WW and Sacks FM. Cholesterol-lowering effects of dietary fiber: A meta-
analysis. Am J Clin Nutr. 1999;69:30–42.
16. Anderson JW, Zettwoch N, Feldman T, Tietyen-Clark J, Oeltgen P and Bishop CW. Cholesterol-
lowering effects of psyllium hydrophilic mucilloid for hypercholesterolemic men. Arch Intern Med.
1988;148:292–296.
17. Behall KM, Scholfield DJ and Hallfrisch J. Effect of beta-glucan level in oat fiber extracts on blood lipids
in men and women. J Am Coll Nutr. 1997;16:46–51.
18. Gerhardt AL and Gallo NB. Full-fat rice bran and oat bran similarly reduce hypercholesterolemia in
humans. J Nutr. 1998;128:865–869.
19. Olson BH, Anderson SM, Becker MP, Anderson JW, Hunninghake DB, Jenkins DJ, LaRosa JC et al.
Psyllium-enriched cereals lower blood total cholesterol and LDL cholesterol, but not HDL cholesterol,
in hypercholesterolemic adults: Results of a meta-analysis. J Nutr. 1997;127:1973–1980.
20. Romero AL, Romero JE, Galaviz S and Fernandez ML. Cookies enriched with psyllium or oat bran
lower plasma LDL cholesterol in normal and hypercholesterolemic men from Northern Mexico. J Am
Coll Nutr. 1998;17:601–608.
21. Whyte JL, McArthur R, Topping D and Nestel P. Oat bran lowers plasma cholesterol levels in mildly
hypercholesterolemic men. J Am Diet Assoc. 1992;92:446–449.
22. DeGroot AP, Luyken R and Pikaar NA. Cholesterol lowering effects of rolled oats. Lancet. 1963;2:303–304.
23. Anderson JW, Story LS, Sieling B, Chen WJL, Pertro MS and Story J. Hypocholesterolemic effects of
oat bran or beans intake for hypercholesterolemic men. Am J Clin Nutr. 1984;40:1145–1155.
24. Ripsin CM, Keenan JM, Jacobs DR, Jr., Elmer PJ, Welch RR, Van Horn L, Liu K et al. Oat products and
lipid lowering. A meta-analysis. JAMA. 1992;267:3317–3325.
25. Thies F, Masson LF, Boffetta P and Kris-Etherton P. Oats and CVD risk markers: A systematic literature
review. Br J Nutr. 2014;112(Suppl 2):S19–S30.
26. Johnston TP, Korolenko TA, Pirro M and Sahebkar A. Preventing cardiovascular heart disease:
Promising nutraceutical and non-nutraceutical treatments for cholesterol management. Pharmacol Res.
2017;120:219–225.
27. Fischer MH, Yu N, Gray GR, Ralph J, Anderson L and Marlett JA. The gel-forming polysaccharide of
psyllium husk (Plantago ovata Forsk). Carbohydr Res. 2004;339:2009–2017.
28. Anderson JW, Jones AE and Riddell-Mason S. Ten different dietary fibers have significantly different
effects on serum and liver lipids of cholesterol-fed rats. J Nutr. 1994;124:78–83.
29. Kritchevsky D, Tepper SA and Klurfeld DM. Influence of psyllium preparations on plasma and liver
lipids of cholesterol-fed rats. Artery. 1995;21:303–311.
30. Turley SD, Daggy BP and Dietschy JM. Cholesterol-lowering action of psyllium mucilloid in the hamster:
Sites and possible mechanisms of action. Metabolism. 1991;40:1063–1073.
31. Coats AJ. The potential role of soluble fibre in the treatment of hypercholesterolaemia. Postgrad Med J.
1998;74:391–394.
32. Everson GT, Daggy BP, McKinley C and Story JA. Effects of psyllium hydrophilic mucilloid on LDL-
cholesterol and bile acid synthesis in hypercholesterolemic men. J Lipid Res. 1992;33:1183–1192.
33. Anderson JW, Allgood LD, Turner J, Oeltgen PR and Daggy BP. Effects of psyllium on glucose and serum
lipid responses in men with type 2 diabetes and hypercholesterolemia. Am J Clin Nutr. 1999;70:466–473.
34. Pal S and Radavelli-Bagatini S. Effects of psyllium on metabolic syndrome risk factors. Obes Rev.
2012;13:1034–1047.
35. Yuan HC, Meng Y, Bai H, Shen DQ, Wan BC and Chen LY. Meta-analysis indicates that resistant starch
lowers serum total cholesterol and low-density cholesterol. Nutr Res. 2018;54:1–11.
36. Nichenametla SN, Weidauer LA, Wey HE, Beare TM, Specker BL and Dey M. Resistant starch type
4-enriched diet lowered blood cholesterols and improved body composition in a double blind controlled
cross-over intervention. Mol Nutr Food Res. 2014;58:1365–1369.
37. Leiss O, von Bergmann K, Streicher U and Strotkoetter H. Effect of three different dihydroxy bile acids
on intestinal cholesterol absorption in normal volunteers. Gastroenterology. 1984;87:144–149.
38. Horton JD, Cuthbert JA and Spady DK. Regulation of hepatic 7 alpha-hydroxylase expression by dietary
psyllium in the hamster. J Clin Invest. 1994;93:2084–2092.
39. Wright RS, Anderson JW and Bridges SR. Propionate inhibits hepatocyte lipid synthesis. Proc Soc Exp
Biol Med. 1990;195:26–29.
40. Veldman FJ, Nair CH, Vorster HH, Vermaak WJ, Jerling JC, Oosthuizen W and Venter CS.
Dietary pectin influences fibrin network structure in hypercholesterolaemic subjects. Thromb Res.
1997;86:183–196.
41. Veldman FJ, Nair CH, Vorster HH, Vermaak WJ, Jerling JC, Oosthuizen W and Venter CS. Possible
mechanisms through which dietary pectin influences fibrin network architecture in hypercholesterolaemic
subjects. Thromb Res. 1999;93:253–264.
42. North CJ, Venter CS and Jerling JC. The effects of dietary fibre on C-reactive protein, an inflammation
marker predicting cardiovascular disease. Eur J Clin Nutr. 2009;63:921–933.
43. Allaire J, Vors C, Couture P and Lamarche B. LDL particle number and size and cardiovascular risk:
Anything new under the sun? Curr Opin Lipidol. 2017;28:261–266.
44. Davy BM, Davy KP, Ho RC, Beske SD, Davrath LR and Melby CL. High-fiber oat cereal compared with
wheat cereal consumption favorably alters LDL-cholesterol subclass and particle numbers in middle-
aged and older men. Am J Clin Nutr. 2002;76:351–358.
45. Lamarche B, Desroches S, Jenkins DJ, Kendall CW, Marchie A, Faulkner D, Vidgen E et al. Combined
effects of a dietary portfolio of plant sterols, vegetable protein, viscous fibre and almonds on LDL particle
size. Br J Nutr. 2004;92:657–663.
46. Ruisinger JF, Gibson CA, Backes JM, Smith BK, Sullivan DK, Moriarty PM and Kris-Etherton P. Statins
and almonds to lower lipoproteins (the STALL Study). J Clin Lipidol. 2015;9:58–64.
47. Jacobs DR, Jr., Meyer KA, Kushi LH and Folsom AR. Whole-grain intake may reduce the risk of ischemic
heart disease death in postmenopausal women: The Iowa Women’s Health Study [see comments]. Am J
Clin Nutr. 1998;68:248–257.
48. Kushi LH, Meyer KA and Jacobs DR, Jr. Cereals, legumes, and chronic disease risk reduction: Evidence
from epidemiologic studies. Am J Clin Nutr. 1999;70:451S–458S.
49. Moreyra AE, Wilson AC and Koraym A. Effect of combining psyllium fiber with simvastatin in lowering
cholesterol. Arch Intern Med. 2005;165:1161–1166.
50. Uusitupa MI, Miettinen TA, Happonen P, Ebeling T, Turtola H, Voutilainen E and Pyorala K. Lathosterol
and other noncholesterol sterols during treatment of hypercholesterolemia with lovastatin alone and with
cholestyramine or guar gum. Arterioscler Thromb. 1992;12:807–813.
51. Vaquero MP, Sanchez Muniz FJ, Jimenez Redondo S, Prats Olivan P, Higueras FJ and Bastida S. Major
diet-drug interactions affecting the kinetic characteristics and hypolipidaemic properties of statins.
Nutr Hosp. 2010;25:193–206.
1. Vanamala J, Radhakrishnan S, Reddivari L and Massey A. Anthocyanins as Apoptotic Regulators. In
Novel Apoptotic Regulators in Carcinogenesis (eds. Chen GG and Lai PBS). Springer, Netherlands,
2012, 93–122.
2. Mursu J et al. Flavonoid Intake and the Risk of Ischaemic Stroke and CVD Mortality in Middle-Aged
Finnish Men: The Kuopio Ischaemic Heart Disease Risk Factor Study. Br. J. Nutr. 2008;100:890–895.
3. Fukumoto LR and Mazza G. Assessing Antioxidant and Prooxidant Activities of Phenolic Compounds.
J. Agric. Food Chem. 2000;48:3597–3604.
4. Kay CD. Aspects of Anthocyanin Absorption, Metabolism and Pharmacokinetics in Humans. Nutr. Res.
Rev. 2006;19:137.
5. Tsao R. Chemistry and Biochemistry of Dietary Polyphenols. Nutrients 2010;2:1231–1246.
6. He J and Giusti MM. Anthocyanins: Natural Colorants with Health-Promoting Properties. Annu. Rev.
Food Sci. Technol. 2010;1:163–187.
7. Wang Y and Ho C-T. Metabolism of Flavonoids. In: Food Factors for Health Promotion (ed. Yoshikawa,
T. (Kyoto)). Karger: Basel, 2009, 61, 64–74.
8. Welch CR, Wu Q and Simon JE. Recent Advances in Anthocyanin Analysis and Characterization.
Curr. Anal. Chem. 2008;4:75–101.
9. Singleton B. Astaxanthin Health Benefits|LIVESTRONG.COM. Available at: https://www.livestrong.
com/article/160675-astaxanthin-health-benefits/. (Accessed: 1st March 2018).
10. Seeram NP and Nair MG. Inhibition of Lipid Peroxidation and Structure–Activity-Related Studies of
the Dietary Constituents Anthocyanins, Anthocyanidins, and Catechins. 2002.
11. Tsuda T, Shiga K, Ohshima K, Kawakishi S and Osawa T. Inhibition of Lipid Peroxidation and the
Active Oxygen Radical Scavenging Effect of Anthocyanin Pigments Isolated from Phaseolus vulgaris
L. Biochem. Pharmacol. 1996;52:1033–1039.
12. Lazze MC et al. Anthocyanins Induce Cell Cycle Perturbations and Apoptosis in Different Human Cell
Lines. Carcinogenesis 2004;25:1427–1433.
13. Hou DX et al. International Journal of Oncology. University of Crete, Faculty of Medicine, Laboratory
of Clinical Virology, 2003, 23.
14. Cvorovic J et al. Oxidative Stress-Based Cytotoxicity of Delphinidin and Cyanidin in Colon Cancer
Cells. Arch. Biochem. Biophys. 2010;501:151–157.
15. Nurmi T et al. Metabolism of Berry Anthocyanins to Phenolic Acids in Humans. J. Agric. Food Chem.
2009;57:2274–2281.
16. McGhie TK and Walton MC. The Bioavailability and Absorption of Anthocyanins: Towards a Better
Understanding. Mol. Nutr. Food Res. 2007;51:702–713.
17. Ichiyanagi T, Shida Y, Rahman MM, Hatano Y and Konishi T. Bioavailability and Tissue Distribution
of Anthocyanins in Bilberry (Vaccinium myrtillus L.) Extract in Rats. J. Agric. Food Chem.
2006;54:6578–6587.
18. Ling ZC, Chun GH, Yuan DZ and Zhao Q. Pharmacological and Nutritional Activities of Potato
Anthocyanins. African J. Pharm. Pharmacol. 2009;2:463–468.
19. Schauss AG et al. Antioxidant Capacity and Other Bioactivities of the Freeze-Dried Amazonian Palm
Berry, Euterpe oleraceae Mart. (Acai). J. Agric. Food Chem. 2006;54:8604–8610.
20. Cretu GC and Morlock GE. Analysis of Anthocyanins in Powdered Berry Extracts by Planar
Chromatography Linked with Bioassay and Mass Spectrometry. Food Chem. 2014;146:104–112.
21. Fang J. Classification of Fruits Based on Anthocyanin Types and Relevance to their Health Effects.
Nutrition 2017;31:1301–1306.
22. Ribeiro da Silva LM, Teixeira de Figueiredo EA, Silva Ricardo NM, Pinto Vieira IG, Wilane de
Figueiredo R, Brasil IM, Gomes CL. Quantification of Bioactive Compounds in Pulps and By-Products
of Tropical Fruits from Brazil. Food Chem. 2014;143:398–404.
23. Koeppen BH and Herrmann K. Flavonoid Glycosides and Hydroxycinnamic Acid Esters of Blackcurrants
(Ribes nigrum). Zeitschrift fϋr Leb. und -forsch. 1977;164:263–268.
24. Wada L and Ou B. Antioxidant Activity and Phenolic Content of Oregon Caneberries. J. Agric. Food
Chem. 2002;50:3495–3500.
25. McGhie TK, Ainge GD, Barnett LE, Cooney JM and Jensen DJ. Anthocyanin Glycosides from Berry
Fruit Are Absorbed and Excreted Unmetabolized by Both Humans and Rats. J. Agric. Food Chem.
2003;51:4539–4548.
26. Wu T, Yin J, Zhang G, Long H and Zheng X. Mulberry and Cherry Anthocyanin Consumption
Prevents Oxidative Stress and Inflammation in Diet-Induced Obese Mice. Mol. Nutr. Food Res.
2016;60:687–694.
27. Qin B and Anderson RA. An Extract of Chokeberry Attenuates Weight Gain and Modulates Insulin,
Adipogenic and Inflammatory Signalling Pathways in Epididymal Adipose Tissue of Rats Fed a Fructose-
Rich Diet. Br. J. Nutr. 2012;108:581–587.
28. Jing P, Zhao S, Ruan S, Sui Z, Chen L, Jiang L and Qian B. Quantitative Studies on Structure–
ORAC Relationships of Anthocyanins from Eggplant and Radish Using 3D-QSAR. Food Chem.
2014;145:365–371.
29. Duymus HG, Göger F and Baser KH. In Vitro Antioxidant Properties and Anthocyanin Compositions
of Elderberry Extracts. Food Chem. 2014;155:112–119.
30. Zheng W and Wang SY. Oxygen Radical Absorbing Capacity of Phenolics in Blueberries, Cranberries,
Chokeberries, and Lingonberries. J. Agric. Food Chem. 2003;51:502–509.
31. Cuevas-Rodríguez EO et al. Characterization of Anthocyanins and Proanthocyanidins in Wild and
Domesticated Mexican Blackberries (Rubus spp.). J. Agric. Food Chem. 2010;58:7458–7464.
32. Xiao T, Guo Z, Sun B and Zhao Y. Identification of Anthocyanins from Four Kinds of Berries and Their
Inhibition Activity to α-Glycosidase and Protein Tyrosine Phosphatase 1B by HPLC–FT-ICR MS/MS.
J. Agric. Food Chem. 2017;65:6211–6221.
33. Petersson EV, Liu J, Sjöberg PJ, Danielsson R and Turner C. Pressurized Hot Water Extraction of
Anthocyanins from Red Onion: A Study on Extraction and Degradation Rates. Anal. Chim. Acta
2010;663:27–32.
34. Grosso G et al. Red Orange: Experimental Models and Epidemiological Evidence of its Benefits on
Human Health. Oxid. Med. Cell. Longev. 2013;2013.
35. Li J, Lim SS, Lee JY, Kim JK, Kang SW, Kim JL and Kang YH. Purple Corn Anthocyanins Dampened
High-Glucose-Induced Mesangial Fibrosis and Inflammation: Possible Renoprotective Role in Diabetic
Nephropathy. J. Nutr. Biochem. 2012;23:320–331.
36. Ju J-H et al. Anti-Obesity and Antioxidative Effects of Purple Sweet Potato Extract in 3T3-L1 Adipocytes
In Vitro. J. Med. Food 2011;14:1097–1106.
37. Ahmed M, Akter MSTS and Eun J-B. Optimization Conditions for Anthocyanin and Phenolic Content
Extraction From Purple Sweet Potato Using Response Surface Methodology. Int. J. Food Sci. Nutr.
2011;62:91–96.
38. Madiwale GP, Reddivari L, Holm DG and Vanamala J. Storage Elevates Phenolic Content and
Antioxidant Activity but Suppresses Antiproliferative and Pro-Apoptotic Properties of Colored-Flesh
Potatoes against Human Colon Cancer Cell Lines. J. Agric. Food Chem. 2011;59:8155–8166.
39. Muñoz-Espada AC, Wood KV, Bordelon B and Watkins BA. Anthocyanin Quantification and Radical
Scavenging Capacity of Concord, Norton, and Marechal Foch Grapes and Wines. J. Agric. Food Chem.
2004;52:6779–6786.
40. Liazid A, Barbero GF, Azaroual L, Palma M and Barroso CG. Stability of Anthocyanins from Red Grape
Skins under Pressurized Liquid Extraction and Ultrasound-Assisted Extraction Conditions. Molecules
2014;19:21034–21043.
41. DeFuria J et al. Dietary Blueberry Attenuates Whole-Body Insulin Resistance in High Fat-Fed Mice by
Reducing Adipocyte Death and Its Inflammatory Sequelae. J. Nutr. 2009;139:1510–1516.
42. Huang H et al. Red Cabbage Microgreens Lower Circulating Low-Density Lipoprotein (LDL),
Liver Cholesterol, and Inflammatory Cytokines in Mice Fed a High-Fat Diet. J. Agric. Food Chem.
2016;64:9161–9171.
43. Frankel EN, Waterhouse AL and Teissedre PL. Principal Phenolic Phytochemicals in Selected California
Wines and Their Antioxidant Activity in Inhibiting Oxidation of Human Low-Density Lipoproteins.
J. Agric. Food Chem. 1995;43:890–894.
44. Oliveira J, da Silva M, Teixeira N, De Freitas V and Salas E. Screening of Anthocyanins and Anthocyanin-
Derived Pigments in Red Wine Grape Pomace Using LC-DAD/MS and MALDI-TOF Techniques.
J. Agric. Food Chem. 2015;63:7636–7644.
45. Mikulic-Petkovsek M, Stampar F, Veberic R and Sircelj H. Wild Prunus Fruit Species as a Rich Source
of Bioactive Compounds. J. Food Sci. 2016;81:C1928–C1937.
46. Gerardi C, Albano C, Calabriso N, Carluccio MA, Durante M, Mita G, Renna M, Serio F and Blando
F. Techno-Functional Properties of Tomato Puree Fortified with Anthocyanin Pigments. Food Chem.
2018;240:1184–1192.
47. Gültekin-Özgüven M, Karadağ A, Duman S, Özkal B and Özcelik B. Fortification of Dark Chocolate
with Spray Dried Black Mulberry (Morus nigra) Waste Extract Encapsulated in Chitosan-Coated
Liposomes and Bioaccessability Studies. Food Chem. 2016;201:205–212.
48. Sui X, Zhang Y and Zhou W. Bread Fortified with Anthocyanin-Rich Extract from Black Rice as
Nutraceutical Sources: Its Quality Attributes and In Vitro Digestibility. Food Chem. 2016;196:910–916.
49. Vlachojannis C, Zimmermann BF and Chrubasik-Hausmann S. Quantification of Anthocyanins in
Elderberry and Chokeberry Dietary Supplements. Phyther. Res. 2015;29:561–565.
50. Kay CD, Pereira-Caro G, Ludwig IA, Clifford MN and Crozier A. Anthocyanins and Flavanones Are
More Bioavailable Than Previously Perceived: A Review of Recent Evidence. Annu. Rev. Food Sci.
Technol. 2017;8:155–180.
51. Fang J. Bioavailability of Anthocyanins. Drug Metab. Rev. 2014;46:508–520.
52. Azzini E, Giacometti J and Russo GL. Antiobesity Effects of Anthocyanins in Preclinical and Clinical
Studies. Oxid. Med. Cell. Longev. 2017;2017.
53. He J, Wallace TC, Keatley KE, Failla ML and Giusti MM. Stability of Black Raspberry Anthocyanins
in the Digestive Tract Lumen and Transport Efficiency into Gastric and Small Intestinal Tissues in the
Rat. J. Agric. Food Chem. 2009;57:3141–3148.
54. Vitaglione P et al. Protocatechuic Acid Is the Major Human Metabolite of Cyanidin-Glucosides. J. Nutr.
2007;137:2043–2048.
55. Mallery SR et al. Effects of Human Oral Mucosal Tissue, Saliva, and Oral Microflora on Intraoral
Metabolism and Bioactivation of Black Raspberry Anthocyanins. Cancer Prev. Res. (Phila).
2011;4:1209–1221.
56. van Duynhoven J et al. Metabolic Fate of Polyphenols in the Human Superorganism. Proc. Natl. Acad.
Sci. U. S. A. 2011;108(Suppl 1):4531–4538.
57. Kirakosyan A, Seymour EM, Wolforth J, McNish R, Kaufman PB and Bolling SF. Tissue Bioavailability
of Anthocyanins from Whole Tart Cherry in Healthy Rats. Food Chem. 2015;171:26–31.
58. Mueller D et al. Human Intervention Study to Investigate the Intestinal Accessibility and Bioavailability
of Anthocyanins from Bilberries. Food Chem. 2017;231:275–286.
59. Cassidy A. Berry Anthocyanin Intake and Cardiovascular Health. Mol. Aspects Med. 2017.
60. Stoner GD et al. Pharmacokinetics of Anthocyanins and Ellagic Acid in Healthy Volunteers Fed Freeze-
Dried Black Raspberries Daily for 7 days. J. Clin. Pharmacol. 2005;45:1153–1164.
61. Cassidy A and Minihane AM. The Role of Metabolism (and the Microbiome) in Defining the Clinical
Efficacy of Dietary Flavonoids. Am. J. Clin. Nutr. 2017;105:10–22.
62. Walle T, Walle UK and Halushka PV. Carbon Dioxide is the Major Metabolite of Quercetin in Humans.
J. Nutr. 2001;131:2648–2652.
63. Kuspradini H. Antioxidant and Toxicity Properties of Anthocyanin Extracted from Red Flower of Four
Tropical Shrubs. Nusant. Biosci. 2016;8:135–140.
64. Lee YM et al. Dietary Anthocyanins Against Obesity and Inflammation. Nutrients 2017;9:1–15.
65. Dragano NRV et al. Freeze-Dried Jaboticaba Peel Powder Improves Insulin Sensitivity in High-Fat-Fed
Mice. Br. J. Nutr. 2013;110:447–455.
66. Kim SY et al. Inhibitory Effect of Anthocyanin-Rich Black Soybean Testa (Glycine max (L.) Merr.) on
the Inflammation-Induced Adipogenesis in a DIO Mouse Model. J. Funct. Foods 2015;14:623–633.
67. Farrell NJ et al. Black Elderberry Extract Attenuates Inflammation and Metabolic Dysfunction in Diet-
Induced Obese Mice. Br. J. Nutr. 2015;114:1123–1131.
68. Charepalli V et al. Anthocyanin-Containing Purple-Fleshed Potatoes Suppress Colon Tumorigenesis via
Elimination of Colon Cancer Stem Cells. J. Nutr. Biochem. 2015;26:1641–1649.
69. Benn T et al. Polyphenol-Rich Blackcurrant Extract Prevents Inflammation in Diet-Induced Obese Mice.
J. Nutr. Biochem. 2014;25:1019–1025.
70. Wu T et al. Blueberry and Mulberry Juice Prevent Obesity Development in C57BL/6 Mice. PLoS One
2013;8:e77585.
71. Qin B and Anderson RA. An Extract of Chokeberry Attenuates Weight Gain and Modulates Insulin,
Adipogenic and Inflammatory Signalling Pathways in Epididymal Adipose Tissue of Rats Fed a Fructose-
Rich Diet. Br. J. Nutr. 2012;108:581–587.
72. Lee M, Sorn SR, Park Y and Park H-K. Anthocyanin Rich-Black Soybean Testa Improved Visceral Fat
and Plasma Lipid Profiles in Overweight/Obese Korean Adults: A Randomized Controlled Trial. J. Med.
Food 2016;19:995–1003.
73. Wright ORL, Netzel GA and Sakzewski AR. A Randomized, Double-Blind, Placebo-Controlled
Trial of the Effect of Dried Purple Carrot on Body Mass, Lipids, Blood Pressure, Body Composition,
and Inflammatory Markers in Overweight and Obese Adults: The QUENCH Trial. Can. J. Physiol.
Pharmacol. 2013;91:480–488.
74. Peiffer DS et al. Dietary Consumption of Black Raspberries or Their Anthocyanin Constituents Alters
Innate Immune Cell Trafficking in Esophageal Cancer. Cancer Immunol. Res. 2016;4:72–82.
75. de Sousa Moraes LF, Sun X, do Carmo Gouveia Peluzio M and Zhu M-J. Anthocyanins/Anthocyanidins
and Colorectal Cancer: What Is Behind the Scenes? Crit. Rev. Food Sci. Nutr. 2017;0:1–13.
76. Larrosa M et al. Polyphenol Metabolites from Colonic Microbiota Exert Anti-Inflammatory Activity on
Different Inflammation Models. Mol. Nutr. Food Res. 2009;53:1044–1054.
77. Charepalli V et al. Eugenia jambolana (Java Plum) Fruit Extract Exhibits Anti-Cancer Activity against
Early Stage Human HCT-116 Colon Cancer Cells and Colon Cancer Stem Cells. Cancers (Basel).
2016;8:29.
78. Reddivari L, Vanamala J, Chintharlapalli S, Safe SH and Miller JC. Anthocyanin Fraction from Potato
Extracts is Cytotoxic to Prostate Cancer Cells through Activation of Caspase-Dependent and Caspase-
Independent Pathways. Carcinogenesis 2007;28:2227–2235.
79. Madiwale GP, Reddivari L, Stone M, Holm DG and Vanamala J. Combined Effects of Storage and
Processing on the Bioactive Compounds and Pro-Apoptotic Properties of Color-Fleshed Potatoes in
Human Colon Cancer Cells. J. Agric. Food Chem. 2012;60:11088–11096.
80. Roopchand DE et al. Dietary Polyphenols Promote Growth of the Gut Bacterium Akkermansia
muciniphila and Attenuate High-Fat Diet-Induced Metabolic Syndrome. Diabetes 2015;64:2847–2858.
81. Zikri NN et al. Black Raspberry Components Inhibit Proliferation, Induce Apoptosis, and Modulate
Gene Expression in Rat Esophageal Epithelial Cells. Nutr. Cancer 2009;61:816–826.
82. Afgar A et al. MiR-339 and Especially miR-766 Reactivate the Expression of Tumor Suppressor Genes
in Colorectal Cancer Cell Lines through DNA Methyltransferase 3B Gene Inhibition. Cancer Biol. Ther.
2016;17:1126–1138.
83. Wang L-S et al. Black Raspberry-Derived Anthocyanins Demethylate Tumor Suppressor Genes through
the Inhibition of DNMT1 and DNMT3B in Colon Cancer Cells. Nutr. Cancer 2013;65:118–125.
84. Elmore S. Apoptosis: A Review of Programmed Cell Death. Toxicol. Pathol. 2007;35:495–516.
85. Brunelle JK and Letai A. Control of Mitochondrial Apoptosis by the Bcl-2 Family. J. Cell Sci.
2009;122:437–441.
86. Harris MH and Thompson CB. The Role of the Bcl-2 Family in the Regulation of Outer Mitochondrial
Membrane Permeability. Cell Death Differ. 2000;7:1182–1191.
87. Shin DY et al. Induction of Apoptosis in Human Colon Cancer HCT-116 Cells by Anthocyanins through
Suppression of Akt and Activation of p38-MAPK. Int. J. Oncol. 2009;35:1499–1504.
88. Lee SH et al. Induction of Apoptosis in Human Leukemia U937 Cells by Anthocyanins through Down-
Regulation of Bcl-2 and Activation of Caspases. Int. J. Oncol. 2009;34:1077–1083.
89. Lo C-W, Huang H-P, Lin H-M, Chien C-T and Wang C-J. Effect of Hibiscus Anthocyanins-Rich Extract
Induces Apoptosis of Proliferating Smooth Muscle Cell via Activation of P38 MAPK and p53 Pathway.
Mol. Nutr. Food Res. 2007;51:1452–1460.
90. Van Laethem A et al. Activation of p38 MAPK Is Required for Bax Translocation to Mitochondria,
Cytochrome C Release and Apoptosis Induced by UVB Irradiation in Human Keratinocytes. FASEB J.
2004;18:1946–1948.
91. Fulda S and Debatin K-M. Extrinsic versus Intrinsic Apoptosis Pathways in Anticancer Chemotherapy.
Oncogene 2006;25:4798–4811.
92. Zhao C, Giusti MM, Malik M, Moyer MP and Magnuson BA. Effects of Commercial Anthocyanin-
Rich Extracts on Colonic Cancer and Nontumorigenic Colonic Cell Growth. J. Agric. Food Chem.
2004;52:6122–6128.
93. Bode U, Hasan C, Hülsmann B and Fleischhack G. Recancostat Compositum Therapy Does Not Prevent
Tumor Progression in Young Cancer Patients. Klin. Pädiatrie 1999;211:353–355.
94. Thomasset S et al. Pilot Study of Oral Anthocyanins for Colorectal Cancer Chemoprevention.
Cancer Prev. Res. (Phila). 2009;2:625–633.
95. Wang L-S et al. A Phase Ib Study of the Effects of Black Raspberries on Rectal Polyps in Patients with
Familial Adenomatous Polyposis. Cancer Prev. Res. (Phila). 2014;7:666–674.
96. Wang L-S et al. Modulation of Genetic and Epigenetic Biomarkers of Colorectal Cancer in Humans by
Black Raspberries: A Phase I Pilot Study. Clin. Cancer Res. 2011;17:598–610.
97. McCullough ML et al. Flavonoid Intake and Cardiovascular Disease Mortality in a Prospective Cohort
of US Adults. Am. J. Clin. Nutr. 2012;95:454–464.
98. Johnson SA et al. Daily Blueberry Consumption Improves Blood Pressure and Arterial Stiffness in
Postmenopausal Women with Pre- and Stage 1-Hypertension: A Randomized, Double-Blind, Placebo-
Controlled Clinical Trial. J. Acad. Nutr. Diet. 2015;115:369–377.
99. Yarahmadi M et al. The Effect of Anthocyanin Supplementation on Body Composition, Exercise
Performance and Muscle Damage Indices in Athletes. Int. J. Prev. Med. 2014;5:1594–1600.
100. Morais CA, de Rosso VV, Estadella D and Pisani LP. Anthocyanins as Inflammatory Modulators and
the Role of the Gut Microbiota. J. Nutr. Biochem. 2016;33:1–7.
1. Visioli, F. and Galli, C. The effect of minor constituents of olive oil on cardiovascular disease: New
findings. Nutr. Rev. 56: 142–147, 1998.
2. USDA Nutrient Database for Standard Reference, Release 12. U.S. Department of Agriculture, Agriculture
Research Service, Nutrient Data Laboratory Home Page, http://www.nal.usda.gov/fnic/ foodcomp, 1998.
3. Freeland-Graves, J.M. and Peckham, G.C. Foundations of Food Preparation. 5th ed. MacMillan,
New York, 1987.
4. Owen, R.W., Mier, W., Giacosa, A., Hull, W.E., Spiegelhalder, B., and Bartsch, H. Identification of
lignans as major compounds in the phenolic fraction of olive oil. Clin. Chem. 46: 976–988, 2000.
5. World Health Organization Study Group. Diet, Nutrition, and the Prevention of Chronic Diseases.
World Health Organization Tech. Rep. Ser. 16, 2003.
6. Ganji, V. and Kafai, M.R. Demographic, health, lifestyle and blood vitamin determinants of serum total
homocysteine concentrations in the third National Health and Nutrition Examination Survey, 1988–1994.
Am. J. Clin. Nutr. 77: 826–833, 2003.
7. Renaud, S., DeLorgeril, M., Delaye, J., Guidollet, J., Jacquard, F., Mamelle, N., Martin, J.L., Monjaud, I.,
Salen, P., and Toubol, P. Cretan Mediterranean diet for prevention of coronary heart disease. Am. J. Clin.
Nutr. 61: 1360–1367, 1995.
8. Baggio, G., Pagnan, A., Muraca, M., Martini, S., Opportuno, A., Bonanome, A., Ambrosio, G.B.,
Ferrari, S., and Crepaldi, G. Olive oil-enriched diet: Effect on serum lipoprotein levels and biliary
cholesterol saturation. Am. J. Clin. Nutr. 47: 960–964, 1998.
9. Elder, K. and Kirchgessner, M. Concentrations of lipids in plasma and lipoproteins and oxidative
susceptibility of low-density lipoproteins in zinc-deficient rats fed linseed oil or olive oil. J. Nutr.
Biochem. 8: 461–468, 1997.
10. Stangl, G.I., Kirchgessner, M., Reichlmayr-Lais, A.M., and Eder, K. Serum lipids and lipoproteins from
rats fed different dietary oils. J. Anim. Physiol. Anim. Nutr. 71: 87–97, 1994.
11. Balasubramaniam, S., Simons, L.A., Chang, S., and Hickie, J.B. Reduction in plasma cholesterol and
increase in biliary cholesterol by a diet rich in n-3 fatty acids in the rat. J. Lipid Res. 26: 684–689, 1985.
12. Scaccini, C., Nardini, M., D’Aquino, M., Gentili, V., Di Felice, M., and Tomassi, G. Effect of dietary oils
on lipid peroxidation and on antioxidant parameters of rat plasma and lipoprotein fractions. J. Lipid Res.
33: 627–633, 1992.
13. Parthasarthy, S., Khoo, J.C., Miller, E., Barnett, J., Witztum, J.L., and Steinberg, D. Low density
lipoprotein rich in oleic acid is protective against oxidative modification: Implication for dietary
prevention of atherosclerosis. Proc. Natl. Acad. Sci. USA 87: 3894–3898, 1990.
14. Nicolaiew, N., Lemort, N., Adorni, L., Berra, B., Montorfano, G., Rapelli, S., Cortesi, N., and Jacotot, B.
Comparison between extra virgin olive oil and oleic acid rich sunflower oil: Effect on postprandial
lipemia and LDL susceptibility to oxidation. Ann. Nutr. Metab. 42: 251–260, 1998.
15. Visioli, F. and Galli, C. Olive oil phenols and their potential effects on human health. J. Agric. Food
Chem. 46: 4292–4296, 1998.
16. Angerosa, F. and DiGiacinto, L. Oxidation des huiles d’olive vierges par le métaux manganese et nickel,
Note 1 (Metal-induced oxidation of virgin olive oils: Manganese and nickel. Note 1), Rev. Fr. Corps
Gras. 40: 41–44, 1993.
17. Visioli, F., Bellomo, G., Montedoro, G.F., and Galli, C. Low-density lipoprotein oxidation is inhibited
in vitro by olive oil constituents. Atherosclerosis 117: 25–42, 1995.
18. Visioli, F. and Galli, C. Oleuropein protects low-density lipoprotein from oxidation. Life Sci. 55:
1965–1971, 1994.
19. Pitsavos, C., Panagiotakos, B.B., Tzima, N., Chrysohoou, C., Economou, M., Zampelas, A., and
Stefanadis, C. Adherence to the Mediterranean diet is associated with total anti-oxidant capacity in
healthy adults: The ATTICA study. Am. J. Clin. Nutr. 82: 694–699, 2005.
20. Miles, E.A., Zoubouli, P., and Calder, P.C. Differential anti-inflammatory effects of phenolic compounds
from extra virgin olive oil identified in human whole blood cultures. Nutrition 21: 389–394, 2005.
21. Serrano-Martinez, M., Palacios, M., Martinez-Losa, E., Lezaun, R., Maravi, C., Prado, M., Martinez,
J.A., and Martinez-Gonzalez, M.A. A Mediterranean dietary style influences TNF-alpha and VCAM- 1
coronary blood levels in unstable angina patients. Eur. J. Nutr. 44: 349–354, 2005.
22. Ruano, J., Lopez-Miranda, J., Fuentes, F., Morena, J.A., Bellido, C., Perez-Martinez, P., Lozano, A.,
Jiménez, Y., and Jiménez, F.P. Phenolic content of virgin olive oil improves ischemic reactive hyperemia
in hypercholesterolemic patients. J. Am. Coll. Cardiol. 46: 1864–1868, 2005.
23. Deiana, M., Aruoma, O.I., Bianchi, M.L.P., Spencer, J.P.E., Kaur, H., Halliwell, B., Aeschbach, R.,
Banni, S., Dessi, M.A. and Corongiu, F.P. Inhibition of peroxynitrite dependent DNA base modification
and tyrosine nitration by the extra virgin olive oil-derived antioxidant hydroxytyrosol. Free Radic. Biol.
Med. 26: 762–769, 1999.
24. Visioli, F., Bellosta, S., and Galli, C. Oleuropein, the bitter principles in olives, enhances nitric oxide
production by murine macrophages. Life Sci. 62: 541–546, 1998.
25. Lahoz, C., Alonso, R., Porres, A., and Mata, P. Las Dietas Enriquecidas en Ácidos Gracos Monoin—
saturadoes y Ácidos Gracos Poliinsaturado Omega 3 Disminuyen la Presion Artersial, sin Modificar la
Concentración de Insulina Plasmática en Sujetos Sanos. Med. Clin. (Barc). 112: 133–137, 1999.
26. Ruiz-Gutierres, V., Muriana, F.J., Guerrero, A., Cert, A.M., and Villar, J. Plasma lipids, erythrocyte
membrane lipids and blood pressure of hypertensive women after ingestion of dietary oleic acid from
two different sources. J. Hypertens. 14: 1483–1490, 1996.
27. Alonso, A. and Martinez-González, M.Á. Olive oil consumption and reduced incidence of hypertension:
The SUN study. Lipids. 39: 1233–1238, 2004.
28. Fito, M., Cladellas, M., de la Torre, R., Marti, J., Alcántara, M., Pujadas-Bastardes, M., Marrugat, J.,
Bruguera, J., López-Sabater, M.C., Vila, J. et al. Antioxidant effect of virgin olive oil in patients with
stable coronary heart disease: A randomized, crossover, controlled, clinical trial. Atheroscleorsis 181:
149–158, 2005.
29. Berrino, F. and Muti, P. Mediterranean diet and cancer. Eur. J. Clin. Nutr. 43: 49–55, 1989.
30. Cohen, L.A., Thompson, D.O., Maeura, Y., Choi, K., Blank, M.E., and Rose, D.P. Dietary fat and
mammary cancer. I. Promoting effects of different dietary fats on N-nitrosomethylurea-induced rat
mammary tumorigenesis. J. Natl. Cancer Inst. 77: 33–42, 1986.
31. Lasekan, J.B., Clayton, M.K., Gendron-Fitzpatrick, A., and Ney, D.M. Dietary olive and safflower oil in
promotion of DMBA-induced mammary tumorigenesis in rats. Nutr. Cancer 13: 153–163, 1990.
32. Zusman, I. Comparative anticancer effects of vaccination and dietary factors on experimentally-induced
cancers. In vivo 12: 675–689, 1998.
33. Simsonsen, N.R., Navajas, J.F.C., Martin-Moreno, J.M., Strain, J.J., Huttnen, J.K., Martin, B.C.,
Thamm, M. et al. Tissue stores of individual monounsaturated fatty acids and breast cancer: The
EURAMIC study. Am. J. Clin. Nutr. 68: 134–141, 1998.
34. Carrol, K.K. Experimental evidence of dietary factors and hormone-dependent cancers. Cancer Res. 35:
3374–3383, 1975.
35. Cohen, L.A., Thompson, D.O., Maeura, Y., Choi, K., Blank, M.E., and Rose, D.P. Dietary fat and
mammary cancer. I. Promoting effects of different dietary fats on N-nitrosomethylurea-induced rat
mammary tumorigenesis. J. Natl. Cancer Inst. 77: 33–42, 1986.
36. Jurkowski, J.J. and Cave, W.T., Jr. Dietary effects of menhaden oil on the growth and membrane lipid
composition of rat mammary tumors. J. Natl. Cancer. Inst. 74: 1145–1150, 1985.
37. Cohen, L.A., Chen-Backlund, J.Y., Sepkovic, D.W., and Sugie, S. Effect of varying proportions of dietary
menhaden corn oil on experimental rat tumor promotion. Lipids 28: 449–456, 1993.
38. Karmali, R.A., Thaler, H.T., and Cohen, L.A. Prostaglandin concentrations and prostaglandin
synthase activity in N-nitrosomethylurea-induced rat mammary adenocarcinoma. Eur. J. Clin. Oncol.
19: 817–823, 1983.
39. Landa, M.C., Frago, N., and Tres, A. Diet and the risk of breast cancer in Spain. Eur. J. Cancer Prev. 3:
313–320, 1994.
40. Martin-Moreno, J.M., Willett, W.C., Gorgojo, L., Banegas, J.R., Rodriguez-Artalejo F., Fernandez-
Rodrigues J.C., Maisonneuve, P., and Boyle, P. Dietary fat, olive oil intake and breast cancer risk. Int. J.
Cancer. 58: 774–780, 1994.
41. Trichopoulou, A., Katsouyanni, K., Stuver, S., Tzala, L., Gnardellis, C., Rimm, E., and Trichopoulos, D.
Consumption of olive oil and specific food groups in relation to breast cancer in Greece. J. Natl. Cancer.
Inst. 87: 110–116, 1995.
42. La Vecchia, C., Negri, E., Franceschi, S., Decarli, A., Giacosa, A., and Lipworth, L. Olive oil, other
dietary fats, and the risk of breast cancer (Italy). Cancer Causes Control. 6: 545–550, 1995.
43. Helsing, E. Traditional diets and disease patterns of the Mediterranean, circa 1960. Am. J. Clin. Nutr. 61
(Suppl.): 1329S–1337S, 1995.
44. Mezzanotte, G., Cislagni, C., Decarli, A., and LaVecchia, C. Cancer mortality in broad Italian geographic
areas, 1975–1977. Tumori 72: 145–152, 1986.
45. Hodge, A.M., English, D.R., McCredie, M.R.E., Severi, G., Boyle, P., Hopper, J.L., and Giles, G.G.
Foods, nutrients and prostate cancer. Cancer Causes Control. 15: 11–20, 2004.
46. Clinton, S.K. and Giovannucci, E. Diet, nutrition, and prostate cancer. Annu. Rev. Nutr. 18: 413–440,
1998.
47. Kolonel, L.N. Fat, meat and prostate cancer. Epidemiol. Rev. 23: 72–81, 2001.
48. Norrish, A.E., Jackson, R.T., Sharpe, S.J., and Skeaff, C.M. Men who consume vegetable oils rich in
monounsaturated fat: Their dietary patterns and risk of prostate cancer (New Zealand). Cancer Causes
Control 11: 609–615, 2000.
49. Franceschi, S., Favero, A., Conti, E., Talamini, R., Volpe, R., Negri, E., Barzan, L., and La Vecchia, C.
Food groups, oils and butter, and cancer of the oral cavity and pharynx. Br. J. Cancer. 80: 614–620, 1999.
50. Panagiotakos, D., and Polychronopoulos, E. The role of Mediterranean diet in the epidemiology of
metabolic syndrome: Converting epidemiology to clinical practice. Lipids Health Dis. 4: 7, 2005 http://
www/lipiworld.com/content/4/1/7
51. Hansen, B.C. The metabolic syndrome X. Ann. N. Y. Acad Sci. 892: 1–24, 1999.
52. Esposito, K., Marfella, R., Ciotola, M., DiPalo, C., Giugliano, F., Giuliano, G., D’Armiento, M., D’Andrea,
F., and Gingliano, D. Effect of a Mediterranean-style diet on endothelial dysfunction and markers of
vascular inflammation in the metabolic syndrome: A randomized trial. JAMA 292: 1440–1446, 2004.
53. Berbert, A.A., Kondo, C.R.M., Almendra, C.L., Matsuo, T., and Dichi, I. Supplementation of fish oil and
olive oil in patients with rheumatoid arthritis. Nutrition 21: 131–136, 2005.
54. Camuesco, D., Galvez, J., Nieto, A., Comalada, M., Rodrigues-Cabezas, M.E., Concha, A., Xaus, J., and
Zarzuelo, A. Dietary olive oil supplemented with fish oil, rich in EPA and DHA (n-3) polyunsaturated
fatty acids, attenuates colonic inflammation in rats with DDS-induced colitis. J. Nutr. 135: 687–694,
2005.
55. Perez-Jimenez, F. International conference on the health effect of virgin olive oil. Eur. J. Clin. Invest.
35: 421–424, 2005.
56. Nocella, C., Cammisotto, V., Fianchini, L., D’Amico, A., Novo, M., Castellani, V., Stefanini, L., Violi, F.,
and Carnevale, R. Extra virgin olive oil and cardiovascular diseases: Benefits for human health. Endocr.
Metab. Immune Disord. Drug Targets 18:(1): 4–13, 2018.
57. Gambino, C.M., Accardi, G., Aiello, A., Candore, G., Dara-Guccione, G., Mirisola, M., Procopio, A.,
Taormina, G., and Caruso, C. Effect of extra virgin olive oil and table olives on the immune inflammatory
responses: Potential clinical applications. Endocr. Metab. Immune Disord. Drug Targets 18(1): 14–22,
2018.
58. Santangelo, C., Vari, R., Scazzocchio, B., De Sanctis, P., Giovannini, C., D’Archivio, M., and Masella, R.
Anti-inflammatory activity of extra virgin olive oil polyphenols: Which role in the prevention and treatment
of immune-mediated inflammatory diseases? Endocr. Metab. Immune Disord. Drug Targets 18(1): 36–50,
2018.
59. Soto-Alarcon, S.A., Valenzuela, R., Valenzuela, A., and Videla, L.A. Liver protective effects of extra
virgin olive oil: Interaction between its chemical composition and the cell-signaling pathways involved
in protection. Endocr. Metab. Immune Disord. Drug Targets 18(1): 75–84, 2018.
1. Derosa G and Maffioli P. Nutraceuticals for the treatment of metabolic diseases: Evidence from clinical
practice. Expert Rev Endocrinol Metab 2015;10(3):297–304.
2. Cicero AF and Colletti A. Role of phytochemicals in the management of metabolic syndrome.
Phytomedicine 2016;23(11):1134–1144.
3. Ginsberg HN. Insulin resistance and cardiovascular disease. J Clin Invest 2000;106:453–458.
4. Derosa G, Limas CP, Macías PC, Estrella A and Maffioli P. Dietary and nutraceutical approach to type 2
diabetes. Arch Med Sci 2014;10:336–344.
5. Pyörälä M, Miettinen H, Laakso M and Pyörälä K. Hyperinsulinemia predicts coronary heart disease risk
in healthy middle-aged men: The 22-year follow-up results of the Helsinki Policemen Study. Circulation
1998;98:398–404.
6. Chen J, Wildman RP, Hamm LL, Muntner P, Reynolds K, Whelton PK and He J; Third National Health
and Nutrition Examination Survey. Association between inflammation and insulin resistance in U.S.
nondiabetic adults: Results from the Third National Health and Nutrition Examination Survey. Diabetes
Care 2004;27(12):2960–2965.
7. Firenzuoli F, Gori L and Lombardo G. The medicinal mushroom Agaricus blazei Murill: Review of
literature and pharmaco-toxicological problems. eCAM 2008;5:3–15.
8. Naohito O, Mai F, Noriko NM, Yoshiyuki A, Masuro M and Toshiro Y. Antitumor β-glucan from the
cultured fruit body of Agaricus blazei. Biol Pharm Bull 2001;24:820–828.
9. Sorimachi K and Koge T. Agaricus blazei water extracts as alternative medicines. Curr Pharm Anal
2008;4:39–43.
10. Vincent M, Philippe E, Everard A, Kassis N, Rouch C, Denom J, Takeda Y et al. Dietary supplementation
with Agaricus blazei Murill extract prevents diet-induced obesity and insulin resistance in rats. Obesity
(Silver Spring) 2013;21(3):553–561.
11. Cui X, Yao XR and Li SL. Analysis of nutritional components in three edible and medicinal plants of
Amorphophallus blume. Acta Nutr Sin 1992;14:221–224.
12. Sun GZ, Huang MS, Wang X, Li Y and Chen SN. An experimental research on the anti-obesity effect
of konjac flour. Acta Nutr Sin 1991;13:161–164.
13. Zhang MY, Huang CY, Wang X, Hong JR and Peng SS. The influence of konjac food on human lipid
metabolism. Acta Nutr Sin 1989;11:25–29.
14. Huang CY, Zhang MY, Peng SS, Hong JR, Wang X and Jiang HJ. Effect of konjac food on the blood
glucose level in diabetics. Acta Nutr Sin 1989;11:360–666.
15. Mao CP, Xie ML and Gu ZL. Effects of konjac extract on insulin sensitivity in high fat diet rats.
Acta Pharmacol Sin 2002;23(9):855–859.
16. Paradis ME, Couture P and Lamarche B. A randomised crossover placebo-controlled trial investigating
the effect of brown seaweed (Ascophyllum nodosum e Fucus vesiculosus) on postchallenge plasma
glucose and insulin levels in men and women. Appl Physiol Nutr Metab 2011;36:913–919.
17. Roy MC, Anguenot R, Fillion C, Beaulieu M, Bèrubé C and Richard D. Effect of a commercially-
available algal phlorotannins extract on digestive enzymes and carbohydrate absorption in vivo. Food Res
Int 2011;44:3026–3029.
18. Derosa G, Cicero AFG, D’Angelo A and Maffioli P. Ascophyllum nodosum and Fucus vesiculosus
on glycemic status and on endothelial damage markers in dysglicemic patients. Phytother Res
2019;33(3):791–797.
19. Sadiq Butt M, Tahir-Nadeem M, Khan MK, Shabir R and Butt MS. Oat: Unique among the cereals.
Eur J Nutr 2008;47:68–79.
20. Battilana P, Ornstein K, Minehira K, Schwarz JM, Acheson K, Schneiter P, Burri J, Jéquier E and Tappy L.
Mechanisms of action of beta-glucan in postprandial glucose metabolism in healthy men. Eur J Clin Nutr
2001;55:327–333.
21. Tappy L, Gügolz E and Würsch P. Effects of breakfast cereals containing various amounts of beta-glucan
fibers on plasma glucose and insulin responses in NIDDM subjects. Diabetes Care 1996;19:831–834.
22. Tapola N, Karvonen H, Niskanen L, Mikola M and Sarkkinen E. Glycemic responses of oat bran products
in type 2 diabetic patients. Nutr Metab Cardiovasc Dis 2005;15:255–261.
23. Pick ME, Hawrysh ZJ, Gee MI, Toth E, Garg ML and Hardin RT. Oat bran concentrate bread products
improve long-term control of diabetes: A pilot study. J Am Diet Assoc 1996;96:1254–1261.
24. Nazare JA, Normand S, Oste Triantafyllou A, Brac de la Perrière A, Desage M and Laville M. Modulation
of the postprandial phase by beta-glucan in overweight subjects: Effects on glucose and insulin kinetics.
Mol Nutr Food Res 2009;53:361–369.
25. Beck EJ, Tapsell LC, Batterham MJ, Tosh SM and Huang XF. Oat beta-glucan supplementation does not
enhance the effectiveness of an energy-restricted diet in overweight women. Br J Nutr 2010;103:1212–1222.
26. Di Pierro F, Putignano P, Villanova N, Montesi L, Moscatiello S and Marchesini G. Preliminary study
about the possible glycemic clinical advantage in using a fixed combination of Berberis aristata and
Silybum marianum standardized extracts versus only Berberis aristata in patients with type 2 diabetes.
Clin Pharmacol 2013;5:167–174.
27. Derosa G, Bonaventura A, Bianchi L, Romano D, D’Angelo A, Fogari E and Maffioli P. Effects of
Berberis aristata/Silybum marianum association on metabolic parameters and adipocytokines in
overweight dyslipidemic patients. J Biol Regul Homeost Agents 2013;27(3):717–728.
28. Costello RB, Dwyer JT, Saldanha L, Bailey RL, Merkel J and Wambogo E. Do cinnamon supplements have
a role in glycemic control in type 2 diabetes? A narrative review. J Acad Nutr Diet 2016;116(11):1794–1802.
29. Beejmohun V, Peytavy-Izard M, Mignon C, Muscente-Paque D, Deplanque X, Ripoll C and Chapal N. Acute
effect of Ceylon cinnamon extract on postprandial glycemia: Alpha-amylase inhibition, starch tolerance test in
rats, and randomized crossover clinical trial in healthy volunteers. BMC Complement Altern Med 2014;14:351.
30. Shrivastava A, Longia GS, Singh SP and Joshi LD. Hypoglycemic and hypolipidemic effect of Cyamopsis
tetragonoloba (guar) in normal and diabetic rats. Ind J Physiol Pharmacol 1987;31:77–83.
31. Mukhtar HM, Ansari SH, Bhat ZA and Naved T. Antihyperglycemic activity of Cyamopsis tetragonoloba
beans on blood glucose levels in alloxan-induced diabetic rats. Pharm Biol 2006;44:10–13.
32. Tormo MA, Gil-Exojo I, Romero de Tejada A and Campillo JE. White bean amylase inhibitor
administered orally reduces glycaemia in type 2 diabetic rats. Br J Nutr 2006;96:539–544.
33. Bundy R, Walker AF, Middleton RW, Wallis C and Simpson HC. Artichoke leaf extract (Cynara
scolymus) reduces plasma cholesterol in otherwise healthy hypercholesterolemic adults: A randomized,
double blind placebo controlled trial. Phytomedicine 2008;a15:668–675.
34. Arion WJ, Canfield WK, Ramos FC, Schindler PW, Burger HJ, Hemmerle H, Schubert G, Below P
and Herling AW. Chlorogenic acid and hydroxynitrobenzaldehyde: New inhibitors of hepatic glucose
6-phosphatase. Arch Biochem Biophys 1997;339:315–322.
35. Matsui T, Ogunwande IA, Abesundara KJ and Matsumoto K. Anti-hyperglycemic potential of natural
products. Mini Rev Med Chem 2006;6:349–356.
36. Panahi Y, Hosseini MS, Khalili N, Naimi E, Soflaei SS, Majeed M and Sahebkar A. Effects of
supplementation with curcumin on serum adipokine concentrations: A randomized controlled trial.
Nutrition 2016;32(10):1116–1122.
37. Luan J, Wareham NJ, Sharp SJ, O’Rahilly S, Balkau B, Flyvbjerg A, Walker M, Højlund K, Nolan
JJ; European Group for the Study of Insulin Resistance: Relationship between Insulin Sensitivity and
Cardiovascular Disease Risk Study Group, Savage DB. Correlation of the leptin: Adiponectin ratio with
measures of insulin resistance in non-diabetic individuals. Diabetologia 2009;52:2345–2349.
38. Zaletel J, Barlovic DP and Prezelj J. Adiponectin-leptin ratio: A useful estimate of insulin resistance in
patients with type 2 diabetes. J Endocrinol Invest 2010;33:514–518.
39. Satoh N, Naruse M, Usui T, Tagami T, Suganami T, Yamada K, Kuzuya H, Shimatsu A and Ogawa Y.
Leptin to-adiponectin ratio as a potential atherogenic index in obese type 2 diabetic patients. Diabetes
Care 2004;27:2488–2490.
40. Kappelle PJ, Dullaart RP, van Beek AP, Hillege HL and Wolffenbuttel BH. The plasma leptin/adiponectin
ratio predicts first cardiovascular event in men: A prospective nested case-control study. Eur J Intern
Med 2012;23:755–759.
41. Martínez-Abundis E, Méndez-Del Villar M, Pérez-Rubio KG, Zuñiga LY, Cortez-Navarrete M, Ramírez-
Rodriguez A and González-Ortiz M. Novel nutraceutic therapies for the treatment of metabolic syndrome.
World J Diabetes 2016;7(7):142–152.
42. Schroeder JA and Flannery-Schroeder E. Use of the herb Gymnema sylvestre to illustrate the principles
of gustatory sensation: An undergraduate neuroscience laboratory exercise. J Undergrad Neurosci Educ.
2005;3:A59–A62.
43. Warren RP, Warren RM and Weninger MG. Inhibition of the sweet taste by Gymnema sylvestre. Nature
1969;223:94–95.
44. Wang Y, Dawid C, Kottra G, Daniel H and Hofmann T. Gymnemic acids inhibit sodium-dependent
glucose transporter 1. J Agric Food Chem 2014;62:5925–5931.
45. Baskaran K, Kizar Ahamath B, Radha Shanmugasundaram K and Shanmugasundaram ER. Antidiabetic
effect of a leaf extract from Gymnema sylvestre in non-insulin-dependent diabetes mellitus patients.
J Ethnopharmacol 1990;30:295–300.
46. Shanmugasundaram ER, Rajeswari G, Baskaran K, Rajesh Kumar BR, Radha Shanmugasundaram K
and Kizar Ahmath B. Use of Gymnema sylvestre leaf extract in the control of blood glucose in insulin-
dependent diabetes mellitus. J Ethnopharmacol 1990;30:281–294.
47. Al-Romaiyan A, Liu B, Asare-Anane H, Maity CR, Chatterjee SK, Koley N, Biswas T et al. A novel
Gymnema sylvestre extract stimulates insulin secretion from human islets in vivo and in vitro. Phytother
Res 2010;24:1370–1376.
48. Blair RM, Henley EC and Tabor A. Soy foods have low glycemic and insulin response indices in normal
weight subjects. Nutr J 2006;5:35.
49. Mudryj AN, Yu N and Aukema HM. Nutritional and health benefits of pulses. Appl Physiol Nutr Metab
2014;39:1197–1204.
50. Thompson SV, Winham DM and Hutchins AM. Bean and rice meals reduce postprandial glycemic
response in adults with type 2 diabetes: A cross-over study. Nutr J 2012;11:23.
51. Ko KP. Isoflavones: Chemistry, analysis, functions and effects on health and cancer. Asian Pac J Cancer
Prev 2014;15:7001–7010.
52. Kim UH, Yoon JH, Li H, Kang JH, Ji HS, Park KH, Shin DH, Park HY and Jeong TS. Pterocarpan-
enriched soy leaf extract ameliorates insulin sensitivity and pancreatic β-cell proliferation in type 2
diabetic mice. Molecules 2014;19:18493–18510.
53. Choi MS, Ryu R, Seo YR, Jeong TS, Shin DH, Park YB, Kim SR and Jung UJ. The beneficial effects
of soybean (Glycine max (L.) Merr.) leaf extracts in adults with prediabetes: A randomized placebo
controlled trial. Food Funct 2014;5:1621–1630.
54. Choquette S, Riesco E, Cormier E, Dion T, Aubertin-Leheudre M and Dionne IJ. Effects of soya isoflavones
and exercise on body composition and clinical risk factors of cardiovascular diseases in overweight
postmenopausal women: A 6-month double-blind controlled trial. Br J Nutr 2011;105:1199–1209.
55. Klein GA, Stefanuto A, Boaventura BC, de Morais EC, Cavalcante Lda S, de Andrade F, Wazlawik E,
Di Pietro PF, Maraschin M and da Silva EL. Mate tea (Ilex paraguariensis) improves glycemic and lipid
profiles of type 2 diabetes and pre-diabetes individuals: A pilot study. J Am Coll Nutr 2011;30(5):320–332.
56. Andersen T and Fogh J. Weight loss and delayed gastric emptying following a South American herbal
preparation in overweight patients. J Hum Nutr Diet 2001;14(3):243–250.
57. Klein G, Kim J, Himmeldirk K, Cao Y and Chen X. Antidiabetes and anti-obesity activity of
Lagerstroemia speciosa. Evid Based Complement Alternat Med 2007;4(4):401–407.
58. Judy WV, Hari SP, Stogsdill WW, Judy JS, Naguib YM and Passwater R. Antidiabetic activity of a
standardized extract (Glucosol) from Lagerstroemia speciosa leaves in type II diabetics. A dose
dependence study. J Ethnopharmacol 2003;87:115–117.
59. Yin J, Zhang H and Ye J. Traditional Chinese medicine in treatment of metabolic syndrome. Endocr Metab
Immune Disord Drug Targets 2008;8:99–111.
60. Ma C, Yu H, Xiao Y and Wang H. Momordica charantia extracts ameliorate insulin resistance by regulating
the expression of SOCS-3 and JNK in type 2 diabetes mellitus rats. Pharm Biol 2017;55(1):2170–2177.
61. Chan EW, Lye PY and Wong SK. Phytochemistry, pharmacology, and clinical trials of Morus alba.
Chin J Nat Med 2016;14(1):17–30.
62. Griffith P. The origins of an important cactus crop, Opuntia ficusindica (cactacea): New molecular
evidence. Am J Bot 2004;91(11):1915–1921.
63. Stintzing FC and Carle R. Cactus stems (Opuntia spp.): A review on their chemistry, technology, and
uses. Mol Nutr Food Res 2005;49(2):175–194.
64. Santos-Zea L, Gutierrez-Uribe JA and Serna-Saldivar SO. Comparative analyses of total phenols,
antioxidant activity, and flavonol glycoside profile of cladode fluors from different varieties of Opuntia
spp. J Agric Food Chem 2011;59(13):7054–7061.
65. Zhang Y, Lu S and Liu YY. Effect of Panax quinquefolius saponin on insulin sensitivity in patients
of coronary heart disease with blood glucose abnormality. Zhongguo Zhong Xi Yi Jie He Za Zhi
2007;27(12):1066–1069.
66. Baintner K, Kiss P, Pfüller U, Bardocz S and Pusztai A. Effect of orally and intraperitoneally administered
plant lectins on food consumption of rats. Acta Physiol Hung 2003;90:97–107.
67. Cicero AF, Derosa G and Gaddi A. What do herbalists suggest to diabetic patients in order to improve
glycemic control? Evaluation of scientific evidence and potential risks. Acta Diabetol 2004;41(3):91–98.
68. Cicero AF, Derosa G, Manca M, Bove M, Borghi C and Gaddi AV. Different effect of psyllium and guar
dietary supplementation on blood pressure control in hypertensive overweight patients: A six-month,
randomized clinical trial. Clin Exp Hypertens 2007;29(6):383–394.
69. Yang J, Wang HP, Zhou L and Xu CF. Effect of dietary fiber on constipation: A meta analysis. World J
Gastroenterol 2012;18(48):7378–7383.
70. Gibb RD, McRorie JW Jr, Russell DA, Hasselblad V and D’Alessio DA. Psyllium fiber improves glycemic
control proportional to loss of glycemic control: A meta-analysis of data in euglycemic subjects, patients
at risk of type 2 diabetes mellitus, and patients being treated for type 2 diabetes mellitus. Am J Clin Nutr
2015;102(6):1604–1614.
71. Ritu M and Nandini J. Nutritional composition of Stevia rebaudiana, a sweet herb, and its hypoglycaemic
and hypolipidaemic effect on patients with non-insulin dependent diabetes mellitus. J Sci Food Agric
2016;96(12):4231–4234.
72. Derosa G and Maffioli P. The cardiometabolic risk: A new concept for old diseases. Nutrafoods
2019;1:40–43.
73. Vijayakumar MV, Singh S, Chhipa RR and Bhat MK. The hypoglycaemic activity of fenugreek
seed extract is mediated through the stimulation of an insulin signalling pathway. Br J Pharmacol
2005;146:41–48.
74. Broca C, Manteghetti M, Gross R, Baissac Y, Jacob M, Petit P, Sauvaire Y and Ribes G. 4-hydroxyisoleucine:
Effects of synthetic and natural analogues on insulin secretion. Eur J Pharmacol 2000;390:339–345.
75. Alamdari KA, Choobineh S and Jadidi JP. Antidiabetic effects of exercise and fenugreek supplementation
in males with NIDDM. Medicina Dello Sport 2009;62:315–324.
76. Sharma RD. Effect of fenugreek seeds and leaves on blood-glucose and serum-insulin responses in
human-subjects. Nutr Res 1986;6:1353–1364.
77. Kassaian N, Azadbakht L, Forghani B and Amini M. Effect of fenugreek seeds on blood glucose and
lipid profiles in type 2 diabetic patients. Int J Vitam Nutr Res 2009;79:34–39.
78. Gopalpura PB, Jayanthi C and Dubey S. Effect of Trigonella foenum-graecum seeds on the glycemic
index of food: A clinical evaluation. Int J Diab Dev Ctries 2007;27:41–45.
79. Madar Z, Abel R, Samish S and Arad J. Glucose-lowering effect of fenugreek in non-insulin dependent
diabetics. Eur J Clin Nutr 1988;42:51–54.
80. Sharma RD and Raghuram TC. Hypoglycemic effect of fenugreek seeds in non-insulin-dependent
diabetic subjects. Nutr Res 1990;10:731–739.
81. Gupta A, Gupta R and Lal B. Effect of Trigonella foenum-graecum (fenugreek) seeds on glycaemic
control and insulin resistance in type 2 diabetes mellitus: A double blind placebo controlled study.
J Assoc Physicians India 2001;49:1057–1061.
82. Teixeira CC and Fuchs FD. The efficacy of herbal medicines in clinical models: The case of jambolan.
83. Prince MS, Kamalakkannan N and Menon VP. Syzigium cumini seed extracts reduce tissue damage in
diabetic rat brain. J Ethnopharmacol 2003;84:205–209.
84. Villasenor IM and Lamadrid MR. Comparative antihyperglycemic potentials of medicinal plants.
85. Kedar P and Chakrabarti CH. Effects of jambolan seed treatment on blood sugar, lipids and urea in
streptozotocin induced diabetes in rabbits. Indian J Physiol Pharmacol 1983;27:135–140.
86. Helmstadter A. Syzygium cumini (L.) Skeels (Myrtaceae) against diabetes—125 years of research.
Pharmazie 2008;63:91–101.
87. Grasso S, Bramanti V, Tomassoni D, Bronzi D, Malfa G, Traini E, Napoli M, Renis M, Amenta F and
Avola R. Effect of lipoic acid and α-glyceryl-phosphoryl-choline on astroglial cell proliferation and
differentiation in primary culture. J Neurosci Res 2014;92:86–94.
88. Derosa G, D’Angelo A, Romano D, Maffioli P. Clinical trial about a food supplement containing alpha
lipoic acid on oxidative stress markers in type 2 diabetic patients. Int J Mol Sci 2016;17(11):1802–1810.
89. McManus RM, Jumpson J, Finegood DT, Clandinin MT and Ryan EA. A comparison of the effects
of n-3 fatty acids from linseed oil and ﬁsh oil in well-controlled type II diabetes. Diabetes Care
1996;19:463–467.
90. Derosa G, Cicero AF, D’Angelo A, Borghi C and Maffioli P. Effects of n-3 PUFAs on fasting plasma
glucose and insulin resistance in patients with impaired fasting glucose or impaired glucose tolerance.
Biofactors 2016;42(3):316–322.
91. Derosa G, Cicero AFG, Fogari E, D’Angelo A, Bonaventura A and Maffioli P. Effects of n-3 PUFA on
insulin resistance after an oral fat load. Eur J Lipid Sci Technol 2011;113:950–960.
1. Cotter EW, Teixeira C, Bontrager A, Horton K, Soriano D. Low-income adults’ perceptions of farmers’
markets and community-supported agriculture programmes. Public Health Nutr. 2017;20:1452–1460.
2. Cawley J, Meyerhoefer C. The medical care costs of obesity: An instrumental variables approach.
J Health Econ. Elsevier B.V. 2012;31:219–230.
3. Finkelstein EA, Trogdon JG, Cohen JW, Dietz W. Annual medical spending attributable to obesity:
Payer-and service-specific estimates. Health Aff. 2009;28.
4. Mizuno TM. Fat mass and obesity associated (FTO) gene and hepatic glucose and lipid metabolism.
Nutrients. 2018;10:E1600.
5. Liu J, Yang X, Yu S, Zheng R. The leptin signaling. Adv Exp Med Biol. 2018;1090:123–144.
6. Austin GL, Ogden LG, Hill JO. Trends in carbohydrate, fat, and protein intakes and association with
energy intake in normal-weight, overweight, and obese individuals: 1971–2006. Am J Clin Nutr.
2011;93:836–843.
7. Hruby A, Hu FB. HHS public access. Pharmacoeconomics. 2015;33:673–689.
8. Slof-Op ‘t Landt MCT, van Furth EF, van Beijsterveldt CEM, Bartels M, Willemsen G, de Geus EJ,
Ligthart L, Boomsma DI. Prevalence of dieting and fear of weight gain across ages: A community sample
from adolescents to the elderly. Int J Public Health. 2017;62:911–919.
9. Santos I, Sniehotta FF, Marques MM, Carraça EV, Teixeira PJ. Prevalence of personal weight control
attempts in adults: a systematic review and meta-analysis. Obesity Reviews. 2017;18(1):32–50.
10. Piernas C, Aveyard P, Jebb SA. Recent trends in weight loss attempts: Repeated cross-sectional analyses
from the health survey for England. Int J Obes. 2016;40:1754–1759.
11. Arciero PJ, Ormsbee MJ, Gentile CL, Nindl BC, Brestoff JR, Ruby M. Increased protein intake and meal
frequency reduces abdominal fat during energy balance and energy deficit. Obesity. 2013;21:1357–1366.
12. Arciero PJ, Edmonds R, He F, Ward E, Gumpricht E, Mohr A, Ormsbee MJ, Astrup A. Protein-pacing
caloric-restriction enhances body composition similarly in obese men and women during weight loss
and sustains efficacy during long-term weight maintenance. Nutrients. 2016;8:476.
13. Zuo L, He F, Tinsley GM, Pannell BK, Ward E, Arciero PJ. Comparison of high-protein, intermittent
fasting low-calorie diet and heart healthy diet for vascular health of the obese. Front Physiol. 2016;7:350.
14. Yudkin J. Diet and coronary heart disease. Br Med J. 1974;4:227.
15. Brown W. Dietary recommendations to prevent coronary heart disease. Ann N Y Acad Sci.
1990;598:376–388.
16. USDA, U.S. Dept. of Health and Human Services. Nutrition and Your Health: Dietary Guidelines for
Americans. 1980.
17. Ogden CL, Fryar CD, Hales CM, Carroll MD, Aoki Y, Freedman DS. Differences in obesity prevalence by
demographics and urbanization in US Children and Adolescents, 2013–2016. JAMA 2018;319:2410–2418.
18. Hales CM, Fryar CD, Carroll MD, Freedman DS, Aoki Y, Ogden CL. Differences in obesity prevalence
by demographic characteristics and urbanization level among adults in the United States, 2013–2016.
JAMA 2018;319:2419–2429.
19. Miles-Chan JL, Dulloo AG, Schutz Y. Fasting substrate oxidation at rest assessed by indirect calorimetry:
Is prior dietary macronutrient level and composition a confounder. Int J Obes. 2015;39:1114–1117.
20. Jung CH, Choi KM. Impact of high-carbohydrate diet on metabolic parameters in patients with type 2
diabetes. Nutrients. 2017;9.
21. Noakes TD, Windt J. Evidence that supports the prescription of low-carbohydrate high-fat diets: A
narrative review. Br J Sports Med. 2017;51(2):133–139.
22. Popkin BM, Adair LS, Ng SW. Global nutrition transition and the pandemic of obesity in developing
countries. Nutr Rev. 2012;70:3–21.
23. Leidy HJ, Armstrong CLH, Tang M, Mattes RD, Campbell WW. The influence of higher protein intake and
greater eating frequency on appetite control in overweight and obese men. Obesity. 2010;18:1725–1732.
24. Kim I-Y, Schutzler S, Schrader A, Spencer H, Kortebein P, Deutz NEP, Wolfe RR, Ferrando AA.
Quantity of dietary protein intake, but not pattern of intake, affects net protein balance primarily through
differences in protein synthesis in older adults. AJP Endocrinol Metab. 2015;308:E21–E28.
25. Arciero PJ, Baur D, Connelly S, Ormsbee MJ. Timed-daily ingestion of whey protein and exercise
training reduces visceral adipose tissue mass and improves insulin resistance: the PRISE study. J Appl
Physiol. 2014;117:1–10.
26. Arciero PJ, Ives SJ, Norton C, Escudero D, Minicucci O, O’Brien G, Paul M et al. Protein-pacing and
multi-component exercise training improves physical performance outcomes in exercise-trained women:
The PRISE 3 study. Nutrients. 2016;8.
27. Ives SJ, Norton C, Miller V, Minicucci O, Robinson J, O’Brien G, Escudero D et al. Multi-modal exercise
training and protein-pacing enhances physical performance adaptations independent of growth hormone
and BDNF but may be dependent on IGF-1 in exercise-trained men. Growth Horm IGF Res. 2017;32:60–70.
28. Arciero PJ, Edmonds RC, Bunsawat K, Gentile CL, Ketcham C, Darin C, Renna M, Zheng Q, Zhang
JZ, Ormsbee MJ. Protein-pacing from food or supplementation improves physical performance in
overweight men and women: The PRISE 2 study. Nutrients. 2016;8.
29. Inoue Y, Qin B, Poti J, Sokol R, Gordon-Larsen P. Epidemiology of obesity in adults: Latest trends.
Curr Obes Rep. 2018;7:276–288.
30. Brevard PB, Ricketts CD. Residence of college students affects dietary intake, physical activity, and
serum lipid levels. J Am Diet Assoc. 1996;96:35–38.
31. Beresford TP. Non-starter lactic acid bacteria (NSLAB) and cheese quality. In: Dairy Process: Improving
Quality. Woodhead Publishing; 2003, pp. 448–469.
32. Dairy Council Digest, Health Enhancing Properties of Dairy Ingredients. 2001;72:7–12.
33. Boirie Y, Dangin M, Gachon P, Vasson M-P, Maubois J-L, Beaufrere B. Slow and fast dietary proteins
differently modulate postprandial protein accretion. Proc Natl Acad Sci. 1997;94:14930–14935.
34. Hall WL, Millward DJ, Long SJ, Morgan LM. Casein and whey exert different effects on plasma amino
acid profiles, gastrointestinal hormone secretion and appetite. Br J Nutr. 2003;89:239.
35. Blomstrand E, Hassmén P, Ekblom B, Newsholme EA. Administration of branched-chain amino acids
during sustained exercise—Effects on performance and on plasma concentration of some amino acids.
Eur J Appl Physiol Occup Physiol. 1991;63:83–88.
36. Trommelen J, van Loon LJC. Pre-sleep protein ingestion to improve the skeletal muscle adaptive response
to exercise training. Nutrients. 2016;8.
37. Kinsey AW, Ormsbee MJ. The health impact of nighttime eating: Old and new perspectives. Nutrients.
2015;7:2648–2662.
38. Report of the Dietary Guidelines Advisory Committee on the Dietary Guidelines for Americans. 2010.
39. Bray GA, Smith SR, De Jonge L, Xie H, Rood J, Martin CK, Most M, Brock C, Mancuso S, Redman LM.
Effect of dietary protein content on weight gain, energy expenditure, and body composition during
overeating: A randomized controlled trial. JAMA 2012;307:47–55.
40. Ebbeling CB, Swain JF, Feldman HA, Wong WW, Hachey DL, Garcia-Lago E, Ludwig DS.
Effects of dietary composition on energy expenditure during weight-loss maintenance. JAMA
2012;307:2627–2634.
41. Wycherley TP, Moran LJ, Clifton PM, Noakes M, Brinkworth GD. Effects of energy-restricted high-
protein, low-fat compared with standard-protein, low-fat diets: A meta-analysis of randomized controlled
trials. Am J Clin Nutr. 2012;96:1281–1298.
42. Santesso N, Akl EA, Bianchi M, Mente A, Mustafa R, Heels-Ansdell D, Schünemann HJ. Effects of
higher-versus lower-protein diets on health outcomes: A systematic review and meta-analysis. Eur J Clin
Nutr. 2012;66:780–788.
43. Arciero PJ, Gentile CL, Martin-Pressman R, Ormsbee MJ, Everett M, Zwicky L, Steele CA. Increased
dietary protein and combined high intensity aerobic and resistance exercise improves body fat distribution
and cardiovascular risk factors. Int J Sport Nutr Exerc Metab. 2006;16:373–392.
44. Arciero PJ, Gentile CL, Pressman R, Everett M, Ormsbee MJ, Martin J, Santamore J et al. Moderate
protein intake improves total and regional body composition and insulin sensitivity in overweight adults.
Metabolism. 2008;57:757–765.
45. Westerterp-Plantenga MS, Lemmens SG, Westerterp KR. Dietary protein—Its role in satiety, energetics,
weight loss and health. Br J Nutr. 2012;108.
46. Krieger JW, Sitren HS, Daniels MJ, Langkamp-Henken B. Effects of variation in protein and carbohydrate
intake on body mass and composition during energy restriction: A meta-regression. Am J Clin Nutr.
2006;83:260–274.
47. Larsen TM, Dalskov S-M, van Baak M, Jebb SA, Papadaki A, Pfeiffer AFH, Martinez JA et al. Diets
with high or low protein content and glycemic index for weight-loss maintenance. N Engl J Med.
2010;363:2102–2113.
48. Isken F, Klaus S, Petzke KJ, Loddenkemper C, Pfeiffer AFH, Weickert MO. Impairment of fat oxidation
under high- vs. low-glycemic index diet occurs before the development of an obese phenotype. Am J
Physiol Metab. 2010;298:E287–E295.
49. Soenen S, Martens EAP, Hochstenbach-Waelen A, Lemmens SGT, Westerterp-Plantenga MS. Normal
protein intake is required for body weight loss and weight maintenance, and elevated protein intake for
additional preservation of resting energy expenditure and fat free mass. J Nutr. 2013;143:591–596.
50. Aragon AA, Schoenfeld BJ, Wildman R, Kleiner S, VanDusseldorp T, Taylor L, Earnest CP et al.
International society of sports nutrition position stand: Diets and body composition. J Int Soc Sports
Nutr. 2017;14:16.
51. Jéquier E. Pathways to obesity. Int J Obes. 2002;26:S12–S17.
52. Areta JL, Burke LM, Ross ML, Camera DM, West DWD, Broad EM, Jeacocke NA et al. Timing and
distribution of protein ingestion during prolonged recovery from resistance exercise alters myofibrillar
protein synthesis. J Physiol. 2013;591:2319–2331.
53. Phillips SM, Moore DR, Tang JE. A critical examination of dietary protein requirements, benefits, and
excesses in athletes. Int J Sport Nutr Exerc Metab. 2007;17(Suppl):S58–S76.
54. Millward DJ, Fereday A, Gibson NR, Pacy PJ. Post-prandial protein metabolism. Bailliere’s Clin
Endocrinol Metab. 1996;10(4):533–549.
55. Acheson KJ, Blondel-Lubrano A, Oguey-Araymon S, Beaumont M, Emady-Azar S, Ammon-Zufferey
C, Monnard I, Pinaud S, Nielsen-Moennoz C, Bovetto L. Protein choices targeting thermogenesis and
metabolism. Am J Clin Nutr. 2011;93:525–534.
56. Norton LE, Layman DK, Bunpo P, Anthony TG, Brana DV, Garlick PJ. The leucine content of a complete
meal directs peak activation but not duration of skeletal muscle protein synthesis and mammalian target
of rapamycin signaling in rats. J Nutr. 2009;139:1103–1109.
57. Pasiakos SM, McClung HL, McClung JP, Margolis LM, Andersen NE, Cloutier GJ, Pikosky MA, Rood
JC, Fielding RA, Young AJ. Leucine-enriched essential amino acid supplementation during moderate
steady state exercise enhances postexercise muscle protein synthesis. Am J Clin Nutr. 2011;94:809–818.
58. Churchward-Venne TA, Breen L, Di Donato DM, Hector AJ, Mitchell CJ, Moore DR, Stellingwerff T
et al. Leucine supplementation of a low-protein mixed macronutrient beverage enhances myofibrillar
protein synthesis in young men: A double-blind, randomized trial1–3. Am J Clin Nutr. 2014;99:276–286.
59. Anthony JC, Anthony TG, Kimball SR, Jefferson LS. Symposium: Leucine as a nutritional signal. J Nutr.
2001;131:856–860.
60. Moore DR, Robinson MJ, Fry JL, Tang JE, Glover EI, Wilkinson SB, Prior T, Tarnopolsky MA, Phillips
SM. Ingested protein dose response of muscle and albumin protein synthesis after resistance exercise in
young men. Am J Clin Nutr. 2009;89:161–168.
61. Drummond SE, Crombie NE, Cursiter MC, Kirk TR. Evidence that eating frequency is inversely related
to body weight status in male, but not female, non-obese adults reporting valid dietary intakes. Int J Obes.
1998;22:105–112.
62. Fábry P, Hejl Z, Fodor J, Braun T, Zvolánková K. The frequency of meals its relation to overweight,
hypercholesterolæmia, and decreased glucose-tolerance. Lancet. 1964;284:614–615.
63. Ruby M, Repka CP, Arciero PJ. Comparison of protein-pacing alone or combined with yoga/stretching
and resistance training on glycemia, total and regional body composition, and aerobic fitness in
overweight women. J Phys Act Heal. 2016;13:754–764.
64. Layman DK. Protein quantity and quality at levels above the RDA improves adult weight loss. J Am Coll
Nutr. 2004;23:631S–636S.
65. Kerksick CM, Arent S, Schoenfeld BJ, Stout JR, Campbell B, Wilborn CD, Taylor L et al. International
society of sports nutrition position stand: Nutrient timing. J Int Soc Sports Nutr. 2017;14.
66. Layman D, Shiue H, Sather C, Erickson D, Baum J. Increased dietary protein modifies glucose and
insulin homeostasis in adult women during weight loss. J Nutr. 2003;133:405–410.
67. Wolever TMS, Mehling C. Long-term effect of varying the source or amount of dietary carbohydrate on
postprandial plasma glucose, insulin, triacylglycerol, and free fatty acid concentrations in subjects with
impaired glucose tolerance. Am J Clin Nutr. 2003;77:612–621.
68. Arciero PJ, Vukovich MD, Holloszy JO, Racette SB, Kohrt WM. Comparison of short-term diet
and exercise on insulin action in individuals with abnormal glucose tolerance. J Appl Physiol.
1999;86:1930–1935.
69. Numata K, Tanaka K, Saito M, Shishido T, Inoue S. Very low calorie diet-induced weight loss reverses
exaggerated insulin secretion in response to glucose, arginine and glucagon in obesity. Int J Obes Relat
Metab Disord J Int Assoc Study Obes. 1993;12:103–108.
70. Medina EA, Afsari RR, Ravid T, Sianna Castillo S, Erickson KL, Goldkorn T. Tumor necrosis factor-α
decreases Akt protein levels in 3T3-L1 adipocytes via the caspase-dependent ubiquitination of Akt.
Endocrinology. 2005;146:2726–2735.
71. Katz J, Tayek JA, Barreye J, Bevilarqa S, Defronzo RA, Ferrannini E, Chandramouli V
et al. Gluconeogenesis and the Cori cycle in 12-, 20-, and 40-h-fasted humans. Am J Physiol.
1998;275:E537–E542.
72. Dong JY, Zhang ZL, Wang PY, Qin LQ. Effects of high-protein diets on body weight, glycaemic control,
blood lipids and blood pressure in type 2 diabetes: Meta-analysis of randomised controlled trials. Br J
Nutr. 2013;110:781–789.
73. Holloszy JO, Hansen PA. Regulation of glucose transport into skeletal muscle. Reviews of physiology
biochemistry and pharmacology. Berlin, Heidelberg: Springer Berlin Heidelberg; 1996, 128, 99–193.
74. Utriainen T, Mäkimattila S, Virkamäki A, Lindholm H, Sovijärvi A, Yki-Järvinen H. Physical fitness
and endothelial function (nitric oxide synthesis) are independent determinants of insulin-stimulated
blood flow in normal subjects. J Clin Endocrinol Metab. 1996;81:4258–4263.
75. De Zwaan M, Burgard MA, Schenck CH, Mitchell JE. Night time eating: A review of the literature. Eur
Eat Disord Rev. 2003;11:7–24.
76. KG B, KJ R. Staying up late and eating in the evening: Recipe for obesity? Sleep. 2011;34:A162.
77. Ormsbee MJ, Gorman KA, Miller EA, Baur DA, Eckel LA, Contreras RJ, Panton LB, Spicer MT.
Nighttime feeding likely alters morning metabolism but not exercise performance in female athletes.
Appl Physiol Nutr Metab. 2016;41:719–727.
78. Romon M, Edme JL, Boulenguez C, Lescroart JL, Frimat P. Circadian variation of diet-induced
thermogenesis. Am J Clin Nutr. 1993;57:476–480.
79. Res PT, Groen B, Pennings B, Beelen M, Wallis GA, Gijsen AP, Senden JMG, Van Loon LJC.
Protein ingestion before sleep improves postexercise overnight recovery. Med Sci Sports Exerc.
2012;44:1560–1569.
80. Groen BBL, Res PT, Pennings B, Hertle E, Senden JMG, Saris WHM, van Loon LJC. Intragastric protein
administration stimulates overnight muscle protein synthesis in elderly men. AJP Endocrinol Metab.
2012;302:E52–E60.
81. Madzima TA, Panton LB, Fretti SK, Kinsey AW, Ormsbee MJ. Night-time consumption of protein or
carbohydrate results in increased morning resting energy expenditure in active college-aged men. Br J
Nutr. 2014;111:71–77.
82. Kinsey AW, Eddy WR, Madzima TA, Panton LB, Arciero PJ, Kim JS, Ormsbee MJ. Influence of night-
time protein and carbohydrate intake on appetite and cardiometabolic risk in sedentary overweight and
obese women. Br J Nutr. 2014;112:320–327.
83. Ormsbee MJ, Kinsey AW, Eddy WR, Madzima TA, Arciero PJ, Figueroa A, Panton LB. The influence
of nighttime feeding of carbohydrate or protein combined with exercise training on appetite and
cardiometabolic risk in young obese women. Appl Physiol Nutr Metab. 2015;40:37–45.
84. Lay AHH, Crabtree DR, Campbell TG, Dreczkowski GM, Galloway SDR, Tipton KD, Witard OC. A
bedtime milk snack does not impact RMR, substrate utilisation and appetite the following morning in
mildly overweight males. Br J Nutr. 2018;119:1355–1365.
85. Leyh SM, Willingham BD, Baur DA, Panton LB, Ormsbee MJ. Pre-sleep protein in casein supplement
or whole-food form has no impact on resting energy expenditure or hunger in women. Br J Nutr.
2018;120:988–994.
86. Ormsbee MJ, Ward EG, Bach CW, Arciero PJ, McKune AJ, Panton LB. The impact of a pre-loaded multi-
ingredient performance supplement on muscle soreness and performance following downhill running. J
Int Soc Sports Nutr. 2015;12.
87. Kinsey AW, Cappadona SR, Panton LB, Allman BR, Contreras RJ, Hickner RC, Ormsbee MJ. The effect
of casein protein prior to sleep on fat metabolism in obese men. Nutrients. 2016;8.
88. Holwerda AM, Kouw IW, Trommelen J, Halson SL, Wodzig WK, Verdijk LB, van Loon LJ. Physical
activity performed in the evening increases the overnight muscle protein synthetic response to presleep
protein ingestion in older men. J Nutr. 2016;146:1307–1324.
89. Dirks ML, Groen BBL, Franssen R, van Kranenburg J, van Loon LJC. Neuromuscular electrical
stimulation prior to presleep protein feeding stimulates the use of protein-derived amino acids for
overnight muscle protein synthesis. J Appl Physiol. 2017;122:20–27.
90. Holwerda AM, Overkamp M, Paulussen KJM, Smeets JSJ, van Kranenburg J, Backx EMP, Gijsen AP,
Goessens JPB, Verdijk LB, van Loon LJC. Protein supplementation after exercise and before sleep does
not further augment muscle mass and strength gains during resistance exercise training in active older
men. J Nutr. 2018;148:1723–1732.
91. Antonio J, Ellerbroek A, Peacock C, Silver T. Casein protein supplementation in trained men and women:
Morning versus evening. Int J Exerc Sci. 2017;10:479–486.
92. Joy J, Vogel R, Shane Broughton K, Kudla U, Kerr N, Davison J, Wildman R, DiMarco N. Daytime
and nighttime casein supplements similarly increase muscle size and strength in response to resistance
training earlier in the day: A preliminary investigation. J Int Soc Sports Nutr. 2018;15.
93. Burk A, Timpmann S, Medijainen L, Vähi M, Ööpik V. Time-divided ingestion pattern of casein-based
protein supplement stimulates an increase in fat-free body mass during resistance training in young
untrained men. Nutr Res. 2009;29:405–413.
94. Jäger R, Kerksick CM, Campbell BI, Cribb PJ, Wells SD, Skwiat TM, Purpura M et al. International
society of sports nutrition position stand: Protein and exercise. J Int Soc Sports Nutr. 2017;14.
95. Halton TL, Hu FB. The effects of high protein diets on thermogenesis, satiety and weight loss: A critical
review. J Am Coll Nutr. 2004;23:373–385.
96. Cuenca-Sanchez M, Navas-Carrillo D, Orenes-Pinero E. Controversies surrounding high-protein diet
intake: Satiating effect and kidney and bone health. Adv Nutr An Int Rev J. 2015;6:260–266.
97. Westerterp-Plantenga MS, Rolland V, Wilson SAJ, Westerterp KR. Satiety related to 24 h diet-induced
thermogenesis during high protein/carbohydrate vs. high fat diets measured in a respiration chamber.
Eur J Clin Nutr. 1999;53:495–502.
98. Lejeune MPGM, Westerterp KR, Adam TCM, Luscombe-Marsh ND, Westerterp-Plantenga MS. Ghrelin
and glucagon-like peptide 1 concentrations, 24-h satiety, and energy and substrate metabolism during a
high-protein diet and measured in a respiration chamber. Am J Clin Nutr. 2006;83:89–94.
99. Pencharz PB, Elango R, Wolfe RR. Recent developments in understanding protein needs—How much
and what kind should we eat? Appl Physiol Nutr Metab. 2016;41:577–580.
100. Phillips SM, Chevalier S, Leidy HJ. Protein “requirements” beyond the RDA: implications for optimizing
health. Appl Physiol Nutr Metab. 2016;41:565–572.
101. Wildman REC, Medeiros DM. Advanced human nutrition. 4th ed. Burlington, MA: Jones, Bartlett; 1999,
p. 608.
102. Bauer J, Biolo G, Cederholm T, Cesari M, Cruz-Jentoft AJ, Morley JE, Phillips S et al. Evidence-based
recommendations for optimal dietary protein intake in older people: A position paper from the prot-age
study group. J Am Med Dir Assoc. 2013;14:542–559.
103. Lemon PW. Is increased dietary protein necessary or beneficial for individuals with a physically active
lifestyle? Nutr Rev. 1996;54:S169–S175.
104. Bowtell JL, Leese GP, Smith K, Watt PW, Nevill A, Rooyackers O, Wagenmakers AJ, Rennie MJ.
Modulation of whole body protein metabolism, during and after exercise, by variation of dietary protein.
J Appl Physiol (Bethesda, Md.: 1985). 1998;85:1744–1752.
105. Anthony JC, Anthony TG, Layman DK. Leucine supplementation enhances skeletal muscle recovery in
rats following exercise. J Nutr. 1999;129:1102–1106.
106. Helms ER, Zinn C, Rowlands DS, Brown SR. A systematic review of dietary protein during caloric
restriction in resistance trained lean athletes: A case for higher intakes. Int J Sport Nutr Exercise Metab.
2014;24:127–138.
107. Antonio J, Peacock CA, Ellerbroek A, Fromhoff B, Silver T. The effects of consuming a high protein
diet (4.4 g/kg/d) on body composition in resistance-trained individuals. J Int Soc Sports Nutr. 2014;11.
108. Antonio J, Ellerbroek A, Silver T, Orris S, Scheiner M, Gonzalez A, Peacock CA. A high protein diet
(3.4 g/kg/d) combined with a heavy resistance training program improves body composition in healthy
trained men and women—A follow-up investigation. J Int Soc Sports Nutr. 2015;12.
109. Antonio J, Ellerbroek A, Silver T, Vargas L, Peacock C. The effects of a high protein diet on indices of
health and body composition—A crossover trial in resistance-trained men. J Int Soc Sports Nutr. 2016;13.
110. Antonio J, Ellerbroek A, Silver T, Vargas L, Tamayo A, Buehn R, Peacock CA et al. A high protein
diet has no harmful effects: A one-year crossover study in resistance-trained males. J Nutr Metab.
2016;2016:1–5.
111. Devries MC, Sithamparapillai A, Brimble KS, Banfield L, Morton RW, Phillips SM. Changes in kidney
function do not differ between healthy adults consuming higher- compared with lower- or normal-protein
diets: A systematic review and meta-analysis. J Nutr. 2018;148:1760–1775.
112. Layman DK, Evans E, Baum JI, Seyler J, Erickson DJ, Boileau RA. Dietary protein and exercise have
additive effects on body composition during weight loss in adult women. J Nutr. 2005;135:1903–1910.
113. Ormsbee MJ, Willingham BD, Marchant T, Binkley TL, Specker BL, Vukovich MD. Protein
supplementation during a 6-month concurrent training program: Effect on body composition and
muscular strength in sedentary individuals. Int J Sport Nutr Exerc Metab. 2018;28:619–628.
1. Jäger R, Purpura M, Shao A, Inoue T, Kreider RB. Analysis of the efficacy, safety, and regulatory status
of novel forms of creatine. Amino Acids. 2011 May;40:1369–83.
2. Kreider RB, Kalman DS, Antonio J, Ziegenfuss TN, Wildman R, Collins R, Candow DG, Kleiner SM,
Almada AL, Lopez HL. International Society of Sports Nutrition position stand: Safety and efficacy of
creatine supplementation in exercise, sport, and medicine. J Int Soc Sports Nutr. 2017;14:18.
3. Bertin M, Pomponi SM, Kokuhuta C, Iwasaki N, Suzuki T, Ellington WR. Origin of the genes for the
isoforms of creatine kinase. Gene. 2007 May 01;392:273–82.
4. Suzuki T, Mizuta C, Uda K, Ishida K, Mizuta K, Sona S, Compaan DM, Ellington WR. Evolution and
divergence of the genes for cytoplasmic, mitochondrial, and flagellar creatine kinases. J Mol Evol. 2004
Aug;59:218–26.
5. Sahlin K, Harris RC. The creatine kinase reaction: A simple reaction with functional complexity. Amino
Acids. 2011 May;40:1363–7.
6. Harris R. Creatine in health, medicine and sport: An introduction to a meeting held at Downing College,
University of Cambridge, July 2010. Amino Acids. 2011 May;40:1267–70.
7. Kerksick CM, Wilborn CD, Roberts MD, Smith-Ryan A, Kleiner SM, Jäger R, Collins R, Cooke M,
Davis JN et al. ISSN exercise & sports nutrition review update: Research & recommendations. J Int Soc
Sports Nutr. 2018 Aug 1;15:38.
8. Meyers S. Sports nutrition market growth watch. Natural Products Insidier: Informa Exhibitions; 2016.
9. Buford TW, Kreider RB, Stout JR, Greenwood M, Campbell B, Spano M, Ziegenfuss T, Lopez H,
Landis J, Antonio J. International Society of Sports Nutrition position stand: Creatine supplementation
and exercise. J Int Soc Sports Nutr. 2007 Aug 30;4:6.
10. Kreider RB, Jung YP. Creatine supplementation in exercise, sport, and medicine. J Exerc Nutr Biochem.
2011;15:53–69.
11. Hultman E, Soderlund K, Timmons JA, Cederblad G, Greenhaff PL. Muscle creatine loading in men.
J Appl Physiol (1985). 1996 Jul;81:232–7.
12. Green AL, Hultman E, Macdonald IA, Sewell DA, Greenhaff PL. Carbohydrate ingestion augments
skeletal muscle creatine accumulation during creatine supplementation in humans. Am J Physiol. 1996
Nov;271:E821–6.
13. Balsom PD, Soderlund K, Ekblom B. Creatine in humans with special reference to creatine
supplementation. Sports Med. 1994 Oct;18:268–80.
14. Harris RC, Soderlund K, Hultman E. Elevation of creatine in resting and exercised muscle of normal
subjects by creatine supplementation. Clin Sci (Lond). 1992 Sep;83:367–74.
15. Negrisoli G, Del Corona L. Hydrosoluble organic salts of creatine. Italy patent 5973199. 1997.
16. Pischel I, Weiss S. New creatine pyruvate derivatives from crystallisation in polar solvents.
Germany. 1996.
17. Pischel I, Weiss S, Gloxhuber C, Mertschenk B. Creatine ascorbates and a method of producing them.
United States patent 5863939. 1999.
18. Abraham S, Jiang S. Process for preparing a creatine heterocyclic acid salt and method of use. United
States. 2005.
19. Godfraind T, Ghiradi P, Ferrari G, Cassagrade C. Creatinol-O-Phosphate having therapeutical action.
United States patent 4376117. 1983.
20. Gastner T, Krimmer HP, Guthner T, Sturm W. Use of guanidine compounds as physiological strengthening
agents in the form of nutritional supplements, animal feed additives, in cosmetics preparations and as
plant stimulants. United States patent 7867948. 2005.
21. Howard AN, Harris RC. Compositions containing creatine. United States patent 5968544. 1999.
22. Edgar G, Shiver HE. The equilibrium between creatine and creatinine, in aqueous solution: The effect
of hydrogen ion. J Am Chem Soc. 1925;47:1179–88.
23. Cannon JG, Orencole SF, Fielding RA, Meydani M, Meydani SN, Fiatarone MA, Blumberg JB, Evans
WJ. Acute phase reponse in exercise: Interaction of age and vitamin E on neutrophils and muscle enzyme
release. Am J Physiol. 1990;259:R1214–R9.
24. Persky AM, Brazeau GA, Hochhaus G. Pharmacokinetics of the dietary supplement creatine. Clin
Pharmacokinet. 2003;42:557–74.
25. Deldicque L, Decombaz J, Zbinden Foncea H, Vuichoud J, Poortmans JR, Francaux M. Kinetics of
creatine ingested as a food ingredient. Eur J Appl Physiol. 2008 Jan;102:133–43.
26. Brosnan ME, Brosnan JT. The role of dietary creatine. Amino Acids. 2016 Aug;48:1785–91.
27. Paddon-Jones D, Borsheim E, Wolfe RR. Potential ergogenic effects of arginine and creatine
supplementation. J Nutr. 2004 Oct;134:2888S–94S; discussion 95S.
28. Braissant O, Henry H, Beard E, Uldry J. Creatine deficiency syndromes and the importance of creatine
synthesis in the brain. Amino Acids. 2011 May;40:1315–24.
29. Wyss M, Braissant O, Pischel I, Salomons GS, Schulze A, Stockler S, Wallimann T. Creatine and creatine
kinase in health and disease--a bright future ahead? Subcell Biochem. 2007;46:309–34.
30. Braissant O, Beard E, Torrent C, Henry H. Dissociation of AGAT, GAMT and SLC6A8 in CNS:
Relevance to creatine deficiency syndromes. Neurobiol Dis. 2010 Feb;37:423–33.
31. Beard E, Braissant O. Synthesis and transport of creatine in the CNS: Importance for cerebral functions.
J Neurochem. 2010 Oct;115:297–313.
32. Sykut-Cegielska J, Gradowska W, Mercimek-Mahmutoglu S, Stockler-Ipsiroglu S. Biochemical and
clinical characteristics of creatine deficiency syndromes. Acta Biochim Pol. 2004;51:875–82.
33. Ganesan V, Johnson A, Connelly A, Eckhardt S, Surtees RA. Guanidinoacetate methyltransferase
deficiency: New clinical features. Pediatr Neurol. 1997 Sep;17:155–7.
34. Hanna-El-Daher L, Braissant O. Creatine synthesis and exchanges between brain cells: What can
be learned from human creatine deficiencies and various experimental models? Amino Acids. 2016
Aug;48:1877–95.
35. Benton D, Donohoe R. The influence of creatine supplementation on the cognitive functioning of
vegetarians and omnivores. Br J Nutr. 2011 Apr;105:1100–5.
36. Burke DG, Chilibeck PD, Parise G, Candow DG, Mahoney D, Tarnopolsky M. Effect of creatine
and weight training on muscle creatine and performance in vegetarians. Med Sci Sports Exerc. 2003
Nov;35:1946–55.
37. Kreider RB, Melton C, Rasmussen CJ, Greenwood M, Lancaster S, Cantler EC, Milnor P, Almada AL.
Long-term creatine supplementation does not significantly affect clinical markers of health in athletes.
Mol Cell Biochem. 2003 Feb;244:95–104.
38. Bender A, Klopstock T. Creatine for neuroprotection in neurodegenerative disease: End of story? Amino
Acids. 2016 Aug;48:1929–40.
39. Kreider RB. Effects of creatine supplementation on performance and training adaptations. Mol Cell
Biochem. 2003 Feb;244:89–94.
40. Casey A, Constantin-Teodosiu D, Howell S, Hultman E, Greenhaff PL. Creatine ingestion favorably
affects performance and muscle metabolism during maximal exercise in humans. Am J Physiol. 1996
Jul;271:E31–7.
41. Greenhaff PL, Casey A, Short AH, Harris R, Soderlund K, Hultman E. Influence of oral creatine
supplementation of muscle torque during repeated bouts of maximal voluntary exercise in man. Clin Sci
(Lond). 1993 May;84:565–71.
42. Vandenberghe K, Goris M, Van Hecke P, Van Leemputte M, Vangerven L, Hespel P. Long-term creatine
intake is beneficial to muscle performance during resistance training. J Appl Physiol (1985). 1997
Dec;83:2055–63.
43. Wallimann T, Tokarska-Schlattner M, Schlattner U. The creatine kinase system and pleiotropic effects
of creatine. Amino Acids. 2011 May;40:1271–96.
44. Kim HJ, Kim CK, Carpentier A, Poortmans JR. Studies on the safety of creatine supplementation. Amino
Acids. 2011 May;40:1409–18.
45. Longo N, Ardon O, Vanzo R, Schwartz E, Pasquali M. Disorders of creatine transport and metabolism.
Am J Med Genet C Semin Med Genet. 2011 Feb 15;157C:72–8.
46. Braissant O. Creatine and guanidinoacetate transport at blood-brain and blood-cerebrospinal fluid
barriers. J Inherit Metab Dis. 2012 Jul;35:655–64.
47. Patra S, Ghosh A, Roy SS, Bera S, Das M, Talukdar D, Ray S, Wallimann T, Ray M. A short review
on creatine-creatine kinase system in relation to cancer and some experimental results on creatine as
adjuvant in cancer therapy. Amino Acids. 2012 Jun;42:2319–30.
48. Santacruz L, Jacobs DO. Structural correlates of the creatine transporter function regulation: The
undiscovered country. Amino Acids. 2016 Aug;48:2049–55.
49. Steenge GR, Simpson EJ, Greenhaff PL. Protein- and carbohydrate-induced augmentation of whole body
creatine retention in humans. J Appl Physiol (1985). 2000 Sep;89:1165–71.
50. Greenwood M, Kreider RB, Earnest CP, Rasmussen C, Almada A. Differences in creatine retention
among three nutritional formulations of oral creatine supplements. J Exerc Physiol Online. 2003;6:37–43.
51. Schlattner U, Klaus A, Ramirez Rios S, Guzun R, Kay L, Tokarska-Schlattner M. Cellular
compartmentation of energy metabolism: Creatine kinase microcompartments and recruitment of B-type
creatine kinase to specific subcellular sites. Amino Acids. 2016 Aug;48:1751–74.
52. Ydfors M, Hughes MC, Laham R, Schlattner U, Norrbom J, Perry CG. Modelling in vivo creatine/
phosphocreatine in vitro reveals divergent adaptations in human muscle mitochondrial respiratory
control by ADP after acute and chronic exercise. J Physiol. 2016 Jun 01;594:3127–40.
53. Wallimann T, Schlosser T, Eppenberger HM. Function of M-line-bound creatine kinase as intramyofibrillar
ATP regenerator at the receiving end of the phosphorylcreatine shuttle in muscle. J Biol Chem. 1984 Apr
25;259:5238–46.
54. Wallimann T, Dolder M, Schlattner U, Eder M, Hornemann T, O’Gorman E, Ruck A, Brdiczka D. Some
new aspects of creatine kinase (CK): Compartmentation, structure, function and regulation for cellular
and mitochondrial bioenergetics and physiology. Biofactors. 1998;8:229–34.
55. Tarnopolsky MA, Parshad A, Walzel B, Schlattner U, Wallimann T. Creatine transporter and
mitochondrial creatine kinase protein content in myopathies. Muscle Nerve. 2001 May;24:682–8.
56. Campos-Ferraz PL, Gualano B, das Neves W, Andrade IT, Hangai I, Pereira RT, Bezerra RN, Deminice
R, Seelaender M, Lancha AH. Exploratory studies of the potential anti-cancer effects of creatine. Amino
Acids. 2016 Aug;48:1993–2001.
57. Balestrino M, Sarocchi M, Adriano E, Spallarossa P. Potential of creatine or phosphocreatine
supplementation in cerebrovascular disease and in ischemic heart disease. Amino Acids. 2016
Aug;48:1955–67.
58. Saraiva AL, Ferreira AP, Silva LF, Hoffmann MS, Dutra FD, Furian AF, Oliveira MS, Fighera MR,
Royes LF. Creatine reduces oxidative stress markers but does not protect against seizure susceptibility
after severe traumatic brain injury. Brain Res Bull. 2012 Feb 10;87:180–6.
59. Rahimi R. Creatine supplementation decreases oxidative DNA damage and lipid peroxidation induced
by a single bout of resistance exercise. J Strength Cond Res. 2011 Dec;25:3448–55.
60. Riesberg LA, Weed SA, McDonald TL, Eckerson JM, Drescher KM. Beyond muscles: The untapped
potential of creatine. Int Immunopharmacol. 2016 Aug;37:31–42.
61. Candow DG, Chilibeck PD, Forbes SC. Creatine supplementation and aging musculoskeletal health.
Endocrine. 2014 Apr;45:354–61.
62. Tarnopolsky MA. Clinical use of creatine in neuromuscular and neurometabolic disorders. Subcell
Biochem. 2007;46:183–204.
63. Kley RA, Tarnopolsky MA, Vorgerd M. Creatine for treating muscle disorders. Cochrane Database Syst
Rev. 2011 Feb 16:CD004760.
64. Tarnopolsky MA. Potential benefits of creatine monohydrate supplementation in the elderly. Curr Opin
Clin Nutr Metab Care. 2000 Nov;3:497–502.
65. Candow DG, Vogt E, Johannsmeyer S, Forbes SC, Farthing JP. Strategic creatine supplementation and
resistance training in healthy older adults. Appl Physiol Nutr Metab. 2015 Jul;40:689–94.
66. Moon A, Heywood L, Rutherford S, Cobbold C. Creatine supplementation: Can it improve quality of life
in the elderly without associated resistance training? Curr Aging Sci. 2013 Dec;6:251–7.
67. Rawson ES, Venezia AC. Use of creatine in the elderly and evidence for effects on cognitive function in
young and old. Amino Acids. 2011 May;40:1349–62.
68. Candow DG. Sarcopenia: Current theories and the potential beneficial effect of creatine application
strategies. Biogerontology. 2011 Aug;12:273–81.
69. Candow DG, Chilibeck PD. Potential of creatine supplementation for improving aging bone health.
J Nutr Health Aging. 2010 Feb;14:149–53.
70. Greenwood M, Kreider RB, Greenwood L, Byars A. Cramping and injury incidence in collegiate football
players are reduced by creatine supplementation. J Athl Train. 2003 Sep;38:216–9.
71. Kreider RB, Wilborn CD, Taylor L, Campbell B, Almada AL, Collins R, Cooke M, Earnest CP,
Greenwood M et al. ISSN exercise & sport nutrition review: Research & recommendations. J Int Soc
Sports Nutr. 2010 Feb 02;7:7.
72. Rodriguez NR, DiMarco NM, Langley S, American Dietetic Association, Dietitians of Canada, American
College of Sports Medicine. Position of the American Dietetic Association, Dietitians of Canada, and
the American College of Sports Medicine: Nutrition and athletic performance. J Am Diet Assoc. 2009
Mar;109:509–27.
73. Thomas DT, Erdman KA, Burke LM. Position of the Academy of Nutrition and Dietetics, Dietitians of
Canada, and the American College of Sports Medicine: Nutrition and Athletic Performance. J Acad Nutr
Diet. 2016 Mar;116:501–28.
74. Geller AI, Shehab N, Weidle NJ, Lovegrove MC, Wolpert BJ, Timbo BB, Mozersky RP, Budnitz DS.
Emergency department visits for adverse events related to dietary supplements. N Engl J Med. 2015 Oct
15;373:1531–40.
75. Zorzela L, Boon H, Mior S, Yager J, Gross A, Vohra S. Serious adverse events associated with pediatric
complementary and alternative medicine. Eur J Integ Med. 2014;6:467–472.
76. FDA. CFSAN Adverse Event Reporting System (CAERS). 2017 [cited 2017 March 27, 2017]; Available
from: https://www.fda.gov/Food/ComplianceEnforcement/ucm494015.htm
77. Gualano B, Rawson ES, Candow DG, Chilibeck PD. Creatine supplementation in the aging population:
Effects on skeletal muscle, bone and brain. Amino Acids. 2016 Aug;48:1793–805.
78. Earnest CP, Almada AL, Mitchell TL. High-performance capillary electrophoresis-pure creatine
monohydrate reduces blood lipids in men and women. Clin Sci (Lond). 1996 Jul;91:113–8.
79. Kreider RB, Ferreira M, Wilson M, Grindstaff P, Plisk S, Reinardy J, Cantler E, Almada AL. Effects of
creatine supplementation on body composition, strength, and sprint performance. Med Sci Sports Exerc.
1998 Jan;30:73–82.
80. Deminice R, de Castro GS, Francisco LV, da Silva LE, Cardoso JF, Frajacomo FT, Teodoro BG, Dos
Reis Silveira L, Jordao AA. Creatine supplementation prevents fatty liver in rats fed choline-deficient
diet: A burden of one-carbon and fatty acid metabolism. J Nutr Biochem. 2015 Apr;26:391–7.
81. Deminice R, Cella PS, Padilha CS, Borges FH, da Silva LE, Campos-Ferraz PL, Jordao AA, Robinson JL,
Bertolo RF et al. Creatine supplementation prevents hyperhomocysteinemia, oxidative stress and cancer-
induced cachexia progression in Walker-256 tumor-bearing rats. Amino Acids. 2016 Aug;48:2015–24.
82. Lawler JM, Barnes WS, Wu G, Song W, Demaree S. Direct antioxidant properties of creatine. Biochem
Biophys Res Commun. 2002 Jan 11;290:47–52.
83. Rakpongsiri K, Sawangkoon S. Protective effect of creatine supplementation and estrogen replacement
on cardiac reserve function and antioxidant reservation against oxidative stress in exercise-trained
ovariectomized hamsters. Int Heart J. 2008 May;49:343–54.
84. Rahimi R, Mirzaei B, Rahmani-Nia F, Salehi Z. Effects of creatine monohydrate supplementation on
exercise-induced apoptosis in athletes: A randomized, double-blind, and placebo-controlled study. J Res
Med Sci. 2015 Aug;20:733–8.
85. Deminice R, Jordao AA. Creatine supplementation decreases plasma lipid peroxidation markers and
enhances anaerobic performance in rats. Redox Rep. 2015 Jun 17;21:31–36.
86. Op ‘t Eijnde B, Urso B, Richter EA, Greenhaff PL, Hespel P. Effect of oral creatine supplementation on
human muscle GLUT4 protein content after immobilization. Diabetes. 2001 Jan;50:18–23.
87. Gualano B, Desp V, Roschel H, Artioli GG, Neves M, Jr., De Sa Pinto AL, Da Silva ME, Cunha MR,
Otaduy MC et al. Creatine in type 2 diabetes: A randomized, double-blind, placebo-controlled trial. Med
Sci Sports Exerc. 2011 May;43:770–8.
88. Op’t Eijnde B, Jijakli H, Hespel P, Malaisse WJ. Creatine supplementation increases soleus muscle
creatine content and lowers the insulinogenic index in an animal model of inherited type 2 diabetes. Int
J Mol Med. 2006 Jun;17:1077–84.
89. Alves CR, Ferreira JC, de Siqueira-Filho MA, Carvalho CR, Lancha AH, Jr., Gualano B. Creatine-
induced glucose uptake in type 2 diabetes: A role for AMPK-alpha? Amino Acids. 2012 Oct;43:1803–7.
90. Smith RN, Agharkar AS, Gonzales EB. A review of creatine supplementation in age-related diseases:
More than a supplement for athletes. F1000Res. 2014;3:222.
91. Canete S, San Juan AF, Perez M, Gomez-Gallego F, Lopez-Mojares LM, Earnest CP, Fleck SJ, Lucia A.
Does creatine supplementation improve functional capacity in elderly women? J Strength Cond Res. 2006
Feb;20:22–8.
92. Wiroth JB, Bermon S, Andrei S, Dalloz E, Hebuterne X, Dolisi C. Effects of oral creatine supplementation
on maximal pedalling performance in older adults. Eur J Appl Physiol. 2001 Jun;84:533–9.
93. Candow DG, Chilibeck PD. Effect of creatine supplementation during resistance training on muscle
accretion in the elderly. J Nutr Health Aging. 2007 Mar-Apr;11:185–8.
94. Candow DG, Zello GA, Ling B, Farthing JP, Chilibeck PD, McLeod K, Harris J, Johnson S. Comparison
of creatine supplementation before versus after supervised resistance training in healthy older adults. Res
Sports Med. 2014;22:61–74.
95. Candow DG, Little JP, Chilibeck PD, Abeysekara S, Zello GA, Kazachkov M, Cornish SM, Yu PH.
Low-dose creatine combined with protein during resistance training in older men. Med Sci Sports Exerc.
2008 Sep;40:1645–52.
96. Chilibeck PD, Candow DG, Landeryou T, Kaviani M, Paus-Jenssen L. Effects of creatine and resistance
training on bone health in postmenopausal women. Med Sci Sports Exerc. 2015 Aug;47:1587–95.
97. Neves M, Jr., Gualano B, Roschel H, Fuller R, Benatti FB, Pinto AL, Lima FR, Pereira RM, Lancha AH,
Jr., Bonfa E. Beneficial effect of creatine supplementation in knee osteoarthritis. Med Sci Sports Exerc.
2011 Aug;43:1538–43.
98. Alves CR, Santiago BM, Lima FR, Otaduy MC, Calich AL, Tritto AC, de Sa Pinto AL, Roschel H, Leite
CC et al. Creatine supplementation in fibromyalgia: A randomized, double-blind, placebo-controlled
trial. Arthritis Care Res (Hoboken). 2013 Sep;65:1449–59.
99. McMorris T, Mielcarz G, Harris RC, Swain JP, Howard A. Creatine supplementation and cognitive performance
in elderly individuals. Neuropsychol Dev Cogn B Aging Neuropsychol Cogn. 2007 Sep;14:517–28.
100. Roitman S, Green T, Osher Y, Karni N, Levine J. Creatine monohydrate in resistant depression: A
preliminary study. Bipolar Disord. 2007 Nov;9:754–8.
101. D’Anci KE, Allen PJ, Kanarek RB. A potential role for creatine in drug abuse? Mol Neurobiol. 2011
Oct;44:136–41.
102. Toniolo RA, Fernandes FB, Silva M, Dias RD, Lafer B. Cognitive effects of creatine monohydrate
adjunctive therapy in patients with bipolar depression: Results from a randomized, double-blind, placebo-
controlled trial. J Affect Disord. 2017 Dec;224:69–75. doi: 10.1016/j.jad.2016.11.029. Epub 2016 Nov 20.
103. Gualano B, de Salles Painelli V, Roschel H, Lugaresi R, Dorea E, Artioli GG, Lima FR, da Silva ME,
Cunha MR et al. Creatine supplementation does not impair kidney function in type 2 diabetic patients: A
randomized, double-blind, placebo-controlled, clinical trial. Eur J Appl Physiol. 2011 May;111:749–56.
104. Cruz-Jentoft AJ, Bahat G, Bauer J, Boirie Y, Bruyere O, Cederholm T, Cooper C, Landi F, Rolland Y et al.
Sarcopenia: Revised European consensus on definition and diagnosis. Age Ageing. 2019 Jan;48(1):16–31.
doi: 10.1093/ageing/afy169.
105. Abellan van Kan G. Epidemiology and consequences of sarcopenia. J Nutr Health Aging. 2009
Oct;13:708–12.
106. Chilibeck PD, Kaviani M, Candow DG, Zello GA. Effect of creatine supplementation during resistance
training on lean tissue mass and muscular strength in older adults: A meta-analysis. Open Access J Sports
Med. 2017;8:213–26.
107. Devries MC, Phillips SM. Creatine supplementation during resistance training in older adults-a meta-
analysis. Med Sci Sports Exerc. 2014 Jun;46:1194–203.
108. Chilibeck PD, Chrusch MJ, Chad KE, Shawn Davison K, Burke DG. Creatine monohydrate and
resistance training increase bone mineral content and density in older men. J Nutr Health Aging. 2005
Sep-Oct;9:352–3.
109. Gerber I, ap Gwynn I, Alini M, Wallimann T. Stimulatory effects of creatine on metabolic activity,
differentiation and mineralization of primary osteoblast-like cells in monolayer and micromass cell
cultures. Eur Cell Mater. 2005 Jul 15;10:8–22.
110. Forbes SC, Candow DG, Krentz J, Roberts M, Young K. Changes in fat mass following creatine
supplementation in adults ≥50 years of age: A meta-analysis. J Funct Morphol Kinesiol. 2019;4(3): 62.
111. Louis M, Lebacq J, Poortmans JR, Belpaire-Dethiou MC, Devogelaer JP, Van Hecke P, Goubel F,
Francaux M. Beneficial effects of creatine supplementation in dystrophic patients. Muscle Nerve. 2003
May;27:604–10.
112. Tarnopolsky MA, Mahoney DJ, Vajsar J, Rodriguez C, Doherty TJ, Roy BD, Biggar D. Creatine
monohydrate enhances strength and body composition in Duchenne muscular dystrophy. Neurology.
2004 May 25;62:1771–7.
113. Cornish SM, Candow DG, Jantz NT, Chilibeck PD, Little JP, Forbes S, Abeysekara S, Zello GA.
Conjugated linoleic acid combined with creatine monohydrate and whey protein supplementation during
strength training. Int J Sport Nutr Exerc Metab. 2009 Feb;19:79–96.
114. Dechent P, Pouwels PJ, Wilken B, Hanefeld F, Frahm J. Increase of total creatine in human brain after
oral supplementation of creatine-monohydrate. Am J Physiol. 1999 Sep;277:R698–704.
115. Lyoo IK, Kong SW, Sung SM, Hirashima F, Parow A, Hennen J, Cohen BM, Renshaw PF. Multinuclear
magnetic resonance spectroscopy of high-energy phosphate metabolites in human brain following oral
supplementation of creatine-monohydrate. Psychiatry Res. 2003 Jun 30;123:87–100.
116. Pan JW, Takahashi K. Cerebral energetic effects of creatine supplementation in humans. Am J Physiol
Regul Integr Comp Physiol. 2007 Apr;292:R1745–50.
117. Watanabe A, Kato N, Kato T. Effects of creatine on mental fatigue and cerebral hemoglobin oxygenation.
Neurosci Res. 2002 Apr;42:279–85.
118. Rae C, Digney AL, McEwan SR, Bates TC. Oral creatine monohydrate supplementation improves brain
performance: A double-blind, placebo-controlled, cross-over trial. Proc Biol Sci. 2003 Oct 22;270:2147–50.
119. McMorris T, Harris RC, Howard AN, Langridge G, Hall B, Corbett J, Dicks M, Hodgson C. Creatine
supplementation, sleep deprivation, cortisol, melatonin and behavior. Physiol Behav. 2007 Jan 30;
90:21–8.
120. McMorris T, Harris RC, Swain J, Corbett J, Collard K, Dyson RJ, Dye L, Hodgson C, Draper N. Effect
of creatine supplementation and sleep deprivation, with mild exercise, on cognitive and psychomotor
performance, mood state, and plasma concentrations of catecholamines and cortisol. Psychopharmacology
(Berl). 2006 Mar;185:93–103.
121. Ling J, Kritikos M, Tiplady B. Cognitive effects of creatine ethyl ester supplementation. Behav
Pharmacol. 2009 Dec;20:673–9.
122. Ostojic SM. Guanidinoacetic acid as a performance-enhancing agent. Amino Acids. 2016 Aug;48:1867–75.
123. Ostojic SM, Ostojic J, Drid P, Vranes M. Guanidinoacetic acid versus creatine for improved brain
and muscle creatine levels: A superiority pilot trial in healthy men. Appl Physiol Nutr Metab. 2016
Sep;41:1005–7.
124. Stockler-Ipsiroglu S, van Karnebeek CD. Cerebral creatine deficiencies: A group of treatable intellectual
developmental disorders. Semin Neurol. 2014 Jul;34:350–6.
125. Nasrallah F, Feki M, Kaabachi N. Creatine and creatine deficiency syndromes: Biochemical and clinical
aspects. Pediatr Neurol. 2010 Mar;42:163–71.
126. Mercimek-Mahmutoglu S, Stoeckler-Ipsiroglu S, Adami A, Appleton R, Araujo HC, Duran M,
Ensenauer R, Fernandez-Alvarez E, Garcia P et al. GAMT deficiency: Features, treatment, and outcome
in an inborn error of creatine synthesis. Neurology. 2006 Aug 08;67:480–4.
127. Stromberger C, Bodamer OA, Stockler-Ipsiroglu S. Clinical characteristics and diagnostic clues in inborn
errors of creatine metabolism. J Inherit Metab Dis. 2003;26:299–308.
128. Battini R, Alessandri MG, Leuzzi V, Moro F, Tosetti M, Bianchi MC, Cioni G. Arginine:glycine
amidinotransferase (AGAT) deficiency in a newborn: Early treatment can prevent phenotypic expression
of the disease. J Pediatr. 2006 Jun;148:828–30.
129. Stockler-Ipsiroglu S, van Karnebeek C, Longo N, Korenke GC, Mercimek-Mahmutoglu S, Marquart I,
Barshop B, Grolik C, Schlune A et al. Guanidinoacetate methyltransferase (GAMT) deficiency:
Outcomes in 48 individuals and recommendations for diagnosis, treatment and monitoring. Mol Genet
Metab. 2014 Jan;111:16–25.
130. Valtonen M, Nanto-Salonen K, Jaaskelainen S, Heinanen K, Alanen A, Heinonen OJ, Lundbom N,
Erkintalo M, Simell O. Central nervous system involvement in gyrate atrophy of the choroid and retina
with hyperornithinaemia. J Inherit Metab Dis. 1999 Dec;22:855–66.
131. Nanto-Salonen K, Komu M, Lundbom N, Heinanen K, Alanen A, Sipila I, Simell O. Reduced brain
creatine in gyrate atrophy of the choroid and retina with hyperornithinemia. Neurology. 1999 Jul
22;53:303–7.
132. Heinanen K, Nanto-Salonen K, Komu M, Erkintalo M, Alanen A, Heinonen OJ, Pulkki K, Nikoskelainen
E, Sipila I, Simell O. Creatine corrects muscle 31P spectrum in gyrate atrophy with hyperornithinaemia.
Eur J Clin Invest. 1999 Dec;29:1060–5.
133. Vannas-Sulonen K, Sipila I, Vannas A, Simell O, Rapola J. Gyrate atrophy of the choroid and retina. A
five-year follow-up of creatine supplementation. Ophthalmology. 1985 Dec;92:1719–27.
134. Sipila I, Rapola J, Simell O, Vannas A. Supplementary creatine as a treatment for gyrate atrophy of the
choroid and retina. N Engl J Med. 1981 Apr 09;304:867–70.
135. Evangeliou A, Vasilaki K, Karagianni P, Nikolaidis N. Clinical applications of creatine supplementation
on paediatrics. Curr Pharm Biotechnol. 2009 Nov;10:683–90.
136. Verbruggen KT, Knijff WA, Soorani-Lunsing RJ, Sijens PE, Verhoeven NM, Salomons GS,
G oorhuis-Brouwer SM, van Spronsen FJ. Global developmental delay in guanidionacetate

methyltransferase deficiency: Differences in formal testing and clinical observation. Eur J Pediatr. 2007
Sep;166:921–5.
137. Ensenauer R, Thiel T, Schwab KO, Tacke U, Stockler-Ipsiroglu S, Schulze A, Hennig J, Lehnert W.
Guanidinoacetate methyltransferase deficiency: Differences of creatine uptake in human brain and
muscle. Mol Genet Metab. 2004 Jul;82:208–13.
138. Ogborn DI, Smith KJ, Crane JD, Safdar A, Hettinga BP, Tupler R, Tarnopolsky MA. Effects of creatine
and exercise on skeletal muscle of FRG1-transgenic mice. Can J Neurol Sci. 2012 Mar;39:225–31.
139. Banerjee B, Sharma U, Balasubramanian K, Kalaivani M, Kalra V, Jagannathan NR. Effect of creatine
monohydrate in improving cellular energetics and muscle strength in ambulatory Duchenne muscular
dystrophy patients: A randomized, placebo-controlled 31P MRS study. Magn Reson Imaging. 2010
Jun;28:698–707.
140. Felber S, Skladal D, Wyss M, Kremser C, Koller A, Sperl W. Oral creatine supplementation in Duchenne
muscular dystrophy: A clinical and 31P magnetic resonance spectroscopy study. Neurol Res. 2000
Mar;22:145–50.
141. Radley HG, De Luca A, Lynch GS, Grounds MD. Duchenne muscular dystrophy: Focus on pharmaceutical
and nutritional interventions. Int J Biochem Cell Biol. 2007;39:469–77.
142. Adhihetty PJ, Beal MF. Creatine and its potential therapeutic value for targeting cellular energy
impairment in neurodegenerative diseases. Neuromolecular Med. 2008;10:275–90.
143. Verbessem P, Lemiere J, Eijnde BO, Swinnen S, Vanhees L, Van Leemputte M, Hespel P, Dom R.
Creatine supplementation in Huntington’s disease: A placebo-controlled pilot trial. Neurology. 2003 Oct
14;61:925–30.
144. Dedeoglu A, Kubilus JK, Yang L, Ferrante KL, Hersch SM, Beal MF, Ferrante RJ. Creatine therapy
provides neuroprotection after onset of clinical symptoms in Huntington’s disease transgenic mice.
J Neurochem. 2003 Jun;85:1359–67.
145. Andreassen OA, Dedeoglu A, Ferrante RJ, Jenkins BG, Ferrante KL, Thomas M, Friedlich A, Browne
SE, Schilling G et al. Creatine increase survival and delays motor symptoms in a transgenic animal
model of Huntington’s disease. Neurobiol Dis. 2001 Jun;8:479–91.
146. Ferrante RJ, Andreassen OA, Jenkins BG, Dedeoglu A, Kuemmerle S, Kubilus JK, Kaddurah-Daouk R,
Hersch SM, Beal MF. Neuroprotective effects of creatine in a transgenic mouse model of Huntington’s
disease. J Neurosci. 2000 Jun 15;20:4389–97.
147. Matthews RT, Yang L, Jenkins BG, Ferrante RJ, Rosen BR, Kaddurah-Daouk R, Beal MF. Neuroprotective
effects of creatine and cyclocreatine in animal models of Huntington’s disease. J Neurosci. 1998 Jan
01;18:156–63.
148. Bender A, Samtleben W, Elstner M, Klopstock T. Long-term creatine supplementation is safe in aged
patients with Parkinson disease. Nutr Res. 2008 Mar;28:172–8.
149. Hass CJ, Collins MA, Juncos JL. Resistance training with creatine monohydrate improves upper-body
strength in patients with Parkinson disease: A randomized trial. Neurorehabil Neural Repair. 2007
Mar-Apr;21:107–15.
150. Bender A, Koch W, Elstner M, Schombacher Y, Bender J, Moeschl M, Gekeler F, Muller-Myhsok B,
Gasser T et al. Creatine supplementation in Parkinson disease: A placebo-controlled randomized pilot
trial. Neurology. 2006 Oct 10;67:1262–4.
151. Komura K, Hobbiebrunken E, Wilichowski EK, Hanefeld FA. Effectiveness of creatine monohydrate in
mitochondrial encephalomyopathies. Pediatr Neurol. 2003 Jan;28:53–8.
152. Tarnopolsky MA, Parise G. Direct measurement of high-energy phosphate compounds in patients with
neuromuscular disease. Muscle Nerve. 1999 Sep;22:1228–33.
153. Tarnopolsky MA, Roy BD, MacDonald JR. A randomized, controlled trial of creatine monohydrate in
patients with mitochondrial cytopathies. Muscle Nerve. 1997 Dec;20:1502–9.
154. Andreassen OA, Jenkins BG, Dedeoglu A, Ferrante KL, Bogdanov MB, Kaddurah-Daouk R, Beal
MF. Increases in cortical glutamate concentrations in transgenic amyotrophic lateral sclerosis mice are
attenuated by creatine supplementation. J Neurochem. 2001 Apr;77:383–90.
155. Choi JK, Kustermann E, Dedeoglu A, Jenkins BG. Magnetic resonance spectroscopy of regional brain
metabolite markers in FALS mice and the effects of dietary creatine supplementation. Eur J Neurosci.
2009 Dec;30:2143–50.
156. Derave W, Van Den Bosch L, Lemmens G, Eijnde BO, Robberecht W, Hespel P. Skeletal muscle
properties in a transgenic mouse model for amyotrophic lateral sclerosis: Effects of creatine treatment.
Neurobiol Dis. 2003 Aug;13:264–72.
157. Drory VE, Gross D. No effect of creatine on respiratory distress in amyotrophic lateral sclerosis.
Amyotroph Lateral Scler Other Motor Neuron Disord. 2002 Mar;3:43–6.
158. Ellis AC, Rosenfeld J. The role of creatine in the management of amyotrophic lateral sclerosis and other
neurodegenerative disorders. CNS Drugs. 2004;18:967–80.
159. Mazzini L, Balzarini C, Colombo R, Mora G, Pastore I, De Ambrogio R, Caligari M. Effects of creatine
supplementation on exercise performance and muscular strength in amyotrophic lateral sclerosis:
Preliminary results. J Neurol Sci. 2001 Oct 15;191:139–44.
160. Vielhaber S, Kaufmann J, Kanowski M, Sailer M, Feistner H, Tempelmann C, Elger CE, Heinze HJ,
Kunz WS. Effect of creatine supplementation on metabolite levels in ALS motor cortices. Exp Neurol.
2001 Dec;172:377–82.
161. Hultman J, Ronquist G, Forsberg JO, Hansson HE. Myocardial energy restoration of ischemic damage by
administration of phosphoenolpyruvate during reperfusion. A study in a paracorporeal rat heart model.
Eur Surg Res. 1983;15:200–7.
162. Thelin S, Hultman J, Ronquist G, Hansson HE. Metabolic and functional effects of creatine phosphate
in cardioplegic solution. Studies on rat hearts during and after normothermic ischemia. Scand J Thorac
Cardiovasc Surg. 1987;21:39–45.
163. Osbakken M, Ito K, Zhang D, Ponomarenko I, Ivanics T, Jahngen EG, Cohn M. Creatine and cyclocreatine
effects on ischemic myocardium: 31P nuclear magnetic resonance evaluation of intact heart. Cardiology.
1992;80:184–95.
164. Thorelius J, Thelin S, Ronquist G, Halden E, Hansson HE. Biochemical and functional effects of creatine
phosphate in cardioplegic solution during aortic valve surgery—A clinical study. Thorac Cardiovasc
Surg. 1992 Feb;40:10–3.
165. Boudina S, Laclau MN, Tariosse L, Daret D, Gouverneur G, Bonoron-Adele S, Saks VA, Dos Santos P.
Alteration of mitochondrial function in a model of chronic ischemia in vivo in rat heart. Am J Physiol
Heart Circ Physiol. 2002 Mar;282:H821–31.
166. Laclau MN, Boudina S, Thambo JB, Tariosse L, Gouverneur G, Bonoron-Adele S, Saks VA, Garlid
KD, Dos Santos P. Cardioprotection by ischemic preconditioning preserves mitochondrial function and
functional coupling between adenine nucleotide translocase and creatine kinase. J Mol Cell Cardiol.
2001 May;33:947–56.
167. Conorev EA, Sharov VG, Saks VA. Improvement in contractile recovery of isolated rat heart after
cardioplegic ischaemic arrest with endogenous phosphocreatine: Involvement of antiperoxidative effect?
Cardiovasc Res. 1991 Feb;25:164–71.
168. Sharov VG, Saks VA, Kupriyanov VV, Lakomkin VL, Kapelko VI, Steinschneider A, Javadov SA.
Protection of ischemic myocardium by exogenous phosphocreatine. I. Morphologic and phosphorus
31-nuclear magnetic resonance studies. J Thorac Cardiovasc Surg. 1987 Nov;94:749–61.
169. Anyukhovsky EP, Javadov SA, Preobrazhensky AN, Beloshapko GG, Rosenshtraukh LV, Saks VA.
Effect of phosphocreatine and related compounds on the phospholipid metabolism of ischemic heart.
Biochem Med Metab Biol. 1986 Jun;35:327–34.
170. Sharov VG, Afonskaya NI, Ruda MY, Cherpachenko NM, Pozin E, Markosyan RA, Shepeleva, II,
Samarenko MB, Saks VA. Protection of ischemic myocardium by exogenous phosphocreatine (neoton):
Pharmacokinetics of phosphocreatine, reduction of infarct size, stabilization of sarcolemma of ischemic
cardiomyocytes, and antithrombotic action. Biochem Med Metab Biol. 1986 Feb;35:101–14.
171. Ellery SJ, LaRosa DA, Cullen-McEwen LA, Brown RD, Snow RJ, Walker DW, Kett MM, Dickinson H.
Renal dysfunction in early adulthood following birth asphyxia in male spiny mice, and its amelioration
by maternal creatine supplementation during pregnancy. Pediatr Res. 2017 Feb 01;5:16.
172. LaRosa DA, Ellery SJ, Snow RJ, Walker DW, Dickinson H. Maternal creatine supplementation during
pregnancy prevents acute and long-term deficits in skeletal muscle after birth asphyxia: A study of
structure and function of hind limb muscle in the spiny mouse. Pediatr Res. 2016 Dec;80:852–60.
173. Ellery SJ, Walker DW, Dickinson H. Creatine for women: A review of the relationship between creatine and
the reproductive cycle and female-specific benefits of creatine therapy. Amino Acids. 2016 Aug;48:1807–17.
174. Ellery SJ, LaRosa DA, Kett MM, Della Gatta PA, Snow RJ, Walker DW, Dickinson H. Dietary creatine
supplementation during pregnancy: A study on the effects of creatine supplementation on creatine
homeostasis and renal excretory function in spiny mice. Amino Acids. 2016 Aug;48:1819–30.
175. Dickinson H, Ellery S, Ireland Z, LaRosa D, Snow R, Walker DW. Creatine supplementation during
pregnancy: Summary of experimental studies suggesting a treatment to improve fetal and neonatal
morbidity and reduce mortality in high-risk human pregnancy. BMC Pregnancy Childbirth. 2014 Apr
27;14:150.
176. Bortoluzzi VT, de Franceschi ID, Rieger E, Wannmacher CM. Co-administration of creatine plus
pyruvate prevents the effects of phenylalanine administration to female rats during pregnancy and
lactation on enzymes activity of energy metabolism in cerebral cortex and hippocampus of the offspring.
Neurochem Res. 2014 Aug;39:1594–602.
177. Vallet JL, Miles JR, Rempel LA. Effect of creatine supplementation during the last week of gestation on
birth intervals, stillbirth, and preweaning mortality in pigs. J Anim Sci. 2013 May;91:2122–32.
178. Ellery SJ, Ireland Z, Kett MM, Snow R, Walker DW, Dickinson H. Creatine pretreatment prevents birth
asphyxia-induced injury of the newborn spiny mouse kidney. Pediatr Res. 2013 Feb;73:201–8.
179. Dickinson H, Ireland ZJ, Larosa DA, O’Connell BA, Ellery S, Snow R, Walker DW. Maternal dietary
creatine supplementation does not alter the capacity for creatine synthesis in the newborn spiny mouse.
Reprod Sci. 2013 Sep;20:1096–102.
180. Ireland Z, Castillo-Melendez M, Dickinson H, Snow R, Walker DW. A maternal diet supplemented with
creatine from mid-pregnancy protects the newborn spiny mouse brain from birth hypoxia. Neuroscience.
2011 Oct 27;194:372–9.
181. Cornish SM, Chilibeck PD, Burke DG. The effect of creatine monohydrate supplementation on sprint
skating in ice-hockey players. J Sports Med Phys Fitness. 2006 Mar;46:90–8.
182. Dawson B, Vladich T, Blanksby BA. Effects of 4 weeks of creatine supplementation in junior swimmers
on freestyle sprint and swim bench performance. J Strength Cond Res. 2002 Nov;16:485–90.
183. Grindstaff PD, Kreider R, Bishop R, Wilson M, Wood L, Alexander C, Almada A. Effects of creatine
supplementation on repetitive sprint performance and body composition in competitive swimmers. Int J
Sport Nutr. 1997 Dec;7:330–46.
184. Juhasz I, Gyore I, Csende Z, Racz L, Tihanyi J. Creatine supplementation improves the anaerobic
performance of elite junior fin swimmers. Acta Physiol Hung. 2009 Sep;96:325–36.
185. Silva AJ, Machado Reis V, Guidetti L, Bessone Alves F, Mota P, Freitas J, Baldari C. Effect of creatine
on swimming velocity, body composition and hydrodynamic variables. J Sports Med Phys Fitness. 2007
Mar;47:58–64.
186. Stone MH, Sanborn K, Smith LL, O’Bryant HS, Hoke T, Utter AC, Johnson RL, Boros R, Hruby J et al.
Effects of in-season (5 weeks) creatine and pyruvate supplementation on anaerobic performance and
body composition in American football players. Int J Sport Nutr. 1999 Jun;9:146–65.
187. Bemben MG, Bemben DA, Loftiss DD, Knehans AW. Creatine supplementation during resistance
training in college football athletes. Med Sci Sports Exerc. 2001 Oct;33:1667–73.
188. Hoffman J, Ratamess N, Kang J, Mangine G, Faigenbaum A, Stout J. Effect of creatine and beta-alanine
supplementation on performance and endocrine responses in strength/power athletes. Int J Sport Nutr
Exerc Metab. 2006 Aug;16:430–46.
189. Chilibeck PD, Magnus C, Anderson M. Effect of in-season creatine supplementation on body composition
and performance in rugby union football players. Appl Physiol Nutr Metab. 2007 Dec;32:1052–7.
190. Claudino JG, Mezencio B, Amaral S, Zanetti V, Benatti F, Roschel H, Gualano B, Amadio AC, Serrao
JC. Creatine monohydrate supplementation on lower-limb muscle power in Brazilian elite soccer players.
J Int Soc Sports Nutr. 2014;11:32.
191. Kerksick CM, Rasmussen C, Lancaster S, Starks M, Smith P, Melton C, Greenwood M, Almada A,
Kreider R. Impact of differing protein sources and a creatine containing nutritional formula after 12
weeks of resistance training. Nutrition. 2007 Sep;23:647–56.
192. Kerksick CM, Wilborn CD, Campbell WI, Harvey TM, Marcello BM, Roberts MD, Parker AG, Byars
AG, Greenwood LD et al. The effects of creatine monohydrate supplementation with and without
D-pinitol on resistance training adaptations. J Strength Cond Res. 2009 Dec;23:2673–82.
193. Galvan E, Walker DK, Simbo SY, Dalton R, Levers K, O’Connor A, Goodenough C, Barringer
ND, Greenwood M et al. Acute and chronic safety and efficacy of dose dependent creatine nitrate
supplementation and exercise performance. J Int Soc Sports Nutr. 2016;13:12.
194. Volek JS, Kraemer WJ, Bush JA, Boetes M, Incledon T, Clark KL, Lynch JM. Creatine supplementation
enhances muscular performance during high-intensity resistance exercise. J Am Diet Assoc. 1997
Jul;97:765–70.
195. Volek JS, Mazzetti SA, Farquhar WB, Barnes BR, Gomez AL, Kraemer WJ. Physiological responses to
short-term exercise in the heat after creatine loading. Med Sci Sports Exerc. 2001 Jul;33:1101–8.
196. Volek JS, Ratamess NA, Rubin MR, Gomez AL, French DN, McGuigan MM, Scheett TP, Sharman
MJ, Hakkinen K, Kraemer WJ. The effects of creatine supplementation on muscular performance and
body composition responses to short-term resistance training overreaching. Eur J Appl Physiol. 2004
May;91:628–37.
197. Branch JD. Effect of creatine supplementation on body composition and performance: A meta-analysis.
Int J Sport Nutr Exerc Metab. 2003 Jun;13:198–226.
198. Lanhers C, Pereira B, Naughton G, Trousselard M, Lesage FX, Dutheil F. Creatine supplementation and
lower limb strength performance: A systematic review and meta-analyses. Sports Med. 2015 Sep;45:1285–94.
199. Rawson ES, Clarkson PM. Acute creatine supplementation in older men. Int J Sports Med. 2000
Jan;21:71–5.
200. Aguiar AF, Januario RS, Junior RP, Gerage AM, Pina FL, do Nascimento MA, Padovani CR, Cyrino
ES. Long-term creatine supplementation improves muscular performance during resistance training in
older women. Eur J Appl Physiol. 2013 Apr;113:987–96.
201. Tarnopolsky MA, MacLennan DP. Creatine monohydrate supplementation enhances high-intensity
exercise performance in males and females. Int J Sport Nutr Exerc Metab. 2000 Dec;10:452–63.
202. Ziegenfuss TN, Rogers M, Lowery L, Mullins N, Mendel R, Antonio J, Lemon P. Effect of creatine
loading on anaerobic performance and skeletal muscle volume in NCAA division I athletes. Nutrition.
2002 May;18:397–402.
203. Ayoama R, Hiruma E, Sasaki H. Effects of creatine loading on muscular strength and endurance of
female softball players. J Sports Med Phys Fitness. 2003 Dec;43:481–7.
204. Johannsmeyer S, Candow DG, Brahms CM, Michel D, Zello GA. Effect of creatine supplementation and
drop-set resistance training in untrained aging adults. Exp Gerontol. 2016 Oct;83:112–9.
205. Ramirez-Campillo R, Gonzalez-Jurado JA, Martinez C, Nakamura FY, Penailillo L, Meylan CM,
Caniuqueo A, Canas-Jamet R, Moran J et al. Effects of plyometric training and creatine supplementation on
maximal-intensity exercise and endurance in female soccer players. J Sci Med Sport. 2016 Aug;19:682–7.
206. Nelson AG, Arnall DA, Kokkonen J, Day R, Evans J. Muscle glycogen supercompensation is enhanced
by prior creatine supplementation. Med Sci Sports Exerc. 2001 Jul;33:1096–100.
207. Cooke MB, Rybalka E, Williams AD, Cribb PJ, Hayes A. Creatine supplementation enhances muscle
force recovery after eccentrically-induced muscle damage in healthy individuals. J Int Soc Sports Nutr.
2009 Jun 02;6:13.
208. Santos RV, Bassit RA, Caperuto EC, Costa Rosa LF. The effect of creatine supplementation upon
inflammatory and muscle soreness markers after a 30 km race. Life Sci. 2004 Sep 03;75:1917–24.
209. Deminice R, Rosa FT, Franco GS, Jordao AA, de Freitas EC. Effects of creatine supplementation on
oxidative stress and inflammatory markers after repeated-sprint exercise in humans. Nutrition. 2013
Sep;29:1127–32.
210. Kreider RB, Klesges R, Harmon K, Grindstaff P, Ramsey L, Bullen D, Wood L, Li Y, Almada A.
Effects of ingesting supplements designed to promote lean tissue accretion on body composition during
resistance training. Int J Sport Nutr. 1996 Sep;6:234–46.
211. Kreider RB, Klesges R, Lotz D, Davis M, Cantler E, Grindstaff P, Ramsey L, Bullen D, Wood L,
Almada A. Effects of nutritional supplementation during off–season college football training on body
composition and strength. J Exerc Physiol Online. 1999;2:24–39.
212. Earnest CP, Snell PG, Rodriguez R, Almada AL, Mitchell TL. The effect of creatine monohydrate
ingestion on anaerobic power indices, muscular strength and body composition. Acta Physiol Scand.
1995 Feb;153:207–9.
213. Greenwood M, Kreider RB, Melton C, Rasmussen C, Lancaster S, Cantler E, Milnor P, Almada A.
Creatine supplementation during college football training does not increase the incidence of cramping
or injury. Mol Cell Biochem. 2003 Feb;244:83–8.
214. Cancela P, Ohanian C, Cuitino E, Hackney AC. Creatine supplementation does not affect clinical health
markers in football players. Br J Sports Med. 2008 Sep;42:731–5.
215. Schroder H, Terrados N, Tramullas A. Risk assessment of the potential side effects of long-term creatine
supplementation in team sport athletes. Eur J Nutr. 2005 Jun;44:255–61.
216. Rosene JM, Whitman SA, Fogarty TD. A comparison of thermoregulation with creatine supplementation
between the sexes in a thermoneutral environment. J Athl Train. 2004 Mar;39:50–5.
217. Twycross-Lewis R, Kilduff LP, Wang G, Pitsiladis YP. The effects of creatine supplementation on
thermoregulation and physical (cognitive) performance: A review and future prospects. Amino Acids.
2016 Aug;48:1843–55.
218. Watson G, Casa DJ, Fiala KA, Hile A, Roti MW, Healey JC, Armstrong LE, Maresh CM. Creatine use
and exercise heat tolerance in dehydrated men. J Athl Train. 2006 Jan-Mar;41:18–29.
219. Weiss BA, Powers ME. Creatine supplementation does not impair the thermoregulatory response during
a bout of exercise in the heat. J Sports Med Phys Fitness. 2006 Dec;46:555–63.
220. Wright GA, Grandjean PW, Pascoe DD. The effects of creatine loading on thermoregulation and
intermittent sprint exercise performance in a hot humid environment. J Strength Cond Res. 2007
Aug;21:655–60.
221. Beis LY, Polyviou T, Malkova D, Pitsiladis YP. The effects of creatine and glycerol hyperhydration on
running economy in well trained endurance runners. J Int Soc Sports Nutr. 2011 Dec 16;8:24.
222. Easton C, Calder A, Prior F, Dobinson S, I’Anson R, MacGregor R, Mohammad Y, Kingsmore D,
Pitsiladis YP. The effects of a novel “fluid loading” strategy on cardiovascular and haematological
responses to orthostatic stress. Eur J Appl Physiol. 2009 Apr;1;05:899–908.
223. Easton C, Turner S, Pitsiladis YP. Creatine and glycerol hyperhydration in trained subjects before
exercise in the heat. Int J Sport Nutr Exerc Metab. 2007 Feb;17:70–91.
224. Kilduff LP, Georgiades E, James N, Minnion RH, Mitchell M, Kingsmore D, Hadjicharlambous M,
Pitsiladis YP. The effects of creatine supplementation on cardiovascular, metabolic, and thermoregulatory
responses during exercise in the heat in endurance-trained humans. Int J Sport Nutr Exerc Metab. 2004
Aug;14:443–60.
225. Polyviou TP, Easton C, Beis L, Malkova D, Takas P, Hambly C, Speakman JR, Koehler K, Pitsiladis YP.
Effects of glycerol and creatine hyperhydration on doping-relevant blood parameters. Nutrients. 2012
Sep;4:1171–86.
226. Polyviou TP, Pitsiladis YP, Celis-Morales C, Brown B, Speakman JR, Malkova D. The effects of
hyperhydrating supplements containing creatine and glucose on plasma lipids and insulin sensitivity in
endurance-trained athletes. J Amino Acids. 2015;2015:352458.
227. Polyviou TP, Pitsiladis YP, Lee WC, Pantazis T, Hambly C, Speakman JR, Malkova D. Thermoregulatory
and cardiovascular responses to creatine, glycerol and alpha lipoic acid in trained cyclists. J Int Soc
Sports Nutr. 2012 Jun 22;9:29.
228. Lopez RM, Casa DJ, McDermott BP, Ganio MS, Armstrong LE, Maresh CM. Does creatine
supplementation hinder exercise heat tolerance or hydration status? A systematic review with meta-
analyses. J Athl Train. 2009 Mar-Apr;44:215–23.
229. Rosene JM, Matthews TD, McBride KJ, Galla A, Haun M, McDonald K, Gagne N, Lea J, Kasen J, Farias
C. The effects of creatine supplementation on thermoregulation and isokinetic muscular performance
following acute (3-day) supplementation. J Sports Med Phys Fitness. 2015 Dec;55:1488–96.
230. Dalbo VJ, Roberts MD, Stout JR, Kerksick CM. Putting to rest the myth of creatine supplementation
leading to muscle cramps and dehydration. Br J Sports Med. 2008 Jul;42:567–73.
231. Hespel P, Derave W. Ergogenic effects of creatine in sports and rehabilitation. Subcell Biochem.
2007;46:245–59.
232. Hespel P, Op’t Eijnde B, Van Leemputte M, Urso B, Greenhaff PL, Labarque V, Dymarkowski S, Van
Hecke P, Richter EA. Oral creatine supplementation facilitates the rehabilitation of disuse atrophy and
alters the expression of muscle myogenic factors in humans. J Physiol. 2001 Oct 15;536:625–33.
233. Jacobs PL, Mahoney ET, Cohn KA, Sheradsky LF, Green BA. Oral creatine supplementation enhances
upper extremity work capacity in persons with cervical-level spinal cord injury. Arch Phys Med Rehabil.
2002 Jan;83:19–23.
234. Tyler TF, Nicholas SJ, Hershman EB, Glace BW, Mullaney MJ, McHugh MP. The effect of creatine
supplementation on strength recovery after anterior cruciate ligament (ACL) reconstruction: A
randomized, placebo-controlled, double-blind trial. Am J Sports Med. 2004 Mar;32:383–8.
235. Perret C, Mueller G, Knecht H. Influence of creatine supplementation on 800 m wheelchair performance:
A pilot study. Spinal Cord. 2006 May;44:275–9.
236. Kley RA, Vorgerd M, Tarnopolsky MA. Creatine for treating muscle disorders. Cochrane Database Syst
Rev. 2007 Jan 24:CD004760.
237. Sullivan PG, Geiger JD, Mattson MP, Scheff SW. Dietary supplement creatine protects against traumatic
brain injury. Ann Neurol. 2000 Nov;48:723–9.
238. Hausmann ON, Fouad K, Wallimann T, Schwab ME. Protective effects of oral creatine supplementation
on spinal cord injury in rats. Spinal Cord. 2002 Sep;40:449–56.
239. Prass K, Royl G, Lindauer U, Freyer D, Megow D, Dirnagl U, Stockler-Ipsiroglu G, Wallimann T, Priller
J. Improved reperfusion and neuroprotection by creatine in a mouse model of stroke. J Cereb Blood Flow
Metab. 2007 Mar;27:452–9.
240. Adcock KH, Nedelcu J, Loenneker T, Martin E, Wallimann T, Wagner BP. Neuroprotection of creatine
supplementation in neonatal rats with transient cerebral hypoxia-ischemia. Dev Neurosci. 2002;24:382–8.
241. Zhu S, Li M, Figueroa BE, Liu A, Stavrovskaya IG, Pasinelli P, Beal MF, Brown RH, Jr., Kristal BS et al.
Prophylactic creatine administration mediates neuroprotection in cerebral ischemia in mice. J Neurosci.
2004 Jun 30;24:5909–12.
242. Allah Yar R, Akbar A, Iqbal F. Creatine monohydrate supplementation for 10 weeks mediates
neuroprotection and improves learning/memory following neonatal hypoxia ischemia encephalopathy
in female albino mice. Brain Res. 2015 Jan 21;1595:92–100.
243. Rabchevsky AG, Sullivan PG, Fugaccia I, Scheff SW. Creatine diet supplement for spinal cord injury:
Influences on functional recovery and tissue sparing in rats. J Neurotrauma. 2003 Jul;20:659–69.
244. Freire Royes LF, Cassol G. The effects of creatine supplementation and physical exercise on traumatic
brain injury. Mini Rev Med Chem. 2016;16:29–39.
245. Candow DG, Forbes SC, Chilibeck PD, Cornish SM, Antonio J, Kreider RB. Effectiveness of creatine
supplementation on aging muscle and bone: Focus on falls prevention and inflammation. J Clin Med.
2019;8(4). pii: E488. doi: 10.3390/jcm8040488.
1. Chickens. In: Kiple KF, Ornelas KC, editors. The Cambridge World History of Food 1. Cambridge
University Press; 2000.
2. Chicken Eggs. In: Kiple KF, Ornelas KC, editors. The Cambridge World History of Food. Cambridge
University Press; 2000.
3. Cumo CM. Foods that Changed History: How Foods Shaped Civilization from the Ancient World to the
Present. ABC-CLIO; 2015.
4. Gray J, Griffin B. Eggs and dietary cholesterol—Dispelling the myth. Nutr Bull. 2009;34(1):66–70.
5. US Department of Health and Human Services. 2015–2020 Dietary Guidelines for Americans.
Washington (DC): USDA; 2015.
6. Park BS, Park SO. Lipid-lowering mechanism of egg yolk in normal rats. Int J Food Sci Technol.
2016;51(12):2512–9.
7. Qin C, Lv J, Guo Y, Bian Z, Si J, Yang L et al. Associations of egg consumption with cardiovascular disease
in a cohort study of 0.5 million Chinese adults. Heart. 2018;104(21):1756–63. heartjnl-2017-312651.
8. DiMarco DM, Missimer A, Murillo AG, Lemos BS, Malysheva OV, Caudill MA et al. Intake of up
to 3 eggs/day increases HDL cholesterol and plasma choline while plasma trimethylamine-N-oxide is
unchanged in a healthy population. Lipids. 2017;52(3):255–63.
9. Gordon DJ, Probstfield JL, Garrison RJ, Neaton JD, Castelli WP, Knoke JD et al. High-density lipoprotein
cholesterol and cardiovascular disease. Four prospective American studies. Circulation. 1989;79(1):8–15.
10. International Egg Commission. Atlas of the Global Egg Industry September 2013.
11. American Egg Board. The Incredible Egg™ EGGCYCLOPEDIA 2012. Available from: https://
x9wsr1khhgk5pxnq1f1r8kye-wpengine.netdna-ssl.com/wp-content/uploads/eggcyclopedia-fifth-edition.
pdf
12. The Tea & Coffee Trade Journal: Tea and Coffee Trade Journal Company; 1922.
13. Petfood Industry. Egg Products Analyzed by Variety Most Used in Pet Food 2017 [Available from: https://
www.petfoodindustry.com/articles/6800-egg-products-analyzed-by-variety-most-used-in-pet-food]
14. Egg Nutrition Center. Guide to Egg Carton Labels. 2012.
15. American Egg Board. Egg Protein Comparison & Protein Costs 2018 [Available from: https://www.aeb.
org/farmers-and-marketers/protein-comparison]
16. Egg Nutrition Center. The Yolk: A Nutrient Goldmine.
17. Tsai W-T, Hsien K-J, Hsu H-C, Lin C-M, Lin K-Y, Chiu C-H. Utilization of ground eggshell waste as an
adsorbent for the removal of dyes from aqueous solution. Bioresource Technol. 2008;99(6):1623–9.
18. U.N. Food & Agriculture Organization: FAO Statistical Yearbook—United States of America. 2004.
19. Brun LR, Lupo M, Delorenzi DA, Di Loreto VE, Rigalli A. Chicken eggshell as suitable calcium source
at home. Int J Food Sci Nutr. 2013;64(6):740–3.
20. Daengprok W, Garnjanagoonchorn W, Naivikul O, Pornsinlpatip P, Issigonis K, Mine Y. Chicken
eggshell matrix proteins enhance calcium transport in the human intestinal epithelial cells, Caco-2.
J Agric Food Chem. 2003;51(20):6056–61.
21. Schaafsma A, Beelen GM. Eggshell powder, a comparable or better source of calcium than purified
calcium carbonate: Piglet studies. J Sci Food Agric. 1999;79(12):1596–600.
22. Schaafsma A, van Doormaal JJ, Muskiet FA, Hofstede GJ, Pakan I, van der Veer E. Positive effects of
a chicken eggshell powder-enriched vitamin-mineral supplement on femoral neck bone mineral density
in healthy late post-menopausal Dutch women. Br J Nutr. 2002;87(3):267–75.
23. Schaafsma A, Pakan I. Short-term effects of a chicken egg shell powder enriched dairy-based products on
bone mineral density in persons with osteoporosis or osteopenia. Bratisl Lek Listy. 1999;100(12):651–6.
24. Osonwa U. Egg shell powder as a potential direct compression excipient in tablet formulation. West
African J Pharm. 2017;28:107–18.
25. Than M, Lawanprasert P, Jateleela S. Utilization of eggshell powder as excipient in fast and sustained
release acetaminophen tablets. Pharm Sci Asia. 2012;39(3–4):32–8.
26. Wong M, Hendrix MJ, von der Mark K, Little C, Stern R. Collagen in the egg shell membranes of the
hen. Dev Biol. 1984;104(1):28–36.
27. Baker J, Balch D. A study of the organic material of hen’s-egg shell. Biochem J. 1962;82(2):352.
28. Walton H, Cotterill O, Vandepopuliere J. Composition of shell waste from egg breaking plants. Poultry
Sci. 1973;52(5):1836–41.
29. Ruff K, Morrison D, Duncan SA, Back M, Aydogan C, Theodosakis J. Beneficial effects of natural
eggshell membrane versus placebo in exercise-induced joint pain, stiffness, and cartilage turnover in
healthy, postmenopausal women. Clin Interv Aging. 2018;13:285–95.
30. Ruff KJ, DeVore DP, Leu MD, Robinson MA. Eggshell membrane: A possible new natural therapeutic
for joint and connective tissue disorders. Results from two open-label human clinical studies. Clin Interv
Aging. 2009;4:235–40.
31. Ruff KJ, Endres JR, Clewell AE, Szabo JR, Schauss AG. Safety evaluation of a natural eggshell
membrane-derived product. Food Chem Toxicol. 2012;50(3-4):604–11.
32. Ruff KJ, Winkler A, Jackson RW, DeVore DP, Ritz BW. Eggshell membrane in the treatment of pain and
stiffness from osteoarthritis of the knee: A randomized, multicenter, double-blind, placebo-controlled
clinical study. Clin Rheumatol. 2009;28(8):907–14.
33. Danesch U, Seybold M, Rittinghausen R, Treibel W, Bitterlich N. NEM brand eggshell membrane
effective in the treatment of pain associated with knee and hip osteoarthritis: Results from a six-center,
open-label German clinical study. J Arthritis. 2014;3(3):136.
34. Brunello E, Masini A. NEM brand eggshell membrane effective in the treatment of pain and stiffness
associated with osteoarthritis of the knee in an Italian study population. Int J Clin Med. 2016;7(02):169.
35. Wedekind KJ, Ruff KJ, Atwell CA, Evans JL, Bendele AM. Beneficial effects of natural eggshell
membrane (NEM) on multiple indices of arthritis in collagen-induced arthritic rats. Mod Rheumatol.
2017;27(5):838–48.
36. Ruff K, Kopp K, Von Behrens P, Lux M, Mahn M, Back M. Effectiveness of NEM brand eggshell
membrane in the treatment of suboptimal joint function in dogs: A multicenter, randomized, double-
blind, placebo-controlled study. Veterinary Med, Res Reports. 2016;7:113–21.
37. Benson KF, Ruff KJ, Jensen GS. Effects of natural eggshell membrane (NEM) on cytokine production
in cultures of peripheral blood mononuclear cells: Increased suppression of tumor necrosis factor-alpha
levels after in vitro digestion. J Med Food. 2012;15(4):360–8.
38. Ruff KJ, DeVore DP. Reduction of pro-inflammatory cytokines in rats following 7-day oral supplementation
with a proprietary eggshell membrane-derived product. Modern Res Inflammation. 2014;3(01):19.
39. Sim BY, Bak JW, Lee HJ, Jun J, Choi HJ, Kwon CJ et al. Effects of natural eggshell membrane (NEM)
on monosodium iodoacetate-induced arthritis in rats. J Nutr Health. 2015;48(4):310–8.
40. Kawabata A. Prostaglandin E2 and pain—An update. Biol Pharm Bull. 2011;34(8):1170–3.
41. Ruff KJ, Durham PL, O’Reilly A, Long FD. Eggshell membrane hydrolyzates activate NF-kappaB in
vitro: Possible implications for in vivo efficacy. J Inflamm Res. 2015;8:49–57.
42. Faria A, Weiner HL. Oral tolerance: Therapeutic implications for autoimmune diseases. J Immunol Res.
2006;13(2–4):143–57.
43. Shi Y, Kovacs-Nolan J, Jiang B, Tsao R, Mine Y. Antioxidant activity of enzymatic hydrolysates from
eggshell membrane proteins and its protective capacity in human intestinal epithelial Caco-2 cells.
J Funct Foods. 2014;10:35–45.
44. Shi Y, Rupa P, Jiang B, Mine Y. Hydrolysate from eggshell membrane ameliorates intestinal inflammation
in mice. Int J Mol Sci. 2014;15(12):22728–42.
45. Yang T, Li Y, Ma M, Lin Q, Sun S, Zhang B et al. Protective effect of soluble eggshell membrane protein
hydrolysate on cardiac ischemia/reperfusion injury. Food Nutr Res. 2015;59:28870.
46. Ruff KJ. Methods for treating glucose metabolic disorders. Google Patents; 2014.
47. Atomi Y, Shimizu M, Hasebe Y. Insulin resistance-improving agent containing eggshell membrane
component, and composition using the same. Google Patents; 2015.
48. MacLaren D, Morton J. Biochemistry for Sport and Exercise Metabolism. Wiley; 2011.
49. Uldry M, Yang W, St-Pierre J, Lin J, Seale P, Spiegelman BM. Complementary action of the PGC-1
coactivators in mitochondrial biogenesis and brown fat differentiation. Cell Metab. 2006;3(5):333–41.
50. Jia H, Saito K, Aw W, Takahashi S, Hanate M, Hasebe Y et al. Transcriptional profiling in rats and an ex
vivo analysis implicate novel beneficial function of egg shell membrane in liver fibrosis. J Funct Foods.
2013;5(4):1611–9.
51. Sherwin RS. Role of liver in glucose homeostasis. Diabetes Care. 1980;3(2):261–5.
52. Campbell B, Kreider RB, Ziegenfuss T, La Bounty P, Roberts M, Burke D et al. International Society of
Sports Nutrition position stand: Protein and exercise. J Int Soc Sports Nutr. 2007;4(1):8.
53. Hida A, Hasegawa Y, Mekata Y, Usuda M, Masuda Y, Kawano H et al. Effects of egg white
protein supplementation on muscle strength and serum free amino acid concentrations. Nutrients.
2012;4(10):1504–17.
54. Glynn EL, Fry CS, Drummond MJ, Timmerman KL, Dhanani S, Volpi E et al. Excess leucine intake
enhances muscle anabolic signaling but not net protein anabolism in young men and women. J Nutr.
2010;140(11):1970–6.
55. Blomstrand E, Hassmén P, Ekblom B, Newsholme EA. Administration of branched-chain amino acids
during sustained exercise—Effects on performance and on plasma concentration of some amino acids.
Eur J Appl Physiol Occup Physiol. 1991;63(2):83–8.
56. Rahimi MH, Shab-Bidar S, Mollahosseini M, Djafarian K. Branched-chain amino acid supplementation
and exercise-induced muscle damage in exercise recovery: A meta-analysis of randomized clinical trials.
Nutrition. 2017;42:30–6.
57. Mobley CB, Fox CD, Ferguson BS, Pascoe CA, Healy JC, McAdam JS et al. Effects of protein type
and composition on postprandial markers of skeletal muscle anabolism, adipose tissue lipolysis, and
hypothalamic gene expression. J Int Soc Sports Nutr. 2015;12(1):14.
58. Mine Y. Egg Bioscience and Biotechnology. Wiley; 2008.
59. Kovacs-Nolan J, Phillips M, Mine Y. Advances in the value of eggs and egg components for human
health. J Agric Food Chem. 2005;53(22):8421–31.
60. Cunningham F, Proctor V, Goetsch S. Egg-white lysozyme as a food preservative: An overview. Worlds
Poult Sci. 1991;47(2):141–63.
61. Shanbhag T, Shenoy S, Nayak V. Pharmacology for Dentistry. Elsevier Health Sciences; 2014.
62. Deaton J, Dawson H, Hersh T, Meyer C, Healey A. Natural antimicrobial compounds in small intestinal
bacterial overgrowth syndrome. Nat Med J. 2014;6(10).
63. Wang Y, Landheer S, van Gilst WH, van Amerongen A, Hammes H-P, Henning RH et al. Attenuation of
renovascular damage in Zucker diabetic fatty rat by NWT-03, an egg protein hydrolysate with ACE-and
DPP4-inhibitory Activity. PLOS ONE. 2012;7(10):e46781.
64. Giansanti F, Leboffe L, Angelucci F, Antonini G. The nutraceutical properties of ovotransferrin and its
potential utilization as a functional food. Nutrients. 2015;7(11):5453.
65. National Institutes of Health Office of Dietary Supplements. Choline Fact Sheet for Health Professionals
2018. Available from: https://ods.od.nih.gov/factsheets/Choline-HealthProfessional/
66. Food labeling: Revision of the nutrition and supplement facts labels. Final rule. Fed Regist. 2016;
81(103):33741–999.
67. Wallace TC, Fulgoni VL. Assessment of total choline intakes in the United States. J Am Coll Nutr. 2016;
35(2):108–12.
68. Moeller SM, Jacques PF, Blumberg JB. The potential role of dietary xanthophylls in cataract and age-
related macular degeneration. J Am Coll Nutr. 2000;19(sup5):522S–7S.
69. Ma L, Dou H-L, Wu Y-Q, Huang Y-M, Huang Y-B, Xu X-R et al. Lutein and zeaxanthin intake and the risk
of age-related macular degeneration: A systematic review and meta-analysis. Br J Nutr. 2012;107(3):350–9.
70. Chung H-Y, Rasmussen HM, Johnson EJ. Lutein bioavailability is higher from lutein-enriched eggs than
from supplements and spinach in men. J Nutr. 2004;134(8):1887–93.
71. Goodrow EF, Wilson TA, Houde SC, Vishwanathan R, Scollin PA, Handelman G et al. Consumption of
one egg per day increases serum lutein and zeaxanthin concentrations in older adults without altering
serum lipid and lipoprotein cholesterol concentrations. J Nutr. 2006;136(10):2519–24.
72. Vishwanathan R, Goodrow-Kotyla EF, Wooten BR, Wilson TA, Nicolosi RJ. Consumption of 2 and 4
egg yolks/d for 5 wk increases macular pigment concentrations in older adults with low macular pigment
taking cholesterol-lowering statins–. Am J Clin Nutr. 2009;90(5):1272–9.
73. Walk AM, Khan NA, Barnett SM, Raine LB, Kramer AF, Cohen NJ et al. From neuro-pigments to
neural efficiency: The relationship between retinal carotenoids and behavioral and neuroelectric indices
of cognitive control in childhood. Int J Psychophysiol. 2017;118:1–8.
74. Barnett SM, Khan NA, Walk AM, Raine LB, Moulton C, Cohen NJ et al. Macular pigment optical
density is positively associated with academic performance among preadolescent children. Nutr
Neurosci. 2017:1–9.
75. Wilson J, Lowery R, Mobley C, Healy J, Thompson R, Ashton R et al. The effects of fertilized egg yolk
isolates on anabolic and catabolic signaling in skeletal muscle. FASEB J. 2015;29(1 Supplement):819.1.
76. Lee S-J, McPherron AC. Regulation of myostatin activity and muscle growth. Proc Natl Acad Sci USA.
2001;98(16):9306–11.
77. McPherron AC, Lee S-J. Double muscling in cattle due to mutations in the myostatin gene. Proc Natl
Acad Sci USA. 1997;94(23):12457–61.
1. Valenze D. Milk: A Local and Global History. Yale University Press, New Haven; 2011.
2. McGregor RA, Poppitt SD. Milk protein for improved metabolic health: A review of the evidence. Nutr
Metab (Lond). 2013;10(1):46–58.
3. Haug A, Hostmark AT, Harstad OM. Bovine milk in human nutrition—A review. Lipids Health Dis.
2007;6:25–40.
4. Quann EE, Fulgoni VL, Auestad N. Consuming the daily recommended amounts of dairy products
would reduce the prevalence of inadequate micronutrient intakes in the United States: Diet modeling
study based on NHANES 2007–2010. Nutr J. 2015;14:90–100.
5. U.S. Department of Agriculture, Agricultural Research Service. USDA National Nutrient Database for
Standard Reference, Release 28 2016. Nutrient Data Laboratory Home Page. Last Accessed: August 30,
2018. Available at https://ndb.nal.usda.gov/ndb/.
6. Kukovics S, Németh T. Milk major and minor proteins, polymorphisms and non-protein nitrogen. In:
Milk and Dairy Products in Human Nutrition. John Wiley & Sons Ltd, Oxford; 2013.
7. Månsson HL. Fatty acids in bovine milk fat. Food Nutr Res. 2008;52:10–12.
8. Gaucheron F. Milk and dairy products: A unique micronutrient combination. J Am Coll Nutr.
2011;30:400S–9S.
9. U.S. Department of Health and Human Services and U.S. Department of Agriculture. 2015–2020 Dietary
Guidelines for Americans, 8th Edition; Dec 2015. Last Accessed: August 30, 2018. Available at: http://
health.gov/dietaryguidelines/2015/guidelines/.
10. Pereira PC. Milk nutritional composition and its role in human health. Nutrition. 2014;30(6):619–27.
11. Calvo MS, Whiting SJ, Barton CN. Vitamin D fortification in the United States and Canada: Current
status and data needs. Am J Clin Nutr. 2004;80:1710S–6S.
12. Schroeder HW, Cavacini L. Structure and function of immunoglobulins. J Allergy Clin Immunol.
2010;125:S41–S52.
13. MacDonald LE, Brett J, Kelton D, Majowicz SE, Snedeker K, Sargeant JM. A systematic review and
meta-analysis of the effects of pasteurization on milk vitamins, and evidence for raw milk consumption
and other health-related outcomes. J Food Prot. 2011;74(11):1814–32.
14. Lucey JA. Raw milk consumption: Risks and benefits. Nutr Today. 2015;50(4):189–93.
15. Zurera-Cosano G, Moreno-Rojas R, Amaro-Lopez M. Effect of processing on contents and relationships
of mineral elements of milk. Food Chem. 1994;51(1):75–8.
16. Sebastian RS, Goldman JD, Wilkinson Enns C, LaComb RP. Fluid milk consumption in the United
States: What we eat in America, NHANES 2005–2006. Food Surveys Research Group Dietary Data
Brief No. 3. September. 2010.
17. Beydoun MA, Gary TL, Caballero BH, Lawrence RS, Cheskin LJ, Wang Y. Ethnic differences in dairy
and related nutrient consumption among US adults and their association with obesity, central obesity,
and the metabolic syndrome. Am J Clin Nutr. 2008;87(6):1914–25.
18. Deshmukh-Taskar P, Nicklas TA, Yang S-J, Berenson GS. Does food group consumption vary by
differences in socioeconomic, demographic, and lifestyle factors in young adults? The Bogalusa Heart
Study. J Am Diet Assoc. 2007;107(2):223–34.
19. Racey M, Bransfield J, Capello K, Field D, Kulak V, Machmueller D, Preyde M, Newton G. Barriers and
facilitators to intake of dairy products in adolescent males and females with different levels of habitual
intake. Glob Pediatr Health. 2017;4:1–12.
20. Roy BD. Milk: The new sports drink? A review. J Int Soc Sports Nutr. 2008;5:15.
21. Austin SB, Yu K, Liu SH, Dong F, Tefft N. Household expenditures on dietary supplements sold for
weight loss, muscle building, and sexual function: Disproportionate burden by gender and income. Prev
Med Rep. 2017;6:236–41.
22. Bos C, Metges CC, Gaudichon C, Petzke KJ, Pueyo ME, Morens C, Everwand J, Benamouzig R, Tomé D.
Postprandial kinetics of dietary amino acids are the main determinant of their metabolism after soy or
milk protein ingestion in Humans. J Nutr. 2003;133(5):1308–15.
23. Wilkinson SB, Tarnopolsky MA, MacDonald MJ, MacDonald JR, Armstrong D, Phillips SM.
Consumption of fluid skim milk promotes greater muscle protein accretion after resistance exercise
than does consumption of an isonitrogenous and isoenergetic soy-protein beverage. Am J Clin Nutr.
2007;85(4):1031–40.
24. Tipton KD, Elliott TA, Cree MG, Wolf SE, Sanford AP, Wolfe RR. Ingestion of casein and whey
proteins result in muscle anabolism after resistance exercise. Am J Physiol Endocrinol Metab.
2004;36(12):2073–81.
25. Hartman JW, Tang JE, Wilkinson SB, Tarnopolsky MA, Lawrence RL, Fullerton AV, Phillips SM.
Consumption of fat-free fluid milk after resistance exercise promotes greater lean mass accretion
than does consumption of soy or carbohydrate in young, novice, male weightlifters. Am J Clin Nutr.
2007;86(2):373–81.
26. Miller SL, Gaine PC, Maresh CM, Armstrong LE, Ebbeling CB, Lamont LS, Rodriguez NR. The effects
of nutritional supplementation throughout an endurance run on leucine kinetics during recovery. Int J
Sport Nutr Exerc Metab. 2007;17(5):456–67.
27. Thomas K, Morris P, Stevenson E. Improved endurance capacity following chocolate milk consumption
compared with 2 commercially available sport drinks. Appl Physiol Nutr Metab. 2009;34(1):78–82.
28. Karp JR, Johnston JD, Tecklenburg S, Mickleborough TD, Fly AD, Stager JM. Chocolate milk as a
post-exercise recovery aid. Int J Sport Nutr Exerc Metab. 2006;16(1):78–91.
29. Dove ER, Hodgson JM, Puddey IB, Beilin LJ, Lee YP, Mori TA. Skim milk compared with a fruit
drink acutely reduces appetite and energy intake in overweight men and women. Am J Clin Nutr.
2009;90(1):70–5.
30. Pal S, Radavelli-Bagatini S, Hagger M, Ellis V. Comparative effects of whey and casein proteins on satiety
in overweight and obese individuals: A randomized controlled trial. Eur J Clin Nutr. 2014;68(9):980–6.
31. Bendtsen LQ, Lorenzen JK, Bendsen NT, Rasmussen C, Astrup A. Effect of dairy proteins on appetite,
energy expenditure, body weight, and composition: A review of the evidence from controlled clinical
trials. Adv Nutr. 2013;4(4):418–38.
32. Abreu S, Santos R, Moreira C, Santos PC, Vale S, Soares-Miranda L, Mota J, Moreira P. Milk intake is
inversely related to body mass index and body fat in girls. Eur J Ped. 2012;171(10):1467–74.
33. Berkey CS, Rockett HR, Willett WC, Colditz GA. Milk, dairy fat, dietary calcium, and weight gain: A
longitudinal study of adolescents. Arch Pediatr Adolesc Med. 2005;159(6):543–50.
34. Baer DJ, Stote KS, Paul DR, Harris GK, Rumpler WV, Clevidence BA. Whey protein but not soy protein
supplementation alters body weight and composition in free-living overweight and obese adults. J Nutr.
2011;141(8):1489–94.
35. Murphy KJ, Crichton GE, Dyer KA, Coates AM, Pettman TL, Milte C, Thorp AA et al. Dairy foods and
dairy protein consumption is inversely related to markers of adiposity in obese men and wome. Nutrients.
2013;5(11):4665–84.
36. Soedamah-Muthu SS, Ding EL, Al-Delaimy WK, Hu FB, Engberink MF, Willett WC, Geleijnse JM.
Milk and dairy consumption and incidence of cardiovascular diseases and all-cause mortality: Dose-
response meta-analysis of prospective cohort studies. Am J Clin Nutr. 2011;93(1):158–71.
37. Chen GC, Szeto IM, Chen LH, Han SF, Li YJ, van Hekezen R, Qin LQ. Dairy products consumption and
metabolic syndrome in adults: Systematic review and meta-analysis of observational studies. Sci Rep.
2015;5:14606–15.
38. Babio N, Becerra-Tomas N, Martinez-Gonzalez MA, Corella D, Estruch R, Ros E, Sayon-Orea C et al.
PREDIMED Investigators. Consumption of yogurt, low-fat milk, and other low-fat dairy products is
associated with lower risk of metabolic syndrome incidence in an elderly mediterranean population. J
Nutr. 2015;145(10):2308–16.
39. Elwood PC, Givens DI, Beswick AD, Fehily AM, Pickering JE, Gallacher J. The survival advantage of
milk and dairy consumption: An overview of evidence from cohort studies of vascular diseases, diabetes
and cancer. J Am Coll Nutr. 2008;27(6):723S–34S.
40. Gao D, Ning N, Wang C, Wang Y, Li Q, Meng Z, Liu Y, Li Q. Dairy products consumption and risk of
type 2 diabetes: Systematic review and dose-response meta-analysis. PLoS One. 2013;8(9):e73965–79.
41. Gijsbers L, Ding EL, Malik VS, de Goede J, Geleijnse JM, Soedamah-Muthu SS. Consumption of dairy
foods and diabetes incidence: A dose-response meta-analysis of observational studies. Am J Clin Nutr.
2016;103(4):1111–24.
42. Li J, Janle E, Campbell WW. Postprandial glycemic and insulinemic responses to common breakfast
beverages consumed with a standard meal in adults who are overweight and obese. Nutrients.
2017;9(1):32–44.
43. Decode Study Group on behalf of the European Diabetes Epidemiology Group. Glucose tolerance
and cardiovascular mortality: Comparison of fasting and 2-hour diagnostic criteria. Arch Intern Med.
2001;161(3):397–405.
44. Law M, Huot PSP, Lee YT, Vien S, Luhovyy BL, Anderson GH. The effect of dairy and nondairy
beverages consumed with high glycemic cereal on subjective appetite, food intake, and postprandial
glycemia in young adults. Appl Physiol Nutr Metab. 2017;42(11):1201–9.
45. Gunnerud U, Holst JJ, Ostman E, Bjorck I. The glycemic, insulinemic and plasma amino acid responses
to equi-carbohydrate milk meals, a pilot—Study of bovine and human milk. Nutr J. 2012;11:83–91.
46. Pal S, Ellis V, Dhaliwal S. Effects of whey protein isolate on body composition, lipids, insulin and
glucose in overweight and obese individuals. Br J Nutr. 2010;104(5):716–23.
47. Stancliffe RA, Thorpe T, Zemel MB. Dairy attentuates oxidative and inflammatory stress in metabolic
syndrome. Am J Clin Nutr. 2011;94(2):422–30.
48. Hall WL, Millward DJ, Long SJ, Morgan LM. Casein and whey exert different effects on plasma amino
acid profiles, gastrointestinal hormone secretion and appetite. Br J Nutr. 2003;89(2):239–48.
49. Calbet JA, Holst JJ. Gastric emptying, gastric secretion and enterogastrone response after administration
of milk proteins or their peptide hydrolysates in humans. Eur J Nutr. 2004;43(3):127–39.
50. Hoefle AS, Bangert AM, Stamfort A, Gedrich K, Rist MJ, Lee YM, Skurk T, Daniel H. Metabolic
responses of healthy or prediabetic adults to bovine whey protein and sodium caseinate do not differ. J
Nutr. 2015;145(3):467–75.
51. Rideout TC, Marinangeli CPF, Martin H, Browne RW, Rempel CB. Consumption of low-fat dairy foods
for 6 months improves insulin resistance without adversely affecting lipids or bodyweight in healthy
adults: A randomized free-living cross-over study. Nutr J. 2013;12:56–64.
52. Mortensen LS, Hartvigsen ML, Brader LJ, Astrup A, Schrezenmeir J, Holst JJ, Thomsen C, Hermansen
K. Differential effects of protein quality on postprandial lipemia in response to a fat-rich meal in type 2
diabetes: Comparison of whey, casein, gluten, and cod protein. Am J Clin Nutr. 2009;90(1):41–8.
53. Westphal S, Taneva E, Kästner S, Martens-Lobenhoffer J, Bode-Böger S, Kropf S, Dierkes J, Luley C.
Endothelial dysfunction induced by postprandial lipemia is neutralized by addition of proteins to the
fatty meal. Atherosclerosis. 2006;185(2):313–9.
54. Weisse K, Brandsch C, Zernsdorf B, Nkengfack Nembongwe GS, Hofmann K, Eder K, Stangl GI. Lupin
protein compared to casein lowers the LDL cholesterol:HDL cholesterol-ratio of hypercholesterolemic
adults. Eur J Nutr. 2010;49(2):65–71.
55. Steinmetz KA, Childs MT, Stimson C, Kushi LH, McGovern PG, Potter JD, Yamanaka WK. Effect
of consumption of whole milk and skim milk on blood lipid profiles in healthy men. Am J Clin Nutr.
1994;59(3):612–8.
56. Buonopane GJ, Kilara A, Smith JS, McCarthy RD. Effect of skim milk supplementation on blood
cholesterol concentration, blood pressure, and triglycerides in a free-living human population. J Am
Coll Nutr. 1992;11(1):56–67.
57. Elwood PC, Pickering JE, Givens DI, Gallacher JE. The consumption of milk and dairy foods and the
incidence of vascular disease and diabetes: An overview of the evidence. Lipids. 2010;45(10):925–39.
58. Soedamah-Muthu SS, Verberne LD, Ding EL, Engberink MF, Geleijnse JM. Dairy consumption and
incidence of hypertension: A dose-response meta-analysis of prospective cohort studies. Hypertension.
2012;60(5):1131–7.
59. Ballard KD, Bruno RS. Protective role of dairy and its constituents on vascular function independent of
blood pressure-lowering activities. Nutr Rev. 2015;73(1):36–50.
60. Maki KC, Rains TM, Schild AL, Dicklin MR, Park KM, Lawless AL, Kelley KM. Effects of low-fat dairy
intake on blood pressure, endothelial function, and lipoprotein lipids in subjects with prehypertension or
stage 1 hypertension. Vasc Health Risk Manag. 2013;9:369–79.
61. Fekete ÁA, Giromini C, Chatzidiakou Y, Givens DI, Lovegrove JA. Whey protein lowers blood
pressure and improves endothelial function and lipid biomarkers in adults with prehypertension and
mild hypertension: Results from the chronic Whey2Go randomized controlled trial. Am J Clin Nutr.
2016;104(6):1534–44.
62. Yoshizawa M, Maeda S, Miyaki A, Misono M, Choi Y, Shimojo N, Ajisaka R, Tanaka H. Additive
beneficial effects of lactotripeptides intake with regular exercise on endothelium-dependent dilatation
in postmenopausal women. Am J Hypertens. 2010;23(4):368–72.
63. Mah E, Bruno RS. Postprandial hyperglycemia on vascular endothelial function: Mechanisms and
consequences. Nutr Res. 2012;32(10):727–40.
64. Ballard KD, Mah E, Guo Y, Pei R, Volek JS, Bruno RS. Low-fat milk ingestion prevents postprandial
hyperglycemia-mediated impairments in vascular endothelial function in obese individuals with
metabolic syndrome. J Nutr. 2013;143(10):1602–10.
65. Fekete AA, Givens DI, Lovegrove JA. The impact of milk proteins and peptides on blood pressure and
vascular function: A review of evidence from human intervention studies. Nutr Res Rev. 2013;26(2):177–90.
66. Ballard KD, Kupchak BR, Volk BM, Mah E, Shkreta A, Liptak C, Ptolemy AS et al. Acute effects of
ingestion of a novel whey-derived extract on vascular endothelial function in overweight, middle-aged
men and women. Br J Nutr. 2013;109(5):882–93.
67. Bordoni A, Danesi F, Dardevet D, Dupont D, Fernandez AS, Gille D, Nunes Dos Santos C et al.
Dairy products and inflammation: A review of the clinical evidence. Crit Rev Food Sci Nutr.
2017;57(12):2497–525.
68. Nestel PJ, Pally S, MacIntosh GL, Greeve MA, Middleton S, Jowett J, Meikle PJ. Circulating inflammatory
and atherogenic biomarkers are not increased following single meals of dairy foods. Eur J Clin Nutr.
2011;66(1):25–31.
69. Drouin-Chartier J-P, Brassard D, Tessier-Grenier M, Côté JA, Labonté M-È, Desroches S, Couture
P, Lamarche B. Systematic review of the association between dairy product consumption and risk of
cardiovascular-related clinical outcomes. Adv Nutr. 2016;7(6):1026–40.
70. Castiglioni S, Cazzaniga A, Albisetti W, Maier JA. Magnesium and osteoporosis: Current state of
knowledge and future research directions. Nutrients. 2013;5(8):3022–33.
71. Bikle DD. Vitamin D and bone. Curr Osteoporos Rep. 2012;10(2):151–9.
72. Sato Y, Iki M, Fujita Y, Tamaki J, Kouda K, Yura A, Moon JS et al. Greater milk intake is associated
with lower bone turnover, higher bone density, and higher bone microarchitecture index in a population
of elderly Japanese men with relatively low dietary calcium intake: Fujiwara-kyo Osteoporosis Risk in
Men (FORMEN) Study. Osteoporos Int. 2015;26(5):1585–94.
73. Kalkwarf HJ, Khoury JC, Lanphear BP. Milk intake during childhood and adolescence, adult bone
density, and osteoporotic fractures in US women. Am J Clin Nutr. 2003;77(1):257–65.
74. Eysteinsdottir T, Halldorsson TI, Thorsdottir I, Sigurdsson G, Sigurethsson S, Harris T, Launer LJ,
Gudnason V, Gunnarsdottir I, Steingrimsdottir L. Milk consumption throughout life and bone mineral
content and density in elderly men and women. Osteoporos Int. 2014;25(2):663–72.
75. Goulding A, Rockell JEP, Black RE, Grant AM, Jones IE, Williams SM. Children who avoid drinking
cow’s milk are at increased risk for prepubertal bone fractures. J Am Diet Assoc. 2004;104(2):250–3.
76. Nielsen SJ, Popkin BM. Changes in beverage intake between 1977 and 2001. Am J Prev Med.
2004;27(3):205–10.
77. Davoodi H, Esmaeili S, Mortazavian AM. Effects of milk and milk products consumption on cancer: A
review. Compr Rev Food Sci Food Saf. 2013;12(3):249–64.
78. Aune D, Navarro Rosenblatt DA, Chan DS, Vieira AR, Vieira R, Greenwood DC, Vatten LJ, Norat T.
Dairy products, calcium, and prostate cancer risk: A systematic review and meta-analysis of cohort
studies. Am J Clin Nutr. 2015;101(1):87–117.
79. Ursin G, Bjelke E, Heuch I, Vollset SE. Milk consumption and cancer incidence: A Norwegian prospective
study. Br J Cancer. 1990;61(3):456–9.
80. Yu Y, Li H, Xu K, Li X, Hu C, Wei H, Zeng X, Jing X. Dairy consumption and lung cancer risk: A meta-
analysis of prospective cohort studies. Onco Targets Ther. 2016;9:111–6.
81. Dong JY, Zhang L, He K, Qin LQ. Dairy consumption and risk of breast cancer: A meta-analysis of
prospective cohort studies. Breast Cancer Res Treat. 2011;127(1):23–31.
82. Guo Y, Shan Z, Ren H, Chen W. Dairy consumption and gastric cancer risk: A meta-analysis of
epidemiological studies. Nutr Cancer. 2015;67(4):555–68.
83. Wang Y, Li S. Worldwide trends in dairy production and consumption and calcium intake: Is promoting
consumption of dairy products a sustainable solution for inadequate calcium intake? Food Nutr Bull.
2008;29(3):172–85.
84. Rautiainen S, Wang L, Lee IM, Manson JE, Buring JE, Sesso HD. Dairy consumption in association with
weight change and risk of becoming overweight or obese in middle-aged and older women: A prospective
cohort study. Am J Clin Nutr. 2016;103(4):979–88.
85. Rosell M, Håkansson NN, Wolk A. Association between dairy food consumption and weight change
over 9 y in 19,352 perimenopausal women. Am J Clin Nutr. 2006;84(6):1481–8.
86. Beck AL, Heyman M, Chao C, Wojcicki J. Full fat milk consumption protects against severe childhood
obesity in Latinos. Prev Med Rep. 2017;8:1–5.
87. Drouin-Chartier J-P, Côté JA, Labonté M-È, Brassard D, Tessier-Grenier M, Desroches S, Couture P,
Lamarche B. Comprehensive review of the impact of dairy foods and dairy fat on cardiometabolic risk.
Adv Nutr. 2016;7(6):1041–51.
88. Engel S, Elhauge M, Tholstrup T. Effect of whole milk compared with skimmed milk on fasting blood
lipids in healthy adults: A 3-week randomized crossover study. Eur J Clin Nutr. 2018;72(2):249–54.
89. Sanders TA, Lewis FJ, Goff LM, Chowienczyk PJ, on behalf of the RISCK Study Group. SFAs do not
impair endothelial function and arterial stiffness. Am J Clin Nutr. 2013;98(3):677–83.
90. Alonso A, Zozaya C, Vazquez Z, Alfredo Martinez J, Martinez-Gonzalez MA. The effect of low-fat
versus whole-fat dairy product intake on blood pressure and weight in young normotensive adults. J Hum
Nutr Diet. 2009;22(4):336–42.
91. Drouin-Chartier JP, Gagnon J, Labonte ME, Desroches S, Charest A, Grenier G, Dodin S, Lemieux S,
Couture P, Lamarche B. Impact of milk consumption on cardiometabolic risk in postmenopausal women
with abdominal obesity. Nutr J. 2015;14:12–21.
92. Sjogren P, Rosell M, Skoglund-Andersson C, Zdravkovic S, Vessby B, de Faire U, Hamsten A, Hellenius
M-L, Fisher RM. Milk-derived fatty acids are associated with a more favorable LDL particle size
distribution in healthy men. J Nutr. 2004;134(7):1729–35.
93. Bjornshave A, Hermansen K. Effects of dairy protein and fat on the metabolic syndrome and type 2
diabetes. Rev Diabet Stud. 2014;11(2):153–66.
94. Kratz M, Baars T, Guyenet S. The relationship between high-fat dairy consumption and obesity,
cardiovascular, and metabolic disease. Eur J Nutr. 2013;52(1):1–24.
95. Rice BH, Cifelli CJ, Pikosky MA, Miller GD. Dairy components and risk factors for cardiometabolic
syndrome: Recent evidence and opportunities for future research. Adv Nutr. 2011;2(5):396–407.
96. Parvez S, Malik KA, Ah Kang S, Kim HY. Probiotics and their fermented food products are beneficial
for health. J Appl Microbiol. 2006;100(6):1171–85.
97. Heaney RP. Dairy intake, dietary adequacy, and lactose intolerance. Adv Nutr. 2013;4(2):151–6.
98. Deng Y, Misselwitz B, Dai N, Fox M. Lactose intolerance in adults: Biological mechanism and dietary
management. Nutrients. 2015;7(9):8020–35.
99. Stephenson LS, Latham MC. Lactose intolerance and milk consumption: The relation of tolerance to
symptoms. Am J Clin Nutr. 1974;27(3):296–303.
100. Di Rienzo T, D’Angelo G, D’Aversa F, Campanale MC, Cesario V, Montalto M, Gasbarrini A, Ojetti V.
Lactose intolerance: From diagnosis to correct management. Eur Rev Med Pharmacol Sci. 2013;17:18–25.
101. Misselwitz B, Pohl D, Fruhauf H, Fried M, Vavricka SR, Fox M. Lactose malabsorption and intolerance:
Pathogenesis, diagnosis and treatment. United European Gastroenterol J. 2013;1(3):151–9.
102. de Vrese M, Stegelmann A, Richter B, Fenselau S, Laue C, Schrezenmeir J. Probiotics-compensation for
lactase insufficiency. Am J Clin Nutr. 2001;73(2 Suppl):421S–9S.
103. Itan Y, Jones BL, Ingram CJ, Swallow DM, Thomas MG. A worldwide correlation of lactase persistence
phenotype and genotypes. BMC Evol Biol. 2010;10:36–46.
104. Wilt TJ, Shaukat A, Shamliyan T, Taylor BC, MacDonald R, Tacklind J, Rutks I, Schwarzenberg SJ, Kane
RL, Levitt M. Lactose intolerance and health. Evid Rep Technol Assess (Full Rep, No. 192). 2010:1–410.

Preview PDF

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Preview PDF

Uploaded by

Copyright:

Available Formats

Handbook of Nutraceuticals

and Functional Foods

© 2020 by Taylor & Francis Group, LLC

No claim to original U.S. Government works

Printed on acid-free paper

International Standard Book Number-13: 978-1-4987-0372-7 (Hardback)

Unit I Overview of Nutraceuticals and Functional Foods

Chapter 1 Nutraceuticals and Functional Foods............................................................................3

Chapter 2 Regulation of Nutraceuticals and Functional Foods................................................... 23

Unit II Plant-Derived Nutraceuticals

Chapter 3 Lycopene: Food Sources, Properties, and Effects on Human Health......................... 37

Chapter 4 Lutein in Neural Health and Disease.......................................................................... 55

Chapter 6 The Role of Tocopherols in Health........................................................................... 105

Chapter 7 Health Benefits of Green Tea.................................................................................... 127

Chapter 8 Scientific, Legal, and Regulatory Considerations for Cannabidiol........................... 147

Chapter 9 Coffee as a Functional Beverage............................................................................... 159

Chapter 10 Dietary Fiber and Coronary Heart Disease.............................................................. 173

Chapter 11 Anthocyanins and Their Health Benefits.................................................................. 189

Chapter 12 Olive Oil and Health Benefits................................................................................... 211

Chapter 13 Nutraceutical Herbs and Insulin Resistance............................................................. 223

Unit III Food Nutraceuticals from Animals

Chapter 14 Protein as a Functional Food Ingredient for Optimizing Weight Loss

Chapter 15 Nutraceutical Application of Creatine....................................................................... 267

Chapter 16 Chicken Eggs and Human Health............................................................................. 295

Chapter 17 Dairy Milk: A Functional Beverage for Human Health...........................................307

Investigative opportunities are clearly endless. Large-scale epidemiological studies routinely

Richard S. Bruno, PhD, is a professor of human nutrition at The

Richard S. Bruno Douglas S. Kalman

Victoria Burgess Chad M. Kerksick

Amy D. Mackey Sharon A. Ross

1.2 DEFINING NUTRACEUTICALS AND FUNCTIONAL FOODS

1.3 CLASSIFYING NUTRACEUTICAL FACTORS

and to reduce free radical or platelet-dependent thrombotic activity. Accordingly, nutraceutical

1.4 FOOD AND NONFOOD SOURCES OF NUTRACEUTICAL FACTORS

1.5 NUTRACEUTICAL FACTORS IN SPECIFIC FOODS

β-Glucan Conjugated Linoleic Acid (CLA) Saccharomyces boulardii (yeast)

1.6 MECHANISM OF ACTION

1.7 CLASSIFYING NUTRACEUTICAL FACTORS BASED ON CHEMICAL NATURE

As scientific investigation continues, several hundred substances will probably be deemed

FIGURE 1.1 Organizational scheme for nutraceuticals.

1.7.1 Isoprenoid Derivatives (Terpenoids)

FIGURE 1.2 Isoprene.

FIGURE 1.3 The mevalonic acid pathway.

CH3 CH3 CH2

H3C CH2 H3 C H3C

Limonene Menthol Myrcene

FIGURE 1.5 Structure of select monoterpenes.

FIGURE 1.6 Examples of triterpenes.

FIGURE 1.7 Production of plant phenolic molecules via phenylalanine.

1.7.3 Carbohydrates and Derivatives

FIGURE 1.10 Basic tannin structure formed from phenolic units.

1.7.4 Fatty Acids and Structural Lipids

1.7.5 Amino Acid –Based

162. Campbell S, Stone W, Whaley S, Krishnan K. Development of gamma (gamma)-tocopherol as a

You might also like