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LOUIS S. PREMKUMAR, PhD
PROFESSOR OF PHARMACOLOGY
LOUIS S. PREMKUMAR, PhD
Copyright © 2014 by Louis S. Premkumar, PhD.
Library of Congress Control Number: 2013922064
ISBN: Hardcover 978-1-4931-5001-4
Softcover 978-1-4931-5000-7
eBook 978-1-4931-5002-1
All rights reserved. No part of this book may be reproduced or transmitted in any
form or by any means, electronic or mechanical, including photocopying, recording,
or by any information storage and retrieval system, without permission in writing
from the copyright owner.
The Fascinating Facts about Ingredients in Spices and Healthy food—is for general
health information only. The descriptions in this book are not to be used as a
substitute for medical advice, diagnosis or treatment of any health condition or
problem. Readers should not rely on information provided in this book for their
own health problems. Any questions regarding your own health should be addressed
to your own physician or other healthcare provider. The information provided in
this book with the understanding that the author and publisher are not providing
medical, psychological, or nutritional counseling services. The information should
not be used in place of a consultation with a competent health care or nutrition
professional. Liability for individual actions or omissions based upon the contents of
this book is expressly disclaimed.
This book was printed in the United States of America.
Rev. date: 03/19/2014
To order additional copies of this book, contact:
Xlibris LLC
1-888-795-4274
www.Xlibris.com
Orders@Xlibris.com
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CONTENTS
Preface ...................................................................................................13
Chapter 1: Introduction ......................................................................19
Chapter 2: Basic Nutritional Requirements of the Organisms .............30
Chapter 3: Neurobiology of Appetite,
Feeding, Satiation, and Satiety ...........................................58
Chapter 4: Spices That Appeal to Nostrils (Olfaction)
and Palate (Gustation) .......................................................95
Chapter 5: Ingredients in Spices
That Produce Health Benefits .........................................106
Chapter 6: Ingredients in Foods
That Produce Health Benefits .........................................158
Chapter 7: Microbiota of the Intestinal
Tract and its Role in Disease ............................................205
7
DEDICATION
This book is dedicated to my parents. My father is 87 years of age and
has never been admitted to a hospital. He keeps up a routine physical
activity, eats nutritious healthy food garnished with spices consisting of
vegetables, fruits, legumes and plenty of home made yogurt.
9
ACKNOWLEDGEMENTS
I would like to thank Somaja Louis, Kathleen Louis, Mahendra Bishnoi
and Patricia Steffen for critically reading the manuscript.
11
IMPORTANT TABLES
IN THE BOOK
Table 1: Sources of Vitamins and their Effects ......................................47
Table 2: Essential Minerals ...................................................................50
Table 3: Triglyceride Levels ...................................................................51
Table 4: Cholesterol Levels ...................................................................51
Table 5: Low-Density Lipoprotein (LDL) Levels ..................................52
Table 6: Very-Low-Density Lipoprotein (VLDL) Levels .......................52
Table 7: High-Density Lipoprotein (HDL) Levels ................................53
Table 8: Blood Sugar Levels ..................................................................53
Table 9: Normal and Abnormal Blood Pressure Measures .....................54
Table 10: Diet-Related Diseases in the
United States of America .......................................................54
Table 11: Important Risk Factors for
Heart Disease in US ..............................................................55
Table 12: Life Style Modification to
Control Blood Pressure ..........................................................56
Table 13: Caloric Values of Milk ........................................................187
Table 14: of Sugar Content in Fruits
and Their Glycemic Index ...................................................188
Table 15: List of Phytochemicals, Their Sources,
and Health Benefits ............................................................189
13
PREFACE
For centuries, there have been implications that healthy food garnished
with exotic spices and condiments provides vital ingredients that help
ward off diseases and promote longevity. Obviously, it appears to be true
based on the evidence that people who consume healthy, wholesome
food as individuals or as a group in certain parts of the world, the
so-called blue regions, have enjoyed health benefits, using longevity as a
metric. For example, Seventh-day Adventists with their pure vegetarian
diet have a lower incidence of heart disease, diabetes, and certain types
of cancers; Kuna Indians in Panama, who consume large quantities of
unprocessed cocoa-containing beverages, show lower incidence of heart
disease; and finally, Inuit Eskimos of Iceland, whose staple food consists
of large quantities of fatty fish with high levels of omega-3 fatty acids,
suffer from lower incidence of heart disease and stroke. More recently,
the Mediterranean diet, which consists of olive oil, fresh produce, fish,
and wine, has been shown to reduce the incidence of grave diseases.
However, these claims are marred with ambiguities of health benefits
because large-scale randomized clinical trials have not been undertaken.
Even reputed institutions, such as the National Institutes of Health
(NIH), Federal Drug Administration (FDA), and European Food Safety
Authority (EFSA), have promulgated skepticism.
The purpose of writing this book is not to add to the list of books
that provides anecdotal evidences of the health benefits of spices and
food ingredients but to undertake a thorough, objective analysis of the
known active ingredients in spices and condiments and to critically
evaluate the lines of scientific evidence that exist for the claims of health
benefits, utilizing experimental observations and large evidence-based
scientific studies, where available. The ultimate proof of health benefits
14 Louis s. Premkumar, PhD
will be presented by the identification of specific receptors and the effects
brought about by active ingredients selectively binding to these receptors.
Some of the evidences include scientific publications from my own
laboratory.
If there are specific receptors in the body for the active ingredients
in spices, although the health benefits cannot be demonstrated readily,
they have to be taken seriously. The reason that health benefits have
not been demonstrated convincingly for certain ingredients is because
the effect may not be readily quantifiable. Furthermore, if there is a
receptor, there has to be an endogenous ligand for it in the body. An
example that is often referred to are the effects of opioids and cannabis.
These are plant products whose active ingredients are morphine and
tetrahydrocannabinol (THC), respectively induce significant effects when
ingested in minute quantities. Intriguingly, the compound cannabidiol in
cannabis, which is considered to be inert, has recently revealed its efficacy
as a wonder drug to treat refractory epilepsies in children. Morphine is
used as a painkiller in intractable pain conditions. When its receptors
are activated (more likely, when overactivated), pain is relieved but also
contributes to euphoria (a sense of well-being) and engages the reward
pathways in the brain circuitry that leads to drug dependence. Endorphin
and enkephalin are the endogenous ligands for morphine receptors. A
general sense of well-being is achieved when the levels of these peptides
are increased by strenuous exercise—a natural pain reliever and a
self-applauder of the accomplishment. This is the basis for people who
indulge in compulsive exercise routines.
The important point being emphasized is that when the effect or
the untoward effect is glaring, because of a perceivable or a measurable
physiological response, an active ingredient may be considered to elicit
a significant effect. However, even when the physiological effect is
significant, but not easily perceivable, then the effect of a particular
ingredient goes unnoticed, and the effectiveness can be questioned as a
myth. For example, some vitamins are needed in very minute quantities
(vitamin B12, 1 μg [1 part per million], and vitamin D, 5 μg), and there
are no immediate measurable effects. However, lack of vitamins will
manifest as a disease over a period of time; the lack of vitamin B12 will
cause anemia, and the lack of vitamin D will lead to rickets in children.
This is an exciting time to write this book because now the specific
receptors for several of these active ingredients are being identified,
cloned, and characterized, which means a specific hypothesis can
15Fascinating Facts about Phytonutrients in sPices and healthy Food
be proposed and tested experimentally to infer a scientific validity.
For example, there are more than four thousand chemicals in dried
tobacco leaves, but nicotine is the key ingredient that acts on specific
receptors, which stimulate the central nervous system, engage the reward
pathways, and compel one to smoke. Nicotine acts on specific neuronal
acetylcholine receptors in the brain. Similarly, coffee beans have several
ingredients, but caffeine is the ingredient that binds to specific adenosine
receptors in the brain that normally inhibit neurotransmission, thereby
reversing the inhibition and stimulating the neurons in the central
nervous system. It is also necessary to identify the molecules other than
the proposed active ingredients since there are several chemical molecules
in these plant products.
For other spice ingredients, specific receptors are being identified.
For example, the specific receptor for the active ingredient in hot chili
peppers is capsaicin, which activates a member of a recently identified
family of receptors called as transient receptor potential (TRP) channels,
known as TRP vanilloid 1 (TRPV1). The receptor for the active
ingredients in garlic (allicin), yellow mustard (allyl isothiocyanate), and
cinnamon (cinnamaldehyde) has been identified to be TRP ankyrin 1
(TRPA1). Specific receptors for other ingredients will be identified in the
future; of course, it is an evolving field. The idea is to provide a scientific
basis for consuming food with spices and condiments that will provide
health benefits by warding off diseases and promoting longevity. The
active ingredient of turmeric is called curcumin. The claimed effects of
curcumin range from relieving flatulence to curing Alzheimer’s disease
and cancer. However, the bioavailability of curcumin is very low, meaning
that when it is consumed orally, it is not available systemically to produce
actions either because it is not absorbed or it is metabolized rapidly by
the liver (known as first-pass metabolism). Several potent drugs have
failed to enter clinical trials because of low bioavailability. It is important
to emphasize that these ingredients can cause significant effects locally
in the gastrointestinal (GI) tract by preventing absorption of certain
nutrients and causing the release of gut hormones that are involved in
appetite and satiety. Activation of TRPA1 channels causes the release of
glucagon-like peptide-1 (GLP-1), a potent hormone and can promote
insulin release and control blood glucose levels. It is fascinating to learn
that during a specific type of bariatric surgery procedure (Roux-en-Y) that
involves transposition of the ileum (a part of the small intestine), which
is directly connected to the upper end of the stomach, unexpectedly, the
16 Louis s. Premkumar, PhD
GLP-1 levels increased by severalfold. In patients who had been taking
insulin for controlling diabetes, the surgery completely reversed the
requirement of insulin within a few days before being discharged from
the hospital. When food is directly exposed to the ileum, certain food
ingredients are able to stimulate specialized cells in the small intestine
called enteroendocrine cells, which cause the release of GLP-1. In normal
conditions, these ingredients may not be available because of the high
acidity (pH 2-3) of the stomach and due to other gastric enzymes that
are released during digestion of food, which may destroy the active
ingredients. It is also possible that the active ingredients are absorbed
before reaching the ileum. This further emphasizes the local effects of
food ingredients in the GI tract although they have low bioavailability.
Some of the receptors activated by food ingredient are ion channels with
high calcium permeability. Excessive calcium influx can cause cell death
in rapidly proliferating cells and prevent cancer growth.
It is becoming evident that the commensal microorganisms dwelling
in the gut have significant effect on the health benefits. Incidence
of colon cancer has been associated with food habits, especially high
intake of processed meat. High-fiber diet has been shown to decrease
the incidence of colon cancer. Although, a clear genetic predisposition
has been demonstrated for the chance of getting colon cancer, there
are certain microorganisms that harbor the colonic flora, such as
Bacteroides and Clostridium, that have been associated with increased
incidences of cancer. Probiotic treatment has been shown to produce
health benefits; most of the probiotics contain the bacterial genera
Lactobacillus and Bifidobacterium. The lower incidence of intestinal
cancer in people in Asian countries eating food containing spices may
be because of the antibacterial effects of the ingredients that subdue
certain bacterial species. High-fat and high-sugar Western diet increased
the Firmicutes and decreased Bacteroidetes as compared to low-fat and
high-polysaccharide diet. Further, in obese individuals, there is an
increased number of Firmicutes and lower number of Bacteroidetes;
thus an elevated ratio between these organisms portends the tendency
to develop obesity. Subduing microbiota by spice ingredients can partly
explain the claim that spicy food protects one from gaining excess weight.
A fascinating finding was recently published that carnitine from red
meat, and its addition in high-energy drinks and health supplements,
is metabolized by microbiota to trimethylamine N-oxide (TMAO),
which is absorbed into the system. The blood levels of TMAO are more
17Fascinating Facts about Phytonutrients in sPices and healthy Food
correlative than the levels of cholesterol with regard to predisposition to
develop atherosclerosis and coronary artery disease.
Several monographs and books have been written, covering this
topic extensively. Most of them list anecdotal evidences quoting
published results, where experiments have been performed in in-vitro
(outside the body) conditions by using unphysiological concentrations
of active ingredients if known or using concentrated plant extracts to
obtain positive results. These experiments are generally performed in
in-vitro conditions using cell lines, which are immortalized and rapidly
proliferating cells. There is some validity to the observations made in
these experiments because higher concentrations of some of the active
ingredients can be achieved when the ingredients are in direct contact
with the cells of the GI tract. Further, oral consumption may have
the ability to prevent the development of gastrointestinal cancers by
eliminating rapidly multiplying cells by activating/inhibiting a variety
of pathways. The role of ingredients subduing the microbiota can exert
significant effects. Further, the bioavailability (the amount of the active
ingredient that is absorbed and available for action in the body) is very
low for some of these compounds and unknown for others. If one
looks at the comments of the authors who have researched and written
extensively in these areas, it is perplexing. A review by a well-known
curcumin researcher concludes, “Most of the biomolecules that
curcumin binds to are integral components of cell signaling pathways
and therefore may be pharmacologically relevant. However, most of the
direct interaction data obtained to date are based on in vitro studies.
Only limited studies have shown functional consequences of curcumin
interaction. In many instances, what may occur in vivo is still not clear.
In spite of numerous reports showing pleiotropic activity, curcumin has
yet not been approved for treatment of any human disease, even though
it has been reported to be safe for humans at gram dosages.” Another
book chapter concludes, “In summary, ginger has been reported to
possess diverse pharmacological properties, although its specific biological
targets are largely unknown and remain to be determined. However,
in spite of the lack of specific mechanistic information, use of ginger
appears to be safe and its effects are mighty and amazing in its many
applications.”
In summary, food containing beneficial ingredients has to be
consumed in moderation. The beneficial effects are not observed
immediately but over a period of months or years. These ingredients
18 Louis s. Premkumar, PhD
make the food more palatable so that one can enjoy eating vegetables,
greens, and legumes. All the healthy ingredients can prevent or delay
developing a disease. Once a disease has manifested, the only option to
combat is to consult with a physician and take appropriate medications
that have been unequivocally proven to be effective in large clinical
trials. For example, once a major coronary artery that supplies blood to
the heart muscle is occluded, there are no remedies other than increasing
the patency of the blood vessel by placing a stent or performing a bypass
surgery to reroute the blood flow. Similarly, when pancreatic beta cells
are destroyed and the production of insulin is ceased, one must take
insulin injections to survive. However, following a healthy lifestyle and
consuming food with healthy ingredients can reduce the dosage of the
medications, along with the side effects of the drugs, allowing one to have
a high-quality and productive life with normal life-expectancy.
19
CHAPTER 1
Introduction
Large and energetic animals, such as elephants and lions respectively,
require large quantities of food to maintain their energy requirements
for body mass as well as for physical activities. Herbivorous animals, like
elephants, spend most of the day seeking food and consuming 650-770
pounds of food consisting of grass, shrubs, fruits, etc., per day, by living
in the forests. They have developed a sense to consume the right kind
of vegetation to fulfill the nutritional requirements of their bodies and
to survive. It is hard to comprehend that the elephant is able to gather
the right kind of vegetation that provides a diet enriched with minerals
and vitamins necessary for its well-being. It is intriguing how well their
taste buds are developed or how they know to get the right vegetation
during different seasons. On the other hand, carnivorous animals, like
lions, have to ingest raw meat in large quantities to maintain the energy
required to subdue the next prey before they become too weak. This
complex balance to fulfill the instinct of survival is fascinating. The
smaller and less powerful animals, which become prey to larger animals,
have to survive to maintain the ecobalance. The only incentive for
animals is to survive, and their entire lives are dedicated to finding food
that nourishes them to procreate and propagate their respective species. It
is mind-boggling how these animals are able to acquire a balanced diet;
perhaps nutritious food without supplements is sufficient for healthy
living.
When it comes to human beings, the purpose of existence takes a
totally different meaning although the basic premise is to survive by
ingesting food and to procreate. As humans have evolved, the amount
20 Louis s. Premkumar, PhD
of time spent on finding food has dramatically diminished. Now, the
availability of food is taken for granted; not much time is spent on
finding food for survival. These days we try to obtain food that is more
appetizing, rather than just to fulfill hunger. In the earlier days, man
spent the entire day looking for food to survive whereas now only a
miniscule amount of time is spent on finding food. The whole day, except
for the time one is asleep, is available to dedicate to other activities of life.
This has also changed the roles of men and women. In the olden days,
men worked outdoors to find food, either by cultivating or by hunting,
and women prepared the food for the men to nourish them and to make
them continue the job of bringing food. Similarly, in certain parts of the
world, some households (mainly in joint families) have access to food
that is available as easily as in the West, but the amount of time spent on
preparing food for the entire family still could take a whole day. These
days processed, well-prepared, and precooked food is readily available,
which changes the dynamics and the meaning of life in that one has
ample time to pursue other interests.
Over the centuries, humans have refined the art of cooking, and
food is now very appetizing. Since food tastes good, it is not consumed
when one is hungry or when blood glucose levels dictate food intake.
A tendency has developed to consume food all the time, not solely to
fulfill hunger. Further, premade and appetizing food is readily available
to consume and enjoy. Extra condiments, including spices, improve the
quality of food. Spices provide the necessary aroma for food although
most spices do not have taste or caloric value. There are some spices that
do not have pleasant taste or aroma. For example, the main component
of the hot chili pepper, capsaicin neither has taste nor smell, but it is
pungent and imparts a zesty feeling. However, dried and ground chili
powder has an attractive red color. It is not clear whether the color has
anything to do with the desire to consume. Capsaicin specifically activates
its receptors in the nerve terminals and generates action potentials; when
the impulse reaches a certain part of the brain, the pungency is perceived.
Further, a neuronal network activity is set up; a sense of satisfaction or
fulfillment is achieved by stimulating the satiation and satiety centers in
the brain.
The olfactory functions of certain animals have developed to an
extent that they are able to detect an oderant of only a few molecules.
Although some animals possess extraordinary senses of smell, it is not
clear whether they possess the same senses of taste and the resulting
21Fascinating Facts about Phytonutrients in sPices and healthy Food
perception of flavor. During evolution, humans have developed a sense
of smell and taste, and the combination of both culminates in flavor.
Further, during this process, humans have developed an exquisite sense
of taste. For example, a perfectly grilled steak with some rawness of the
meat according to one’s taste is more preferable and a perfectly crusted
crisp stromboli or soufflé are made to perfection to satisfy one’s palate.
A restaurant in Chicago exploits this characteristic by serving food
on an air pillow that releases different types of aroma when the food is
being consumed. It is fascinating that people who suffer from the loss of
olfactory function (anosmia) seem to have lost the appreciation for food
due to the inability to sense the flavors.
Texture of the food is a very important quality since food that has
the right texture provides an extra incentive to take another bite. A
perfectly crispy potato chip is tastier than the same chip being soft and
soggy. Similarly, bakery products with the perfect texture impart a sense
of craving. Freshly unpacked or freshly baked cookies taste better because
of the crispiness. Even a mixture of textures by adding chocolate chips,
marshmallows, or macadamia nuts in cookies or ice creams brings about
a complete sense of satisfaction and craving. Also, the appearance of the
food has a lot to do with the satisfaction it provides. All these attributes
can be explained by the activation of different modalities of sensory
perception due to the nerve endings that carry gustatory, olfactory, visual,
chemical, thermal (both hot and cold), and mechanical sensations (such
as crispiness) to the satiety centers of the brain and deliver the perfect
input to experience the sense of satisfaction. The food industries exploit
these attributes to market their products. In our everyday life, one is able
to experience these feelings—breakfast cereal that is freshly soaked; a
crunchy fresh apple, and a perfectly chilled milk shake, Coke, or beer.
In medicine, most of the chemical compounds are derived from plant
products, and synthetic chemistry has made modifications to make these
chemicals pure, more potent, and more specific to a particular receptor,
which means avoiding serious adverse effects. Further, minute quantities
of these compounds can induce significant physiological effects. Another
intriguing question is, why do living creatures have receptors for
chemicals produced in plants that are inedible?
It almost appears that during evolution or creation, these aspects
have been taken into consideration so that animals and humans can get
benefits from consuming these plant products that have medicinal value.
However, what have to be taken into consideration are the amount of
22 Louis s. Premkumar, PhD
the active ingredient ingested, its bioavailability, and the ability to attain
the necessary plasma concentration to activate the receptors. These
chemicals may fulfill the sensory curiosity by acting locally at the site of
direct contact to sensory receptors but may not reach the concentrations
necessary in the systemic circulation.
Some of these plant ingredients have no taste or smell but have
the ability to stimulate certain parts of the central nervous system and
produce defined and desired effects. There are several plant ingredients
that may appear inert because there are no immediate effects associated
with their consumption except for the aroma. It is possible that these
ingredients bring about effects that are beneficial for the health in the
long term. Several of the plant products we consume provide us with
nutrition and quantities of vitamins that are very essential. There are
several ions that are needed for the body, and the only source for them is
from food. The important ions in the body are sodium (Na+), potassium
(K+), calcium (Ca2+), magnesium (Mg2+), manganese (Mn2+), copper
(Cu2+), iron (Fe2+), zinc (Zi2+), etc. Most abundant ion is Na+; a tendency
to consume salt (NaCl) is to provide the amount of this ion distributed in
the extracellular surface.
There are other plant-based ingredients, such as opioids, that
activate reward pathways to make one feel euphoric, which is a very
enjoyable and rewarding feeling. Once one has experienced this realm of
feelings, one wishes to enter such a realm often, which is free of pain,
reality, and responsibility. The next stage in this process is to attain this
realm at any cost, which compels one to consume, which culminates in
addiction. Opioids, such as morphine, induce their effects by binding to
their receptors located in the presynaptic terminals and inhibit synaptic
transmission. Inhibition of synaptic transmission in the spinal cord leads
to pain relief, which is the fundamental purpose of using morphine as
a painkiller. However, morphine receptors are also present in the brain
regions involved in reward pathways. When these regions are activated by
altering the normal balance, euphoria and dissociation from the reality
ensue, which are considered to be important incentives to repeated
ingestion of morphine or morphine-like drugs.
Similarly, cannabis consumption has been claimed to cause pain
relief, increase appetite, reduce nausea, and induce euphoria. But the
effects are not as distinct as the effects of morphine, because it acts on
a different set of receptors (cannabinoid receptors, CB1 and CB2) and
clearly has a euphoric effect. The cry for legalization has to be analyzed
23Fascinating Facts about Phytonutrients in sPices and healthy Food
carefully. The effects of cannabis are always compared with nicotine
and caffeine, which are just stimulants of the central nervous system.
The effects of cannabinoids cannot be equated to nicotine, because
of its mind-altering effects and it has a component of habituation or
drug-seeking behavior (addiction). Any drug that has a mind-altering
property will affect alertness and alter reflex time (may increase or
decrease, depending on the dose), cognition, perception to surroundings,
and motor coordination. The endogenous agonist for cannabinoid
receptors has been identified by researchers from Hebrew University,
Israel, and has been named anandamide because it causes one to feel
happy (anandam is a Sanskrit word for “happiness,” and structurally it is
a lipid amide).
Capsaicin is a plant ingredient from hot chili peppers that activates
TRPV1, and it is proposed that chronic pain conditions may be
associated with the overexpression of these receptors. Anandamide also
activates the capsaicin receptor called vanilloid receptor 1 (VR1), or
transient receptor potential vanilloid 1 (TRPV1). Interestingly, these
receptors are also temperature and acid sensitive; in fact, the capsaicin
receptor can be activated precisely at 42°C. Activation of these receptors
generates an action potential that is carried by the nerve and completes
the reflex arc, which prevents injury from contact with the hot surfaces.
Impulses carried by thermal pain-sensing neurons are nonmyelinated;
therefore, they carry the impulses slower, which is demonstrated by
our inability to remove the area of contact instantaneously because
nonmyelinated fibers conduct slowly.
However, it is intriguing how birds are able to tolerate the pungency
of hot chili peppers; in fact, a parrot’s favorite treat is a hot chili pepper.
TRPV1 in birds do not have the capsaicin-binding site; therefore, the
receptor cannot be activated by capsaicin, and the information is not
transmitted to the brain to feel the pungency. Interestingly, since birds do
not sense the pungency of hot chili peppers, in order to prevent squirrels
from eating the bird food, it is laced with hot chili powder, which is a
patented discovery. Squirrels, being mammals, have the TRPV1 receptor
with the capsaicin-binding site, which allows them to taste the pungency
and hence makes the bird food unpalatable.
The ability of capsaicin receptor activation by capsaicin itself,
temperature, and acidic solutions can be demonstrated by the
suffering following inadvertent consumption of piping-hot, spicy
chili garnished with vinegar. It is also manifested by profuse sweating
24 Louis s. Premkumar, PhD
during consumption of spicy, hot food. The mechanism may be due to
vasodilation caused by the activation of capsaicin receptors as a result
of its ability to cause calcium influx and release a potent vasoactive
substance called calcitonin gene-related peptide (CGRP). Although
sweating is observed while consuming capsaicin-containing food, it
is clear that this is an inherent mechanism by which body temperature
is maintained. This can be further demonstrated by antagonists for
capsaicin receptors, which would have become next-generation analgesics
but encountered a roadblock in clinical trials. Blocking capsaicin
receptors, although relieved pain, induced hyperthermia, halting all the
clinical trials for the drugs.
Intriguingly, several drugs in the market are isolated from plant
ingredients that have specific receptors in the body. For example, digoxin,
a drug that was isolated from the foxglove plant (Digitalis lanata), was
introduced to treat dropsy (the conditions that retain fluid in the body).
Now, it is mainly used for cardiac-rhythm disturbances, especially in
atrial fibrillation, to protect the ventricles from an increased rate of the
atrium, by slowing the conductance through the A-V node. Digoxin
binds to the Na/K ATPase pump in the nanomolar range. It is a very
potent drug and has a low therapeutic index, which means the range
between the therapeutic dose and lethal dose is narrow. Therefore, it
has to be used with extreme caution. Further, the level of extracellular
potassium ions can modify the binding of digoxin. Intriguingly,
digoxin binds to the receptor with higher affinity when the extracellular
potassium level is low, which occurs when patients suffer from heart
failure and with patients who also take diuretics to prevent water and salt
retention.
Aspirin (considered to be a wonder drug) was originally obtained
from the bark of the white willow (Salix alba). Even after a century of
its discovery, the novel effects of aspirin are being identified and tested
in large clinical trials. Originally, aspirin was found to relieve pain by
inhibiting cyclooxygenase 1 and 2 (COX-1 and COX-2) enzymes that
are involved in the production of prostaglandins during inflammation.
Aspirin binds to a receptor and inhibits thromboxane A2 activity, thereby
preventing platelet aggregation in lower doses resulting in thinning of
blood. The major resurgence of aspirin is due to its ability to prevent
heart attacks when taken in small doses (80 mg, baby aspirin). The latest
protocol to treat acute coronary syndrome (at the time of a heart attack)
involves the ingestion of four crushed aspirins immediately. It has been
25Fascinating Facts about Phytonutrients in sPices and healthy Food
shown in large clinical trials that long-term use of aspirin prevents various
types of cancer, including melanoma. Once the active ingredient is
known and the receptor is characterized, scientists can validate the effects
with certainty in animal models and by utilizing knock-out (the gene
coding for a receptor can be disrupted) or knock-in (the gene coding for a
receptor can be over expressed) genetic strategies.
Therefore, the health benefits of ingredients in spices and healthy
food have not been fully demonstrated because the effects cannot be
readily measurable or quantifiable. Most of the spices add exquisite flavor
to the food, but for some people they do not have a pleasant taste and
must become an acquired taste or flavor. For some ingredients, such as
capsaicin (from hot chili) and curcumin (from turmeric root), there is
neither taste nor smell. However, capsaicin—and curcumin-containing
powders are red and yellow respectively, which may satisfy visual curiosity.
But it should be pointed out that although the ingredient in chili
pepper induces pain, it is considered to produce an exquisite sensation
in lower concentrations. Although spices and other ingredients do not
have nutritional value as we know, they contribute to the overall health
by inducing specific effects in miniscule quantities. In general spices are
sweet-smelling. The active ingredients in some spices have been isolated
for decades, but the receptors on which they act and bring about the
purported effects have been largely speculative. There are three aspects
that have to be taken into account: (1) the active ingredient has to be
identified, and there may be more than one active ingredient; (2)
the receptor on which the active ingredient binds and brings about
the effect has to be identified and characterized; and (3) the biological
consequences resulting in health benefits have to be studied and
documented in clinical trials.
If the beneficial or harmful effects are subtle, they escape the
attention of the scientific community until the cumulative effect results
in a health benefit or hazard. Some of these ingredients can cause
harmful effects. Therefore, it is extremely important and necessary to
understand the fundamental mechanism and the exact quantity of the
active ingredient that is being ingested. There are several plant products
available as nutraceuticals in the market that contain active ingredients
known to induce health benefits. Since they are plant products, they do
not undergo strict scientific scrutiny and need not be approved by the
FDA for marketing. The most important danger being ignored is that
the exact quantities of the active ingredients in these preparations are not
26 Louis s. Premkumar, PhD
known and are not standardized. Because of the unknown quantities of
the active ingredients, there are ambiguities and uncertainties in their
effectiveness; the quantity of active ingredients can vary from preparation
to preparation. The active ingredients in nutraceuticals can vary because
of the manufacturing practices that are using the barks versus the leaves,
the season during which the plant is grown, the quality of the soil, the
extent of rainfall, and the exact species being cultivated. There are several
cases of outright adulteration to lower the cost as well as to meet with
the demands of the market when imported from developing countries,
such as China and India. One such ingredient that athletes consume is
ephedra (from Ephedra sinica), which is known to improve performance.
The active ingredient in ephedra preparations is ephedrine, which is
a sympathomimetic amine. It mimics the actions of an overactivated
sympathetic system, which is responsible for preparing one for fight and
flight. In extreme cases, the known active ingredient is a pure form of a
drug that is added to the nutraceuticals to fulfill the claim and satisfy the
customers.
It is fascinating to learn that Pelargonium extract does not contain
1,3-dimethylamylamine (DMAA), which was recently brought to
the attention of the FDA, but it is deliberately added to natural
products. This product is sold as a weight-loss agent and muscle-growth
supplement. DMAA is an adrenergic agent that can suppress appetite
and cause vasoconstriction to the extent that deprivation of blood supply
to muscles promotes their overgrowth. In some nutraceuticals used to
treat asthma, pure forms of steroids have been added. Recently, the
FDA has issued a warning for natural products that are sold to reduce
blood glucose levels and contain metformin, a prescription antidiabetic
drug. The number of natural products flooding the market without
proper regulation after the Dietary Supplement Health and Education
Act of 1994 (DSHEA) has made the supplement manufacturers rich and
rendered the public at risk.
The effectiveness of the nutraceuticals cannot be clearly documented.
Since the quantity of the active ingredient and the anxiety state of the
individual are not known, when consumed, it sometimes results in an
overdose, and the outcomes could be fatal. Further, the sympathetic
tone controls the blood pressure and heart rate. When the sympathetic
tone is constantly enhanced, the cardiovascular system is remodeled as
a result of increased blood pressure and heart rate; the thickness of the
heart muscle is, in turn, increased (cardiac hypertrophy). When all these
27Fascinating Facts about Phytonutrients in sPices and healthy Food
three elements are combined with intense physical exertion, it can lead to
rhythm disturbances in the heart and finally culminate into ventricular
fibrillation, resulting in sudden cardiac death.
As discussed, all plant products are not beneficial. In Chinese herbal
medicine, one plant product commonly used for weight loss is from
the creeper plant Aristolochia clematitis or A. fangchi. In Taiwan, where
one in three women has been taking Aristolochia, documents high level
of kidney cancers and is nicknamed as the land of dialysis. In some of
the weight-loss clinics in Belgium, women who used herbal products
containing Aristolochia fangchi reported to clinics with kidney failure.
This triggered a warning from regulatory agencies, such as the FDA. In
Balkans, an endemic nephropathy has been observed in the Danube River
valley. It was suspected that Aristolochia poisoning may be responsible
for the kidney and urothelial cell carcinoma. Arthur Grollman and his
colleagues embarked on a challenge to identify the causes of endemic
nephropathy among Balkans. They tested the hypothesis that aristolochic
acid may be responsible for the nephropathy, based on the finding that
wheat crop is contaminated by the Aristolochia plant growing among
the wheat crop. It was found that aristolochic acid induced mutations
in the tumor-suppressor protein p53 by forming adducts. The inability
to suppress tumor growth is the mechanism responsible for the upper
urinary tract carcinoma.
Further, there are single nucleotide polymorphisms (SNPs) that have
been identified in genes that alter the characteristics of a receptor, which
can account for individual variations in drug/ingredient sensitivity or
insensitivity. This might also be applicable to food ingredients. Therefore,
the ability or inability to tolerate spices may be related to SNPs or
how constant ingestion of spices results in tolerance due to receptor
desensitization or anaphylactic reaction to some ingredients. Examples
are morphine-induced tolerance and sensitivity to peanuts, which comes
about by a protein initiating an anaphylactic reaction in some individual.
Since these reactions are violent and life-threatening, one must pay
attention to consumption of certain ingredients and medications.
In the process, there are several spices that have exotic smell and
probably have no taste that are incorporated into food. It has been
demonstrated that an exotic aroma consists of odorants molecules and
activates the olfactory and the the gustatory senses; both culminate in
providing the flavor for a particular food. The exquisite sense of taste is
the result of a combined balance between the olfactory and gustatory
28 Louis s. Premkumar, PhD
senses. Generally, this is accomplished by adding gentle-smelling spices to
the food, which do not contribute to the taste. It is not clear whether
it is the gentle smell that makes the food taste better or both the smell
and taste contribute to a more appetizing meal. During viral or bacterial
infections that affect the upper respiratory tract, the sense of smell is lost
because the nerve endings are obstructed or damaged, and the food often
tastes bland or completely tasteless. All of us have experienced how the
taste of food is not appreciated as much when we are sick; it is due to our
inability to process the olfactory sensation because of nasal congestion. It
appears that the combined sense of flavor is what is mostly appreciated,
rather than the individual senses of smell and of taste. During radiation
therapy for nasopharyngeal cancer, the taste of food is lost for months
until the nerve terminals are regenerated.
Sensitization is a process where there is an exaggerated response
to a normal stimulus whereas desensitization is a blunted response
to a stronger stimulus. There is a caveat where the phenomenon of
tachyphylaxis occurs when a response is blunted due to the repeated
application of a given stimulus. This can apply to any sensation, whether
it is a physiological or psychological stimulus. These are fundamental
properties of the body’s ability to cope with changing conditions.
Sensitization can occur as a result of phosphorylation of the receptors or
increased number of receptors, which augments the associated functions.
Desensitization is a cellular mechanism that terminates the response in a
timely fashion to prevent overactivation of the system. There are several
mechanisms by which this is accomplished. If it is an ion channel, it
goes into a desensitized state so that when the stimulus is on (binding
of an agonist or heat stimulus in a heat-sensitive channel), the channel is
in a nonconducting, or desensitized, state. There is another mechanism
by which the receptors are internalized, thereby preventing them from
eliciting a response. Tolerance is a process of diminished cellular response
that develops over time. Tolerance develops in the case of morphine
because the second messenger (cAMP) is getting depleted and in the
case of alcohol consumption, tolerance develops because alcohol is
metabolized rapidly due to enhanced metabolizing-enzyme induction.
The same phenomenon occurs in taste receptors; for example, hot
chili pepper-induced pungency can be dramatically reduced by repeated
consumption. Those who are used to eating hot chili pepper-containing
food often develop tolerance, compared to those who do not. In those
who are not accustomed, a sense of numbness occurs as soon as tasting,
29Fascinating Facts about Phytonutrients in sPices and healthy Food
and this is because of Ca2+-induced desensitization of the receptor. In
order to quench the pungency, it is advised to consume milk because
Ca2+ in the milk promotes desensitization. Tolerance is a term that
generally describes one’s ability or need to consume more to attain the
same desired physiological effect. This applies to the consumption of
alcohol, abuse of substances such as cocaine, heroin, and painkillers,
such as morphine, and of course, the ability to eat hot chili peppers. But
there are distinct molecular mechanisms associated with each of these
phenomena. In general, the rule of thumb is that when a receptor is
overactivated, its sensitivity and expression levels decrease, and when the
receptor is underactivated or antagonized, its sensitivity and expression
levels increase to compensate for the necessary signal. The reason that
some drugs (blockers) should not be discontinued abruptly, but the
dose should be tapered slowly, is because of the increased number of
receptors—a sudden rebound effect could occur. For example, this
sudden disruption of administration can cause blood pressure or heart
rate to increase suddenly and uncontrollably.
Composition of microbiota (colonies of microorganisms in the
GI tract) has become an important area, and the functions include
breakdown of complex carbohydrates, regeneration of cholesterol from
conjugated bile acids, metabolism of substances that can reenter the
circulation, and synthesis of vitamins. Prebiotics are used to improve
the commensal bacterial colonies whereas probiotics can repopulate the
desired colonies. An altered ratio between colonies in the GI tract has
been linked to obesity. Since ingredients in spices exhibit different levels
of antibacterial efficacy, the addition of spices can be a determinant factor
in the composition of gut microbiota. More interestingly, subduing or
eliminating the microbiota by bacteriostatic and/or bacteriocidal spice
ingredients can influence the health outcomes.
30
CHAPTER 2
Basic Nutritional Requirements
of the Organisms
The fundamental requirements of life—the food that nourishes the
body, along with the water we ingest and the air we breathe—participate
in a variety of biochemical processes to sustain life. For the biochemical
processes to proceed efficiently, certain minerals and vitamins are needed
in minute quantities. Living creatures seek food from a variety of sources
to fulfill their instinct of survival. Single-cell and multi-cell organisms
process nutrients differently, which ultimately provide energy for the
cellular function and survival. The fundamental nutrients that are needed
to sustain life and that we consume on a daily basis are glucose (which
are obtained from carbohydrates), amino acids (some are synthesized, and
some are from food) and fatty acids. The energy needed for the cellular
activity is produced by processes that convert glucose and fatty acids to
adenosine triphosphate (ATP) in the mitochondria, an intracellular
organelle known as the powerhouse of the cell. ATP provides energy by
phosphorylating several targets. Metabolism of glucose produces thirty
molecules of ATP; when fatty acids are utilized, forty-two molecules of
ATP are produced. ATP produced from fatty acids is more efficient than
from carbohydrates. In other words, 1 g of fatty acid can produce 9 kcal
of energy as compared to 1 g of carbohydrate, which can produce 4 kcal
of energy. Further, fatty acids can be stored in a water-free environment
as compared to carbohydrates; therefore, the amount of energy per unit
stored by fatty acids is six times that of glycogen. Polar bears survive
hibernation for seven months mainly by converting fatty acids into
31Fascinating Facts about Phytonutrients in sPices and healthy Food
energy. During feeding season, they require high-fat diet to store energy
to survive. Further, the number of ATP molecules produced in the
presence of oxygen (aerobic) is thirty-eight whereas in the absence of
oxygen (anaerobic), only two ATP molecules are produced.
The importance of the need of ATP generation from glucose can
be appreciated when the blood glucose levels go down; within seconds,
one becomes light-headed and can lose consciousness, suggesting the
utmost dependence of the nervous system to glucose. This is commonly
observed in people with diabetes, who inject insulin for controlling
high blood glucose levels. Since insulin promotes glucose entry into
cells and facilitates its utilization, the blood glucose levels decrease.
Therefore, those who are diagnosed to have insulin-dependent diabetes
are instructed to consume food soon after an insulin injection. However,
in the heart, for the muscle contraction, mostly the needed energy is
produced from fatty-acid metabolism rather than glucose metabolism;
therefore, the heart is not as susceptible to low blood glucose levels as
the brain. In humans, a large proportion of glucose is utilized to generate
ATP to sustain the functions of the human brain as compared to the
other animals because the size of the brain as compared to the body mass
is large in humans.
The glucose utilization of the nervous tissue is very high because of
the energy requirements. The complexity of human brain is revealed by
the sheer number of neurons and the connectivity between them. There
are one hundred billion neurons in human brain, and each neuron makes
50,000-150,000 connections between each other. The communication
between neurons occurs at a specialized junction called a synapse, which
is not a continuous structure. There is a gap between the presynaptic
and postsynaptic neurons. The impulses are transmitted as a result of
the release of a neurotransmitter that binds to the postsynaptic cell
and generates a postsynaptic potential. When these smaller potentials
summate when the postsynaptic cell is sufficiently depolarized, it
generates an action potential (a fundamental electrical event in excitable
cells needed for muscle contraction and nerve transmission) by allowing
Na+ and Ca2+ to enter the cell rapidly, followed by allowing K+ to exit
the cell to bring the membrane potential to a resting state, ready for the
generation of the next action potential. In the brain, there is a balance
between excitation (mostly mediated by glutamate) and inhibition
(mostly mediated by gamma-aminobutyric acid, GABA). Enhanced
inhibition silences (hyperpolarizes) the neurons by preventing them from
32 Louis s. Premkumar, PhD
generating an action potential, which is brought about by antianxiety
drugs, like diazepam (Valium).
The major energy source for the body comes from glucose; therefore,
one must ingest a required amount of glucose; the excess glucose is
stored in the liver as glycogen. Pure form of glucose, which can be
directly utilized by the body, is from sweet-tasting food. Humans have an
insatiable desire to consume sweet-tasting food and beverages. The reason
for this is to ingest high-energy food without hesitation so that the energy
requirement of the body can be met quickly before losing consciousness.
When one is hungry and thirsty after a hard day’s physical work outdoors
or after an intense sporting event in a hot summer day, chilled high-sugar
beverages are the most desired. This is because of the need for the body to
cool down and to provide the necessary energy. The high-energy drinks
available in the market fulfill this need. However, consumption of these
drinks without physical activity will lead to weight gain by storage of
excess energy.
Always the body controls the blood sugar levels by promoting the
entry of glucose into cells so that glucose can be utilized to produce
energy in the form of ATP. Insulin resistance occurs because of the
inability to utilize insulin to its maximal effect when receptors do not
function adequately or when the fat tissue binds insulin; the insulin is
not utilized for the promotion of the glucose into cells. In this condition,
the blood glucose levels tend to be higher, requiring the pancreatic beta
cells to produce more insulin, resulting in increased levels of circulating
insulin. Like any other overworked system, the insulin-producing beta
cells tend to degenerate. In normal individuals, as soon as the food
is ingested, pancreatic beta cells release only the required amount of
insulin to promote glucose intake into cells, thereby maintaining the
blood glucose levels at an optimum level (between 80 and 120 mg/dL).
But the important point to consider is that blood glucose levels higher
than 126 mg/dL is considered hyperglycemia, the first sign of diabetes.
In insulin-dependent diabetes, it is estimated that more than 50-70%
of the beta-cell destruction has already occurred by the time the disease
is diagnosed. The remaining 30-50% of beta cells will carry the load
of producing insulin to meet the body’s need, resulting in hypertrophy
(undesirable, excessive growth) of pancreatic beta-cell islets due to
overwork, ultimately leading to their destruction. At this stage, the ability
of the body to produce insulin is almost lost, and exogenous insulin has
to be administered to promote glucose utilization and maintain normal
33Fascinating Facts about Phytonutrients in sPices and healthy Food
blood glucose levels. This is classified as insulin-dependent type 2
diabetes mellitus. In type 1 diabetes, because of various causes, including
autoimmunity (the body develops antibodies against its own beta cells) or
infection, the beta cells are completely destroyed, and there is no insulin
production from the pancreatic beta cells, resulting in total dependence
on insulin. The major signs of diabetes are excessive urination (polyuria)
due to osmotic diuresis because of increased glucose in the blood, as a
result increased thirst (polydipsia), and increased appetite or excessive
food intake (polyphagia), especially to sweet-tasting food occurs, making
the situation dire.
The good news is that diabetes is no longer a deadly disease; there
are effective medications, including insulin injections. If the drugs are
properly used and there are changes in lifestyle and food habits, one
can have normal life span. Gladys Lester Dull was diagnosed with type
1 diabetes in 1924 at the age of six, three years following the discovery
of insulin in 1921. She lived a full life span and died at the age of
eighty-nine. In an interview she said, “I have never missed a shot in all
these years. To date, I have had over sixty thousand of them.” It works
out to be two injections per day.
Food consumed from a variety of sources provides energy for the
body; the measure of the energy is in kilocalories (kcal). There are several
important processes that are needed for the utilization of the food:
digestion, absorption, utilization, storage, and elimination of excess
undigested food from the body. Generally, available food groups provide
us with the balanced nutrition with all the necessary requirements for
a long, healthy living. Some foods provide several important nutrients,
such as milk and dairy products, as compared to polished rice, which
provides only carbohydrates but not other vital nutrients. Therefore, the
prepacked food has been fortified with minerals and vitamins to replace
those lost in processing. The excess food is stored as fat in adipose tissue,
which can be utilized when the body runs out of energy.
Basic Essential Nutrients
The form of food that provides major energy requirement is
carbohydrates, which are digested to yield glucose. There are two forms
of carbohydrates: those that are (1) broken down and absorbed, such as
sugars (found in vegetables, fruits, milk, and processed food) and starch
34 Louis s. Premkumar, PhD
(found in rice, bread, cereals, and potatoes); and (2) unable to be digested
to yield glucose (nonstarch polysaccharides) and generally referred to as
fiber, which is subdivided into (1) soluble fiber (found in pulses, oats,
barley, rye, fruits, and vegetables), which controls the cholesterol and
glucose levels by reducing glucose and cholesterol absorption, and (2)
insoluble fiber (in whole-grain cereals and fruits and vegetables), which
provides the needed bulk for the undigested materials to be eliminated
from the body on a regular basis, which is very important for good health.
The next important source of energy is obtained from fat, or lipids.
Lipids are necessary to form cell membranes and as carriers of fat-soluble
vitamins (A, D, E, and K). Fatty acids are classified as saturated,
monounsaturated, and polyunsaturated. Saturated fats and triglycerides
are high in animal products, such as butter, red meat, eggs, milk, lard,
and suet, and in some blended vegetable oils, such as coconut oil and
palm oil. Saturated fats increase cholesterol levels, which can lead to
cardiovascular diseases that begin with atherosclerosis (fatty deposits in
blood vessels supplying vital organs), which results in narrowing of blood
vessels, including the coronary artery, which results in ischemic heart
disease, depriving the heart muscle of oxygen and nutrients, leading to
a heart attack. Controlling the blood lipid levels and preventing blood
clotting by anticoagulants, such as aspirin, can prevent the development
of atherosclerosis. Monounsaturated fats are from olive oil and rapeseed
oil, and polyunsaturated fats are from soya, corn, sunflower, and sesame
oils—both of which are less likely to increase blood lipid levels.
Blood lipids come in different forms, such as cholesterol, high-density
lipoproteins (HDL; H for healthy), low-density lipoproteins (LDL; L for
lousy), and triglycerides. Cholesterol levels should be less than 200 mg/
dL; 200-239 mg/dL is moderate risk, and greater than 240 mg/dL is
high-risk. HDL (healthy) less than 40 mg/dL is high-risk, 40-59 mg/dL
is beneficial, and greater than 60 mg/dL is a health benefit. LDL (lousy)
less than 100 mg/dL is preferred, 100-129 mg/dL poses a health risk, and
130-159 mg/dL poses a real health risk. Triglycerides less than 150 mg/
dL is normal, 150-199 mg/dL poses a risk, 200-499 mg/dL is high-risk,
and greater than 500 poses a real risk. The levels of very low-density
lipoprotein (VLDL) are becoming a critical measure; less than 100 mg/dL
is considered healthy, and more than 160 mg/dL is considered high-risk
(see Tables 3, 4, 5, 6, 7).
More than 70 percent of the cholesterol is synthesized in the liver.
Cholesterol has a steroid structure and serves as a precursor for generating
35Fascinating Facts about Phytonutrients in sPices and healthy Food
steroid hormones and bile acids (needed for fat digestion) and as building
blocks of cell membrane. Cholesterol is transported from the liver by
low-density lipoproteins. LDLs are less stable, since they contain more
lipid and less proteins. LDL gets deposited where there is inflammation
or a slight damage or nick in the blood vessels and promotes the process
of atherosclerosis and is therefore considered dangerous. On the other
hand HDL removes cholesterol from the blood and transports it to the
liver to be destroyed. VLDLs can be more unstable given the very low
density of proteins.
Fat is broken down to release glycerol and fatty acids. Glycerol can
be converted to glucose by the liver. Fatty acids are classified as saturated,
monounsaturated, and polyunsaturated fatty acids. Saturated fatty acids
have a hydrogen atom attached to each carbon atom with the notation
CnH(2n+1)COOH. Monounsaturated fatty acids have the notation
CnH(2n-1)COOH, which have one double bond. Polyunsaturated fatty
acids have the notation CnH(2n-3)COOH, which have three double
bonds, or CnH(2n-5)COOH, which have five double bonds. A process
of hydrogenation adds hydrogen. Saturated fats (animal fat, vegetable
shortenings, coconut oil, etc.) can arrange themselves in a compact
fashion because of uniform structure, have a higher melting point and
are solid at room temperature (22-23oC). The harder the fat, the crispier
the chip and the flakier the crust it makes. Saturated fatty acids are not
readily metabolized causing them to be in the circulation for a longer
period, contributing to the increased fat content in the blood facilitating
undesirable effects.
Polyunsaturated fatty acids (PUFAs) like linoleic acid (n-6 or omega-6
fatty acid) alpha-linolenic acid (n-3 or omega-3 fatty acid) cannot be
synthesized in the body. Omega-6 fatty acids are synthesized from linoleic
acid and the omega-3 fatty acids are synthesized from alpha-linolenic
acid (ALA). Poultry, eggs, and vegetable oils provide omega-6 fatty acids
that are necessary for formation of cell membranes. Fish oils, flaxseed
oil, and sesame seed oil provide omega-3 fatty acids, which are known
to induce beneficial effects by improving neuronal cell functions and
regulate distribution of fatty acids and act as carriers so that cardiovascular
functions can be improved and cardiovascular diseases can be prevented.
Consumption of omega-3 polyunsaturated fatty acids is usually in the
form of marine oils from fish. Fish oil contains both docosahexaenoic acid
(DHA) and eicosapentaenoic acid (EPA). However, ALA from flaxseed oil
and sesame seed oil has to be converted to EPA and DHA.
36 Louis s. Premkumar, PhD
Eicosanoids are metabolic products produced from omega-6 fatty acids
such as prostaglandins. Leukotrienes are proinflammatory and contribute
to subclinical inflammation, which is known to promote cardiovascular
and inflammatory diseases such as arthritis. When the levels of omega-3
fatty acids are increased, they compete for the enzymes for metabolism,
resulting in reduced production of harmful eicosanoids produced by
omega-6 fatty acids and increased production of useful eicosanoids from
omega-3 fatty acids. The production of omega-6 fatty acid arachidonic
acid levels is also decreased. It has been proposed that omega-3
eicosanoids can counteract omega-6 eicosanoids. Aspirin can prevent
the production of inflammatory omega-6 eicosenoids prostaglandins
and platelet-aggregating eicosanoid troboxane A2 and protect against
cardiovascular complications, especially the formation of atherosclerosis,
which is facilitated by inflammation and platelet aggregation.
Further, it has been recently discovered by researchers in Harvard
University, Massachusetts, that metabolism of omega-3 fatty acids can
give rise to a novel group of compounds that can resolve (resolvins)
inflammation and protect (protectins) from deleterious effects. They
are hydroxylated derivaties of DHA (D-resolvins and protectin D1) and
EPA (E-resolvins). Interestingly, aspirin, by its lipoxygenase activity by
hydroxylation step at C17, can form 17R D class resolvins from DHA,
which is a stereoisomer of 17S D class resolvins formed conventionally.
This is a significant additional advantage of taking aspirin.
Two receptors have been described for 17S-RvD1: one of them,
human GPR32, has no other known ligands while ALX is a receptor
for the arachidonic acid-derived lipoxin A4. Both receptors seem to act
as high-affinity binding sites for RvD1. ChemR23, a G-protein-coupled
receptor that was described as a specific receptor for RvE1.
D class resolvins are effective in experimental microbial sepsis,
ischemia-reperfusion injury to the kidneys, colitis, and inflammatory
pain in a mouse model and probably involve TRP channels. In the
sepsis model, they decreased cytokine production and neutrophil
recruitment and increased peritoneal mononuclear cells and macrophage
phagocytosis. Protectin D1 is effective in brain ischemia-reperfusion
and retinal oxidative injury, asthma, fatty liver, the metabolic syndrome,
atherosclerosis, and ischemia-reperfusion injury. PD1, RvD1, and RvE1
have been shown to reduce neovascularization in the retina that can
happen in diabetes and other conditions, a leading cause of blindness.
PD1 has been reported as a protective factor regulating amyloid beta
37Fascinating Facts about Phytonutrients in sPices and healthy Food
secretion in Alzheimer’s disease. RvE1 was the first resolvin that was
characterized and reported to reduce neutrophil infiltration, prevent
connective tissue and bone loss, promote healing of diseased tissues,
and regenerate lost soft tissue and bone. RvE1 has attenuated severity of
peritonitis and colitis and has prevented neovascularization. It is being
currently developed clinically for applications in dry eye syndromes.
Transfats are produced from polyunsaturated fatty acids that are
subjected to a process of hydrogenation that modifies their structure.
Partial hydrogenation results in the double bonds that can exist in cis or
trans isomers, meaning direction of the double bond or side chain can
be above or below the plane. By chemical processing, the cis isomers can
be made trans isomers (transfats), which are resistant to metabolism.
Therefore, transfats are added to processed food to increase the shelf
life by preventing the food from becoming rancid. It has been clearly
shown that transfats can promote formation of atherosclerosis. Therefore,
prevention of developing atherosclerosis is preferred, rather than treating
and trying to reverse the process, which is almost impossible. Transfats
increase total cholesterol, increase LDL cholesterol, and decrease
HDL cholesterol levels. Transfats also interfere with the utilization of
omega-3 fatty acids. Omega-3-rich fatty acids reduce the synthesis of
LDL apoprotein B. Fats and carbohydrates are converted and stored as
triglycerides in the fatty tissues. People with an unfavorable lipid profile
and hyperglycemia are considered to have metabolic syndrome and have a
high risk of developing cardiovascular disease.
Given the health hazards caused by fat-enriched food, government
guidelines recommend that only 35% of the energy can be obtained
from fat (saturated fat 11%, polyunsaturated fats 6.5%, and trans fats
2%). Led by New York, measures have been implemented in some state
governments in the United States to ban the use of trans fats altogether
for food preparations because of proven health hazards they could cause.
FDA has recently issued a warning and a proposal to ban transfats.
The other nutrient that is essential for the body is in the form of
amino acids (some of them cannot be synthesized and are called essential
amino acids), which are necessary to synthesize peptides, which are small
amino-acid chains (e.g., endorphin and enkephalin) and large amino-acid
chains (e.g., insulin). Proteins are very large amino-acid chains that are
necessary for a variety of structural and functional elements, ion channels,
enzymes, and hormones, which control several functions in the body. The
amino acids can be converted to glucose to generate needed energy by a
38 Louis s. Premkumar, PhD
process called gluconeogenesis. The main source of amino acids is from
milk, meat, eggs, cereals, beans, lentils, and nuts.
Vitamins
Vitamins are nutrients essential for numerous functions in the body
(see Table 1). They are required in micromolar (a millionth of a gram)
quantities. Vitamins that are water-soluble (vitamins B1 [thiamine],
B2 [riboflavin], B6, and B12 and folic acid, niacin, biotin, pantothenic
acid, and vitamin C) can be easily absorbed and transported via the
blood and utilized wherever needed. On the other hand, there are
fat-soluble vitamins (A, D, E, and K), which are stored in body-fat
depots and can supply the body’s need for a longer period. Vitamins
such as vitamin A are essential for growth and differentiation; vitamin
D is involved in mineral metabolism; most members of vitamin B
complex act as cofactors/coenzymes in a variety of metabolic processes.
Vitamins such as vitamin C and vitamin E act as antioxidants to
reduce oxidative stress. Although severe vitamin deficiencies cause
serious diseases, the effectiveness of vitamins cannot be measured in
the short term. Thiamine deficiency causes beriberi, which affects
muscular, nervous, cardiovascular, and gastrointestinal systems, leading
to emotional disturbances, sensory deficits, and altered cardiac rhythm.
Severe cases can lead to heart failure and death. Niacin deficiency leads
to pellagra, manifested by severe skin lesions, and symptoms include
diarrhea, dermatitis, dementia, and death. Vitamin C deficiency leads to
scurvy (since vitamin C is needed for collagen formation, which affects
mucous-membrane formation) and results in bleeding of gums. Some
animals are able to synthesize vitamin C; higher primates lack an enzyme
called L-gulonolactone oxidase, and therefore, they are dependent on
supply from food sources. Individuals with vitamin C deficiency appear
pale, lethargic, and depressed and exhibit signs of peripheral neuropathy.
Vitamin D deficiency in children can lead to osteomalacia, manifested
by softening of bones as a result of defective calcium and magnesium
metabolism, leading to fractures. Other symptoms include bone pain,
muscle weakness, and dental problems. But severe, long-standing
vitamin D deficiency can lead to rickets, a condition where bone
formation is affected and children will develop bowlegs. In developed
countries vitamin deficiency is not a problem, but excessive use of dietary
39Fascinating Facts about Phytonutrients in sPices and healthy Food
supplements in the form of vitamins may not be helpful—rather they can
be harmful.
Levels of vitamin D3 less than 30 ng/ml have been correlated with
higher levels of asthma in children up to the age of eighteen. The normal
level of vitamin D3 is expected to be higher than 50 ng/ml. There are
several food additives that have been associated with increased attacks of
asthma; natural flavoring agents, hydrolyzed proteins, and monosodium
glutamate all have shown to increase the incidence of asthma. The
glutamate receptors expressed in the airway can be activated by these
agents.
Some vitamins are required in such minute quantities (see Table 1)
it will take a long time to manifest their deficiency. In several studies,
loading the body with large quantities of vitamins has not proven to
be beneficial. In fact, it has been shown that excessive consumption of
vitamins can be detrimental, especially promoting growth of certain
cancers.
In 1994, the Dietary Supplement Health and Education Act
(DSHEA) was passed to control the use of supplements in the USA
without undergoing strict regulatory control by the FDA. Recently, it
has been shown that vitamin supplements do not induce any measurable
health benefits. Most of the processed food available in the United States
and Western countries have been fortified with minerals and vitamins.
Further, a very low percentage of the dietary supplements sold in the
market have proven to be efficacious. All that this act is concerned about
is the safety of the product rather than efficacy.
Antioxidant is a most commonly misinterpreted word in the
health-food literature. There is a balance between the production
and removal of oxidants. Oxidants produced during metabolism are
considered to be harmful; therefore, the role of antioxidants takes center
stage in every nutritional food and food supplements. In fact, oxidants
are necessary for some vital functions. Overuse of antioxidants can tilt the
balance. Vitamin C is the antioxidant considered to cure diseases ranging
from common cold to cancer as preached by two-time Nobel laureate
Linus Pauling; this is proven to be wrong. In fact, studies from National
Institutes of Health suggest that overuse of vitamin C promotes cancer
growth. Some of the oxidizing agents are useful in activating certain
enzymes and transcription factors. The basic idea is that physiological
levels of oxidants are needed in the body for normal and efficient
functions. Excessive consumption of antioxidants may undermine
40 Louis s. Premkumar, PhD
the beneficial effects of low concentrations of oxidants by completely
eliminating useful reactive oxidant species or products from the system.
Furthermore, the bioavailability (the amount that gets absorbed and
is available systemically) of ingredients in supplements when orally
consumed is not clear.
Minerals
There are several monovalent and divalent cations (positively charged)
and anions (negatively charged) that are important for a variety of
functions. Ions that are in large quantities, such as sodium (Na+),
potassium (K+), and chloride (Cl−), are responsible for ion conduction
across the cell membrane and maintenance of the ionic imbalance
between intracellular and extracellular fluids. For example, Na+ is the
major extracellular ion (140 mM), and K+ is the major intracellular
ion (140 mM). The separation of these ions by the cell membrane
develops a gradient that provides the driving force for ion movement
for generating an action potential in cells. Other important ions that are
required in reasonable quantities are calcium (Ca2+, 2 mM), magnesium
(Mg2+, 2 mM), and iron (Fe3+, measured in terms of hemoglobin—
men: 12-15 mg/dL; women: 13-17 mg/dL). Ca2+ is critical in causing
neurotransmitter and hormone release and muscle contraction.
Intracellular Mg2+ is important in a variety of biochemical processes;
extracellular Mg2+ protects neurons from Ca2+-induced neurotoxicity
by blocking a receptor called N-methyl-D-aspartate receptor, and Mg2+
levels are critical to prevent developing cardiac-rhythm disturbance
associated with long QT syndrome. In fact, the treatment option for
long QT syndrome-induced cardiac-rhythm disturbances is intravenous
administration of MgSO4 to supplement Mg2+. Fe3+ is needed for
the oxygen-carrying capacity of blood by hemoglobin. Fluoride (Fl-),
phosphorus (PO4
-), and zinc (Zn2+) are present in small quantities and are
important for vital cellular functions. Zn2+ is released along with insulin
from the pancreatic beta cells. However, there are ions that are needed in
trace quantities, which include copper (Cu2+), chromium (Cr2+), iodide
(I-), manganese (Mn2+), molybdenum (Mb2+), tin (Sn2+), and selenium
(Se2+), which mainly maintain enzyme functions. Ca2+ can be obtained
from food such as milk, cheese, and yogurt, and other minerals are
obtained from fortified food.
41Fascinating Facts about Phytonutrients in sPices and healthy Food
Potassium is an important ion inside the cells. The potassium
concentration inside and outside the cells controls the membrane
potential of cells. If the membrane potential is more negative, the cells
are less excitable, and if the membrane potential is less negative, they are
more excitable. When it comes to the cardiac cell membrane, both low
potassium (hypokalemia) and high potassium (hyperkalemia) can induce
problems. If there is low potassium in the extracellular solution, the
membrane potential is more negative and the membrane is less excitable;
this is true for all the cells except for cardiac cells, which are constantly
beating. When the potassium concentration is low, the action potentials
take longer to repolarize, which can lead to a condition called long QT
syndrome. The QT interval is measured by the electrocardiogram,
which shows that the action potential duration is prolonged, causing
the membrane potential to be depolarized for a longer period, making
the cardiac cells more excitable. A specific type of arrhythmia can
be precipitated called torsades de pointes, which can lead to serious
heart-rhythm disturbances and can lead to sudden cardiac death. There are
two important ions that have to be kept up; they are potassium (K+) and
magnesium (Mg2+). The foods that contain higher levels of potassium are
bananas, cantaloupe, honeydew melon, kidney beans, oranges, potatoes,
peas, sweet potatoes, tomatoes, and dried fruits, such as prunes and raisins.
Magnesium can be obtained from greens, avocados, nuts, and legumes.
Sodium (Na+) is an important extracellular ion in the body. Most
of the foods we consume have high quantities of sodium. Therefore,
it is difficult to develop Na+ deficiency. All that we will have to watch
for is to reduce sodium levels. Higher sodium levels can increase blood
pressure as reported by nutritionists at the National Heart, Lung, and
Blood Institute; they say that the daily intake of sodium should not
exceed 1500 mg (one tsp salt contains about 2400 mg). Therefore,
normal consumption of salt should not exceed ½ tsp. There are processes
called desensitization and sensitization, which are explained in chapter
1. Basically, during desensitization, the sensitivity of a receptor to a
given concentration of a chemical is blunted, which means a higher
concentration of the chemical is required to sense the taste. Sensitization
is the opposite of desensitization, where lower concentration of the
chemical is sufficient to feel the sense of taste. In modern diet and in
processed food, the excessive salt and sugar has caused the salt and sugar
receptors to be in a desensitized state urging one to consume even more
salt and sugar.
42 Louis s. Premkumar, PhD
Phosphorus is an essential nutrient required for proper cell
functioning, regulation of calcium, and strong bones and teeth. A
deficiency in phosphorus can lead to lowered appetite, anemia, muscle
pain, improper bone formation (rickets), numbness, and a weakened
immune system. Phosphorus is found in almost every food, and as such,
deficiency is rare. Conversely, consuming too much phosphorus causes
the body to remove calcium from the bones into blood in an attempt to
restore balance. This transfer of calcium weakens bones and can cause
calcification of internal organs and increase the risk of heart attack
and other vascular diseases. High levels of phosphorous in carbonated
beverages are a great concern.
For the production of ATP, several enzymes are needed to metabolize
glucose, and the enzymes require cofactors and metal ions to hasten the
metabolism; Mg2+ and Mn2+ are needed for several biochemical events.
Ca2+ is the key ion to form bones and mediate neurotransmission
and cardiac—and skeletal-muscle contraction. Fe2+ is needed to form
hemoglobin so that blood can carry oxygen, which is fundamental for
the production of energy. There are several oxidant molecules that are
produced during metabolism, and the oxidants have to be removed by
endogenous antioxidants. Manganese or copper and zinc dismutases
are key enzymes. Certain cells in the body, such as those in the skin
and the gut, are constantly multiplying. Cells divide, and the division
requires synthesis of membrane lipids from fatty acids, protein synthesis
from amino-acids, and DNA replication from DNA synthesis (dividing
cells have to replicate almost three billion base pairs). Trace elements are
needed for all these biochemical processes.
Although, the raw food materials contain all the nutrients, some of
them are naturally edible (fruits) whereas others have to be made edible
by cooking (potato). However, in humans, the senses of smell and taste,
which culminate into flavor, take priority by cooking with addition of
flavorful ingredients. Therefore, the food has to be tasty so that the food
is enjoyable as well as able to nourish the body. It is always advised to eat
vegetables, but one of the main reasons people avoid eating healthy food
such as vegetables, greens, and legumes is because they do not taste good
if not well prepared. Spices and condiments add flavor and make them
appetizing, delicious, and wanting to consume. It is not clear whether
animals and other living creatures have developed the intricate sensitivity
to appreciate the flavor and enjoy the food. The taste, the smell, and
the flavor help us to consume food with a purpose. A perfectly salted or
43Fascinating Facts about Phytonutrients in sPices and healthy Food
slightly oversalted food tastes the best because Na+ is an essential element
for the body. Therefore, there is an inherent tendency to enjoy salty
(NaCl-containing) food. Of course, sweet-tasting food is always enjoyable
as indicated; there is a preference to consume sugars, such as glucose and
fructose (two times sweeter than glucose), as the major nutrient that is
needed to generate energy. Similarly, fatty foods, such as butter, lard, etc.,
taste better so that we can consume the needed calories in the form of fat,
which can be stored.
From a historical perspective, it can be inferred that human beings do
not need any food supplements, provided that healthy, wholesome food is
garnished with spices and condiments. These are consumed in moderation
(1000-2000 cal) on a daily basis, combined with mandatory, brisk, but not
strenuous physical activity (equivalent to six thousand to eight thousand
steps or equivalent to walking three to four miles) three to four times a
week. This is also supplemented with excellent medications, if diagnosed
with initial stages of cardiovascular disease, such as hypertension or angina
pectoris, or diabetes. These practices will lead to high-quality life with
expected life span. The main idea is to prevent a disease before it strikes by
identifying the telltale signs of the disease and adopting a suitable lifestyle.
Sometimes, there are no efforts made to recognize the early stages of a
disease because the initial stages of cardiovascular diseases do not present
any symptoms. For example, in hypertension, unless the blood pressure
is very high (>200/>130 mmHg), there are no presenting symptoms;
coronary artery disease (unless greater than 90% of one of the major
arteries is blocked and restricts blood supply to meet with the energy
requirement) presents with no symptoms; high cholesterol and triglyceride
levels have no symptoms. Initial stages of high blood glucose levels in
diabetes exhibit no symptoms. Once the disease has reached an advanced
stage, the only option is medical intervention. Following a procedure such
as bypass surgery or placement of a stent, the lifestyle changes imposed
and the restrictions on food are so severe, one may not be able to go for
a long and exhilarating jog or eat one’s most favorite food. One has to be
on a blood thinner for the rest of one’s life and live in constant fear of
excessive bleeding from minor injuries and recurrence of the condition
that can lead to sudden cardiac death. The main message being proclaimed
is that to avoid developing the disease in the first place, especially the
preventable diseases (diabetes and heart disease) is the best.
Further, the health cost is so enormous in the United States. Some
of these procedures can cost tens or hundreds of thousands of dollars, if
44 Louis s. Premkumar, PhD
not covered by insurance; the whole wealth of the family will be spent
in a single interventional procedure, leaving one bankrupt. Even if
there is insurance coverage, the insurers pay such large amounts; it may
not be profitable for them to be in business. It is a major drain on the
government, especially in countries where the health coverage is provided
to all. Although it is such a noble idea to provide health care to all,
personal responsibility is paramount, and one must avoid abusing the
body without respect for what one eats and drinks.
Physical appearance, an important attribute of human beings, is no
longer considered as an asset to have a healthy, trim-looking body. Of
course, in a subtle manner, physical appearance interferes with everyday
life; if one wants to be an actor or actress, one has to have reasonable
talent for acting, but a physically fit body will be more desirable because
it is going to be a public spectacle, and also one may require extreme
physical fitness to fulfill certain demanding roles.
Basically, before eating anything, one has to ask whether the food
being consumed is needed for the body at this time. Further, maintain
a routine. Eat breakfast at a given time, preferably cereals with skim
milk and fruits. Once in a while one can indulge in sausage, bacon,
poached eggs, hash browns, and French toast. No one could be spared
from developing coronary artery disease by eating sausage and bacon for
breakfast often, double-cheese hamburger for lunch, and steak for dinner
often without being an athlete or involved in demanding physical activity.
Once the body weight reaches a threshold, one is left with mental and
physical malaise to correct it. As indicated, once the body mass index is
high, one has to consume enough food to nourish the body mass and has
to carry the mass around while engaging in physical activities.
But also one can use this information as a self-guide to improve one’s
own health as well as to proclaim to others the good news of eating food
with healthy ingredients with a purpose. In developed and developing
countries, like India and China, the quality of life is getting better; people
are able to afford luxuries, which include enjoying high-calorie, fatty
food. But what is not being realized is that the life span may be cut short
with avoidable diseases, such as hypertension, coronary artery disease,
and diabetes, depriving the time with family one has built, of service to
the society, and also from reaping the benefits of the hard-earned success.
All these diseases are unequivocally related to lifestyle choices such as
excessive alcohol consumption, cigarette smoking, and unhealthy food
choices. Just eating unhealthy, high-calorie (high-carbohydrate, high-fat)
45Fascinating Facts about Phytonutrients in sPices and healthy Food
food, even with vegetarians (milk products, such as butter, butter oil, or
ghee), makes one prone to develop cardiovascular diseases. This book also
will point out wherever appropriate how to prevent diabetes and heart
disease, which are clearly associated with sudden changes in lifestyle.
High-calorie diet leads to overweight and obesity and insulin resistance
and predisposes one for developing type 2 diabetes, even in children.
Increased pace of life (excess stress) combined with high-calorie, high-fat
diet and lack of physical activity leads to hypertension and coronary
artery disease. A condition called metabolic syndrome manifests as a
result of overweight combined with heart disease. It is clear that these
diseases can be prevented or delayed until old age by eating healthy food
laced with healthy ingredients from spices and other nutrients. A recent
study in human volunteers, reported from Penn State University, showed
that the same food, when garnished with spices (pepper, cinnamon,
cloves, cardamom, etc.), had lowered the blood pressure and triglyceride
levels significantly.
The life expectancy of a mouse was lengthened twice of its normal
life expectancy simply by restricting calorie intake. The mouse fed with
half the normal daily calories was the longest-lived mouse, which has
been entered in the Guinness World Records by a researcher in Southern
Illinois University School of Medicine. It is not only the healthy eating
but also the extent of caloric input that can have an impact on health.
Ingredients in spices not only enhances the flavor but also activates the
nerve endings in the mouth, stomach, and the GI tract to send impulses
to the satiation and satiety centers, which provide the sense of satisfaction
and can limit the caloric intake (see Chapter 3). This was demonstrated
by a scientist in Georgetown University: oleoylethanolamide, which
stimulates the vagal nerve by activating the capsaicin receptor TRPV1,
can send impulses to satiety centers. Oleoylethanolamide is produced in
the small intestine after feeding. The structure of oleoylethanolamide is
related to the endocannabinoid anandamide. It also activates PPAR-alpha
and promotes lipolysis and is considered as an endogenous ligand for a
novel cannabinoid receptor, GPR119.
Garnishing or supplementing food with spices, without any
caloric values, simply because of their sweet aroma, makes the food
flavorful. Food is expected to be flavorful so that it is more enjoyable by
stimulating a myriad of sensory inputs. Therefore, people go to extreme
lengths, taking extreme measures and implementing exquisite techniques
to achieve this, which suggests the collusion of smell and taste, thereby
46 Louis s. Premkumar, PhD
imparting flavor. Garnishing ingredients are included into cooking
without one realizing their health benefits. This book goes into great
details to describe the active ingredients and their physiological effects
(see Chapters 5 and 6). Spices are added to make the food more palatable.
Some of the spices cause one to enter into a realm of craving, suggesting
that there may be an important biological need for their consumption.
In addition, the existence of specific high-affinity receptors for these
plant ingredients in human body is justified. Cinnamon, garlic, ginger,
turmeric, etc., are appealing food ingredients for a long period of time,
but now we know that there are specific receptors whose activation can
cause release of vasoactive peptides from the peripheral nerve terminals as
well as release of hormones from the gut. Even stimulating the satiation
and satiety centers to halt continued excessive food consumption is
considered a phenomenal health benefit.
Active ingredients in hot chili pepper, such as capsaicin, can induce
a variety of biological effects, including the release of neuroactive
peptides, modulation of synaptic transmission, and pain transduction. A
high-affinity receptor called TRPV1 has been cloned and characterized;
an endogenous ligand, anandamide, has been identified. Vinegar is
added to the garnish, but now we know the active component in vinegar,
acetic acid, has been shown to impart health benefits. If the process of
fermentation is allowed to continue, alcohol is converted to acetic acid.
It is intriguing that the aged dry wine that has high acetic-acid content
may be responsible for the health benefits. Yogurt has lactic acid and is
formed by bacteria that ferment food, vegetables, kombucha, sauerkraut,
sour pickles, kosher dill, types of cheese, etc.
Moderate quantities of alcohol consumed or small quantities
added while cooking can cause vasodilation and induce health benefits.
However, indiscriminate use of alcohol can cause major health hazards.
The major source of calories in beer is from the alcohol content. Alcohol
is considered to be a high-calorie food. Light beer (12 oz) contains
100-150 cal whereas regular beer (12 oz) contains 150-200 cal. 12 oz
of beer contains more calories than 5 oz of wine or 1.5 oz of liquor (80
proof). There are 7 cal per gram of alcohol as compared to fat, which
contains 9 cal per gram, and carbohydrates, which contain only 4 cal per
gram. In reality, two regular beers is equivalent to a double cheeseburger,
a roast beef sandwich, or two slices of cheese pizza. Beer consumption
reduces the risk of developing kidney stones, and this may be because of
the fluid volume or the vasodilation of blood vessels.
47Fascinating Facts about Phytonutrients in sPices and healthy Food
Concluding Remarks
Eating a balanced healthy diet that contains all the nutrients, vitamins,
and minerals is sufficient for healthy living. The amount of calorie intake
must be cautiously watched. The major source of excess calories comes
from fatty food. Although a tablespoon of butter or oils contains around
one hundred calories, it is the saturated or solid nature of butter or lard
that is harmful to health. Solid fats are difficult to get metabolized and
circulate in the blood for a longer time, which adds to the triglyceride
levels and is also converted to glucose and free fatty acids. The beneficial
effects of omega-3 fatty acids have been further validated by the discovery
that resolvins and protectins synthesized from omega-3 fatty acids
and have several physiological functions. Elevated glucose levels lead
to diabetes, and an unfavorable lipid profile leads to vascular diseases,
including coronary artery disease, by forming atherosclerotic plaques
in the blood vessels. Vitamin and mineral deficiency must be promply
recognized and supplemented, especially in children, during pregnancy,
and in the elderly.
Table 1: Sources of Vitamins and their Effects
Vitamin Functions
Daily
requirement
in
micrograms
Deficiency Source Remarks
A
(retinol)
Eyesight,
appetite,
taste, skin,
bone growth,
immune system,
reproduction
800 Night blindness
Carrots, yellow
fruits, broccoli,
greens, squash,
tomato, sweet
potatoes,
pumpkin, liver,
egg yolk
Lipid-soluble,
stored in fat
tissue, overdose
can be dangerous,
destroyed by fatty
acids
C
(ascorbic acid)
Immune system,
antioxidant,
protects from
viruses and
bacteria, collagen
synthesis, iron
absorption
60,000
Scurvy,
tiredness,
bleeding gums,
slow wound
healing
Citrus fruits,
kiwifruit,
berries,
tomato, greens,
black pepper,
potato
Lipid-soluble,
destroyed by
boiling, overdose
can result in
diarrhea and
nausea
48 Louis s. Premkumar, PhD
DBone and teeth
formation 5
Osteoporosis
(bone loss),
osteomalacia
(bone
weakness),
rickets in
children
Synthesized
by exposure to
sunlight, cod
liver oil, fatty
fish, milk, egg
yolk
Lipid-soluble
and can be
accumulated,
overdose can
be dangerous,
destroyed by
mineral oil
E
(tocopherol)
Antioxidant,
fighting
infection, cell
membrane
formation
10,000
Tiredness,
anemia, red
tongue, fertility
issues
Nuts, soybean
oil, canola oil,
sunflower oil,
wholegrain
products,
greens, eggs
tofu, avocado
Interaction
with warfarin
(bleeding),
overdose risk
of worsening
heart failure,
reduces the
risk of macular
degeneration,
destroyed by
heat, oxygen, and
iron
K
Promotes
blood clotting,
maintains blood
calcium for bone
formation
60 Interferes with
blood clotting
Greens,
brussels
sprouts,
broccoli,
cabbage, liver
Lipid-soluble,
reduces the
effectiveness of
blood thinners
B1 (thiamine)
Neuronal
growth, muscle
growth,
supports energy
metabolism
1400
Tingling,
confusion,
loss of balance
and appetite,
exhaustion,
inability to
concentrate
Greens, cereal,
tomato,
watermelon,
sunflower
seeds, milk,
liver, meat,
nuts, wheat
germ
Water-soluble, no
risk of overdose,
destroyed by
temperature,
alcohol, and
coffee
B2
(riboflavin)
Growth of
skin, nails, and
hair, supports
eyesight,
involved in
metabolism of
proteins, fat, and
carbohydrates
1600
Itchy eyes
and mucus
membranes,
cracked lips
Greens,
broccoli,
mushrooms,
eggs, milk,
liver, seafood
Water-soluble, no
risk of overdose,
destroyed by
alcohol and light
B3 (niacin,
nicotinic acid)
Growth of skin
and nervous
and digestive
systems, energy
metabolism
35,000
Pellagra, skin
and nervous
system
disorders
Greens, nuts,
legumes,
potatoes,
tomato, eggs,
liver, meat,
and fish
Reduces LDL
and increases
HDL cholesterol,
flushing, overdose
can cause liver
damage
49Fascinating Facts about Phytonutrients in sPices and healthy Food
H (biotin,
coenzyme R)
Growth,
production, and
metabolism of
amino acids,
fatty acids,
and glucose
and involved
in glycogen
synthesis
50
Dermatitis,
hair loss,
neurological
symptoms
Greens,
vegetables,
peanuts,
egg yolk,
liver, berries,
produced by
gut microflora
Consumption of
raw eggs causes
biotin deficiency
by binding to
avidin
B5
(pantothenic
acid)
Needed for
synthesis of
coenzyme-A,
involved in
amino-acid,
fatty-acid, and
carbohydrate
metabolism
6000
Neurological
symptoms,
irritability,
fatigue,
numbness,
paresthesia, and
muscle cramps
Whole-grain
cereals,
legumes,
avocados,
yogurt,
mushrooms,
eggs, meat,
fish, poultry
Deficiency is rare,
overdose is rare,
supplementation
is not required
B6
(pyridoxine)
Skin, red blood
cells, and
neuronal health,
absorption and
metabolism of
amino acids,
fatty acids, and
carbohydrates
2000 Skin
inflammation
Fish, meat
(chicken and
pork), beans,
whole grains,
bananas,
tomato,
broccoli,
spinach,
squash,
potatoes, white
rice
Destroyed by
contraceptives,
heat, alcohol, and
estrogen
Folate, or folic
acid
Production of
red blood cells,
essential or
prevent birth
defects, DNA
synthesis for cell
division
200
Spina bifida,
cleft palate,
cleft lip
Carrots,
tomatoes,
greens,
green beans,
broccoli,
asparagus,
okra, legumes
Water-soluble, no
risk of overdose,
destroyed by
water, sunlight,
and heat
B12
(cobalamine)
Used in new cell
synthesis, helps
break down fatty
acids and amino
acids, supports
nerve-cell
maintenance
1
Tingling,
numbness,
tiredness,
anemia,
cognition
Eggs, shellfish,
meats, poultry,
milk, cheese
No danger of
overdose, it can
be only obtained
from animal
food sources.
Vegans have to
be supplemented
by injection.
Homocysteine
levels may be
reduced.
50 Louis s. Premkumar, PhD
Table 2: Essential Minerals
Mineral What the mineral does Significant food sources
Sodium
Maintains fluid and electrolyte
balance, supports muscle
contraction and nerve-impulse
transmissions
salt, soy sauce, bread, milk, meats
Chloride Maintains fluid and electrolyte
balance, aids in digestion salt, soy sauce, milk, eggs, meats
Potassium
Maintains fluid and electrolyte
balance, cell integrity, muscle
contractions and nerve-impulse
transmission
potatoes, acorn, squash, artichoke,
spinach, broccoli, carrots, green
beans, tomato juice, avocado,
grapefruit juice, watermelon,
banana, strawberries, cod, milk
Calcium Formation of bones and teeth,
supports blood clotting
milk, yogurt, cheddar cheese, swiss
cheese, tofu, sardines, green beans,
spinach, broccoli
Phosphorus Formation of cells, bones, and
teeth, maintains acid-base balance
all animal foods (meats, fish,
poultry, eggs, milk)
Magnesium
Supports bone mineralization,
protein building, muscular
contraction, nerve-impulse
transmission, immunity
spinach, broccoli, artichokes, green
beans, tomato juice, navy beans,
pinto beans, black-eyed peas,
sunflower seeds, tofu, cashews,
halibut
Iron
Part of the protein hemoglobin
(carries oxygen throughout body’s
cells)
artichoke, parsley, spinach,
broccoli, green beans, tomato juice,
tofu, clams, shrimp, beef, liver
Zinc
A part of many enzymes, involved
in production of genetic material
and proteins, transports vitamin A,
taste perception, wound healing,
sperm production, and the normal
development of the fetus
spinach, broccoli, green peas, green
beans, tomato juice, lentils, oysters,
shrimp, crab, turkey (dark meat),
lean ham, lean ground beef, lean
sirloin steak, plain yogurt, swiss
cheese, tofu, ricotta cheese
Selenium Antioxidant, works with vitamin
E to protect body from oxidation seafood, meats, and grains
Iodine
Component of thyroid hormones,
which help regulate growth,
development, and metabolic rate
Iodized salt, seafood, bread, milk,
cheese
51Fascinating Facts about Phytonutrients in sPices and healthy Food
Copper
Necessary for the absorption
and utilization of iron, supports
formation of hemoglobin and
several enzymes
meats, water
Manganese Facilitates many cell processes widespread in foods
Fluoride
Involved in the formation of
bones and teeth, helps to make
teeth resistant to decay
fluoridated drinking water, tea,
seafood
Chromium
Associated with insulin and is
required for the release of energy
from glucose
vegetable oils, liver, brewer’s yeast,
whole grains, cheese, nuts
Molybdenum Facilitates many cell processes legumes, organ meats
Table 3: Triglyceride Levels
Triglyceride level in
mg/dL
Triglyceride level in
mmol/L
Remarks
<151 <1.7 Normal, low-risk
151-199 1.7-2.25 Above normal
200-499 2.26-5.65 Above normal, some risk
>499 >5.65 High level, high-risk
Triglyceride level less than 150 mg/dL is normal, 150-199 mg/dL poses a
risk, 200-499 mg/dL is high-risk, and greater than 500 poses a real risk.
Table 4: Cholesterol Levels
Cholesterol level in
mg/dL
Cholesterol level in
mmol/L
Remarks
<200 <1.7 Normal, low-risk
200-239 1.7-2.25 Above normal
>240 2.26-5.65 High-risk
Cholesterol levels should be less than 200 mg/dL; 200-239 mg/dL is
moderate-risk, and greater than 240 mg/dL is high-risk.
52 Louis s. Premkumar, PhD
Table 5: Low-Density Lipoprotein (LDL)
LDL cholesterol level
mg/dL
LDL cholesterol level
in mmol/L
Remarks
<100 <1.7 Normal, low-risk
100-129 1.7-2.25 Above normal
130-159 2.26-5.65 High-risk
LDLs carry cholesterol throughout the body for utilization. If the
cholesterol levels are higher than needed, LDLs cannot deliver cholesterol
and hence circulate in the blood, and if there is an injury, they can get
between the blood vessel wall and form deposits called plaques. When
the plaques get larger, they can occlude blood supply, initiating the
development of coronary artery disease and, if large enough to occlude
blood supply, manifest as ischemic heart disease, associated with angina
(pain in the chest and back). If the plaque ruptures, it can form total
occlusion of the blood vessel, leading to complete lack of blood supply to
the heart, causing a heart attack, leading to death of heart muscle.
Table 6: Very-Low-Density Lipoprotein (VLDL)
LDL cholesterol level
in mg/dL
LDL cholesterol level
in mmol/L
Remarks
<100 <1.7 Normal, low-risk
100-129 1.7-2.25 Above normal
130-159 2.26-5.65 Above normal, risk
>160 >5.65 High-risk
Very-low-density lipoprotein contains high amount of triglycerides.
It is difficult to measure the values; it is expressed as a percentage
of triglyceride value. The value of VLDL should be between 5 and
30 mg/dL.
53Fascinating Facts about Phytonutrients in sPices and healthy Food
Table 7: High-Density Lipoprotein (HDL)
LDL cholesterol level
in mg/dL
LDL cholesterol level
in mmol/L
Remarks
<40 for men <50 for
women
<1.03 Normal, low-risk
40-59 1.03-1.55 Above normal
>60 >1.55 High-risk
HDLs act as cholesterol scavengers removing excess cholesterol from
blood and carrying it to the liver, where it is broken down. Higher levels
of HDL are good; the higher the levels of HDL in the blood, the lower
the levels of LDL in the blood. Therefore, the ratio of LDL and HDL
cholesterol is important.
Table 8: Blood Sugar Levels
Fasting After food HBA1c Remarks
mg/dL mmol/L mg/dL mmol/L
80-100 4.4-5.5 170-200 9.4-11.1 <7 Normal
101-125 5.6-6.9 190-230 10.5-12.7 7-8 Impaired, prediabetic
>126 >7 220-300 12.2-16.6 >8 Diabetic
It is important to control blood sugar levels at the impaired or
prediabetic state. When the fasting blood sugar level is greater than
126 with low plasma insulin, the disease is considered to be just
beginning. In fact, it has been shown that by that time 50-70% of the
insulin-secreting pancreatic beta cells have already been destroyed, which
means if the blood sugar level is not strictly controlled, the disease will
progress to cause eye, heart, and kidney damage, and soon will become
insulin-dependent diabetes because all the insulin-producing cells are
destroyed.
54 Louis s. Premkumar, PhD
Table 9: Normal and Abnormal Blood Pressure Measures
Classification Systolic blood pressure in
mmHg
Diastolic blood pressure in
mmHg
Normal <120 <80
Prehypertension 120-139 80-89
Stage 1
hypertension
140-159 90-99
Stage 2
hypertension
>160 >100
The Joint National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure (JNC) seventh report suggests the blood
pressure ranges fall under this classification. Prehypertension stage has to
be recognized, and one must adopt a lifestyle to reduce the blood pressure.
If this is ineffective, drug treatment should be considered. Since elevated
blood pressure has no symptoms, allowing high blood pressure to continue
will lead to thickening of blood vessels, a prerequisite for developing
coronary artery disease. Uncontrolled blood pressure also leads to
thickening of the cardiac muscles, which can lead to heart failure, initially
to diastolic heart failure (inability to relax and fill properly) and finally to
systolic heart failure (inability to contract efficiently to pump blood).
Table 10: Diet-Related Diseases in the United States of America
Disease Number in millions Percentage Remarks
Heart Disease 81.1 37 Risk factor, high
cholesterol and other
lipids, diabetes,
metabolic syndrome,
overweight, obesity,
sedentary lifestyle,
and smoking. High
sodium, low potassium,
and excessive alcohol
consumption.
Hypertension 74.5 adults 34
Prehypertension 78.8 36
55Fascinating Facts about Phytonutrients in sPices and healthy Food
Diabetes 24 adults 11 Type 2 Diabetes
Prediabetes 78 35 Impaired glucose
tolerance, fasting levels
>115 but <125
Cancer 1 in 2 Americans will
be diagnosed with
cancer during their
lifetime.
41 Dietary factors are
associated with
cancers of the breast
(postmenopausal,
endometrial), colon,
kidney, mouth,
pharynx, and
esophagus.
Osteoporosis 1 in 2 American
women and 1 in 4
men ages fifty and
older will have a
fracture related to
weak bones.
50% women
25% men
Adequate calcium and
vitamin D combined
with physical
activity can prevent
osteoporosis.
Source: Dietary Guidelines of Americans, 2010
Table 11: Important Risk Factors for Heart Disease in US
(over 20 years of age)
Risk Factor Definition US Prevalence
Diabetes Fasting blood glucose greater than
126mg/dL
20 million (9.5%)
Tobacco Cigarette smoking 46 million (20.9%)
Hypertension Blood pressure greater than
140/90 mm Hg
72 million (33.6%)
Abnormal lipid Total cholesterol greater than
200 mg/dL
105 million (48.4%)
Overweight Body mass index greater than
25 kg/m2
140 million (66%)
Physical Activity No regular exercise 154 million (69.9%)
Source Circulation 2007; 115:e69-e171
56 Louis s. Premkumar, PhD
Table 12: Life Style Modification to Control Blood Pressure
Modification Recommendation Reduction in SBP
Weight reduction Maintain BMI=18.5-25 5-20 mm Hg/10 kg lost
DASH eating plan Fruits, vegetable, low fat 8-14 mm Hg
Restrict sodium Less than 2-4 gms/day
(1/2 teaspoon)
2-8 mm Hg
Physical Activity Exercise at least 30 min/day 4-10 mm Hg
Moderate alcohol Less 2 drinks/day for men and
less than 1 drink for women
2-4 mm Hg
BMI—body mass index, SBP-systolic blood pressure, DASH-dietary approaches
to stop hypertension
Source JAMA 2003;289:2560-2572
57Fascinating Facts about Phytonutrients in sPices and healthy Food
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Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality
in Randomized Trials of Antioxidant Supplements for Primary and
Secondary Prevention: Systematic Review and Meta-analysis. JAMA
2007;297:842-57.
Menotti A, Kromhout D, Blackburn H, Fidanza F, Buzina R, Nissinen
A. Food intake patterns and 25-year mortality from coronary heart
disease: cross-cultural correlations in the Seven Countries Study.
The Seven Countries Study Research Group. Eur J Epidemiol
1999;15:507-15.
Serhan CN, Clish CB, Brannon J, Colgan SP, Chiang N, Gronert K.
Novel functional sets of lipid-derived mediators with
antiinflammatory actions generated from omega-3 fatty acids
via cyclooxygenase 2-nonsteroidal antiinflammatory drugs and
transcellular processing. J Exp Med. 2000;192:1197-204.
Soldavini J, Kaunitz JD. Pathobiology and potential therapeutic value of
intestinal short-chainFatty acids in gut inflammation and obesity. Dig
Dis Sci. 2013;58:2756-66.
Soni MG, Thurmond TS, Miller ER 3rd, Spriggs T, Bendich A, Omaye
ST. Safety of vitamins and minerals: controversies and perspective.
Toxicol Sci. 2010;118:348-55
U.S. Department of Health and Human Services, U.S. Department of
Agriculture. Dietary Guidelines for Americans. 2010.
Uusi-Rasi K, Kärkkäinen MU, Lamberg-Allardt CJ. Calcium intake
in health maintenance—a systematic review. Food Nutr Res.
2013;16;57.
Visiedo F, Bugatto F, Sánchez V, Cózar-Castellano I, Bartha JL,
Perdomo G. High glucose levels reduce fatty acid oxidation and
increase triglyceride accumulation in human placenta. Am J Physiol
Endocrinol Metab. 2013;305:E205-12.
Weylandt KH, Chiu CY, Gomolka B, Waechter SF, Wiedenmann
B. Omega-3 fatty acids and their lipid mediators: towards an
understanding of resolvin and protectin formation. Prostaglandins
Other Lipid Mediat. 2012;97:73-82.
World Cancer Research Fund/American Institute for Cancer Research:
Food, Nutrition, Physical Activity and the Prevention of Cancer. 2nd
Edition, 2007. pp.93-94.
58
CHAPTER 3
Neurobiology of Appetite,
Feeding, Satiation, and Satiety
These days food intake has become a routine; it is a time-honored
phenomenon rather than a task of fulfilling the physiological need of
hunger. Breakfast in the morning could consist of cereals, fruits, bacon,
sausages, and poached eggs. Lunch could include a healthy tuna sandwich
and salad or a double-cheese-bacon burger or a full-fledged buffet with
ice cream, brownies, and/or cheesecake as desserts. Dinner is considered
to be the best meal of the day for the working family since everybody has
just come back from school or work, and dinnertime is between 5:00-7:00
p.m. There is often not enough time to do elaborate cooking from scratch;
therefore, families depend on processed food, takeaway, or fast food.
Throughout the day, high-calorie, high-caffeine beverages are consumed
along with high-calorie snacks to prevent dehydration or to keep one
awake and alert. This routine continues for most of one’s life, which
is also critically dependent on the social strata. In this fast-paced world,
socioeconomic status determines the type of food one consumes, which is
dependent upon the type of work, time of work, duration of work, and the
environment of the workplace. Large corporations provide great facilities
as perks, such as a healthy food-serving cafeteria, a place for a brisk walk
during lunchtime, physical activity centers, good working conditions, and
an atmosphere and flexible time schedule to care for the family, etc. If one
is higher up on the ladder of the social strata, the picture is even rosier.
The basic premise is that food is consumed not because it is needed
but because it is available and also to fulfill the timely commitment.
59Fascinating Facts about Phytonutrients in sPices and healthy Food
Some of these aspects have been dealt with in the introduction (see
Chapters 1 and 2). The average daily calorie requirement is 1500-2500
cal per day: for a sedentary adult female, 1500-2000, and for a male
2000-2500; for a moderately active adult female, 1800-2200, and for a
male 2200-2800; for an active adult female, 2000-2500, and for a male
2500-3000. The basic idea is that the amount of food intake should equal
the expenditure. A mismatch of less than 0.5% (7.5-12.5 extra calories,
equal to an extra bite of a brownie) will result in overweight and obesity
over time. If the mismatch is in the opposite direction, the body weight is
lost. The mismatch must be recognized earlier; otherwise, the battle is lost
quickly. In fact, the extent of the mismatch will determine how quickly
overweight becomes noticeable and leads to obesity and portends all kinds
of health risks, chief among them are diabetes and heart disease. A recent
study from National Institutes of Health concludes that the longer one
stays overweight, the higher the risk of developing cardiovascular disease.
A study conducted by Mayo Clinic concludes that there is a direct
correlation between memory loss and a high-calorie diet. Additionally,
USA Today reported that elderly people who consume more than 2200
cal a day exhibited mild cognitive impairment (MCI) as compared to
those who consumed less than 1500 cal per day. MCI is a condition
between normal forgetfulness and the early stages of Alzheimer’s disease.
Body mass index (BMI) is a measure determined by the body weight
divided by the square of an individual’s height. A BMI value between
18.5 and 25 can be considered normal, while a lower value is considered
underweight and a value over 25 is considered overweight. A BMI value
greater than 30 is considered obesity, and greater than 40 is considered
morbid obesity.
The expenditure of the energy depends upon the amount of
physical activity one engages in a given day. If the lifestyle is sedentary,
since there is less demand for energy, food intake must be cautiously
curtailed. These individuals require other forms of physical activity to
expend energy. Using a computer for recreational purposes—such as
playing competitive games, being on the Facebook, watching a movie
with the clarity of a Retina display, or gathering information on a topic
of interest—can unknowingly consume many hours. Spending a lot
of time in front of the computer is a major cause of weight gain and
obesity in the adolescent population. The first sign is developing insulin
resistance (even though insulin levels are adequate, it is not utilized
well), which leads to an increase in blood glucose levels. If this increase
60 Louis s. Premkumar, PhD
is not corrected by losing the excess weight naturally, the condition
will lead to type 2 diabetes mellitus in the long run. This happens
because of an increased demand for producing insulin as a result of
constant high blood glucose levels. The insulin-producing cells in the
pancreas depend on the level of ATP that is produced from glucose to
cause insulin release. ATP is a necessary molecule that blocks a set of
potassium channels that causes depolarization of the pancreatic beta cell,
which causes calcium influx, since calcium is an important ion needed
for insulin release. During the constant need for producing ATP due to
high blood sugar levels, reactive oxygen species are produced, and the
pancreatic beta cells are destroyed due to excessive oxidative stress. Finally,
this condition will lead to insulin-dependent diabetes in that one has
to take insulin injections because the insulin-producing capacity of the
pancreas is lost significantly, as in type 1 diabetes mellitus, where the beta
cells are destroyed by infection or autoimmunity. The body produces
antibodies against its own beta cells in the pancreas and destroys the
insulin-producing beta cells.
There is a balance between energy consumption and expenditure. If
one is involved in physically demanding jobs, the consumption of large
quantities of food is needed to meet the energy needs. For example, great
athletes, like Michael Phelps, consume a calorically rich diet. During his
rigorous exercise routines, he consumes 8000-10,000 cal for breakfast and
expends the same or higher amount of calories during intense training.
In Phelps’s autobiography, Beneath the Surface, he writes, “Start with
three sandwiches of fried eggs, cheese, lettuce, tomato, fried onions, and
mayonnaise; add one omelet, a bowl of grits, and three slices of French
toast with powdered sugar; then wash down with three chocolate chip
pancakes.” Now that he has completed his career, it will be interesting
to see whether he consumes the same amount of calories, and if he does,
whether he will be able to burn off the calories to prevent him from
gaining weight.
The satiation or satiety centers are designed to receive signals from
the periphery to attest the fullness, and therefore, when the expenditure is
not equaled to consumption, the excess energy is stored in the form of fat,
leading to weight gain. Satiation is defined as the sense of satisfaction as
the food is being consumed, which signals the termination of a meal. On
the other hand, satiety is defined as the sense to prevent food consumption
between meals by integration of sensory, hormonal, and cognitive
processes. Initially, the weight gain may not be noticeable because of lack
61Fascinating Facts about Phytonutrients in sPices and healthy Food
of exercise; the muscle mass decreases and the fat mass increases. If one is
cognizant of the expenditure side of the equation, the food consumption
can be adjusted accordingly to fit into the change in routine. One also
develops leptin resistance, which calls for overeating, because the satiation
or satiety centers are not informed to terminate food consumption.
Once the body weight is increased, the body mass and the surface
area increase, causing the energy requirement to increase and the ability
to do physical activity to decrease. There is a threshold, and once it is
crossed, it becomes difficult to balance the mismatch between energy
consumption and expenditure. It is like walking uphill while the
inclination is constantly changing to an extent that one loses the battle to
curtail food intake to lose weight.
Since excessive food intake combined with a sedentary lifestyle
can lead to weight gain and obesity, the food intake can be controlled
by following a single-serve strategy. The volume or quantity of the
food intake can be controlled, if not the caloric value. Since the caloric
value varies so much from day to day, the excess in a given day can be
balanced. When one goes on vacation, it can be combined with higher
physical activity, so one may indulge in overeating for a few days. Self-will
issue plays a key role if one is determined and has a strong willpower;
it is possible to achieve anything, including the adherence to healthy
eating. Single-serve limit at any meal is a worthwhile practice to adopt
for healthy living. Given the variety of delicious food available, the taste,
the flavor, and the exquisite details involved in food preparations make
one feel that one is losing out on one of the most enjoyable pleasures
of life. The pleasure associated with food consumption involves the
reward-related neuronal circuitry in specific brain regions.
The consequences of weight gain are enormous; adolescent weight
gain occurs at the prime of one’s life, such as during senior years of high
school, and continues through the college years. Overweight and obesity
can have a serious impact and can be great impediments in several aspects
of life. Being overweight affects the ability to concentrate on schoolwork
at physiological (ability to work hard by keeping fit and awake) and
psychological (inability to concentrate) levels. Overweight individuals
become discouraged, depressed, and despondent. It is claimed that people
overeat because of emotional stress; individuals who are depressed tend to
indulge in binge eating. This is an attempt to avoid unpleasant feelings
by overeating comfort or junk foods that have high calorie values and, of
course, drinking high-calorie and alcoholic beverages. These days the drug
62 Louis s. Premkumar, PhD
treatment for depression is dispensed indiscriminately, without a second
thought. One of the side effects of antidepressants, such as selective
serotonin reuptake inhibitors (SSRIs), is weight gain. As described in this
book, serotonin plays a key role in appetite and food intake.
The preventable diseases, such as obesity, diabetes, hypertension, and
coronary artery disease, are lifelong diseases associated with poor eating
habits and lack of exercise. Once diagnosed and treated, the restrictions
on lifestyle are so severe, it is worth the efforts to avoid or delay
developing the disease in the first place.
It becomes the collective responsibility of the parents, restaurants,
and food and beverage manufacturers to make sure children and young
adults are educated to eat healthy and follow a healthy lifestyle. What
metric is used to measure the amount of addeded salt and sugar? Is it by
testing volunteers who are already addicted to salt and sugar, whose taste
receptors have been desensitized? It is proposed that lowering the salt and
sugar levels in small quanities over time (months to years) may resensitize
the receptor to get the same sensation with lower healthy levels. The
food manufacturers should seriously consider this proposal. The most
expensive restaurants serve the least amount of food, but the food is
delicious prepared with utmost care and with exquisite details. However,
food served in medium-range restaurants tend to be greasy, salty, and
fatty, with large portions and an unlimited supply of sugary beverages.
Restaurants that adopt buffet-style serving contribute significantly to
overweight and obesity of the population. The more often one consumes
these kinds of food, the higher chances of developing preventable
diseases, such as diabetes and heart disease. Acquiring preventable diseases
is a great burden to oneself, to the family, and to society; and it especially
adds to the health costs of others.
For all food, there is an associated memory, so one expects how food
should taste, but the expectations can vary. Further, it is impossible
to consume one’s favorite food for every meal. Sometimes one eats to
survive, and other times one survives to eat.
Why Do We Start Eating?
There are several mechanisms and a number of endogenous peptide
hormones produced in the body that plays a role in food consumption.
As indicated earlier, a routine is followed for food consumption. The
63Fascinating Facts about Phytonutrients in sPices and healthy Food
routine has changed in that food consumption is now dictated by
the time to eat rather than by hunger. If one follows the single-serve
strategy, when the time for the next meal arrives, the hunger dictates
food intake. There are several cues for food intake that trigger hunger.
A good-smelling food increases the desire; for example, the aroma of
freshly baked confectionaries, meat being cooked on a grill, or seasoning
from garnishing spices all increase the urge and stimulate appetite. In
a recent experiment, supermarkets produced artificial food aroma in
the aisles, and this improved the sales considerably. Similarly, fragrance
circulated via air-conditioning vents has increased the chances of selling
a home. This is because one associates good smells with a better mood
and a favorable mind-set, a motivating factor for developing exotic
fragrances. Similarly, in the animal kingdom, the strong olfactory signals
induced by pheromones stimulate procreation. The appearance of the
food enhances the desire to eat. This process is brought about by visual
signals invoking associated memories of a particular food, but it can
be disappointing when the expectations are not met. Even olfaction is
associated with sound; the sense is called smound, which is, perhaps,
the reason for playing music in restaurants while consuming aromatic
food. In these conditions, although one is not hungry, there is a desire to
consume food.
Another major factor in eating is the blood glucose and lipid levels,
which dictate the necessity to consume food. When blood glucose level
is low, if left unnoticed, the condition can lead to loss of consciousness,
which tends to be gradual as compared to cardiac dysfunction, which
usually occurs suddenly. The signs of hypoglycemia are light-headedness,
increased heart rate, perspiration, etc. All are related to an increase
in sympathetic tone that is triggered in order to replenish the most
important energy source, glucose.
If beta-adrenergic-receptor blockers are used for controlling blood
pressure, managing cardiac-rhythm disturbances or decreasing oxygen
demand in ischemic/coronary artery disease, an increase in sympathetic
tone does not occur, and the warning signs of hypoglycemia could go
unnoticed, leading to loss of consciousness. Therefore, people who
are being treated for diabetes with insulin and who are also taking beta
receptor blockers should be more cautious because of the lack of warning
signs. This is because certain neurons in the central nervous system are
exquisitely sensitive to glucose levels. In cardiac cells, the main source of
energy for heart cells is derived from fatty-acid metabolism.
64 Louis s. Premkumar, PhD
Intriguingly, the major hormone whose level increases to signal food
consumption is ghrelin. There are a number of hormones released from
various parts of the gut whose signaling works to curtail food intake.
However, when the levels of these hormones are low, food intake is
facilitated.
Ghrelin is an important hunger hormone released from the cells
in the lining of the stomach, and neuropeptide Y (NPY) is a critical
stimulator of feeding behavior, which is abundantly expressed in the
brain. Leptin is produced in fat cells, adipocytes, and functions as a
hormone in the satiety centers of the brain and reduces feeding behavior.
The action of leptin is related to inhibiting NPY synthesis and release.
Adiponectin is an anti-inflammatory peptide released from fat cells
that regulates energy balance, influences the metabolism of sugars and
fats, and improves insulin sensitivity. Fatty tissues function almost as
an endocrine organ by releasing various hormones. Peptide YY (PYY)
slows digestion, reduces appetite, and dramatically reduces food intake.
Cholecystokinin (CCK) is released from the duodenum in response to
high-fat or high-protein diet and induces a sense of fullness, especially to
fatty food.
Insulin is an important enzyme that decides whether the glucose
is to be used for energy or stored as fat. Insulin levels are directly
impacted by the ratio of carbohydrates to fiber, fat, and protein.
Thyroid hormone plays an important role in regulating metabolism
and promotes imbalance between other hormones. Stress hormones,
such as cortisol, are associated with food craving and binge eating.
Cortisol can block weight loss and conserve and store energy as a result
of misinterpretation of the signal as malnourishment. Hence the advice
is not to skip meals, because cortisol levels are higher when one is
starving. Melatonin is a hormone known to control circadian rhythm.
Sleep deprivation and shift work influence the health with altered
leptin, ghrelin, and growth hormone levels. Sex hormones, such as
estrogen, progesterone, and testosterone, play a role in appetite and
food intake. Estrogen is involved in hunger regulation and satiety effects
of serotonin. Imbalance between estrogen and progesterone triggers
premenstrual craving and storage of abdominal fat during premenopause
and menopause. Testosterone deficiency can lead to loss of muscle mass
in both men and women.
65Fascinating Facts about Phytonutrients in sPices and healthy Food
Why Do We Stop Eating?
The main signal is from the stomach; when the stomach distends, signals
are sent to the satiation centers in the brain that, in turn, instruct to
terminate continued eating. Therefore, the volume of food ingested
is critical for the distention. Unless the required amount of food is
consumed, the distention is inadequate to activate the mechanical
sensors to elicit a response and transduce the information to the satiation
or satiety centers of the brain. There is an ongoing intense debate
whether liquid food consumption in the form of energy drinks and
shakes could trigger the signals of satiation and satiety. If large portions
of food are consumed daily, the capacity of the stomach increases over
time. Therefore, until a larger quantity of food is consumed, the
mechano-satiation signal is not evoked.
In order to maintain a smaller-capacity stomach, the amount of food
consumed must be curtailed. To reduce the capacity of the stomach, food
intake must be gradually reduced over a period (months to years) so that
the capacity of the stomach can be reduced, and at the same time, the
sense of fullness is achieved by triggering the mechano-satiation signal.
Further, when food is absorbed, blood glucose levels increase; in response,
insulin is released and acts as a hormone at the satiation center. But the
inverse is also true in that insulin promotes its storage and facilitates
glucose entry into cells, causing blood sugar levels to decrease, initiating
the next cycle of food consumption. Each of these hormones will be
discussed in detail in the following sections. The question is, why do we
need so many signaling molecules and signaling processes? As indicated in
all biological processes, a balance between an excitatory (“do” system) and
an inhibitory (“do not do” system) exists. They are in a perfect balance,
or in homeostasis. When this balance is disrupted, the condition is
manifested as a disease. Excessive uncontrolled food consumption can be
considered as a disease if it leads to overweight or obesity.
The reason we stop eating is due to a sense of fullness leading to loss
of hunger signals. The other reason is that the pleasurable feeling or the
sense of reward is no longer appealing. There are sensations of fullness
perceived in the central nervous system in response to peripheral inputs
by stimulating the nerve endings in the gastrointestinal tract; the nerves
that carry satiation information are vagus and glossopharyngeal nerves.
Substances that are released into the bloodstream from specialized cells
in the gut following food intake can directly act on receptors expressed
66 Louis s. Premkumar, PhD
in the satiation or satiety centers in the brain. Hormones such as
cholecystokinin (CCK), released from the gut, and leptin, released from
adipocytes, play an important role in sending signals to the satiation or
satiety center of the brain to stop food consumption.
It is also important to note that the weight, volume, and energy
content of the food are critical in causing the release of hormones that
convey the message to the brain and alert to terminate food intake.
Studies have been conducted by incorporating varied amounts of fat
in yogurt, but the satiation can be associated with the distention of
the stomach rather than the energy content. CCK and GLP-1 control
the pyloric pressure and stomach motility and contraction to delay the
emptying of the food. When the food stays in the stomach longer, it
promotes satiation.
Brain imaging studies have been undertaken to delineate the role of
the brain regions that might be involved. From these studies, it can be
gleaned that sensory-specific satiation is an important driver for choices
of food, halting excess food consumption. Therefore, depending upon
the availability and choice of food, the normal sense of satiation can
be overridden, causing people to consume excessive amounts of food.
Imaging studies reveal that taste and olfactory stimuli are represented in
the amygdala and orbitofrontal cortex.
There is an emotional and reward pathway associated with food
intake, which involves the corticolimbic pathway. The areas include
the nucleus accumbens, ventral tegmental area, striatum, orbitofrontal
cortex, insular cortex, and anterior cingulated cortex. The orbitofrontal
cortex regulates visual, olfactory, and gustatory functions. Specifically,
anterolateral orbitofrontal cortex is associated with hyperphagia.
Using bitter compounds, such as quinine, it was confirmed
during imaging that evasiveness can be observed to unpleasant food.
Stomach distention resulting in enhanced mechanical force activating
mechanosensors was demonstrated in human subjects using a balloon
inflation technique. It has been also shown that upon infusion of tomato
soup into the stomach, the subjects expressed a sense of satisfaction
as compared to infusion into the duodenum, suggesting the role of the
stomach (volume and distention) in sending the sensory information to
the higher centers of the brain Imaging studies show that the prefrontal
cortex’s neuronal activity is enhanced, which is associated with satiety.
This is confirmed by the fact that people who have impaired prefrontal
cortex suffer from hyperphagia (excessive eating). Other brain areas that
67Fascinating Facts about Phytonutrients in sPices and healthy Food
have been shown to be involved are hypothalamus (involved in regulation
of food intake), hippocampus (involved in memory formation), thalamus
(integrates sensory information to the cortex), and insular and temporal
cortex (involved in processing sensory information associated with food
consumption); there was a decrease in neuronal activity in these areas. In
imaging studies, decreased neuronal activity was observed in all limbic or
paralimbic areas in satiety conditions than in hunger conditions.
The imaging studies have been useful to show that distinct areas of
the brain are involved in sensing taste and odor in understanding the
role of taste and odor. In orbitofrontal cortex, the activation produced by
the eaten food to satiation decreased, but there was no similar decrease
for the odor of the food not eaten in the meal, indicating orbitofrontal
cortex is related to olfactory and sensory-specific satiety. The medial
orbitofrontal cortex was activated when chocolate was liked whereas
the lateral orbitofrontal cortex was activated when it becames aversive.
The role of food odor in food consumption can be gleaned from the
observation that when the nostrils are constantly exposed to odor during
cooking, the food does not taste good, and aversiveness develops soon
after cooking. As the saying goes, the cook who prepared the food does
not enjoy the food. Using the imaging technique, the rate of pleasantness
of the food could be correlated with the extent of neuronal firing. But it
does not differentiate inhibitory and excitatory neuronal firing, which is a
limitation while trying to interpret imaging data.
Food intake regulates body temperature by thermogenesis (heat
production in the body by altering metabolism), which, in turn, controls
satiety. Hunger depends on the amount of ATP produced during glucose
metabolism as a result of oxidative phosphorylation. In higher altitude,
lower oxygen levels can lead to reduced appetite. But when the temperature
is low, thermogenesis increases to counterbalance reduced appetite.
Protein-rich food induces higher thermogenesis as compared to food rich
in carbohydrate and fat content. Consumption of higher carbohydrate—
and fat-containing food lowers thermogenesis and leads to obesity.
The Gut-Brain Axis
It is quite obvious that the organ that comes in contact with food has
to send signals to the brain to regulate eating. Therefore, it is essential
to know at what point in time this signal is experienced; once it crosses
68 Louis s. Premkumar, PhD
the threshold, the fine-tuning is lost. As experienced during alcohol
consumption, there is a time at which one feels tipsy (one to two drinks),
and after that, there is a feeling of warmth and loss of inhibition to talk
or perform, and this instigates excessive eating and drinking (three to four
drinks), beyond which there is no measurable effect until one gets drunk
and becomes immobile. Another factor is how quickly one drinks because
there is a time delay (even if it is short) for the alcohol to be absorbed and
bring about the effects. One may consume too much quickly as happens
in freshmen in college dorms. Before the consumed alcohol takes effect,
another drink is forced upon you. If the consumption is too quick, it can
lead to alcohol-induced death.
Similarly, in food intake, it takes time for the hormonal actions to
begin to initiate signals to the brain satiation and satiety centers. This
requires a longer time than alcohol consumption, because alcohol has
to be just absorbed. The first signal from the stomach is the distention,
which comes from filling, then the food ingredients activate a variety
of signaling molecules; some of them activate the vagus nerve directly
to send the information to the brain whereas others are mediated by
hormones secreted to the bloodstream, and the signal has to reach the
satiation or satiety centers in the brain from the small intestine. One
way to maximize the signal transduction and achieve a balance is to
eat slowly. Sometimes it is suggested to fill the stomach with water
or an inert substance that is not absorbed to prime the volume—or
distention-dependent signal-transduction process.
The vagus nerve is the conduit by which information from the
gastrointestinal tract is sent to the brain. It carries sensory information,
and the cell bodies of which are embedded in nodose ganglion and
terminate at the dorsal vagal complex (DVC) of the brain stem.
The brain stem expresses insulin receptors (IR) and CCK2R (both
gastrin and CCK act on these receptors). Ghrelin also acts on GHS-RI
receptors. DVC has projections to the hypothalamus, which has several
nuclei that are involved in feeding behavior, such as the arcuate nucleus
(ARC), paraventricular nucleus (PVN), ventromedial nucleus (VMN),
dorsomedial nucleus (DMN), and lateral hypothalamic area (LHA).
ARC has two types of neurons that express specific types of receptors to
neuropeptides and are involved in enhanced food intake (neuropeptide
Y [NPY] and agouti-related peptide [AgRP]) and suppression of food
intake (pro-opiomelanocortin [POMC] and cocaine-amphetamine-
regulated transcript [CART]). NPY is the most abundant peptide in
69Fascinating Facts about Phytonutrients in sPices and healthy Food
the CNS; administration of NPY increased food intake. AgRP is a
potent and selective antagonist of melanocortin 3 receptor (MC3R)
and melanocortin 4 receptor (MC4R). From POMC, alpha-MSH is
produced, which acts on MC3R and MC4R receptors; the knockout
of MC4R results in hyperphagia and obesity. CART is the third most
abundant transcript in the hypothalamus; administration of CART into
the PVN and ARC increased food intake.
Levels of glucose are exquisitely sensed by the brain since low
blood glucose levels lead to lightheadedness and quickly lead to
unconsciousness. Glucose-sensing neurons are found in the LHA, ARC,
and VMN. There are neurons excited by glucose and neurons inhibited
by glucose.
The peripheral nerve endings express chemo—and mechanoreceptors
to sense the ingredients in the food and the distention or stretch of
the stomach, respectively. Like other sensory systems, the vagus nerve
senses and transduces information to certain specific regions of the
brain that control hunger, appetite, satiation, and satiety, which are
necessary for the need to eat tasty and nutritious food and the need to
stop eating after consumption of an appropriate quantity. The vagus
nerve is involved in food-induced negative feedback that determines
the meal size. Blocking the impulses increases the meal size. Since the
vagus is innervating the whole gastrointestinal tract, different regions of
the gastrointestinal tract can send appropriate information; fatty-acid
signal is sensed at the jejunum. There are several TRP channels expressed
at the vagus nerve: TRPV1, TRPA1, TRPV2, etc. TRPV1 senses the
pungent food ingredients, such as capsaicin, acid, etc; TRPA1 senses
allicin, active ingredient in garlic; AITC, in mustard; cinnamaldehyde,
in cinnamon; etc. They are also activated by other endogenous ligands,
like anandamide and 2-arachidonylglycerol (2-AG). These receptors are
expressed at the peripheral nerve terminals and also in enteroendocrine
cells when activated; they release a variety of gut hormones. Monosodium
glutamate—fed animals showed reduced weight gain, fat deposition,
and plasma leptin concentrations. Omega-3 polyunsaturated fatty
acids reduced inflammation in the hypothalamus and improved the
whole body’s insulin resistance and reduced fat deposition. Fructose is
commonly used in processed food; when fructose is metabolized in the
brain, it has opposite effect of glucose on the AMP-activated kinase/
malonyl-CoA signaling system, and the feeding is enhanced.
70 Louis s. Premkumar, PhD
Intermittent and periodic vagus-nerve stimulation by electrical
means is a therapeutic option for some conditions such as epilepsies and
in chronic pain conditions indicating vagus nerve is involved in complex
brain functions. Vagus-nerve stimulation significantly reduced food intake
and weight gain, even when fed with high-fat diet. Vagal-nerve stimulation
resulted in decreased leptin but increased ghrelin and nesfatin levels.
Food ingredients, when exposed to enteroendocrine cells, release
hormones into the bloodstream and induce effects on the central and
peripheral nervous system. These cells are expressed throughout the
intestine. K-enteroendocrine cells (K-cells) are expressed in upper small
intestine, L-enteroendocrine cells (L-cells) are expressed in the lower
small intestine (ileum) and large intestine (colon), and enterochromaffin
(EC) cells are expressed in epithelial cells of the gut. K-cells release
glucose-induced insulinotropic polypeptide (GIP), L-cells release
GLP-1 and GLP-2, and EC cells release serotonin or 5-HT. GLP-1
and GLP-2 are involved in glucose homeostasis by promoting beta-cell
health in the pancreas. The significant effects of hormone released from
enteroendocrine cells were revealed by ileal transposition bariatric surgery.
Following this surgical procedure, the food ingredients are directly
exposed to L-cells of the ileum, and the release of GLP-1 is triggered.
GLP-1 has several functions; especially they are able to preserve the health
of beta cells and promote their growth, prevent beta-cell apoptosis, and
enhance insulin release. Because of these effects, patients who have been
insulin-dependent, soon after surgery, became insulin-independent, and
the blood glucose levels were normalized before substantial weight loss.
Appetite Enhancers
Ghrelin
Ghrelin is a peptide hormone that increases appetite and stimulates
feeding, secreted by the A-cells in the gastric mucosa in the fundus of the
stomach and, to a lesser extent, by the duodenum, small intestine, and
pancreas. The levels rise before a meal, which is responsible for craving
for the food intake, and the levels decline following a meal. The action
of ghrelin is opposite of that of leptin; increased levels of leptin induce a
sense of satiation and satiety.
71Fascinating Facts about Phytonutrients in sPices and healthy Food
Ghrelin is a key stimulator of growth-hormone secretion from the
pituitary gland. The levels of growth hormone during adolescence are
very critical for the growth. Excessive stimulation of growth hormone
leads to acromegaly (gigantism), and lack of growth hormone leads to
dwarfism. Therefore, it is essential to get the right amount of growth
hormone at the right time to attain optimum growth. Ghrelin undergoes
acylation by the enzyme ghrelin-O-acetyl transferase (GOAT), which is
necessary for its binding to growth-hormone receptor. Higher quantities
of unacylated form in the circulating blood are increased by diet-induced
obesity. Peripheral administration of ghrelin reduces the hypothalamic
responsiveness of neuropeptide Y (NPY) and agouti-related peptide.
Inhibiting GOAT chronically reduces body weight and food intake and
leads to decreased adiposity and improved glucose tolerance. The receptor
for ghrelin is growth hormone secretagogue receptor (GHSR), which is
a G-protein-coupled receptor expressed in peripheral and central nerve
endings of the vagus nerve, which carries the information from the gut to
hypothalamus.
Once released, it acts on cells in the arcuate nucleus, where several
of the hunger-stimulating and hunger-inhibiting hormone receptors are
expressed. The action of ghrelin can be regulated by leptin and insulin.
Ghrelin also engages the cholinergic-dopaminergic reward pathways,
a response responsible for compulsive eating. It is proposed that
communication between the signal derived from the stomach to the brain
satiation or satiety centers may involve ghrelin in a way that mechanical
signal of distention is not conveyed to the satiation or satiety centers
adequately, leading to overeating. Researchers from University College
London report that individuals who carry the high-risk FTO variant of
ghrelin gene showed high levels of ghrelin even after a meal as compared
to individuals who carry low-risk FTO. Interestingly, the levels of ghrelin
have been found to be low in obesity, suggesting a blunted responsiveness
of this system.
The levels of ghrelin are increased in several conditions that promote
feeding behavior, such as depression, sleep deprivation, and stress,
suggesting an association between ghrelin and obesity. Attempts are
being made to prevent the circulating levels of ghrelin, which include
development of a vaccine.
72 Louis s. Premkumar, PhD
Neuropeptide Y (NPY)
It is a peptide involved in promoting appetite and reducing energy
expenditure by physical activity. It is released from cells located in
the arcuate nucleus of the hypothalamus. NPY increases sympathetic
tone and aggravates peripheral vascular disease. NPY causes the release
of corticotropin-releasing hormone (CRH). Increased activity of
NPY-expressing neurons and agonists of NPY causes increased food
intake; on the other hand NPY receptor antagonists decrease food
intake. There are several factors involved in obesity, such as insulin
resistance, mutation in leptin receptor, and increased blood levels of
glucocorticosteroids (which stimulates gluconeogenesis and increase in
NPY levels). High stress and high-fat and high-sugar diet can stimulate
NPY release. NPY is released along with NE from sympathetic nerve
terminals, when stressed NPY levels can be higher. NPY activates
G-protein-coupled receptors that are common to neuropeptide Y, peptide
YY, and pancreatic polypeptide (see section peptide YY in this chapter).
Agouti-Related Protein
NPY-expressing neurons are also involved in producing another
neuropeptide known as agouti-related peptide (AgRP). AgRP is expressed
by the adrenal gland and hypothalamus, which then increases appetite
and decreases metabolism. Leptin inhibits NPY production. Since the
same neurons also produce AgRP, the levels of which will be decreased
by leptin. On the other hand, the levels of AgRP are increased by the
hormone ghrelin. In transgenic mice, overexpression of AgRP leads
to excessive eating. Polymorphism in this gene has been liked to eating
disorders, such as anorexia nervosa. AgRP mRNA level has been shown to
be down-regulated in anxiety disorders, leading to binge eating.
Opioid Peptides
Opioid receptors, especially μ-opioid receptors (MOR), have been
implicated in mechanisms underlying appetite, feeding, satiation, satiety,
and reward components of food consumption. In animal models, MOR
agonists promote not only the intake of high-caloric food (fat and sugar)
73Fascinating Facts about Phytonutrients in sPices and healthy Food
but also the intake of noncaloric, appetizing food (saccharin and salt). A
reduction in food intake was observed when antagonists of MOR were
administered. This effect has been shown in humans: MOR antagonists
caused significant decrease in food intake that was more pronounced for
food that had an emotional-preference component that can be gleaned
from reduction in subjective pleasantness. Targeting MOR could be a
therapeutic strategy that might depend on the levels of endogenous MOR
agonists, such as enkephalin and endorphin, which determine the basic
opioidergic tone.
Nociceptin/Orphanin FQ and Nocistatin
Nociceptin/orphanin FQ stimulates feeding by inhibiting activation
of neurons containing oxytocin and vasopressin. Nocistatin, which
is derived from the same precursor as nociception/orphanin FQ,
antagonizes the effect directly without affecting the oxytocin—and
vasopressin-containing neurons.
VGF-Derived Prohormone (TLQP-21)
High levels of TLQP-21 seen in arcuate, paraventricular, supraoptic, and
suprachiasmatic nuclei are involved in food intake, satiation, and satiety.
Administration of TLQP-21 acutely caused reduction in food intake
whereas chronic use reduced food intake and body weight. VGF-null
mice are thin, small, hyperactive, and infertile and exhibit enhanced
metabolism. Diurnal variations are also observed in its expression.
Endocannabinoids
Most of the hormones are peptides, but there are lipid-signaling
molecules. They are produced in a stimulus-dependent manner
by phospholipase D from N-acylphosphatidylethanolamines.
Oleoylethanolamide is considered to be a satiation or satiety factor; the
effect is mediated by activation of peroxisome proliferator-activated
receptor-alpha (PPAR-alpha) and also by activation of TRPV1.
Oleoylethanolamide is produced locally in the duodenum and stimulates
74 Louis s. Premkumar, PhD
the vagus nerve terminals innervating the duodenum that expresses
TRPV1. On the other hand, anandamide also can activate TRPV1 and
mediate this response. Anandamide also activates CB1 receptors expressed
in the neurons and modulates food intake and contributes the sense of
satiation and satiety.
The major active ingredient in marijuana, delta-9-
tetrahydrocannabinol (THC), regulates food intake. Experiences after
smoking or consuming marijuana suggest there is a perception of
prolongation of time, yet appetite and food intake are increased. It is
useful to combat anorexia in cancer patients who are on chemotherapy,
further suggesting a role in food appetite and food intake. An endogenous
molecule that acts as an endocannabinoid, anandamide was identified in
1992. The main use of marijuana was recreational, and it was anecdotally
noted that cannabis increased appetite and food intake. However, it
was confirmed by administration of CB1 receptor antagonist that
reduced food intake was induced by intrahypothalamic administration
of endocannabinoid, anandamide. As discussed, several hypothalamic
nuclei control appetite, feeding, satiation, and satiety. Cannabinoid
receptors have been found in several regions of the hypothalamus,
particularly in higher levels of expression in ventromedial hypothalamus.
It has been demonstrated that the endocannabinoid levels were increased
in hypothalamus because of defective leptin signaling. Obese mice or
rats with altered leptin signaling showed higher levels of anandamide in
the hypothalamus but not in other parts of the brain. Treatment with
leptin reduced anandamide levels and 2-arachidonoyl glycerol levels
in hypothalamus. Anandamide levels are also increased by chocolate
consumption; chocolates are rich in N-acylethanolamines, which block
the breakdown of anandamide in the brain and increase its levels.
Serotonin or 5-Hydroxytryptamine (5-HT)
5-HT is present in neurons innervating the gut as well as in the
enteroendocrine cells. Major source of 5-HT in the gut comes from
enterochromaffin (EC) cells. The release of 5-HT occurs as a result of
chemicals (tastants and olfactants) in the gut as well as by mechanical
distention during the transit of the food. There are seven different types
of 5-HT receptors, the activation of which can increase gut motility
and reduce transit times. Activation of 5HT4 receptors expressed in the
75Fascinating Facts about Phytonutrients in sPices and healthy Food
enteric neurons, in turn, activates the cholinergic neurons innervating the
smooth-muscle cells of the gut. Colorectal distension has been shown to
be mediated by 5HT3 receptors expressed in afferent neurons because
5HT3 antagonist can block this effect. 5-HT-receptor antagonists have
been considered for treatment of obesity because they decrease appetite;
this action occurs at the level of hypothalamic structures, such as arcuate,
paraventricular, and ventromedial nuclei. There are several lines of
evidence to support this idea: (1) the major neurotransmitter in the limbic
system is 5HT, and (2) selective serotonin reuptake inhibitors (SSRIs)
used in depression and chronic pain conditions can promote weight gain.
Insulin
Insulin decreases blood sugar levels by increasing peripheral utilization
and decreasing hepatic glucose production. This increases appetite in
order to replenish glucose. GLP-1 and GIP are secreted from intestinal
mucosa and enhance insulin secretion from beta cells. Insulin levels
independent of glucose levels increase hunger and fluid intake. Some
studies have shown that insulin has an appetite-suppressing effect in lean
individuals but not in obese individuals, which may be due to insulin
resistance. Endogenous insulin is more effective in inducing appetite as
compared to exogenous administration, which is likely due to GLP-1 and
GIP release by food intake manifesting their effects.
Appetite Suppressors
Leptin
Leptin is mainly released from white adipose tissues and also, to some
extent, from brown adipose tissues. It is a serendipitous finding in a
company (Jackson Laboratories, Maine, USA) that during breeding, some
mice became morbidly obese, and the mice were found to be overeaters.
Subsequent analysis revealed that the obese mice had a mutation in
the leptin peptide that could not bind to the leptin receptor. Based on
this, mutant mouse lines have been developed that have mutations in
the leptin hormone (ob/ob) or mutation in the leptin receptor (db/db).
These mice are extensively used for diabetes and obesity research. Leptin
76 Louis s. Premkumar, PhD
acts on its receptors in the hypothalamus and controls energy intake and
expenditure; in general, food intake is regulated as needed. The effects
may be mediated by reducing the effects of anandamide, a cannabinoid,
and a TRPV1-receptor stimulant. It also counteracts the action of
another peptide called neuropeptide Y by inhibiting NPY-containing
neurons, which promote food intake. It increases the production of
alpha-MSH by stimulating alpha-MSH—expressing neurons, which
suppress appetite. Reduced leptin levels are associated with increased
appetite and food intake. The effects produced by leptin are considered
to be long-term as compared to short-term effects induced by CCK and
GLP-1. Melatonin increases leptin levels in the presence of insulin, a
signal that might be important to suppress appetite while asleep.
Based on these findings, it is logical that administration of leptin
will cause weight loss. However, bioavailability of leptin is poor in
that following an injection, the required circulating levels could
not be achieved because it is being destroyed, and there is also lack of
compliance for repeated injection as a result of immunological reactions
at the site of injection. Fc-leptin, a more potent and soluble form, has
been proven to be promising. The arcuate nucleus of the hypothalamus,
which expresses high levels of TRPV1 and neuropeptides Y (NPY), may
play an important role.
Leptin receptors are expressed in the hindbrain (nucleus of the
solitary tract), midbrain (ventral tegmental area), and hypothalamus
(lateral hypothalamic areas, arcuate nucleus and ventromedial
hypothalamus, paraventral nucleus of hypothalamus, and medial preoptic
nucleus). Leptin receptors are coupled to a complex second messenger
pathway, eventually leading to regulation of gene expression. Activation
of leptin receptors autophosphorylates Janus kinase-2 (Jak2) bound
to box 1 or 2 motif. The phosphorylated site binds to SH2 domain in
tyrosine phosphatase-2 and activates extracellular signal regulated kinase
(ERK). Phosphorylated tyrosine mediates signal transduction and
activates transcription 3, 5 (STAT 3, 5). STAT3 and STAT5 lead to
increased expression of suppressor of cytokine signaling-3 (SOC3), which
acts as a feedback inhibitor and negatively regulates leptin receptor. The
leptin receptor also activates phosphoinositide 3-kinase (PI3K) by an
unknown pathway. STAT3 alters transcriptional regulation. It appears
in neurons that STAT3 is involved in modulating K+ channels in that
it blocks off K+ channels, depolarizes the neurons, and generates action
potentials, thereby modulating neuronal firing.
77Fascinating Facts about Phytonutrients in sPices and healthy Food
Nesfatin-1
Nesfatin is yet another peptide that is expressed in hypothalamus and
nucleus tractus solitarius. It is involved in suppressing appetite and
producing a sense of satisfaction. There appears to be a relationship
between nesfatin receptors and cannabinoid receptors. The activation
of peroxisome proliferator—activated receptors (PPARs) is involved in
the production of nesfatin-1. Nesfatin-1 is derived from nucleobindin-2
and has a role in inhibiting feeding in paraventricular nucleus of the
hypothalamus. It has been shown that starvation decreases and refeeding
increases nesfatin levels. Nesfatin-1 is expressed along with glucose- and
insulin-responding cells that might be a trigger for nesfatin-1 release.
Alpha-Melanocyte—Stimulating Hormone
As the name suggests, it is involved in melanocyte stimulation, which
is responsible for pigmentation of the skin and hair. It is also known as
melanocortin. Melanocortin activates several types of melanocortin
receptors (MC1, MC3, and MC4). The activation of MC1 receptor
is involved in pigmentation, and the activation of MC3 and MC4
receptors is involved in appetite, metabolic activity, and feeding and
sexual behavior. It is fascinating to learn that specific stimulation of
these receptors can be exploited to produce effects as a sunscreen or to
treat sexual dysfunction. In fact, afamelanotide (Melanotan) is in clinical
trials as an agent to prevent damage caused by exposure to sun, and
bremelanotide, which activates specifically MC3 and MC4 receptors,
for sexual dysfunction. It is suggested that there is a relationship between
skin color and variety of traits, including sexual behavior, based on these
underpinnings.
Melanin-Concentrating Hormone
Another peptide that controls pigmentation, the melanin-concentrating
hormone is a peptide that is synthesized, stored, and released from the
lateral hypothalamus. Its involvement in feeding and sleep cycles is
revealed by animals with deleted melanin-concentrating-hormone gene.
These animals show lower food intake and tend to be lean. Two different
78 Louis s. Premkumar, PhD
receptors have been cloned: MCR1 and MCR2. Drug industries are
targeting these receptors to develop therapies for obesity (Handlon and
Zhou 2006; Luthin 2007). As indicated, antagonists will reduce food
intake, and agonists may be useful in diseases where muscle wasting
occurs, and especially in bone diseases, such as osteoporosis. It has been
implicated to play a role in depression and anxiety disorders as well.
Orexin
Orexin is a neuropeptide or neurotransmitter produced from a small
number of cells in the hypothalamus. It is also called hypocretin. When
injected into the brain, it induces wakefulness and promotes food intake
and energy expenditure. These actions are reminiscent of amphetamine
and its effects. When the gene is deleted in mice, the brown adipose
tissues could not be formed from preadipocytes, resulting in reduced
thermogenesis. As expected, the lack of orexin-induced narcolepsy (a
sleep disorder causing excessive sleep) can lead to obesity. The basic
notion is that the lack of orexin inhibits differentiation of brown adipose
tissues and promotes loss of thermogenesis, and the energy expenditure
is curtailed. Doberman pinschers suffering from narcolepsy have been
attributed to a mutation in orexin receptors. Therefore, if orexin receptors
are blocked, they will promote sleep. The pharmaceutical company
Merck has developed a drug suvorexant that blocks orexin action and
promotes sleep. It is also promising that a blockade of orexin receptors
decreases self-administration of alcohol and nicotine. Orexin system
is a good target for drug development. Agonists can be useful to treat
narcolepsy, and antagonists can be used to treat insomnia. Thermogenesis
and energy expenditure can be regulated by interfering with this system.
It has been proposed that certain autoimmune diseases may selectively
affect hypocretin-producing cells.
Obestatin
Obestatin, another hormone involved in food intake that has been
recently discovered, is related to ghrelin and encoded by the same gene
(breaks into two peptides). Obestatin is a peptide hormone released
from the cells in the stomach wall and small intestine. The presence
79Fascinating Facts about Phytonutrients in sPices and healthy Food
was identified by bioinformatics technology, and it is related to ghrelin.
As discussed earlier, ghrelin increases appetite, food intake, and
growth-hormone release whereas obestatin appears to mediate opposing
functions and is considered to be an anorectic peptide.
Cholecystokinin (CCK)
It is secreted from the cells lining the small intestine, especially the
duodenum, instructing the stomach to slow the digestion if the fat
content is high and functioning as satiation signal. The most potent
stimulus for release of CCK is the presence of fat in the duodenum. Once
released, it stimulates contractions of the gall bladder and common bile
duct, resulting in delivery of bile into the gut.
Administration of CCK reduced food intake in the short term. CCK
cannot cross the blood-brain barrier; therefore, the observed effects are
due to activation of peripheral receptors probably expressed in the vagal
nerve. CCK aids the release of digestive juices from pancreas and also
releases bile from the gall bladder. In the intestine, CCK acts on CCK-A
receptors.
Cholecystokinin acts as a neuromodulator or neurotransmitter in
certain brain regions by acting on CCK-B receptors and may underlie the
action of suppressing appetite. CCK can also induce anxiety states. CCK
is also released from pituitary and adrenal medullary cells.
The main mechanism by which the appetite is suppressed is by
delaying the transit of the gastric content. CCK can activate receptors in
the vagus nerve that express CCK-A, which carries the information to the
nucleus tractus solitarius and then to the higher centers. CCK acts as a
stimulating agent by modulating the hot chili pepper receptor (TRPV1).
Therefore, consumption of chili peppers and the activation of TRPV1
in the gut can have a role in appetite suppression. Oleoylethanolamide
and n-3 fatty acids can activate TRPV1 and may be able to release CCK
in the brain and is thereby involved in appetite suppression. Several
food ingredients are capable of releasing CCK and inducing a higher
sense of satiation and reducing food intake. CCK release is triggered by
fat and protein content. Long-chain fatty acids are more effective than
short-chain fatty acids in releasing CCK.
Human studies have revealed that intravenous administration of
CCK suppressed food intake by around 20%. It appears from these
80 Louis s. Premkumar, PhD
studies that a full stomach is a prerequisite for the appetite-suppressing
effects of CCK. Another interesting effect is associated with reduced
analgesic effect of morphine during its chronic use. CCK at the
brain-stem neurons facilitates transmission through the descending
pain pathway and contributes to chronic morphine-induced tolerance.
CCK antagonists were developed for reducing gastric-acid secretion and
to prevent some types of colon cancers, but these drugs were found to
enhance analgesic effects of morphine and, of course, reduced anxiety
states.
Glucagon-Like Peptide-1 (GLP-1)
GLP-1 is an incretin hormone secreted by the L-cells of the ileum and
colon in response to ingestion of glucose, fat, and other nutrients. The
best characterized effect of GLP-1 is insulin release. As the name suggests,
GLP-1 suppresses glucagon secretion. The insulin release by GLP-1
is glucose dependent. It acts as a braking mechanism at the level of
ileum and delays gastric emptying and induces satiety. GLP-1 release is
dependent on oral glucose or carbohydrate load. Intravenous infusion of
glucose does not increase the levels of GLP-1. These days, a combination
of insulin and GLP-1 is administrated to regulate hyperglycemia
in diabetes. GLP-1 is rapidly inactivated by dipeptidyl peptidase-4
inhibitors of this enzyme and is used as a strategy to treat diabetes.
In human studies, intravenous administration of GLP-1(7-36) reduced
hunger and food intake in nonobese men by 12%. Since the biologically
active form of GLP-1(7-36) is degraded by dipeptidyl peptidase-4 to the
inactive form GLP-1(9-36), continuous intravenous infusion of GLP-1(7-36)
induced a long-term change in appetite suppression and reduced body
weight.
The role of different food ingredients in causing GLP-1 release in
response to food intake has not been fully investigated. In obese patients,
after a radical bariatric surgery called Roux-en-Y gastric bypass, where
the ileum is connected to the stomach, the reversal of type 2 diabetes is
attributed to increased GLP-1 levels. In fact, the effect was so dramatic
those who were insulin-dependent, within two weeks after surgery, before
substantial weight loss, became insulin-independent. The observation
following bariatric surgery suggests that food comes in direct contact with
lower ileal segments, where GLP-1—producing L-enteroendocrine cells
81Fascinating Facts about Phytonutrients in sPices and healthy Food
are expressed. From research laboratories at the Southern Illinois School
of Medicine, it has been shown that spices that activate TRP channels
cause GLP-1 release. This may support the claim that consumption
species can regulate blood sugar levels.
Glucose-Dependent Insulinotropic Polypeptide (GIP)
Gut-derived peptides and the regulation of pancreatic beta-cell health
have become important in recent years. Once such peptide hormone
released from K-enteroendocrine cells (K-cells) of the small-intestine is
GIP, a forty-two-amino-acid polypeptide. It is referred to as an incretin
that improves pancreatic beta-cell health and function and stimulates
adipogenesis in normal humans. An effect related to GIP-mediated
glucagon release has been suggested during fasting and hypoglycemic
conditions. GIP is released into the circulation in response to oral load
of glucose and other nutrients. It is rapidly destroyed by the endoprotease
dipeptidyl peptidase-4 (DPP-4). It has functions other than its action on
the pancreas. GIP brings about its action by activation of a GPRC of the
type B, which increases the levels of cyclic AMP. The downstream effects
include the activation of MAP-kinase-signaling pathways and increased
transcription of antiapoptotic agent Bcl-2 and decreased transcription of
proapoptotic agent BAX, resulting in reduced pancreatic beta-cell death.
Bombesin, or Gastrin-Releasing Peptide (GRP)
Bombesin is a peptide neuromodulator or neurotransmitter appearing
to be involved in appetite and feeding and originally extracted from
toad skin of Bombina bombina. In humans, a similar peptide called
neuromedin B, U, and S is released from the cell lining the gut lumen.
It is also called gastrin-releasing peptide because it releases gastrin from
the G-cells of the stomach. GRP can stimulate secretion of CCK from
the gut and delay gastric emptying by stimulating antrum and pyloric
contractions. It acts in the brain regions along with CCK and curtails
food intake. Neuromedin B is originally purified from pig spinal cord,
and the receptor is linked to G-protein-coupled receptor, Gs, and
modulates its functions by increasing cAMP levels and stimulates
CREB-associated pathways.
82 Louis s. Premkumar, PhD
In humans, food intake was significantly reduced after administration
of GRP. Infusion of GRP in the presence of loxiglumide, a CCK-receptor
blocker, resulted in similar decrease in food intake, suggesting the
effect of GRP is not due to release of CCK. When the food intake was
compared in response to GRP administration with nonobese and obese
subjects, the food intake in obese subjects was not significantly different
as compared to nonobese individuals, suggesting that this system is
blunted in obese individuals.
Somatostatin
Somatostatin, a tetradecapeptide, is released from the D-cells of upper
GI tract. Somatostatin and its receptors are expressed in hypothalamus,
portending its role in the regulation of appetite, food intake, satiation,
and satiety. The role of somatostatin in feeding has not been clearly
delineated. In a human study, administration of somatostatin suppressed
food intake and reduced the sense of hunger. The release of GIP and
GLP-1 was also suppressed by an analogue of somatostatin, octreotide.
The somatostatin level remains elevated after a meal, and the receptor
expression has been shown to be increased after fasting. Five receptors
have been identified, and the activation of somatostatin receptor 2
(SSTR2) stimulates peristalsis and mediates a descending neuronal signal
that relaxes smooth muscles.
In inflammatory bowel disease, the D-cell population is decreased,
leading to reduced release of somatostatin. Somatostatin is a major
inhibitory hormone that can alter the release of other hormones in the
gut, including release of proinflammatory agents. This reduced inhibitory
effect on proinflammatory cytokine release can account for inflammation
associated with several bowel diseases. In inflammatory bowel disease L-,
K- and D-cell populations decrease, impacting the release of vital peptides
from these cells.
Cocaine-and-Amphetamine-Regulated Transcript (CART)
There are endogenous ligands for receptors that have been identified by
using exogenous ligands, such as cocaine, amphetamine, morphine, and
cannabinoids, and one such peptide is CART. CART is able to induce
83Fascinating Facts about Phytonutrients in sPices and healthy Food
behavioral effects similar to those of cocaine and amphetamine, and
it is expressed in reward centers of the brain, such as ventral tegmental
area (VTA) and nucleus accumbens. Since in certain circumstances and
in certain individuals, eating becomes compulsive, therefore, CART
has been implicated to play a significant role in controlling appetite
and feeding. The expression and function of CART are regulated
by peripheral neuronal inputs and by circulating peptide hormones,
such as leptin, cholecystokinin, ghrelin, and neuropeptide Y. CART is
mainly an appetite suppressant, like leptin. Based on these observations,
phenyltropanes and related compounds have been synthesized and
tested to reduce food intake and to combat cocaine and amphetamine
addiction.
Neuromedin U
Neuromedin U is produced in the suprachiasmatic nucleus of the
hypothalamus. Neuromedin U acts on NmUR1 and NmUR2 receptors,
which are G-protein coupled. Administration of NmU appears to cause
allodynia (increased pain sensitivity to innocuous mechanical stimuli)
and hyperalgesia (enhanced pain sensation to noxious stimulus), and
the receptors are expressed in spinal dorsal horn and in sensory neurons.
In the brain, it is expressed in high levels in paraventricular nucleus of
hypothalamus, and one of its effects is to increase plasma levels of
corticosterone by releasing corticotrophin-releasing hormone from
the hypothalamus. The other related peptide is Neuromedin S, and its
distribution is specific to suprachiasmatic nucleus, a site that controls
circadian rhythm. Neuromedin S is found in the brain and is related to
neuromedin U. It has appetite suppressant effects.
Adiponectin
It is a polypeptide synthesized and released from the adipose tissue, and
structurally, it is similar to tumor necrosis factor alpha (TNF-alpha). It
is involved in controlling blood glucose levels and fatty-acid metabolism.
Increased levels of adiponectin have been associated with beneficial
effects of certain metabolic diseases, such as obesity, atherosclerosis,
type 2 diabetes, and nonalcoholic fatty liver disease. Administration of
84 Louis s. Premkumar, PhD
adiponectin and leptin has been shown to reverse insulin resistance. An
herbal supplement containing berberine has been claimed to be effective
in reducing obesity by increasing the circulating levels of adiponectin.
A preparation of raspberry ketones has been marketed as a fat-burning
supplement. It has been claimed that adiponectin levels are increased
following consumption of raspberry ketones.
Amylin
Amylin, or islet amyloid polypeptide, is released from pancreatic beta
cells along with insulin and mediates several physiological processes,
which include gastric-acid and pancreatic-enzyme secretion, glucagon
release, and delaying gastric emptying. Amylin exerts its action by acting
on several brain regions, such as area postrema, nucleus of the solitary
tract (NTS), lateral parabrachial nucleus, and central amygdaloid nucleus.
Selective targeting of regions by ablation has shown to decrease food
intake. Peripheral administration of amylin inhibited neurons activated
in the hypothalamus after fasting. Acute peripheral injection of amylin
reduces food intake and decreases meal size, but administration of amylin
receptor antagonists increases meal size by blocking endogenous release
of amylin. It is considered to not only mediate short-term satiation signal
but also play a role in signaling adipose tissues. Amylin effects may be
related to effects of leptin because leptin-deficient mice (ob/ob) have
attenuated response to the anorexic effects of amylin. This activation
is inhibited by mice lacking amylin. In the hypothalamus, following
leptin administration, phosphorylated signal transducer and activator of
transcription 3 (pSTAT3) is activated.
Based on these effects, a combination therapy has been advocated.
In humans, coadministration of the amylin analogue pramlintide
and leptin analogue metreleptin produced greater loss of body mass
in the combination therapy as compared to individual therapy, and
the combination also caused enhanced lipid metabolism and insulin
sensitivity. In another study, a combination of pramlintide and
sibutramine or phenteramine was found to be more effective than when
treated as individual agents.
85Fascinating Facts about Phytonutrients in sPices and healthy Food
Peptide Tyrosine YY
It is a peptide that belongs to the PP-fold family of receptors, which
include NPY and PP. PP-fold peptides activate Y1-Y6 receptors. These
receptors regulate food intake and body weight and are coupled to
inhibitory Gi-coupled receptors that inhibit adenylate cyclase and
decrease cAMP levels and maintain energy homeostasis by homeostatic
and hedonic circuits.
PYY is secreted from enteroendocrine L-cells in the distal gut. It
was a hormone thought to control the food transit, but recently it has
become apparent that it plays a role in the central control of appetite. The
levels of PYY in the blood increase soon after a meal and settle to a lower
level. Vasoactive intestinal peptide (VIP), CCK, and vagal impulses play
a role in its maintenance levels. It has been shown that consistency and
composition of the nutrient and caloric value play a role in its release.
There are two forms of PYY (PYY1-36 and PYY3-36); the shorter form is
due to its cleavage by membrane dipeptidyl peptidase-4 (DPP-4).
PYY1-36 binds to Y1, Y2, and Y5 receptors, whereas PYY3-36 binds to
the Y2 receptor, which is expressed in the central nervous system. The
receptors are expressed in several parts of the brain, higher levels in the
hypothalamus (supraoptic nucleus) and medial ARC nucleus. PYY can
cross the blood-brain barrier and act on medial ARC, where orexigenic
NPY/AgRP neurons are expressed. Alpha-MSH levels are modulated
by NPY. PYY inhibits ARC NPY neurons and secondarily disinhibits
anorectic POMC neurons. PYY can also activate vagal nerve terminals,
sending signal to the brain stem and regulating neuronal activity of
ARC neurons. PYY also increases energy expenditure, postprandial
thermogenesis, and resting metabolic state.
PYY3-36 levels are high in anorexia nervosa and low in obesity. In
obesity, high levels lead to impaired satiation and increase food intake.
In humans, peripheral administration of PYY3-36 reduces food intake
and increases neuronal activity in brain regions known to be involved in
appetite. The main issue is, PYY3-36 has a short half-life. Clinical trials of
nasal spray of PYY3-36, a combination of PYY3-36 and PP (obinepitide) and
PYY3-36 and GLP-1, have shown to significantly reduce food intake.
86 Louis s. Premkumar, PhD
Enterostatin
It is a pentapeptide that, when administered peripherally or centrally,
reduces food intake, particularly fat intake. It is released from the
gastric mucosa and mucosal epithelia from the small intestine of the
gastrointestinal tract by pancreatic colipase, a coenzyme required for an
enzyme activity of pancreatic lipase. When peripherally administered, it
activates the vagal afferents, and the information is sent to hypothalamic
centers. Certain strains of rats with low levels of enterostatin tend to be
obese and have a tendency to consume more fat-containing meals. Obese
individuals exhibit low levels of colipase activity. Insulin secretion is
also reduced by enterostatin. A role of CCK has been suggested because
enterostatin had no significant effect in CCK knockout animals.
Resistin
Resistin was discovered as a peptide hormone released from the
adipocytes in 2001 by researchers from University of Pennsylvania. It was
so named because it was found to be released from the adipose tissues and
caused insulin resistance when injected. Excessive adipose tissue around
the waist is known to cause insulin resistance. Now it is becoming clear
that larger adipose tissue mass is associated with development of insulin
resistance. Insulin resistance is the first step of developing hyperglycemia,
which means insulin is not utilized well to transport glucose from the
blood into tissues. Therefore, blood glucose levels increase in the blood.
The insulin levels tend to be higher because of hyperglycemia; the
pancreatic beta cells are forced to produce more insulin. This excessive
stress on the beta cells makes them become hypertrophic and eventually
leads to beta-cell death. At this stage hyperglycemia is associated with
reduced insulin levels, which is insulin-dependent type 2 diabetes
mellitus. Levels of resistin have been shown to correlate with increased
levels of an array of proinflammatory agents.
Calcitonin Gene-Related Peptide (CGRP) family
The peptides grouped under this family are calcitonin, alpha-CGRP,
beta-CGRP, adrenomedullin, intermedin, and amylin. They act on
87Fascinating Facts about Phytonutrients in sPices and healthy Food
calcitonin receptors and calcitonin-receptor-like receptors (CRLR).
Adrenomedullin and amylin interact differently with CRLR and the
receptor-activity-modifying proteins (RAMPs). Adrenomedullin forms
a subfamily of AM1-5. CGRP is released from terminals of peripheral
nerves.
CGRP and adrenomedullin are considered to be central anorectic
agents, the receptors for which are expressed in the hypothalamus.
Adrenomedullin shares sequence homology with CGRP and competes
with its binding. Administration of adrenomedullin centrally decreases
food intake. The effect is mediated by adrenomedullin binding to its
own receptor as well as binding to the CGRP receptor because in the
presence of CGRP receptor antagonist, the food intake decreased only
by 50%. CGRP is a potent vasodilator regulating the microvascular
circulation.
Intermedin is another member of this family, abundantly expressed
in the hypothalamus, pituitary, stomach, and kidney. Intermedin is also
found in the circulating blood, suggesting that it can act at the site of
release as well as systemically. Similar to what was observed with CGRP
and AM, IMD can also regulate food and water intake.
Oxyntomodulin (OXM)
Oxyntomodulin is a product of proglucagon gene released in response
to food intake from L-enteroendocrine cells of the jejunum along
with GLP-1 and PYY. It is a thirty-seven-amino-acid peptide and
has glucagon-like activity. It decreases food intake by delaying gastric
emptying and increasing energy expenditure, lowers incretin (GIP,
GLP-1) activity, and inhibits gastric-acid secretion. The anorexic activity
can be blocked by GLP-1 receptor antagonists, and this action is not
seen in GLP-1-receptor knockout mice, suggesting that the actions are
mediated by GLP-1 receptor. Although the potency is low, the anorexic
effect is comparable. Oxyntomodulin also acts on its own receptor
because the cardiovascular effects of oxyntomodulin are intact in GLP-1
receptor knockout mice.
88 Louis s. Premkumar, PhD
Glucagon
Glucagon is released in response to reduced blood glucose levels from
the alpha cells of the pancreas, which are located at the circumference of
the islets. It is released during stress and enhances energy expenditure.
Administration of glucagon decreases the food intake and delays gastric
emptying by stimulation of the vagus nerve but causes hyperglycemia.
Administration of both glucagon and GLP-1 showed greater effect in
diet-induced obesity.
Pancreatic Polypeptide (PP)
Pancreatic polypeptide belongs to the family of peptides that includes
peptide YY (PYY) and neuropeptide Y (NPY). In comparison to NPY,
which is orexigenic (enhances food intake), PYY and PP are anorexigenic
peptides that are released from PP-cells of pancreatic islets and from
L-cells within intestinal mucosa of the ileum and large intestine,
respectively. PYY and PP are released during the postprandial period and,
when administered, significantly reduce food intake, and this effect is
blunted in people who are obese. It is believed that the information is
carried via the vagus nerve. The cell bodies of the vagus nerve located in
nodose ganglion express receptors for PP and PYY and induce a calcium
response in neurons when applied.
Thyrotropin-Releasing Hormone (TRH)
The paraventricular nucleus of the hypothalamus plays a significant
role in energy balance. The thyrotropin-releasing hormone (TRH) and
corticotrophin-releasing hormone (CRH) play a critical role in food
intake and expenditure. Some of the anti-inflammatory agents have been
shown to induce anorexia as a result of suppressing TRH. From several
studies it is clear that TRH may play a role in appetite, food intake,
thermogenesis, and satiety.
89Fascinating Facts about Phytonutrients in sPices and healthy Food
Vasoactive Intestinal Peptide (VIP)
Vasoactive intestinal peptide (VIP) belongs to the glucagon family of poly
peptides. VIP is distributed in the peripheral tissue and regulates vascular
tone. In hypothalamus VIP is co-localized with corticotropin-releasing
hormone (CRH), which can cause the release of adrenocorticotropic
hormone (ACTH). ACTH causes the release of glucocorticoid (cortisol)
and mineralocorticoid (adlosterone) steroid hormones from adrenal
cortex. VIP activates G-protein—coupled receptors (VPAC1 and VPAC2)
and increases the cAMP levels to mediate cellular functions. These
receptors also bind pituitary adenylate cyclase-activating polypeptide
(PACAP). In the blood vessels, increase in cAMP levels causes
vasodilation similar to activation of beta 2 adrenergic receptors. VIP plays
a role in food intake, administration of VIP in the hypothalamic region,
and significantly reduced food intake. VIP administation is accompanied
by an increase in plasma corticosterone levels, suggesting that CRH
function is closely associated with the VIP-induced anorexigenic effect.
B-Type Natriuretic Peptide
Atrial natriuretic peptide released from distended atrium portends
the diagnosis of heart failure. B-type natriuretic peptide (BNP) is
released from cardiac myocytes during heart failure. The decreased
appetite in heart failure may be due to a variety of reasons including
the medication the patients are on. However, in a group of healthy
volunteers, administration of BNP caused a sense of satiation and satiety
as compared to control subjects. In consensus with reduced appetite, the
fasting-induced increase of ghrelin levels was inhibited. There was no
change in other peptide hormone levels involved in satiation and satiety,
such as peptide YY, GLP-1, leptin, adiponectin, etc.
Glucose
It has been postulated that there are glucose receptors in the brain that
can detect changes in glucose utilization. As we discussed earlier, excessive
reduction in glucose levels (<40 mM) results in unconsciousness;
however, there are warning signs—perspiration and palpitation—that
90 Louis s. Premkumar, PhD
tell one to consume food before that stage. Administration of
2-deoxy-D-glucose, which competitively inhibits glucose utilization
increases hunger and thirst in humans. Direct administration of glucose
into the duodenum decreased hunger than intravenous administration,
suggesting that glucoreceptors in the gut are responsible for the signal
transmission to the satiation or satiety centers of the brain. It is suggested
that GLP-1 released from the gut can activate the vagal nerve to transmit
information.
Miscellaneous
Secretin
This hormone is secreted in response to acid in the duodenum by the
S-cells and released into the lumen or into blood. It regulates pH within
the duodenum and inhibits gastric-acid secretion. Its effect on the biliary
system is very similar to what was seen in the pancreas—it stimulates
biliary duct cells to secrete bicarbonate and water, which expands the
volume of the bile and increases its flow out into the intestine. It plays a
role in osmoregulation at the hypothalamus, pituitary gland, and kidneys.
By its peripheral and central actions, it reduces food intake.
Gastrin
Hormone gastrin is released from the G-cells of the antrum of the
stomach and duodenum in response to distention of the stomach,
vagal-nerve stimulation, food content, etc., and stimulates the secretion
of acid in the stomach. Gastrin also stimulates the growth and maturation
of the parietal cells and controls the valves and the secretion of other
gastrointestinal enzymes. Increased expression of gastrin can influence
stomach carcinogenesis. It has been recently reported by a researcher from
Columbia University that gastrin, stimulating the secretion of gastric
acid, plays an important role in Helicobacter pylori—induced stomach
cancer. Helicobacter infection can enhance expression of gastrin.
91Fascinating Facts about Phytonutrients in sPices and healthy Food
Concluding Remarks
Given the number of signaling peptides involved in appetite, hunger,
satiation, and satiety, it is suggested that there is a perfect harmony
between “do” and “do not do” systems. The main goal of healthy living
is not to interfere or tamper with the balance. A similar balance exists
within the excitatory and inhibitory control of the brain. The brain has
to be ingrained with the idea to develop aversion to consume unhealthy
food. There is no magic way to lose weight; it takes as long to lose as to
gain weight. Healthy eating will restrict the calorie input, and garnishing
with spices ingredient stimulates the nerve endings and enteroendocrine
cells in the gut to release peptide hormones. Neuronal activity and the
peptide hormone levels send the signals of satiation or satiety to the
brain. Of course, subduing the microbiota can prevent recirculation
of cholesterol and other substances by preventing their metabolism.
Microbiota-synthesized metabolites can stimulate vagal nerve activity
and alter CNS functions. Further, it is not easy to interfere with multiple
systems, because these peptides not only control appetite, satiation, and
satiety but are also involved in other functions. For example, GLP-1
causes insulin release and improves the health of pancreatic beta cells.
However, it plays a role in suppressing appetite. Similarly, morphine
agonists are not only analgesics but also promote or suppress food intake.
There are genetic predispositions for overeating and obesity. As discussed,
a mutation in leptin or its receptor leads to overweight in animals just by
overeating since the signals that are generated to stop eating as a result
of satiation are no longer functioning. Recently, a mutation has been
linked to higher levels of ghrelin even after a meal, which portends the
genetic disposition to gain weight. As human beings, we should be able to
distinguish between good and bad, which applies to every aspect of life.
Choosing good and healthy food will promote good health and result in a
long and productive life.
92 Louis s. Premkumar, PhD
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95
CHAPTER 4
Spices That Appeal to Nostrils (Olfaction)
and Palate (Gustation)
Sense of Smell (Olfaction)
Olfaction, the sense of smell, is well developed in mammals. Animals
are able to smell pheromones, which are essential for courtship, mating,
and procreation. Olfaction is the strongest at the time of ovulation; even
in humans, a heighted sense of smell is perceived. During pregnancy,
the olfactory and gustatory receptors are sensitized or modified, and the
craving for certain food and tastes is enhanced. The power of olfaction
is multifaceted; sometimes unexpected substances induce powerful
emotions. In animals, tears act as a source of pheromones chemosignal.
But in humans tearing is associated with the sense of sadness and
melancholy. In a study, tears were collected from female volunteers
watching a sad movie in isolation. Then the male volunteers were not
exposed to events other than sniffing the tear. After sniffing the tear,
there was an increase in the galvanic skin response, reduction in salivary
testosterone levels, and reduction in arousal. These findings were further
confirmed by neuronal activity using magnetic resonance imaging
of the areas of the brain that are normally associated with sad feelings,
suggesting that the sense of smell can trigger powerful emotions.
Dogs, such as scent hounds and bloodhounds, are very sensitive
to smell (hundred thousand to a million times more sensitive than
humans). 4% of the brain is dedicated to olfaction in dogs as compared
to 0.1% in humans, given the size difference in the brain volume (1⁄5).
96 Louis s. Premkumar, PhD
The areas of the olfactory epithelium are larger in dogs (170 sq cm)
than in humans (10 sq cm). The interesting aspect is our ability to smell
thousands of odorants with specificity. It is proposed that the odorant
molecules bind to specific receptors at the terminals nerves innervating
the nasal cavity, thereby generating an action potential that carries the
information to the brain in order to perceive the smell. It is not fully
understood, given the number of neurons and how the vast array of
chemical molecules is perceived. It is also possible that the final coding
process may include spatial and temporal coding attributes. Further, a
fascinating phenomenon is the ability of these receptors to desensitize,
which is a concentration and time-dependent phenomenon. It is clearly
demonstrated that after entering a foul-smelling area, within seconds
one realizes that the foul smell is not as bad as it used to be. This is a
protective mechanism to prevent overactivation of the receptors that
may lead to nausea and vomiting. Longer duration of action may be a
result of optimal concentration of the odorant that delays desensitization
since the process is concentration dependent. If the chemical is able to
modify the receptor covalently, the duration of action will be longer.
It is also possible that continued activation of the receptor induces
persistent depolarization, which leads to a loss of the ability for the
neuron to generate action potentials (i.e., Na+ channels are activated and
subsequently inactivated in a voltage- and time-dependent manner).
Persistent depolarization does not allow the Na+ channels to enter the
closed state so that they can be reactivated to generate an action potential
at the nerve terminal.
Compared to taste, there are numerous odorants, and the ability to
discriminate among them makes the system more complex. The encoding
of odor may be related to the distribution of the receptors in the epithelia
mosaic and their ability to generate action potentials. The spatial and
temporal processing of impulses may underlie this complex coding. The
inability to smell is called anosmia; it can be complete or partial. Partial
anosmia is called hyposmia. The senses of smell and taste culminate in
detecting flavor; therefore, it is possible that people with anosmia tend to
lose the sense of taste. Appreciation of flavor depends on whether the loss
of olfaction is from birth or developed after having the sensation. This
is similar to blindness; those who have been blind from birth may not
appreciate the magical nature of vision. The reason for anosmia is either
the peripheral sensing apparatus is faulty, or there is a permanent wiring
defect in the brain.
97Fascinating Facts about Phytonutrients in sPices and healthy Food
All of us have experienced the loss of flavor during sinus infections;
the nerve endings that are responsible for carrying the sensation of
smell are either covered by phlegm or partially desensitized or damaged
during the inflammatory process. The food tastes bland since one can
compare to a prior experience. It is possible that the lack of sensory input
may affect the wiring at the level of the somatosensory cortex, leading
to a lessened sense of smell, thereby having the lessened sense of flavor.
It is possible that there is a spectrum from hyperosmia to hyposmia to
anosmia. Depending on where one is in the spectrum, their ability to
appreciate the flavor may vary. Further, desensitization may play a role.
If one is constantly exposed to a certain odorant, the sense for that
particular odorant may become defective in the long run. In fact, when
there is a lack of peripheral input, the part of the brain responsible for
the function is atrophied or taken over by other sensations. This can be
observed in people who lack certain sensations but are extraordinarily
gifted or exhibit amplification of other senses. In fact, defect in the
appreciation of flavor can be equated to defects in the vision. Mostly,
a defect in vision appears to be peripheral, which can be corrected by
different powered glasses. Vision is a constant experience that is used
every day; therefore, alterations in brain circuitry may not be generally
altered. Fascinating experiments have been done in animals, showing that
deprivation of light can alter brain circuitry, leading to defective vision.
Similarly, in young frogs, the implantation of an extra eye in between the
two eyes can make functional connections under appropriate conditions.
All these changes in brain circuits can be grouped under a phenomenon
called activity-dependent plasticity. When the brain receives constant
inputs, the neurons make appropriate connections between them. After
all, the brain has one hundred billion neurons, and each of them makes
fifty thousand to one hundred thousand connections between each
other. Activity-dependent changes can be appreciated due to the fact
that when muscle cells are put under constant activity, the muscle cells
grow. Similarly, when heart cells are strained by constant, uncorrected
hypertension, the heart muscle cells grow, leading to a condition called
cardiac hypertrophy. This can lead to ischemic heart disease and finally to
heart failure. The importance of activity-dependent brain function can be
appreciated from the suggestion that if brain cells are constantly used, one
can prevent the premature death of brain cells and prevent developing
Alzheimer’s disease.
98 Louis s. Premkumar, PhD
Most spices we consume come from plant products except for a
few pure chemicals that could have been plant products originally.
Most spices do not have a pleasant taste but have a pleasant aroma.
Therefore, in small quantities, they are sweet-smelling, and one has to get
acclimatized to the smell. Most often the spices are used in combination.
When combined, they activate several olfactory receptors as well as taste
receptors. As far as the scientific discovery goes, we have more receptors
that sense odor than the receptors that sense taste. The number of
odorants the nose can sense is in the hundreds and thousands whereas
there are only five receptors that are associated with the sense of taste.
They are sweet, bitter, salty, sour, and umami. In fact, it is perceived that
humans have the ability to taste a large number of tastants. The large
number of taste sensations probably comes from the combination of
smell and taste, which results in the sensation of flavor.
These senses are carried by nerve endings that have specific types
of receptors, and when the receptors are activated, the nerve terminals
depolarize, resulting in the generation of an action potential that
propagates to an appropriate area of the brain, imparting a particular
sensation. It is not fully understood how the brain is able to interpret
these different sensations simply by virtue of an action potential
arriving at a particular area of the brain. For example, when we
touch a hot surface, a set of neurons are activated because they have
heat-sensing receptors, and when one touches a cold surface, another
set of cold-sensing receptors are activated, resulting in the generation
of action potentials in two different neuronal populations. Action
potentials are propagated through second-, third-, and fourth-order
neurons before reaching a particular area of the brain (the somatosensory
cortex). Action potentials are propagated between neurons by a complex
mechanism called synaptic transmission. Neurons do not make direct
contact between each other; there is a gap between them called a synapse.
When the action potential arrives at the terminal, voltage-gated calcium
channels are opened, allowing calcium to enter the terminal. Calcium
is one of the necessary ions to cause fusion of the neurotransmitter-
containing vesicle to the surface of the membrane; during the process,
glutamate (a major excitatory neurotransmitter) or GABA (an inhibitory
neurotransmitter) is released. Glutamate activates two types of
receptors on the terminals of the other neurons (postsynaptic), thereby
causing depolarization. One type is called the AMPA receptor, which
is responsible for fast synaptic transmission, whereas the other type is
99Fascinating Facts about Phytonutrients in sPices and healthy Food
called the NMDA receptor, which activates slowly and decays slowly,
allowing calcium entry, and sets up long-lasting changes in the brain.
These changes include synaptogenesis and memory formation. On the
other hand, when GABA binds to its receptor, it activates a chloride
(Cl-) current. Since a chloride ion is negatively charged, instead of
depolarization, hyperpolarization occurs, and the membrane potential
becomes more negative, and it becomes harder to generate an action
potential. Hence, GABA is called as an inhibitory neurotransmitter. It is a
braking system to prevent overactivation.
Generally, it is considered that smell and taste converge to contribute
to flavor to appreciate the full extent of culinary experience. A complexity
that has been recently added to the mix is the convergence of smell and
sound called smound. The olfactory sensation is received by the auditory
neurons. This can account for a condition called synesthesia, in which
people sense sight and sound, touch and taste, smell and sound at the
same time.
Sense of Taste (Gustation)
In contrast to olfaction, there are only five different taste sensations.
Taste and smell sensations are transduced by the glossopharyngeal and
trigeminal nerves and provide the sense of flavor. It is during exhalation
that olfaction contributes to flavor whereas during inhalation the sense of
smell is felt. The five different taste sensations are sweet, salty, bitter, sour,
and umami. The combined activation of these receptors is able to carry
nerve impulses simultaneously, with varying intensity, and culminate into
a myriad of subtleties of taste sensation. This aspect has been exploited by
the food industries by adding the right amounts of tastants, including a
bitter tastant to impart an aftertaste. When a mouthful is swallowed, the
residual lingering taste develops a craving for the next mouthful until the
whole available food is consumed. This can be experienced by a freshly
opened packet of potato chips, especially those with flavors of extra
condiments, such as sour cream and high salt. The crispiness of the chip
that imparts a crunchy sensation transduces the mechanical sensitivity
along with all the five tastes to enhance the experience.
Several structurally diverse molecules have been shown to activate the
sweet-taste receptors. But the degree of sweetness is what differs; glucose
is less sweet in comparison to sucrose, which is a disaccharide formed by
100 Louis s. Premkumar, PhD
the combination of fructose and glucose. Fructose is the sweetest (73%
sweeter than glucose). Some alcohols are very sweet. Saccharin, which has
both sweet and bitter tastes, has no structural similarity to other sweet
tastants. Similarly, the bitter taste has degrees of variation as indicated by
saccharin, which can probably activate both sweet and bitter receptors.
Several plant products taste bitter; it has been observed that gorillas are
attracted toward bitter-tasting food. It is not clear whether they enjoy
the bitter taste or if they do not have the ability to sense bitter tastants.
Given the complex development of the olfactory function in dogs, it
is not clear whether the gustatory system has developed as well. Even
in humans, the ability to taste different tastants varies widely, hence
the reference to people who enjoy sweet-tasting products as having a
sweet tooth. The sensitivity of these receptors may be also enhanced
during hypoglycemia and diminished during hyperglycemia. The plant
product stevioside, obtained from Stevia rebaudiana, activates the sweet
receptors and provides one with the sense of sweet taste without the
consumption of pure sugar. Interestingly, the whole plant extract still
provides the sweet taste but has been shown to cause infertility and is
used in certain parts of South America as an abortifacient. However, the
pure ingredient from this plant, rebaudioside A, is devoid of this action.
This is a warning issued by the Food and Drug Administration of United
States; the whole plant extracts are not always safe as most natural health
supplements claim.
In diseases such as diabetic peripheral neuropathy, the nerve integrity
is compromised. There is a stage of hypersensitivity in the early stages
and a phase of hyposensitivity in the later stages. Therefore, people with
diabetes may have heightened or lessened sensitive sweet receptors. At
later stages, since the sensitivity is reduced, as a consequence, instead
of reducing sugar intake, a higher amount of sugar is consumed to
experience the same sweet taste, worsening hyperglycemia.
Generally, bitter-tasting foods are aversive in order to avoid their
ingestion. However, several plant alkaloids taste bitter, including most
of the spices human beings crave. However, most of the spices have a
pleasant odor. Therefore, the question is whether the craving is due to
their taste or smell or if this is an all-encompassing sensation. Therefore,
in order to experience a perfect sense of exquisite taste, sensory modalities
such as smell and taste have to be integrated. Further, instead of one
tastant or one odorant, an array of chemicals activating at the right
intensity provides the perfect flavor for the food. Professional tea tasters
101Fascinating Facts about Phytonutrients in sPices and healthy Food
are hired to blend teas that taste good with teas that smell good to
provide the perfect flavor. There can be as many as forty varieties of tea
with differing qualities in taste and smell. Ironically, neither the taste nor
the odor is eventually considered to be the hallmark of a good tea but its
ability to activate the central nervous system by its caffeine content.
Sensitization and desensitization are major components of any
biological system. This is indicated by the fact that in hypoglycemic
conditions the taste receptors have to be sensitized so that intensely
sweet-tasting products can be consumed to increase the blood glucose
levels rapidly. At the same time, during hyperglycemic conditions, the
sweet receptor has to be less sensitized so that less-sugary substances can
be consumed.
Furthermore, physical and chemical senses are important. For
example, a Coke at room temperature or at higher temperatures tastes
sugary and not very enjoyable or palatable. However, a perfectly chilled
Coke is the most delicious beverage. These beverages are not popular
in developing countries because of lack of refrigeration facilities; the
perfectly chilled Coke is not available. Of course, the enhanced amount
of caffeine and sugar poses a health risk when too much of these
beverages are consumed. When the temperature is cold, the sweet taste is
exaggerated and the bitter taste is dulled. Similarly, drinking a cold beer
gives immense pleasure rather than a beer stored at room temperature
because the bitter taste of the hops is dulled by the cold temperature.
The salty, sweet, bitter, umami, and sour tastes are perceived by the
tongue by activating specific receptors. Type 1 cells sense salty; type 2
cells sense sweet, bitter, and umami; and type 3 cells sense sour. All these
receptors are G-protein coupled (GPCRs). The type 1 receptor is not well
characterized as a salt-sensing receptor, because the amiloride-insensitive
sodium taste receptors are not expressed in these cells, but these cells
are known to be expressed with triphosphate diphosphohydrolase-2
(NTPDase-2) and oxytocin. The type 2 receptor is the alpha-gustducin,
which is a sweet—and bitter-tasting receptor. A knockout of
alpha-gustducin gene causes animals to lose both sweet and bitter
sensations. T2Rs sense bitter taste. For umami and sweet perception, taste
receptor type 1 (T1R1) and T1R2 and T1R3 form heterodimers. T1R1a
and T1R3 form a complex to sense the umami taste. T1R2 and T1R3
form a complex to taste sweetness. The signal transduction involves the
activation of the G-protein-coupled receptor alpha-gustducin, which is
coupled to phospholipase C beta 2 (PLC beta 2). PIP2 is hydrolyzed to
102 Louis s. Premkumar, PhD
IP3 and DAG. IP3 releases calcium from intracellular stores and activates
a TRP channel, TRPMelastatin 5 (TRPM5), which depolarizes the cell,
causing ATP release. ATP acts as a neurotransmitter and mediates signal
transduction.
The G-protein-coupled receptor GPR93 can sense proteins and is
involved in proteolytic and fatty-acid degradation processes. Short-chain
fatty acids activate GPR43 (FFA2) and GPR41 (FFA3), long-chain
fatty acids activate GPR40 (FFA3), and medium—and long-chain
fatty acids activate GPR120. GPR119 is activated by ethanolamide
and oleoylethanolamide (OEA), and GPR131 is activated by bile acid.
L-amino acids are sensed by metabotropic glutamate receptors (mGluR),
Ca2+-sensing receptors (CaR), and GPCR family C, group 6, subtype
A (GPCRC6A). Sodium glucose cotransporter-1 (SGLT-1) expressed
in L-enteroendocrine cells is also important in sensing certain food
ingredients.
It is becoming evident that the receptors that sense taste on our
tongues are expressed throughout the gastrointestinal tract and act as
chemosensors. Taste receptors are also present in the cells lining the
stomach, pancreas, and enteroendocrine cells of the GI tract. All these
receptors are G-protein-coupled receptors, and when the food ingredients
bind to the receptor, activation triggers the second messenger cascades,
and the second messengers trigger various intracellular processes
including the activation of ion channels on the cell membrane. A good
example is signal transduction that involves sweet taste. Sweet-receptor
activation increases intracellular Ca2+ levels, which, in turn, activates the
receptor TRPM5. Activation of TRPM5 depolarizes the nerve terminal,
and an action potential develops, and the information is sent to the brain,
where it is interpreted as sweet taste.
The other type of cell in the GI tract is the brush border cells, which
express taste receptors, and they are less well characterized. These cells
also express alpha-gustducin. The main role of enteroendocrine cells
is to sense sugars and maintain the blood glucose levels by secreting a
peptide called glucagon-like peptide-1 (GLP-1), which is an incretin. It
appears that these cells in the GI tract utilize the same second messenger
system as in the tongue, and it is documented that the vagus nerve
carries the information from the GI tract to the central nervous system.
Stimulation of brush border cells with tastants also releases GLP-1 and
peptide YY (PYY). Both alpha-gustducin and TRPM5 receptors are
predominately expressed in these cells but are not involved in the release
103Fascinating Facts about Phytonutrients in sPices and healthy Food
of other neuropeptides or neurochemicals, such as ghrelin, gastrin,
histamine, and 5-HT. Recent studies suggest that these cells may contain
endogenous opioids that are secreted into the lumen in response to food
ingredients. Constipation induced by certain food ingredients could be
due to the release of endogenous opioids, as opioids are known to slow
gastric motility. It has been reported that the brush border cells express
T1R3 receptors and ghrelin; secretion of ghrelin may be related to
food ingredients that activate T1R3 receptors, which detect sugar and
aminoacids in the gustatory system. It is possible that the types of food
that contain certain ingredients are able to activate these receptors, and
the release of hormones eventually can control appetite, food intake, and
transit time.
Animal studies have been performed to study the effects of bitter
tastants. In order to demonstrate the role of bitter tastants activating the
receptors in the GI tract, the bitter tastants were directly delivered to the
stomach via a tube. The activation of receptors by bitter tastants has been
shown to transmit information via the vagus nerve and these animals
developed flavor aversion and delayed gastric emptying.
It can be demonstrated that after excessive consumption of
bitter-tasting substances in large quantities, nausea and vomiting is
induced, most likely due to the activation of these receptors. Since the
information is not conveyed to the taste centers, it does not mean that
these drugs do not have an effect. Input from the viscera carried by vagal
nerves that control several involuntary functions, including respiratory
and cardiovascular functions, can be modulated by vagal nerve activation
and include information sent to the satiety centers of the brain. It has
been shown that consumption of probiotics can alter CNS functions by
sending information via the vagus nerve. The active ingredient in hot
chili peppers, capsaicin, activates the ion channel TRPV1, and a pungent
sensation is felt in the mouth. Once swallowed, it might still activate the
receptors that send information via the vagus to control other functions
although the burning sensation is not felt. The local concentrations
of these compounds are so high that they can induce local effects on
the cells that express these receptors. Since these channels are highly
calcium permeable, excess Ca2+ induces cell death—a strong possibility
to eliminate mutated cells that might develop into polyps or cancer.
Further, to eliminate the bitter or harmful substances after ingestion,
there has to be a mechanism to eliminate the toxic substances to preserve
the species.
104 Louis s. Premkumar, PhD
Concluding Remarks
The wholesome enjoyment of food consumption involves the
participation of several senses, and the olfactory and gustatory systems are
particularly relevant—and the combination culminates in flavor, which
is an exquisite sensation. As mentioned earlier, several spices do not
have a pleasant taste but possess exotic aroma. Similarly, several healthy
nutrients do not have aroma or taste, but have vivid colors. Therefore,
these properties make the food appetizing and palatable and entice the
consumption to nourish the body, but at the same time allowing one to
indulge in over-eating. Furthermore, sensitization and desensitization of
the sensory system play a role in determining the amount of consumption
of salt, sugar, and fat. The amount of salt, sugar, and fat to be
incorporated is empirically decided by food manufacturers. The amounts
added are always on the higher end, because the receptors are rendered
in their desensitized state, urging the consumption of higher quantities,
which is detrimental to health. Finally, the taste receptors expressed in
the tongue are also found throughout the gastrointestinal tract, and the
activation of which can release peptide hormones and mediate diverse
physiological functions.
105Fascinating Facts about Phytonutrients in sPices and healthy Food
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Bellisle F, Drewnowski A, Anderson GH, Westerterp-Plantenga
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106
CHAPTER 5
Ingredients in Spices
That Produce Health Benefits
In this book, a spice is defined as a garnishing agent of food, which,
when consumed in small quantities, has health benefits; it has no taste or
caloric value (but may contain mineral and vitamins) but has a pleasant
smell or a zesty sensation that adds flavor to the food and sometimes
compels its consumption. Active ingredients in spices are capable of
activating specific receptors at the nerve endings in the tongue and
nose to initiate a specific sensory input as well as release hormones from
nerve terminals and form enteroendocrine cells locally throughout the
gastrointestinal tract.
Although for centuries spices have been popular, traded, used for
enhancing flavor, and claimed to produce health benefits, the active
ingredients and the mechanism/s by which health benefits is/are induced
is/are largely elusive. Investigations have been undertaken using water
or organic solvents of plant products, but the active ingredient is not
known, especially given the large number of chemicals present in these
extracts. It was thought that pungent substances present in hot chili
peppers caused irritation to the affected area, and the redness associated
was due to tissue damage. Now, we know that pungency is due to the
activation of specific receptors at the nerve terminal that generates a
receptor potential; when the membrane potential reaches the threshold,
an action potential is generated, and the information is transduced to the
brain, imparting the warm and burning sensation. These receptors are ion
channels and are highly calcium permeable. Calcium is an important ion
107Fascinating Facts about Phytonutrients in sPices and healthy Food
required for neurotransmitter and hormone release. When these receptors
are activated, calcium influx causes the neuro-/vasoactive substances
to be released, causing vasodilation and extravasation, and results in
redness and swelling. The substances that are released include histamine,
bradykinin, calcitonin gene-related peptide (CGRP), and substance P
(SP). Some of the spider toxins and snake and bee venoms also activate
this specific receptor.
In 1997, researchers from University of California, San Francisco,
cloned the receptor for the active ingredient in hot chili pepper,
capsaicin, and named it a vanilloid receptor because capsaicin has a
vanilloid moiety in its structure. The vanilloid receptor has a sequence
homology to a receptor cloned from a mutant fruit fly (Drosophila
melanogaster), which produced a transient response to continuous
light; therefore, it was renamed as transient receptor potential vanilloid
1 (TRPV1). Subsequently, several TRP channels have been cloned
and are considered to be targets for active ingredients in spices. The
transient receptor potential ankyrin 1 (TRPA1) is a receptor that carries
sensory information from the periphery, which is activated by active
ingredients in garlic (allicin), cinnamon (cinnamaldehyde), wasabi (allyl
isothiocyanate), and mustard (allyl isothiocyanate), and the transient
receptor potential melastatin 8 (TRPM8) is activated by menthol from
mint leaves. For some of the spices, the detailed information, including
the mechanism of action, is provided whereas for others, the information
is lacking, and the purported effects described are merely anecdotal.
But intense research is ongoing to identify the active ingredients in
spices and their targets, acting on which the physiological responses are
brought about.
Garlic has always been suggested to be good for health. This concept
always raised a concern whether it is a myth. New research shows that
substances in garlic, such as allicin, can activate a specific target, TRPA1,
an ion channel expressed in sensory neurons, pancreatic beta cells,
and enteroendocrine cells of the gastrointestinal tract. Activation can
initiate impulse generation in the neurons that carry information to
the satiety centers in the brain, cause blood vessel dilation, and cause
insulin and other hormones to be released. It has also been shown that
down-regulation of angiotensin converting enzyme, which produces
angiotensin, a potent vasoconstrictor, prevents plaque formation in the
arteries. Those who consumed garlic extract regularly showed a reduction
108 Louis s. Premkumar, PhD
in plaque progression in 50% of the patients, reported from University of
California Medical Center, Los Angeles.
Sheila West from Penn State University has recently proven that it
is no longer a myth but that spices have significant health benefits. In
fact, there is a significant reduction up to 30% in triglyceride levels after
a high-fat meal when the fatty meal was garnished with turmeric (has
the active ingredient curcumin) and cinnamon (has the active ingredient
cinnamaldehyde). Triglyceride is a critical fat constituent, its levels in the
blood increase after a high-fat meal. Triglyceride levels are determined
routinely in the lipid profile test. The level of triglycerides has to be lower
than 150 mg/dL for cardiovascular health. Triglycerides are derived from
diets containing high carbohydrates (especially fructose), fried food, and
red meat. Triglyceride facilitates the process of developing atherosclerosis,
which is responsible for narrowing the coronary arteries, the occlusion
of which leads to a heart attack. Atherosclerosis can also occur in carotid
arteries as well as in the peripheral blood vessels.
Other spices that are used for garnishing, such as rosemary, oregano,
cinnamon, turmeric, black pepper, cloves, garlic, and paprika powder,
have antioxidant effect. Sheila West’s group has tested this and has shown
a 13% increase in antioxidant effect and 20% improvement in insulin
response. In this quantitative study, the antioxidant effects derived from
spices are equivalent to 5 oz of red wine and 1.4 oz of dark chocolate.
Description of Individual Spices
Anise
Anise (Pimpinella anisum) belongs to the family Apiaceae. The seeds are
used for cooking, and the oil obtained from the seeds can be useful to
flavor food. It imparts a distinctive aroma to confectionaries and is used
as a flavoring agent in liquid medications, such as cough syrups. It is
considered to induce health benefits as a spice that improves digestion,
is considered soothing, and has stimulatory and carminative properties
in the gut. It has been claimed that the anise oil is useful in menstrual
cramps. The active ingredient is anethole, a phytoestrogen. Anethole is
present in the liquor absinthe, which produces psychoactive effects.
Paramethoxyamphetamine, which has psychotropic properties, is
109Fascinating Facts about Phytonutrients in sPices and healthy Food
synthesized from anethole. Anise oil has antimicrobial, antifungal, and
insecticidal properties.
Star anise belongs to the family Schisandraceae, genus Illicium, and
species verum. It is used as a spice in Asian cooking. The active ingredient
in star anise is shikimic acid, a precursor for producing anti-influenza
drug oseltamivir (Tamiflu), which is a neuraminidase inhibitor and
prevents release of new viral particles.
Asafoetida
Asafoetida is obtained from Ferula assafoetida and belongs to the family
Apiaceae. The spice is obtained from the sap of the roots that solidifies
into grayish-white resin. The spice is available as a powder. In its pure
form it has an unpleasant smell and taste, but when used in small
quantities in lentil soups or lentil-containing vegetable curries, it imparts
a distinctive aroma and taste. It is claimed useful for flatulence and
respiratory conditions, such as bronchitis, asthma, and whooping cough.
The resin contains chemicals such as asaresinotannols, azulene, bassorine,
ferulic acid, and umbelliferone. Some of these ingredients are also present
in small quantities in carrots, garden angelica, and coriander.
Basil
Basil (Ocimum basilicum) belongs to the family Lamiaceae. Basil
originated from India and is mostly used in Italian cuisine. Basil and
oregano have the ingredient (E)-beta-caryophyllene, which is an agonist
of cannabinoid receptor 2 (CB2), which is involved in anti-inflammatory
actions. Eugenol is one of the active ingredients in basil, which is the
same ingredient in clove; citral is another ingredient that provides the
citrus smell to basil; camphene is an active ingredient in the African blue
basil; anethole is an active ingredient in licorice and basil.
Basil contains flavonoids, such as orientin, vicenin, hydroxycinnamic
acid, and chicoric acid, and can help protect the immune system. Basil
exhibits antibacterial properties because of the volatile acids, such as
cineole, estragole, eugenol, linalool, limonene, myrcene, and sabinene.
Because of these properties, these compounds can be used as natural
food preservatives. Eugenol has been shown to have anti-inflammatory
110 Louis s. Premkumar, PhD
properties by blocking the cyclooxygenase enzyme, an effect shared by
several over-the-counter anti-inflammatory drugs. Like other greens,
it has vitamin A and other minerals, especially magnesium, which
can have antioxidant properties and prevent fatty-acid oxidation and
provide cardiovascular health. Eugenol activates TRP channels TRPV1
and TRPV3. TRPV1 is expressed in sensory neurons and plays a role in
pain transmission. TRPV3 is expressed in keratinocytes and establishes
communication between skin and sensory nerve terminals.
Bay Leaves
Bay leaves (Cinnamonium tamala) belong to the family Lauraceae. The
dried leaves are commonly used in Indian and Mediterranean cooking to
flavor rice, stew, curry, etc. The leaves are not consumed but added for
aroma and flavor. The leaves are also used as insect repellent. The active
ingredients include (−)-β-caryophyllene, a natural bicyclic sesquiterpene
that is a constituent of many essential oils; linalool, a naturally occurring
terpene alcohol chemical found in many flowers and spice plants;
and eugenol, a phenylpropene, an allyl chain-substituted guaiacol. As
discussed earlier, eugenol can activate TRPV1 and TRPV3 channels.
Black Pepper
Black pepper (Piper nigrum) belongs to the family Piperaceae. The plant
grows as a creeper around trees, the unripe fruit is harvested and dried,
and the yellow pepper is the dried fruit.
It can be used as a whole or as a powder. Freshly ground pepper
has a better aroma; therefore, in some restaurants, it is freshly ground
and sprinkled on the food after serving. It induces a zesty sensation and
stimulates nerve endings, which gives the pungent taste. It imparts a
flavor and mild hotness to the food. The hotness is due to piperine, and
the pungency is quantified to be 100,000 Scoville units as compared to
ghost peppers, which has a score of 1,000,000 Scoville units. It is also
used to treat conditions such as sore throat and bronchitis; freshly ground
powder is consumed along with honey as a mixture or added to hot milk
along with turmeric. It improves digestion and acts as a carminative
(prevents the formation of gas in the gut). The active ingredients have
111Fascinating Facts about Phytonutrients in sPices and healthy Food
been isolated; the main ingredient is piperine. Other alkaloids present in
black pepper include chavicine and piperidine. Piperine acts on a specific
sensory receptor that has been cloned and identified recently and is called
transient receptor potential vanilloid 1 (TRPV1). The main ingredient
that activates TRPV1 potently is capsaicin from hot chili peppers.
Piperine is known to inhibit the liver metabolizing enzyme (CYP3A4)
thereby increasing the bioavailability of other drugs. It has been shown
to increase the bioavailability of curcumin significantly. Activation
of TRPV1 has been shown to cause the release of gastric acid in the
stomach; however, recent studies from Josai International University,
Japan, report a reduction in gastric-acid secretion. It is experienced that it
is not the hot food that causes acidity in the stomach, but the fatty food.
Caraway
Caraway (Carum carvi) belongs to the family Apiaceae. It is similar in
appearance to fennel or curcumin seeds. The seeds are used as a spice
in confectionaries. The seeds and the oil aid digestion as a carminative.
It has been suggested to be effective in endocrine disorders, including
thyroid disorders. Caraway water is useful to treat flatulence and colic
in infants. The seeds contain volatile oil, and the active component is
carvene, but its actions are not fully established.
Cardamom
Cardamom (Elettaria cardamomum) belongs to the family Zingiberaceae.
There are two varieties of cardamom: black and yellow. The dried
fruit pod and the seeds are used as flavoring agents in milk, coffee, tea
drinks, confectionaries, and a variety of desserts. Cardamom tea is very
popular in certain parts of Asia. It does not have a pleasant taste; the
seeds can be powered and used for cooking curry and for garnishing
a variety of desserts. It is used as a flavoring agent along with other
spices to cook spicy rice, meat, and vegetable curries. Rice dishes, such
as biriyani, are cooked with mixture of spices; one of the main spices
is cardamom. It was used to treat emphysema, flatulence, heartburn,
indigestion, laryngitis, and vaginitis. It is an ingredient to aid digestion,
as a carminative, and to treat colds and inflammation and is considered
112 Louis s. Premkumar, PhD
to be an aphrodisiac. The aromatic extract contains many essential oils
and chemicals. Borneol is a bicyclic terpene that has anti-inflammatory
actions and induces analgesia. It is claimed that borneol can be useful in
treating gallstones.
Chili Pepper
Chili pepper (Capsicum annuum or frutescens) belongs to the family
Solanaceae. The nonpungent bell peppers belong to the species annuum,
and hot peppers belong to the species frutescens. Dried and powdered C.
annuum is paprika, which is a coloring and a seasoning agent. Generally,
in the Western countries, the term spicy is associated with hotness,
pungency, or zestiness. In fact, a spicy dish can be made without being
chili pepper-hot. The dried fruit, the crushed fruit, the dried fruit
powder, and the fresh, unripe, and matured fruit are common forms of
its use. Most of the spicy dishes, such as curried rice (pulao or biriyani),
curries (meat or vegetable), and curry wraps contain chili powder as an
important ingredient. Chili powder has no taste or smell but induces a
zesty feeling on the tongue. Depending upon the hotness of the pepper
and the quantity being used, a dish could become intolerable to consume,
leaving a sense of burning pain in the areas of contact and painful
sensation on the tongue. Fresh peppers are rich sources of vitamin C.
There are several varieties of hot chili pepper, with different shapes
and sizes and a great variation in hotness. The hotness in chili peppers
is due to the chemical content of capsaicin, which binds to its receptor
(TRPV1) and transmits painful, noxious sensation to the brain. Other
capsinoids have been isolated and purified. The degree of hotness can
be quantified by Scoville scale. Scoville unit is the pungency of alcoholic
extract and the number of times the extract has to be diluted to lose its
pungency. Sweet bell pepper has the score of 0 Scoville units and the
habanero, savina, and naga jolokia (ghost peppers) are calibrated with
the score of 400,000, 600,000, and 1,000,000 Scoville units, respectively.
For example, ghost-pepper extract has to be diluted one million times to
lose its pungency. Commercially available pepper spray has the score of
2,500,000 Scoville units, and the police-grade pepper spray has the score
of 5,500,000 Scoville units. There are different natural chemicals that can
bind to the receptors with different affinities. Pure chemicals obtained
from a cactus Euphorbia resinifera/poissonii, resiniferatoxin/tinyatoxin,
113Fascinating Facts about Phytonutrients in sPices and healthy Food
have the Scoville score of 16,000,000,000/5,300,000,000, respectively.
Capsaicin and dihydrocapsaicin have the Scoville score of 16,000,000
and 15,000,000, respectively. Shogaol from ginger has the score of
160,000 units, piperine from pepper has the score of 100,000 units, and
gingerol from ginger has a score of 60,000 Scoville units. Resiniferatoxin
and tinyatoxin are used as pesticides. Extracts of Sichuan and melegueta
peppers evoke pungent sensations mediated by different alkylamides,
such as sanshool and shogaol; both activate TRPV1 and TRPA1 channels.
It is one of the well-studied spices, and the receptor on which
capsaicin acts and brings about its effects is undisputable. Before
the identification of the receptor in 1997, it was considered that the
pungency was due to tissue injury and tissue damage. In fact, the skin
exposed to chili pepper can become red and swollen. Now we know that
the action of capsaicin has two components when it binds to its receptor:
(1) a component of sending the impulses to the brain (afferent function)
and (2) a component of releasing vaso-/neuroactive substances, such as
histamine, bradykinin, calcitonin gene-related peptide (CGRP), and
substance P (SP), from the peripheral nerve terminals (efferent action).
It is known after the cloning of the receptor that the effects mediated
by capsaicin are by binding to the receptor called vanilloid receptor. It
was called vanilloid receptor because of the vanilloid moiety in capsaicin
molecule. However, it was realized that a receptor with a sequence
homology was identified in the eye of the fruit fly (Drosophila melagascar)
in 1987, by researchers in Johns Hopkins University, Baltimore, which
was involved in generating a sustained receptor potential when exposed
to light. A mutant receptor expressing fly photoreceptor, when exposed to
light, produced a transient receptor potential, hence renamed as transient
receptor potential vanilloid 1 (TRPV1). Since then, several TRP channels
have been cloned, and the present count is around twenty-eight.
A capsaicin receptor is an ion channel. When activated, sodium
and calcium ions enter the cell. In the periphery, when activated, it
causes the nerve terminal to depolarize and generate an action potential,
which carries the information to the brain via the spinal cord and higher
brain regions to somatosensory cortex. If the intensity of stimulus is
strong enough, it induces pain so that painful stimuli can be avoided.
After extensive studies, it is known that the receptor is also activated by
noxious temperatures; in fact, the receptor is activated precisely at 42°C.
This temperature range of activation protects the body from harmful
heat stimuli by coordinating withdrawing from the area of contact so
114 Louis s. Premkumar, PhD
that there will not be a burn injury. It is also activated by a variety of
chemicals, particularly by protons in acidic solutions. It undergoes
calcium-induced desensitization. The activation of the receptor by
capsaicin, temperature, and acid can be gleaned by the intense painful
feeling when one inadvertently takes a mouthful of spicy, hot chili dish,
garnished with vinegar, brought right out of the oven. The antidote for
consuming spicy food to quench the pungency is to consume milk or
milk products. The calcium in the milk facilitates the desensitization of
the receptor, thereby relieving the suffering.
This highlights the concept of sensitization and desensitization,
which are important biological safety mechanisms built in to avoid excess
activation (see Chapter 1). When capsaicin binds to the receptor, an
ion channel opens, but when constantly activated, the receptor enters a
conformation state called desensitization state, which is a ligand-bound
state, but the channel pore is not permeable to ions. The channel has to
go through the closed state before opening again. On the other hand,
sensitization is a phenomenon where the receptor activity is increased.
Based on this, TRPV1 receptor overexpression and overactivity have been
attributed in certain painful conditions.
In fact, excess activation of any calcium-permeable channel can
lead to calcium-induced cell death, and neurons are more susceptible
for such an event. It is believed that the highly calcium-permeable
neurotransmitter receptor in the brain called N-methyl-D-aspartate
receptor is responsible for cell death in several neurodegenerative diseases,
which include dementia, Alzheimer’s disease, and irreversible cell death
after a stroke.
For all the spices, the bioavailability is a concern, given the amount
being consumed and the extent of absorption from the gut. Therefore,
the purported effects have to be attributed in relevance to their systemic
concentrations that can be achieved. As compared to tens or hundreds
of micromolar ranges of concentrations of active ingredients required to
activate their receptors (such as curcumin and allyl isothiocyanate), the
concentrations of capsaicin required to activate TRPV1 are in nanomolar
range. Further, although capsaicin is highly lipid-soluble, but because
of the pungency, the amount of its consumption is restricted. However,
the effectiveness of its semisystemic distribution can be appreciated by
blushing because of vasodilation and profuse perspiration of the head and
neck regions brought about while consuming hot chili pepper-containing
food, which implicates its effects beyond local activation of its receptors.
115Fascinating Facts about Phytonutrients in sPices and healthy Food
In painful conditions, topical capsaicin application has been
useful to treat conditions such as localized pain, arthritis, diabetic
peripheral neuropathy, shingles, and psoriasis. Animal studies show
that experimental arthritis can be delayed by capsaicin administration.
It is known that TRPV1 is overactive in various painful conditions.
Therefore, developing an antagonist is a priority for several
pharmaceutical companies. Unfortunately, the antagonists were effective
in certain modalities of pain, but they caused an unexpected side effect
of hyperthermia; the body temperature increased by about 3°C, which
means, although the pain is relieved, a sterile fever is induced.
In cardiovascular conditions, lipoprotein oxidation has been shown
to contribute to atherosclerosis formation in arteries. Moderate amount
of chili pepper-containing food reduced the oxidation of lipoprotein. The
pain associated with ischemic heart disease can be relieved by localized
application of capsaicin on the chest wall. In order to avoid burning
pain, a local anesthetic is applied before the application of capsaicin. The
cardiovascular effect could also be due to its antimicrobial effects that can
subdue the microbiota and prevent metabolism of bile acid, which can
reduce the recirculating cholesterol.
Altered expression of TRPV1 is found in cancers involving the
prostate, bladder, pancreas, tongue, skin, liver, and colon. Capsaicin
can induce its effects by causing calcium influx through TRPV1
overexpressed in cancerous cells, which can lead to cell death by apoptosis
or necrosis. This action will be very effective in cancers involving the
GI tract. For other cancers, the inadequate systemic concentrations of
capsaicin are a concern.
In diabetes, consuming a chili-containing meal showed a decrease in
the amount of insulin required to combat the postprandial increase in
glucose. These effects are more significant in patients with higher BMI.
Chili-containing meal also decreased C-peptide and insulin secretion and
increased the insulin clearance from levels, suggesting a favorable effect
on postprandial hyperinsulinomia. TRPV1 is expressed in pancreatic
beta cells, and calcium flux through TRPV1 leads to insulin release.
The levels of capsaicin required to induce these effects are not clear.
However, if TRPV1 is expressed in enteroendocrine cells, capsaicin can
act locally to cause glucose-dependent insulinotropic polypeptide (GIP)
and glucagon-like peptide-1 (GLP-1) release and contribute to glucose
homeostasis. The pain associated with diabetic neuropathy can be
alleviated by local application of capsaicin-containing creams. It takes
116 Louis s. Premkumar, PhD
about two weeks for the pain relief because the nerve terminals have to be
desensitized or destroyed to experience the effect.
TRPV1 agonists might lead to weight loss by suppressing appetite
whereas antagonists might help prevent insulin resistance and obesity.
Capsaicin has been reported to increase oxygen consumption and
thermogenesis. There are data that support a potential neurogenic
mechanism by which TRPV1-sensitive sensory neurons may regulate
energy and fat metabolism. Capsaicin prevents adipogenesis by apoptotic
mechanism. Capsaicin or N-oleoylethanolamide, an endogenous ligand
of TRPV1, reduced food intake by conveying information through vagus
nerve and affecting satiety centers. TRPV1 knock out animals, when fed
with high-fat diet although the food intake was the same, they gained less
weight as compared to their wild-type counterparts.
Although there is no direct evidence that hot chili pepper-containing
spicy food increases stomach acid secretion, in certain conditions such as
gastroesophageal reflux disease (GERD), increased expression of TRPV1
in the esophagus can induce burning sensation. Capsaicin has been
shown to worsen the condition in patients with irritable bowel syndrome
(IBS) and Crohn’s disease. Although activation of TRPV1 has been
shown to cause the release gastric acid in the stomach, a Japanese study
reports otherwise.
Urinary hyperreflexia is a condition that has been shown to be
related to overexpression of TRPV1 in the nerve terminals innervating
the bladder. A treatment option includes intravesicular irrigation with
resiniferatoxin, an ultrapotent TRPV1 agonist that can induce nerve
terminal desensitization or ablation. It is not clear whether the systemic
effects of consuming chili pepper-containing spicy food can induce a
favorable effect in these conditions. However, excretion of capsaicin
through the kidneys can accumulate in the bladder and can exert an effect.
Cocoa
Cocoa (Theobroma cacao) plant belongs to the family Sterculiaceae.
Although raw cocoa is bitter, it has a very good flavor, especially
when processed into milk chocolates. Chocolate is considered
to be a high-calorie food mainly because of its processed nature.