4 FREE RADICALS IN VARIOUS DISEASE PREVENTION

4.1. FREE RADICALS

The compound that loses or gains a single electron and thus has an unpaired electron in
its outermost orbit is extremely unstable and very highly reactive. Such compounds are
known as free radicals Free radicals usually exist for only extremely short periods of
time, of that onder nanoseconds (10) or less, before they react with another molecule
either gaining or lowing a single electron in order to achieve a stable configuration.
However, this reaction in Turn generates another molecule with an unpaired electron
Each time a radical reacts with a molecule while losing the unpaired electron achieving
stability, it generates another radical in terms which is again short lived and highly
reactive This is a chain reaction. Some radicals are relatively stable. This applies
especially to those formed from molecules with aromatic rings or configured double
bond systems. A single unpaired electron can be distributed or delocalized through such
a system of double bond and the resultant radical is less reactive and longer lived than
most radicals Compounds capable of forming relatively stable radicals are important in
quenching radical chain reaction. Their radical often has a lifetime long enough to
permit two such stable radicals to come together, react with each other, and to terminate
the chain. Vitamins and carotenes are especially important in quenching radicals
reactions in biological systems

Free radicals are involved in many pathological conditions such as many types of
diabetes neurodegenerative diseases, cardiovascular diseases (CVDs), cancer, cataracts,
asthma theumatoid arthritis, inflammation, burns, intestinal tract diseases, progerias
and ischemic Ischemic pathologies

SOURCES OF OXYGEN FREE RADICALS

In biological systems the most damaging radicals are those derived from oxygen the so
called reactive oxygen species. They arise in the given four ways

As a result of normal oxidative metabolism, and especially reactions involving the re

asidation of reduced Flavin coenzyme As a part of action of macrophages in killing
invading microorganism. This means that infection can lead to considerable increase in
the total radical burden in the body. This may be an important factor in the
protein-energy deficiency disease Kwashiorkor

As a result of non-enzymatic reaction of a variety of metal ions in free solution (and

especially iron and copper with oxygen, Normally such reactive metal ions are not
presented I in free solutions to any significant extent, but are bound to transport protein
in plasma) e or storage protein and enzymes (in cells). As a result of the exposure to
ionizing radiation -X-rays, the radiation from radioactive isotopes and ultraviolet
radiation from sunlight. Tissue Damage by Oxygen Radicals

Radicals may interact with any compounds present in the cell, and the result may be
initiation of cancer, inheritable mutations, atherosclerosis, and coronary heart diseases
or autoimmune diseases. The most important potentially damaging, such interactions
are With DNA in nucleus, causing chemical changes in the nucleic acid bases or break in
DNA strand. This damage may result in heritable mutations if the damage is to ovaries
or testes or the induction of cancer in other tissues.

With individual amino acids in proteins. This results in a chemical modification of the
protein, which may therefore be recognized as foreign by the immune system leading to
the production of antibodies that will also react with the normal unmodified body
protein. This may be an important factor in the development of autoimmune disease .
With the unsaturated fatty acids in cell membranes. If the damage is severe enough, it
will result in lysis of membrane and cell death. Less severe damage does not kill the cell.
but oxidation of unsaturated fatty acids leads to formation of very reactive dialdehydes.
These react especially with DNA, causing chemical modifications and hence may either
result in mutation or initiation of cancer,

Tubetes mellitus is a complex syndrome involving severe insulin dysfunction in

compugation with gross abnormalities in glucose homeostasis and lipid metabolism.
The disease is generally broken down into two major subgroups. One group is insulin
dependent diabetes mellitus (IDDM) which is also referred to as 'juvenile onset
diabetes' or Type I diabetes. The second group is referred to as non-insulin dependent
diabetes mellitus NIDDMO which is also termed as 'maturity onset diabetes' or Type II
diabetes. In the former variety of the disease, there is a total or near total loss of insulin
secretion from the islets of Langerhans in the pancreas resulting in disinhibition of
gluconeogenesis, soaring blood glucose levels and gross loss of muscle and fat. The
diabetes mellitus can be translated as eet excessive urine' indicating both; loss of
excessive blood glucose via the urine. In the lither type of diabetes, insulin secretions
are low or tardy so those blood glucose levels rise hyperglycaemic range (10Mm versus
5Mm for normal), IDDM is most evident in the young whereas is NIDDM is strongly age
related.

The Cause of Diabetes

Free radicals and oxidative stress may act as a common pathway to diabetes itself as
well as to its later complications. For example, the selective cytotoxicity of auoxan is a
function of three factors efficient uptake, oxidant production by redox coupling of the
drug with intracellular reductant (ascorbate and thiols) couples with low levels of
glutathione peroxidase in the islets. Auoxan toxicity in vitro and in vivo can be inhibited
by metal chelating agents, hydroxyl radical scavenger and lipid soluble antioxidants.
Desferrioxamine blocks diabetes induces by multiple low doses of streptozotocin (STZ)
suggesting that transition metals catalysed free radical reactions may contribute to STZ
toxicity but the situation is clouded by the confusing effects to other free radical
modifiers as well as islet killing during insulitis. It can be easily be speculated that STZ, a
glycone-nitrosourea, may induce diabetes by producing inappropriate no response.

The major symptoms are thirst, hunger, emaciation, and weakness, eventually lead to
coma. DMis associated with the increased production of free radicals or decreased
activity of the antioxidant systems, which leads to development of oxidative stress. The
hyperglycemic condition induces increased free radical production via four different
routes namely.

1) Increased glycolysis, results in increased ratio between the rate of oxidation of G3P to
1,3- DPG, following increased NADH/NAD ratio (redox imbalance).

2) Activated sorbitol (or polyol) pathway, causes the accumulation of both sorbitol and
fructose, results in decreased reduced GSH and increased NADH/NAD ratio.

3) Autoxidation of glucose, results in the generation of different free radicals such as H:O
OH, O and keto aldehydes.
4) Non enzymatic protein glycation, results in the formation of ACEs which upon
interacting with RAGES generate oxidative stress.

Both mitochondrial and non-mitochondrial derived ROS contribute to oxidative stress

during DM. Under normal conditions, the electron transport chain complexes I and III
are the key sites of superoxide production. However, the increased glucose levels in DM
lead to increased glycolysis resulting in the augmented generation of pyruvate, thus
raising the inner mitochondrial membrane potential upwards, followed by
mitochondrial dysfunction

4.1.2 FREE RADICAL IN INFLAMMATION

the phagocytic leukocytes (eg, neutrophils, monocytes, macrophages and eosinophils)

that and increased ROS production at electron transport chain complex II. It is becoming
increasingly apparent that certain types of inflammatory tissue injuries are medicated
by reactive oxygen metabolites. The liveliest sources of these oxidizing agents are in
Various Disease Prevention vade the tissue. These reactive radicals and oxidants may
injure cells and tissues directly idative degradation of essential cellular components as
well as injure cells indirectly by Sing the protease/anti protease balance that normally
exist within the tissue aterstitium. It is becoming increasingly apparent that in addition
to promoting cytotoxicity, active oxygen metabolites may initiate and/or amplify
inflammation via up regulation of several genes involved in the inflammatory response,
such as those that code for pro-inflammatory cytokines and adhesion molecules. This
may occur by activation of certain cription factors, such as nuclear transcription on the
immune and inflammatory ponse. Essential nutrients such as vitamin C and E may
protect against oxidant medicated inflammation and tissue damage by virtue of their
ability to scavenge free radicals by their ability to inhibit the activation of Nf-K

413 FREE RADICAL IN ISCHEMIC REPERFUSION INJURY Oxygen free radicals'

involvement in ischemia and reperfusion injury to brain - Evidence is pented which
implicates increased oxygen radical during ischemia reperfusion of gerbil bran
Salicylate which reacts with hydroxyl free radicals to yield dihyroxybenzoic acid (DHBA)
was used as an in vivo trap.

Brain ischemia for at least 5 minutes followed by the reperfusion yielded significantly
increased brain DHBA without reperfusion or with only 2 minutes of ischemia and then
reperfusion. The production of DHBA was not increased. The increased level of DHBA in
brain correlated with ischemia reperfusion mediated behavioural modification of
gerbils by salicylate administration did not protect against the behaviour changes.

414 CANCER

It is one of the leading causes of death in humans. Free radicals cause different types of
chemical changes in DNA, thus they could be mutagenic and involved in the etiology of
cancer. Cancer cells in particular, in comparison to normal cells, have higher levels of
ROS and are more susceptible to mitochondrial dysfunction due to their higher
metabolic rate. Cancer cells display elevated levels of oxidative stress due to activation
of oncogenes and low of tumor suppressors ROS by altering the growth signals and gene
expression cause continuous proliferation of cancer cells. ROS can damage DNA by
inducing base modifications, deletions, strand breakage, chromosomal rearrangements
and hyper- and hypo-methylation of DNA.

4141 Colorectal Cancer

Colorectal cancer (CRC) is the third most common cancer worldwide, accounting for
608,000 deaths per year. The gastrointestinal tract, particularly the colon and rectum, is
continuously exposed to ROS originating from both endogenous and exogenous sources.
Colon cancer originates from the epithelial cells that line the bowel

These cells divide rapidly and have a high metabolic rate. Since the intestinal mucosa is
constantly confronting with diet and bacterial-derived oxidants and carcinogens, an
unrestrained production of free radicals, redox imbalance, and DNA damage occurs,
finally leads to an altered intestinal metabolic homeostasis with cancer as an endpoint.
The human colorectal tumors have increased levels of nitric oxide (NO), 8-oxodG in DNA
and lipid peroddes
4142 Breast Cancer

Damage to the breast epithelium by ROS can lead to fibroblasts proliferation,

hyperplasia of rysthelium cellular atypia and breast cancer. In majority of breast
carcinomas the oxidative stress can be induced by the over expression of thymidine
phosphorylase enzyme which catabolizes thymidine to thymine and
2-deoxy-D-ribose-1- phosphate; the latter is a powerful reducing sugar that rapidly
glycates proteins, generating oxygen radicals within the carcinoma cell. Another breast
specific mechanism of oxidative stress induction involves a mammary gland specific
lactoperoxidase enzyme catalyzed one electron oxidation of 17-g oestradiol to a reactive
phenoxyl radical

4.1.4.3 Prostate Cancer

The ROS produced are responsible for the cellular proliferation of prostate cancer cells.
Over

expression of NADPH oxidase (Nox]) protein is an early event in the development of

prostate cancer. Prostrate tumors have considerably higher levels of ROS and Nox1
levels The superoxide produced by NOXO in prostate cancer cells facilitates cellular
immortality through resistance to programmed cell death which results in
cancer-promoting effect. 4.1.4.4 Lung Cancer Lung cancer has been the most commonly
diagnosed cancer and is the central cause of cancer death in men worldwide Lung
cancer mortality account 30% of all cancer related deaths. Odative stress plays an
important role in lung inflammation and lung cancer

Cigarette Smoking is the most crucial environmental risk factor in lung cancer etiology.
It is estimated that smoking accounts for 80% of global lung cancer burden in males and
50% in females Cigarette smoke particulate matter contains complex mixture of
numerous carcinogens and stable ROS with very long half-lives. These ROS can damage
the tissues resulting in progressive transformation of cells into the malignant form,
which leads to increased frequency of mutations by the oxidative damage to DNA and,
eventually leading to lung cancer. Smokers develop lung cancer a 10-fold higher than
non-smokersve Ricals in Various Disease Prevention

235 Lang cancer (LC) and chronic obstructive pulmonary disease (COPD) commonly
coexist in nkers and the presence of COPD increases the risk of developing LC

LLLS Badder Cancer Badder cancer is one of the most common cancers across the
world, ranking the fourth and ainen and women, respectively. The most common risk
factors for bladder cancer are smoking, exposure to industrial carcinogens (aromatic
amines), high levels of intake and diet. Chidative stress critically contributes to the
development of bladder ar Various lines of evidence reported an increased oxidative
stress in patients with mast cancer. Increased NO levels have been reported in bladder
cancer patients. This NO es matrix metalloproteinases (MMP), especially prolidase
activity, which is red in the terminal step of collagen degradation. Significantly higher
serum prolidase abes were reported in patients with bladder cancer than healthy
controls. Therefore. ased probidase activity may, in part, play a role in the pathogenesis
of bladder cancer. Endemiological studies reveal that low levels of antioxidants are
associated with an aced risk of cancer.

Sicant increase in total oxidant status levels and decrease in total antioxidant status we
observed in patients with bladder cancer. Significantly lower levels of plasma protein, tal
thiol groups and protein bound thiol groups and elevated levels of Protein carbonyl pops
were observed in bladder cancer patients than in healthy controls.

415 ATHEROSCLEROSIS

Aberosclerosis is a condition commonly referred to as hardening of the arteries

Hyperlipidemia is a major risk factor for atherosclerosis. Elevated levels of oxidized low
density lipoprotein (LDL), glucose and free fatty acids are found in patients with
therosclerosis, T2D, and obesity. A profound imbalance of oxidants and antioxidants.
muting in oxidative stress is observed in atherosclerosis. In the vessel wall, endothelial
smooth muscle cells (SMCs) and macrophages are sources of free radicals. Endothelial
duction leads to increased endothelial permeability, up regulation of endothelial aesion
molecules, and inflammatory cell infiltration into the arterial wall. A substantial da has
been shown that ROS are involved in endothelial injury, dysfunction, and lesion Pion The
ROS dependent activation of the MMP's results in the degradation of alextracellular
matrices and promotes smooth muscle cell migration. Cigarette king contain large
amount of free radicals and may down-regulate key exogenous and dogmous
antioxidants such as vitamin-D, carotenes, GPx and SOD and can lead to the planction of
monocytes and vascular smooth muscle cells. The proatherogenic agents such dained
lipids, high glucose and cigarette constituents give rise to increased free radical236

FU A Text Book of Dietary Supplements and Nutraceuticals

production. The endothelial nitric oxide synthase (eNOS) derived NO plays an important
role in maintaining vascular tone and vasoreactivity, vasodialation, platelet aggregation
and in maintaining balance between smooth muscle cell growth and differentiation.
Decreased NO bioavailabilty is the one of the major feature of the CVDs. During reduced
availability of BH4 or L-Arg, eNOS becomes uncoupled from a NO to a Oy state. The O*
formed can interact with NO to produce ONOO, a damaging and cytotoxic free radical
with potential to disturb cardiovascular function. ONOO reduces the bioavailability of
NO leading to reduced endothelial vascular regulatory capacity and increased vascular
dysfunction. ONOO also inactivates the BH4 cofactor effectively amplifying the damaging
effects of eNOS uncoupling the endothelium. Mitochondrial DNA damage is frequently
observed in human atherosclerosis in both circulating and vessel wall cells. Oxidative
stress mediated damaged mitochondrial DNA that escape autophagy induces a potent
inflammatory response in atherosclerosis. Malfunction of DNA repair leads to defects in
cell proliferation, apoptosis, and mitochondrial dysfunction, which in turn leads to
ketosis, hyperlipidemia, and increased fat storage, promoting atherosclerosis and the
metabolic syndrome.

4.1.6 FREE RADICALS IN BRAIN METABOLISM AND PATHOLOGY

Reactive oxygen metabolites (ROM), namely superoxide and hydroxyl free radicals and
hydrogen peroxide, are produced as a consequence of the physiological metabolic
reactions and functioning of the central nervous system. ROM have also been implicated
in the actiopathogenic processes of a number of pathological conditions of the brain.
While primarily indirect, evidence for this view is accumulating, and credence for the
participation of free radical oxidative interactions in promoting tissue injury in such
conditions as brain trauma, ischaemia, and toxicity, and in neurodegenerative diseases
such as Parkinson's disease. Alzheimer's dementia, multiple sclerosis, and
lipofuscinosis, is growing • Neurodegenrative Disease

The central nervous system (CNS) is particularly susceptible to the oxidants due to the
presence of high lipid content, high consumption of oxygen, and low levels of
antioxidant enzymes, for example, SOD is localized primarily in neurons, and GSH and
GPx are localized in astrocytes. The lipid peroxidation by ROS leads to progressive loss
of membrane fluidity, decreases membrane potential, and increases permeability to ions
such as Ca2+ The regions of the brain such as hippocampus, substantia nigra, and the
striatum are particularly susceptible to attack by free radicals. The oxidative stress state
has been also implicated in several neurodegenerative diseases such as Alzheimer's,
Parkinson's, Huntington's, lateral amyotrophic sclerosis, and multiple Sclerosis.Radicals
in Various Disease Prevention

Parkinson's Disease (PD)

Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons involve in

kaming memory and motor control), especially in the midbrain area called the
substantia niga, accompanied by deposition of inclusion bodies (Lewy bodies) of
a-synuclein. The edox imbalance causes oxidative damage to these neurons and begins
to alter the synthesis and metabolic pathway of dopamine leads to a further increase in
oxidative stress because of quinine formation. The characteristic clinical symptoms of
PD include, jerky movements, rembling of the hands and lips, and tremors. Dopamine, a
neurotransmitter, can also act as a metal chelator, has the ability to generate HO: via
Fenton reaction. Ceruloplasmin (an extracellular ferroxidase required for regulating
cellular iron load and transport) oxidation s in the decreased ferroxidase activity
followed by the accumulation of intracellular pon in neurons in PD. The increased levels
of Fe mediate the production of hydroxyl radicals, results in the damage of dopaminergic
neurons in PD

Alzheimer's Disease (AD)

Alzheimer's disease (AD) is characterized by the accumulation of amyloid protein

plaques Girmed from the improper folding and processing of amyloid b precursor
protein-ABPP) and intracellular neurofibrillary tangles made up of abnormal and
hyperphosphorylated tau protein. The hyperphosphorylated tau protein aggregates
binds to Fe, results in the production of neurofibrillary tangles. The Amyloid-b peptide
(Ab) can chelate with transition metal ions (Cu, Zn2 And Fe), and produce HO via
transition metal mediated alysis and finally gives toxic OH radical. The lipid peroxidation
is also extensive in AD patients, which can induce neuronal death by multiple
mechanisms such as impairment of function of ion pumps (both Na/K-ATPase and
Ca-ATPase), glucose transporters and glutamate transporters. The other oxidative
markers of protein damage such as protein carbonyls and 3-nitrotyrosine have been
also observed in AD patients.

Multiple Sclerosis (MS)

MS is an autoimmune neuronal disorder characterized by impaired nerve conduction

due to demylination of central nervous system (CNS). The activated
microglia/macrophages te the MS by the generation of ROS that can induce lipid
peroxidation, results in the deylination and damage of neurons. Elevated Thiobarbituric
acid reactive substances (TEARS) levels and reduced protein SH groups, the
representatives of oxidation and slightly reduced SOD shows by MS patients. Apart from
ROS generation, an impaired irony metabolism also considered to play a major role in
pathogenesis of disease.238

41.7 FREE RADICAL IN KIDNEY DAMAGE

Reactive oxygen species (ROS) age generally considered as tonic molecules, and are
often associated with tissue injury. A large body of accruing evidence also suggests that
ROS may play important roles in normal biological process, and consistent with this is
the fact that healthy normal cells generate ROS

Oxidative stress has a critical role in the pathophysiology of several kidney diseases, and
many complications of these diseases are mediated by oxidative stress, oxidative stress-
related mediators, and inflammation, diabetes-associated kidney disease is a major
cause of all new cases of end-stage kidney disease. All diabetic patients are considered
to be at risk for nephropathy. Clinically control of blood sugar level and blood pressure
regulations are two parameters to the prevention of diabetic nephropathy. Currently the
proposed mechanism is the glomerular hyperfiltration/hypertension hypothesis.
According to this hypothesis, diabetes leads to increased glomerular hyperfiltration and
a resultant increased glomerular pressure. This increased glomerular pressure leads to
damage to glomerular cells and to development of focal and segmental
glomerulosclerosis. The mechanism by which hyperglycemia causes free radical
generation thus causes 05 to be complex. Increased blood glucose promotes
glycosylation of circulator and cellular protein and may initiate a series of autooxidation
reactions that culminate in the formation and accumulation of advanced glycosylation
end-products (AGES) in tissues. The AGEs have oxidizing potential and promote tissue
damage by oxygen-free radicals. Hypertension is one of the major causes of
development of renal failure. Key regulator of this pathology is 05 Renal artery stenosis
is the most common cause of secondary hypertension and may lead to deterioration of
renal function and ischemic nephropathy.

Glomeruli are often infiltrated with leukocytes and macrophages, and a large body of
experimental evidence suggests that they, through in part free radical mechanism, may
play a role in glomeruli injury. Neutrophil occupy a central role in glomerular injury in
certain models as demonstrated by the marked reduction in the rates of protein
excretion and attenuation in endothelial and epithelial injury with neutrophil depletion.
Key mechanisms. through which neutrophils inflict glomerular damage, involve the
generation of reactive oxygen species particularly hydrogen peroxide. Another pathway
for glomerular damage is the neutrophil-dependent hypochlorus/ myeloperoxidase
system. Activated neutrophils have been shown to release copious amounts of the highly
injurious acid from hydrogen peroxide and halides such as chloride. Platelet activation,
which itself may be triggered by the myeloperoxidase-hydrogen peroxide system,
represents an additional source of inflammatory and mitogenic agents including platelet
derived growth factor, platelet co-factor 4, platelet activating factor (PAF) and
thromboxane. Platelets in turn enhance the free radical response of activated
neutrophils possibly through their stores of adenine navodes. Thus by recruiting
additional pathways for tissue injury such as platelet Avation, as well as generation
hypochlorus acid, the myelo-peroxidase-hydrogen peroxide estem promotes glomerular
injury. Yet another mechanism for hydrogen peroxide- cilitated injury is based on the
degradation of glomerular basement mem-brane by metalloproteinases derived from
neutrophils. Metalloenzymes such as collagenase and gelatinase reside within
neutrophils in a dormant state. Activation is necessary before these mzymes can
degrade basement membrane. These investigators noted that catalase but not speroxide
dismutase inhibited degradation of glomerular basement membrane by Atrated
neutrophils. Metal chelators, inhibitors of myeloperoxidase and scavengers of
pochlorous acid also inhibited degradation of basement membrane by supernatant
otracts for activated neutro-phils. These findings suggest that oxidants derived from the
myeloperoxidase-hydrogen peroxide-halide system activate the proteolytic capacity of
metalloproteinases towards the glomerular basement membrane
Foot processes fusion of the glomerular epithelial cells and a paucity of prolix-ferative or
rative changes, findings that are similar to human minimal change disease, characterize
be histologic lesion. The aminonucleoside of puromycin is metabolized to hypoxanthine
and the availability of hypoxanthine would serve as substrate for xanthine oxidase there
by perating Attenuation in rates of protein excretion was observed with depannol
(xanthine oxidase inhibitor) and superoxide dismutase. Generation of hydrogen
peruuide is also implicated in the loss of glomerular permselectivity in this model. In
addition to glomerular damage, puromycin also induces an acute tubulo-interstitial
nephritis. It is possible that the generation of hydroxyl and other reactive species may
also ntribute to acute tubulo-interstitial injury.

The administration of an antibody to the tubular epithelial antigen,(Fx1A), induces

proteinuria in rats and a glomerular lesion characterized by thickening of the capillary
loops and the subepithelial immune deposits, thus resembling clinical membranous
nephropathy. in this model glomerular leak of macromolecules is dependent on
comple-ment but not on trophils. Iron chelators and scavengers of hydroxyl ion reduced
proteinuria in this disease model. Such beneficial effects were exerted in the absence of
alterations in the deposition of antibody an complement in the glomeruli. These data
suggest that the in-situ binding of the anti-Fxl A antibody trigger the generation of
hydroxyl ion leading to pomerular injury. The findings in these models indicate that
Immune reactants may evoke the pmeration of reactive oxygen species by intrinsic
glomerular constituents. The role of free radicals in biology and medicine continue to
evolve and their role in kidney disease and transplantation are no exception. The newer
findings that cellular redox states influence2401

ỤA Text Book of Dietary Supplements and Nutraceuticals

signals transduction and that oxidant by activating transcription factors induce several
pathologically relevant genes provide basis to explain how free radical-involvement can
account for a wide variety of renal disease processes, including diabetic nephropathy

4.18 FREE RADICAL MUSCLE DAMAGE

Skeletal muscle contains a variety of potential sites for the generation of free radical
species together with a multi-faceted defence system to prevent the deleterious effects
of these substances Oxidative skeletal muscle contains substantial numbers of
mitochondria and is subjected to large changes in oxygen flux during exercise. Muscle
tissue is unique in its requirement and ability to undertake very rapid and co-ordinated
changes in energy supply and oxygen flux during contraction. The phenomenon of
muscle pain after unaccustomed or excessive exercise is well known and experienced by
most people at some time. In many cases this pain can be shown to reflect structural
damage to the tissue induced by the exercise and free radical species are involved in this
damaging process. The capacity of muscle to deal with increased radical production also
appears to be enhanced in oxidative fibres with this tissue containing relatively high
concentrations and activity of a number of different antioxidant materials and enzymes.

There is increased free radical activity in muscle during exhaustive aerobic exercise
where the muscle is contracting in a primarily concentric or isometric manner. However,
this type of exercise does not normally lead to significant muscle damage implying that
the well- developed muscle antioddant system is usually capable of preventing cell
damage due to this increased free radical activity. Where exercise is of a type likely to
cause muscle damage e. during eccentric muscle activity) there is much less convincing
evidence for increased free radical activity or for a primary protective role of
antioxidants. There is. however, evidence for involvement of the cell-mediated immune
system in the secondary damage which is a characteristic of substantial eccentric
contractile activity, and this may generate oxygen radicals contributing to the secondary
tissue damage. During high intensity oxidative exercise increased formation of oddising
free radicals (probably of mitochondrial origin) can damage muscle tissue and that
training regimens or antioxidant supplementation may reduce this by elevating muscle
antioxidant capacity.

Free radicals found as a possible pathogenic mechanism in various muscle diseases

Knowledge of the role of vitamin E and selenium deficiency in the aetiology of the
animal disorders, incorrectly termed 'nutritional muscular dystrophy, initially prompted
studies of the role of these antioxidants and of the possible involvement of free radicals
in the human muscular dystrophies. Free radicals to play a role in the pathogenesis of
malignant hyperthermia and of muscle damage induced by alcohol abuse or periods of
ischaemia and

419 FREE RADICALS INVOLVEMENT IN OTHER DISORDERS

4151 Cardiovascular Diseases (CVD)

Cardiovascular diseases are a class of pathologies involving the heart and blood vessels
arteries, capillaries, and veins). They include cardiac diseases, vascular diseases of the
brain and kidney, and peripheral arterial disease. Most of the people are dying due to
CVDs compared to other diseases.

4192 Hypertension (HT)

Hypertension (HT) is a major health problem worldwide account 40% of the total adult
population. P'ersons with hypertension are at an increased risk for stroke, heart disease.
kidney failure, and premature mortality. Free radical induced oxidative stress in part
contributes to endothelial dysfunction and development of hypertension. Increased ROS
generation eliminates NO by forming ONOO, thus reducing NO bioavailability which
leads to decreased endothelium-dependent vasodilation resulting in hypertension. A
decrease in NO bioavailability and an increase in oxidative stress are present in human
hypertension. Oxidation-induced impairment of NO also results in reduced opposition
to the vasoconstrictive and hypertensive effects of angiotensin II. Angiotensin II
decreases NO hoavailability by promoting oxidative stress.

4193 Cataract

It is the most common cause of the visual impairment affecting about 25 people
throughout the world, with the highest incidence occurring in developing countries. It is
characterized by opacity of the eye lens that reduces the amount of incoming light and
results in visual impairment. Although a number of factors such as genetic factors,
diabetes, aging, smoking, drugs, malnutrition, radiation (x-rays and UV rays) and
alteration in both endocrine and enzymatic equilibrium have been implicated in cataract
formation, the free radical induced oxidative stress is considered as one of the major
underlying mechanism of cataract disorder. Oxidation of proteins, lipids and DNA is seen
in cataract lenses. Proteins se sulfhydryl (-5H) groups become cross linked by non
disulfide bonds, form high molecular aggregates and become insoluble. The oxidative
stress induced lipid peroxidation product such as HNE induce the fragmentation of lens
proteins contributing towards the opacity of the lens. The cornes absorbs the light in the
range of above 300 nm results in the activation of tryptophan, to form N-formyl
kynurenine, 3-hydroxy kynurenine and other photoproducts. These photoproducts
gradually accumulate in the centre of the lens are capable of generating singlet oxygen
which induce protein damage leading to the loss of transparency Cataract lens have an
intracellular ionic imbalance (ie. altered ionic homeostasis) than normal lens. The ROS
induced by UV rays in sunlight alters the ionic homeostasis results in the increased
levels of Ca and Na, coupled with the decreased levels of Mg and K in the lens. The
increased calcium activates calpains, a family of calcium dependent non lysosomal
cysteine proteases, which degrade lens proteins such as crystalline proteins results in
opaque lens characteristic of cataract.

4.1.9.4 Rheumatoid Arthritis (RA)

RA is chronic multisystem disease of unknown cause which affects approximately 1-2%

of the total world population and women are affected more than men.

The disease is characterized by synovial and systemic inflammation with joint swelling,
morning stiffness, destruction of articular tissues, joint deformities, fatigue, loss of
appetite and weakness. It is believed to be a T-lymphocyte driven disease in which a
sudden influx of T-cells into the affected joints is followed by an increased number of
macrophages and fibroblasts drawn the release of cytokines particularly IL-1 and
TNF-alpha.
This cytokine release and subsequent migration is thought to be responsible for the
chronic inflammation and characteristic changes in RA.

Several lines of evidence suggest a role for oxidative stress in the pathogenesis of RA.
Both ROS and RNS damage cartilage. Tissue injury in inflammation results in NO
production by articular chondrocytes and synovial fibroblasts and elevated levels of NO
are observed in the serum and synovial fluid of RA patients. The free radicals,
particularly NO and O, inhibit the synthesis of matrix components like proteoglycans by
chondrocytes and also damage the extracellular matrix through activation and up
regulation of matrix metalloproteinases. The HOCL produced by myeloperoxidase
(MPO) in neutrophils, chlorinate the tyrosine residues to form 3-chlorotyrosine and
damage the collagen, thus implicated in arthritogenesis. RA patients have increased
plasma MPO concentrations.

Elevated levels of MDA, NO, protein carbonyls, oxidized hyaluronic acid and oxidized
LDL have been reported in RA patients. These oxidized LDL can be ingested in large
quantities by monocytes results in the formation of Foam cells that are present in
atherosclerotic plaques of vessles and have also been found in RA synovial fluid.
Cigarette smoking is also considered as the most established environmental factor for
RA. Both particulate and gaseous phases of smoke contain high concentrations of free
radicals that can interact with DNA and could cause genetic mutations and activation
responsible for the development of RA.

41.95 Asthma

Free radicals are involved in various respiratory diseases such as respiratory distress
wyndrome, chronic obstructive pulmonary disease, chronic bronchitis, asthma. Asthma
is the most common disorders of the airways of the lungs and is one of the major global
health problems. It is characterized by chronic inflammation of the airways involving
variable and ncurrent airflow obstruction and bronchial hyper activity associated with
airway remodelling Airway remodeling is a dynamic process involving mucous
hypersecretion, collagen deposition, wall thickening, myocyte hypertrophy and
hyperplasia, myo broblasthy perplasia, vascular proliferation and alterations in airway
elastic fibers, all of which culminate in persistent structural alterations of the airway. NO
is endogenously produced in mammalian airways by NOS and is known to regulate
many aspects of human asthma, including modulation of airway and vascular
smoothmuscle tone and the inflammation. Increased production of airway NO is a key
factor in the development of airway hyper responsiveness.

RCS are produced both intracellularly by lung parenchymal cells and extracellularly by
lung macrophages. Increased generation of oxidants have been reported in asthma
patients than in healthy individuals who provoked airway inflammation by inducing
diverse pro inflammatory mediators including macrophages, neutrophils and
eosinophils. Numerous studies have suggested that oxidative stress is caused by
overproduction of various free radicals or by an insufficient antioxidant defense system
in asthma and thus it contributes to the tissue damage which is induced by
inflammatory cells. Elevated levels of oxidative stress markers such as H2O2,
8-isoprostane, nitric oxide, and carbon monoxide were reported in exhaled air of
asthmatic patients. Increased MDA levels, and Protein carbonyls; decreased protein
sulfhydryl and antioxidant activity were observed in plasma, broncho alveolar lavage
(BAL) fluid and exhaled air of asthamatic patients

4.1.10 FREE RADICAL THEORY OF AGING

The free radical theory of aging arose in 1954 from a consideration of the aging
information from the premise that a single common process; modifiable by genetic
evidence and environmental factors, was responsible for the aging and death of living
things. The theory postulates that aging is caused by free radical reactions i.e. these
non-specific, essentially neversible reactions may be involved in production of aging
changes associated with the environment, disease and an intrinsic aging process. It
predicts that the life span of an organism can be increased by slowing the rate of
initiation of random free radical reactions and/or decreasing their chain length. The
former should be achieved by decreasing ingestion of easily oxidized dietary
components, calorie intake and temperature, the latter should be achieved by increasing
the concentration of free radical inhibitors in the organisin ee by increasing the
resistance of its constituents to free radical attack.

42 ANTIOXIDANT

In foods, antioxidants have been defined as 'substances that in small quantities are able
to prevent or greatly retard the oxidation of easily oxidisable materials such as fats,
therefore, in food science antioxidants are usually equated with chain-breaking
inhibitors of lipid peroxidation, but not exclusively so. Many antioxidants have been
studied and are used in a wide range of foods including beverages. Therefore, for foods
and beverages, antioxidants are molecules that can be equated with the protection of
macromolecules from oxidation. In biological systems the accepted definition is that
antioxidant is any substance that, when present at low concentrations compared to
those of an oxidisable substrate, significantly delays or prevents oxidation of that
substrate. This is a broader definition encompassing many vulnerable macromolecules
(eg. DNA, lipids and proteins) that can be affected by oxidation. In biological terms, it is
accepted that any molecule that can retard or prevent the action of oxidants could be
considered to be an antioxidant. Such a broad definition means that compounds that
inhibit specific oxidizing enzymes, react with oxidants before they damage molecules,
sequester dangerous metal ions or even repair systems such as in transport proteins,
can fit the definition. Antioxidants can also be defined as substances that trap harmful
forms of oxygen and prevent them from damaging cells. Mechanistic definitions of
antioxidants are usually focused on the ability to be a hydrogen donor or an electron
donor. Many of the frequently cited assays of antioxidant capacity can be broadly
categorized as either hydrogen transfer assays or single electron transfer reaction based
assays. These assays measure the radical scavenging capacity or the reducing ability,
respectively, not the preventative antioxidant capacity of the sample.

4.2.1 ANTIOXIDANTS PROCESS

Antioxidants block the process of oxidation by neutralizing free radicals. In doing so, the
antioxidants themselves become oxidized. How do they work? The two possible
pathways are chain-breaking and preventive 25 Chain-breaking: When a free radical
release or abstracts an electron, a second radical is formed. This molecule then turns
around and does the same thing to a third molecule, continuing to generate more
unstable products. The process continues until termination occurs, either the radical is
stabilized by a chain- breaking antioxidant such as carotene and vitamins C and E, or it
simply decays into a harmless product. Preventive: Antioxidant prevents oxidation by
reducing the rate of chain initiation. That is, by scavenging initiating radicals, such
antioxidants can thwart anoxidation chain from ever setting in motion. They can also
prevent oxidation by stabilizing ansition metal radicals such as copper and iron.

42.2 MECHANISMS

If a compound inhibits the formation of free alkyl radicals in the initiation step, or if the
chemical compound interrupts the propagation of the free radical chain, the compound
can delay the start or slow the chemical reaction rate of lipid oxidation. The initiation of
free radical formation can be delayed by the use of metal chelating agents, singlet
oxygen inhibitors and peroxide stabilizers. The propagation of free radical chain
reaction can be minimized by the donation of hydrogen from the antioxidants and the
metal chelating

42.3 TYPES OF ANTIOXIDANTS

Antonidant system includes, antioxidant enzymes (eg. SOD, GPs and reductase, CAT,
etc.), trient-derived antioxidants (eg, ascorbic acid, tocopherols and tocotrienols,
carotenoids, glutathione and lipoic acid), metal binding proteins (eg, ferritin, lactoferrin,
albumin, and ceruloplasmin) and numerous other antioxidant phytonutrients present in
a wide variety of plant foods. Dietary antioxidants, such as water-soluble vitamin C and
phenolic compounds. as well as lipid-soluble vitamin E and carotenoids, present in
vegetables contribute both to the first and second defense lines against oxidative stress.
The main source for dietary ptake of vitamin E is plant food (vegetables, fruits, seeds,
and seed oils). Sunflower seeds, olive oil and almonds are rich sources of a tocopherol.
While other seeds and seed oils generally contain more y-tocopherol than a-tocopherol,
the opposite is true for green leaves.B-Tocopherol and 8-tocopherol are the least
abundant, and so, in general, are the different tocotrienols

4.2.4 NATURAL ANTIOXIDANTS

Natural antioxidant system is sorted in two major groups, enzymatic and non-
enzymatic Non-enzymatic antioxidants: Non-enzymatic antioxidants include direct
acting antioxidants, which are extremely important in defence against oxidative stress.
Most of them, including ascorbic and lipoic acid, polyphenols and carotenoids, are
derived from dietary sources. The cell itself synthesises a minority of these molecules.
Indirectly acting antioxidants mostly include chelating agents and bind to redox metals
to prevent free radical generation.

The antioxidant reaction of a-tocopherol is not a reaction with oxygen. Many molecules
react with oxygen, but they do so without being antioxidants. B-Carotene, for example,
readily reacts with oxygen, but it is by no means an efficient antioxidant. The basis of an
antioxidant reaction is not the removal of oxygen but the interception of the
autoxidation radical chain process which is not perpetuated by oxygen but by the fatty
acid. 1. p- Carotene

Carotenoids are a widespread group of naturally occurring fat-soluble colorants.

Carotene (BC) is a naturally occurring orange-colored carbon-hydrogen carotenoid,
abundant in yellow-orange fruits and vegetables and in dark green, leafy vegetables. It is
also the most widely distributed carotenoid in foods. BC undergoes trans (E) to cis (2)
isomerization, whereas the (all-E)-form is the predominant isomer found in
unprocessed carotene rich plant foods.

2. Phenolic antioxidants

Phenolic compounds, especially flavonoids, possess different biological activities, but

the most important are antioxidant activity, capillary protective effect, and inhibitory
effectFree elicited in various stages of tumour. Phenolics are able to scavenge reactive
oxygen species due to their electron donating properties. Their antioxidant effectiveness
depends on the stability in different systems, as well as number and location of hydroxyl
groups. x Selenium

Selenium (Se) is an essential trace element and its deficiency in humans has been linked
to increased risk of various diseases, such as cancer and heart diseases. Good food
sources of selenium include fish, shellfish, red meat, grains, eggs and chicken. Vegetables
can also be a good source if grown in selenium-rich soils. This mineral is thought to help
fight cell damage by oxygen-derived compounds and thus may help protect against
cancer. It is best to get selenium through foods, as large doses of the supplement form
can be toxic. The level of Se generally depends on its level in soil.84 Selenium is a
mineral, not an antioxidant nutrient. However, it is a component of antioxidant enzymes.
4. Enzymatic antioxidants

Antioxidant enzymes are capable of stabilising, or deactivating free radicals before they
attack cellular components. They act by reducing the energy of the free radicals or by
giving up some of their electrons for its use, thereby causing it to become stable. In
addition, they may also interrupt with the oxidising chain reaction to minimize the
damage caused by free radicals. By reducing exposure to free radicals and increasing the
intake of antioxidant enzyme rich foods or antioxidant enzyme supplements, our body's
potential to reducing the risk of free radical related health problems is made more
palpable. Antioxidant enzymes are, therefore, absolutely critical for maintaining optimal
cellular and systemic health.

4.2.5 ENDOGENOUS ANTIOXIDANTS

Oxidative stress (OXS) constitutes a disturbance caused by an imbalance between the

generation of free radicals and antioxidant system, which causes damage to
biomolecules. This, in turn, may lead the body to the occurrence of many chronic
degenerative diseases. Therefore, it is very important to know the functioning of those
endogenous antioxidants systems to prevent such diseases. To understand the role of
the transcription factor NrF; in regulating the processes of antioxidant defence, it must
also know the role of many of the endogenous antioxidants that occur because of its
activation.

Endogenous antioxidants are made by our bodies. Because they are produced by our
own bodies and not obtained from food sources, endogenous antioxidants are far more
potent than exogenous antioxidants. Endogenous antioxidants repair all of the free
radical damage by initiating cell regeneration from the inside on out

42.5.1 Enzymatic and non-enzymatic antioxidant defence

Different types of the oxidants produced in cells require that cells have different types of
antioxidants defence parameters. The major cellular antioxidant are enzymatic
substances such as super oxide dismutase (SOD), Se-dependent glutathione peroxidase
(GPX), catalase (CAT), glutathione reductase(GR) and various non-enzymatic low
molecular substances such as: glutathione, retinoids, carotenoids, ascorbicacid,vitamin
E, albumin, uric acid, bilirubin, transferrin, ceruloplasmin which act as various
scavengers for different types of reactive oxygen species.

SOD, glutathione peroxidase and catalase are the key enzymatic antioxidants of this
defence system by which the free radicals that are produced during metabolic reactions
are removed. Antioxidants present in cells, function to prevent the damage done by
oxidative stress Non enzymatic antioxidants work by interrupting free radical chain
reactions. The non- enzymatic antioxidants are represented by molecules characterised
by the ability to rapidly inactivate radicals and oddants

4.2.5.2 Superoxide dismutase (SOD)

Superoxide dismutase is an enzyme that helps breakdown potential harmfull oxygen

molecules in cells, which might prevent damage to tissues. It is being researched to see if
it can help conditions where oxygen molecules are believed to play a role in disease. The
foods are rich sources of SOD, such as broccoli, cabbage, or barley grass, are also good
sources of minerals (Zn,Cu and Mn) that our bodies use to make our own SOD These
antioxidant enzymes serve as the body's most potent defense against free radicals and

ensuring inflammatory reactions. In short they play an important role in reducing the

oxidative damage and inflammation.

SOD are a group of key enzymes functioning as the first line of antioxidant defense by
the virtue of the ability to convert highly reactive superoxide radicals (dismutation) into
hydrogen peroxide and molecular oxygen. They have identified four isozymes of SOD

1) SODI is a metalloprotein binding Cu and Zn ions that are localized in the cytosol of the
cell. 2) SOD2 localize in the mitochondria and it is associated with Mn or Fe ions.

3) SOD3 localization is extracellular and also associated with Cu, Zn although it has a
high molecular weight and it has high affinity for heparin and heparin sulphates. 4)
SOD4 associated with Ni and found in various aerobic bacteria found in soil of class of
streptomyces
1233 Catalase

Catalase use in cheese production. The enzyme catalase is known to catalyse the
breakdown d hydrogen peroxide into oxygen and water. Hydrogen peroxide metabolism
is mainly regulated by this enzyme. Catalase is a common enzyme found in nearly all
living organisms. ilt has one of the highest turnover of all enzymes as it has the capacity
to decompose more than one million molecules of hydrogen peroxide per molecule of
enzyme. is used as an important enzyme in many in many biotechnological areas
including bioremediation.

Catalase is the tetrameric porphyrin containing enzyme that is located mainly in

peroxisomes. It catalases the conversion of hydrogen peroxide to water and molecular
oxygen in two steps

Catalase-Fe (III)+ H:0,→ Compound (D) Compound (1)+ H₂O: Catalase-Fe (III) + 2H₂O
+0,

Catalase along with other antioxidant enzymes have been considered as biomarkers of
anidative stress in various organs. 4234 Glutathione Peroxidase (GPx)

This enzyme can exist in two forms: Selenium- dependant and selenium - independent.
each different subunits and different active sites. GPx catalyses reduction of hydrogen
peroxide or organic peroxide (ROOH) to water or alcohol, this process occur in the
presence of GSH, which is converted into GSSG (oxidised glutathione peroxidase) during
this reaction. The reaction has special significance in the protection of polyunsaturated
fatty acid located within the cell membrane where the enzyme function as a part of a
multicomponent antioxidant defense system within the cell. There are four isoforms in
humans: () cytosol and mitochondria (GPx1) (1)cytosol (GP-2) (i)extracellular (GP3)
(iv) phospholipid peroxide (GPx4). The kidney and liver are the organs with the highest
amount of GPx. Found that in many other organs and tissues, such as the dorsal root
ganglion the GPx is the first enzyme that is activated under high level of EROS, indicating
the importance of this enzyme has a first line of defence against stress oxidative.

4253 Glutathione

GSH/Glutathione (GSH-L-r-glutamyl-l-cysteinyl-glycine) is a non-protein thiol that

reaches millimolar concentrations in most cell types. It's reduced form is biologically
active. It functions as an antioxidant defense against reactive yg or nitrogen species
(ROS/RNS) as also with detoxication enzymes like GSH perodases and GSH-S
transferases. The GSH / Glutathione disulfide is the major redox couple in animal cell.

Mitochondrial production is exerted by GSH vs radical and oxidant species by the

contribution of a group of nutrients that can directly or indirectly protect mitochondria
from oxidative damage and improve mitochondrial function Other mechanisms includes
increasing cofactors of mitochondrial enzymes that increase the kinetic constant of
enzyme activity, which represent protecting mechanisms from further cxidation.
42.54 Viamin C-ascorbic acid
Vitamin C lascorbic acid and ascorbate) is a six-carbon lactone which is synthesized
from ghose by many animals. Vitamin C is a water-soluble vitamin. As such, it scavenges
free radicals that are in an aqueous (water). When there is insufficient vitamin C in the
diet, humans suifer from the potentially lethal deficiency disease scurvy.

Vitamin C is an electron donor (reducing agent or antioxidant), and probably all of its
biochemical and molecular functions can be accounted for by this function. Vitamin C
acts as an electron donor for 11 enzymes. Gastric juice vitamin C may prevent the
formation of N- nitroso compounds, which are potentially mutagenic. High intakes of
vitamin C correlate with reduced gastric cancer risk, but a cause and effect relationship
has not been established. Vitamin C protects low-density lipoproteins ex nie against
oxidation and may function similarly in the blood.

Vitamin C plays an important role in the production of collagen. Collagen gives your skin
elastic properties. As people get older, their skin contains lower levels of collagen. Most
anti- aging creams, therefore, include plenty of Vitamin C. This keeps the skin young and
healthy by improving elasticity. A common feature of vitamin C deficiency is anaemia.
The antioxidant properties of vitamin C may stabilize folate in food and in plasma, and
increased excretion of oxidized folate derivatives in human scurvy was reported. But the
ascorbic acid free radical is very stable because of its resonance structure, ommon
feature of vitamin C deficiency is anaemia. The antioxidant properties of vitamin C may
stabilize folate in food and in plasma, and increased excretion of oxidized folate
derivatives in human scurvy was reported. Vitamin C promotes absorption of soluble
non-haem iron possibly by chelation or simply by maintaining the iron in the reduced
(ferrous, Fe2+) form. The effect can be achieved with the amounts of vitamin C obtained
in foods. Antioxidant foods and ingredients are an important component of the food
industry. In the past, antioxidants were used primarily to control oxidation and retard
spoilage, but today many are used because of putative health benefits. However the
traditional message that oxidative stress, which involves the production of reactive
oxygen species (ROS), is the bases for chronic diseases and ageing is being re-examined.
It is imperative that the food industry be aware of progress in this field to present the
science relative to foods in a forthright and clear manner. This may mean re-examining
the health implications of adding large amounts of antioxidants to foods. Ascorbic acid
can act as an antioxidant owing to its ability to react with free radicals, undergoing a
single electron oxidation to yield poorly reactive intermediate, the ascorbylFree Radicals
in Various Disease Prevention

251

madal which disaproportionates to ascorbate and dehydroascorbate Thus, ascorbic acid

can react with the toxic, reactive oxygen species superoxide anion and hydroxyl radical
De antioxidant effienciency of ascorbic acid is greatest at low concentration of the
vitamin Vitamin C is an electron donor and this property accounts for all its known
functions. As an electron donor, Vitamin C is potent water-soluble antioxidant in
humans. Vitamin C is essary for growth, development and repair of all body tissues. It is
involved in many body functions of collagen, absorption of iron, the immune system,
wound healing and the maintenance of cartilage, bones and teeth.

Vitamin E

Vitamin E is a generic description for all tocopherol (Toc) and tocotrienol (Toc-3)
derivatives. Tocopherols have a phytyl chain, while tocotrienols have a similar chain but
with three duble bonds at positions 3,7 and 11. Both tocopherols and tocotrienols have
four isomers, designated as a-, -, y and &, which differ by the number and position of
methyl groups on the chroman ring. All of these -amolecules possess antioxidant
activity, although tocopherol -Toc) is chemically and biologically the most active
a-Tocopherol is the major vitamin E in wo and exerts the highest biological activity.
Tocopherols are present in polyunsaturated vegetable oils and in the germ of cereal
seeds, whereas tocotrienols are found in the aleurone and subaleurone layers of cereal
seeds and in palm oils.

Vitamin E functions solely as a lipid antioxidant or whether it may also be required for
the function of some other critical but unkown metabolic factor, current information
indicates that all of its nutritional effects are consistent with its role as a biological
antioxidant Vamin E is thought to have basic functional importance in the maintenance
of membrane integrity in virtually all cells of the body It's antioxidant function involves
the reduction of the radicals, thus protecting against the potentially deleterious
reactions of such highly mactive oxidising species.

Tocopherols/Vitamin E molecule is a fat soluble vitamin 8 forms that important

antioxidant Vitamin E is often used in skin creams and lotions because it is believed to
play a role in couraging skin healing and reducing scarring after injuries such as burns
Alpha Tocopherol is the most active form of vitamin E in humans, and is a powerful

biological antinidant 4238-Lipoic add

Alpha lipoic acid is a short chain fatty acid which contains sulphur in their structure. It is
a potential antionidant. Alpha lipoic acid can deliver antioxidant activity in nonpolar and
polar mediums and present antioxidant effects in it's oxidized (LA) and reduced (DHLA)
I dihydrolipocacid) forms LA can actuate its antioxidant effect in any subcellular
compartment of the body, and it is effective in recharging enzymes in the mitochondria.
Diabetes mellitus and neuro degenerative diseases can be controlled with LA due to the
antioxidant properties of lipoate or dihydrolipoatesystem, influencing tissue
concentration of reduced forms of other antioxidants

4.2.39 Melatonin

Melatomin's Functions as an antioxidant includes

a) Direct free radical scavenging Stimulation of antioxidative enzymes

o Increasing the efficiency of mitochondrial oxidative phosphorylation and reducing

electron leakage and augmenting the efficiency of other antioxidants. The role of
melatonin as a powerful antioxidant may extend into the inner reaches of the cell, the
mitochondria.

Melatonin functions as an apex antioxidant or the main antioxidant. It scavenges free

radicals, induces the production of other antioddant enzymes and helps to make energy

4.2.6 SYNTHETIC ANTIOXIDANTS

inherent instability of natural antioxidants, several synthetic antioxidants have been

used to

producing reaction more efficient so fewer free radicals are formed. Synthetic
antioxidants are chemically synthesized compounds since they do not occur in nature
and are added to food as preservatives to help prevent lipid oxidation. Due to
thestabilize fats and oils. Butylated hydroxytoluene (BHT) and butylated hydroxyanisole
(BHA) were originally developed to protect petroleum from oxidative gumming.
However, these compounds have been used as antioxidants in human foods since 1954
and are perhaps the most common antioxidants used in those foods today. BHIT and
BILA not only have similar names, but similar structures and antioxidant activity and
are often used together in fats and oils Despite the fact that both BHIT and BHA are
included in the list of substances that are "generally accepted as safe". BHA and BHT,
may both be important inhibitors of carcinogenesis, probably by way of their
antioxidant function. Thus, there have been some attempts to remove these
antioxidants, TBHQ (tert-butylhydroxyquinone) is another synthetic antioxidant which
is widely used in the feed industry. Like BHT and BHA. TBHQ has a benzene ring or
phenol structure. Other examples of synthetic antioxidants are propyl gallate (PG),
dodecyl gallate (DG), octylgallate (OG) and ethylene diaminetetraacetic acid

1) Batylated hydroxy Toulene (BHT)

Batylated hydroxy toluene (BHT) is a most commonly used antioxidant recognized as

safe for use in foods containing fats, pharmaceutically, petroleum products rubber and
oil industries. In accelerating the antioxidant discovery process researchers have
designed and synthesized a series of BHT derivatives targeting to improve its
antioxidant properties to be having a wide range of antioxidant activities markedly
enhanced radical scavenging abay and other physical properties. Butylated hydroxy
anisole intended to be used as an antioxidant in feeding stuffs for a animal species and
categories BILA is rapidly absorbed from the gastrointestinal tract it

21 Matylated hydroxy anisole (BHA)

metabolise rapidly and excreted as such and as metabolites in the urine and fances

43 FUNCTIONAL FOODS FOR CHRONIC DISEASE PREVENTION

Functional foods describe the importance of foods in promoting health and preventing
diseases aside their primary role of providing the body with the required amount of
essential nutrients such as proteins, carbohydrates, vitamins, fats, and oils needed for its
healthy survival This review explains the interaction of functional food bioactive
compounds including polyphenols (phenolic acids hydroxybenzoic acids and
hydroxycinnamic acids), flavonoids [flavonols, flavones, flavanols, flavanones,
isoflavones proanthocyanidins), stilbenes, and lignans), terpenoids, carotenoids,
alkaloids, omega-3 and polyunsaturated fatty acids, among others with critical enzymes
(a-amylase, a-glucosidase, angiotensin-converting enzyme [ACEL acetylcholinesterase
[ACHEL and arginase) linked to some degenerative diseases (type-2 diabetes,
cardiovascular diseases Ihypertension neurodegenerative diseases [Alzheimer's
diseasel and erectile dysfunction). Different functional food bioactive compounds may
synergistically/additively confer an overwhelming protection against these
degenerative diseases by modulating/altering the activities of these critical enzymes of
physiological importance

Chronic disease, including cardiovascular disease (CVD), cancer and diabetes cause
substantial disability and death. For example, CVD accounted for 30% of all deaths in the
United States during 2004, with direct and indirect cost of CVD in the United States for
2008 estimated at $448.5 billion. Major modifiable risk factor CVD includes high blood
pressure high blood cholesterol, tobacco use, diabetes, physical inactivity, and poor
nutrition. The role of diet and nutrition as determinants of chronic diseases is well

recognized. The evolution of human diet

over the past 10,000 years has adversely affected a number of dietary parameters
known to be related to health, including glycemic load, fatty acid composition,
macronutrient composition, micronutrient composition, acid/base load,
sodium-potassium ratio and fibre content.

Many of antioxidant compounds possess anti-inflammatory, antiatherosclerotic,

antitumor, antimutagenic, anticarcinogenic, antibacterial and antiviral activities to
greater or lesser extent. In many cases, increased oxidative stress is a widely associated
in the development and progression of diabetes and its complications which are usually
accompanied by increased production of free radicals or failure of antioxidant defense.
Though the intake of natural antioxidants has been reported to reduce risk of cancer,
cardiovascular diseases, diabetes and other diseases associated with aging, Leukocytes
and other phagocyte destroy bacteria, parasites and virus-infected cells with NO, O HO,
and OCI-, which are powerful oxidants and protect humans from infection. However,
they also cause oxidative damage and mutation to DNA and participate in the
carcinogenic process if remain unchecked.

Health benefits and risks

Due to the power of natural antioxidants to prevent the generation of free radicals, it is
found that they are particularly useful in preventing certain diseases. However, though it
is apparent that natural antioxidants have many positive effects on health, it should also
be taken into consideration that they could also have harmful effects if taken in excess