This document provides an overview of free radicals and oxidative stress. It discusses how free radicals are generated endogenously through normal cellular processes and exogenously through environmental exposures. Free radicals can be both beneficial at low levels through cell signaling, but harmful at high levels by damaging cellular components like DNA, lipids, and proteins. This oxidative damage is implicated in many chronic diseases like cancer, cardiovascular disease, neurodegenerative diseases, and arthritis. The body produces antioxidant enzymes and obtains antioxidants from food sources to counteract oxidative stress. Common dietary antioxidants discussed include vitamins C and E, beta-carotene, and others.

1. UNIVERSITY OF BAGHDAD – COLLEGE OF MEDICINE
2018
Free Radicals
CLS - Pathology
MO H A M M E D AL I BA S S I M

2. 1
CONTENTS:
1. Introduction ……………….………………………...... 2
2. Generation of free radicals …………………………... 3
3. Beneficial effects of free radicals ……………………. 5
4. Harmful effect of free radicals on cellular level ……. 6
5. Free radicals and pathogenesis ……………………… 8
 Cancer and oxidative stress
 Cardiovascular disease and oxidative stress
 Neurodegenerative disease and oxidative stress
 Ocular disease and oxidative stress
 Kidney disease and oxidative stress
 Rheumatoid arthritis and oxidative stress
 Fetus and oxidative stress
6. Antioxidants ………………………………………… 12
7. Antioxidant process ………………………………… 14
8. Common nutrient antioxidants …………………….. 15
 Vitamin E
 Vitamin c
 Beta-carotene
 Lycopene
 Selenium
 Flavonoids
 Omega-3 and omega-6 fatty acids
9. Summary ………………………..…………………… 21
10.References …………………………………………… 22

3. 2
Introduction
Oxygen is an essential and fundamental term for life. Cells use oxygen to
produce energy for normal cell activities, Free radicals are normal
consequence of ATP production in the mitochondria. These by-products
are in general reactive oxygen species (ROS) and reactive nitrogen
species (RNS). These two species are referred collectively as ROS/RNS.
The phrases "free radicals" and "reactive oxygen species" (ROS) are
frequently used interchangeably although this is not always correct. The
physiological state of increased steady-state ROS level along with certain
physiological effects has been called oxidative stress. These species play
a dual role. As benefit compounds at low or moderate levels. And as toxic
compounds at high concentrations by generation of oxidative stress .The
delicate balance between their two antagonistic effects is clearly an
important aspect of life [1-5]. Free radicals are, by definition, species
which contain an odd number of electrons. They may be positively
charged, negatively charged, or neutral and all three types are important
[6].
)1(Fig
Oxidative stress plays a major role in the development of chronic and
degenerative diseases such as cancer, arthritis, aging, autoimmune

4. 3
disorders, cardiovascular and neurodegenerative diseases. The human
body has several mechanisms to face the oxidative stress by producing
antioxidants, which are either naturally produced in the body, or supplied
from out the body through foods and/or supplements. Endogenous and
exogenous antioxidants act as “free radical scavengers” by preventing
and repairing damages caused by ROS/RNS, and therefore can improve
the immune defense system and lower the risk of cancer and degenerative
diseases [7-11].
:Generation of free radicals
ROS/RNS are generated from either exogenous or endogenous sources.
Exogenous ROS/RNS result from: air and water pollution, cigarette
smoking (both active and passive), cars smoke, alcohol, heavy or
transition metals like lead and mercury, certain drugs such as
cyclosporine and gentamycin, industrial solvents, cooking (smoked meat,
used oil.) and ionizationg radiation like UV [12]. After the penetration
and entrance of these exogenous compounds into the body by different
routes, they decomposed or metabolized into free radicals.

5. 4
]13[2FIGURE
Endogenous free radicals formation, are continuously happen in the cells
as a consequence of both enzymatic and non-enzymatic reactions.
Endogenous free radicals are produced in the body by four different
mechanisms: first, from the normal metabolism of oxygen requiring
nutrients [14]. Secondly, white blood cells (WBC) destroy parasites,
bacteria and viruses by using oxidants (free radicals) such as nitric oxide,
super oxide and hydrogen peroxide. This is done by the release of free
radicals into the phagolysosomes inside the white blood cell to destroy
invading pathogenic microbes as a part of the body’s defense mechanism
against diseases [15]. Thirdly other cellular components called
peroxisomes produce hydrogen peroxide as a by-product of the
degradation of fatty acids and other molecules [16]. Finally an enzyme in
the cells called cytochrome P450 is one of the body’s primary defenses
against toxic chemicals ingested with food (detoxification).

6. 5
FIGURE 3 [17]
:eneficial effects of free radicalsB
At low or moderate level, ROS and RNS are necessary to the cellular
structures to maturate and can act as weapons for the host defense system.
In fact, phagocytes like monocytes, microphages and neutrophils release
free radicals to kill the pathogens inside them as a part of the body
defense mechanism against invading pathogenic microbes [18].

7. 6
FIGURE 4 [19]
The importance of ROS in the body is clearly exemplified in the patients
with chronic granulomatous disease (CGD). A diverse group of
hereditary diseases in which certain cells of the immunity system are
incapable to generate ROS (most important the superoxide (O2
•–
)) due to
defect in NADPH oxidase phagocyte system, thereby resulting to the
formation of granulomata and persist infection in many organs [20,21].
Other benefits of ROS and RNS involve important roles in cell signaling
and homeostasis [22]. As a brief, low or moderate levels of free radicals
are vital to human health.
:cellular levelonarmful effects of free radicalsH
Free radicals are normally in balance in the body, but when free radicals
produced in excess amount or failure of body to neutralize the free
radicals, a state of oxidative stress occur, a deleterious state that alter and

8. 7
damage the cell structures. In general the harmful effects of these ROS
are most often:
1. Damage of nucleic acid RNA and DNA.
2. Lipid peroxidation.
3. Oxidation of amino acids of proteins
4. Deactivation of certain enzymes by oxidation of co-factors [23].
Lipid peroxidation is an oxidative degradation of lipids (especially
polyunsaturated fatty acids) in which a free radical steal electrons the
lipids, resulting in damage of lipid membrane of the cell. This process
lead to the formation of malondialdehyde (MDA) which is a reactive and
potential mutagenic compound [24].Proteins also are targets, which it
may be damaged by these ROS, lead to structural changes and loss of
enzyme activity as well as damaging the cytoskeleton of the cell.
Oxidative damage to DNA leads to many oxidative DNA lesions which
can cause DNA mutations.
FIGURE 5 [25]

9. 8
:Free radicals and pathogenesis
The body has many mechanisms to counteract these harmful attacks, but
if the balance not regulated properly, accumulative oxidative stress
induces a variety of chronic and degenerative diseases as well as aging
process.
Cancer and oxidative stress:
Oxidative stress is linked to age-related cancer development. Free
radicals are mutagenic that cause direct damage to the DNA. At low level
ROS promotes cancer cell survival and progression due to that cell cycle
progression regulated by growth factors and tryrosine kinase receptors
need modest level of ROS for activation as well as that chronic
inflammation a major mediator of cancer is regulated by ROS [26]. On
the other hand high levels of ROS suppress the cancer cells growth by the
sustained activation of cell cycle inhibitors and by causing the cancer
cells to death that is a result of damaging the macromolecules [27, 28]. In
deed most of chemotherapeutic and radiotherapy agents kill the cancer
cells by increasing the ROS stress. Then moderate or modest level of
ROS is required for cancer cells survival, whereas high levels kill them.
Also ROS play role in invasiveness and metastasis of cancer cells [29,
30].
Cardiovascular disease and oxidative stress:
Oxidation stress has negative outcomes related to cardiovascular diseases
[31]. Oxidation stress can cause cardiovascular disease by its harm
influence on the endothelial layer of blood vessels [32]. It can cause
injury by oxidizing cellular constituents, disruption of proteins and by
diminishing nitric oxide bioactivity. Blood sample from ischemic heart

10. 9
disease patients has been shown to contain evidence of oxidative stress
agents in the blood sample [33]. ROS are implicated in atherosclerosis
process, including oxidative modification of low protein density (LDL)
before being atherogenic and endothelial dysfunction [34].
FIGURE 6 [35]
Neurodegenerative disease and oxidative stress:
The brain uses up to 20% of the body's inspired oxygen due to high
activity of the brain.
Thus, oxidative stress is likely to occur in it. Oxidation stress is
suspected to play important role in neurodegenerative diseases including
Alzheimer's disease, Parkinson's disease, Huntington's disease ,
Depression, and multiple sclerosis [36,37].In a case of Alzheimer's
disease ,many studies have demonstrated that oxidative stress play key
role in loss of neurons and the progression to dementia [38]. B-amyloid
production, which is toxic peptide found in brains of Alzheimer patients

11. 10
is due to oxidative stress in the brain and plays an important role the
degenerative process of disease [39].
Ocular disease and oxidative stress:
Oxidative stress is involved in age related macular degeneration and
cataract by altering the photosensitive and non photosensitive cells of the
eye [40]. Free radicals act on the crystalline proteins in the lens and
aggregate and cross link them causing cataract [41]. In retina prolonged
exposure to radiation can cause inhibiting mitosis the retinal pigmented
epithelium (RPE), choroids and photoreceptors outer segmented has been
associated with lipid peroxidation [42].
Kidney disease and oxidative stress:
Oxidative stress plays a major role in many diseases of kidney like
nephritis, proteinuria, chronic renal failure and glomerular diseases [43].
Many drugs cause nephrotoxicity mainly because increasing of oxidative
stress by lipid peroxidation like some antibiotics and chemotherapy drugs
[44]. Also many heavy and transmitted metals such as lithium, lead and
mercury are strong free radicals inducers that induce many different
forms of nephropathy and carcinogenicity.
Rheumatoid arthritis and oxidative stress:
Rheumatoid arthritis (RA) is a long term autoimmune disorder affects
joints characterized by chronic inflammation [45]. Pathogenesis of RA is
due to generation of free radicals at the side of inflammation. Oxidative
damage and inflammation were proved in various rheumatic diseases by
increasing levels of isoprostanes (prostaglandin like compounds formed
from catalyzed peroxidaton by free radicals of essential free fatty acids)

12. 11
and prostaglandins in synovial fluid and serum compared with normal
[46].
Fetus and oxidative stress:
Oxidative stress is involved in many mechanisms of fetal growth
restriction and pre-eclampsia [47]. Some reports indicate that there are
elevated blood levels of lipid peroxidation products (MDA and
isoprostanes) in pre-eclamptic pregnancy and intrauterine growth
retardation. That has been suggested that free radicals play some role in
the causing of these conditions [48].
Overall, free radicals have been implicated in the pathogenesis of at least
50 diseases.

13. 12
FIGURE 7 [49]
:ANTIOXIDANTS
The body has several mechanisms to counteract the free radicals and
prevent damage cause by them on the body cells by producing
antioxidant. By definition antioxidant is simply, a molecule that inhibits
the oxidation of other molecules [50].

14. 13
FIGURE 8 [51]
Antioxidants can be classified into two major groups, enzymatic and non
enzymatic groups , non enzymatic group also can be divided into nutrient
antioxidants like ascorbic acid and into metabolic antioxidant like uric
acid. Some of these antioxidants are produced endogenously including
enzymes, enzymes cofactor and low molecular weight molecules. Also
many non enzymatic antioxidants are obtained exogenously from natural
food sources. These dietary antioxidants in role can be classified into
varies classes [52].

15. 14
FIGURE 9 [53]
:Antioxidant process
Antioxidants block the oxidation process by neutralizing the oxidative
stress, as a result, the antioxidants themselves become oxidized and that
is why we always need a constant replenish resources of antioxidants.
Two ways of action can be done by antioxidant. One is the chain-
breaking and the other is the prevention. For the chain breaking, when a
free radical steals an electron, a second radical is formed. This molecule
then turns around and does the same thing to third molecule, and this
mode of chain action continues to generate more and more unstable
products until either the free radical is stabilized by a chain-breaking
antioxidant such as vitamin E, C, beta carotene, or it simply decays into

16. 15
an inoffensive harmless product. Classic example of such this chain
reaction is lipid peroxidation. For the prevention way, antioxidant
enzymes like superoxide dismutase (SOD), catalase and glutathione
peroxidase (GPx) can prevent oxidation by reducing the rate of chain
initiation. That is, by scavenging the initiating free radicals, actually such
antioxidants can depress the oxidation chain from ever setting in motion.
They can also stabilize the transition metal radicals like copper and iron
[54].
:Common nutrient antioxidants
Antioxidants form dietary food play an important role in helping the
endogenous antioxidants for the neutralizing the oxidative stress.
Deficiency of nutrient antioxidant food is one of the causes of numerous
degenerative and chronic diseases. Each nutrient has its special and
unique structure and antioxidant properties [55].
Vitamin E
Vitamin E is a fat soluble vitamin that has high potent antioxidant action.
Vitamin E is a chiral compound with eight stereoisomers: α, β, γ, δ
tocopherol and α, β, γ, δ tocotrienol. Only α-tocopherol is the most
bioactive form in humans [56]. Due to the fat solubility, Vitamin E is the
safeguard of cell membranes from damage by free radicals. Its
antioxidant function mainly is the protection of lipid from peroxidation.
So, vitamin E has been proposed for the prevention against colon,
prostate and breast cancer, some cardiovascular diseases, ischemia,
cataract, arthritis and some neurodegenerative diseases like Alzheimer’s
disease [57].

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Top 10 vitamin E food list:
mg/100 g150Wheat germ oil
mg/100 g95Almond oil
mg/100 g44Canola oil
mg/100 g41Sunflower oil
mg/100 g34Safflower oil
mg/100 g26Almonds
mg/100 g19Wheat germ
mg/100 g15Hazelnuts
mg/100 g14Olive oil
mg/100 g8.4Peanut
]58[1TABLE
Important to mention that, cooking and storage may destroy the natural α-
tocopherol (vitamin E) in foods
:Vitamin C
Also known as ascorbic acid, is a water soluble vitamin. It is essential for
collagen, carnitine and neurotransmitters synthesis [59].
Health benefits of vitamin C are antioxidant, anti-atherogenic, anti-
carcinogenic, immunomodulator. The positive effect of vitamin C is
reducing the incidence of stomach cancer, and in preventing lung and
colorectal cancer. Vitamin C works synergistically with vitamin E to
quench free radicals and also regenerates the reduced form of vitamin E
[60].

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Top 10 vitamin C food list:
mg/100 g228.3Guavas
mg/100 g127.7Bell peppers
mg/100 g120Kale
mg/100 g92.7Kiwifruit
mg/100 g89.2Broccoli
mg/100 g60.9Papaya
mg/100 g60Snow peas
mg/100 g58.8Strawberries
mg/100 g53.2Oranges
mg/100 g22.8Tomatoes
]61[2TABLE
:carotene-Beta
Beta-carotene is a fat soluble member of carotenoids which considered as
provitamin because it can be converted to active vitamin A inside the
body. Beta-carotene is converted into retinol (also known as vitamin A1)
which is essentially for vision. Beta-carotene like other all caretenoids is
a powerful strong antioxidant and is the best quencher of singlet oxygen
[62].
Top 10 beta-carotene food list:
μg/100 g11509Sweet potato
μg/100 g8332Carrots
μg/100 g6288Dark green leafy vegetables (Spinach)
μg/100 g5226romaine lettuce
μg/100 g4570Butternut
μg/100 g2020Cantaloupe melon

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μg/100 g1624Sweet red peppers
μg/100 g2163Dried apricots
μg/100 g1250Peas (cooked)
μg/100 g929Broccoli (cooked)
]63[3TABLE
:Lycopene
Is a carotenoid, possesses antioxidant and anti-proliferative properties in
animal and in vitro studies on breast, prostate and lung cancer cell lines.
Also has anticancer activity but still controversial in humans [64]. Some
nutritionists even consider lycopene a stronger antioxidant than even
beta-carotene! Lycopene has been found to be very protective,
particularly for prostate cancer. Several studies have found associations
between high intake of lycopene and reduced incidence of prostate
cancer, though not all studies have produced consistent results [65]. In
addition diets rich in lycopene prevent heart disease, lower bad
cholesterol, work as anti-aging and slowing down degenerative diseases.
This is mainly due to the high level of antioxidant quality contained in it.
:Top 10 Lycopene food list
μg/100 g5204Guavas
μg/100 g4532Watermelon
μg/100 g3041Tomatoes (cooked)
μg/100 g1828Papaya
μg/100 g1135Grapefruit
μg/100 g484Sweet red peppers (cooked)
μg/100 g30Asparagus (cooked)

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μg/100 g20Red (purple) cabbage
μg/100 g3Mango
μg/100 g1Carrots
]66[4TABLE
:Flavonoids
Flavonoids are polyphenolic compounds which are present in most plants.
According to the chemical structure, over 4000 flavonoids have been
identified. Beneficial health effect is mainly due to their potent
antioxidant activity [67]. They have been reported to prevent or delay a
number of chronic and degenerative diseases such as cancer,
cardiovascular diseases, arthritis, aging, cataract, memory loss, stroke,
Alzheimer’s disease, inflammation, infection. Every plant contains a
unique combination of flavonoids, which is why different herbs, all rich
in these substances, have very different effects on the body [68].
Flavonoid-rich foods: red peppers, strawberries, citrus fruits, broccoli,
Brussels sprouts, Tropical fruits, garlic, spinach, cocoa, herbal teas. For
example, green tea is known to be the greater healthiest beverage on the
planet. Many health benefits of green tea reside it its powerful antioxidant
activity, anti-carcinogenic, antihypercholesterolemic, antibacterial and
anti-inflammatory activities [69].
Omega-3 and omega-6 fatty acids:
They are essential long-chain polyunsaturated fatty acids, human body
cannot synthesize them. They should be driven from diet. Omega-3 fatty
acids can be found in fish oils, algae, nut oils and walnut [70]. There are
three major dietary types of omega-3 fatty acids: eicosapentaenoic acid

21. 20
(EPA), docosahexaenoic acid (DHA) and alpha-linolenic acid (ALA).
EPA and DHA are abundant in fish and are directly used by the body;
while ALA is found in nuts and has to be converted to DHA and EPA by
the body. Dietary sources of omega-6 fatty acids include vegetable oils,
nuts, cereals, eggs, poultry. It is important to maintain an appropriate
balance of omega-3s and omega-6s in the diet, as these two substances
work together to promote health [71]. Omega-3 fatty acids help reduce
inflammation, and most omega-6 fatty acids tend to promote
inflammation. An inappropriate balance of these essential fatty acids
contributes to the development of disease while a proper balance helps
maintain and even improve health of the body. A healthy diet should
consist of about 2-4 times more omega-6s than omega-3s. In American
diet, omega-6s are 14-25 times more abundant than omega-3s, that
explains the rising rate of inflammatory disorders in the USA [72].
Omega-3s may also increase activity of antioxidant enzymes
manufactured by the body and prevent chronic ailments such as heart
disease, stroke, memory loss, depression, arthritis, cataract, cancer.
Omega-6s improve diabetic neuropathy, eczema, psoriasis, osteoporosis,
and aid in cancer treatment [73].

22. 21
:Summary
Free radicals are species contain one or more free electrons that are
produced in the body or introduced from an outside source. Free radicals
have necessary presence and beneficial duties in the body when they are
found in moderate levels. But when they accumulate in excessive
amounts in the body, problems begin.
The implication of oxidative stress in the etiology of several chronic and
degenerative diseases suggests that antioxidant therapy represents a
promising avenue for treatment in the future.
In the meantime, it is recommended to avoid oxidant sources and must be
considered as possible as taking diet rich in antioxidants and change our
lifestyle toward the right direction. Indeed, our health depends in a large
extent on our lifestyle choices.

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