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Oxidative stress is a normal phenomenon in the body. Under normal conditions, the physiologically important intracellular levels of reactive oxygen species (ROS) are maintained at low levels by various enzyme systems participating in the in vivo redox homeostasis. Therefore, oxidative stress can also be viewed as an imbalance between the prooxidants and antioxidants in the body. For the last two decades, oxidative stress has been one of the most burning topics among the biological researchers all over the world. Several reasons can be assigned to justify its importance: knowledge about reactive oxygen and nitrogen species production and metabolism; identification of biomarkers for oxidative damage; evidence relating manifestation of chronic and some acute health problems to oxidative stress; identification of various dietary antioxidants present in plant foods as bioactive molecules; and so on. This review discusses the importance of oxidative stress in the body growth and development as well as proteomic and genomic evidences of its relationship with disease development, incidence of malignancies and autoimmune disorders, increased susceptibility to bacterial, viral, and parasitic diseases, and an interplay with prooxidants and antioxidants for maintaining a sound health, which would be helpful in enhancing the knowledge of any biochemist, pathophysiologist, or medical personnel regarding this important issue.
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Review Article
Oxidative Stress, Prooxidants, and Antioxidants: The Interplay
Anu Rahal,
1
Amit Kumar,
2
Vivek Singh,
3
Brijesh Yadav,
4
Ruchi Tiwari,
2
Sandip Chakraborty,
5
and Kuldeep Dhama
6
1
Department of Veterinary Pharmacology and Toxicology, Uttar Pradesh Pandit, Deen Dayal Upadhayay Pashu
Chikitsa Vigyan Vishwa Vidyalaya Evam Go-Anusandhan Sansthan (DUVASU), Mathura 281001, India
2
Department of Veterinary Microbiology and Immunology, Uttar Pradesh Pandit, Deen Dayal Upadhayay Pashu
Chikitsa Vigyan Vishwa Vidyalaya Evam Go-Anusandhan Sansthan (DUVASU), Mathura 281001, India
3
Department of Animal Husbandry, Kuchaman, Rajasthan 341508, India
4
Department of Veterinary Physiology, Uttar Pradesh Pandit, Deen Dayal Upadhayay Pashu Chikitsa Vigyan Vishwa
Vidyalaya Evam Go-Anusandhan Sansthan (DUVASU), Mathura 281001, India
5
Animal Resources Development Department, Pt. Nehru Complex, Agartala 799006, India
6
Division of Pathology, Indian Veterinary Research Institute, Izatnagar, Bareilly 243122, India
Correspondence should be addressed to Amit Kumar; balyan@gmail.com
Received  May ; Revised November ; Accepted November ; Published  January 
AcademicEditor:AfafK.El-Ansary
Copyright ©  Anu Rahal et al. is is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Oxidative stress is a normal phenomenon in the body. Under normal conditions, the physiologically important intracellular levels of
reactive oxygen species (ROS) are maintained at low levels by various enzyme systems participating in the in vivo redox homeostasis.
erefore, oxidative stress can also be viewed as an imbalance between the prooxidants and antioxidants in the body. For the last two
decades, oxidative stress has been one of the most burning topics among the biological researchers all over the world. Several reasons
can be assigned to justify its importance: knowledge about reactive oxygen and nitrogen species production and metabolism;
identication of biomarkers for oxidative damage; evidence relating manifestation of chronic and some acute health problems to
oxidative stress; identication of various dietary antioxidants present in plant foods as bioactive molecules; and so on. is review
discusses the importance of oxidative stress in the body growth and development as well as proteomic and genomic evidences of its
relationship with disease development, incidence of malignancies and autoimmune disorders, increased susceptibility to bacterial,
viral, and parasitic diseases, and an interplay with prooxidants and antioxidants for maintaining a sound health, which would be
helpful in enhancing the knowledge of any biochemist, pathophysiologist, or medical personnel regarding this important issue.
1. Introduction
Man and animals are exposed to a large number of biological
and environmental factors like alterations in feed and hus-
bandry practices, climatic variables, transportation, regroup-
ing, the therapeutic and prophylactic activities, various stres-
sors, and so forth. e ability of the man and animal to ght
against these factors is important for maintenance of their
health and productivity. Today, the entire world is witnessing
an upsurge in chronic health complications like cardiovascu-
lar disease, hypertension, diabetes mellitus, dierent forms
of cancer, and other maladies. Medical surveys suggest that
diet may serve as a potential tool for the control of these
chronic diseases [, ]. Regular chewing of tobacco along with
inadequate diet is the most prominent nding to mortality
due to lung cancer in USA []. Diets rich in fruit and veg-
etables have been reported to exert a protective eect against
a variety of diseases, particularly the cardiovascular disease
and cancer []. e primary nutrients thought to provide
protection aorded by fruit and vegetables are the antioxi-
dants [, ]. In an analysis, Potter [] reviewed  epidemi-
ological studies, the majority of which showed a protective
eect of increased fruit and vegetable intake and concluded
that the high content of polyphenolic antioxidants in fruits
and vegetables is probably the main factor responsible for
the benecial eects. is awareness has led to a tremendous
increase in the proportion of fruits and vegetables rich in
antioxidant molecules on the dining table in the last two
Hindawi Publishing Corporation
BioMed Research International
Volume 2014, Article ID 761264, 19 pages
http://dx.doi.org/10.1155/2014/761264
BioMed Research International
decades, but still the risk of chronic health problems refuses
to decline, rather it upsurged with an enhanced vigour, giving
rise to a very important question—why? If the health associ-
ated problems are due to oxidative stress and the dietary con-
stituents are potent antioxidants, then the question of prob-
lem arrival should not be there. What happens when these
antioxidants reach the body tissues of interest or are there
other factors still to be unrevealed?
2. Stress
e term stress” has been used in physics since unknown
time as it appears in the denition of Hookes law of , but
its rst use in the biological science dates back to Sir Hans
SelyeslettertotheEditorofNaturein.Atthattime,itwas
not accepted, but later on, aer the famous address of Hans
Selye at the prestigious College of France, it received approval
among scientic community, but dening stress again trou-
bled Selye over several years. Today, stress can be dened
as a process of altered biochemical homeostasis produced
by psychological, physiological, or environmental stressors
[]. Any stimulus, no matter whether social, physiological,
orphysical,thatisperceivedbythebodyaschallenging,
threatening, or demanding can be labeled as a stressor. e
presence of a stressor leads to the activation of neurohor-
monal regulatory mechanisms of the body, through which
it maintains the homeostasis []. e overall physiological
impact of these factors and the adaptation ability of the body
determine the variations in growth, development, productiv-
ity, and health status of the animals []. ese alterations
canbeviewedasaconsequenceofgeneraladaptationsyn-
dromeaspostulatedbyHansSelye[]andusuallyreturnto
their normal status once the stimulus has disappeared from
the scene. Strong and sustained exposure to stress [, ,
] may result in higher energy negative balance and may
ultimately result in reduction in adaptation mechanisms,
increase in the susceptibility to infection by pathogens,
declineinproductivity,andnallyahugeeconomicalloss
[, , ].
Many of us puzzle between distress, stress, and oxidative
stress. Distress diers from stress, which is a physiological
reactionthatcanleadtoanadaptiveresponse[]. Distress
is comparatively dicult to dene and generally refers to a
state in which an animal cannot escape from or adapt to
the external or internal stressors or conditions it experiences
resultinginnegativeeectsuponitswell-being[]. Stress
leads to adaptation but distress does not. Stress is a commonly
used term for oxidative stress. Any alteration in homeostasis
leadstoanincreasedproductionofthesefreeradicals,much
above the detoxifying capability of the local tissues []. ese
excessive free radicals then interact with other molecules
within cells and cause oxidative damage to proteins, mem-
branes, and genes. In this process they oen create more
free radicals, sparking o a chain of destruction. Oxidative
damagehasbeenimplicatedinthecauseofmanydiseases
such as cardiovascular diseases, neuronal degeneration, and
cancer and has an impact on the body’s aging process too.
An altered response to the therapeutic agents has also been
observed []. External factors such as pollution, sunlight,
and smoking also trigger the production of free radicals.
Most importantly, stress is one of the basic etiologies of
disease []. It can have several origins like environmental
extremes for example, cold, heat, hypoxia, physical exercise
or malnutrition (Figure ).
On the basis of duration and onset, stress might be acute
and chronic stress. e stress due to exposure of cold or heat
is generally of acute type and is released with the removal of
cause. Similarly, stress due to physical exercises or complete
immobilization []isalsoacuteinnature.enutritional
and environmental stresses, where the causes persist for a
longer period of time, are chronic stress.
2.1. Cold Stress. Cold stress is evident whenever the temper-
ature falls below 
C and the body experiences severe cold
related illness and permanent tissue damage. An acute cold
stress (
Cforhours)inratscausesprofoundreduction
in contraction amplitude with an increase in heart rate in the
isolated heart preparations []. e decrease in amplitudes is
associated with inadequate ATP formation. While changing
perfusion of poststress isolated heart, myocardial rigidity
furtherslowsdownandthisseemedtobeassociatedwith
activated glycolysis. ere are no signs of cardiomyocytic
lesion aer cold stress. Reduced coronary ow is the only
abnormal eect of acute cold stress under these conditions.
High cardiac resistance to the damaging eect of cold is
likely to be related to increased processes of glycolysis and
glycogenolysis in the cardiomyocytes. e activity of succi-
nate dehydrogenase also gets elevated indicating the inuence
of cold stress on the Krebs cycle []. Coronary blood ow
isalsoreducedandlateronresultsinanalteredbasophils
activity in the myocardium [].
2.2. Physical Exercise and Stress. Health benets of regular
physical exercise are undebatable. Both resting and contract-
ingskeletalmusclesproducereactiveoxygenandnitrogen
species (ROS, RNS). Low physiological levels of ROS are
generated in the muscles to maintain the normal tone and
contractility, but excessive generation of ROS promotes con-
tractile dysfunction resulting in muscle weakness and fatigue
[].isisperhapsthereasonwhyintenseandprolonged
exercise results in oxidative damage to both proteins and
lipids in the contracting muscle bers [].
Regular exercise induces changes in both enzymatic and
nonenzymatic antioxidants in the skeletal muscle. Further-
more, oxidants can modulate a number of cell signaling path-
ways and regulate the expression of multiple genes in eukary-
otic cells. is oxidant-mediated change in gene expression
involves changes at transcriptional, mRNA stability, and sig-
nal transduction levels. e magnitude of exercise-mediated
changes in superoxide dismutase (SOD) activity of skeletal
muscle increases as a function of the intensity and duration
of exercise [, ]. Mild physical activity increases nuclear
factor-kappa B(NF-𝜅B) activity in the muscle of rats as well
as the gene expression for manganese superoxide dismutase
(MnSOD) and endothelial nitric oxide synthase (eNOS) [].
BioMed Research International
Prooxidant
Exogenous
Pathogens
Bacteria
Virus
Fungus
Parasite
Drugs
Toxicants
Dietary
ingredients
Lipids
Carbohydrates
Highly
processed
food
Antioxidants
Transition
metals
Pesticides
Drug residuesClimate
Endogenous
Endogenous
metabolites
Drug
metabolites
Cellular
metabolism
Ion ux
Anxiety
Ischemia
Environmental
pollution
Pathophysiology
F : General classication of prooxidants.
2.3. Chronic Stress. Chronic stress signicantly alters limbic
neuroarchitecture and function and potentiates oxidative
stress [] and emotionality in rats []. Chronic restraining
of laboratory animals has been found to increase aggres-
sion, potentiate anxiety, and enhance fear conditioning [].
Chronic immobilization induces anxiety behavior and den-
dritic hypertrophy in the basolateral amygdala, which persist
beyond a recovery period. Restraint of rats causes increased
mucin release, as measured by [H] glucosamine incorpo-
ration and goblet cell depletion, prostaglandin E (PGE)
secretion, and mast cell activation in colonic explants [].
Upregulation of the neurotensin precursor mRNA in the
paraventricular nucleus of the hypothalamus aer immobi-
lization has also been reported []. Neurotensin stimulates
mucin secretion from human colonic goblet cell line by a
receptor mediated mechanism [].
2.4. Nutritional Stress. Nutrition is one of the most signicant
external etiologies for oxidative stress including its char-
acteristics, type and quality, ratio of the various nutrients,
dietary balance with regard to protein, carbohydrates, fats,
macro- and trace elements, and so forth. Feed exercises a
considerable inuence over the physiological condition and
thus the homeostasis of the animal body [, , ].
BioMed Research International
Feeding of endogenous or exogenous antioxidants can sensi-
tively regulate glycolysis and the Warburg eect in hepatoma
cells []. Fasting induces an increase in total leukocytes
counts, eosinophils, and metamyelocytes in the blood prole,
accompanied by a decrease in the basophils and monocytes,
a typical stress leukogram produced in the animal body due
to the increased endogenous production of cortisol from the
adrenal glands during oxidative stress [, , ]. e
leukocytosis with neutrophilia associated with fasting may be
a consequence of an inammatory reaction, caused by the
direct action of ammonia on the rumen wall [, ]. e
monocytopenia may be a result of adaptation and defense
mechanism undergoing in the body and leads to higher
susceptibility to pathogens [, ].
Nutritional stress causes adrenal gland hyperfunction
and, thus, an increased release of catecholamines in the blood,
with a simultaneous inhibition of the production of insulin in
the pancreas [, , ]. e process of glycogenolysis is
observed in the rst  hours of fasting [, , ]. ere-
aer, gluconeogenesis from amino acid precursors and lipol-
ysisfromglycerol,aswellasfromlactatethroughtheCori
cycle, maintain a regular supply of glucose. Lactate gets trans-
formed into pyruvate and participates in the gluconeogenesis
along with the deaminated amino acids. e increased
production of catecholamines (epinephrine and dopamine)
owing to fasting results in peripheral vasoconstriction and
redistribution in blood which is expressed as erythrocytosis,
leukocytosis, and neutrophilia [].
2.5. Hypoxic Stress. Hypoxia is known to stimulate mito-
chondria to release ROS (mROS). Under hypoxic conditions,
mitochondria participate in a ROS burst generated at com-
plex III of the electron transport chain []. Hypoxia and
reoxygenation result in reversible derangement of ATPase
and architecture of mitochondrial membrane. Cardiac hemo-
dynamic parameters, which decline immediately under
hypoxic conditions, recover during reoxygenation [], but
the biochemical and histopathological studies provide a com-
plicated pattern []. High CAT (carboxyatractyloside) sensi-
tivityoftheATPaseisobservedatminofhypoxia.einitial
phase in hypoxic perfusion (< min) exhibits a steep increase
of ADP contents and ATPase activities and a drastic fall of
ATP/ADP ratios in mitochondria, as well as in tissues. Fur-
thermore, the number of ATPase particles visible at the inner
aspect of mitochondrial membrane decreases. During the
second phase of hypoxic perfusion (from min onwards),
the count of ATPase particles visible at the inner mito-
chondrial membrane further decreases. ATPase activities
uctuate, retaining close contact with the membrane dur-
ing hypoxia. e mitochondrial ultrastructural damage
becomes more evident. High-energy phosphates reserves of
myocardiumcouldhelpmyocardialcellstomaintaintheir
structural integrity []. ATP/ADP ratios attain values of
almost . During reoxygenation (aer min of hypoxia),
the levels of mitochondrial adenine nucleotides, oxidative
phosphorylation rate, and respiratory control index increase
within  min and then slightly decline again. e ATP/ADP
ratio is diminished in the course of reoxygenation. ATPase
activity also decreases within  min of reoxygenation and
the ADP/O ratio reaches control values. e ATPase activity
gains its highest sensitivity towards catalase at  min of
reoxygenationattainingavaluesimilartothatofminof
hypoxic perfusion.
3. Stress and Well-Being
Each cell in the human body maintains a condition of home-
ostasis between the oxidant and antioxidant species [].
Up to –% of the pulmonary intake of oxygen by humans
is converted into ROS []. Under conditions of normal
metabolism, the continuous formation of ROS and other free
radicals is important for normal physiological functions like
generation of ATP, various catabolic and anabolic processes
and the accompanying cellular redox cycles. However, exces-
sive generation of free radicals can occur due to endogenous
biological or exogenous environmental factors, such as chem-
ical exposure, pollution, or radiation.
ere are ROS subgroups: free radicals such as superoxide
radicals (O
2
∙−
) and nonradical ROS such as hydrogen perox-
ide (H
2
O
2
)[]. e primary free radicals generated in cells
aresuperoxide(O
2
) and nitric oxide (NO). Superoxide is
generated through either incomplete reduction of oxygen in
electron transport systems or as a specic product of enzy-
matic systems, while NO is generated by a series of specic
enzymes (the nitric oxide synthases). Both superoxide and
NO are reactive and can readily react to form a series of other
ROS and RNS.
Generally, mitochondria are the most important source
of cellular ROS where continuous production of ROS takes
place []. is is the result of the electron transport chain
located in the mitochondrial membrane, which is essential for
the energy production inside the cell [, ]. Additionally,
some cytochrome  enzymes are also known to produce
ROS [].
4. Biochemical Basis of Stress
Several endogenous cells and cellular components participate
in initiation and propagation of ROS (Table )[].
All these factors play a crucial role in maintenance of cel-
lular homeostasis. A stressor works by initiating any of these
mechanisms. Oxidative stress occurs when the homeostatic
processes fail and free radical generation is much beyond
the capacity of the body’s defenses, thus promoting cellular
injury and tissue damage. is damage may involve DNA and
proteincontentofthecellswithlipidperoxidationofcellular
membranes, calcium inux, and mitochondrial swelling and
lysis [, , ]. ROS are also appreciated as signaling
molecules to regulate a wide variety of physiology. It was rst
proposed in the s when hydrogen peroxide was shown
to be required for cytokine, insulin, growth factor, activator
protein- (AP-), and NF-𝜅B signaling [, ]. e role of
hydrogen peroxide in promoting phosphatase inactivation by
cysteine oxidation provided a likely biochemical mechanism
by which ROS can impinge on signaling pathways []. e
role of ROS in signaling of cytochrome c mediated apop-
tosis is also well established []. ROS can cause reversible
BioMed Research International
T : Endogenous mediators of oxidative stress.
Leakage of free radicals
Membrane-bound enzymes NADPH oxidase
Electron transport systems Mixed function oxidases
Activation of oxygen
Soluble cell constituents
Transition metals, thiol containing proteins, quinine
derivatives, epinephrine, metalloproteins, hemeproteins,
and avoproteins
Xenobiotic metabolizing enzymes
Cyt P

-dependent monooxygenases, Cyt b
,and
NADPH-dependent cytochrome reductases
ROS generation/propagation
Soluble cytosolic enzymes Xanthine oxidase, superoxide dismutase, catalase
Phagocytic cells
Neutrophils, macrophages, and monocytes involved in
inammation, respiratory burst, and removal of toxic
molecules
Local ischemia Damaged blood supply due to injury or surgery
posttranslational protein modications to regulate signaling
pathways. A typical example of the benecial physiological
role of free radicals is a molecule of nitric oxide (NO).
NOisformedfromargininebytheactionofNO-synthase
(NOS) []. NO is produced by constitutive NOS during
vasodilating processes (eNOS) or during transmission of
nerveimpulses(nNOS).Inthepresenceofstressors,NOis
produced by catalytic action of inducible NOS (iNOS) and
is at higher concentrations []. NO can cause damage to
proteins, lipids, and DNA either directly or aer reaction with
superoxide, leading to the formation of the very reactive
peroxynitrite anion (nitroperoxide) ONOO– [].
Lipid peroxidation of polyunsaturated lipids is one of
themostpreferredmarkersforoxidativestress.eproduct
of lipid peroxidation, malondialdehyde, is easily detected in
blood/plasma and has been used as a measure of oxidative
stress. In addition, the unsaturated aldehydes produced from
these reactions have been implicated in modication of cellu-
lar proteins and other constituents []. e peroxidized lipid
can produce peroxy radicals and singlet oxygen.
5. Physiological Role of Stress
Stress has a signicant ecological and evolutionary role and
may help in understanding the functional interactions among
life history traits []. Stress leads to a number of phys-
iological changes in the body including altered locomotor
activity and general exploratory behavior. e physiological
role of ROS is associated with almost all of the body processes,
for example, with reproductive processes []. Since under
physiological conditions a certain level of free radicals and
reactive metabolites is required, complete suppression of FR
formation would not be benecial []. One further benecial
example of ROS seen at low/moderate concentrations is the
induction of a mitogenic response.
Stress leads to activation of hypothalamic-pituitary-
adrenal axis. e increased endogenous catecholamine
release has been observed in cold environmental conditions.
e activity of succinate dehydrogenase also gets elevated
indicating the inuence of ROS as evident in cold environ-
mental conditions []. Coronary blood ow is reduced and
an altered basophils activity in the myocardium is also
observed [].
Free radicals play an irreplaceable role in phagocytosis
as one of the signicant microbicidal systems [], or in
several biochemical reactions, for example, hydroxylating,
carboxylating, or peroxidating reactions, or in the reduction
of ribonucleotides []. At present, free radicals and their
metabolites are assumed to have important biomodulating
activities and a regulatory ability in signal transduction
process during transduction of intercellular information [].
Among the reactive oxygen species, H
2
O
2
best fullls the
requirements of being a second messenger []. Its enzy-
matic production and degradation, along with its functional
requirement for thiol oxidation, facilitate the specicity for
time and place that are required in signaling. Both the ther-
modynamic and kinetic considerations support that among
dierent possible oxidation states of cysteine, formation of
sulfenic acid derivatives or disuldes can be applicable as
thiol redox switches in signaling. H
2
O
2
readily diuses across
biological membranes, and so it is well-suited as a diusible
messenger [, ].
Inthepresenceoftransitionmetalssuchasironorcopper,
H
2
O
2
cangiverisetotheindiscriminatelyreactiveand
toxic hydroxyl radical (HO
)byFentonchemistry.Increasing
evidence indicates that H
2
O
2
is a particularly an intrigu-
ing candidate as an intracellular and intercellular signaling
molecule because it is neutral and membrane permeable
[, ].
Specically, H
2
O
2
can oxidize thiol (–SH) of cysteine
residues and form sulphenic acid (–SOH), which can get
glutathionylated (–SSG), form a disulde bond (–SS–) with
adjacent thiols, or form a sulfenyl amide (–SN–) with amides
[]. Each of these modications modies the activity of the
target protein and thus its function in a signaling pathway.
Phosphatases appear to be susceptible to regulation by ROS
in this manner, as they possess a reactive cysteine moiety
in their catalytic domain that can be reversibly oxidized,
which inhibits their dephosphorylation activity []. Specic
examples of phosphatases known to be regulated in this
manner are PTPb, PTEN, and MAPK phosphatases [].
BioMed Research International
Physical
Bacteria
Viruses
Necrosis/other
disorders
Damage to
DNA
Transcription
factors
inhibited
Telomere
shortening
Ageing
Endobiotic or
xenobiotic
Peroxidases
Carcinogen/
mutation
Pituitary
Endocrine
dysfunction
Alzheimer’s
disease
Proinammatory
mediators
Change in Ca
homeostasis
Hypertension
Chronic
inammation
Cardiovascular
disease
Autoimmune
disorder
Renal
damage/
apoptosis
Hepatic
damage
Limited ATP
generation
Energy
crisis
Protein
kinase
Parkinson’s
disease
Phagocytes/
other cell organelles
Cytosolic
enzyme
ROS
PKc
NADPH
oxidase
Mitochondrial oxidative burst
Hepatocellular,
cervical, colon,
breast cancers
Immune
dysfunction
Neurological
disorders
XME
Electron
transport
Susceptible
to infection
s
a
tor
y
s
Ati
am
m
m
m
a
a
a
e
e
e
e
e
d
e
iato
r
r
r
r
r
h
dys
dys
dy
dy
dys
dy
dys
dy
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
fun
fun
fun
fun
ct
c
d
T
s
Tl
Smoking
UV/X rays
External stimuli (drugs/toxicants/environment/nutrition/physical)
Internal agents
(disease/ischemia/
necrosis)
Macrophage-
fatty acid-binding
protein-4 (aP2)
O
2
H
2
O
2
H
2
O
Hypothalamo-
pituitary-
adrenal axis
NF-𝜅B
Alternative in
protein/lipid
CYP
450
modulation
Antioxidants
GSH
NADPH
ioredoxin vitamins E
and C and trace metals
such as selenium
OH
al
st
sti
ti
i
i
i
i
i
i
mul
mul
l
mul
mu
mul
mul
mul
mul
mul
m
mul
mul
mu
m
u
m
i
i
i (
i
i
i
i
i
i
i
dr
dru
ru
ru
u
u
g
gs
gs/
t
Food
V
iruses
Cardioprotective
Altered
xenobiotic bio-
transformation
ROS
ROS
O
2
∙−
F : Oxidative stress and disease development.
Any emotional stress leads to a decrease in sympathetic out-
owaswellasenergyproductionofthetissues[].
6. Oxidative Stress
e harmful eect of free ROS and RNS radicals causing
potential biological damage is termed oxidative stress and
nitrosative stress, respectively [].isisevidentinbio-
logical systems when there is either an excessive production
of ROS/RNS and/or a deciency of enzymatic and nonenzy-
matic antioxidants. e redox stress/oxidative stress is a com-
plex process. Its impact on the organism depends on the type
of oxidant, on the site and intensity of its production, on the
composition and activities of various antioxidants, and on the
ability of repair systems [].
e term “ROS” includes all unstable metabolites of
molecular oxygen (O
2
) that have higher reactivity than O
2
like superoxide radical (O
2
) and hydroxyl radical (HO
)
and nonradical molecules like hydrogen peroxide (H
2
O
2
).
ese ROS are generated as byproduct of normal aerobic
metabolism, but their level increases under stress which
proves to be a basic health hazard. Mitochondrion is the
major cell organelle responsible for ROS production [, ].
It generates ATP through a series of oxidative phosphory-
lation processes. During this process, one- or two-electron
reductions instead of four electron reductions of O
2
can
occur, leading to the formation of O
2
or H
2
O
2
,andthese
species can be converted to other ROS. Other sources of
ROS may be reactions involving peroxisomal oxidases [],
cytochrome P- enzymes [], NAD (P)H oxidases [],
or xanthine oxidase [].
7. Oxidative Stress and Diseases
Today the world is experiencing a rise in age related chronic
health diseases like cardiovascular disorders, cancer, and
so forth and their associated negative health impacts and
mortality/casualty []. Some metabolic diseases like
diabetes are also associated with an enhanced level of lipoper-
oxidation (Figure ).
e central nervous system (CNS) is extremely sensitive
to free radical damage because of a relatively small total
antioxidant capacity. e ROS produced in the tissues can
inict direct damage to macromolecules, such as lipids,
nucleic acids, and proteins []. e polyunsaturated fatty
acids are one of the favored oxidation targets for ROS.
Oxygen-free radicals, particularly superoxide anion radical
(O
2
∙−
), hydroxyl radical (OH
∙−
), and alkylperoxyl radical
(
OOCR), are potent initiators of lipid peroxidation, the role
of which is well established in the pathogenesis of a wide
range of diseases. Once lipid peroxidation is initiated, a prop-
agation of chain reactions will take place until termination
BioMed Research International
products are produced. erefore, end products of lipid
peroxidation, such as malondialdehyde (MDA), -hydroxy-
-nonenol (-HNE), and F-isoprostanes, are accumulated
in biological systems. DNA bases are also very suscep-
tible to ROS oxidation, and the predominant detectable
oxidation product of DNA bases in vivo is -hydroxy--
deoxyguanosine. Oxidation of DNA bases can cause muta-
tions and deletions in both nuclear and mitochondrial DNA.
Mitochondrial DNA is especially prone to oxidative damage
due to its proximity to a primary source of ROS and its
decient repair capacity compared with nuclear DNA. ese
oxidative modications lead to functional changes in various
typesofproteins(enzymaticandstructural),whichcanhave
substantial physiological impact. Similarly, redox modulation
of transcription factors produces an increase or decrease in
their specic DNA binding activities, thus modifying the
gene expression.
Among dierent markers of oxidative stress, malondi-
aldehyde (MDA) and the natural antioxidants, metalloen-
zymes Cu, Zn-superoxide dismutase (Cu, Zn-SOD), and
selenium dependent glutathione peroxidase (GSHPx), are
currently considered to be the most important markers [
]. Malondialdehyde (MDA) is a three-carbon compound
formed from peroxidized polyunsaturated fatty acids, mainly
arachidonic acid. It is one of the end products of membrane
lipid peroxidation. Since MDA levels are increased in various
diseases with excess of oxygen free radicals, many relation-
ships with free radical damage were observed.
Cu, Zn-SOD is an intracellular enzyme present in all
oxygen-metabolizing cells, which dismutates the extremely
toxic superoxide radical into potentially less toxic hydrogen
peroxide. Cu, Zn-SOD is widespread in nature, but being a
metalloenzyme, its activity depends upon the free copper and
zinc reserves in the tissues. GSHPx, an intracellular enzyme,
belongs to several proteins in mammalian cells that can
metabolize hydrogen peroxide and lipid hydroperoxides.
8. Oxidative Stress and Altered
Immune Function
e relationship between oxidative stress and immune func-
tion of the body is well established. e immune defense
mechanism uses the lethal eects of oxidants in a benecial
manner with ROS and RNS playing a pivotal role in the killing
of pathogens. e skilled phagocytic cells (macrophages,
eosinophils, heterophils), as well as B and T lymphocytes,
contain an enzyme, the nicotinamide adenine dinucleotide
phosphate (NADPH) oxidase [, ], which is responsible
for the production of ROS following an immune challenge. At
the onset of an immune response, phagocytes increase their
oxygen uptake as much as – folds (respiratory burst).
e O
∙−
generatedbythisenzymeservesasthestarting
material for the production of a suite of reactive species.
Direct evidence also certies production of other powerful
prooxidants, such as hydrogen peroxide (H
2
O
2
), hypochlor-
ous acid (HOCl), peroxynitrite (ONOO–), and, possibly,
hydroxyl (OH
)andozone(O
3
) by these cells. Although the
use of these highly reactive endogenous metabolites in the
cytotoxic response of phagocytes also injures the host tissues,
the nonspecicity of these oxidants is an advantage since they
take care of all the antigenic components of the pathogenic
cell [].
Several studies have demonstrated the interdependency
of oxidative stress, immune system, and inammation.
Increased expression of NO has been documented in dengue
and in monocyte cultures infected with dierent types of viral
infections. Increased production of NO has also been accom-
panied with enhancement in oxidative markers like lipid
peroxidation and an altered enzymatic and nonenzymatic
antioxidative response in dengue infected monocyte cultures
[]. More specically, the oxygen stress related to immune
system dysfunction seems to have a key role in senescence, in
agreement with the oxidation/inammation theory of aging.
Moreover, it has been revealed that reduced NADPH oxidase
is present in the pollen grains and can lead to induction of
airway associated oxidative stress. Such oxidative insult is
responsible for developing allergic inammation in sensitized
animals. ere is triggering of production of interleukin
(IL)-alongwithproinammatorycytokines,namely,tumor
necrosis factor (TNF)-alpha and IL-. ere is initiation
of dendritic cell (DC) maturation that causes signicant
upregulation of the expression of cluster of dierentiation
(CD)-,  and  with a slight overexpression of CD- in
the membrane. So altogether, innate immunity locally may
be alleviated due to oxidative stress induced by exposure to
pollen. is in turn helps in participation to initiate adaptive
immune response to pollen antigens [].
e immune status directly interplays with disease pro-
ductionprocess.eroleofphysicalandpsychological
stressors contributes to incidences and severity of various
viral and bacterial infections. Both innate as well as acquired
immune responses are aected by the altered IFN-𝛾secretion,
expression of CD, production of the acute-phase proteins,
and induction of TNF-𝛼. Fatal viral diseases produce severe
oxidative stress (OS) leading to rigorous cellular damage.
However, initiation, progress, and reduction of damages are
governedbytheredoxbalanceofoxidationandantioxida-
tion. e major pathway of pathogenesis for cell damage is via
lipidperoxidationparticularlyinmicrosomes,mitochondria,
and endoplasmic reticulum due to OS and free radicals
[, ]. All the factors responsible for the oxidative stress
directly or indirectly participate in immune system defense
mechanism. Any alteration leading to immunosuppression
can trigger the disease production (Table ).
9. Oxidative Stress and Incidence of
Autoimmune Diseases
Oxidative stress can induce production