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Chronic Inflammation and Oxidative Stress as a Major Cause of Age- Related Diseases and Cancer



Chronic inflammation is a pathological condition characterized by continued active inflammation response and tissue destruction. Many of the immune cells including macrophages, neutrophils and eosinophils are involved directly or by production of inflammatory cytokine production in pathology of chronic inflammation. From literatures, it is appear that there is a general concept that chronic inflammation can be a major cause of cancers and express aging processes. Moreover, many studies suggest that chronic inflammation could have serious role in wide variety of age-related diseases including diabetes, cardiovascular and autoimmune diseases. Inflammatory process induces oxidative stress and reduces cellular antioxidant capacity. Overproduced free radicals react with cell membrane fatty acids and proteins impairing their function permanently. In addition, free radicals can lead to mutation and DNA damage that can be a predisposing factor for cancer and age-related disorders. This article reviews the antioxidant defense systems, free radicals production and their role in cancer and age related diseases and also some of the recent patent relevant to the field. Study of the role of free radicals in human diseases can help the investigators to consider the antioxidants as proper agents in preventive medicine, especially for cancer and aging processes.
Recent Patents on Inflammation & Allergy Drug Discovery 2009, 3, 73-80 73
1872-213X/09 $100.00+.00 © 2009 Bentham Science Publishers Ltd.
Chronic Inflammation and Oxidative Stress as a Major Cause of Age-
Related Diseases and Cancer
Nemat Khansari*, Yadollah Shakiba and Mahdi Mahmoudi
Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
Received: August 1, 2008; Accepted: August 27, 2008; Revised: September 12, 2008
Abstract: Chronic inflammation is a pathological condition characterized by continued active inflammation response and
tissue destruction. Many of the immune cells including macrophages, neutrophils and eosinophils are involved directly or
by production of inflammatory cytokine production in pathology of chronic inflammation. From literatures, it is appear
that there is a general concept that chronic inflammation can be a major cause of cancers and express aging processes.
Moreover, many studies suggest that chronic inflammation could have serious role in wide variety of age-related diseases
including diabetes, cardiovascular and autoimmune diseases. Inflammatory process induces oxidative stress and reduces
cellular antioxidant capacity. Overproduced free radicals react with cell membrane fatty acids and proteins impairing their
function permanently. In addition, free radicals can lead to mutation and DNA damage that can be a predisposing factor
for cancer and age-related disorders.
This article reviews the antioxidant defense systems, free radicals production and their role in cancer and age related
diseases and also some of the recent patent relevant to the field. Study of the role of free radicals in human diseases can
help the investigators to consider the antioxidants as proper agents in preventive medicine, especially for cancer and aging
Keywords: Chronic inflammation, cancer, age-related diseases, free radicals, DNA damage, antioxidant, angiogenesis.
Inflammation is a protective mechanism employed by
tissues against endogenous and exogenous antigens. The
relationship between chronic inflammation and many can-
cers has been recognized [1]. Chronic inflammation is a pro-
longed pathological condition characterized by mononuclear
immune cell infiltration [monocytes, macrophages,
lymphocytes, and plasma cells], tissue destruction and
fibrosis. However, chronic inflammation exerts its cellular
side effects mainly through excessive production of free
radicals and depletion of antioxidants [2]. Aging may be
defined as a progressive decline in the physiological
functions of an organism after the reproductive phase of its
life. The idea that, aging is the result of free radical damage,
is often credited to Denham Harman, who proposed this
theory based on this observation that, irradiation induces the
formation of free radicals, shortens life span, and produces
changes that resemble aging processes [3]. His work has
gradually triggered intense researches into understanding the
role of free radicals in biological systems. The main aim of
this review is to analyze the role of free radicals, which are
by products of chronic inflammation, in carcinogenesis and
In the last two decades, there has been a considerable
amount of interest in the role of reactive oxygen species
(ROS) and reactive nitrogen species (RNS) in clinical
*Address correspondence to this author at the Professor of Immunology,
Department of Immunology, School of Medicine, Tehran University of
Medical Sciences, Tehran, Iran; Tel/Fax: +98-21-66419536;
medicine. A free radical is defined as any chemical species
that contains unpaired electrons. This unpaired electron
usually produces a highly reactive free radical.
In biological systems, the most common source of free
radicals is oxygen.
The harmful effects and biological damage caused by
ROS and RNS is termed oxidative stress and nitrosative
stress [4]. Unfavorable side effects occur when there is an
imbalance between overproduction of ROS/RNS and
decrease of antioxidant molecules in body. Generally, ROS
and RNS play dual roles in body: deleterious and beneficial
effects [5]. Usually the beneficial effects of ROS involve
defense against microbial pathogens. This role occurs by low
concentration of these molecules. However, overproduction
of ROS or RNS can damage and inhibit the normal functions
of lipids, proteins and DNA. This effect is due to
intracellular reduction of O2 into ROS or free radicals, which
is toxic to cells and tissues [6].
ROS can be produced from both endogenous and
exogenous cellular substances. Potential endogenous sources
include mitochondria, cytochrome P450, peroxisomes, and
inflammatory cells activation [7]. Mitochondria generate
significant quantities of hydrogen peroxide and use ~90% of
cellular O2. During the mitochondrial process of reducing
oxygen for production of water, several short-lived inter-
mediates are produced, including superoxide (O2), hydrogen
peroxide (H2O2) and the hydroxyl radical [OH]. Superoxide
and hydroxyl radicals are toxic to cells. Cell destruction also
causes further free radical generation [6].
Additional endogenous sources of cellular reactive
oxygen species are neutrophils, eosinophils and macro-
phages. Activated macrophages initiate increase in oxygen
74 Recent Patents on Inflammation & Allergy Drug Discovery 2009, Vol. 3, No. 1 Khansari et al.
uptake and give rise to a variety of reactive oxygen species,
including O2, nitric oxide (NO) and hydrogen H2O2 [8].
Liver macrophages {Kupffer cells} participate in free
radical-induced hepatotoxicity and liver cancer by producing
inflammatory cytokines [9]. Recent investigations suggest
that there is a direct relationship between Kupffer cells,
inflammatory cytokines, and liver tumor promotion [10].
In addition, intracellular formation of free radicals can
occur by environmental sources including ultraviolet light,
ionizing radiation, and pollutants such as paraquat and
ozone. All of these sources of free radicals, both enzymatic
and nonenzymatic, have the potential to inflict oxidative
damage on a wide range of biological macromolecules [11].
The cell membrane is one of the most susceptible sites to
ROS damage. Free radicals can react with cell membrane
fatty acids and form lipid peroxides. Lipid peroxides
accumulation can lead to production of carcinogenesis agents
like malondialdehyde [12]. Cell membrane damage via lipid
peroxidation can permanently impair fluidity and elasticity
of the membrane, which can lead to the cell rupture. These
changes are particularly significant in long-lived cells such
as neurons [13].
The proteins are another main targets for free radicals
attack. Overproduced radicals can react with protein
aminoacids to oxidize and cross-link them. Radical-protein
reactions can impair the function of important cellular and
extracellular proteins like enzymes and connective tissue
proteins permanently. Based on many investigations,
accumulation of tissue and cell damage is much higher in
aged individuals. In fact, it has been estimated that oxidized
protein in old animals may compose 30-50% of the total
cellular protein [14].
DNA is also highly susceptible to free radical attacks. An
oxygen radical interaction with DNA can break its strands or
delete a base. This DNA damage can be a lethal event for an
organism. The rate of DNA damage inflicted by free radicals
is considerably high; it is estimated that in average more than
10,000 oxidative hits occur each day in the DNA of a human
cell [15]. Although cellular repair system corrects much of
these damages, but the radical induced DNA lesion that
accumulate with age, can be an important etiology aging of
processes [6].
Mitochondria are the main cellular organelles that are
involved in free radical production. Mitochondria consume
about 90% of the cellular oxygen and are the most
susceptible organelles to oxidative damage. Mitochondrial
DNA contains histone that is highly susceptible to reactive
oxygen damage. Moreover, mitochondria contain more than
100 different enzymes, involved in ATP production, which
continuously interact with free radicals. Decrease activity of
some of these enzymes during the aging process might be
due to the long time interaction of these enzymes with free
radicals. It has been estimated that the number of oxidative-
induced damages in mitochondrial DNA is ten times higher
than nuclear DNA. It has been shown that mitochondrial
DNA damage accumulates with age and can have an
important role in cellular aging too [15]. It should be also
noted that DNA repair is much less efficient in mitochondria
than in the nucleus [16].
The lack of equilibrium between free radical production
in mitochondria and anti-oxidant defense mechanisms in this
organelle may leads to leak of these harmful reactant to
cytoplasm or connective tissues, hence damaging tissues
and/or cells. Based on these facts, mitochondria can have a
very important intermediatory role in age-related tissue
degradation and aging processes [17].
In order to neutralizing the threat of free radicals to the
tissues and cells, a wide variety of antioxidant and repair
systems has been evolved. Defense mechanisms against
oxidative stress can be divided into: antioxidant, preventative
and repair mechanisms, and physical defenses. Many
enzymes participate in free radical neutralizing processes
include: glutathione peroxidase, superoxide dismutase
(SOD), and catalase. The non-enzymatic antioxidants that
participate in oxidative stress defense include: ascorbic acid
(Vitamin C), alpha-tocopherol (Vitamin E), glutathione
(GSH), carotenoids, and flavinoids. In the normal and
healthy cells, there is a precise balance between free radicals
production and the level of antioxidant molecules, but under
oxidative stress condition, the balance has been tilted
towards excessive of oxidative radicals.
It is well understood that reduced-glutathione is an
important cellular antioxidant molecule in the mitochondria
and cell nucleus. Glutathione is considered to be the most
powerful, versatile, and important antioxidant in the body.
Glutathione is synthesized in the body from three amino
acids: Cysteine, glutamine and glycine. Cysteine is one of
the sulfur containing amino acids used for the synthesis of
glutathione (this amino acid is very critical in detoxification).
When an electron of the GSH is lost then it becomes
oxidized. When the level of oxidized form of this molecule is
increased then they linked with each other by a disulfide
bridge to form glutathione disulfide or oxidized glutathione
The main protective roles of glutathione against oxidative
stress are: [i] glutathione is a cofactor for other detoxifying
enzymes like glutathione peroxidase (GPx), and glutathione
transferase [ii] GSH participates in amino acid transport
through the plasma membrane; [iii] GSH scavenges hydroxyl
radicals and singlet oxygen directly, detoxifying hydrogen
peroxide and lipid peroxides by the catalytic action of
glutathione peroxidase; [iv] Glutathione is able to reduce
oxidized Vitamin C and Vitamin E back to their unoxidized
state. Moreover, GSH in the nucleus involves in mechanisms
that are necessary for DNA repair and expression [18].
The interaction of the cellular immune system with
endogenous and/or exogenous antigens results generation of
ROS and RNS, leading to signaling cascades that trigger the
production of proinflammatory cytokines and chemokines
[19]. Inflammation is the primary immune system reaction to
Chronic Inflammation & Cancer Recent Patents on Inflammation & Allergy Drug Discovery 2009, Vol. 3, No. 1 75
eliminate pathogens or other stimuli in order to restore the
cells to normal state or replace destroyed tissue with scar
[20]. After activation, innate immune system cells secrete
proinflammatory cytokines and chemokines that induce
ROS/RNS production [21]. In the innate immune system,
macrophages play a pivotal role in eliminating the pathogen
through the generation of reactive oxygen species including
superoxide, nitric oxide, hydrogen peroxide, hydroxyl
radical, peroxynitrite and hydrochlorous acid (Hocl) [22].
Inflammation reaction continues until the pathogens are
eliminated and the tissue repair process be completed [23].
Continued active inflammation response can lead to cell
damage or cellular hyperplasia following ROS overpro-
duction from inflammatory cells. During inflammation ROS
can interact with DNA in mitotic cells resulting in permanent
genomic mutation such as point mutations, gene deletions, or
gene rearrangement [24]. During inflammation cellular
antioxidant systems respond to free radical overproduction
by activating genes involved in DNA repair [25]. In chronic
inflammation the rate of ROS induced DNA damage is
extensive because this condition leads to depletion of cellular
antioxidants. Chronic inflammation predisposes cells for
transformation due to induction of recurrent DNA damage
by inflammatory cells, hence higher frequency of mutation
[26]. In addition, chronic inflammation induces increase of
growth factor production and growth-supporting stimuli.
Over all, it seems that chronic inflammations facilitates
cellular malignancy and transformation [27]. Based on these
facts, inflammation is considered to be a major precursor for
cancer development. To further elucidate the relationship
between chronic inflammation and ROS content in tissues,
we will review the role of inflammatory cytokines in
production of free radicals.
Cytokines are soluble mediators of intracellular commu-
nications. They contribute to a chemical signaling language
that regulates development, tissue repair, haemopoiesis,
inflammation, and the specific and non-specific immune
responses. Binding of cytokines to their receptors initiates
transmission of extracellular information into the cytoplasm
and the nucleus [28]. Cytokine receptors are usually directly
linked to the ion channels or G proteins. The information is
transmitted by various signaling pathways like nuclear factor
B and mitogen-activated protein kinase (MAPK) [29]. It
has been recognized that a variety of cytokines induces ROS
production in nonphagocytic cells by binding to their
specific receptors. Some of the well-known activated growth
factor receptors that induce ROS include: epidermal growth
factor (EGF) receptor, platelet-derived growth factor (PDGF)
receptor and vascular endothelial growth factor (VEGF)
receptor [30]. Inflammatory cytokines such as IL-1, IL-6,
TNF-, and IFN- have been shown to generate ROS in
nonphagocytic cells too [31]. The ROS produced by cytokine
induction can be an important signal for other biological
effects in cells such as proliferation and programmed cell
death [23]. For instance, TNF- enhances ROS production
by neutrophils, while IL-1-, TNF-, and IFN- stimulate the
expression of inducible nitric oxide synthase (iNOS) in
inflammatory and epithelial cells [32]. In animal models of
multiple myeloma, plasma cells require IL-6 for growth,
which is provided by macrophages in the chronically-
inflamed tissue [33]. IL-6 is stimulated by PGE2 derived
from cyclooxygenase-2 (COX-2), which is elevated in
inflammatory macrophages. This process can be inhibited by
anti-inflammatory drugs [34, 35]. TNF- is another
important inflammatory cytokine that is secreted mainly
from activated macrophages and induces ROS production in
many types of cells. TNF- Knockout mice show significant
decrease of skin tumor development in response to DMBA
[36]. IL-8 is an inflammatory chemokine, derived from
monocytes, macrophages, and endothelial cells, that has
important role in tumor angiogenesis. In addition, its role in
many types of tumors including: colon, bladder, lung, and
stomach cancer has been described [37].
Many studies have demonstrated the direct relationship
between chronic inflammation and cancer [32]. It has been
estimated that chronic infection and the associated
inflammation contribute to approximately one-quarter of all
cancer cases worldwide [38-40].
A wide variety of chronic inflammatory conditions
predispose susceptible cells to neoplastic transformation
[41]. Inflammation is a multistep process that includes
injury, repair, and resolution. Inflammation process exerts its
effects on other cells through messenger molecules such as
cytokines, prostaglandins, chemokines and angiogenic
factors [42]. ROS/RNS and inflammatory cytokines, like
TNF- activate a transcription factor called nuclear factor
kappa-B (NFB) by phosphorylation and subsequent
proteasomal degradation. After that, NFB migrate to
nucleus and activates specific gene transcription [23]. NFB
induces the expression of genes involved in cell proli-
feration, apoptosis and carcinogenesis [43]. NFB can also
induce production of proinflammatory cytokines, which will
enhance the inflammatory responses. In normal state NFB
is inhibited by its inhibitory protein (IB) which can down
regulate the inflammatory response.
The main chemical effectors in inflammatory response
are free radical species derived from oxygen. Free radicals
may act as direct or indirect damaging agents through their
reaction with other chemical or structural components in
target cells. ROS can also recruit other inflammatory cells
leading to additional ROS production and amplify the
damage [32].
Chronic inflammation is also associated with
angiogenesis [44]. Macrophages, platelets, fibroblasts, and
tumor cells are a major source of angiogenic factors such as:
basic fibroblast growth factor, vascular endothelial growth
factor, prostaglandins-E1 and E2 [37]. These inflammatory
angiogenic mediators augment the production of ROS/RNS
and subsequently, increase the risk of cancer [45]. Pros-
taglandins are derived from the metabolism of arachidonic
acid in inflammatory cells, and have been shown to
contribute to cancer development by many researches [46,
47]. It has been suggested that Prostaglandins can increase
the risk of cancer by inducing the expression of inflam-
matory cytokines, which in turn enhance ROS and RNS
76 Recent Patents on Inflammation & Allergy Drug Discovery 2009, Vol. 3, No. 1 Khansari et al.
Cyclooxygenase (COX) is a key enzyme responsible for
the biosynthesis of prostaglandins from arachidonic acid.
COX exists in two isoforms commonly referred to as COX-1
and COX-2. During inflammation COX-2 is the main
enzyme that is unregulated in the macrophages. This enzyme
is also expressed in noninflammatory cells such as fibro-
blasts, epithelial and endothelial cells. Bacterial infections
and inflammatory cytokines increase COX-2 expression [48,
49]. Many research and investigations revealed that COX-2
production is increased in many cancers such as colon,
breast, lung, esophagus, and head and neck cancer. Studies
from COX-2 transgenic mice and knockout mice confirm
that COX-2 plays a role in colon cancer development, both
through angiogenesis and through the activation of different
oncogenes, including v-src, v-ha-ras, her-2/neu and wnt [50].
Free radicals react with membrane phospholipids gene-
rating hydroperoxides, lipoperoxides and toxic aldehydes
such as MDA, which in turn may alter membrane
permeability and microcirculation.
It is now known that many oncogenes act by inhibiting
apoptosis, thereby conferring a survival advantage to
preneoplastic and malignant cells. On the other hand, several
chemotherapeutic drugs exert their action by promoting cell
death via increasing ROS production [51]. Carcinogenesis
may be mediated by ROS and RNS directly by chronic
inflammation (oxidation, nitration of nuclear DNA/RNA or
lipids), or may be mediated indirectly by the products of
ROS/RNS, proteins, lipids, and carbohydrates that are
capable of forming DNA adducts [52]. ROS can also
increase the expression of transcriptional factors such as c-
fos and c-jun involved in neoplastic transformation and
enhancement of tumor angiogenesis [32].
To date, more than 100 oxidized DNA products have
been identified. ROS-induced DNA damage involves single
or double stranded DNA breaks; purine, pyrimidine or
deoxyribose modifications; DNA intrastrand adducts; and
DNA-protein crosslinks [53]. DNA damage can result in
either transcriptional arrest or induction/replication errors, or
genomic instability, which all these processes are associated
with carcinogenesis [54].
The importance of OH in DNA damage process is not
completely understood because it has a very short half-life
and must be produced directly adjacent to DNA to induce
damage. However, peroxynitrite (ONOO-) can diffuse within
cells, and cause damage during chronic inflammation [55].
The less reactive molecules such as nitric oxide (NO) can be
released from innate immune cells specially macrophages
and act on neighboring cells, leading to somatic mutations
and cancer [56]. Nitric oxide can react with superoxide and
form ONOO-. This reactive intermediate can induces
oxidative DNA damage. Moreover, ONOO- participates to
the formation of 8-oxo-7, 8-dihydro-20-deoxyguanosine and
8-nitroguanine, which are biomarkers for inflammation-
induced carcinogenesis [57-59]. It has been recognized that
8-nitroguanosine is a highly mutagenic molecule and can
give rise to G>T transversions [60,61]. In lung and liver
cancer, G>T transversions have been observed in vivo in the
ras gene and the p53 tumor suppressor gene [62]. These
findings indicate that ROS and RNS may participate in
carcinogenesis, by both activation of proto-oncogenes and
inactivation of tumor suppressor genes.
Oxidative damage to mitochondria is also implicated in
carcinogenesis. Hydrogen peroxide and other ROS activate
nuclear genes that regulate the biogenesis, transcription and
replication of the mitochondrial genome. Recently, a large
amount of evidence supports mitochondria involvement in
carcinogenesis [5]. MtDNA fragments have been found
inserted into nuclear DNA, suggesting a possible mechanism
of oncogene activation. As noted previously, MtDNA is
vulnerable to free radical damage because of the lack of
histone proteins [63-65]. Free radical induced MtDNA
damage reflects as mitochondrial respiratory chain dysfunc-
tion, which in turn increases the production of hydroxyl
radicals and further DNA damage [66, 67]. Mutations and
altered expression in mitochondrial genes encoding for
complexes III, IV, V, and I and in the hypervariable regions
of mitochondrial DNA have been identified in various
human cancers [68-70].
Free radicals can alter cell growth and tumor promotion
by activating signaling pathways, which result in the
induction of growth stimulatory proto oncogenes, like c-fos,
c-jun, and c-myc [71]. It has been shown that that phos-
phorylation and poly-ADP-ribosylation of chromosomal
proteins are involved in the transcription of c-fos by
oxidants, and that a pro-oxidant state can promote neoplastic
growth [72, 73]. Cancer promotion can be explained by a
consequence of extensive and continued free-radical related
damage [74].
Many investigations have shown that DNA is not the
only molecule at risk of oxidative damage. In addition to
DNA damage, free radicals interfere with cellular mutation
repair systems in parallel. These interference include:
function of proteins such as DNA repair enzymes, apoptotic
modulators, and the p53 protein which may be modified
during exposure to free radicals. It has been shown that p53
is post-translationally modified at crucial residues after
exposure to NO and its derivatives [75]. Moreover, DNA-
repair and signal-transduction molecules such as DNA-
protein kinases are activated by exposure to NO [75]. NO
can participate in carcinogenesis by influencing the proteins
that are crucial to cell function, including cell-cycle
checkpoints, apoptosis and DNA repair [76].
Generally, there are two types of theories describing the
aging processes: damage-accumulation theories [77] and
genetic theories [78]. Damage accumulation theories include
the “free radical theory”, the “glycation theory”, the “error
catastrophe theory”, the “membrane theory”, the “entropy
theory” and others, among which the “free radical theory” is
probably the most complex approach to explain the aging
processes. The “free radical theory” is based on the fact that
the random deleterious effects of free radicals produced
during O2 metabolism accumulate over time, causing
damage to DNA, lipids, and proteins [79]. The genesis of
aging starts with oxygen, occupying the final position in the
electron transport chain [6]. Even under ideal conditions,
Chronic Inflammation & Cancer Recent Patents on Inflammation & Allergy Drug Discovery 2009, Vol. 3, No. 1 77
some electrons leak from the electron transport chain. These
leaking electrons interact with oxygen to produce superoxide
radicals. Under physiological conditions about 3% of the
oxygen molecules in the mitochondria are converted into
superoxide. As noted above, the primary site of radical
oxygen damage from superoxide radicals is mtDNA.
Therefore, extensive MtDNA damage accumulates over time
and eventually shuts down mitochondria, causing cells to die
and the organism to age. Many correlations between oxygen
consumption and aging have been observed [80]. Lowered
oxygen consumption explains why queen bees live 50 times
longer than actively flying worker bees, and houseflies that
are prevented from flying (by removing their wings) lived
much longer than flying insects. Larger animals consume
less oxygen per unit of body mass than smaller ones, and live
longer. Different rates of ROS generation also influence the
life span of animals. For example, rats and pigeons have
similar metabolic rates but different life spans (rat: 3 years,
pigeon: 30 years). in vitro Experiments show that pigeon
tissues generate ROS more slowly than rat mitochondria.
Caloric restriction in rodents plays an important role in the
aging process and is associated with increased DNA repair
capacity, decreased production of superoxide, and decreased
levels of DNA, lipids, and proteins damage. Longer-lived
species have more efficient antioxidant protective mecha-
nisms (SOD, carotenoids, GSH, glutathione peroxidase, and
Vitamin E) in relation to oxygen uptake rates than do the
short-lived species. Koya disclosed methods of treating a
proliferative disease, such as cancer, with bis (thio-hydrazide
amides) or a tautomer, pharmaceutically acceptable salt,
solvate, clathrate, or prodrug thereof, in combination with
hyperthermia treatment. Also disclosed are methods of
treating a proliferative disease, such as cancer, with bis (thio-
hydrazide amides) or a tautomer, pharmaceutically accep-
table salt, solvate, clathrate, or prodrug thereof, in combi-
nation with radiotherapy [81].
In humans, the level of oxidative DNA damage as
measured by urinary biomarkers can be modulated by caloric
restriction and dietary composition [82]. Consequently,
longevity may depend not only on the basal metabolic rate
but also on dietary caloric intake. The accumulation of free
radical-induced damage to biomolecules is illustrated by an
age-related increase in the serum 8-hydroxydeoxyguanosine
(8-OH-dG) level in disease-free individuals over a range of
15-91 years [5]. Several studies have reported the in vivo and
in vitro accumulation of 8-OH-dG as well as other lesions
with advancing age, both in nuclear and mitochondrial DNA
[83]. DNA repair capacity correlates with species-specific
life span, and this repair activity appears to decline with
advancing age. However, several animal studies reported that
age-related increase in 8-OH-dG in nuclear and
mitochondrial DNA is due to a tissue’s increased sensitivity
to oxidative damage rather than age-related decreased repair
capacity. However, antioxidant level does not change
significantly with advancing age. Human studies have shown
that the level of SOD, GSH, catalase, and ceruloplasmin
were not altered among a wide-range of age groups [84].
Studies in many different animals show that aging is
frequently associated with the accumulation of oxidized
proteins. The role of protein modification in aging is
illustrated by different enzymes isolated from younger
animals that are catalytically more active and more heat
stable than the same enzymes isolated from older animals
[85]. Enzymes derived from young animals exposed to
metal-catalyzed oxidation led to changes in activity and heat
stability similar to those observed during aging. Thus, it was
proposed that ROS-mediated protein damage is involved in
the aging processes.
A number of studies have examined the effects of aging
on lipid peroxidation in mammalian tissues by measuring
thiobarbituric acid-reactive (TBARS) content as a marker of
endogenous lipid peroxidation [86]. It has been reported that
aging is associated with a 50% increase in TBARS in male
rat’s liver, but the effect of aging in female rats was a 50%
decrease in hepatic TBARS. Curiously, the age-dependent
differences in TBARS concentration were not related to
changes in antioxidant molecules [87]. It has been reported
that, age-associated changes are observed in some organs but
are not evident in others. The data for male Wistar rats, for
instance, indicate that TBARS may increase with age in liver
and brain, but not in heart or lung [88]. Myhill et al.
Disclosed a method for reducing the undesirable side effects
of free radicals in a subject by administering to a subject in
need of such antioxidants an effective amount of antioxidant-
promoting composition of the invention [89].
Although fewer similar studies have been carried out in
mice, these studies also have produced conflicting results.
For example, hepatic TBARS concentrations were elevated
in old female C57BL mice but were unaffected by aging in
males [90,91]. The effects of age and gender differ from
those reported for rat liver, where elevated TBARS are
observed in old males, but not in old females [86].
Altogether, the findings suggest that age-associated changes
are species-, strain-, sex-, and tissue-specific, and that
increased lipid peroxidation is not an inevitable consequence
of aging in any organ.
Review of the published data indicates that age-related
changes in antioxidant defenses are quite varied. Many
studies have shown that one or more antioxidant enzymes or
molecules decrease as a consequence of aging. This has led
to the belief that aging is associated with a decrease in
antioxidant status and that age-dependent increases in lipid
peroxidation are consequences of diminished antioxidant
protection [86].
Changes in mitochondrial enzymes differ from those
found in cytosolic enzymes. Significant differences between
young adult and old rats were demonstrated for GSH
peroxidase, superoxide dismutase, and GSSG reductase
activities. These differences included age-related increases as
well as decreases and were different for males than for
females [88]. Heaney et al. utilized fructose and other
monosaccharides for the treatment of cancer. They used
these compounds to mimic or corrupt metabolic pathways of
fructose and/or signal transduction pathways related to
cancer cells for the treatment of cancer [92].
78 Recent Patents on Inflammation & Allergy Drug Discovery 2009, Vol. 3, No. 1 Khansari et al.
In one half century ago, Harman proposed free radical
theory of aging based on his observation that irradiation of
living things will increase free radicals in the body inducing
changes similar to aging processes and shortening their
lifespan [91].
A free radical is any chemical species like: molecule, ion
or atom that contains an unpaired or odd electron in its outer
orbit of its molecule. Most common source of these
chemicals in biological system is oxygen and to a lesser
extends nitrogen molecules. The most abundant source of
free radical formation is mitochondria which use more than
90% of oxygen intake to burn proteins, lipids, and
hydrocarbons and convert them to energy and water (cellular
metabolism and energy production). This is the link between
the high calory theory of aging and free radical theory of
aging. The second source of free radicals is the byproducts of
oxidative burst in activated neutrophils and monocyte/
macrophages in response to inflammation and microbial
infections or even tissue injuries leading to release of pro-
inflammatory cytokines. This is the basis of “inflammation
theory of aging”.
In addition to generation of free radicals, as byproducts
of cellular metabolism and immune response to infection,
intracellular induction of this molecule from environmental
sources such as ultraviolet and ionizing radiation, ozone, etc.
contribute to consumption of free radical scavenging
mechanism (antioxidants) resulting to excessive level of free
radical in the body and leading to oxidative stress.
Many important molecules including proteins, lipids, and
nucleic acid chains are very susceptible to oxidizing
reactions; thus, it is not unexpected to see many deteriorating
events following oxidative stress leading to decrease
longevity of the cells as well as living organisms. In fact,
certain strains of fruit flays that have greater resistance to
oxidative stress, exhibit longer lifespan. Free radical attacks
to macromolecule especially highly susceptible molecules
such as DNA and RNA can knock out bases or cause a
strand breakage with potential to cellular transformation or
even cell apoptosis. It has been estimated more than 10000
oxidative hits to DNA occur in an average human cell per
day [3]. This would describe how oxidative stress can
increase rate of cell transformation (malignancy).
It has been shown that nonsteroidal anti-inflammatory
drugs (NSAID) can prevent incidence of several cancers in
families with history of high cancer risk. It has also been
shown that indomethacine blocks carcinogenesis by reducing
the production certain cytokines called pro-inflammatory
cytokines (IL-1, IL-6, IL-15 and TNF-). Moreover, it has
been demonstrated that those people who regularly take
NSAID show a lower cancer risk [93].
On the basis of these considerations, pro-inflammatory
cytokines are key elements in malignant transformation of
the cells and pro-angiogenic activities leading to cancer;
thus, chronic inflammation should be considered as a high
risk factor for cancer causing especially in elderly people;
since, increase of oxidizing reaction in one hand and immune
senescence in the other hand will predispose the individual to
harbor tumor and die from it. Based on these analogies, it
should be recommended that elderly people should consume
higher anti-oxidant compounds, and take NSAID regularly.
It is also recommended that any chronic inflammatory
disease and /or infection must be taken seriously and treated
effectively as soon as possible by the practitioners.
The authors would like to thank the Department of
Immunology, School of Medicine, TUMS for providing
partial financial support for this article.
[1] Allavena P, Sica A, Solinas G, Porta C, Mantovanii A. The
inflammatory micro environment in tumor progression: The role of
tumor-associated macrophages. Crit Rev Oncol Hematol 2008;
66(1): 1-9.
[2] Hold GL, El-Omar ME. Genetic aspects of inflammation and
cancer. Biochem J 2008 1; 410(2): 225-235.
[3] Harman D. Free radical theory of aging: history. In: Emerita I,
Chance B Eds., Free Radicals and Aging, Birkhauser-Verlag, Basel
1992; 1-10.
[4] Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J.
Free radicals and antioxidants in normal physiological functions
and human disease. Int J Biochem Cell Biol 2007; 39(1): 44-84.
[5] Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M. Free
radicals, metals and antioxidants in oxidative stress-induced cancer.
Chem Biol Interact 2006; 160(1): 1-40.
[6] Wickens AP. Ageing and the free radical theory. Respir Physiol
2001; 128(3): 379-391.
[7] Inoue M, Sato EF, Nishikawa M, et al. Mitochondrial generation of
reactive oxygen species and its role in aerobic life. Curr Med Chem
2003; 10(23): 2495-2505.
[8] Conner EM, Grisham MB. Inflammation, free radicals, and
antioxidants. Nutrition 1996; 12(4): 274-277.
[9] Klaunig JE, Kamendulis LM. The role of oxidative stress in
carcinogenesis. Annu Rev Pharmacol Toxicol 2004; 44: 239-267
[10] Roberts RA, Gary PE, Ju C, et al. Role of the Kuppfer cell in
mediating hepatic toxicity and arcinogenesis. Toxicol Sci 2007; 96:
[11] Mateos R, Bravo L. Chromatographic and electrophoretic methods
for analysis of biomarkers of oxidative damage to macromolecules
(DNA, lipids, and proteins). J Sep Sci 2007; 30: 175-179.
[12] Lippman RD. Lipid peroxidation and metabolism in aging. In:
Rothstein, M. Ed Review of Biological Research in Aging, Alan R.
Liss, New York 1983; 1: 315-342.
[13] Ran O, Gu M, Van Remmen H, et al. Glutatione peroxidase 4
protects cortical neurons from oxidative injury and amyloid
toxicity. J Neurosci Res 2006; 84: 202-208.
[14] Stadtman ER. The status of oxidatively modified proteins as a
marker of aging. In: Esser K, Martin GM. Eds. Molecular Aspects
of Aging. Wiley, Chichester 1995; 129-144.
[15] Ames BN, Shigenaga MK, Hagen TM. Oxidants, antioxidants, and
the degenerative diseases of aging. Proc Natl Acad Sci USA 1993;
90(17): 7915-7922.
[16] Linn S. DNA repair in mitochondria: How is it limited? What is its
function? In: Esser K, Martin GM. Eds. Molecular Aspects of
Aging. Wiley, Chichester 1995; 199-225.
[17] Johnson FB, Sinclair D.A, Guarente L. Molecular biology of aging.
Cell1999; 96: 291-302.
[18] Pastoret A, Federici G, Bertini E, Piemonti F. Analysis of
glutathione: Implication in redox and detoxification. Clin Chim
Acta 2003; 333: 19-39.
[19] Ryan KA, Smith MF Jr, Sanders MK, Ernst PB. Reactive oxygen
and nitrogen species differentially regulate Toll-like receptor 4-
mediated activation of NF kappaB and interleukin-8 expression.
Infect Immun 2004; 72: 2123-2130.
[20] Emmendoerffer A, Hecht M, Boeker T, Mueller M, Heinrich U.
Role of inflammation in chemical-induced lung cancer. Toxicol
Lett 2000; 112-113: 185-191.
[21] Costa AD, Garlid KD. Intramitochondrial signaling: interactions
among mitoKATP, PKC epsilon, ROS and MPT. Am J Physiol
Heart Circ Physiol 2007; 294: 874-882.
Chronic Inflammation & Cancer Recent Patents on Inflammation & Allergy Drug Discovery 2009, Vol. 3, No. 1 79
[22] Flalkow L, Wang Y, Downey GP. Reactive oxygen and nitrogen
species as signaling molecules regulating neutrophil function. Free
Radic Biol Med 2007; 42: 153-164.
[23] Segal W. How superoxide production by neutrophil leukocytes kill
microbe. Novartis Found Symp 2006; 279: 92-98.
[24] Coussens LM, Werb Z. Inflammation and cancer. Nature 2002;
420: 860-867.
[25] Bartsch H, Nair J. Chronic inflammation and oxidative stress in the
genesis and perpetuation of cancer: Role of lipid peroxidation,
DNA damage and repair. Langenbecks Arch Surg 2006; 391: 499-
[26] Azad N, Rojanasakul Y, Vallyathan V. Inflammation and lung
cancer: roles of reactive oxygen/nitrogen species. J Toxicol Environ
Health B Crit Rev 2008; 11(1): 1-15.
[27] Cook JA, Gius D, Wink DA, Krishna MC, Russo A, Mitchell JB.
Oxidative stress, redox, and the tumor microenvironment. Semin
Radiat Oncol 2004; 14: 259-266.
[28] Haddad JJ. Cytokines and related receptor-mediated signaling
pathways. Biochem Biophys Res Commun 2002 Oct 4; 297(4):
[29] Miyajima A, Kitamura T, Harada N, Yokota T, Arai K. Cytokine
receptors and signal transduction. Annu Rev Immunol 1992; 10:
[30] Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its
receptors. Nat Med 2003; 9: 669-676.
[31] Chapple IL. C Reactive oxygen species and antioxidants in
inflammatory diseases. J Clin Periodontol 1997; 24: 287-296.
[32] Federico A, Morgillo F, Tuccillo C, Ciardiello F, Loguercio C.
Chronic inflammation and oxidative stress in human
carcinogenesis. Int J Cancer 2007; 121(11): 2381-2386.
[33] Dedera DA, Urashima M, Chauhan D, et al. Interleukin-6 is
required for pristaine-induced plasma cell hyperplasia in mice. Br J
Haematol 1996; 94: 53-61.
[34] Hinson RM, Williams JA, Shacter E. Elevated interleukin 6 is
induced by prostaglandin E2 in a murine model of inflammation:
possible role of cyclooxygenase-2. Proc Natl Acad Sci USA 1996;
93: 4885-4890.
[35] Shacter E, Arzadon GK, Williams J. Elevation of IL-6 in response
to a chronic inflammatory stimulus in mice: Inhibition by
indomethacin. Blood 1992; 80: 194-202.
[36] Moore RJ, Owens DM, Stamp G, et al. Mice deficient in tumor
necrosis factor-a are resistant to skin carcinogenesis. Nat Med
1999; 5: 828-831.
[37] Zouki C, Jozsef L, Ouellet S, Paquette Y, Filep JG. Peroxynitrite
mediates cytokine-induced IL-8 gene expression and production by
human leukocytes. J Leukoc Biol 2001; 69: 815-824.
[38] Mantovanii A, Pierotti MA. Cancer and inflammation: A complex
relationship. Cancer Lett 2008 (article in press).
[39] Nathan C. Points of control in inflammation. Nature 2002; 420:
[40] Ames BN, Gold LS, Willett WC. The causes and prevention of
cancer. Proc Natl Acad Sci USA 1995; 92: 5258-5265.
[41] Slaga TJ, Lichti U, Hennings H, Elgjo K, Yuspa SH. Effects of
tumor promoters and steroidal anti-inflammatory agents on skin of
newborn mice in vivo and in vitro. J Natl Cancer Inst 1978; 60:
[42] Hinson RM, Williams JA, Shacter E. Elevated interleukin 6 is
induced by prostaglandin E2 in a murine model of inflammation:
Possible role of cyclooxygenase-2. Proc Natl Acad Sci USA 1996;
93: 4885-4890.
[43] Akira S, Kishimoto T. NF-IL6 and NFkappaB in cytokine gene
regulation. Adv Immunol1997; 65: 1-46.
[44] Jackson JR, Seed MP, Kircher CH, Willoughby DA, Winkler JD.
The codependence of angiogenesis and chronic inflammation.
FASEB J 1997; 11: 457-465.
[45] Shacter E, Arzadon GK, Williams J. Elevation of IL-6 in response
to a chronic inflammatory stimulus in mice: Inhibition by
indomethacin. Blood 1992; 80: 194-202.
[46] Baron JA, Sandler RS. Nonsteroidal anti-inflammatory drugs and
cancer prevention. Annu Rev Med 2000; 51: 511-523.
[47] Prescott SM, Fitzpatrick FA. Cyclooxygenase-2 and
carcinogenesis. Biochim Biophys Acta 2000; 1470: M69-M78.
[48] Howe LR, Dannenberg AJ. A role for cyclooxygenase-2 inhibitors
in the prevention and treatment of cancer. Semin Oncol 2002; 29:
[49] Dannenberg AJ, Altorki NK, Boyle JO, et al. Cyclooxygenase 2: A
pharmacological target for the prevention of cancer. Lancet Oncol
2001; 2: 544-551.
[50] Howe LR, Subbaramaiah K, Brown AM, Dannenberg AJ.
Cyclooxygenase- 2: A target for the prevention and treatment of
breast cancer. Endocr Relat Cancer 2001; 8: 97-114.
[51] Johnstone RW, Ruefli AA, Lowe SW. Apoptosis: A link between
cancer genetics and chemotherapy. Cell 2002; 108: 153-164.
[52] Jabs T. Reactive oxygen intermediates as mediators of programmed
cell death in plants and animals. Biochem Pharmacol 1999; 57:
[53] Valko M, Morris H, Cronin MT. Metals, toxicity and oxidative
stress. Curr Med Chem 2005; 12: 1161-1208.
[54] Marnett LJ. Oxyradicals and DNA damage. Carcinogenesis 2000;
21: 361-370.
[55] Radi R. Peroxynitrite reactions and diffusion in biology. Chem Res
Toxicol 1998; 11; 720-721.
[56] Thomas DD, Liu X, Kantrow SP, Lancaster JR. The biological
lifetime of nitric oxide: implications for the perivascular dynamics
of NO and O2. Proc Natl Acad Sci USA 2001; 98: 355-360.
[57] Inoue S, Kawanishi S. Oxidative DNA damage induced by
simultaneous generation of nitric oxide and superoxide. FEBS Lett
1995; 371: 86-88.
[58] Yermilov V, Rubio J, Becchi M, Friesen MD, Pignatelli B,
Ohshima H. Formation of 8-nitroguanine by the reaction of guanine
with peroxynitrite in vitro. Carcinogenesis 1995; 16: 2045-2050.
[59] Akaike T, Okamoto S, Sawa T, et al. 8-Nitroguanosine formation in
viral pneumonia and its implication for pathogenesis. Proc Natl
Acad Sci USA 2003; 100: 685-690.
[60] Zaki MH, Akuta T, Akaike T. Nitric oxide-induced nitrative stress
involved in microbial pathogenesis. J Pharmacol Sci 2005; 98: 117-
[61] Suzuki N, Yasui M, Geacintov NE, Shafirovich V, Shibutani S.
Miscoding events during DNA synthesis past the nitration-damaged
base 8-nitroguanine. Biochemistry 2005; 44: 9238-9245.
[62] Hsu IC, Metcalf RA, Sun T, Welsh JA, Wang NJ, Harris CC.
Mutational hotspot in the p53 gene in human hepatocellular
carcinomas. Nature 1991; 350: 427-428.
[63] Albring M, Griffith J, Attardi G. Association of a protein structure
of probable membrane derivation with HeLa cell mitochondrial
DNA near its origin of replication. Proc Natl Acad Sci USA 1977;
74: 1348-1352.
[64] Clayton DA. Transcription of the mammalian mitochondrial
genome. Annu Rev Biochem 1984; 53: 573-594.
[65] Yakes FM, Van Houten B. Mitochondrial DNA damage is more
extensive and persists longer than nuclear DNA damage in human
cells following oxidative stress. Proc Natl Acad Sci USA 1997; 94:
[66] Beckman KB, Ames BN. Oxidative decay of DNA. J Biol Chem
1997; 272: 19633-19636.
[67] Berlett BS, Stadtman ER. Protein oxidation in aging, disease, and
oxidative stress. J Biol Chem 1997; 272: 20313-20316.
[68] Fliss MS, Usadel H, Caballero OL, et al. Facile detection of
mitochondrial DNA mutations in tumors and bodily fluids. Science
2000; 287: 2017-2019.
[69] Richard SM, Bailliet G, Paez GL, Bianchi MS, Peltomaki P,
Bianchi NO. Nuclear and mitochondrial genome instability in
human breast cancer. Cancer Res 2000; 60: 4231-4237.
[70] Polyak K, Li Y, Zhu H, et al. Somatic mutations of the
mitochondrial genome in human colorectal tumours. Nat Genet
1998; 20: 291-293.
[71] Carcamo JM, Golde DW. Antioxidants prevent oxidative DNA
damage and cellular transformation elicited by the over-expression
of c-Myc. Mutat Res 2006; 593: 64-79.
[72] Shalon D, Smith SJ, Brown PO. A DNA microarray system for
analyzing complex DNA samples using two-color fluorescent probe
hybridization. Genome Res 1996; 6: 639-645.
[73] Cerutti PA. Prooxidant states and tumor promotion. Science 1985;
227: 375-381.
[74] Hussain SP, Hofseth LJ, Harris CC. Radical causes of cancer. Nat
Rev Cancer 2003; 3[4): 276-285.
[75] Marshall HE, Merchant K, Stamler JS. Nitrosation and oxidation in
the regulation of gene expression. FASEB J 2000; 14: 1889-1900.
[76] Pervin S, Singh R, Chaudhuri G. Nitric oxide-induced cytostasis
and cell cycle arrest of a human breast cancer cell line [MDA-MB-
80 Recent Patents on Inflammation & Allergy Drug Discovery 2009, Vol. 3, No. 1 Khansari et al.
231): potential role of cyclin D1. Proc Natl Acad Sci USA 2001;
98: 3583-3588.
[77] Martinez DE. Rejuvenation of the disposable soma: repeated injury
extends lifespan in asexual annelid. Exp Gerontol 1996; 31: 699-
[78] Martin GM. Modalities of gene action predicted by the classical
evolutionary biological theory of aging. Ann NY Acad Sci 2007;
1000: 14-20.
[79] Gilca M, Stoian I, Atarasiu V, et al. The oxidative hypothesis of
senescence. J Postgrad Med 2007; 53: 207-213.
[80] Figueiredo PA, Mota MP, Appell HJ, Duarte JA. The role of
mitochondria in aging of skeletal muscle. Biogerontology 2008; 9:
[81] Koya, K.: US20080119440 (2008).
[82] Dalle-Donne I, Scaloni A, Giustarini D, Milzani A. Biomarkers of
oxidative damage in human diseases. Clin Chem 2006; 52: 601-
[83] Valko M, Izakovic M, Mazur M, Rhodes CJ, Telser J. Role of
oxygen radicals in DNA damage and cancer incidence. Mol Cell
Biochem 2004; 266: 37-56.
[84] Barnett YA, King CM. Investigation of antioxidant status. DNA-
repair capacity and mutation as a function of age in humans. Mut
Res 1995; 338: 115-128.
[85] Stadtman ER. Role of oxidant species in aging. Curr Med Chem
2004; 11: 1105-1112.
[86] Rikans LE, Hornbrook KR. Lipid peroxidation, antioxidant
protection and aging. Biochim Biophys Acta 1997; 1362: 116-127.
[87] Rikans LE, Moore DR, Snowden CD. Sex-dependent differences in
the effects of aging on antioxidant defense mechanisms of rat liver.
Biochim Biophys Acta 1991; 1074: 195-200.
[88] Perez R, Lopez M, Barja de Quiroga G. Aging and lung antioxidant
enzymes, glutathione, and lipid peroxidation in the rat. Free Radic
Biol Med 1991; 10: 35-39.
[89] Myhill, P.R., Driscoll, W.J.: US20087384655 (2008).
[90] Massie HR, Aiello VR, Banziger V. Iron accumulation and lipid
peroxidation in aging C57BL/6J mice. Exp Gerontol 1983; 18: 277-
[91] Koizumi A, Weindruch R, Walford RL. Influences of dietary
restriction and age on liver enzyme activities and lipid peroxidation
in mice. J Nutr 1987; 117: 361-367.
[92] Heaney, A. P., Hui, H.: WO07025238 (2007).
[93] Ames BN, Shigenaga MK, Hagen TM. Oxidants, antioxidants and
the generative diseases of aging. Proc Natl Acad Sci USA 1993; 90:
... Oxidative stress (OS) and inflammatory responses (IRs) are interdependent processes, closely related to chronic diseases, including NCDs [5][6][7][8][9][10]. OS is an important phenomenon in cells and tissues reflecting an imbalance between the production of pro-oxidant species and the ability of a biological system to counteract/detoxify their harmful effects through antioxidants. ...
... This specific condition can lead to cellular damage affecting intracellular structures, including protein, lipids, and DNA, as well as mitochondrial function, extra-cellular matrix remodelling, and cell growth [9]. The exposure to chronic OS induces a subclinical state of increasing cell damage that builds up over time, facilitating tissue alteration/remodelling, selective system failures, and finally disease [7,9,11]. On the other hand, OS-induced damage to tissues can also trigger an IR and thus the release of inflammatory mediators, which in turn can directly induce OS [12,13]. ...
... In turn, the increased levels of pro-inflammatory cytokines result in the hepatic generation of acutephase proteins, including C-reactive protein (CRP). Its release and secretion further fuel the recruitment and accumulation of inflammatory cells to the damage site, accelerating the production of reactive species and, thereby, further stimulate ongoing OS [7,12,13]. Therefore, the vicious circle linking OS and IRs sustains and amplifies all stages of the disease. ...
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Inflammation and oxidative stress are interlinked and interdependent processes involved in many chronic diseases, including neurodegeneration, diabetes, cardiovascular diseases, and cancer. Therefore, targeting inflammatory pathways may represent a potential therapeutic strategy. Emerging evidence indicates that many phytochemicals extracted from edible plants have the potential to ameliorate the disease phenotypes. In this scenario, ß-caryophyllene (BCP), a bicyclic sesquiterpene, and carnosic acid (CA), an ortho-diphenolic diterpene, were demonstrated to exhibit anti-inflammatory, and antioxidant activities, as well as neuroprotective and mitoprotective effects in different in vitro and in vivo models. BCP essentially promotes its effects by acting as a selective agonist and allosteric modulator of cannabinoid type-2 receptor (CB2R). CA is a pro-electrophilic compound that, in response to oxidation, is converted to its electrophilic form. This can interact and activate the Keap1/Nrf2/ARE transcription pathway, triggering the synthesis of endogenous antioxidant “phase 2” enzymes. However, given the nature of its chemical structure, CA also exhibits direct antioxidant effects. BCP and CA can readily cross the BBB and accumulate in brain regions, giving rise to neuroprotective effects by preventing mitochondrial dysfunction and inhibiting activated microglia, substantially through the activation of pro-survival signalling pathways, including regulation of apoptosis and autophagy, and molecular mechanisms related to mitochondrial quality control. Findings from different in vitro/in vivo experimental models of Parkinson’s disease and Alzheimer’s disease reported the beneficial effects of both compounds, suggesting that their use in treatments may be a promising strategy in the management of neurodegenerative diseases aimed at maintaining mitochondrial homeostasis and ameliorating glia-mediated neuroinflammation.
... There is a strong correlation between oxidative stress and the development of various degenerative diseases such as cancer and other aging-related diseases [65,66]. Extensive in vitro and in vivo studies have been performed to evaluate the antioxidant activity of CGAs [67]. ...
... Therefore, there is enough evidence to support that CGA S can inhibit the formation of reactive oxygen species and play a beneficial role in preventing oxidative and aging-related diseases [65,66]. However, studies indicate that these compounds may also act as potent pro-oxidants. ...
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... One of the factors that causes NCDs, especially HTN, is oxidative stress. Oxidative stress is a key factor in the pathogenesis of chronic diseases through free radicals, leading to biological damage [6]. Oxidative stress, by creating an imbalance between peroxidation and antioxidants, leads to potential changes in endothelial cells and can act as an auxiliary mechanism in causing high blood pressure [7]. ...
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Background Antioxidants intake from diet has been identified as one of the effective factors in the development of hypertension (HTN). The present study aimed to investigate the association between total antioxidant capacity (TAC) and HTN in women. Methods This cross-sectional study was performed using the baseline phase data of the ravansar non-communicable disease cohort study. The TAC was calculated using food items of the food frequency questionnaire. TAC scores were classified into four groups (quartile). The first and fourth quartiles had the lowest and highest TAC scores, respectively. Logistic regression analysis was utilized to estimate the odds ratio. Results A total of 5067 women were included in the study. Women with the highest socioeconomic status (SES) had a significantly higher TAC intake compared to those with the lowest SES (P < 0.001). The participants in the third and fourth quartiles of the TAC had significantly lower odds of HTN, respectively by 21% (OR = 0.79; 95% CI: 0.64, 0.972) and 26% (OR = 0.74; 95% CI: 0.60, 0.91), compared to the first quartile. After adjusting for confounding variables was found to significantly reduce the odds of developing HTN in the fourth quartile of TAC by 22% compared to the first quartile (OR = 0.78; 95% CI: 0.62, 0.97). Conclusion A high dietary TAC was associated to a decreased odd of HTN in women. We could suggest a diet rich in natural antioxidants as it may help prevent development of HTN.
... Peroxyl is also formed from nonlipid substrates, such as proteins [26]. Once formed, peroxyl radicals trigger diverse inflammatory pathways, and are linked to disease development, such as neurodegenerative and cardiovascular disorders [27,28]. Therefore, the combined antioxidant and anti-NF-кB effects of GA4 present in organic foods are very promising for promoting health and preventing inflammatory diseases. ...
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Introduction: Gibberellins (GA) are terpenoids that serve as important plant hormones by acting as growth and response modulators against injuries and parasitism. In this study, we investigated the in vitro anti-NF-кB, anti-Candida, and antioxidant activity of gibberellin A4 (GA4) and A7 (GA7) compounds, and further determined their toxicity in vivo. Methods: GA4 and GA7 in vitro toxicity was determined by MTT method, and nontoxic concentrations were then tested to evaluate the GA4 and GA7 anti-NF-κB activity in LPS-activated RAW-luc macrophage cell culture (luminescence assay). GA4 in silico anti-NF-кB activity was evaluated by molecular docking with the software "AutoDock Vina", "MGLTools", "Pymol", and "LigPlot+", based on data obtained from "The Uniprot database", "Protein Data Bank", and "PubChem database". The GA4 and GA7 in vitro anti-Candida effects against Candida albicans (MYA 2876) were determined (MIC and MFC). GA7 was also evaluated regarding the viability of C. albicans preformed biofilm (microplate assay). In vitro antioxidant activity of GA4 and GA7 was evaluated against peroxyl radicals, superoxide anions, hypochlorous acid, and reactive nitrogen species. GA4 and GA7 in vivo toxicity was determined on the invertebrate Galleria mellonella larvae model. Results: Our data show that GA4 at 30 µ M is nontoxic and capable of reducing 32% of the NF-кB activation on RAW-luc macrophages in vitro. In vitro results were confirmed via molecular docking assay (in silico), since GA4 presented binding affinity to NF-кB p65 and p50 subunits. GA7 did not present anti-NF-кB effects, but exhibited anti-Candida activity with low MIC (94 mM) and MFC (188 mM) values. GA7 also presented antibiofilm properties at 940 mM concentration. GA4 did not present anti-Candida effects. Moreover, GA4 and GA7 showed antioxidant activity against peroxyl radicals, but did not show scavenging activity against the other tested radicals. Both compounds did not affect the survival of G. mellonella larvae, even at extremely high doses (10 g/Kg). Conclusion: Our study provides preclinical evidence indicating that GA4 and GA7 have a favorable low toxicity profile. The study also points to GA4 Citation: Nani, B.D.; Rosalen, P.L.; Lazarini, J.G.; de Cássia Orlandi Sardi, J.; Romário-Silva, D.; de Araújo, L.P.; dos Reis, M.S.B.; Breseghello, I.; Cunha, T.M.; de Alencar, S.M.; et al. A Study on the Anti-NF-кB, Anti-Candida and Antioxidant Activities of Two Natural Plant Hormones: Gibberellin A4 and A7. Pharmaceutics 2022, 14, 1347. https://doi.
... Overproduction of ROS reacts with lipid and cellular proteins to completely impair their function. Furthermore, free radicals can cause mutations and DNA damage, increasing the risk of cancer and age-related diseases [6]. ...
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Abstract Background Boswellia serrate is an ancient and highly valued ayurvedic herb. Its extracts have been used in medicine for centuries to treat a wide variety of chronic infammatory diseases. However, the mechanism by which B. serrata hydro alcoholic extract inhibited pro-infammatory cytokines in zebrafsh (Danio rerio) larvae with LPS-induced infammation remained unknown. Methods LC–MS analysis was used to investigate the extract’s phytochemical components. To determine the toxicity of B. serrata extract, cytotoxicity and embryo toxicity tests were performed. The in-vivo zebrafsh larvae model was used to evaluate the antioxidant and anti-infammatory activity of B. serrata extract. Results According to an in silico study using molecular docking and ADMET, the compounds acetyl-11-keto-boswellic and 11-keto-beta-boswellic acid present in the extract had higher binding afnity for the infammatory specifc receptor, and it is predicted to be an orally active molecule. In both in-vitro L6 cells and in-vivo zebrafsh larvae, 160 µg/mL concentration of extract caused a high rate of lethality. The extract was found to have a protective efect against LPS-induced infammation at concentrations ranged between 10 and 80 µg/mL. In zebrafsh larvae, 80 µg/mL of treatment signifcantly lowered the level of intracellular ROS, apoptosis, lipid peroxidation, and nitric oxide. Similarly, zebrafsh larvae treated with B. serrata extract (80 µg/mL) showed an increased anti-infammatory activity by lowering infammatory specifc gene expression (iNOS, TNF-α, COX-2, and IL-1). Conclusions Overall, our fndings suggest that B. serrata can act as a potent redox scavenger against LPS-induced infammation in zebrafsh larvae and an inhibitor of specifc infammatory genes
... Inflammatory processes induce oxidative stress and reduce cellular antioxidant capacity, causing loss of tissue integrity, impaired protein function, and DNA damage. Consequently, the combination of chronic inflammation and oxidative stress is a major hallmark of age-related diseases (Khansari et al., 2009). For instance, oxidative stress parameters like enhanced levels of malonaldehyde and superoxide anions and decreased SOD activity correlated with inflammation markers, including high sensitive C-reactive protein and fibrinogen, in patients with coronary heart disease (Kotur-Stevuljevic et al., 2007). ...
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... ROS are generated endogenously, but there are also many exogenous sources including cigarette smoke, ultraviolet radiation, and metal-catalyzed reactions [3,4]. Infections, inflammatory processes, especially those that are chronic, ischemia, senescence, physical and psychological stress are the main factors involved in generating oxidative stress in the human body [5]. The accumulation of high amounts of ROS in the skin is associated with structural changes in cell components, the release of inflammatory cytokines, apoptosis, activation of transcription factors such as activator protein 1 (AP-1), mitogen-activated protein kinase (MAPK) and nuclear kappa factor B (NF-kB). ...
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There is growing evidence that oxidative stress is involved in the pathogenesis of numerous conditions, including dermatological diseases. Various markers are available to assess oxidative stress, but none of these can be considered the ideal marker. Recent studies have shown that ischemia-modified albumin (IMA) is not only an indicator of ischemia, but also a marker of oxidative stress. We have conducted a narrative review to evaluate the role of IMA in dermatological diseases. We have identified 24 original articles that evaluated IMA in skin disorders (psoriasis, acne vulgaris, hidradenitis suppurativa, urticaria, vitiligo and Behcet’s disease) and hair disorders (alopecia areata, androgenetic alopecia and telogen effluvium). The results of the studies analyzed reveal that IMA may be considered a new marker of oxidative stress in dermatological diseases and offer new insights into the pathogenesis of these disorders and the theoretical basis for the development of new, effective, targeted therapies. To the best of our knowledge, this is the first review that gathers up data on the role of IMA in dermatological diseases.
Overproduction of reactive oxygen species (ROS) and alterations in metallostasis are common and related hallmarks in several neurodegenerative diseases (NDDs). Nature-based derivatives always represent an attractive tool in MTDL drug design, especially against ROS in NDDs. On this notion, we designed a new series of 8-quinoline-N-substituted derivatives with a natural antioxidant portion (i.e., lipoic, caffeic, and ferulic acids). These compounds were shown to chelate copper, a metal involved in ROS-induced degeneration, and scavenger oxygen radicals in DPPH assay. Then, selected compounds 4 and 5 were evaluated in an in vitro model of oxidative stress and shown to possess cytoprotective effects in 661W photoreceptor-like cells. The obtained results may represent a starting point for the application of the proposed class of compounds in retinal neurodegenerative diseases such as retinitis pigmentosa (RP), comprising a group of hereditary rod–cone dystrophies that represent a major cause of blindness in patients of working age, where the progression of the disease is a multifactorial event, with oxidative stress contributing predominantly.
Inflammation and immunity dysregulation have received widespread attention in recent years due to their occurrence in the pathophysiology of many conditions. In this regard, several pharmacological studies have been conducted aiming to evaluate the potential anti-inflammatory and immunomodulatory effects of phytochemicals. Epimedium, a traditional Chinese medicine, is often used as a tonic, aphrodisiac, and anti-rheumatic agent. Icariin (ICA) is the main active ingredient of Epimedium and is, once ingested, mainly metabolized into Icaritin (ICT). Data from in vitro and in vivo studies suggested that ICA and its metabolite (ICT) regulated the functions and activation of immune cells, modulated the release of inflammatory factors, and restored aberrant signaling pathways. ICA and ICT were also involved in anti-inflammatory and immune responses in several diseases, including multiple sclerosis, asthma, atherosclerosis, lupus nephritis, inflammatory bowel diseases, rheumatoid arthritis, and cancer. Yet, data showed that ICA and ICT exhibited similar but not identical pharmacokinetic properties. Therefore, based on their higher solubility and bioavailability, as well as trends indicating that single-ingredient compounds offer broader and safer therapeutic capabilities, ICA and ICT delivery systems and treatment represent interesting avenues with promising clinical applications. In this study, we reviewed the anti-inflammatory and immunomodulatory mechanisms, as well as the pharmacokinetic properties of ICA and its metabolite ICT.
The combination of natural resources with biologically active biocompatible ionic liquids (Bio-IL) is presented as a combinatorial approach for developing tools to manage inflammatory diseases. Innovative biomedical solutions were constructed combining silk fibroin (SF) and Ch[Gallate], a Bio-IL with antioxidant and anti-inflammatory features, as freeze-dried 3D-based sponges. An evaluation of the effect of the Ch[Gallate] concentration (≤3% w/v) on the SF/Ch[Gallate] sponges was studied. Structural changes observed on the sponges revealed that the Ch[Gallate] presence positively affected the β-sheet formation while not influencing the silk native structure, which was suggested by the FTIR and solid-state NMR results, respectively. Also, it was possible to modulate their mechanical properties, antioxidant activity and stability/degradation in an aqueous environment, by changing the Ch[Gallate] concentration. The architectures showed high water uptake ability and a weight loss that follows the controlled Ch[Gallate] release rate studied for 7 days. Furthermore, the sponges supported human adipose stem cells growth and proliferation, up to 7 days. TNF-α, IL-6 (pro-inflammatory) and IL-10 (anti-inflammatory) release quantification from a human monocyte cell line revealed a decrease in the pro-inflammatory cytokines concentrations in samples containing Ch[Gallate]. These outcomes encourage the use of the developed architectures as tissue engineering solutions, potentially targeting inflammation processes. Statement of Significance : Combining natural resources with active biocompatible ionic liquids (Bio-IL) is herein presented as a combinatorial approach for the development of tools to manage inflammatory diseases. We propose using silk fibroin (SF), a natural protein, with cholinium gallate, a Bio-IL, with antioxidant and anti-inflammatory properties, to construct 3D-porous sponges through a sustainable methodology. The morphological features, swelling, and stability of the architectures were controlled by Bio-IL content in the matrices. The sponges were able to support human adipose stem cells growth and proliferation, and their therapeutic effect was proved by the blockage of TNF-α from activated and differentiated THP-1 monocytes. We believe that these bio-friendly and bioactive SF/Bio-IL-based sponges are effective for targeting pathologies with associated inflammatory processes.
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Cytokines play a vital role in coordinating immune and inflammatory responses. Unlike growth factor receptors with a tyrosine kinase, cytokine receptors have no intrinsic tyrosine kinase activity. Based on their structure, cytokine receptors are classified into several groups. High affinity receptors for IL-2, IL-3, IL-5, IL-6, and GM-CSF are composed of at least two distinct subunits, alpha and beta. The alpha subunits are primary cytokine binding proteins, and the beta subunits are required for formation of high affinity binding sites as well as for signal transduction. The GM-CSF, IL-3, and IL-5 receptors appear to share the same beta subunit in human, and therefore cross-talk among these cytokines may occur at the receptor level. High affinity receptors presumably are linked to various signal transduction pathways that lead to different cytokine functions. Differential expression of the cytokine receptors as well as reorganization of intracellular signalling pathways are critical for development of hemopoietic cells.
S3/7 Intramitochondrial signaling — Interactions among mitoKATP, PKCε, ROS, and MPT Keith D. Garlid, Alexandre D.T. Costa Department of Biology, Portland State University, Portland OR, 97201, USA E-mail: Our aim was to apprehend the pathways by which mitoKATP opening leads to inhibition of the mitochondrial permeability transition (MPT), thereby reducing ischemia–reperfusion injury. We showed previously that mitoKATP is opened by activation of a mitochondrial PKCε, designated PKCε1, that is closely associated with mitoKATP. MitoKATP opening causes an increase in ROS production by Complex I of the respiratory chain. This ROS activates a second pool of PKCε, designated PKCε2, which inhibits the mitochondrial permeability transition (MPT). We measured mitoKATP-dependent changes in mitochondrial matrix volume to further investigate the relationships among PKCε, mitoKATP, ROS, and MPT. We present evidence that (1) H2O2 and NO cause mitoKATP opening that is mediated by PKCε1 and not by direct actions on mitoKATP; (2) superoxide has no effect on mitoKATP opening; (3) H2O2 or NO inhibits MPT opening, and both compounds do so independently of mitoKATP activity via activation of PKCε2; (4) mitoKATP opening induced by PKG, PMA or diazoxide is not mediated by ROS; and (5) mitoKATP-generated ROS activates PKCε1 and induces phosphorylation-dependent mitoKATP opening in vitro and in vivo. Thus, mitoKATP-dependent mitoKATP opening constitutes a positive feedback loop capable of maintaining the channel open after the stimulus is no longer present. This feedback pathway may be responsible for the lasting protective effect of preconditioning, colloquially known as the memory effect. doi:10.1016/j.bbabio.2008.05.106
The disposable soma theory of senescence proposes that aging is the result of the accumulation of somatic damage with age resulting from insufficient somatic maintenance and repair. Comparative studies that show a positive correlation between longevity and DNA excision repair efficiency in mammals provide support for the theory but their validity has been questioned. A more satisfactory approach to investigate the role of somatic damage accumulation in aging would be to manipulate experimentally the levels of somatic repair and observe its effect on longevity. Here I report the results of studies in the asexual annelid Paranais litoralis where I have experimentally extended the worms' lifespan by subjecting them to repeated injury. I propose that repeated injury enhanced the normal level of repair of the worms, resulting in a rejuvenation of the soma. These results provide experimental support for the disposable soma theory of senescence.
Alterations of oxidative phosphorylation in tumour cells were originally believed to have a causative role in cancerous growth. More recently, mitochondria have again received attention with regards to neoplasia, largely because of their role in apoptosis and other aspects of tumour biology. The mitochondrial genome is particularly susceptible to mutations because of the high level of reactive oxygen species (ROS) generation in this organelle, coupled with a low level of DNA repair. However, no detailed analysis of mitochondrial DNA in human tumours has yet been reported. In this study, we analysed the complete mtDNA genome of ten human colorectal cancer cell lines by sequencing and found mutations in seven (70%). The majority of mutations were transitions at purines, consistent with an ROS-related derivation. The mutations were somatic, and those evaluated occurred in the primary tumour from which the cell line was derived. Most of the mutations were homoplasmic, indicating that the mutant genome was dominant at the intracellular and intercellular levels. We showed that mitochondria can rapidly become homogeneous in colorectal cancer cells using cell fusions. These findings provide the first examples of homoplasmic mutations in the mtDNA of tumour cells and have potential implications for the abnormal metabolic and apoptotic processes in cancer.
Almost all (about 95%) of the mitochondrial DNA molecules released by Triton X-100 lysis of HeLa cell mitochondria in the presence of 0.15 M salt are associated with a single protein-containing structure varying in appearance between a 10-20 nm knob and a 100-500 nm membrane-like patch. Analysis by high resolution electron microscopy and by polyacrylamide gel electrophoresis after cleavage of mitochondrial DNA with the endonucleases EcoRI, HindIII, and Hpa II has shown that the protein structure is attached to the DNA in the region of the D-loop, and probably near the origin of mitochondrial DNA replication. The data strongly suggest that HeLa cell mitochondrial DNA is attached in vivo to the inner mitochondrial membrane at or near the origin of replication, and that a membrane fragment of variable size remains associated with the DNA during the isolation. After sodium dodecyl sulfate extraction of mitochondrial DNA, a small 5-10 nm protein is found at the same site on a fraction of the mitochondrial DNA molecules.
The phorbol esters 12-O-tetradecanoylphorbol-13-acetate (TPA) and 12-O-hexadecanoylphorbol-13 acetate (HPA) are not only potent tumor promoters but also potent stimulators of epidermal DNA synthesis and ornithine decarboxylase (ODC) activity in adult mice. However, when applied topically to newborn mice, TPA and HPA have essentially no effect on epidermal and dermal DNA synthesis or on epidermal ODC activity. Exposure of primary cultures of newborn mouse epidermal cells to TPA or HPA markedly stimulated both DNA synthesis and ODC activity. The anti-inflammatory steroids dexamethasone and fluocinolone acetonide (FA) were found to be potent inhibitors of tumor promotion and epidermal DNA synthesis in adult mice. However, when applied topically to newborn mice, FA did not inhibit epidermal or dermal DNA synthesis but stimulated it approximately twofold at 48 hours after FA treatment. In primary cultures of epidermal cells from newborn mice, treatment with dexamethasone or FA caused an early stimulation of DNA synthesis followed by a 50% inhibition of DNA synthesis 2 to 3 days after a 1-hour pulse treatment. Also, DNA synthesis was moderately inhibited when FA was added to primary cultures of dermal fibroblasts. In their reaction to tumor promoters, epidermal cells in culture behaved more like adult than newborn mouse epidermis in vivo, whereas anti-inflammatory steroids gave an intermediate response.
Intraperitoneal (i.p.) injection of a mineral oil such as pristane induces a chronic inflammatory response in mice. This is characterized by a large influx of macrophages and other inflammatory cells into the peritoneal cavity for months after injection of the oil. By using the B9 cell bioassay, it was found that injection of pristane caused a marked and prolonged elevation of interleukin-6 (IL-6) levels in the peritoneal cavities of the mice. IL-6 was undetectable (less than 15 U/mL) in the peritoneal fluids of unprimed mice and during the first week after injecting pristane. From 4 to 20 weeks, the concentration of IL-6 increased to an apparent plateau with concentrations ranging from 200 to 2,000 U/mL. Increasing the dose of pristane did not substantially increase the peritoneal levels of IL-6 established at 20 weeks after pristane treatment. At later times (by day 250), the level decreased to 263 +/- 217 U/mL. However, mice that developed plasma cell tumors around day 300 showed high levels of IL-6 in the ascites fluid (650 to 2,400 U/mL). Serum levels of IL-6 were also elevated in pristane-primed mice but were substantially lower than those found in the peritoneal cavity. Chronic administration of the nonsteroidal anti-inflammatory drug indomethacin decreased the levels of IL-6 by 75% to 80%. Experiments performed in vitro showed that pristane-elicited macrophages secreted low levels of IL-6 constitutively and high levels of IL-6 in the presence of lipopolysaccharide. Both IL-6 and prostaglandin E2 production were inhibited by addition of indomethacin to macrophage cultures in vitro. Treatment of mice with pristane may provide a model system for studying the inflammatory pathways that control IL-6 levels in vivo. The relevance of these results to elucidation of the role of IL-6 in plasma cell tumorigenesis is discussed.
The five major antioxidants enzymes, cytochrome oxidase (COX), GSH, and GSSG, and endogenous and in vitro stimulated lipid peroxidation (TBA-RS) were assayed in the lung of old (28 months) and young (9 months) adult rats due to the almost total absence of data of this kind in this tissue, which is normally exposed to relatively high pO2 throughout life. Catalase, selenium (Se)-dependent GSH peroxidase (GPx), GSH reductase, GSH, GSSG, GSSG/GSH, and in vivo and in vitro TBA-RS showed similar values in old and young animals. The decrease observed for non Se-dependent GPx disappeared when the values were expressed in relation to COX activity. Only superoxide dismutase showed a clear decrease when referred both to protein and COX activity. These results suggest that lung aging is not accelerated in old age due to a decrease in the antioxidant capacity of the tissue. Nevertheless, they are compatible with a continuous damage of the lung tissue by free radicals throughout the life span.
Human hepatocellular carcinomas (HCC) from patients in Qidong, an area of high incidence in China, in which both hepatitis B virus and aflatoxin B1 are risk factors, were analysed for mutations in p53, a putative tumour-suppressor gene. Eight of the 16 HCC had a point mutation at the third base position of codon 249. The G----T transversion in seven HCC DNA samples and the G----C transversion in the other HCC are consistent with mutations caused by aflatoxin B1 in mutagenesis experiments. No mutations were found in exons 5,6,8 or the remainder of exon 7. These results contrast with p53 mutations previously reported in carcinomas and sarcomas of human lung, colon, oesophagus and breast; these are primarily scattered over four of the five evolutionarily conserved domains, which include codon 249 (refs 4-9). We suggest that the mutant p53 protein may be responsible for a selective clonal expansion of hepatocytes during carcinogenesis.