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Phytochemical Antioxidants Modulate Mammalian Cellular Epigenome: Implications in Health and Disease


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Unlabelled: In living systems, the mechanisms of inheritance involving gene expression are operated by (i) the traditional model of genetics where the deoxyribonucleic acid (DNA) transcription and messenger ribonucleic acid stability are influenced by the DNA sequences and any aberrations in the primary DNA sequences and (ii) the epigenetic (above genetics) model in which the gene expression is regulated by mechanisms other than the changes in DNA sequences. The widely studied epigenetic alterations include DNA methylation, covalent modification of chromatin structure, state of histone acetylation, and involvement of microribonucleic acids. Significance: Currently, the role of cellular epigenome in health and disease is rapidly emerging. Several factors are known to modulate the epigenome-regulated gene expression that is crucial in several pathophysiological states and diseases in animals and humans. Phytochemicals have occupied prominent roles in human diet and nutrition as protective antioxidants in prevention/protection against several disorders and diseases in humans. Recent advances: However, it is beginning to surface that the phytochemical phenolic antioxidants such as polyphenols, flavonoids, and nonflavonoid phenols function as potent modulators of the mammalian epigenome-regulated gene expression through regulation of DNA methylation, histone acetylation, and histone deacetylation in experimental models. Critical issues and future directions: The antioxidant or pro-oxidant actions and their involvement in the epigenome regulation by the phytochemical phenolic antioxidants should be at least established in the cellular models under normal and pathophysiological states. The current review discusses the mechanisms of modulation of the mammalian cellular epigenome by the phytochemical phenolic antioxidants with implications in human diseases.
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Phytochemical Antioxidants Modulate Mammalian Cellular
Epigenome: Implications in Health and Disease
Smitha Malireddy,
Sainath R. Kotha,
Jordan D. Secor,
Travis O. Gurney,
Jamie L. Abbott,
Gautam Maulik,
Krishna R. Maddipati,
and Narasimham L. Parinandi
In living systems, the mechanisms of inheritance involving gene expression are operated by (i) the traditional
model of genetics where the deoxyribonucleic acid (DNA) transcription and messenger ribonucleic acid stability
are influenced by the DNA sequences and any aberrations in the primary DNA sequences and (ii) the epigenetic
(above genetics) model in which the gene expression is regulated by mechanisms other than the changes in DNA
sequences. The widely studied epigenetic alterations include DNA methylation, covalent modification of
chromatin structure, state of histone acetylation, and involvement of microribonucleic acids. Significance:
Currently, the role of cellular epigenome in health and disease is rapidly emerging. Several factors are known to
modulate the epigenome-regulated gene expression that is crucial in several pathophysiological states and
diseases in animals and humans. Phytochemicals have occupied prominent roles in human diet and nutrition as
protective antioxidants in prevention/protection against several disorders and diseases in humans. Recent
Advances: However, it is beginning to surface that the phytochemical phenolic antioxidants such as polyphenols,
flavonoids, and nonflavonoid phenols function as potent modulators of the mammalian epigenome-regulated
gene expression through regulation of DNA methylation, histone acetylation, and histone deacetylation in
experimental models. Critical Issues and Future Directions: The antioxidant or pro-oxidant actions and their
involvement in the epigenome regulation by the phytochemical phenolic antioxidants should be at least es-
tablished in the cellular models under normal and pathophysiological states. The current review discusses the
mechanisms of modulation of the mammalian cellular epigenome by the phytochemical phenolic antioxidants
with implications in human diseases. Antioxid. Redox Signal. 17, 327–339.
Introduction: Epigenetic Regulation of Gene Expression
Recent studies with the aid of novel and more advanced
molecular tools have provided deeper insights into the
nuclear architecture, including critical information on the
mechanisms of normal and pathophysiological states of gene
expression. Furthermore, these studies have revealed that the
mechanisms of inheritance involving gene expression are
operated through genetic alterations influencing deoxyr-
ibonucleic acid (DNA) transcription and messenger ribonu-
cleic acid (mRNA) stability through modifications of the
primary DNA sequences and epigenetic alterations involving
the covalent modification of chromatin architecture and post-
translational modifications (77). DNA in its native form is
inaccessible for transcription (46). Nucleosomes, the building
blocks of higher order chromatin structure, consist of 147 base
pairs of DNA wrapped around an octamer of histones (H2A,
H2B, H3, and H4) (46). Short stretches of linker DNA join
nucleosomes to form polymers that are further organized into
tightly compacted native chromatin configuration as seen in
the nucleus and have an appearance of beads on a string.
Chromatin has regions of transcriptionally active euchroma-
tin and inactive heterochromatin. The interconversion of these
two regions for DNA accessibility to transcription factors is
determined by the epigenome components, including his-
tone chaperones, chromatin-remodeling complexes, histone-
and histone variant-modifying enzymes, DNA methylating
agents, noncoding RNAs like the microribonucleic acids
(miRNAs), and other epigenome constituents. Thus, the term
‘‘epigenetics’’ is defined as the stable and perpetual but re-
versible and altered active states of gene expression without
modifying the primary DNA sequences (77).
Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Lipid Signaling, Lipidomics, and Vasculotoxicity Laboratory, Dorothy
M. Davis Heart and Lung Research Institute, Colleges of Medicine and Pharmacy, The Ohio State University, Columbus, Ohio.
Department of Radiology, Harvard Medical School, Boston, Massachusetts.
Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan.
Volume 17, Number 2, 2012
ªMary Ann Liebert, Inc.
DOI: 10.1089/ars.2012.4600
Epigenetic regulation is furthermore involved in tissue-
specific gene expression and silencing. There are different
mechanisms that mediate and regulate the duplication of
chromatin state, which depends on the chromatin domain,
organism, and function. The key components involved in-
clude histone chaperones, chromatin-remodeling factors,
histone-modifying enzymes, RNA components, and the DNA
replication machinery itself. Mechanisms that regulate chro-
matin remodeling, a crucial step in epigenetic alterations, in-
clude DNA methylation, post-translational modifications of
histones, including acetylation, deacetylation, phosphoryla-
tion, poly-adenosine-3¢,5¢-diphosphate (ADP)-ribosylation,
ubiquitination, histone variants, and miRNAs. DNA methyl-
ation is brought about by enzymes called DNA methyl-
transferases (DNMTs), which catalyze the addition of a
methyl group to cytosine (C) located 5¢to guanines (G) on the
phosphodiester bond between cytosine and guanine (CpG)
islands. DNA methylation, an epigenetic mechanism, is
known to attenuate gene expression and has been shown to
play crucial roles in cellular functions. Histones represent a
class of proteins that are extremely arginine rich. Almost
14% of the histone H4 amino acids are arginine residues.
Histone modification involves covalent modification of the
N-terminus tail of histone in determination of the level of gene
expression. Histone acetylation of conserved lysine residues
in histone tails, the signature of transcriptionally active re-
gions, is brought about by the histone acetyltransferase (HATs)
and hypoacetylation by histone deacetylases (HDACs) as seen
in transcriptionally inactive heterochromatin regions (67).
The roles of sirtuins (SIRTs; class III HDACs) are implicated
in physiological and pathophysiological phenomena, includ-
ing inflammation, cellular aging and senescence, cell prolif-
eration, apoptosis, cell differentiation, metabolism, stem cell
pluripotency, and cell cycle regulation (18). Seven different
types of SIRTs have been identified such as SIRT 1–7 in
mammals (7, 18). SIRT1-3 has been well characterized,
whereas SIRT4 and SIRT6 have been reported to have ADP-
ribosylation activity, which may be due to their deacetylation
activity (7). However, SIRT 1, 2, 3, and 5 catalyze deacetyla-
tion. A tight and well-regulated balance between the activities
of HATs and HDACs will maintain a controlled balance be-
tween acetylation and deacetylation of histones, and the epi-
genome actions under normal physiological states in the cells
and any alterations in this balance would lead to patho-
physiological conditions.
Oxidative Stress in Epigenetic Regulation
of Gene Expression and Disease
Oxidative stress has been established as an important
mechanism of either onset or progression of several disease
states or disorders, including myocardial ischemia, cardio-
vascular diseases (CVDs), cerebrovascular diseases, neuro-
logical diseases and disorders, diabetes, renal diseases,
infection and sepsis, pulmonary diseases and disorders, and
obesity (3, 6, 14, 16, 28, 30, 34, 43, 59). Environmental, toxic,
and dietary factors are known to cause oxidative stress by
different mechanisms (40). Oxidative stress is mediated by the
oxygen-derived reactive oxygen species (ROS), reactive ni-
trogen species (RNS), and other oxidants (40). Oxidative stress
is caused by either external oxidants/pro-oxidants or intra-
cellular oxidants. The intracellular oxidants are generated by
either nonenzymatic mechanisms (often involving transition
metals such as iron) or enzymatic catalysis operated by a
variety of oxidases that activate oxygen and convert them into
the ROS or RNS. Cellular membrane lipids containing the
polyunsaturated fatty acids, proteins, and nucleic acids are
vulnerable to the attack by oxidative stress leading to the
pathophysiological alterations (15). It has long been estab-
lished that 4-hydroxy-2-nonenal (4-HNE) is a major lipid
hydroperoxide-derived aldehydic bifunctional electrophile
that reacts with DNA and proteins (53, 74). The lipid
peroxidation-derived electrophilic carbonyl, 4-HNE, has been
shown to inhibit the class II HDAC (mitochondrial SIRT3)
through a thiol mechanism, and this has implications in lipid
peroxidation-mediated alterations of epigenetic regulation
(25). Overall, convincing experimental evidence has shown
that lipid peroxidation is also an important player in the ox-
idative stress-mediated epigenetic regulation of gene expres-
sion. Oxidative stress also brings alterations in the redox
status of the cell, wherein the thiol-redox (glutathione [GSH]
and protein thiols) system crucial for the cellular thiol-anti-
oxidant defense system and cellular metabolic machinery is
jeopardized (61), leading to the oxidative deterioration of the
cell. Cellular systems have evolved several enzymatic and
nonenzymatic antioxidant systems to cope with the surge of
constant oxidative stress. However, the overwhelming pro-
duction of ROS and RNS with their empowering oxidative
stress and the endogenous antioxidant defenses are compro-
mised and lead to the cellular demise. This is one of the often-
recognized mechanisms of either disease onset or progression.
The role of epigenome and epigenetic regulation of gene
expression in several human diseases, including cancer and
CVDs, are becoming compellingly evident (21). At present,
evidence is mounting in favor of oxidative stress modulating
the epigenome, leading toward the regulation of gene ex-
pression (81). Also, recent studies have highlighted the im-
portance of epigenetic alterations in cardiovascular,
neurological, immunological, and other more complex ge-
netic disorders and diseases (21). Taken together, it is
emerging that oxidative stress-modulated regulation of the
epigenetic mechanism of gene expression plays an important
role in certain diseases. Understanding the mechanisms of
epigenetic regulation will lead to the development of novel
therapies for treatment of diseases and the development of
regenerative medicine, and identification of strategies for
preventive intervention. In this regard, antioxidants are seri-
ously sought after to strengthen the cellular antioxidant de-
fense system to combat and counteract the overwhelming
oxidant generation and oxidative stress, thus attenuating or
normalizing the adverse oxidant-mediated epigenetic regu-
lation of gene expression that is responsible for either the
onset or progression of the disease.
Phytochemical Antioxidants: Oxidative Stress,
Disease, and Epigenome
Cellular antioxidant defense machinery has been un-
equivocally established as an oxidative stress-counteracting
entity. Cellular antioxidants comprise both the (i) nonenzy-
matic molecules and (ii) enzymes. The nonenzymatic antiox-
idants consist of the thiol antioxidants such as GSH and other
thiols and small-molecule antioxidants (vitamins C, A, D, and
E). Apart from GSH, most of the antioxidants make their entry
into the cells through nutrition and diet. Also, the function of
these nonenzymatic antioxidants is regulated by the redox
state of the cell and vice versa. Antioxidant supplementation/
treatment has been adopted for either prevention of or pro-
tection against several disorders and pathophysiological
states wherein oxidative stress has been established as a
causative mechanism (5). The immunomodulatory and anti-
inflammatory effects of polyphenols have been documented
(26, 39). The beneficial effects of moderate consumption of red
wine on lessening the coronary heart disease are accredited to
the wine polyphenols such as anthocyanosides, catechins,
proanthocyanidins, stilbenes, and phenolic compounds (19).
Naturally occurring phytochemical antioxidants have occu-
pied a prominent position as effective antioxidants for the
prevention and/or treatment of several disorders and dis-
eases among humans (32, 70, 71). The premise for this has
been the antioxidant actions of the phytochemicals as free-
radical scavengers, oxidative stress relievers, and lipoperox-
idation inhibitors (68). Phytochemical antioxidants include
simple molecule antioxidants such as vitamins C, E, and K;
plant pigments such as carotenoids (b-carotene), xantho-
phylls, lycopene, anthocyanins, and phaeophytins; and sec-
ondary plant metabolites, including simple phenolics to more
complex polyphenols (13). Some of these phytochemical
polyphenols, in addition to acting as antioxidants, will also
function as pro-oxidants that cause oxidative stress (42, 62).
The pro-oxidant action of tea polyphenols has been linked to
their anticancer actions (23, 42). Polyphenols are known for
their complexing abilities (chelation) with trace metals. Poly-
phenols have been shown to attenuate the iron-induced DNA
damage by complexation with iron and keeping the Fe in the
+3 state after oxidation of Fe in the +2 state in presence of
molecular oxygen (63). Two major pathways of biosynthesis
of the phytochemical polyphenols in plants have been iden-
tified: (i) the shikimate pathway and (ii) the polyketide or
acetate pathway (57). Structurally, the plant polyphenol has a
phenolic or a benzene ring with a hydroxyl group attached,
and also certain substituents such as ester and glycosides
present as functional groups (73). The majority of the plant
polyphenols have two or three hydroxyl groups, and hence
FIG. 1. Classification of plant phenols. Here, phenols of plant origin are broadly divided into three major groups such as (i)
phenolic acids, (ii) flavonoids, and (iii) nonflavonoid polyphenols. Flavonoids are further divided into several classes.
Flavonoids such as kaempferol, quercetin, and myricetin fall under the class of flavonols. Genistein and daidzein are
classified under the class of isoflavones and thereby are called the soy isoflavones. (-)-epigallocatechin-3-gallate (EGCG) falls
under the class of flavanols. These phytochemical phenols as secondary metabolites in plants have definitive roles in plants as
the ultraviolet (UV) protectants, wound-healing action, and disease and pest resistance. Primarily, these compounds have
established protective actions against oxidative stress as potent, naturally occurring antioxidants.
they are called dihydric or trihydric polyphenols, respec-
tively. The classification of plant polyphenols is based on (i)
the number of phenolic or benzene rings present and (ii) the
number and type of substituents present on the phenolic
rings. Phytochemical polyphenols are broadly classified into
(i) simple phenols (ferulic and gallic acids), (ii) stilbenes (di-
hydrophenols such as resveratrol), (iii) chalcones, and (iv)
flavonoids (Fig. 1) (57). Flavonoids, a family of the most bio-
active complex phytochemical polyphenols, are further di-
vided into seven classes such as (i) flavonols, (ii) flavanols, (iii)
flavones, (iv) flavanones, (v) flavanonols, (vi) isoflavones, and
(vii) anthocyanins (73). Simple phenolic and polyphenolic
secondary plant metabolites are known to play crucial roles in
plants as protectants against oxidative stress and ultraviolet
(UV) radiation, wound healing, defense against microbes,
fungi, herbivores, plant competitors, and disease resistance in
plants (2, 20). However, the mechanism of such protection
and their physiological roles in plants are not completely
understood. Nevertheless, flavonoids have been shown to
exhibit a plethora of biological effects, including antibacterial,
antiviral, analgesic, antiallergic, hepatoprotective, cytostatic,
apoptotic, estrogenic, and antiestrogenic functions (31).
Animals and humans obtain these phytochemical poly-
phenols from diet or nutritional supplementation. The ma-
jority of the phytochemical polyphenols are present in their
native state in plants as polymers or as glycosylated molecules
(conjugated to sugars), wherein the sugar moiety is termed as
the ‘‘glycone’’ and the polyphenol is called the ‘‘aglycone’’
(76). Most of the polyphenols in the dietary plant sources
occur as complex molecules linked to the sugar residues
(O-glycosides), but some occur as C-glycosides. Polyphenol
O-glycosides undergo hydrolysis in the lumen of the intes-
tine, and the sugar residue is released upon the action of b-
glucosidase, setting the aglycone free. On the other hand, the
C-glycosides are resistant to the intestinal enzymatic hydro-
lysis (9). It is interesting to note that the polyphenols, after the
uptake by the intestinal cells, undergo metabolic biotrans-
formation similar to the xenobiotics by the involvement of
phase-I and phase-II enzymes (9). Bacteria in the large intes-
tine catalyze the conversion of aglycones of polyphenols
causing the heterocyclic B-ring opening and cleavage after
which the metabolites are absorbed and reach circulation (9).
Similar to the intestine, the liver also metabolizes poly-
phenols, and circulating polyphenols are in the form of
b-glucuronides and esters of sulfate with trace levels of
aglycones. Polyphenols that are hydrophobic can easily be
transported into the intestinal cells through the plasma
membrane. Nevertheless, the phytochemical polyphenol
metabolism is complex, and it is challenging to identify
whether the parent molecule or its metabolite is biologically
active. In recent times, plant polyphenols have been the at-
traction as effective antioxidants (from diet or supplementa-
tion) in prevention and treatment of several diseases,
including CVDs, cerebrovascular diseases, Alzheimer’s dis-
ease, airway disease, and cancer, with a focus to alleviate the
oxidative stress as the causative mechanism in those diseases
(17, 24, 38, 51, 70, 71, 80). In spite of the beneficial effects of the
phytochemical polyphenolic antioxidants in humans, their
mechanisms of action (physiology and pharmacology) in the
mammalian systems (including humans) are just emerging.
The regulation of gene expression by dietary polyphenols in
cellular models such as the vascular endothelial cells is evi-
dent (56, 57). One of the noteworthy current discoveries that
have emerged from the phytochemical–antioxidant inter-
actions in mammalian model systems is their nature of
modulating the mammalian epigenome (21). Totally, novel
disciplines such as nutrigenetics and nutrigenomics have
emerged with a focus on the phytochemical nutrient–gene in-
teractions toward cancer prevention in which signaling path-
ways, networks, and epigenetic phenomena are investigated
(22). Hence, this review focuses on the relevant studies on cer-
tain selected phytochemical phenolic antioxidants that have
been shown to mediate the modulation of the mammalian
epigenome and its relevance in the prevention of and protec-
tion against diseases.
Mechanisms of Epigenetic Regulation of Diseases:
Role of Phytochemical Antioxidants
As overviewed earlier, epigenetic alterations in DNA are
inheritable, which lead to the modulation of gene expression
without involving any changes in the primary sequences of
DNA. However, chemical alterations in the histone proteins
and/or DNA by covalent modifications brought by certain
enzymes are the causative mechanisms for the epigenetic al-
terations and subsequent modulation of gene expression. It is
progressively more evident that DNA methylation, an epi-
genetic phenomenon catalyzed by DNMTs using the methyl
donor, S-adenosylmethionine (SAM), leads to anomalous
DNA methylation (hypermethylation), and this is associated
with certain diseases, including cancer and CVDs (21). Me-
thylation of CpG islands is a common occurrence in the
pathological tissues such as cancer (29). Transcription of
methylated genes is either arrested or suppressed. Global
hypomethylation of DNA and hypermethylation at specific
sites of DNA are generally encountered in the tumors (21).
DNA hypomethylation is known to enhance the expression of
proto-oncogenes leading to an elevated cancer risk. DNA
hypermethylation is also associated with certain cancers. Diet
has been known to affect the DNA methylation status, espe-
cially folate, which is the precursor for SAM, the substrate for
DNMT that catalyzes DNA methylation. Dietary phyto-
chemical polyphenols have been identified to modulate DNA
methylation and subsequent epigenetic regulation of gene
expression with a change in the outcome of cancer and CVDs.
Wherever DNA hypermethylation catalyzed by DNMTs is
encountered as a key mechanism in a disease such as cancer,
DNMT inhibitors can be promising drugs in the chemother-
apy of cancer (29). However, certain phytochemicals, espe-
cially the polyphenols, are emerging as modulators of DNA
methylation and appear as promising drugs in the treatment
of cancer and myocardial pathologies (9, 36).
Post-translation modifications of nuclear proteins, the his-
tones, play a crucial role in the epigenetic regulation of gene
expression. Two important modifications of histones are (i)
acetylation and (ii) deacetylation. Histone acetylation is cat-
alyzed by the histone acetyltransferases (HATs). Histone
deacetylation is catalyzed by 11 different HDACs, which are
divided into 4 classes based on their homologies (37). These
HDACs are distributed in the cytoplasm, mitochondria, and
nucleus. There are seven members of HDACs called SIRTs
(SIRT1–SIRT7) present in the cytoplasm, mitochondria, and
nucleus, which catalyze the deacetylation of histones (37). A
tight balance between the acetylation and deacetylation of
histones is maintained under normal states, but if that balance
is altered due to the abnormal activities of either HATs or
HDACs, then that will result in pathological situations as seen
in cancer (37, 41). HDAC inhibitors have been focused as
therapeutic molecules in cancer chemotherapy. Once again,
phytochemical polyphenols have been shown to act as HDAC
inhibitors with potential in prevention and therapy of certain
diseases, including cancer and CVDs (10, 36).
Phytochemical Polyphenols As Modulators
of Epigenome: Disease Prevention and Therapy
Polyphenols are a major group of phytochemicals with an-
tioxidant actions, disease prevention properties, and thera-
peutic actions. However, polyphenols have recently captured
attention as the modulators of epigenome. Although humans
consume most of the polyphenols through diet, they also can
be ingested or administered as isolated compounds from
plant sources for prevention or treatment of certain diseases
(50). Green tea contains several polyphenols, including (-)-
epicatechin, ( -)-epicatechin-3-gallate (ECG), ( -)-epigallocatechin,
and ( -)-epigallocatechin-3-gallate (EGCG) (48). Green tea as a
beverage is also seriously consumed worldwide as a health-
promoting drink due to the presence of phytochemicals, which
are considered to act as anticancer agents, retain healthy heart,
and prevent cataract. EGCG is a predominant polyphenol
present in green tea that has been shown to possess anticancer,
antitumor, and anti-inflammatory actions (Fig. 2) (52). In a
study on the human breast cancer cells (MCF-7 and MDA-MB-
231 cells), EGCG and the novel prodrug of EGCG (pro-EGCG)
have been shown to inhibit cell proliferation and transcription
of the human telomerase reverse transcriptase (hTERT), the
catalytic subunit of telomerase that is crucial in sustaining the
telomere chain length and tumor formation, the latter being
through the epigenetic regulation of the estrogen receptor (11,
52). In this study, hypomethylation of the hTERT promoter re-
gion and histone deacetylation through the inhibition of DNMT
and HAT, respectively, have contributed to the inhibition
FIG. 2. Chemical structures of different phytochemical polyphenol antioxidants (A–G). Phytochemical polyphenols have
their structural origin from the simple phenolic (benzene) ring and having two or more hydroxyl (OH) groups offer their
polyphenolic nature and name of their class of compounds. These are compounds that are bioactive natural products and act
as free-radical quenchers, potent antioxidants, trace metal-complexing molecules, pro-oxidants, and regulators of cell pro-
liferation. More strikingly, they are emerging as the modulators of epigenetic regulation of gene expression.
of hTERT transcription in the breast cancer cells under the
treatment of EGCG and pro-EGCG. Moreover, EGCG and pro-
EGCG also have caused the chromatin remodeling (alterations)
leading to hTERT-repressor binding in the regulatory sites. This
study reveals that the green tea polyphenol EGCG and its novel
prodrug cause inhibition of proliferation of breast cancer cells
through epigenetic mechanisms involving inhibition of DNMT
and HAT and resulting in DNA hypomethylation and histone
deacetylation (Fig. 3). The importance of estrogen receptor-a
(Era) in clinical prognosis and in the therapy of breast cancer has
been emphasized, because ERa-deficient breast cancers do not
respond to the therapies aimed at the hormone targets (49).
Having this as the premise, it has been revealed that in the
breast cancer cells (MDA-MB-231 cells), the green tea poly-
phenol (EGCG) alone or in combination with the HDAC in-
hibitor (trichostatin A) offered reactivation of the ERa
expression in the ERa-deficient breast cancer cells (49). This has
also led to the estradiol action in the ERa-deficient breast cancer
cells through the action of the ERareceptors in response to
estradiol treatment. In this context, EGCG has been found to
cause chromatin remodeling through modulation of histone
acetylation and DNA methylation, leading to the reactivation of
ERa(49). This study indicates that the green tea polyphenol,
EGCG, can reactivate ERatoward effective treatment of hor-
mone-resistant breast cancer. To establish the anticancer actions
of EGCG against skin cancer through epigenetic regulation, a
study has been conducted on the reactivation of the tumor
suppressor genes (Cip1/p21 and p16
cells (55). This study reveals that EGCG suppresses global DNA
methylation, DNMT activity, and HDAC activity; lowers
DNMT protein and mRNA; and increases histone acetylation in
histones H-3 and H-4 in the skin cancer cells. Along these lines,
ECGC has been observed to cause activation of expression of
the tumor suppressor genes. This study presents convincing
results that the green tea polyphenol, EGCG, is an epigenetic
modulator that may be useful as an epigenetic drug in skin
cancer therapy.
With intent to show the anticancer actions of EGCG, a study
has been conducted on the epigenetic anticancer effects of
EGCG on the UV-B radiation-induced skin cancer in vivo in a
hairless mouse model (54). In this study, the green tea poly-
phenol, EGCG, has been applied on the affected skin as a
topical cream. The results reveal that the EGCG as topical
cream inhibits the UV-B-induced skin papillomas and carci-
nomas and also inhibits global DNA methylation. Further-
more, this study demonstrates that the EGCG topical
application as a cream on the skin appears as a promising
epigenetic therapeutic strategy for the treatment of skin pho-
tocarcinogenesis. The antimelanoma action of EGCG has been
investigated in the human melanoma cell line (A-375 cells)
with a focus on the epigenetic action of EGCG (58). In this
study, the HDAC inhibitor drug, Vorinostat, has also been
used in conjunction with EGCG. The results reveal that the
antimelanoma effects of Vorinostat are more pronounced than
those of EGCG, but the combined treatment of EGCG and
Vorinostat has been more dramatic in causing the anti-
melanoma effects. Thus, it is clear from this study that EGCG
can be used as a combination drug along with a known HDAC
inhibitor for use in the epigenetic therapy of melanoma.
Dietary phytochemical antioxidants are also known to ex-
ert immunomodulatory effects, including upkeep of im-
munotolerance and autoimmunity suppression. Along those
lines, a study has been launched to investigate modulation of
the regulatory T cells by EGCG through epigenetic regulation
(78). Regulatory T cells are crucial for the immunotolerance
and autoimmunity suppression. The results of this study re-
veal that EGCG decreases DNMT expression and global DNA
methylation through induction of forkhead box p3 (Foxp3)
gene expression substantiating the epigenetic actions EGCG
and modulation of immunity by EGCG. Thus, it appears that
the green tea polyphenol, EGCG, also acts as an epigenetic
immunomodulator. Overall, consumption of green tea has
been attributed to the lower incidences of various cancers
such as gastric, esophageal, ovarian, pancreatic, skin, and
colorectal cancers (48). The cancer-preventive actions of green
tea are linked to the presence of the bioactive natural product
in the tea such as EGCG. Many studies have shown that
EGCG directly inhibits the DNMT activity by directly inter-
acting with the enzyme, causes demethylation of DNA, and
reactivates methylation-silenced genes (48). This mechanism
of action of EGCG in causing modulation of DNA methyla-
tion through the regulation of DNMTs and leading to epige-
netic regulation of gene expression has been demonstrated in
several cancer models, substantiating the epigenetic antican-
cer action of EGCG (48, 49).
Curcumin As a Modulator of Epigenome:
Disease Prevention and Therapy
Curcumin (diferuloylmethane) is a polyphenolic ingredient
of turmeric (the most popular and common Asian Indian
FIG. 3. Mechanism of EGCG-induced apoptosis in cancer
cells through epigenetic regulation of telomerase. Accord-
ing to Berletch et al. (11) and Meeran et al. (52), EGCG inhibits
both deoxyribonucleic acid (DNA) methyltransferase
(DNMT) and histone acetyltransferase (HAT), leading to the
DNA demethylation and histones H3 and H4 deacetylation
of the human telomerase– reverse transcriptase (hTERT)
promoter, respectively. These events result in the epigenome
regulation and chromatin restructuring involving hTERT
messenger ribonucleic acid (mRNA) downregulation and
inhibition of telomerase and ultimately cancer cell death
(apoptosis). However, these studies have not provided any
links between the antioxidant actions of EGCG and its epi-
genetic regulation of apoptosis of the cancer cells.
curry spice; golden spice) obtained from the rhizomes of the
plant, Curucuma longa (Fig. 2). Recently, curcumin has gained
tremendous attention of the nutritionists, biomedical scien-
tists, pharmacologists, drug discovery scientists, clinicians,
and, above all, the common man worldwide as a preventive
molecule or therapeutic agent for several disorders and dis-
eases, which is substantiated by anecdotal accounts and sci-
entific investigations. However, curcumin has long been
known for its anticancer actions causing necrosis and apo-
ptosis and arrest of division in cancer cells (33, 35). Curcumin
has been identified as a pro-oxidant in generating ROS
(causing oxidative stress) and as an antioxidant (protecting
against oxidative stress) in cellular systems. The oxidative
stress induced by curcumin has been considered as the
probable mechanism of action of the compound to act as an
anticancer agent. The biphasic action of curcumin depends
upon its concentration that is used in experiments, for ex-
ample, at higher concentrations (*50 lM) curcumin acts as a
pro-oxidant and at lower doses (*10 lM), the same acts as an
antioxidant (35). Although several studies have revealed
multiple mechanisms/targets for the anticancer action of
curcumin, the epigenetic regulation by curcumin in different
disease states (models), including cancer, is sprouting (33). A
study on the human hepatoma cells reveals that curcumin
treatment lowers histone acetylation (hypoacetylation) by
inhibiting the HAT activity and without an effect on the
HDAC activity, which is linked with the enhancement of ROS
production in cells (35). This study suggests that HAT is the
target for curcumin, and its anticancer action could be at-
tributed to its epigenome regulatory actions wherein ROS are
apparently involved. On the other hand, curcumin has been
shown to inhibit the HDAC activity in medulloblastoma (brain
tumor) cells and to decrease medulloblastoma growth (tumor
xenografts) in vitro and in vivo (44). In this study, curcumin has
been observed to cause apoptosis and cell cycle arrest (G2/M
phase) followed by the inhibition of HDAC activity in me-
dulloblastoma cells. Also, the study reveals that curcumin
enhances the survival of the mice that received the medullo-
blastoma tumor xenograft (44). Overall, this study features the
importance of curcumin as an antimedulloblastoma agent
with an epigenetic target in its path of action. Upon screening
33 carboxylate derivatives to identify potent HDAC inhibitors
in HeLa cell nuclear extract an in vitro assay system, it has been
identified that curcumin has the highest potency along with
chlorogenic acid as compared to the established HDAC in-
hibitor, sodium butyrate (12). This study reveals that curcumin
is a potent natural phytochemical polyphenol HDAC inhibitor
with an ability to modulate the epigenome through regulation
of histone acetylation.
Phosphodiesterases (PDEs) catalyze the hydrolysis of cyclic
nucleotides such as cyclic adenosine-3¢,5¢-monophosphate
and cyclic guanosine-3¢,5¢-monophosphate in cells and thus
take crucial part in cell-signaling events responsible for cell
division (1). Using the B16F10 melanoma cells, it has been
shown that curcumin inhibits cell proliferation through PDE1-
5 involvement. In this study, curcumin has also exerted epi-
genetic modulatory effectors such as inhibiting the expression
of the epigenetic integrator ubiquitin-like containing PHD
and ring finger domains 1 (UHRF1), and DNMT1 with up-
stream targeting of PDE1 and resulting in the antiproliferative
effects in the melanoma cells (1). Thus, this study also dem-
onstrates that curcumin exerts its epigenome-modulating ef-
fects in its action as an anticancer agent. The epigenetic
regulation of HATs, HDACs, DNMTs, and miRNAs and as-
sociated modulation of gene expression by curcumin in con-
junction with its anticancer actions and clinical utilization
have been highlighted (66).
In addition to its anticancer actions, curcumin has been also
shown to offer protection against inflammation, neurode-
generative diseases, autoimmune pathologies, and cardio-
vascular and lung disorders, while the epigenetic mechanisms
of cardioprotective and lung-protective actions of curcumin
are just budding (4, 8, 65, 79). Curcumin, as an antioxidant,
has been reported to offer protection against several patho-
physiological states (79). Especially, it has been demonstrated
in studies with animal models that curcumin protects against
cardiac hypertrophy and heart failure involving epigenetic
regulation by HAT (79). One of the established mechanisms of
epigenetic regulations of gene expression is maintaining a
tight balance between the acetylation and deacetylation by a
controlled regulation of the activities of HATs and HDACs.
A specific transcription factor such as the hypertrophy-
responsive transcription factor requires p300 (adenovirus
E1A-associated protein), which also acts as a HAT bringing
out the chromatin remodeling (79). p300-HAT has also been
shown to be responsible for the cardiomyocyte growth and
differentiation in the course of development (79). However,
the activity of p300-HAT has been elevated during cardiac
hypertrophy, and by inhibiting the p300-HAT activity, it has
been possible to protect against the cardiac hypertrophy.
Curcumin has been established as an inhibitor of p300-HAT
(79). Thus, it is conclusive that curcumin protects against
cardiac hypertrophy through modulation of epigenetic regu-
lation that is mediated by p300-HAT. As histone acetylation
mediated by HAT has been established as a critical player in
the development of the heart, its inhibition or attenuation by
curcumin has been studied in the cardiomyocytes (72). Cur-
cumin has been revealed to inhibit p300-HAT in cardiomyo-
cytes causing decreased acetylation of histone H3 in the
promoter regions of certain cardiac-specific genes responsible
for the cardiogenesis (72). This observation has been associ-
ated with curcumin-induced cell morphological alterations,
inhibition of the HAT (p300-HAT) activity, decreased acety-
lation of histone H3, and suppression of cardiac-specific gene
expression confirming curcumin-mediated modulation of
epigenetic regulation of cardiomyocyte gene expression dur-
ing cardiogenesis. This study also underscores the importance
of curcumin as a therapeutic compound in alleviating con-
genital myocardial diseases and cardiac hypertrophy through
epigenetic regulation.
Mechanisms behind several debilitating lung diseases in
humans are complex, and specific targets in the onset and
progression of those lung diseases such as chronic obstructive
pulmonary diseases (COPDs) for pharmacological (drug) in-
tervention are being constantly hunted. In this regard, specific
and effective drugs are also highly warranted. Multiple
mechanisms operating behind COPD have been documented,
including the role of ROS, oxidative stress, membrane lipid
deterioration by lipid peroxidation, loss of cellular thiol (GSH)
redox, weakened antioxidant defense system, and other
complex signaling mechanisms (65). Several therapeutic in-
terventions, such as antioxidant therapy, thiol-redox and GSH
boosting, enhancement of antioxidant defenses, enzyme ac-
tivators, spin traps for reactive radicals have been sought after
for the COPD therapy (65). Among those, polyphenols and
curcumin have been described as therapeutic agents for
COPD. More strikingly, the role of epigenome in the curcumin
therapy of COPD has been brought to the lime light (8).
HDAC, especially HDAC2, has been recognized to play an
important role in the inflammatory gene expression and in-
flammatory lung pathologies, including COPD, asthma, and
airway diseases, since histone acetylation upregulates the
lung inflammatory genes and causes lung inflammation (8).
Therefore, any pharmacological activation of HDAC appears
to offer therapeutic intervention for lung inflammatory dis-
eases. Curcumin has been suggested as a possible HDAC2
activator in protecting against the inflammatory lung dis-
eases, but the challenge lies in its inhibitory action on HAT (8).
However, the epigenetic mechanisms of protective action of
curcumin on inflammatory lung diseases have to be thor-
oughly investigated prior to its clinical use.
Flavonoids As Modulators of Epigenome:
Disease Prevention and Therapy
Flavonoids comprise a major group of phytochemicals, and
they fall under polyphenol category with diverse chemical
structures. Although their source of entry into humans is diet,
there is a growing interest in flavonoids for their disease-
preventive and therapeutic actions. Flavonoids have been es-
tablished as potent and naturally available antioxidants with
properties to relieve oxidative stress, disease prevention, and
protection (60). However, the epigenome-regulating actions of
flavonoids are just surfacing (27). Flavonoids—in particular,
isoflavones, flavonols, and catechins—have been emphasized
as the phytochemical polyphenol regulators of the epigenome
with a focus on DNA methylation, histone acetylation, and
chromatin alterations (27). Here, the findings of some selected
studies dealing with the flavonoid-modulated epigenetic reg-
ulation with a relevance to diseases are discussed.
In the human leukemia-60 cells (HL-60 cells), quercetin
(Fig. 2) has been shown to exert epigenetic modulations in-
volving activation of HAT and inhibition of HDAC, leading to
histone acetylation (45). This study revealed that quercetin
induces Fas ligand-mediated apoptosis in HL-60 cells that is
associated with the epigenetic regulation through HAT and
HDAC (Fig. 4). Soybean isoflavones have been identified as
phytochemical therapeutic flavonoids for the treatment of
colorectal cancer wherein the isoflavones suppress metastasis
of the tissue through epigenetic modulation of DNA meth-
ylation and histone modifications (47). In particular, this
study highlights genistein, one of the soybean isoflavones, as
an effective epigenetic modulator of the colorectal cancer
metastasis, and dietary genistein may be beneficial for colo-
rectal cancer (Fig. 2) (47). Genistein, through epigenetic
modulations, including chromatin remodeling and DNA
methylation, leads to the activation of tumor suppressor
genes and suppression of the survival of cancer cells (82).
Genistein has also been shown to inhibit the DNMT activity,
which causes inhibition of DNA methylation and thus may be
acting as an anticancer agent (48). Genistein has been ob-
served to enhance the acetylation of histones H3 and H4 in the
transcription sites of p21 and p16 with which the upregulation
of the tumor suppressor genes in prostate cancer cells (82).
The cell-cycle arrest results from the genistein-induced
downregulation of cyclins from the upregulation of p21 and
p16 in prostate cancer cells. From this study, genistein appears
as a promising anticancer flavonoid that operates through
epigenetic regulation of gene expression. An association be-
tween genistein consumption and the low mortality rate
among Asian women with breast cancer has been docu-
mented (48). In various experimental cellular models of cancer
such as the prostate, esophagus, and colon cancer cells, gen-
istein has been shown to act as an anticancer flavonoid (48).
Although multiple mechanisms of the anticancer actions of
genistein, such as inhibition of DNA mutation, suppression of
FIG. 4. Mechanism of quercetin-
induced apoptosis of cancer cells
through epigenetic regulation of
Fas ligand (Fas L) expression. As
investigated by Lee et al. (45),
quercetin inhibits the histone dea-
cetylase (HDAC) activity and acti-
vates HAT through the upstream
activation of the extracellular-
regulated kinase (ERK) and Jun
N-terminus kinase ( JNK). Here, the
transactivation of c-jun/AP-1 is in-
volved. Thus, the epigenome is
regulated by quercetin, leading to
apoptosis of the cancer cells (me-
dulloblastoma) through elevation
of histone H3 acetylation, which
causes downstream upregulation of
Fas L. In this study, no attempt has
been made to establish the connec-
tion between the antioxidant ac-
tions of quercetin and its epigenetic
regulation of apoptosis of the me-
cancer cell division, antiangiogenic effect, and stimulation of
cell differentiation have been reported, the mechanism of
epigenetic regulation of gene expression by genistein while
exerting its anticancer actions is becoming more evident. An
important discovery that has led to the understanding of the
estrogenic activity of genistein in which prenatal exposure to
genistein permanently affects the erythropoiesis in fetus and
alters the gene expression and DNA methylation in hemato-
poietic cells (75). Also, ligands for isoflavones in the ERa-
mediated HAT activity have been identified, and genistein
has been observed to cause modulation of the HAT activity
and extent of histone acetylation (64). These studies under-
score the estrogenic nature of the phytoestrogen and genistein
and their effects on ERa, which may be seriously considered
for use as an anticancer agent.
Isoflavones of dietary origin have been documented to
offer vascular protection in different experimental models
and humans through protection against oxidative stress
and upregulation of the antioxidant-signaling mechanisms
(69). Dietary isoflavones have been shown to elevate the
production of nitric oxide and ROS in the vessel wall and
enhance the activities of antioxidant enzymes in the vas-
cular endothelial and smooth muscle cells, which are at-
tributed to the estrogenic activities of isoflavones that
upregulate the genes for antioxidant enzymes in those
vascular cells. Although the isoflavones offer vasculopro-
tection and, in particular, are capable of inhibiting HAT
andDNMT(69),theexactepigenetic mechanism of pro-
tection of vascular endothelial and smooth muscle cells
needs to be established.
FIG. 5. Proposed mechanisms
of epigenetic regulation by
phytochemical polyphenol
antioxidants and the link be-
tween reactive oxygen species
(ROS) and oxidative stress
and antioxidative and non-
antioxidative pathways in
physiological and pathophys-
iological states. Stress, diet,
chemicals, drugs, and envi-
ronmental factors cause oxi-
dative stress through ROS
and thiol-redox dysregula-
tion, which result in epigen-
ome alterations resulting in
chromatin restructuring through
modulations in DNMT,
HDACs, and HAT and sub-
sequent changes in DNA
methylation and histone acet-
ylation. Thus, the regulation
of gene expression is brought
by the alterations in the epi-
genome. Phytochemical poly-
phenol antioxidants may act
either as (i) antioxidants re-
lieving the oxidative stress
and/or (ii) direct modulators
of DNMT, HDACs, and
Conclusions: Critical Issues and Future Directions
Studies conducted so far have provided convincing evi-
dence that phytochemical antioxidants (polyphenols and
flavonoids such as quercetin and curcumin) do modulate
epigenetic regulation of gene expression, which could stand
out as a plausible target for the intervention of certain dis-
eases by the phytochemicals of choice (Fig. 5). In cancer bi-
ology, the phytochemical-modulated epigenome actions
have picked up the pace, and the clinical use of phyto-
chemical polyphenols as epigenetic therapeutics is promis-
ing. However, with respect to other diseases and disorders,
studies on the epigenome actions of phytochemical antioxi-
dants are nascent. The most important aspects of phyto-
chemical antioxidants that should be understood thoroughly
are (i) the metabolism of the phytochemicals in mammalian
and human cells in vitro and in vivo to identify the active
metabolite of the phytochemical that is responsible for its
pharmacological actions and (ii) precise cellular targets (re-
ceptors or proteins) for either the parent phytochemical
molecule or its cellular metabolites under normal physio-
logical and pathological states. In this regard, specific bio-
active metabolites of a particular phytochemical antioxidant
of choice, in target cells and their normal counterparts, have
to be identified and characterized (Fig. 5). In addition, the
redox biology of these phytochemical antioxidants in the
cellular milieu has to be established as most of these natural
compounds have a dual behavior of acting either as a pro-
oxidant or as an antioxidant. The question that still remains
to be answered is whether the redox-active phytochemical
antioxidant that causes epigenetic regulation is either de-
pendent upon the oxidants generated through the pro-
oxidant actions or the antioxidant nature of the phyto-
chemical polyphenol antioxidant (Fig. 6). In spite of the
well-established fact that the phytochemical polyphenolics
are among the most effective naturally occurring antioxi-
dants, there is a void bridging their antioxidant actions and
redox-signaling mediation to their epigenetic regulatory
actions. It is high time to establish whether the epigenome
regulatory actions of the phytochemical polyphenol antiox-
idants are related or unrelated to their antioxidative actions
(Fig. 6). So far, laboratory studies conducted offer convinc-
ing evidence in favor of a connection between the chromatin
remodeling and epigenetic regulation of gene expression,
and this should be established or verified in the preclinical
and clinical studies.
Funding support from the International Academy of Oral
Medicine and Toxicology (IAOMT); Dorothy M. Davis Heart
& Lung Research Institute; the Division of Pulmonary, Al-
lergy, Critical Care, and Sleep Medicine of the Ohio State
University College of Medicine; and the National Institutes of
Health (HL 093463) is acknowledged.
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Address for correspondence:
Dr. Narasimham L. Parinandi
Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine
Dorothy M. Davis Heart and Lung Research Institute
Colleges of Medicine and Pharmacy
The Ohio State University College of Medicine
473 W. 12th Ave.
Columbus, OH 43210
Date of first submission to ARS Central, March 4, 2012; date of
acceptance, March 11, 2012.
Abbreviations Used
4-HNE ¼4-hydroxy-2-nonenal
ADP ¼adenosine-3¢,5¢-diphosphate
COPDs ¼chronic obstructive pulmonary diseases
CpG ¼phosphodiester bond between cytosine
and guanine
CVD ¼cardiovascular disease
DNA ¼deoxyribonucleic acid
DNMT ¼DNA methyltransferase
ECG ¼(-)-epicatechin-3-gallate
EGCG ¼(-)-epigallocatechin-3-gallate
ERK ¼extracellular-regulated kinase
Era¼estrogen receptor-a
Foxp3 ¼forkhead box p3
GSH ¼glutathione
H2A ¼histone 2A
H2B ¼histone 2B
H3 ¼histone 3
H4 ¼histone 4
HAT ¼histone acetyltransferase
HDAC ¼histone deacetylase
HL-60 cells ¼human leukemia-60 cells
hTERT ¼human telomerase reverse transcriptase
JNK ¼Jun N-terminus kinase
miRNA ¼micro-ribonucleic acid
mRNA ¼messenger ribonucleic acid
PDE ¼phosphodiesterase
pro-EGCG ¼pro-drug of (-)-epigallocatechin-3-gallate
RNA ¼ribonucleic acid
RNS ¼reactive nitrogen species
ROS ¼reactive oxygen species
SAM ¼S-adenosylmethionine
SIRT ¼sirtuin
UHRF1 ¼ubiquitin-like containing PHD and ring
finger domains 1
UV ¼ultraviolet
... Consequently, quercetin reduced levels of the COX-2 protein. Generally, a COX-2 decrease is considered beneficial for successful cancer chemoprevention [174][175][176][177]. Furthermore, quercetin may induce significant histone hyperacetylation at 75 and 100 µM concentrations in human leukemia cells, suggesting the possible role of histone hyperacetylation in the anticancer activity of quercetin in vitro [178,179]. In conclusion, numerous studies have shown that quercetin may affect the activation of different signaling pathways and chromatin remodeling, and act as a chemopreventive agent [1-4,13,177 -182]. ...
... Some of the proposed mechanisms of epigenetic regulation by different polyphenolic antioxidants were summarized by Malireddy et al. [178]. They suggest that flavonoids may act either as (i) antioxidants, attenuating oxidative stress; and/or as (ii) direct modulators of DNMT, HDACs, and HATs. ...
... It also seems possible that metabolites formed by biotransformation of flavonoids by the cellular phase-I and phase-II xenobiotic-metabolizing enzymes regulate the cellular epigenome via signaling cascades. According to Malireddy et al. [178], for now, it is unclear whether the epigenetic regulation by redox-active phytochemicals is dependent either upon the oxidants produced by the prooxidant actions or the antioxidant nature of polyphenol antioxidants. ...
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In recent years, interest in natural products such as alternative sources of pharmaceuticals for numerous chronic diseases, including tumors, has been renewed. Propolis, a natural product collected by honeybees, and polyphenolic/flavonoid propolis-related components modulate all steps of the cancer progression process. Anticancer activity of propolis and its compounds relies on various mechanisms: cell-cycle arrest and attenuation of cancer cells proliferation, reduction in the number of cancer stem cells, induction of apoptosis, modulation of oncogene signaling pathways, inhibition of matrix metalloproteinases, prevention of metastasis, anti-angiogenesis, anti-inflammatory effects accompanied by the modulation of the tumor microenvironment (by modifying macrophage activation and polarization), epigenetic regulation, antiviral and bactericidal activities, modulation of gut microbiota, and attenuation of chemotherapy-induced deleterious side effects. Ingredients from propolis also ”sensitize“ cancer cells to chemotherapeutic agents, likely by blocking the activation of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). In this review, we summarize the current knowledge related to the the effects of flavonoids and other polyphenolic compounds from propolis on tumor growth and metastasizing ability, and discuss possible molecular and cellular mechanisms involved in the modulation of inflammatory pathways and cellular processes that affect survival, proliferation, invasion, angiogenesis, and metastasis of the tumor.
... This association can be explained by the capacity of lycopene to scavenge free oxygen radical products, which would otherwise engage PON1 activity and decrease it [151]. Furthermore, lycopene (and other dietary antioxidants) may exert its effects through modulation of gene expression through regulation of DNA methylation [148]. Methylation of the CpGrich region overlapping a gene's promoter is considered a mechanism for inhibiting a gene's expression [149]. ...
... Proposed mechanisms of antioxidant effects of lycopene; (original figure, based on data from[77,120,[142][143][144][145][146][147][148][149]). ...
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... Phytochemicals, are produced in plants to protect themselves from the environmental stress and infections. Phytochemicals play a preventive role in the treatment of diabetes and cancer [25][26][27] . Primary metabolites produced in plants are maintained plant cells, while secondary metabolites are responsible for normal growth, development and defense of plants 28 . ...
... Also, many epidemiological and experimental research have been studying the anti-inflammatory and immune modulation activities of polyphenols [20,21]. The ability of these natural compounds to modify the expression of several pro-inflammatory genes like multiple cytokines, lipoxygenase, nitric oxide synthases cyclooxygenase, in addition to their antioxidant characteristics such as ROS (reactive oxygen species) scavenging contributes to the regulation of inflammatory signaling [22,23]. Also, we know that in inflammatory and immune reactions, many immune cells play an important role. ...
... Polyphenols have demonstrated anti-inflammatory properties and have been helpful in the treatment of a number of diseases [28]. In addition to their antioxidant properties, the actions of these natural compounds help control the expression of multiple inflammatory genes [29,30]. Our findings may support the neuroprotective effect of dietary anthocyanin in the central nervous system in elderly companion dogs [31], given that C3G can downgrade the expression of inflammatory cytokines in the brain cortex region of APPswe/PSEN1dE9 mice [22]. ...
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Like humans, the accumulation of amyloid-beta oligomers in the brains of aged dogs leads to cognitive dysfunction. Our study investigated the effects of dietary flavonoids in pet foods on cognitive dysfunction. All nine dogs (six species) recruited were older than seven years, and cognitive function was measured using a questionnaire before and after applying pet food containing cyanidin-3-O-glucoside, the main component of honeyberries. Physical examination, blood tests, cognitive dysfunction scores, and serum amyloid-beta oligomers were measured. After 90 days of pet food administration, a physical examination revealed no abnormalities in weight, body temperature, heart rate, or respiratory rate. However, the cognitive dysfunction score and serum amyloid-beta oligomers (AβO) marker levels were significantly reduced after 90 days. Inflammation and antioxidant levels were slightly, but not significantly, changed. Our results suggest that pet food containing anthocyanins effectively improves cognitive dysfunction scores and decreases serum AβO levels.
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Sustenance of smallholder poultry production as an alternative source of food security and income is imperative in communities exposed to hydrocarbon pollution. Exposure to hydrocarbon pollutants causes disruption of homeostasis, thereby compromising the genetic potential of the birds. Oxidative stress-mediated dysfunction of the cellular membrane is a contributing factor in the mechanism of hydrocarbon toxicity. Epidemiological studies show that tolerance to hydrocarbon exposure may be caused by the activation of genes that control disease defense pathways like aryl hydrocarbon receptor (AhR) and nuclear factor erythroid 2p45-related factor 2 (Nrf2). Disparity in the mechanism and level of tolerance to hydrocarbon fragments among species may exist and may result in variations in gene expression within individuals of the same species upon exposure. Genomic variability is critical for adaptation and serves as a survival mechanism in response to environmental pollutants. Understanding the interplay of diverse genetic mechanisms in relation to environmental influences is important for exploiting the differences in various genetic variants. Protection against pollutant-induced physiological responses using dietary antioxidants can mitigate homeostasis disruptions. Such intervention may initiate epigenetic modulation relevant to gene expression of hydrocarbon tolerance, enhancing productivity, and possibly future development of hydrocarbon-tolerant breeds.
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Most synthetic immunomodulatory medications are extremely expensive, have many disadvantages and suffer from a lot of side effects. So that, introducing immunomodulatory reagents from natural sources will have great impact on drug discovery. Therefore, this study aimed to comprehend the mechanism of the immunomodulatory activity of some natural plants via network pharmacology together with molecular docking and in vitro testing. Apigenin, luteolin, diallyl trisulfide, silibinin and allicin had the highest percentage of C-T interactions while, AKT1, CASP3, PTGS2, NOS3, TP53 and MMP9 were found to be the most enriched genes. Moreover, the most enriched pathways were pathways in cancer, fluid shear stress and atherosclerosis, relaxin signaling pathway, IL-17 signaling pathway and FoxO signaling pathway. Additionally, Curcuma longa, Allium sativum, Oleu europea, Salvia officinalis, Glycyrrhiza glabra and Silybum marianum had the highest number of P-C-T-P interactions. Furthermore, molecular docking analysis of the top hit compounds against the most enriched genes revealed that silibinin had the most stabilized interactions with AKT1, CASP3 and TP53, whereas luteolin and apigenin exhibited the most stabilized interactions with AKT1, PTGS2 and TP53. In vitro anti-inflammatory and cytotoxicity testing of the highest scoring plants exhibited equivalent outcomes to those of piroxicam.
Long pepper (LP), soursop (SS), green vein kratom (GK), and red vein kratom (RK) leaf ethanolic extracts were prepared using an ultrasonic device, followed by dechlorophyllization by the sedimentation process. Antioxidant and antimicrobial activities of the extracts were studied. Highest yield and total phenolic content were found in RK extract (p < 0.05). In general, RK extract showed the lowest minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) toward four bacteria (Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, and Shewanella sp.), when compared with other extracts. Addition of GK extract at 600 mg/kg retarded chemical changes and lowered microbiological growth in Nile tilapia mince within 12 days at 4 °C. Lipid oxidation was also impeded with the aid of GK extract. Therefore, GK extract inhibited both spoilage and pathogenic bacteria, and prevented lipid oxidation, thus extending the shelf‐life of tilapia mince.
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Curcumin (Cur), a well-known dietary pigment derived from Curcuma longa, is a promising anticancer drug, but its in vivo target molecules remain to be clarified. Here we report that exposure of human hepatoma cells to Cur led to a significant decrease of histone acetylation. Histone acetyltransferase (HAT) and histone deacetylase (HDAC) are the enzymes controlling the state of histone acetylation in vivo. Cur treatment resulted in a comparable inhibition of histone acetylation in the absence or presence of trichostatin A (the specific HDAC inhibitor), and showed no effect on the in vitro activity of HDAC. In contrast, the domain negative of p300 (a most potent HAT protein) could block the inhibition of Cur on histone acetylation; and the Cur treatment significantly inhibited the HAT activity both in vivo and in vitro. Thus, it is HAT, but not HDAC that is involved in Cur-induced histone hypoacetylation. At the same time, exposure of cells to low or high concentrations of Cur diminished or enhanced the ROS generation, respectively. And the promotion of ROS was obviously involved in Cur-induced histone hypoacetylation, since Cur-caused histone acetylation and HAT activity decrease could be markedly diminished by the antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT) or their combination, but not by their heat-inactivated forms. The data presented here prove that HAT is one of the in vivo target molecules of Cur; through inhibiting its activity, Cur induces histone hypoacetylation in vivo, where the ROS generation plays an important role. Considering the critical roles of histone acetylation in eukaryotic gene transcription and the involvement of histone hypoacetylation in the lose of cell viability caused by high concentrations of Cur, these results open a new door for us to further understand the molecular mechanism involved in the in vivo function of Cur.
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Cancers are the largest cause of mortality and morbidity in industrialized countries. Several new concepts have emerged in relation to mechanisms that contribute to the regulation of carcinogenesis processes and associated inflammatory effects such as the modulation of innate immune cells and adaptive immune cells that could infiltrate the tumor. In the tumor microenvironment, there is a delicate balance between antitumor immunity and tumor-originated proinflammatory activity, which weaken antitumor immunity. Consequently; modulation of immune cells and inflammatory processes represent attractive targets for therapeutic intervention in malignant diseases with the goal to restore the sensitivity of cancer cells to chemotherapies and to overcome resistance to current cytotoxic therapies. Numerous studies have reported interesting properties of dietary polyphenols in anticancer strategies notably by their pleiotropic properties on cancer cells, immune cells and inflammation. This review is dedicated to the current knowledge of the mechanisms of polyphenols (resveratrol, curcumin, genistein and epigallocatechin) against cancers through a modulation of the immune system and the pro-inflammatory mediator production. We describe the effects of polyphenols on the adaptative and innate immune cells that could infiltrate the tumor. Reduction of chronic inflammation or its downstream consequences may represent a key mechanism in the fight of cancer development and polyphenols could reduce various pro-inflammatory substance productions through targeting signal transduction or through antioxidant effects. Lastly, we analyze key molecular links between inflammation and tumor progression through nuclear factors such as NFκB or microRNAs.
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Polyphenols are the biggest group of phytochemicals, and many of them have been found in plant-based foods. Polyphenol-rich diets have been linked to many health benefits. This paper is intended to review the chemistry and biochemistry of polyphenols as related to classification, extraction, separation and analytical methods, their occurrence and biosynthesis in plants, and the biological activities and implications in human health. The discussions are focused on important and most recent advances in the above aspects, and challenges are identified for future research.
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Introduction: Nowadays the 'redox hypothesis' is based on the fact that thiol/disulfide couples such as glutathione (GSH/GSSG), cysteine (Cys/CySS) and thioredoxin ((Trx-(SH)2/Trx-SS)) are functionally organized in redox circuits controlled by glutathione pools, thioredoxins and other control nodes, and they are not in equilibrium relative to each other. Although ROS can be important intermediates of cellular signaling pathways, disturbances in the normal cellular redox can result in widespread damage to several cell components. Moreover, oxidative stress has been linked to a variety of age-related diseases. In recent years, oxidative stress has also been identified to contribute to drug-induced liver, heart, renal and brain toxicity. Areas covered: This review provides an overview of current in vitro and in vivo methods that can be deployed throughout the drug discovery process. In addition, animal models and noninvasive biomarkers are described. Expert opinion: Reducing post-market drug withdrawals is essential for all pharmaceutical companies in a time of increased patient welfare and tight budgets. Predictive screens positioned early in the drug discovery process will help to reduce such liabilities. Although new and more efficient assays and models are being developed, the hunt for biomarkers and noninvasive techniques is still in progress.
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Polyphenols are natural substances with variable phenolic structures and are elevated in vegetables, fruits, grains, bark, roots, tea, and wine. There are over 8000 polyphenolic structures identified in plants, but edible plants contain only several hundred polyphenolic structures. In addition to their well-known antioxidant effects, select polyphenols also have insulin-potentiating, anti-inflammatory, anti-carcinogenic, anti-viral, anti-ulcer, and anti-apoptotic properties. One important consequence of ischemia is neuronal death and oxidative stress plays a key role in neuronal viability. In addition, neuronal death may be initiated by the activation of mitochondria-associated cell death pathways. Another consequence of ischemia that is possibly mediated by oxidative stress and mitochondrial dysfunction is glial swelling, a component of cytotoxic brain edema. The purpose of this article is to review the current literature on the contribution of oxidative stress and mitochondrial dysfunction to neuronal death, cell swelling, and brain edema in ischemia. A review of currently known mechanisms underlying neuronal death and edema/cell swelling will be undertaken and the potential of dietary polyphenols to reduce such neural damage will be critically reviewed.
Respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), are a significant and increasing global health problem. These diseases are characterized by airway inflammation, which develops in response to various stimuli. In asthma, inflammation is driven by exposure to a variety of triggers, including allergens and viruses, which activate components of both the innate and acquired immune responses. In COPD, exposure to cigarette smoke is the primary stimulus of airway inflammation. Activation of airway inflammatory cells leads to the release of excessive quantities of reactive oxygen species (ROS), resulting in oxidative stress. Antioxidants provide protection against the damaging effects of oxidative stress and thus may be useful in the management of inflammatory airways disease. Resveratrol, a polyphenol that demonstrates both antioxidative and anti-inflammatory functions, has been shown to improve outcomes in a variety of diseases, in particular, in cancer. We review the evidence for a protective role of resveratrol in respiratory disease. Mechanisms of resveratrol action that may be relevant to respiratory disease are described. We conclude that resveratrol has potential as a therapeutic agent in respiratory disease, which should be further investigated.
Green tea (Camellia sinensis) is rich in catechins, of which (−)-epigallocatechin-3-gallate (EGCG) is the most abundant. Studies in animal models of carcinogenesis have shown that green tea and EGCG can inhibit tumorigenesis during the initiation, promotion and progression stages. Many potential mechanisms have been proposed including both antioxidant and pro-oxidant effects, but questions remain regarding the relevance of these mechanisms to cancer prevention. In the present review, we will discuss the redox chemistry of the tea catechins and the current literature on the antioxidant and pro-oxidative effects of the green tea polyphenols as they relate to cancer prevention. We report that although the catechins are chemical antioxidants which can quench free radical species and chelate transition metals, there is evidence that some of the effects of these compounds may be related to induction of oxidative stress. Such pro-oxidant effects appear to be responsible for the induction of apoptosis in tumor cells. These pro-oxidant effects may also induce endogenous antioxidant systems in normal tissues that offer protection against carcinogenic insult. This review is meant point out understudied areas and stimulate research on the topic with the hope that insights into the mechanisms of cancer preventive activity of tea polyphenols will result.
In this short review we report selected examples from recent literature to show the potential of natural-derived, low molecular weight polyphenols as antitumor agents. The two major groups of polyphenol analogues have been reviewed here, namely flavonoids and stilbenoids. Notwithstanding these limitations, we listed 75 compounds, many of them representing only the most potent member in a library. In addition, many studies afforded useful SARs which may be the basis for future optimization. In this regard, it is worth highlighting the close structural relationships connecting some families of tubulin inhibitors, namely analogues of chalcones, combretastatin A-4, and resveratrol. Some interesting hybrid molecules have already been obtained, such as chalcone-combretastatin and chalcone-resveratrol hybrids. The optimization of natural polyphenols reputed to be anticarcinogenic has also been addressed to improve their metabolic stability and a number of analogues, which are more stable to metabolic conversion and display comparable or higher antitumor activity than the parent compound, have been obtained. In some cases analogues with higher lipophilicity showed higher activity than the parent compound, in particular stilbenoids, flavanols, and flavone derivatives. Table 1 summarizes the main biological data on the natural-derived polyphenols cited within this review. As a whole, this survey of recently reported, natural-derived polyphenols, though not exhaustive, clearly indicates that intensive research is being carried out in the area of antitumor polyphenol analogues and suggests that in the near future some polyphenolic leads may become useful anticancer drugs or adjuvants in cancer therapy.
Alzheimer's disease (AD) is the most prevalent neurodegenerative disease and most common cause of dementia. However, there is no known way to halt or cure the neurodegenerative disease. Oxidative stress is a cardinal hallmark of the disease and has been considered as therapeutic target for AD treatment. Several factors may contribute to oxidative stress in AD brains. First, mitochondrion is a key player that produces reactive oxygen species (ROS). Mitochondrial dysfunction found in AD patients may exaggerate generation of ROS and oxidative stress. Second, amyloid-beta peptide generates ROS in the presence of metal ions such as Fe(2+) and Cu(2+). Third, activated glial cells in AD brains may produce excessive amount of superoxide and nitric oxide through NADPH oxidase and inducible nitric oxide synthase, respectively. Increased ROS can cause damage to protein, lipid and nucleic acids. Numerous studies demonstrated that natural polyphenolic compounds protect against various neurotoxic insults in vitro and in vivo AD models. In these studies, dietary polyphenolic compounds exhibit neuroprotective effects through scavenging free radicals and increasing antioxidant capacity. Furthermore, they could facilitate the endogenous antioxidant system by stimulating transcription. Some epidemiological and clinical studies highlighted their therapeutic potential for AD treatment. In this review, we will briefly discuss causes of oxidative stress in AD brains, and describe antioxidant neuroprotective effects and therapeutic potential for AD of selected natural polyphenolic compounds.
Nutritional genomics reflects gene/nutrient interactions, utilising high-throughput genomic tools in nutrition research. The field also considers the contribution of individual genotypes to wellness and the risk of chronic disease (nutrigenetics), and how such genetic predisposition may be modified by appropriate diets. For example, high consumption of brassicaceous vegetables, including broccoli, has regularly associated with low cancer risk. Bioactive chemicals in broccoli include glucosinolates, plant pigments including kaempferol, quercetin, lutein and carotenoids, various vitamins, minerals and amino acids. Cancer prevention is hypothesised to act through various mechanisms including modulation of xenobiotic metabolising enzymes, NF-E2 p45-related factor-2 (Nrf2)-mediated stress-response mechanisms, and protection against genomic instability. Broccoli and broccoli extracts also regulate the progression of cancer through anti-inflammatory effects, effects on signal transduction, epigenetic effects and modulation of the colonic microflora. Human intervention studies with broccoli and related foods, using standard biomarker methodologies, reveal part of a complex picture. Nutrigenomic approaches, especially transcriptomics, enable simultaneous study of various signalling pathways and networks. Phenotypic, genetic and/or metabolic stratification may identify individuals most likely to respond positively to foods or diets. Jointly, these technologies can provide proof of human efficacy, and may be essential to ensure effective market transfer and uptake of broccoli and related foods.