doi:10.1017/S004393391300010X
Molecular targets of dietary
phytochemicals for the alleviation of heat
stress in poultry
K. SAHIN1*, C. ORHAN1, M.O. SMITH2 and N. SAHIN1
1
Department of Animal Nutrition, Faculty of Veterinary Science, Firat University,
Elazig, Turkey ; 2Department of Animal Science, The University of Tennessee, TN,
USA
*Corresponding author: [email protected]
Heat stress compromises performance and productivity through reducing feed
intake, while decreasing nutrient utilisation, growth rate, egg production, egg
quality and feed efficiency, leading to economic losses in poultry. High
temperatures can lead to oxidative stress associated with a reduced antioxidant
status in the bird in vivo, as reflected by increased oxidative damage and lowered
plasma concentrations of antioxidants. Several strategies are currently available to
alleviate the negative effects of high environmental temperature on the performance
of poultry. However, as it is expensive to cool buildings in which animals are housed,
many efforts are focused on dietary manipulation. In terms of reducing the negative
effects of environmental stress, antioxidants are used in poultry feed because of the
reported benefits of these supplements, including their anti-stress effects. In this
review, the mode of action of these supplements is investigated, and evidence is
presented showing that phytochemicals can alter several cell signalling pathways.
The agents include epigallocatechin-3-gallate (EGCG; green tea), lycopene (tomato)
and resveratrol (red grapes, peanuts and berries). The cell-signalling pathways
inhibited by EGCG include transcription factors (nuclear factor kappa-lightchain-enhancer of activated B cells (NF-κB)) and nuclear factors (erythroidderived 2-like 2 (Nrf2)) and activator protein-1 (AP-1) that regulate
cyclooxygenase-2 (COX-2). This review will also address some of the mechanisms
proposed for the heat stress preventive activity of EGCG, lycopene and resveratrol
focusing on the induction of antioxidant enzymes (phase II enzymes) through the
activation of the antioxidant response element (ARE) transcription system.
Keywords: heat stress; phytochemicals; poultry
Introduction
There are considerable numbers of experimental studies suggesting an association
© World's Poultry Science Association 2013
World's Poultry Science Journal, Vol. 69, March 2013
Received for publication May 1, 2012
Accepted for publication July 23, 2012
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Molecular targets of phytochemicals in heat stress: K. Sahin et al.
between the intake of phytochemicals (plant-derived substances such as lycopene), and
reduced negative effects of heat stress in poultry (Sahin et al., 2008; Tuzcu et al., 2008;
Sahin et al., 2012). Phytochemicals have been shown to exert their positive health
benefits directly, by affecting specific molecular targets such as genes, or indirectly as
stabilised conjugates affecting metabolic pathways (Kelloff et al., 2000; Aggarwal and
Shishodia, 2006). The aim of most studies is to understand and formulate mechanistic
pathways by which these naturally-derived substances can alter the fate of a cell. In
particular, the antioxidant effects of phytochemicals have been implicated as stressalleviation agents (Sahin et al., 2008; Tuzcu et al., 2008; Sahin et al., 2011). In
recent years, EGCG, lycopene and resveratrol have become the subject of more
intensive investigations in poultry (Sahin et al., 2008; 2010; 2012). In a
comprehensive analysis of experimental studies on the relation of tomato powder
consumption and stress prevention, Sahin et al. (2011) reported that most of the
reviewed studies have found an inverse association between tomato intake or blood
lycopene level and stress. The anti-stress effects of these and other phytochemicals
were found within diverse hepatic cells (Sahin et al., 2010; 2012). While it has been
shown that lycopene alleviates heat stress in a dose-dependent manner (Sahin et al.,
2011), the biochemical processes involved in the anti-stress effects of phytochemicals are
not completely understood. In this review, we will primarily address the mechanisms
proposed for the stress alleviation activity of selected phytochemicals (e.g. tomato
lycopene, EGCG, resveratrol) that target multiple cellular signalling pathways. The
phytochemicals, described here, do indeed show great potential for modulating
multiple targets such as transcription factors [e.g., NF-κB, AP-1, Nrf2].
Molecular action of heat stress in poultry
Heat stress is one of the important obstacles in poultry operations. High ambient
temperature does not only compromise welfare and health status (Mashaly et al.,
2004), but adversely affects survival (Bogin et al., 1996), performance (Wolfenson et
al., 1979; Yalcin et al., 2001), and product quality (Smith, 1974; Sandercock et al.,
2001). It is well established that heat stress can lead to a reduction in the birds’ defence
mechanisms (immunosuppression) (Thaxton and Siegel, 1970). It has been speculated
that levels of serum corticosteroids increase as a result of the increased activity of the
adrenal gland due to stress, which then suppresses cell proliferation factor or IL-2 (Siegel,
1995). The impact of environmental temperature depends on the degree of habituation of
the bird. In addition, heat stress causes molecular changes and has been shown to elevate
inflammatory markers such as interleukin-6 (IL-6), C - reactive protein (CRP), and
tumour necrosis factor (TNF) (Hargreaves et al., 1996; Etches et al., 2008; Sahin et
al, 2009a). Heat stress generates reactive oxygen species (ROS), possibly by disrupting
the electron transport assemblies within the membrane (Ando et al., 1997; Mujahid et al.,
2005), which could further modulate the activities of transcription factors such as the
nuclear factor erythroid 2-related factor 2 (Nrf-2) (Na and Surh, 2008), and inflammatory
transcription factor, nuclear factor-κB (NF-κB) (Ali and Mann, 2004). Heat and oxidative
stress adversely affects the structure and physiology of the cell, causing impairment of
transcription, RNA processing, translation, oxidative metabolism, and membrane
structure and function (Mager and De Kruijff, 1995; Iwagami, 1996). Hormonal and
metabolic changes, secretion of inflammatory markers (Hargreaves et al., 1996; Etches et
al., 2008) and a decrease in the level of vitamins and minerals have also been reported in
response to stress (Sahin and Kucuk, 2003; Sahin et al., 2009b).
Research over the last decade has shown that several phytochemicals reduce the
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negative effects of stress (Table 1). The active components of dietary phytochemicals that
most often appear to be protective against stress include EGCG, lycopene, resveratrol,
genistein, vitamin C and vitamin E (Table 1 and Figure 1). These dietary agents are
believed to suppress oxidative stress and the inflammatory processes that lead to
transformation and hyperproliferation. However, stress is a multistep process that can
be activated by any of various environmental factors (e.g. high or low ambient
temperature, transportation). These factors are known to modulate the transcription
factors (e.g., NF-κB, AP-1, Nrf2) and growth factor signalling pathways.
Table 1 Molecular targets of dietary phytochemicals in heat stressed poultry.
Name
Active compound
Molecular target
References
Tea
(Camellia sinensis)
Tomato
EGCG
↓NF-κB, ↓AP-1, ↓COX-2, ↑HO-1,
↑Nrf2, ↑GSH-Px, ↑CAT, ↑SOD
↓NF-κB, ↑Nrf2, ↑HO-1, ↑GSH-Px,
↑CAT, ↑SOD
↓NF-κB, ↑Nrf2, ↓Hsp70, ↓Hsp90,
↑GSH-Px, ↑CAT, ↑SOD
↓NF-κB, ↑Nrf2, ↑HO-1, ↑GSH-Px,
↑CAT, ↑SOD
Tuzcu et al., 2008;
Sahin et al., 2010
Sahin et al., 2008;
Sahin et al., 2011
Sahin et al., 2012
Grapes
(Vitis vinifera)
Turmeric
(Curcuma longa)
Lycopene
Resveratrol
Curcumin
Sahin et al.
unpublished data
NF-kB, nuclear factor kappa B; COX-2, cyclooxygenase-2; HO, haeme oxygenase; Nrf, NF-E2-related factor;
GSH-px, glutathione peroxidase; CAT, catalase; SOD, superoxide dismutase.
Figure 1 Dietary phytochemicals and their chemical structures.
Molecular targets
NUCLEAR FACTOR-KAPPA B (NF-ΚB)
The nuclear factor kappa light-chain-enhancer of activated B cells (NF-κB) is one of
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the transcription factors responsible for controlling DNA transcription and is involved in
cellular responses to a number of stimuli including free radicals (Gilmore, 2006). Under
normal conditions, NF-κB dimmers (first discovered in the nucleus by Sen and Baltimore
in 1986), reside in the cytoplasm. NF-κB is activated by stress, diet, chemotherapeutic
agents, free radicals, inflammatory stimuli, cytokines and the presence of carcinogens
(Aggarwal and Shishodia, 2006). Upon activation, it is translocated to the nucleus, where
it induces the expression of more than 200 genes that have been shown (Figure 2) to
suppress apoptosis and induce cellular transformation, proliferation, invasion, metastasis
and inflammation (Aggarwal and Shishodia, 2006; Gupta et al., 2010). The NF-κB
inducers act through distinct signalling pathways that converge during the activation
of an IκB kinase (IKK). This activation initiates IκB phosphorylation at specific
amino-terminal serine residues followed by ubiquitination at lysine residues and
subsequent degradation by 26S proteasome (Gupta et al., 2010). The activated NF-κB
binds to specific sequences of DNA called response elements in nucleus. Increased
expression of NF-κB in heat-stressed quails could be related to their activation
(Nelson et al., 2004; Gilmore, 2006) and translocation (Itoh et al., 1999; Yamamoto
et al., 2008; Nguyen et al., 2009), respectively, to overcome oxidative stress caused by
exposure to heat stress (Figure 2).
Figure 2 NF-κB as prime molecular targets for alleviation and cytoprotection with anti-inflammatory and
antioxidant phytochemicals (Adapted from Surh and Na, 2008.)
Several dietary phytochemicals, such as EGCG (Sahin et al., 2010), resveratrol (Manna
et al., 2000; Sahin et al., 2012), curcumin (Singh and Aggarwal, 1995) and lycopene
(Sahin et al., 2011) have been found to be potent inhibitors of NF-κB. These inhibitors
may block any one or more steps in the NF-κB signalling pathway, including the signals
that activate the NF-κB cascade, translocation of NF-κB into the nucleus, DNA binding
of the dimers, or interactions with the basal transcriptional machinery. Numerous studies
from our laboratory have shown that the agents derived from plants including EGCG,
lycopene, resveratrol, and curcumin exert numerous biological effects that are pertinent to
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Molecular targets of phytochemicals in heat stress: K. Sahin et al.
human medicine. These include antioxidant, antimicrobial, antiproliferative,
antimutagenic, and antiaging effects through the suppression of NF-κB (Mukthar and
Ahmad, 2000; Trevisanato and Kim, 2000). Yang et al. (2001) reported that EGCG
suppresses NF-κB activation by inhibiting IKK activity, as do various other
phytochemicals. In one study (Sahin et al., 2010), it was reported that increasing
dietary EGCG extracted from green tea, inhibited NF-κB expression by 42% in the
hepatic cells of quail reared under heat stress. Decreases in NF-κB expression in
response to increasing supplemental EGCG level were greater in the thermoneutral
environment than under heat stress (environmental temperature x EGCG level
interaction effects). It was additionally reported that hepatic MDA level was positively
correlated with expression of NF-κB and activities of antioxidant enzymes were
negatively correlated with expression of NF-κB (Sahin et al., 2010). Lycopene, found
in tomatoes and other red fruits and vegetables, such as carrots, watermelons and
papayas, has been shown to inhibit NF-κB activity and to modulate inflammatory
pathways (Gupta et al., 2011). A study from our laboratory has shown that, NF-κB
p65 subunit level increased in the nuclear fraction of the liver from heat stressed quails,
and tomato powder supplementation attenuated the response in a dose-dependent manner
(Sahin et al., 2011). We also reported that resveratrol can suppress the activation of
several transcription factors including NF-κB, and can inhibit protein kinases including
inhibitor of NF-κB (IκBα) kinase (IKK), mitogen-activated protein kinase (MAPK) and
protein kinase B (Akt) (Sahin et al., 2012). Thus, one of the probable mechanisms by
which dietary phytochemicals exercise their anti-stress properties is through the
suppression of the NF-κB signalling pathway.
ACTIVATOR PROTEIN-1 (AP-1)
Activator protein-1 (AP-1), a redox-sensitive transcription factor, modulates gene
expression responses to oxidative and electrophilic stresses presumably via sulphydryl
modification of critical cysteine residues found on this protein and/or other upstream
redox-sensitive molecular targets (Nair et al., 2007; 2010). AP-1 is a heterodimeric
protein composed of proteins complexes of members of the basic leucine zipper
(bZIP) protein families, including the Jun (c-Jun, JunB, and JunD) and Fos (c-Fos,
FosB, Fra-1, and Fra-2) families, Maf (c-Maf, MafB, MafA, Maf G/F/K, and Nrl) and
Jun dimerisation partners (JDP1 and JDP2) (Shaulian and Karin, 2002; Nair et al., 2010).
Many stimuli, including growth factors and oncoproteins, are potent inducers of AP-1
activity; and it is induced by tumour necrosis factor (TNF) and interleukin 1 (IL-1), as
well as by a variety of environmental stresses, such as high ambient temperature
(Aggarwal and Shishodia, 2006). AP-1 activation is linked to growth regulation, cell
transformation, inflammation, and innate immune responses (Aggarwal and Shishodia,
2006).
Several phytochemicals, such as EGCG (Orhan et al., 2012), resveratrol (Manna et al.,
2000) and curcumin (Aggarwal and Shishodia, 2006), have been shown to suppress the
AP-1 activation process. Manna et al. (2000) reported that resveratrol inhibited TNFdependent AP-1 activation in U-937 cells, and that pretreatment with resveratrol strongly
attenuates TNF-activated JNK and MEK kinases. A study from our laboratory has shown
that increasing dietary EGCG supplementation inhibited AP-1 expression in hepatic cells
from quail reared under heat stress (Orhan et al., 2012). These studies suggest that
several phytochemicals target the AP-1 signalling pathway in stressed poultry.
CYCLOOXYGENASE-2 (COX-2)
The cyclooxygenase (COX) enzymes, specifically the isozymes COX-1 and COX-2,
are involved in the conversion of arachidonic acid into inflammatory prostaglandins.
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Prostaglandins play critical roles in numerous biologic processes, including the regulation
of immune function, kidney development, reproductive biology, and gastrointestinal
integrity. Whereas COX-1 is expressed in most tissues, COX-2 is increasingly
expressed under inflammatory conditions (Williams et al., 1999; Gupta et al., 2011).
Depending upon the stimulus and the cell type, several transcription factors including
NF-κB and AP-1 can stimulate COX-2 transcription (Aggarwal and Shishodia, 2006).
Thus, all the dietary agents that can suppress these transcription factors have the potential
to inhibit COX-2 expression. Numerous studies continue to report that dietary
phytochemicals including EGCG (Orhan et al., 2012), curcumin (Aggarwal and
Shishodia, 2006), and resveratrol (Subbaramaiah et al., 1998) have been shown to
suppress COX-2. Recently, it was shown that heat stress significantly increased the
level of COX-2, c-Jun and c-Fos, the principal components of AP-1 protein, and that
EGCG intake caused reduction in their levels thereby indicating a response to
supplementation (Orhan et al., 2012).
NUCLEAR FACTOR-ERYTHROID 2-RELATED FACTOR 2 (NRF2) /
HAEMEOXYGENASE-1 (HO-1) PATHWAY
Nuclear Factor-Erythroid 2-Related Factor 2 (Nrf2) is a redox-sensitive transcription
factor (Nair et al., 2007) and plays a role in induction of phase II detoxifying/antioxidant
defence mechanisms to cope with oxidative stress through enhancing the expression of a
number of enzymes, such as NAD(P)H quinone oxidoreductase 1, glutamate-cysteine
ligase, haeme oxygenase-1, glutathione S-transferase, and UDP-glucuronosyltransferase
(Na and Surh, 2008). Nrf-2 is a key transcription factor that controls the cellular
antioxidant response against oxidants. Under normal physiological conditions, a
cytoskeleton binding protein called Kelch-like erythroid CNC homologue (ECH)associated protein 1 (Keap1) binds to Nrf-2, thereby repressing its translocation into
the nucleus, which is required for Nrf-2 activation. Covalent modification or oxidation of
critical cysteine residues in Keap1 has been hypothesized to facilitate the dissociation of
Keap1–Nrf-2 complex or increase the stability of Nrf-2 (Kobayashi et al., 2006; Na and
Surh, 2008). The cysteine residues serve as molecular sensor for recognizing the altered
intracellular redox-status triggered by electrophiles or ROS (Dinkova-Kostova et al.,
2002; Na and Surh, 2008). Beside this, post-transcriptional changes in Nrf-2 directly
modulate the Nrf-2-Keap1 signalling. Phosphorylation of Nrf-2 on its serine and
threonine residues by protein kinase C (PKC), phosphoinositol 3-kinase (PI3K), and
mitogen activated protein kinases (MAPKs) have been reported to activate Nrf-2 (Yu
et al., 2000; Na and Surh, 2008) (Figure 3). Further, MAPK and protein kinase B (PKB,
Akt) are associated with the modulation of antioxidant response element (ARE)-driven
gene expression via Nrf-2 (Yu et al., 2000; Li et al., 2007). It has been found (Sahin et
al., 2010) that heat stress is associated with transcription factor induction, and resulted in
an increase in the expression of NFκB and a decrease in the expression of Nrf2 when
birds were kept at high ambient temperature (Figure 3). HO-1 is responsible for the
conversion of haeme to biliverdin and carbon monoxide, and its induction is crucial in
the cellular adaptive response to oxidative injury (Na and Surh, 2008). Although HO-1
has a cytoprotective function in normal cells, abnormally elevated constitutive expression
of HO-1 in chronic diseases can confer growth advantage.
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Figure 3 Nrf2 as molecular targets for alleviation and cytoprotection with anti-inflammatory and
antioxidant phytochemicals (Adapted from Surh and Na, 2008).
Numerous reports indicate that dietary phytochemicals like EGCG (Na and Surh, 2008;
Sahin et al., 2010) and curcumin (Shen et al., 2006) can activate Nrf2 and induce
expression of antioxidant or phase two detoxifying enzymes. Garg and Maru (2009)
reported that curcumin increased ARE-binding of Nrf2 and induced the activity as well as
expression of GST and NQO1 and their mRNA transcripts, and the liver and lung of mice
treated with dietary curcumin had reduced oxidative stress and inflammation. A number
of studies from our laboratory have shown that the phytochemicals derived from plants
exert their anti-stress effects through the activation of Nrf2/HO-1 pathways (Figure 4).
EGCG from green tea mediate its effects by regulating the transcription factor Nrf2 and
Nrf2 regulated HO-1 (Na and Surh, 2008). It has been reported that increasing dietary
EGCG supplementation enhanced Nrf2 expression by 59%, and these changes in Nrf2
expression due to supplemental EGCG was greater in the thermoneutral environment
than under heat stress (Sahin et al., 2010). In the same study, hepatic MDA level was
negatively correlated with activities of antioxidant enzymes and expression of Nrf2 and
activities of antioxidant enzymes were positively correlated with expression of Nrf2
(Sahin et al., 2010). These data ascertain that polyphenols act as modifiers for signal
transduction pathways through enhancing Keap-1 dissociation from Nrf2 that occur in
response to stressors, which are accompanied by suppression of lipid peroxidation and
elevation of antioxidant enzyme activities. Lycopene may increase the nuclear
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translocation of Nrf-2 leading to enhanced expression of several phase-II detoxifying
enzymes as well as other antioxidant enzymes/proteins (Lian and Wang, 2008). In a
study, lycopene has been reported to stimulate the release of Nrf-2 from Keap1 by
forming covalently bound adducts with Keap (Ben-Dor et al., 2005). It has been
reported that Nrf-2 accumulation increased in the nuclear fraction of the liver of heatstressed quails when using tomato powder supplementation as a lycopene source (Sahin
et al., 2011). The expression of liver Hsp70 and Hsp90 was greater, while Nrf2
expression was lower in quails exposed to high ambient temperature compared to
those in a thermoneutral environment (Sahin et al., 2009b; 2012). Expression of
Hsp70 and Hsp90 was inhibited, whereas Nrf2 expression was enhanced with
increasing dietary resveratrol supplementation. Increase in Nrf2 expression in response
to the increasing supplemental resveratrol level was greater in the thermoneutral
environment than high ambient temperature conditions (Sahin et al., 2012). These
authors have shown that curcumin mediates its anti-stress effects by regulating the
transcription factor Nrf2 and HO-1 (Unpublished data). These results suggest that
these phytochemical agents specifically targeting Nrf/HO-1 pathway could be
promising agents for the alleviation of heat stress.
Figure 4 The Effects of heat stress phytochemicals on NF-κB and Nrf2 pathways.
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Conclusions
Exposure to heat stress enhanced NF-κB expression and suppressed Nrf2 expression in
hepatic cells. It is clear that numerous phytochemicals (e.g. EGCG, lycopene and
resveratrol) can interfere with multiple cell-signalling pathways in stressed poultry,
and that these compounds can be used in their natural form in larger doses for the
alleviation of heat stress. Alterations in transcription factors occurred at a greater rate
in quails subjected to heat stress than in those reared under the thermoneutral stress
condition. As a result, EGCG, lycopene and resveratrol elicit antioxidant effects through
inhibiting NF-κB expression and activating Nrf2 expression, which were activated and
suppressed in the heat stress environment. More studies are needed to validate the
usefulness of these agents either alone or in combination.
References
AGGARWAL, B.B. and SHISHODIA, S. (2006) Molecular targets of dietary agents for prevention and
therapy of cancer. Biochemical Pharmacology 71: 1397-1421.
ALI, S. and MANN, D.A. (2004) Signal transduction via the NF-kappaB pathway: a targeted treatment
modality for infection, inflammation and repair. Cell Biochemistry and Function 22: 67-79.
ANDO, M., KATAGIRI, K., YAMAMOTO, S., WAKAMATSU, K., KAWAHARA, I., ASANUMA, S.,
USUDA, M. and SASAKI, K. (1997) Age-related effects of heat stress on protective enzymes for peroxides
and microsomal monooxygenase in rat liver. Environmental Health Perspectives 105: 726-733.
BEN-DOR, A., STEINER, M., GHEBER, L., DANILENKO, M., DUBI, N., LINNEWIEL, K., ZICK, A.,
SHARONI, Y. and LEVY, J. (2005) Carotenoids activate the antioxidant response element transcription
system. Molecular Cancer Therapeutics 4: 177-186.
BOGIN, E., AVIDAR, Y., PECH-WAFFENSCHMIDT, V., DORON, Y., ISRAELI, B.A. and
KEVHAYEV, E. (1996) The relationship between heat stress, survivability and blood composition of the
domestic chicken. European Journal of Clinical Chemistry and Clinical Biochemistry 34: 463-469.
DINKOVA-KOSTOVA, A.T., HOLTZCLAW, W.D., COLE, R.N., ITOH, K., WAKABAYASHI, N.,
KATOH, Y., YAMAMOTO, M. and TALALAY, P. (2002) Direct evidence that sulfhydryl groups of
Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants.
Proceedings of the National Academy of Sciences of the United States of America 99: 11908-11913.
ETCHES, R., JOHN, J.M. and GIBBINS, A.M.V. (2008) Behavioural, physiological, neuroendocrine and
molecular responses to heat stress, in: DAGHIR, N.J. (Ed.) Poultry Production in Hot Climates, Second
Edition, pp. 48-79 (CAB International, Wallingford, UK).
GARG, R. and MARU, G. (2009) Dietary curcumin enhances benzo(a)pyrene-induced apoptosis resulting in a
decrease in BPDE-DNA adducts in mice. Journal of Environmental Pathology, Toxicology and Oncology 28:
121-131.
GILMORE, T.D. (2006) Introduction to NF-kappaB: players, pathways, perspectives. Oncogene 25: 66806684.
GUPTA, S.C., SUNDARAM, C., REUTER, S. and AGGARWAL, B.B. (2010) Inhibiting NF-κB activation
by small molecules as a therapeutic strategy. Biochimica et Biophysica Acta 1799: 775-787.
GUPTA, A., KUMAR, A. and KULKARNI, S.K. (2011) Targeting oxidative stress, mitochondrial
dysfunction and neuroinflammatory signalling by selective cyclooxygenase (COX)-2 inhibitors mitigates
MPTP-induced neurotoxicity in mice. Progress in Neuro-Psychopharmacology and Biological Psychiatry
35: 974-981.
HARGREAVES, M., DILLO, P., ANGUS, D. and FEBBRAIO, M. (1996) Effect of fluid ingestion on
muscle metabolism during prolonged exercise. Journal of Applied Physiology 80: 363-366.
ITOH, K., WAKABAYASHI, N., KATOH, Y., ISHII, T., IGARASHI, K., ENGEL, J.D. and
YAMAMOTO, M. (1999) Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2
through binding to the amino-terminal Neh2 domain. Genes and Development 13: 76-86.
IWAGAMI, Y. (1996) Changes in the ultrastructure of human cells related to certain biological responses under
hyperthermic culture conditions. Human Cell 9: 353-366.
KELLOFF, G.J., CROWELL, J.A., STEELE, V.E., LUBET, R.A., MALONE, W.A., BOONE, C.W.,
KOPELOVICH, L., HAWK, E.T., LIEBERMAN, R., LAWRENCE, J.A., ALI, I., VINER, J.L. and
SIGMAN, C.C. (2000) Progress in cancer chemoprevention: development of diet-derived chemopreventive
agents. Journal of Nutrition 130: 467-471.
World's Poultry Science Journal, Vol. 69, March 2013
121
Molecular targets of phytochemicals in heat stress: K. Sahin et al.
KOBAYASHI, A., KANG, M.I., WATAI, Y., TONG, K.I., SHIBATA, T., UCHIDA, K. and
YAMAMOTO, M. (2006) Oxidative and electrophilic stresses activate Nrf2 through inhibition of
ubiquitination activity of Keap1. Molecular and Cellular Biology 26: 221-229.
LI, H.Y., ZHONG, Y.F., WU, S.Y. and SHI, N. (2007) NF-E2 related factor 2 activation and heme oxygenase1 induction by tert-butylhydroquinone protect against deltamethrin-mediated oxidative stress in PC12 cells.
Chemical Research in Toxicology 20: 1242-1251.
LIAN, F. and WANG, X.D. (2008) Enzymatic metabolites of lycopene induce Nrf2-mediated expression of
phase II detoxifying/antioxidant enzymes in human bronchial epithelial cells. International Journal of Cancer
123: 1262-1268.
MAGER, W.H. and De KRUIJFF, A.J. (1995) Stress-induced transcriptional activation. Microbiological
Reviews 59: 506-531.
MANNA, S.K., MUKHOPADHYAY, A. and AGGARWAL, B.B. (2000) Resveratrol suppresses TNFinduced activation of nuclear transcription factors NF-kappa B, activator protein-1, and apoptosis:
potential role of reactive oxygen intermediates and lipid peroxidation. The Journal of Immunology 164:
6509-6519.
MASHALY, M.M., HENDRICKS, G.L., KALAMA, M.A., GEHAD, A.E., ABBAS, A.O. and
PATTERSON, P.H. (2004) Effect of heat stress on production parameters and immune responses of
commercial laying hens. Poultry Science 83: 889-894.
MUJAHID, A., YOSHIKI, Y., AKIBA, Y. and TOYOMIZU, M. (2005) Superoxide radical production in
chicken skeletal muscle induced by acute heat stress. Poultry Science 84: 307-314.
MUKHTAR, H. and AHMAD, N. (2000) Tea polyphenols: prevention of cancer and optimizing health. The
American Journal of Clinical Nutrition 71: 1698-1704.
NA, H.K. and SURH, Y.J. (2008) Modulation of Nrf2-mediated antioxidant and detoxifying enzyme induction
by the green tea polyphenol EGCG. Food and Chemical Toxicology 46: 1271-1278.
NAIR, S., BARVE, A., KHOR, T.O., SHEN, G.X., LIN, W., CHAN, J.Y., CAI, L. and KONG, A.N. (2010)
Regulation of Nrf2- and AP-1-mediated gene expression by epigallocatechin-3-gallate and sulforaphane in
prostate of Nrf2-knockout or C57BL/6J mice and PC-3 AP-1 human prostate cancer cells. Acta
Pharmacologica Sinica 31: 1223-1240.
NAIR, S., LI, W. and KONG, A.N. (2007) Natural dietary anti-cancer chemopreventive compounds: redoxmediated differential signalling mechanisms in cytoprotection of normal cells versus cytotoxicity in tumour
cells. Acta Pharmacologica Sinica 28: 459-472.
NELSON, D.E., IHEKWABA, A.E., ELLIOTT, M., JOHNSON, J.R., GIBNEY, C.A., FOREMAN, B.E.,
NELSON, G., SEE, V., HORTON, C.A., SPILLER, D.G., EDWARDS, S.W., MCDOWELL, HP.,
UNITT, J.F., SULLIVAN, E., GRIMLEY, R., BENSON, N., BROOMHEAD, D., KELL, D.B. and
WHITE, M.R. (2004) Oscillations in NF-kappaB signalling control the dynamics of gene expression.
Science 306: 704-708.
NGUYEN, T., NIOI, P. and PICKETT, C.B. (2009) The Nrf2-antioxidant response element signalling
pathway and its activation by oxidative stress. The Journal of Biological Chemistry 284: 13291-13295.
ORHAN, C., TUZCU, M., GENCOGLU, H., SAHIN, N. and SAHIN, K. (2012) Epigallocatechin-3-gallate
inhibits activation of AP-1, COX-2 and heat shock proteins in liver of quail reared under heat stress
(Unpublished).
SAHIN, K., ORHAN, C., AKDEMIR, F., TUZCU, M., IBEN, C. and SAHIN, N. (2012) Resveratrol
protects quail hepatocytes against heat stress: modulation of the Nrf2 transcription factor and heat shock
proteins. Journal of Animal Physiology and Animal Nutrition 96: 66-74.
SAHIN, K., ORHAN, C., TUZCU, M., ALI, S., SAHIN, N. and HAYIRLI, A. (2010) Epigallocatechin-3gallate prevents lipid peroxidation and enhances antioxidant defense system via modulating hepatic nuclear
transcription factors in heat-stressed quails. Poultry Science 89: 2251-2258.
SAHIN, K., SAHIN, N., KUCUK, O., HAYIRLI, A. and PRASAD, A.S. (2009a) Role of dietary zinc in
heat-stressed poultry: a review. Poultry Science 88: 2176-2183.
SAHIN, N., ORHAN, C., TUZCU, M., SAHIN, K. and KUCUK, O. (2008) The effects of tomato powder
supplementation on performance and lipid peroxidation in quail. Poultry Science 87: 276-283.
SAHIN, N., TUZCU, M., ORHAN, C., ONDERCI, M., EROKSUZ, Y. and SAHIN, K. (2009b) The effects
of vitamin C and E supplementation on heat shock protein 70 response of ovary and brain in heat-stressed
quail. British Poultry Science 50: 259-265.
SAHIN, K. and KUCUK, O. (2003) Heat stress and dietary vitamin supplementation of poultry diets. Nutrition
Abstracts and Reviews. Series B: Livestock Feeds and Feeding 73: 41-50.
SAHIN, K., ORHAN, C., AKDEMIR, F., TUZCU, T., ALI, S. and SAHIN, N. (2011) Tomato powder
supplementation activates Nrf-2 via ERK/Akt signalling pathway and attenuates heat stress-related responses
in quails. Animal Feed Science and Technology 65: 230-237.
SANDERCOCK, D.A., HUNTER, R.R., NUTE, G.R., MITCHELL, M.A. and HOCKING, P.M. (2001)
Acute heat stress-induced alterations in blood acid-base status and skeletal muscle membrane integrity in
broiler chickens at two ages: implications for meat quality. Poultry Science 80: 418-425.
122
World's Poultry Science Journal, Vol. 69, March 2013
Molecular targets of phytochemicals in heat stress: K. Sahin et al.
SEN, R. and BALTIMORE, D. (1986) Inducibility of kappa immunoglobulin enhancer-binding protein Nfkappa B by a posttranslational mechanism. Cell 47: 921-928.
SHAULIAN, E. and KARIN, M. (2002) AP-1 as a regulator of cell life and death. Nature Cell Biology 4: 131136.
SHEN, G., XU, C., HU, R., JAIN, M.R., GOPALKRISHNAN, A., NAIR, S., HUANG, M.T., CHAN, J.Y.
and KONG, A.N. (2006) Modulation of nuclear factor E2-related factor 2-mediated gene expression in mice
liver and small intestine by cancer chemopreventive agent curcumin. Molecular Cancer Therapeutics 5: 3951.
SIEGEL, H.S. (1995) Stress, Strains and Resistance. British Poultry Science 36: 3-22.
SINGH, S. and AGGARWAL, B.B. (1995) Activation of transcription factor NF-kappa B is suppressed by
curcumin (diferuloylmethane) [corrected]. The Journal of Biological Chemistry 270: 24995-5000.
SMITH, A.J. (1974) Changes in the average weight and shell thickness of eggs produced by hens exposed to
high environmental temperatures. A review. Tropical Animal Health and Production 6: 237-244.
SUBBARAMAIAH, K., CHUNG, W.J., MICHALUART, P., TELANG, N., TANABE, T., INOUE, H.,
JANG, M., PEZZUTO, J.M. and DANNENBERG, A.J. (1998) Resveratrol inhibits cyclooxygenase-2
transcription and activity in phorbol ester-treated human mammary epithelial cells. The Journal of Biological
Chemistry 273: 21875-21882.
SURH, Y.J. and NA, H.K. (2008) NF-kappaB and Nrf2 as prime molecular targets for chemoprevention and
cytoprotection with anti-inflammatory and antioxidant phytochemicals. Genes and Nutrition 2: 313-317.
THAXTON, P. and SIEGEL, H.S. (1970) Immunodepression in young chickens by high environmental
temperature. Poultry Science 49: 202-205.
TREVISANATO, S.I. and KIM, Y.I. (2000) Tea and health. Nutrition Reviews. 58: 1-10.
TUZCU, M., SAHIN, N., KARATEPE, M., CIKIM, G., KILINC, U. and SAHIN, K. (2008)
Epigallocatechin-3-gallate supplementation can improve antioxidant status in stressed quail. British
Poultry Science 49: 643-648.
WILLIAMS, C.S., MANN, M. and DUBOIS, R.N. (1999) The role of cyclooxygenases in inflammation,
cancer, and development. Oncogene 18: 7908-7916.
WOLFENSON, D., FERI, Y.F., SNAPIR, N. and BERMAN, A. (1979) Effect of diurnal or nocturnal heat
stress on egg formation. British Poultry Science 20: 167-174.
YALCIN, S., OZKAN, S, TURKMUT, L. and SIEGEL, P.B. (2001) Responses to heat stress in commercial
and local broiler stocks. 1. Performance traits. British Poultry Science 42: 149-152.
YAMAMOTO, T., SUZUKI, T., KOBAYASHI, A., WAKABAYASHI, J., MAHER, J., MOTOHASHI, H.
and YAMAMOTO, M. (2008) Physiological significance of reactive cysteine residues of Keap1 in
determining Nrf2 activity. Molecular and Cellular Biology 28: 2758-2770.
YANG, F., OZ, H.S., BARVE, S., DE VILLIERS, W.J., MCCLAIN, C.J. and VARILEK, G.W. (2001)
The green tea polyphenol ( )-epigallocatechin-3-gallate blocks nuclear factor-kappa B activation by inhibiting
I kappa B kinase activity in the intestinal epithelial cell line IEC-6. Molecular Pharmacology 60: 528-533.
YU, R., CHEN, C., MO, Y.Y., HEBBAR, V., OWUOR, E.D., TAN, T.H. and KONG, A.N. (2000)
Activation of mitogen-activated protein kinase pathways induces antioxidant response element-mediated
gene expression via a Nrf2-dependent mechanism. The Journal of Biological Chemistry 275: 39907-39913.
World's Poultry Science Journal, Vol. 69, March 2013
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