Molecular targets of dietary phytochemicals for the alleviation of heat ...

Molecular targets of dietaryphytochemicals for the alleviation of heatstress in poultryK. SAHIN1*, C. ORHAN1, M.O. SMITH2 and N. SAHIN1

1Department 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 feedintake, while decreasing nutrient utilisation, growth rate, egg production, eggquality and feed efficiency, leading to economic losses in poultry. Hightemperatures can lead to oxidative stress associated with a reduced antioxidantstatus in the bird in vivo, as reflected by increased oxidative damage and loweredplasma concentrations of antioxidants. Several strategies are currently available toalleviate the negative effects of high environmental temperature on the performanceof 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 negativeeffects of environmental stress, antioxidants are used in poultry feed because of thereported benefits of these supplements, including their anti-stress effects. In thisreview, the mode of action of these supplements is investigated, and evidence ispresented 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 pathwaysinhibited by EGCG include transcription factors (nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)) and nuclear factors (erythroid-derived 2-like 2 (Nrf2)) and activator protein-1 (AP-1) that regulatecyclooxygenase-2 (COX-2). This review will also address some of the mechanismsproposed for the heat stress preventive activity of EGCG, lycopene and resveratrolfocusing on the induction of antioxidant enzymes (phase II enzymes) through theactivation of the antioxidant response element (ARE) transcription system.

Keywords: heat stress; phytochemicals; poultry

Introduction

There are considerable numbers of experimental studies suggesting an association

doi:10.1017/S004393391300010X

© World's Poultry Science Association 2013World's Poultry Science Journal, Vol. 69, March 2013Received for publication May 1, 2012Accepted for publication July 23, 2012 113

between the intake of phytochemicals (plant-derived substances such as lycopene), andreduced 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 healthbenefits directly, by affecting specific molecular targets such as genes, or indirectly asstabilised conjugates affecting metabolic pathways (Kelloff et al., 2000; Aggarwal andShishodia, 2006). The aim of most studies is to understand and formulate mechanisticpathways by which these naturally-derived substances can alter the fate of a cell. Inparticular, the antioxidant effects of phytochemicals have been implicated as stress-alleviation agents (Sahin et al., 2008; Tuzcu et al., 2008; Sahin et al., 2011). Inrecent years, EGCG, lycopene and resveratrol have become the subject of moreintensive investigations in poultry (Sahin et al., 2008; 2010; 2012). In acomprehensive analysis of experimental studies on the relation of tomato powderconsumption and stress prevention, Sahin et al. (2011) reported that most of thereviewed studies have found an inverse association between tomato intake or bloodlycopene level and stress. The anti-stress effects of these and other phytochemicalswere found within diverse hepatic cells (Sahin et al., 2010; 2012). While it has beenshown 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 arenot completely understood. In this review, we will primarily address the mechanismsproposed for the stress alleviation activity of selected phytochemicals (e.g. tomatolycopene, EGCG, resveratrol) that target multiple cellular signalling pathways. Thephytochemicals, described here, do indeed show great potential for modulatingmultiple 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 ambienttemperature does not only compromise welfare and health status (Mashaly et al.,2004), but adversely affects survival (Bogin et al., 1996), performance (Wolfenson etal., 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’ defencemechanisms (immunosuppression) (Thaxton and Siegel, 1970). It has been speculatedthat levels of serum corticosteroids increase as a result of the increased activity of theadrenal 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 ofthe bird. In addition, heat stress causes molecular changes and has been shown to elevateinflammatory markers such as interleukin-6 (IL-6), C - reactive protein (CRP), andtumour necrosis factor (TNF) (Hargreaves et al., 1996; Etches et al., 2008; Sahin etal, 2009a). Heat stress generates reactive oxygen species (ROS), possibly by disruptingthe 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 thenuclear factor erythroid 2-related factor 2 (Nrf-2) (Na and Surh, 2008), and inflammatorytranscription factor, nuclear factor-κB (NF-κB) (Ali and Mann, 2004). Heat and oxidativestress adversely affects the structure and physiology of the cell, causing impairment oftranscription, RNA processing, translation, oxidative metabolism, and membranestructure and function (Mager and De Kruijff, 1995; Iwagami, 1996). Hormonal andmetabolic changes, secretion of inflammatory markers (Hargreaves et al., 1996; Etches etal., 2008) and a decrease in the level of vitamins and minerals have also been reported inresponse to stress (Sahin and Kucuk, 2003; Sahin et al., 2009b).Research over the last decade has shown that several phytochemicals reduce the

Molecular targets of phytochemicals in heat stress: K. Sahin et al.

114 World's Poultry Science Journal, Vol. 69, March 2013

negative effects of stress (Table 1). The active components of dietary phytochemicals thatmost 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 arebelieved to suppress oxidative stress and the inflammatory processes that lead totransformation and hyperproliferation. However, stress is a multistep process that canbe activated by any of various environmental factors (e.g. high or low ambienttemperature, transportation). These factors are known to modulate the transcriptionfactors (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 EGCG ↓NF-κB, ↓AP-1, ↓COX-2, ↑HO-1, Tuzcu et al., 2008;(Camellia sinensis) ↑Nrf2, ↑GSH-Px, ↑CAT, ↑SOD Sahin et al., 2010Tomato Lycopene ↓NF-κB, ↑Nrf2, ↑HO-1, ↑GSH-Px, Sahin et al., 2008;

↑CAT, ↑SOD Sahin et al., 2011Grapes Resveratrol ↓NF-κB, ↑Nrf2, ↓Hsp70, ↓Hsp90, Sahin et al., 2012(Vitis vinifera) ↑GSH-Px, ↑CAT, ↑SODTurmeric Curcumin ↓NF-κB, ↑Nrf2, ↑HO-1, ↑GSH-Px, Sahin et al.(Curcuma longa) ↑CAT, ↑SOD 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 incellular responses to a number of stimuli including free radicals (Gilmore, 2006). Undernormal conditions, NF-κB dimmers (first discovered in the nucleus by Sen and Baltimorein 1986), reside in the cytoplasm. NF-κB is activated by stress, diet, chemotherapeuticagents, free radicals, inflammatory stimuli, cytokines and the presence of carcinogens(Aggarwal and Shishodia, 2006). Upon activation, it is translocated to the nucleus, whereit induces the expression of more than 200 genes that have been shown (Figure 2) tosuppress apoptosis and induce cellular transformation, proliferation, invasion, metastasisand inflammation (Aggarwal and Shishodia, 2006; Gupta et al., 2010). The NF-κBinducers act through distinct signalling pathways that converge during the activationof an IκB kinase (IKK). This activation initiates IκB phosphorylation at specificamino-terminal serine residues followed by ubiquitination at lysine residues andsubsequent degradation by 26S proteasome (Gupta et al., 2010). The activated NF-κBbinds to specific sequences of DNA called response elements in nucleus. Increasedexpression 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; Yamamotoet al., 2008; Nguyen et al., 2009), respectively, to overcome oxidative stress caused byexposure to heat stress (Figure 2).

Figure 2 NF-κB as prime molecular targets for alleviation and cytoprotection with anti-inflammatory andantioxidant phytochemicals (Adapted from Surh and Na, 2008.)

Several dietary phytochemicals, such as EGCG (Sahin et al., 2010), resveratrol (Mannaet 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 inhibitorsmay block any one or more steps in the NF-κB signalling pathway, including the signalsthat activate the NF-κB cascade, translocation of NF-κB into the nucleus, DNA bindingof the dimers, or interactions with the basal transcriptional machinery. Numerous studiesfrom our laboratory have shown that the agents derived from plants including EGCG,lycopene, resveratrol, and curcumin exert numerous biological effects that are pertinent to



human medicine. These include antioxidant, antimicrobial, antiproliferative,antimutagenic, and antiaging effects through the suppression of NF-κB (Mukthar andAhmad, 2000; Trevisanato and Kim, 2000). Yang et al. (2001) reported that EGCGsuppresses NF-κB activation by inhibiting IKK activity, as do various otherphytochemicals. In one study (Sahin et al., 2010), it was reported that increasingdietary EGCG extracted from green tea, inhibited NF-κB expression by 42% in thehepatic cells of quail reared under heat stress. Decreases in NF-κB expression inresponse to increasing supplemental EGCG level were greater in the thermoneutralenvironment than under heat stress (environmental temperature x EGCG levelinteraction effects). It was additionally reported that hepatic MDA level was positivelycorrelated with expression of NF-κB and activities of antioxidant enzymes werenegatively correlated with expression of NF-κB (Sahin et al., 2010). Lycopene, foundin tomatoes and other red fruits and vegetables, such as carrots, watermelons andpapayas, has been shown to inhibit NF-κB activity and to modulate inflammatorypathways (Gupta et al., 2011). A study from our laboratory has shown that, NF-κBp65 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 ofseveral transcription factors including NF-κB, and can inhibit protein kinases includinginhibitor of NF-κB (IκBα) kinase (IKK), mitogen-activated protein kinase (MAPK) andprotein kinase B (Akt) (Sahin et al., 2012). Thus, one of the probable mechanisms bywhich dietary phytochemicals exercise their anti-stress properties is through thesuppression 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 sulphydrylmodification of critical cysteine residues found on this protein and/or other upstreamredox-sensitive molecular targets (Nair et al., 2007; 2010). AP-1 is a heterodimericprotein 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) andJun 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-1activity; and it is induced by tumour necrosis factor (TNF) and interleukin 1 (IL-1), aswell as by a variety of environmental stresses, such as high ambient temperature(Aggarwal and Shishodia, 2006). AP-1 activation is linked to growth regulation, celltransformation, 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 theAP-1 activation process. Manna et al. (2000) reported that resveratrol inhibited TNF-dependent AP-1 activation in U-937 cells, and that pretreatment with resveratrol stronglyattenuates TNF-activated JNK and MEK kinases. A study from our laboratory has shownthat increasing dietary EGCG supplementation inhibited AP-1 expression in hepatic cellsfrom quail reared under heat stress (Orhan et al., 2012). These studies suggest thatseveral 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.



Prostaglandins play critical roles in numerous biologic processes, including the regulationof immune function, kidney development, reproductive biology, and gastrointestinalintegrity. Whereas COX-1 is expressed in most tissues, COX-2 is increasinglyexpressed under inflammatory conditions (Williams et al., 1999; Gupta et al., 2011).Depending upon the stimulus and the cell type, several transcription factors includingNF-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 potentialto inhibit COX-2 expression. Numerous studies continue to report that dietaryphytochemicals including EGCG (Orhan et al., 2012), curcumin (Aggarwal andShishodia, 2006), and resveratrol (Subbaramaiah et al., 1998) have been shown tosuppress COX-2. Recently, it was shown that heat stress significantly increased thelevel of COX-2, c-Jun and c-Fos, the principal components of AP-1 protein, and thatEGCG intake caused reduction in their levels thereby indicating a response tosupplementation (Orhan et al., 2012).

NUCLEAR FACTOR-ERYTHROID 2-RELATED FACTOR 2 (NRF2) /HAEMEOXYGENASE-1 (HO-1) PATHWAYNuclear 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/antioxidantdefence mechanisms to cope with oxidative stress through enhancing the expression of anumber of enzymes, such as NAD(P)H quinone oxidoreductase 1, glutamate-cysteineligase, haeme oxygenase-1, glutathione S-transferase, and UDP-glucuronosyltransferase(Na and Surh, 2008). Nrf-2 is a key transcription factor that controls the cellularantioxidant response against oxidants. Under normal physiological conditions, acytoskeleton binding protein called Kelch-like erythroid CNC homologue (ECH)-associated protein 1 (Keap1) binds to Nrf-2, thereby repressing its translocation intothe nucleus, which is required for Nrf-2 activation. Covalent modification or oxidation ofcritical cysteine residues in Keap1 has been hypothesized to facilitate the dissociation ofKeap1–Nrf-2 complex or increase the stability of Nrf-2 (Kobayashi et al., 2006; Na andSurh, 2008). The cysteine residues serve as molecular sensor for recognizing the alteredintracellular redox-status triggered by electrophiles or ROS (Dinkova-Kostova et al.,2002; Na and Surh, 2008). Beside this, post-transcriptional changes in Nrf-2 directlymodulate the Nrf-2-Keap1 signalling. Phosphorylation of Nrf-2 on its serine andthreonine residues by protein kinase C (PKC), phosphoinositol 3-kinase (PI3K), andmitogen activated protein kinases (MAPKs) have been reported to activate Nrf-2 (Yuet 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)-drivengene expression via Nrf-2 (Yu et al., 2000; Li et al., 2007). It has been found (Sahin etal., 2010) that heat stress is associated with transcription factor induction, and resulted inan increase in the expression of NFκB and a decrease in the expression of Nrf2 whenbirds were kept at high ambient temperature (Figure 3). HO-1 is responsible for theconversion of haeme to biliverdin and carbon monoxide, and its induction is crucial inthe cellular adaptive response to oxidative injury (Na and Surh, 2008). Although HO-1has a cytoprotective function in normal cells, abnormally elevated constitutive expressionof HO-1 in chronic diseases can confer growth advantage.



Figure 3 Nrf2 as molecular targets for alleviation and cytoprotection with anti-inflammatory andantioxidant 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 induceexpression 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 asexpression of GST and NQO1 and their mRNA transcripts, and the liver and lung of micetreated with dietary curcumin had reduced oxidative stress and inflammation. A numberof studies from our laboratory have shown that the phytochemicals derived from plantsexert 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 andNrf2 regulated HO-1 (Na and Surh, 2008). It has been reported that increasing dietaryEGCG supplementation enhanced Nrf2 expression by 59%, and these changes in Nrf2expression due to supplemental EGCG was greater in the thermoneutral environmentthan under heat stress (Sahin et al., 2010). In the same study, hepatic MDA level wasnegatively correlated with activities of antioxidant enzymes and expression of Nrf2 andactivities of antioxidant enzymes were positively correlated with expression of Nrf2(Sahin et al., 2010). These data ascertain that polyphenols act as modifiers for signaltransduction pathways through enhancing Keap-1 dissociation from Nrf2 that occur inresponse to stressors, which are accompanied by suppression of lipid peroxidation andelevation of antioxidant enzyme activities. Lycopene may increase the nuclear



translocation of Nrf-2 leading to enhanced expression of several phase-II detoxifyingenzymes as well as other antioxidant enzymes/proteins (Lian and Wang, 2008). In astudy, lycopene has been reported to stimulate the release of Nrf-2 from Keap1 byforming covalently bound adducts with Keap (Ben-Dor et al., 2005). It has beenreported that Nrf-2 accumulation increased in the nuclear fraction of the liver of heat-stressed quails when using tomato powder supplementation as a lycopene source (Sahinet al., 2011). The expression of liver Hsp70 and Hsp90 was greater, while Nrf2expression was lower in quails exposed to high ambient temperature compared tothose in a thermoneutral environment (Sahin et al., 2009b; 2012). Expression ofHsp70 and Hsp90 was inhibited, whereas Nrf2 expression was enhanced withincreasing dietary resveratrol supplementation. Increase in Nrf2 expression in responseto the increasing supplemental resveratrol level was greater in the thermoneutralenvironment than high ambient temperature conditions (Sahin et al., 2012). Theseauthors have shown that curcumin mediates its anti-stress effects by regulating thetranscription factor Nrf2 and HO-1 (Unpublished data). These results suggest thatthese phytochemical agents specifically targeting Nrf/HO-1 pathway could bepromising agents for the alleviation of heat stress.

Figure 4 The Effects of heat stress phytochemicals on NF-κB and Nrf2 pathways.



Conclusions

Exposure to heat stress enhanced NF-κB expression and suppressed Nrf2 expression inhepatic cells. It is clear that numerous phytochemicals (e.g. EGCG, lycopene andresveratrol) 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 thealleviation of heat stress. Alterations in transcription factors occurred at a greater ratein quails subjected to heat stress than in those reared under the thermoneutral stresscondition. As a result, EGCG, lycopene and resveratrol elicit antioxidant effects throughinhibiting NF-κB expression and activating Nrf2 expression, which were activated andsuppressed in the heat stress environment. More studies are needed to validate theusefulness of these agents either alone or in combination.

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Molecular targets of dietary phytochemicals for the alleviation of heat ...

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