Dietary polyphenols, oxidative stress and antioxidant and anti-inflammatory effects

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ScienceDirect Dietary polyphenols, oxidative stress and antioxidant and anti-inflammatory effects Hua Zhang and Rong Tsao Phenolic compounds including phenolic acids, flavonoids and proanthocyanidins are widely distributed in plants as a protective mechanism against biotic and abiotic stresses. Fruits, vegetables, grains, spices and herbs are the richest source of dietary polyphenols. High intake of these foods has been linked to lowered risk of most common degenerative and chronic diseases that are known to be caused by oxidative stress. This review intends to summarize briefly recent progress on the chemistry and biochemistry of dietary polyphenols, their antioxidant and anti-inflammatory activities, and the underlying molecular mechanisms of their involvement in inflammation mediated metabolic diseases are also discussed. Perspectives for future research are also briefly discussed. Address Guelph Research and Development Centre, Agriculture and Agri-Food Canada, 93 Stone Road West, Guelph, Ontario, Canada N1G 5C9 Corresponding author: Tsao, Rong ([email protected])

Current Opinion in Food Science 2016, 8:33–42 This review comes from a themed issue on Functional foods and nutrition Edited by Rotimi Aluko For a complete overview see the Issue and the Editorial Available online 9th February 2016 http://dx.doi.org/10.1016/j.cofs.2016.02.002 2214-7993/Crown Copyright # 2016 Published by Elsevier Ltd. All rights reserved.

Introduction Dietary polyphenols are one of the most important groups of natural antioxidants and chemopreventive agents found in human diets including fruits, vegetables, grains, tea, essential oils and their derived foods and beverages. Epidemiological, clinical and nutritional studies strongly support the evidence that dietary phenolic compounds enhance human health by lowering risk and preventing the onset of degenerative diseases including cancers, cardiovascular diseases and metabolic disorders [1]. The term ‘phenolics’ can be construed as compounds that possess an aromatic ring bearing one hydroxyl group, whereas ‘polyphenols’ can have one or more aromatic rings bearing more than one hydroxyl group. However, these two terms are often used interchangeably in most literature, therefore will be treated similarly in the present review. Phenolic www.sciencedirect.com

compounds can be divided into several sub-groups according their structural characteristics, however, those commonly found in plant food can be categorized into three main sub-groups: phenolic acids, flavonoids and non-flavonoids [2]. Phenolic acids are hydroxyl derivatives of aromatic carboxylic acids which have a single phenolic ring and can be further divided into two main types, the benzoic acids and cinnamic acids, based on the C1-C6 or C3-C6 backbone as shown in Figure 1. About 30% of the free or bound forms of dietary phenolics in plants are phenolic acids. Flavonoids contain two phenolic rings (Ring A and Ring B) linked by a three carbon bridge that is usually an oxygenated heterocycle (Ring C), having a common C6-C3-C6 skeleton structure (Figure 1). The antioxidant and anti-inflammatory activities as well as other biological functions of polyphenols have been largely attributed to the particular chemical structures. The aromatic feature and highly conjugated system with multiple hydroxyl groups make these compounds good electron or hydrogen atom donors, neutralizing free radicals and other reactive oxygen species (ROS). Being part of the plants’ chemical defence, polyphenols of plants exist as glycosides, acylglycosides and other conjugated forms rather than aglycones. Invasion by insects or microorganisms or abiotic stress can inactivate enzymes which hydrolyze the glycosides to release aglycones that are generally more active. Phenolic glycosides in human foods are less absorbed than their respective aglycones in the digestive tract, thus the form of dietary polyphenols may affect the outcome of their health benefits. While a large body of evidence exists for the in vitro antioxidant and anti-inflammatory effects of polyphenols, these effects are not always validated in vivo, in fact many conflicting results have been reported. The inconsistency between observations in the in vitro and in vivo studies raise new questions and challenges, particularly those related to the roles of polyphenols and their metabolites in inflammation related health issues such as colonic degenerative diseases [3]. While free or simple conjugates of polyphenols are absorbed in the upper gastrointestinal (GI) tract, their bioavailability is very low compared to the vitamin antioxidants [3]. Phenolic compounds are also metabolized after intestinal uptake before being delivered to different tissues or organs by blood circulation to exert their various effects. The unabsorbed phenolics and those bound to cell wall materials can be further metabolized or released by the gut microbiota in the colon [4]. These metabolites or bound phenolics can therefore Current Opinion in Food Science 2016, 8:33–42

34 Functional foods and nutrition

Figure 1

POLYPHENOLS trans-Resveratrol

Secoisolariciresinol

Phenolic acids

Anthocyanins

Flavonols

Stilbenes

Chalcones

FLAVONOIDS

Lignans

Flavanols

Flavanones

Ellagic acids

Flavones

Isoflavones

Naringenin

Kaempferol R=H R=OH Quercetin

Condensed Tannins

Monomers

Procyanidins

Dimers

Oligomers

Polymers

n=2

n=2-7

n>7

Current Opinion in Food Science

Schematic classification of polyphenols, including phenolic acids, flavonoids and other polyphenols.

positively affect local inflammatory status, or indirectly act as prebiotics to promote the growth of probiotics, leading to improved gut health [4]. Chronic inflammation is the intrinsic cause for the development of many chronic health conditions, including degenerative diseases and metabolic syndromes [5]. The immune-inflammatory response is a defense mechanism for preventing the onset of infections caused by wound or microbial invasion. However, an unsuccessfully maintained immune homeostasis leads to chronic inflammatory responses which are harmful to tissues or can cause progressive damages. The immune-inflammatory, signalling, and metabolic effects are the main pillars that physiologically connect the polyphenols and different chronic diseases. An in-depth understanding of the implication of dietary polyphenols in regulating these effects is a prerequisite to developing effective dietary intervention for inflammatory disease prevention strategies. The ability of dietary polyphenols to reduce inflammation is considered to be from the following functions: firstly, acting as antioxidants; secondly, interfering with oxidative stress signalling; thirdly, suppressing Current Opinion in Food Science 2016, 8:33–42

the pro-inflammatory signalling transductions. The biological implication of phenolic compounds is not only based on directly reacting with ROS but also agonistically activating cellular signalling pathways. The preventive effects of administration of dietary phenolic compounds on chronic diseases have been examined in recent studies. This paper is to provide a review of recent progresses in polyphenol research, with a special focus on their antioxidant and anti-inflammatory effects, and the underlying molecular mechanisms.

Biological implications of phenolic compounds Like most secondary metabolites, phenolic compounds are the front line defence of plants. They are perhaps the most important non-nutrient bioactive groups in human diet simply because of the fact that plants are the main dietary portion for humans, and phenolics are more abundant than other phytochemicals in plant foods. Among the various potential health benefits of dietary polyphenols, their ability to suppress oxidation stands out as they have been constantly found to act as strong antioxidants, being able to prevent oxidative damage and reduce inflammation. High www.sciencedirect.com

Polyphenols and anti-inflammation Zhang and Tsao 35

intake of phenolics-rich fruits, vegetables and whole grains reduces risk of cancer, cardiovascular disease, chronic inflammation and metabolic disorders [6]. The mechanisms of the antioxidant and anti-inflammatory effects of the phenolic compounds are generally considered to arise from their ability in scavenging free radicals, restoring antioxidant enzyme activities and in regulating cytokine-induced inflammation. The following discussions will therefore be focused on the latest advances in these mechanisms. Antioxidant activity

Exposure to harmful stimuli such as physical injury, chemical and mechanical stress, metabolic disorders, redox imbalance, and absence of oxygen or glucose are all known to contribute to compromised immune regulatory functions, which may induce autoimmune diseases [7]. These stimuli can cause acute or chronic, localized or systemic inflammations. Acute inflammation involves the release of cell-derived mediators such as cytokines, prostaglandins and ROS that are produced to protect cells and tissues. Physiologically produced ROS such as nitric oxide (NO), hydroxyl radical (OH) and superoxide anion (O2) from various types of immune cells or respiratory burst in neutrophils are beneficial to human health because of their role in preventing pathogen invasion, depleting malignant cells and improving wound healing. However, persistent and long term immune responses can cause homeostatic imbalance of the immune regulatory functions, leading to irreversibly damage of the tissues. Over exposure to various stimuli such as pollutants, smoke, drugs, xenobiotics, ionizing radiation and heavy metal ions, induce excess ROS production, the main exogenous causative factor for oxidative stress. Vital biomolecules including lipids, proteins and DNA can be irreversibly and permanently damaged by highly reactive intermediates such as ROS [8,9]. Dietary phenolics are powerful antioxidants in vitro, being able to neutralize free radicals by donating an electron or hydrogen atom to a wide range of reactive oxygen, nitrogen and chlorine species, including O2, OH, peroxyl radicals RO2, hypochlorous acid (HOCl) and peroxynitrous acid (ONOOH) [10]. Phenolics interrupt the propagation stage of the lipid autoxidation chain reactions as effective radical scavengers or act as metal chelators to convert hydroperoxides or metal prooxidants into stable compounds. Phenolic compounds as metal chelators can directly inhibit Fe3+ reduction thereby reducing the production of reactive OH of Fenton reaction [11]. Both phenolic acids and flavonoids possess effective radical scavenging activity, however, the metalchelating potential and reducing power can vary depending on their structural features. The mode of the antioxidant activity of phenolics can be based either on hydrogen atom transfer (HAT) or single www.sciencedirect.com

electron transfer by proton transfer (SET-PT) [10]. However, the antioxidant potential of a particular phenolic compound primarily depends on the number and position of hydroxyl groups in the molecule. For instance, flavonols such as quercetin containing the 3-hydroxy group have shown relatively higher antioxidant activity than those without in neutralizing free radicals [2]. Degree of hydroxylation also affects the antioxidant activity [10]. Longer distance separating the carbonyl group and the aromatic ring of a phenolic acid seemed to increase the antioxidant activity such as in the case of cinnamic acid and derivatives versus benzoic acids. Hydroxyl groups on benzoic ring at the ortho-position and/or para-position can lead to elevated antioxidant activity compared to other positions and unsubstituted phenol [12]. In addition, increased number of hydroxyl aromatic rings such as flavonoids have been shown higher antioxidant activity compared with phenolic acids. The catechol moiety in ring B, the 2,3-double bound and conjugated 4-oxo group in ring C and 3-hydroxyl and 5-hydroxyl moiety of flavonoids have been considered important for their high metal chelating activity and free radical scavenging activity [13]. While phenolic compounds are strong antioxidants, it should be pointed out that when a phenolic molecule loses an electron or when it acts as a reducing agent, the molecule itself becomes a radical, albeit a relatively stable one; its oxidized intermediates can also become prooxidants. Interaction between polyphenols and transition metal ions can result in prooxidant formation [14], and the oxidized intermediates or oxidation products, such as semiquinones and quinones may become prooxidants and have adverse effects to human health when present at high concentrations [15]. The human GI tract may be where these prooxidants are formed as a result of ingesting high doses polyphenolics and the presence of abundant metal ions [16]. Polyphenols therefore can be a double-edged sword; on the one hand, when used properly in the form of food or functional food, they are strong antioxidants against excess oxidative stress such as ROS, thus beneficial to health, on the other, they can display prooxidant activity when consumed in high doses such as by taking supplements [14]. Assessment of the antioxidant activity of polyphenols is mostly carried out in chemical models and for phenolic extracts. Several such antioxidant assay methods including ferric reducing antioxidant power (FRAP), oxygen radical absorbance capacity (ORAC), 2,2-diphenyl-1picrylhydrazyl (DPPH) and photochemiluminescence (PCL) have been developed as quick assessment and screening tools, however, none of these in vitro methods, individually or collectively are relevant to the actual physiology of the human body [10]. Due to the low bioavailability, the physiological concentration of phenolics or their metabolites is in fact too low for many of the Current Opinion in Food Science 2016, 8:33–42

36 Functional foods and nutrition

chemical-based assays. The recently developed cellbased antioxidant assay (CAA) is one step closer to the physiological condition, and the activity can be measured at physiologically relevant concentrations of phenolics and other phytochemical antioxidants [17]. However, rapid metabolism and low solubility of the phenolic compounds often result in low bioavailability in vivo. The plasma concentration of flavonoids is typically less than 1 mmol/L which is insufficient to exert significant antioxidant activities via direct radical scavenging or reducing power measurable by the existing in vitro assay methods. The complex intrinsic antioxidant system also

makes it difficult to verify the systemic antioxidant effects of the low-level absorbed phenolic compounds in vivo. Dietary polyphenols are first depolymerized and/or deconjugated (e.g. deglycosylation) in the GI tract and colon, and then the original phenolics and their microbial bioconversion products successively undergo liver phase I and II metabolism, and finally are absorbed in the systemic circulation and carried to the tissues and organs to exert biological effects or excreted in the urine after glucuronidation, sulphation and O-methylation [3]. The antioxidant activities of these metabolites are normally decreased due to conformational change-mediated blockage of phenolic

Figure 2

IL1β P2X7R P2X7R

TNFR TNFR

O2.–

O2

IL1β

ROS Rac1

Pl3K

Phox

TLR TLR

ATP

PDGFR PDGFR

TNFα

PKC

ATP Cap1 ROS Antioxidants

NLRP3

Ras

ProIL1β

Raf p53

p38

Antioxidants

MAPK IκBα

JNK

ERK

Cap3

Mito-O2.– IκBα

AP1

ROS Apotosis

NF-κB Keap1

Maf

NF-κB

Pro-inflammatory Cytokines (TNF-α, IL-6,IL8,IL1β et al.)

AP1

NRF2

NRF2

ARE Transcription

Antioxidant Enzymes (SOD, CAT,GR,Gpx, PRXs, et al) Current Opinion in Food Science

Summary of molecular signalling transductions regulated by ROS. ROS diffused into the cell or bursted from mitochondria stimulate activations of MAPKs, NFkB pathways as well as Nrf2 associated pathways. Activation of MAPKs and NFkB leads to stimulating the inflammatory transcription factors to up-regulate pro-inflammatory mediators (e.g. TNF-a, IL-6, IL-8 and IL-1 b). Disassociation of Nrf2 results in the transcription of antioxidant enzymes, such as glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT), heme oxygenase-1 (HO-1) and release of endogenous antioxidant glutathione (GSH). Both endogenous and exogenous antioxidants can directly scavenge ROS or suppressing NF-kB activated pro-inflammatory signal transduction, thereby attenuating oxidative stress. Arrows indicate activation, whereas perpendicular lines show inhibition. Adapted from [20]. Current Opinion in Food Science 2016, 8:33–42

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Polyphenols and anti-inflammation Zhang and Tsao 37

hydroxyl groups [18]. The indigested phenolic compounds including unabsorbed flavonoids, proanthocyanidins, conjugated and bound phenolics are digested by colonic microflora to release bioactive metabolites that may participate in regulation of gut microbiota or be uptaken by colonic epithelia to exert antioxidant and anti-inflammatory effects [4]. Metabolism of dietary phenolic compounds have also been confirmed in vitro under cell culture conditions [19].

dissociation of the Keap1/Nrf2 complex [23]. Effects on the cross-link between AhR and Nrf2 signalling pathways are the key molecular mechanism underlying the ability of polyphenols in promoting endogenous antioxidant defensive system based on SOD, CAT, GPx and GR, to restore the cellular redox homeostasis [23]. As demonstrated in Table 1, the agonistic regulatory effect by these dietary polyphenols on AhR has been linked to chemopreventive epigenetic factors in the immune, integumentary system, and nervous and other physiological systems.

Anti-oxidative stress activities

Excessive accumulation of ROS or depletion of intermediates with antioxidant capacity alters the redox balance and leads to oxidative stress (Figure 2). An integrated cellular enzymatic redox system consisted of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR) and peroxiredoxins (PRXs) is a cellular defence mechanism that maintains the oxidative equilibrium [20]. However, this mechanism is deficient under oxidative stress from excess ROS [9]. Phenolic compounds are produced by plant cells in response to stress such as microbial infection as a defence mechanism [21]. Such protective property of phenolic compounds may enable themselves to exert similar effects in mammalian systems after consumption of food containing these compounds. This has been recently recognized and developed into a novel theory termed xenohormesis [21]. Dietary polyphenols are one of the most important xenobiotics with physiological relevance to human health. Consumption or supplementation of dietary polyphenols has been shown to be able to restore the redox homeostasis and prevent systemic or localized inflammation by enhancing activities of the antioxidant enzymes SOD, CAT, GPx and GR (Figure 2). Expressions of these detoxifying and antioxidant enzymes are modulated by a key transcription factor nuclear factor erythroid-related factor (Nrf)-2 which can be activated by ROS at cellular level. Nrf2 translocates into nucleus and regulates antioxidant-responsive elements (ARE)-mediated transcriptions of various genes encoding the above mentioned antioxidant enzymes [22]. The Nrf2-Keap1 pathway controls modulation of the redox homeostasis and detoxification (Figure 2). Polyphenols may induce Nrf2 activation to up-regulate cellular antioxidant enzymes [22]. Dietary polyphenols, especially flavonoids, are also capable of triggering Nrf2 translocation to induce subsequent activation of the endogenous antioxidant actions through ligand interaction with cytosolic aryl hydrocarbon receptor (AhR) [23]. Flavonols and isoflavones and their derivatives have shown agonistic potential to regulate AhRmediated signalling in cells [24]. Several flavonols and flavones, including quercetin, luteolin, apigenin and chrysin, have been confirmed as AhR agonistic regulators [23]. Involvements of polyphenols in this pathway are illustrated in Figure 3. The effects of dietary polyphenols on oxidative stress via activation of the AhR/Nrf2 pathway are summarized in Table 1. Polyphenols including flavonoids and their metabolites are not only AhR agonists but also induce www.sciencedirect.com

In addition, polyphenols can also suppress oxidative stress by reducing inflammatory responses via interfering with nuclear factor kappa B (NFkB) and mitogen-activated protein kinase (MAPK) controlled inflammatory signalling cascades [25]. Activation of these cellular processes leads to innate magnification of regulatory immune responses. As a result, pro-inflammatory cytokines, including interleukin (IL)-1b, IL-6, IL-8, tumour necrosis factor (TNF)-a and interferin (IFN)-g, are released into the circulation system which, if not properly regulated, can trigger irreversible systemic inflammation and disrupted immune homeostasis. While many polyphenols have shown regulatory activity on reducing pro-inflammatory biomarkers, the underlying mechanisms of these compounds are still not well understood.

Anti-inflammatory effects

Both oxidative stress and inflammation can cause pathogenesis of chronic diseases and metabolic disorders, and the anti-oxidative stress activity and anti-inflammatory Figure 3

PL IL1β

TLR-1

Cytoplasma

ROS

PL

AhR

NLRP3 PL

Keap1 NRF2 MAPs

IKK

NF-κB/IκB SIRT1

JNK

PL

P38

NFκB/AP-1 Pro-inflammatory cytokines (IL-8, IL-6, IL1-β,TNF-α)

Inflammation

Current Opinion in Food Science

Illustrated mechanism for dietary polyphenols attenuating oxidative stress mediated inflammatory signalling events. Dietary polyphenols agonistic interacting with AhR induces the activation of Nrf 2 signalling transduction in a cross-talk manner. PL: polyphenols. Arrows indicate positive inputs (activation), whereas perpendicular lines show negative inputs (inhibition). Current Opinion in Food Science 2016, 8:33–42

38 Functional foods and nutrition

Table 1 Anti-oxidative stress activities by flavonoids via activation of AhR/Nrf2 pathway Phenolic compounds

Protective effects

Biomarkers

Mechanisms

Keratinocytes

[41]

Hepatic cell line HepG2 cells

[42]

AhRR expression#

Regulating AhR or Nrf2 activation

Benzo(a)pyrene induced Caco-2 cells

[43]

CYP1A, NQO1, GSTP1#

Modulating AhR/Nrf2 pathway

TCDD induced Hepatic cells

[44]

CYP1B1 and CYP2E1, g-GCS, NQO1 and HO-1" IL-6, TNF-a, IL-1b and p65# GST, NQO1;" MCP-1, VCAM-1#

Stimulation of AhR/ Nrf2-Keap1 pathway

7,12-Dimethylbenz (a)anthracene induced rats

[45]

Modulation of AhR/Nrf2 pathway

Primary vascular endothelial cells

[46]

SOD1, GSR, NQO1 and GST"

Stimulation of AhR/Nrf2 pathway

C57BL/6 mice

[47]

GSH, GSH/GSSG"

Inducing AhR/Nrf2 activation

Wistar rats

[48]

CYP1A1#

Activation AhR

TCDD ex vivo induced Rat liver

[49]

Plant polyphenols modulation of inflammatory responses

MCP-1 and IP-10 IL-8, TNFa, and IL-6#

Quercetin, isoquercitrin, rutin, and taxifolin

Quercetin, but not its 3-O-glycosides isoquercitrin and rutin, induces AhR activation and CYP1A1 expression Flavonoids may regulate AhR and Nrf2 pathway differently in Caco-2 cells Luteolin modulates expression of drugmetabolizing enzymes Protecting hepatocellular architecture in rats experiencing oxidative stress Protecting endothelial cells against PCB 126-induced inflammation Decreasing PCB 126-induced oxidative stress Green and black tea supplementation reduced CYP2C, 2E1, and 3A activities and protein expression and induced CYP1A1 and/or CYP1A2 activity Suppression of the activity of CYP1A1

CYP1A1"

Luteolin

Tangeretin

EGCG

Green tea diet

Green and black tea beverages

Catechins in tea

Ref.

Impairing phosphorylation EGFR induced NFkB via regulating AhR signalling Activation AhR

Plant polyphenols

Flavonoids (Quercetins or kaempferol)

Cell/Animal models

Heme oxygenase-1:(HO)-1; CYPs, cytochrome P450-dependent monooxygenases; EpRE, electrophile responsive element; GI-GPx: gastrointestinal glutathione peroxidase; PXR, pregnane receptor; AhR: aryl hydrocarbon receptor; NQO1, NAD(P)H: quinone oxidoreductase 1; IL: interleukin; TNF-a: tumour necrosis factor-alpha; NFkB-p65: a subunit of NFkB transcription complex; EGCG: epigallocatechin gallate; PCB: polychlorinated biphenyls; GST: glutathione S-transferase; g-GCS: glutamate-cysteine ligase;MCP1: monocyte chemotactic protein-1; IP-10: interferon gamma-induced protein-10; EGFR: epidermal growth factor receptor; TCDD: 2,3,7,8-tetrachlorodibenzo-p-dioxin.

effects of phenolics can essentially affect similar biomarkers. Over production of mitochondrial ROS promotes synthesis of pro-inflammatory cytokines through activation of the nucleotide-binding oligomerization domain, leucine-rich repeat-containing gene family, and pyrin domain-containing 3 (NLRP3) inflammasome as shown in Figure 2. NLRP3 is a key node that crosslinks the signalling cascades between redox response and inflammation. As previously mentioned, an increased release of inflammasome is induced by NLRP3 in response to cytoplasmic ROS as illustrated in Figure 2. The inflammasome further triggers the release of cytokine IL-1b from cytoplasm into the extracellular environment Current Opinion in Food Science 2016, 8:33–42

and subsequently activates Toll-like receptor (TLR)-1 mediated inflammatory signalling. TLRs are conserved components of immune system, but also have been identified in other tissues such as liver and GI tract. Activation of TLR-1 by IL-1 triggers NFkB-activated and MAPK-induced pro-inflammatory signalling transductions, producing cytokines such as IL-1b, IL-6, IL-8, TNF-a and IFN-g. This series of reactions finally leads to amplification of inflammatory events resulting in systemic inflammation. In the last five years, numerous in vivo and in vitro studies have shown that dietary phenolic compounds have protective effects on inflammation through modulating NLRP3 activation (Table 2). Hori and colleagues identified that www.sciencedirect.com

Polyphenols and anti-inflammation Zhang and Tsao 39

Table 2 Modulation of oxidative stress mediated inflammation by phenolic compounds Phenolic compounds Phenolic acids containing propolis extract

Apigenin

Homoplantaginin

Quercetin and allopurinol

Luteoloside

Anti-inflammation Inhibition of inflammasome mediated inflammatory responses Inhibition of LPS-induced inflammation Inhibition of palmitic acid-induced Inflammation Amelioration of kidney injury

Biomarkers

Mechanisms

Cell/animal models

IL-1b, casp-1#

Interfering with inflammasome pathway

[26]

casp-1, IL-1b#

Inhibition of NLRP3 inflammasome activation Suppressing ROSsensitive thioredoxininteracting protein Inhibition of NLRP3 inflammasome activation and increasing PPAR expression Inhibition of NLRP3 inflammasome activation Inhibition of NLRP3 inflammasome activation Modulation of NLRP3 inflammasome activation

Ex vivo LPS-stimulated macrophage from C57BL/6 and Caspase-1/ mice THP-1 cells

Endothelial Cells

[50]

STZ-induced rat model

[51]

HCC

[52]

Cerulein-induced rat model

[53]

Monosodium UrateInduced C57BL/6, human macrophage THP-1 cells MCT-induced rats

[54]

Human metastatic melanoma cells Murine macrophage and Prg-IgAN mouse model; mouse model of HF diet-induced obesity

[56]

IL-1b, ICAM-1, and MCP-1, casp-1, IL-1b# IL-1b and IL-18#

Supression of metastasis and proliferation of HCC Modulates ASC expression

ROS, NLPR3, casp-1, IL-1b#

Catechin

Migration of gouty inflammation

IL-1b#

Ellagic acid

Prevention of inflammasome assocaited PAH

EGCG

Suppression of melanoma growth Inducing autophagy and ameliorating hepatic inflammation

IL-1b, IL-2, IL-4, IL-6, IL-10, IFN-g, MIP-1, MDA, NLPR3, casp;# SOD" NLRP1, IL-1b, NFkB#

Rutin

Resveratrol

casp-1, IL-1b, ASCNLRP3, IL-18, TNF-a#

IL-1b, NLPR3;# IL-1b, TNF-a, IL6;# liver TG"

Inhibition of NLRP3 inflammasome activation Inhibition of NLRP3 activation Inhibition of NLRP3 activation

Ref.

[28]

[55]

[29,30]

Cas-1: caspase-1; LPS: lipopolysaccharide; MCT: monocrotaline; PAH: pulmonary artery hypertension; MDA: malondialdehyde; MIP-1: macrophage inflammatory protein-1; HCC: hepatocellular carcinoma cells; ICAM-1: intercellular adhesion molecule-1; STZ: streptozotocin; ASC: apoptosis associated speck-like CARD containing protein; EGCG: epigallocatechin-3-gallate; HF: high fat, TG: triglyceride.

green propolis extracts rich-in cinnamic acids such as pcoumaric acids inhibited inflammasome mediated secretion of IL-1b and activation of caspase (caps)-1 from ex vivo inflamed mouse macrophages [26]. Flavonoids such as apigenin and procyanidin B2 were also able to inhibit inflammasome activation and IL-1b secretion in LPS-induced human macrophages [27,28]. Resveratrol, a stilbene phenolic compound found in red grapes, also inhibited NLRP3 activation induced autophagy to preserve mitochondrial function in both in vitro and in vivo studies; it also ameliorated hepatic inflammation in high-fat diet-induced obesity mouse model [29,30]. Current evidence suggests that the effect of dietary phenolic compounds on inhibition of NLRP3 activation is possibly due to their antioxidant action towards the ROS, as illustrated in Figure 3. NLRP3 activation is highly associated with development of inflammatory metabolic symptom and degenerative diseases such as type-2 diabetes and Alzheimer’s disease. Consumption of polyphenols-rich foods such as fruits and vegetables lowers www.sciencedirect.com

incidences of degenerative disseises caused by oxidative stress and inflammation [31]. In addition to reducing oxidative stress-mediated inflammation, phenolic compounds can also attenuate the proinflammatory cytokine-induced activation of NFkB via different molecular mechanisms (Figure 4). However, the key molecule from the upstream of the NFkB pathway targeted by polyphenols has only been identified in very recent years. Vogel and colleagues identified a cross-talk between AhR and RelB/A, both are NFkB subunits controlling its activation [32]. The RelB/AhR complex is also involved in redox management due to binding with the xenobiotic responsive element. Dietary flavonoids are known as AhR agonistic regulator and involved in modulating AhR mediated signalling pathways [23]. However, it is not known whether flavonoids or other polyphenols can regulate the formation of RelB/A/AhR complex to attenuate NFkB-mediated pro-inflammatory signalling Current Opinion in Food Science 2016, 8:33–42

40 Functional foods and nutrition

Figure 4

PL TNFα

TNFR

Cytoplasma

PL

TRADD

PL

PPARγ PL

AhR MAP3K/2K

RelB

IKK

IκB

JNK

RelA

P38

PL

SIRT1

NFκB

AP-1

Pro-inflammatory cytokines (IL-8, IL-6, IL1-β,TNF-α)

Inflammation

Current Opinion in Food Science

Putative mechanism for dietary polyphenols directly attenuating TNF-a induced MAPKs and NF-kB controlled signalling cascades. The agonistic activation of AhR mediated a cross-talk between AhR and NF-kB in response to TNF-a stimulation, thereby blocking RelA/B translocations to attenuating inflammatory response. Dietary polyphenols also can stimulate PPARg or SIRT1 mediated signalling to interfere with TNF-a-induced MAPKs and NFkB pro-inflammatory signalling transductions, resulting the mitigation of inflammation. PL: polyphenols. Some interactions activate signalling pathways (arrows) whereas perpendicular lines show negative regulation.

transduction. A study to explore this new mechanism is therefore of importance to better understanding the molecular basis of the anti-inflammatory action of dietary polyphenols. Meanwhile, studies have demonstrated that quercetin or kaempferol supplementations resulted in modulation of inflammation or insulin resistance in adipocytes through activation of peroxisome proliferator-activated receptor (PPAR)-g, a nuclear receptor regulating fatty acid decomposition and glucose metabolism [33,34]. A variety of phenolic compounds, especially flavonoids and their metabolites, have been found to agonistically regulate PPAR-g activation through ligand interaction [35]. Current findings suggest that phenolic compounds from dietary sources such as plant foods, herbs and spices can trigger PPAR-g to exert agonistic effects on inflammatory transcription factors, leading to suppression of inflammation and preventive effect on metabolic diseases. In addition, a nicotinamide adenosine dinucleotide-dependent protein deacetylase sirtuin (SIRT)-1 has been found to regulate epigenetic gene silencing in response to stress, regulate the NFkB signalling transductions and increase insulin sensitivity [36]. Since SIRT-1 interacts with PPAR-g coactivator (PGC-1a), flavonoids activated PPAR-g can therefore affect SIRT-1-regulated signalling transductions including the transcriptional factor NFkB [37]. Resveratrol, a typical polyphenol found in red wine, Current Opinion in Food Science 2016, 8:33–42

was found to act as an agonist on SIRT-1 to protect cells from inflammatory damages [38]. Current evidences strongly support that dietary phenolics can act as regulatory molecules and have the ability to attenuate NFkB mediated inflammatory signalling transduction [39] (Figure 4). Despite the low absorption rate of the dietary phenolics, studies have shown that low concentrations of these compounds with physiological relevance can still modulate the expression of various inflammatory biomarkers via different signalling pathways as discussed above. Effects on these biomarkers are targets of therapeutical drugs, therefore the ability of dietary phenolics on the same pro-inflammatory cytokines and other signalling molecules can have significantly positive impact on prevention of chronic non-communicate diseases caused by oxidative stress. The agonistic function of dietary phenolics is the uppermost feature implicated in their anti-inflammatory mechanisms.

Summary Consumption of foods rich in phenolic compounds as high as 1 g per day is considered safe and beneficial for chronic disease prevention [40]. Phenolic compounds are the largest group of natural antioxidants of human diets and have direct and indirect antioxidant and anti-inflammatory activities that help mitigate the oxidative stress at the cellular level. Current research indicates that phytochemicals including polyphenols are strong antioxidants against ROS as radical scavengers in vitro, however, such actions may have some drawbacks as these compounds can act as prooxidants at high doses. Moreover, such direct radical scavenging activity or reducing power of polyphenols is observed only at concentrations significantly higher than the physiological levels found in vivo. Increasing evidence shows that the in vivo antioxidant and anti-inflammatory effects of polyphenols and their metabolites arise from their ability in modulating cellular signalling transductions. Recent studies have established that these compounds do have significant modulatory effect on cellular biomarkers related to oxidative stress and inflammation, which lead to reduced risk of many chronic diseases. Recent in vitro and in vivo results indeed have revealed that low concentrations of phenolics enhance antioxidant enzyme activities, inhibit pro-inflammatory cytokines and directly attenuate NFkB-mediated or oxidative stress-induced inflammatory signalling pathways. By reviewing the chemistry and biochemistry of dietary polyphenols, and possible roles and mechanisms on oxidative stress and inflammation related biomarkers, it is hoped that future efforts in polyphenols research can focus on increasing the bioaccessibility, bioavailability from processing and formulation of phenolics-rich functional foods, and ultimately develop functional foods or nutraceuticals that do reduce health risk of chronic diseases through the modulatory effects of polyphenols thereof. www.sciencedirect.com

Polyphenols and anti-inflammation Zhang and Tsao 41

Acknowledgment This work was supported by the A-Base funding of Agriculture & Agri-Food Canada (J-000237.001.02).

References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as:  of special interest  of outstanding interest 1.

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