Next Article in Journal
Role of Selenoprotein F in Protein Folding and Secretion: Potential Involvement in Human Disease
Next Article in Special Issue
Vitamin D: Nutrient, Hormone, and Immunomodulator
Previous Article in Journal
Evaluation Tool Development for Food Literacy Programs
Previous Article in Special Issue
The Role of Vitamin E in Immunity
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

The Immunomodulatory and Anti-Inflammatory Role of Polyphenols

1
Cellular and Molecular Medicine Department, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H8L1, Canada
2
School of Nutrition, Faculty of Health Sciences, University of Ottawa, Ottawa, ON K1H8L1, Canada
*
Author to whom correspondence should be addressed.
Nutrients 2018, 10(11), 1618; https://doi.org/10.3390/nu10111618
Submission received: 30 September 2018 / Revised: 17 October 2018 / Accepted: 23 October 2018 / Published: 2 November 2018
(This article belongs to the Special Issue Diet and Immune Function)

Abstract

:
This review offers a systematic understanding about how polyphenols target multiple inflammatory components and lead to anti-inflammatory mechanisms. It provides a clear understanding of the molecular mechanisms of action of phenolic compounds. Polyphenols regulate immunity by interfering with immune cell regulation, proinflammatory cytokines’ synthesis, and gene expression. They inactivate NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) and modulate mitogen-activated protein Kinase (MAPk) and arachidonic acids pathways. Polyphenolic compounds inhibit phosphatidylinositide 3-kinases/protein kinase B (PI3K/AkT), inhibitor of kappa kinase/c-Jun amino-terminal kinases (IKK/JNK), mammalian target of rapamycin complex 1 (mTORC1) which is a protein complex that controls protein synthesis, and JAK/STAT. They can suppress toll-like receptor (TLR) and pro-inflammatory genes’ expression. Their antioxidant activity and ability to inhibit enzymes involved in the production of eicosanoids contribute as well to their anti-inflammation properties. They inhibit certain enzymes involved in reactive oxygen species ROS production like xanthine oxidase and NADPH oxidase (NOX) while they upregulate other endogenous antioxidant enzymes like superoxide dismutase (SOD), catalase, and glutathione (GSH) peroxidase (Px). Furthermore, they inhibit phospholipase A2 (PLA2), cyclooxygenase (COX) and lipoxygenase (LOX) leading to a reduction in the production of prostaglandins (PGs) and leukotrienes (LTs) and inflammation antagonism. The effects of these biologically active compounds on the immune system are associated with extended health benefits for different chronic inflammatory diseases. Studies of plant extracts and compounds show that polyphenols can play a beneficial role in the prevention and the progress of chronic diseases related to inflammation such as diabetes, obesity, neurodegeneration, cancers, and cardiovascular diseases, among other conditions.

Graphical Abstract

1. Introduction

Numerous studies have attributed to polyphenols a broad range of biological activities including but not limited to anti-inflammatory, immune-modulatory, antioxidant, cardiovascular protective and anti-cancer actions [1,2,3,4,5]. Polyphenols are ubiquitously made by plants and are present either as glycosides esters or as free aglycones [6]. More than 8000 structural variants exist in the polyphenol family. Polyphenols are bioactive compounds found in fruits and vegetables contributing to their color, flavor, and pharmacological activities [1]. They are classified according to their chemical structures into flavonoids such as flavones, flavonols, isoflavones, neoflavonoids, chalcones, anthocyanidins, and proanthocyanidins and nonflavonoids, such as phenolic acids, stilbenoids, and phenolic amides [7]. The majority of these molecules are metabolites of plants, they are made of several aromatic rings with hydroxyl moieties [8]. Their chemical structures contribute to their classification into different classes. Considering gastrointestinal digestion, some—but not all—polyphenols are absorbed in the small intestine, for example, anthocyanins and the majority of remaining polyphenols except flavonoids are usually stable; these later are unstable in the duodenum. Unabsorbed polyphenols must be hydrolyzed first by digestive enzymes then glycosides with high lipid contents are absorbed by epithelial cells [9,10].
In recent years, consumers prefer using natural food ingredients as additives because of their safety and availability. Applications of phenolic compounds to multiple fresh perishable foods show that they are worthy to be used as preservatives in foods and can be creditable alternatives to synthetic food additives. In this sense, polyphenolic compounds start to substitute chemical additives in food. Different methods like spraying, coating and dipping treatment of food are currently applied in food technology preceding packaging as effective alternatives [11]. Grape seeds and olive oil polyphenols’ rich extracts can be used as food additives for their anti-oxidant properties [12]. Various polyphenols like grape polyphenols demonstrate an efficient role as additives in fish and fish products for their anti-oxidant properties in order to prevent lipid oxidation and quality deterioration of polyunsaturated fatty acids [13]. In addition polyphenolic compounds like flavonols, p-coumaric, and caffeic acids can be used as food preservatives for their antimicrobial activity [11].
Back to inflammation, continuous inflammation is known to be a major cause linked to different human disorders involving cancer, diabetes type II, obesity, arthritis, neurodegenerative diseases, and cardiovascular diseases [14,15]. Polyphenols derived from botanic origin have shown anti-inflammatory activity in vitro and in vivo highlighting their beneficial role as therapeutic tools in multiple acute and chronic disorders [16,17,18,19,20]. Accordingly, many epidemiological and experimental researches have been studying the anti-inflammatory and immune modulation activities of dietary polyphenols [15,21]. The ability of these natural compounds to modify the expression of several pro-inflammatory genes like multiple cytokines, lipoxygenase, nitric oxide synthases cyclooxygenase, in addition to their anti-oxidant characteristics such as ROS (reactive oxygen species) scavenging contributes to the regulation of inflammatory signaling [22,23]. This review will discuss the immunomodulatory effects of dietary polyphenols, their anti-inflammatory abilities, the different mechanisms and pathways involved in reducing inflammation and their contribution to protect from different chronic inflammatory diseases with a focus on their anti-cancer activity.

2. Polyphenols and Inflammation

The immune modulation effect of polyphenols is supported by different studies: some polyphenols impact on immune cells populations, modulate cytokines production, and pro-inflammatory genes expression [24,25]. For example, cardioprotective effects of resveratrol present in red wine grape and nuts were mainly attributed to its anti-inflammatory properties. In vivo and in vitro studies demonstrate that resveratrol can inhibit COX, inactivate peroxisome proliferator-activated receptor gamma (PPARγ) and induce eNOS (endothelial nitric oxide synthase) in murine and rat macrophages [26,27,28]. Likewise, a resveratrol analog, RVSA40, inhibits the pro-inflammatory cytokines TNF-α (Tumor necrosis factor alpha) and IL-6 (interleukin-6) in RAW (Murine macrophages cell line) 264.7 macrophages [29]. Another example is the non-flavonoid curcumin found in turmeric plants and mustard. Curcumin was shown to reduce the expression of inflammatory cytokines: TNF and IL-1, adhesion molecules like ICAM-1 (intercellular adhesion molecule-1) and VCAM-1 (vascular cell adhesion molecule-1) in human umbilical vein endothelial cells and inflammatory mediators like prostaglandins and leukotriens. It also inhibits certain enzymes involved in inflammation like COX in mice (cyclooxygenase), LOX (lipoxygenase) in, human endothelial cells MAPK (mitogen-activated protein Kinase), and IKK (inhibitor of kappa kinase). Moreover, curcumin downregulates NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) and STAT3 (signal transducer and activator of transcription) and reduces the expression of TLR-2 (toll-like receptor-2) and 4 while, in vivo, it upregulates PPARγ (Peroxisome proliferator-activated receptor gamma) in male adult rats [30,31,32,33,34,35]. Caffeic acid phenethyl ester suppresses TLR4 activation and LPS-mediated NF-κB in macrophages, Quercetin was also shown to inhibit leukotriens biosynthesis in human polymorphonuclear leukocytes [36,37]. COX2 expression is also attenuated by ECGC (Epigallocatechin gallate) in colon cancer cell and androgen-independent PC-3 cells of human prostate cancer, gingerol in and piceatannol (EGCG analog found in Norway spruces) leading to NFκ B inactivation [30,38,39,40]. Furthermore, polyphenols, such as Gingerol and Quercetin can activate the production of adiponectin known for its anti-inflammatory effects [30,39]. Similarily, EGCG blocks NFκ B activation in human epithelial cells and downregulates the expression of iNOS (inducible nitric oxide synthase), NO (nitric oxide) production in macrophages resulting in its immunomodulation [38,40,41]. A series of in vitro studies found that other polyphenols like oleanolic acid, curcumin, kaempferol-3-O-sophoroside, EGCG and lycopene inhibit high mobility group box1 protein, an important chromatin protein that interacts with nucleosomes, transcription factors, and histones regulating transcription and playing a key role in inflammation [35]. All of these examples support the anti-inflammatory effects of polyphenols.
Polyphenols’ use is associated with a direct change in the count and differentiation of specific immune cells. An increase in T helper 1(Th1), natural killer (NK), macrophages and dendritic cells (DCs) in Peyer’s patches and spleen is associated with oral administration of polyphenols extracted from the fruit date in male C3H/HeN mice [24]. In humans, the count of regulatory T cells (Treg or suppressor T cells) characterized by the (CD4 + CD25 + Foxp3+) phenotype and involved in immune tolerance and autoimmune control can be boosted by polyphenols [42,43,44]. In vivo, Epigallocatechin-3-gallate, found in green tea and injected to Laboratory inbred strain (BALB)/c mice, rises the number of functional Treg in spleens, pancreatic lymph nodes, and mesentheric lymph nodes [45]. Similarly, in vitro treatment of Jurkat T cells with EGCG or green tea upsurges the expression of Foxp3 and IL10. Baicalin, a flavone, extracted from Huangqin herb, induces Foxp3 expression in HEK 293 T cells and triggers functional Treg from splenic CD4 + CD25− T cells [46]. Additionally, flavonoids show an agonistic effect of aryl hydrocarbon receptor (AhR) and bind xenobiotic-responsive elements in promoter regions of certain genes, including Foxp3 rising its expression [47].
Th1 and Th17 populations are also affected by polyphenols: EGCG reduces the differentiation of Th1 and reduces the numbers of Th17 and Th9 cells in specific pathogen-free C57/BL6 female mice [48]. Other polyphenols like Baicalin show a reduction of Th17 differentiation in vitro and a diminution of IL-17 expression [49].
Macrophages are affected by polyphenols as well. Macrophages are known to be a key player in the inflammatory response. They initiate inflammation by secreting pro-inflammatory mediators and cytokines like IL-6 and TNF-α [50]. Polyphenols repress macrophages by inhibiting cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), thus they reduce the production of TNF-α, interleukine-1-beta (IL-1-β) and IL-6 expression [51]. Chinese propolis [52] containing ferulic acid and coumaric acid, an extract of Lonicera japónica Thunb) [53] or Kalanchoe gracilis [54] are a good example in this case as per demonstrated by in vitro studies using RAW 264.7 cells.

3. Polyphenol and Cytokine Modulation

Cytokines are important mediators’ proteins, essential in networking communication for immune system. Cytokines can be produced by lymphocytes (lymphokines), or monocytes (monokines) with pro-inflammatory and anti-inflammatory effects. Cytokines with chemotactic activities are termed chemokines. The equilibrum between pro-inflammatory cytokines (IL-1β, IL-2, TNFα, Il-6, IL-8, IFN-γ…) and anti-inflammatory cytokines (IL-10, IL-4, TGFβ) are thought to be an important parameter in immune response homeostasis and inflammation underlining many disease [55]. In vivo and in vitro studies demonstrate that polyphenols affect macrophages by inhibiting multiple key regulators of inflammatory response such as the inhibition of TNF-α, IL-1-β, and IL-6 [51].
In humans, consumption of bilberries is associated with a decreased inflammation score in patients’ blood, reflected by decreasing serum levels of IL-6, IL-12, and high sensitivity C reactive protein [56]. Moreover, clinical trials have shown the ability of polyphenol-enriched extra virgin olive oil to reduce IL-6 and C-reactive protein expression in stable coronary heart disease patients [57].
In lipopolysaccharide (LPS)-treated BALB/c mice, a model system of inflammation olive vegetation water show ability to inhibit the production of tumor necrosis factor-alpha usually activated by inflammation [58]. Flavonoids, as well, play an important anti-inflammatory effect by influencing cytokines’ secretion. Several flavonoids are found able to inhibit the expression of various pro-inflammatory cytokines and chemokines like TNFα, IL-1β, IL-6, IL-8, and MCP-1 (monocyte chemoattractant protein-1) in multiple cell types such as LPS-activated mouse primary macrophages, activated human mast cell line, activated human astrocytes, human synovial cells, and human peripheral blood mononuclear cells [59,60,61,62,63,64]. In murine RAW 264.7 macrophages stimulated by LPS, Chinese propolis as well as extract of Lonicera japónica Thunb (Caprifoliaceae) or Kalanchoe gracilis demonstrated inhibitory effects on TNF-α, IL-1-β, and IL-6 [52,53,54]. Similarly, certain polyphenol analogs, like curcumin analog EF31, have shown the ability to inhibit the expression and secretion of TNF-α, IL-1-β, and IL-6 in mouse Raw 264.7 macrophages [65].
Likewise, reduction of the secretion of TNF-α and IL-6 without IL-1β modulation is observed with extracts of chamomile, meadowsweet, willow bark, and isolated polyphenols such as quercetin existing in these extracts in THP1 macrophages [66]. Extract of Cydonia oblonga inhibits TNF-α and Interleukin 8 while it increases IL-10 and IL-6 in THP-1monocytes stimulated with LPS. The reduction in TNF-α levels limits the acute inflammatory response [67,68]. Other cytokines like IFNγ might also be inhibited by certain polyphenols. For example, kaempferol reduces the production of IFN-γ in a dose-dependent manner in spleen cells and T cell lines [69].
Certain polyphenols exert their effects on the balance between pro- and anti-inflammatory cytokines production such as quercetin and catechins, they enhance IL-10 release while they inhibit TNFα and IL-1β [59,70]. Extract of Cydonia oblonga also inhibits the effects of TNF-α and Interleukin 8 (IL-8) while it raises IL-10 in the same type of monocytes [67,68]. Modulation of inflammatory cytokines is one of many common mechanisms by which polyphenols in general exert their immunomodulatory effects.

4. Polyphenols, Inflammation, and Modulation of Different Signaling Pathways

4.1. NFκ B Signaling Pathway

NF-κB or nuclear factor kappa-light-chain-enhancer of activated B cells is a complex protein that plays a key role in deoxyribonucleic acid (DNA) transcription, cytokine production and cell survival. It controls immune, inflammation, stress, proliferation and apoptotic responses of a cell to multiple stimuli [58].
The expression of a large number of genes involved in inflammation is controlled by NF-κB such as COX-2, VEGF (vascular endothelial growth Factor), pro-inflammatory cytokines (IL-1, IL-2, IL-6, and TNFα), chemokines (e.g., IL-8, MIP-1α, and MCP-1), adhesion molecules, immuno-receptors, growth factors, and other agents involved in proliferation and invasion [71].
NFκ B is located in the cytoplasm, it exists as an inactive non-DNA-binding form. Iκ B proteins (Iκ Bs), are inhibitors proteins that are associated with NFκ B resulting in its inactivation. Iκ Bs include Iκ Bα, Iκ Bβ, Iκ Bγ, Iκ Bε, Bcl-3, precursors p100 and p105 [72]. Under stimulatory conditions, Iκ B kinase (IKK) phosphorylate IκB proteins leading to successive ubiquitination, consequent degradation of the inhibitory proteins and release of NFκ B dimer. This later can translocate into the nucleus and prompts the expression of particular genes [72]. Different mechanisms regulate NFκ B activity as per the accumulation and degradation of Iκ B, the phosphorylation of NFκ B, the hyper-phosphorylation of IKK, and the processing of NFκ B precursors [73,74,75]. Thus, the inhibition of NFκB can be of a great benefit in controlling inflammatory conditions [76]. Several polyphenols modulate NFκ B activation and reduce inflammation [77,78]. Quercetin blocks the nuclear translocation of p50 and p65 subunits of NFκ B and represses the expression of pro-inflammatory associated genes, NOS and COX-2 in RAW264.7 macrophages [79]. It inhibits the phosphorylation of Iκ Bα protein both in vitro (using macrophages) and in vivo (using dextran sulfate sodium (DSS) rat colitis model) leading to inactivation of the NFκ B pathway [80]. In human mast cells, quercetin prevents the degradation of Iκ Bα, as well as the nuclear translocation of p65 resulting in reduction of TNFα, IL-1β, IL-6 and IL-8 [63]. It can modulate chromatin remodeling, for example it blocks the recruitment of a histone acetyl transferase called CBP/p300 to the promoters of interferon-inducible protein 10 (IP-10) and macrophage inflammatory protein-2 (MIP-2) genes in primary murine small intestinal epithelial cell. As a result, it inhibits the expression of these pro-inflammatory cytokines [81]. Quercetin can block the activation of IKK, NFκ B, and it reduces the ability of NFκ B to bind DNA in microglia treated by LPS and IFN-γ in mouse BV-2 microglia [82]. Luteolin, too, blocks NFκ B activation and inhibits pro-inflammatory genes expression and the cytokines production in murine macrophages RAW 264.7 and mouse alveolar macrophages; it also inhibits IKKs in LPS-induced epithelial and dendritic cells [83]. In addition, in co-cultured intestinal epithelial Caco-2 and macrophage RAW 264.7 cells, luteolin represses NF-ĸ B activation and TNF-α secretion [84]. Likewise, Genistein represses LPS-induced activation of NF-ĸ B in monocytes and reduces the inflammation by inhibiting NF-ĸ B activation upon adenosine monophosphate activated protein kinase stimulation in LPS-stimulated macrophages RAW 264.7 [83,85]. Galangin, as well, stops the degradation of Iĸ Bα and the translocation of p65 NF-ĸ B, repressing the expression of TNF-α, IL-6, IL-1β, and IL-8 in mast cell [86]. EGCG counteracts the activation of IKK and the degradation of Iκ Bα and inhibits NFκ B in culture respiratory epithelial cells and in vivo in male Wistar rats [87,88]. Furthermore, EGCG blocks DNA binding of NFκ B which reduces the expression of IL-12p40 and iNOS in murine peritoneal macrophages [89,90]. Catechin and epichatechin reduce NFκ B activity in PMA-induced Jurkat T cells. Flavonoids can modulate NFκ B activation cascade at early phases by affecting IKK activation and regulation of oxidant levels or at late phases by affecting binding of NF-κ B to DNA in jurkat Tcells [91]. Hydroxytyrosol, and resveratrol inhibit NFκ B activation, and the expression of VCAM-1 in LPS-stimulated human umbilical vein endothelial cells [92]. In summary, polyphenols can modulate NFκ B activation cascade at different steps such as by affecting IKK activation and regulating of the oxidant levels or by affecting binding of NF-κ B to DNA leading to an important anti-inflammatory effect responsible for their potential value in treating chronic inflammatory conditions (Figure 1).

4.2. MAPK Signaling Pathway

The mitogen-activated protein kinases (MAPK) are a highly conserved family of serine/threonine protein kinases. They play a key role in a range of fundamental cellular processes like cell growth, proliferation, death and differentiation. They regulate gene transcription and transcription factor activities involved in inflammation. Extracellular signal-related kinases, like (extracellular signal-related kinases (ERK))-1/2, c-Jun amino-terminal kinases (JNK1/2/3), p38-MAP kinase (α, β, δ, and γ), and ERK5 are different groups of MAPKs expressed in mammals. These are later activated by MAP kinase kinases (MAPKK) which might be triggered by some MAPKK kinases (MAPKKK) [93]. MAPK, in its turn, cross-talks with other pathways such as NFκB, thus the complexity of the MAPK signaling pathway and its interactions. Stress and mitogens activate MAPK signaling: For example, ERK1/2 route is triggered by mitogens and growth factors while JNK and p38 cascade are stimulated by stress [94,95,96,97]. Preclinical data propose an anti-inflammatory role of JNK and p38 cascades inhibitors [98,99].
Polyphenols’ activity is specific, it depends on the cell types as well as the structure of the polyphenol itself [100]. Polyphenols can block TNF α release by modulating MAPK pathway at different levels of the signaling pathway. Luteolin reduces TNFα liberation by LPS-activated mouse macrophages, it blocks ERK1/2 and p38phosphorylation [100]. In epithelial cells, luteolin, as well as other polyphenols such as chrysin and kaempferol block TNFα triggered ICAM-1 expression by inhibiting ERK, JNK and P38 [100,101]. Quercetin blocks the phosphorylation of ERK, JNK in THP-1 activated human monocytes, while in murine macrophages RAW 246.7 triggered by LPS it blocks the phosphorylation and the activation of JNK/SAPK (stress activated protein kinases), ERK1/2, and p38 leading to a reduction in the transcription and expression of TNF-α expression [102]. EGCG reduces inflammation in various cell types by exerting an anti-MAPK activity. It reduces IL-12 expression in LPS-activated murine macrophages by prohibiting p38 MAPK phosphorylation [89,103]. In addition, EGCG is found to play a protective role in autoimmune-induced tissue damage caused by Sjogren’s syndrome: it protects human salivary glands from TNF-α induced cytotoxicity by acting on p38 MAPK1. In vivo, in female ICR mice, EGCG inhibits phorbol ester-induced activation of NFκB and CREB (cAMP response element-binding protein—a cellular transcription factor) in mouse skin by blocking the activation of p38 MAPK [104]. Polyphenols concentration plays as well a role in their modulatory activities on signaling pathways: in human coronary artery endothelial cells, the activation of the MAPKs pathways (p38, ERK1/2, and JNK) and the repression of the plasminogen activator inhibitor by catechin and quercetin is time and dose dependent [105]. The ability of polyphenolic compounds to block MAPK pathways (Figure 1) endowed these bioactive substances with therapeutic potential to protect against inflammation.

4.3. Arachidonic Acid Signaling Pathway

Arachidonic acid (AA) is liberated by membrane phospholipids upon phospholipase A2 (PLA2) cleavage. Cyclooxygenase (COX) or lipoxygenase (LOX) metabolize it and produce, respectively, prostaglandins (PGs) and thromboxane A2 (TXA2) by COX, and hydroxyeicosatetraenoic acids and leukotrienes (LTs) by LOX [106]. The COX family involves different members (COX1, COX-2, and COX-3). COX-2 is responsible of the production of important quantity of prostaglandins, its expression is triggered by lipopolysaccharide and pro-inflammatory cytokines [107]. The ability of polyphenols to reduce the release of arachidonic acid, prostaglandins, and leukotrienes is considered one of their most important anti-inflammatory mechanisms (Figure 1). Their action is mainly realized by their ability to inhibit cellular enzymes, such as PLA2, COX, and LOX [21,108,109,110,111]. Quercetin blocks COX and LOX in various cell types such as rat peritoneal leukocyte, murine leukocytes, and guinea pig epidermis [110,112,113]. Similarly, red wine reduces COX-2 expression in old male F344 rats [114]. In LPS activated murine macrophages, green tea polyphenols not only suppress NF-κB and MAPK pathways but also constrain the expression of COX-2 and the release of prostaglandin (PGE2) in RAW 264.7 macrophages [115,116]. Equally, a reduction in the release of PGE2 is observed with other polyphenols, such as kaempferol in culture of LPS-stimulated human whole blood cells [117]. Extra virgin olive oil rich with more than 30 phenolic compounds inhibit 5-LOX in human activated leukocytes reducing leukotriene B4 and suppresses eicosanoids production by animal and human cells in vitro [118,119]. Finally, certain polyphenols show structural and functional similarities with specific anti-inflammatory drugs. A phenolic compound—oleocanthal—demonstrates a natural anti-inflammatory property and exhibits structural similarities to the ibuprofen (a well-known anti-inflammatory drug). Oleocanthal—like ibuprofen—inhibits COX-1 and COX-2 activities in a dose-dependent manner [120].

5. Polyphenols, Oxidative Stress, and Inflammation

Higher production of reactive oxygen species (ROS) is associated with oxidative stress and protein oxidation [121]. In its turn inflammatory molecules and different inflammatory signals (i.e., peroxiredoxin2) are triggered by protein oxidations [122]. Furthermore, overproduction of ROS can prompt tissue injury that might initiates the inflammatory process [123,124,125,126,127]. Therefore, the classical antioxidant actions of polyphenols undoubtedly contribute to their anti-inflammatory roles by interrupting the ROS-inflammation cycle (Figure 2). Polyphenols are known for their antioxidant activities; they scavenge a wide-ranging selection of ROS. Polyphenols can scavenge radicals and chelate metal ions, for example quercetin chelates iron ion [128]. They also inhibit multiple enzymes responsible of ROS generation [129]. In fact, free metal ions, as well as highly reactive hydroxyl radical release, is increased by the formation of ROS. To the opposite, polyphenols are able to chelate metal ions like Fe2+, Cu2+, and free radicals which lead to a reduction of highly oxidizing free radicals [130].
Transition metal ions, like Fe+2, Cu2+, Co2+, Ti3+, or Cr5+, results in OH• formation from H2O2 [131,132]. Curcumin is able to chelate transition metal (Cu2+ and Fe2+) ions. Alike, EGCG and quercetin chelate Fe2+ (iron ion) [128]. Polyphenols like apocynin, reservatol, and curcumin can inhibit NOX (NADPH oxidase) causing a reduction in the generation of O2• during infections consecutively in endothelial cells in THP1-monocytes [133,134,135]. Additionally, polyphenols can attenuate the mitochondrial ATP synthesis by blocking the mitochondrial respiratory chain and ATPase. As a result, ROS production is diminished. Curcumin [136], EGCG [137], phenolic acids [138], capsaicin [139], quercetins [140], anthocyanins [140], and resveratrol analogs [141] inhibit xanthine oxidase. Thus, they reduce ROS production. Polyphenols affect the activity of cyclooxygenase, lipoxygenase, and NOS (nitric oxide synthase) as per found in RAW 264.7 macrophes [142]. These enzymes are known to metabolize arachidonic acid and their inhibition moderates the production of key mediators of inflammation (prostaglandins, leukotrienes, and NO …) [142]. Polyphenols can also restrain LPS-induced iNOS gene expression in cultured macrophages, decreasing oxidative harm [143]. Finally, they may act by upregulating endogenous antioxidant enzymes. In vivo, curcumin can stimulate antioxidant enzymes like superoxide dismutase (SOD), catalase, and glutathione (GSH) peroxidase (Px) which lead to ROS detoxification [144]. Likewise, EGCG rises SOD and GSH-Px activities with augmented amount of cellular glutathione [145]. In conclusion, polyphenols exert the anti-inflammatory action by different mechanisms: Radical scavenging, metal chelating, NOX inhibition, tempering the mitochondrial respiratory chain, inhibition of certain enzymes involved in ROS production, like xanthine oxidase and upregulation of endogenous antioxidant enzymes.

6. Polyphenols, Chronic Diseases and Cancer

Referring to the previously cited roles of polyphenols in maintaining tissue homeostasis by targeting different signaling pathways and referring to their antioxidant, anti-inflammation, and protection against pro-inflammation properties; polyphenols play a beneficial role in the prevention and the process of chronic diseases related to inflammation.
Various polyphenolic compounds show protective actions in diabetes, obesity, neurodegeneration, cancers, and cardiovascular diseases, among other conditions [30,146,147,148,149,150,151,152,153,154].

6.1. Polyphenols and Insulin Resistance

Polyphenols reduce insulin resistance. They promote glycolysis by activation of AMPK (AMP- activated protein kinase) or inhibition of mTORC1 and PI3K/AkT in vivo (in rats), ex vivo (in rats’ muscles strips) and in vitro (in C2C12 myoblasts and HELA cells) [148,149,155,156]. Additionally, AMPK activation by polyphenols increases glucose uptake by positively affecting eNOS imitating muscle contraction and in vivo activity of insulin [148,149,150]. Similarly, it is found that polyphenols lower insulin resistance by inhibiting PI3K/AkT and JNK of activation of the AMPK-SirT1-PGC1α axis (i.e., gingerol and anthocyans, and their ability to protect from diabetes and reduce insulin resistance using in vivo, ex vivo and in vitro studies [26,27,28,148,149,155]. In addition, polyphenols attenuate glucose intake from carbohydrates by inhibiting rats’ α-glucosidase [157]. Lastly, polyphenols, like falvonoids, can improve insulin secretion by reducing apoptosis of pancreatic β–cells [145].

6.2. Polyphenols and Inflammatory Cardiovascular Diseases (CVD)

Meta-analysis studies have reported that an intake of three cups of tea per day reduces CVD by 11% [151] while adequate intake of red wine is associated with 32% lower risk of cardiovascular disease (CVD) [158]. Soy and cocoa flavonoids contribute to the prevention of CVD as per meta-analysis of randomized controls trial [159]. Polyphenols exert their protective effects in CVD due to their anti-hypertensive potentials. Resveratrol inhibits ACE (angiotensin converting enzyme) and PDE (phosphodiesterase) and upregulates eNOS (endothelial NOS) resulting in a reduction in high blood pressure as per multiple in vivo and in vitro studies [26,27,28,155,156,160]. In addition, flavanols and flavonols exert their CVD prevention role by reducing the manifestations of age-related vascular injury. They reduce nicotinamide adenine dinucleotide phosphate (NADPH) oxidase by affecting MAPK signaling and downregulating NF-κB in aged rats [161,162,163]. At the end, the antioxidant action of polyphenols and their ability to suppress LDL oxidation leads to endothelium-protective activity [164].
Certain polyphenols like resveratrol and anthocyanins protect from CVD by multiple mechanisms; they have (1) antihypertensive properties, they inhibit eNOS, and (2) inhibit NFκB mediated expression of VCAM and ICAM expression as per previously discussed [39,165]. Polyphenols can also reduce LDL oxidation or improve LDL/HDL ratio. For example, flavanones such as hesperetin in orange juice reduce LDL/HDL ratio while quercetin inhibits LDL oxidation with elevated paraoxonase and eliminate atherogenic lesions referring to in vitro and in vivo studies (using human male subjects) [166].

6.3. Polyphenols and Inflammatory Neurological Diseases

Polyphenols show protective effects in neurological disease [152,153]. High flavonoid intake can reduce by 50% dementia and aging. More precisely, it lowers the incidence of Parkinson’s and delays the onset of Alzheimer’s disease as per different epidemiological studies [167,168,169,170]. EGCG has neuroprotective properties due to its antioxidant (SOD, GSHPx) activities and cellular GSH contents and ability to reduce ROS contents. Similarly, anthocyanins neuroprotective characteristics are related to the improvement of oxidative stress and reduction of Aβ deposition [38,171,172]. Other mechanisms of polyphenols protection in neurodegenerative diseases is modulation of neuronal and glial signaling pathways [173]. Polyphenols can downregulate NF-κB related with iNOS generation in glial cells [174,175,176]. Moreover, their ability to inhibit monoamine oxidase plays a positive role in cognition, depression, and learning ability in vivo in male laca mice [172].

6.4. Polyphenols and Inflammatory Obesity

Polyphenols exert their anti-obesity effect by activation of AMPK (5’ adenosine monophosphate-activated protein kinase) leading to a reduction of cholesterol, fatty acid synthesis, and triglyceride formation by inhibiting HMG-CoA reductase and acetyl CoA carboxylase. Furthermore, they can inhibit genes involved in adipocyte differentiation and triglyceride accumulation. They block mTORC1 and repress specific signals associated with diminished levels of PPARγ and C/EBP α/δ mRNA throughout adipogenesis (in an experimental model of sepsis) and in vitro [30,146]. They can improve energy expenditure, stop the maturation of preadipocytes into adipocytes and increase the expression of adiponectin (a hormonal protein with a role in regulating glucose levels and breaking down fatty acids). For example, capsaicin enhances the energy spending in adipose tissue. Capsaicin diminishes intracellular triglycerides and improves brown adipose tissue thermogenesis. Furthermore, in clinical studies, capsaicin is found able to increase satiety [30,177,178]. EGCG inhibits MEK/ERK and PI3K/AKT pathways leading to inactivation of preadipocytes maturation by downregulating the expression of different genes like PPARγ and C/EBPα that are associated with adipogenesis [38,41,146,179]. Certain polyphenols can increase adiponectin such as gingerol and curcumin in serum of human subjects based on randomized controlled trial [180,181].

6.5. Polyphenols and Cancer

Clinical and epidemiological studies have reported that polyphenols have chemo-preventive and anticancer efficacy [182,183,184]. Polyphenol compounds have the ability to inhibit the proliferation of different types of cancer such as prostate, bladder, lung, gastrointestinal, breast, and ovarian cancers [154]. For instance, quercetin, resveratrol, green tea polyphenols [185], epigallocatechin-3-gallate [186], and curcumin [187] have demonstrated efficacy as anticancer compounds. Several studies reported that polyphenols are able to prevent cancer initiation (cyto-protective), progression, recurrence, and metastasis to distant organs (cytotoxic) as per different epidemiological, in vitro, and in vivo studie [188,189,190]. However, a dichotomy exists between polyphenols’ antioxidant effects in normal cells, and their potential pro-oxidant effects in cancer cells [154,188].
Recent studies illustrated a direct correlation between ROS in intracellular signaling cascade and carcinogenesis [191]. Oxidative stress targets proteins, lipids, and DNA/RNA causing changes that increase the risks of mutagenesis. ROS/RNS (reactive nitrogen species) overproduction over a prolonged period of time damages cellular structure and functions and causes somatic mutations such as pre-neoplastic and neoplastic transformations that may lead to cell death by necrotic and apoptotic processes [192]. Polyphenols compounds contain hydroxyl groups that donate their protons to reactive oxygen species (ROS) [193]. Moreover, they reduce the activity of phase I enzymes, primarily cytochrome P450 enzymes (CYPs), such as CYP1A1 and CYP1B1 which lead to prevent the formation of reactive and carcinogenic metabolites in human bronchial epithelial cells [194]. They also can induce phase II enzymes that initiate the formation of polar metabolites which are readily excreted from the body [195]. Certain dietary polyphenols such as flavonoids reduce cellular formation of ROS which protects from the oxidation of DNA [193].
In addition to their anti-oxidant properties, pro-oxidant characteristic of polyphenols is important in treating and preventing cancer. Pro-oxidant activity can be initiated by certain conditions such as superoxide leakage [196]. The pro-oxidant activities of polyphenols in cancer cells can result in inducing apoptosis [197], cell cycle arrest [198] and inhibiting the proliferation signaling pathways (i.e., epidermal growth factor receptor/mitogen activated protein kinase, phosphatidylinositide 3-kinases/protein kinase B, as well as NF-ĸB) [199]. For example, polyphenols from apple are able to inhibit the proliferation of human bladder transitional cell carcinoma (TCC, TSGH-8301 cells), inducing G2/M cell cycle arrest, and promoting apoptosis [200]. In human papilloma virus-18-positive HeLa cervical cancer cells, green tea polyphenols can induce cell cycle arrest at the subG1 phase and apoptosis through caspases activation [201]. Flavonoids, such as quercetin, induce apoptosis in many cancer cells such as leukemic U937 cell [202], prostate cancer cells [203], hepatic cancer cells [204], among other types. A combination of quercetin with resveratrol and catechin inhibits breast cancer progression in vitro and in vivo by inducing apoptosis in carcinogenic breast cells [205]. In addition, polyphenols can reduce cancer metastasis such as quercetin [206,207].
Sufficient studies have reported that NF-κB signaling pathways are closely related to cancer metastasis. Polyphenols can disrupt the metastatic potential of cancer by inhibiting NF-κB activity [208]. Curcumin is a good example [209,210,211] of decreasing cancer metastasis in mice by suppressing NF-κB expression and down-regulating VEGF (vascular endothelial growth factor), COX-2, and MMP-9 (matrix metallopeptidase-9) expression in tissues of the breast, brain, lung, liver, and spleen [212,213]. Moreover, the strength of metastasis is associated to the epithelial-to-mesenchymal transition (EMT) [214]. There is robust evidence that polyphenols compounds can modulate EMT and its related signaling pathways [215]. For example, EGCG, a flavan-3-ol, induces apoptosis and significantly reduces colony formation and cell migration in nasopharyngeal carcinoma (NPC) and cancer stem cells (CSC) in different cell lines [216]. Luteolin and quercetin reverse the migration and invasiveness of metastatic cells by reducing the expression of mesenchymal markers and transcriptional factors on the cell membrane (i.e., twist, snail, and N-cadherin) and upregulating adhesion molecules such as E-cadherin [217]. Thus, through variable mechanisms, polyphenols broadly downregulate inflammation origination, progression, and evolution to cancers (Figure 3).
In order to emphasize on the beneficial health effects of polyphenols, different medications containing polyphenols are FDA-approved as pharmaceutical drugs. Polyphenon® E, a standardized green tea polyphenol preparation, is an FDA-approved medication to treat genital warts [218]. Another significant event in the use of polyphenols as pharmaceuticals is the FDA approval of crofelemer (a medication rich in oligomeric proanthocyanidin) to manage HIV associated non-infectious diarrhea.

7. Conclusions

In conclusion, the vast number of published studies proved the immunomodulatory role of polyphenols in vivo and in vitro. Different underlying regulatory mechanisms are now well elucidated. These data highlight the promising role of polyphenols in prevention and therapy of diseases with underlining inflammatory conditions, including cancer, neurodegenerative diseases, obesity, type II diabetes, and cardiovascular diseases. However, the role of polyphenols in modulating multiple inflammatory cellular pathways should be further investigated. Many questions remain unanswered about the usage of polyphenols in clinical setting. The role of the microbiota in degrading these polyphenols should be further studied. The notion of bioavailability and its impact on biofunctionality should also be revisited. It is generally believed that polyphenol activity is principally located in the gut where their immunoprotective and anti-inflammatory activities are initiated and subsequently ensuring systemic anti-inflammatory effects. Since different polyphenols can have multiple intracellular targets, additional data is needed to determine the consequences of the interaction or the synergistic effects between multiple polyphenolic compounds or polyphenols and commonly used medications. Moreover, further in vivo and meta-analysis studies in humans are necessary to fully reveal the mechanisms of action of polyphenols in several physiological conditions in order to produce important insights into their prophylactic and therapeutic uses.

Author Contributions

N.Y. wrote all parts of the paper and prepared all Figures as well as the graphabstract except cancer and polyphenol paragraph and Figure 3; N.A. wrote cancer and polyphenol paragraph and prepared Figure 3; M.J. collected some papers and revised the Figures and their design; C.M. revised and guided the work.

Funding

This research received no external funding.

Acknowledgments

Special thanks to uOttawa libraries especially health sciences library and Morisset library and the department of “Nutrition Sciences”.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

ROSReactive oxygen species
COXCyclooxygenase
NOXNADPH oxidase
SODSuperoxide dismutase
GSHGlutathione
PxPeroxidase
PLA2Phospholipase A2
PGsProstaglandins
LTsLeukotrienes
MAPKMitogen-activated protein Kinase
IKKInhibitor of kappa kinase
NFκBNuclear factor kappa-light-chain-enhancer of activated B cells
Th1T helper 1
NKNatural killer
DCsDendritic cells
ECGCEpigallocatechin gallate
TregRegulatory T cells
AhRAryl hydrocarbon receptor
iNOSInducible nitric oxide synthase
LPSLipopolysaccharide
MCP-1Monocyte chemoattractant protein-1
VEGFVascular endothelial growth Factor
ILInterleukin
JNKc-Jun amino-terminal kinases
CREBcAMP response element-binding protein
AAArachidonic acid
AMPKAMP-activated protein kinase
ERKExtra-cellular signal regulated kinases
ATPAdenosine triphosphate
CVDCardiovascular disease
PI3KPhosphatidylinositide 3-kinases
AktProtein kinase B
LDLLow density lipoprotein
HDLHigh density lipoprotein
RNSReactive nitrogen species
PPARγPeroxisome proliferator-activated receptor gamma
CYPsCytochrome P450 enzymes
MMP-9Matrix metallopeptidase-9
NPCNasopharyngeal carcinoma
CSCsCancer stem cells
EMTEpithelial-to-mesenchymal transition
FDAFood and drug administration
ICAMIntercellular adhesion molecule
VCAMVascular cell adhesion molecule
HIVHuman immunodeficiency diarrhea
HMG-CoA3-Hydroxy-3-methyl-glutaryl-coenzyme A
VEGFVascular endothelial growth factor
TLRToll-like receptor
NONitric oxide
eNOSEndothelial nitric oxide synthase
PDEPhosphodiesterase
ACEAngiotensin converting enzyme

References

  1. Recio, M.; Andujar, I.; Rios, J. Anti-Inflammatory Agents from Plants: Progress and Potential. Curr. Med. Chem. 2012, 19, 2088–2103. [Google Scholar] [CrossRef] [PubMed]
  2. Eberhardt, M.V.; Lee, C.Y.; Liu, R.H. Antioxidant Activity of Fresh Apples. Nature 2000, 405, 903–904. [Google Scholar] [CrossRef] [PubMed]
  3. Spagnuolo, C.; Russo, M.; Bilotto, S.; Tedesco, I.; Laratta, B.; Russo, G.L. Dietary Polyphenols in Cancer Prevention: The Example of the Flavonoid Quercetin in Leukemia. Ann. N. Y. Acad. Sci. 2012, 1259, 95–103. [Google Scholar] [CrossRef] [PubMed]
  4. Andriantsitohaina, R.; Auger, C.; Chataigneau, T.; Étenne-Selloum, N.; Li, H.; Martínez, M.C.; Schini-Kerth, V.B.; Laher, I. Molecular Mechanisms of the Cardiovascular Protective Effects of Polyphenols. Br. J. Nutr. 2012, 108, 1532–1549. [Google Scholar] [CrossRef] [PubMed]
  5. Vauzour, D.; Rodriguez-Mateos, A.; Corona, G.; Oruna-Concha, M.J.; Spencer, J.P.E. Polyphenols and Human Health: Prevention of Disease and Mechanisms of Action. Nutrients 2010, 2, 1106–1131. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Ma, Y.; Kosinska-Cagnazzo, A.; Kerr, W.L.; Amarowicz, R.; Swanson, R.B.; Pegg, R.B. Separation and Characterization of Soluble Esterified and Glycoside-Bound Phenolic Compounds in Dry-Blanched Peanut Skins by Liquid Chromatography-Electrospray Ionization Mass Spectrometry. J. Agric. Food Chem. 2014, 62, 11488–11504. [Google Scholar] [CrossRef] [PubMed]
  7. Tsao, R. Chemistry and Biochemistry of Dietary Polyphenols. Nutrients 2010, 2, 1231–1246. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  8. Cheynier, V. Polyphenols in Food Are More Complex Then Often Thought. Am. J. Clin. Nutr. 2005, 81, 223–229. [Google Scholar] [CrossRef] [PubMed]
  9. Mosele, J.I.; Macia, A.; Romero, M.-P.; Motilua, M.-J.; Rubio, L. Application of in Vitro Gastrointestinal Digestion and Colonic\nfermentation Models to Pomegranate Products (Juice, Pulp and Peel\nextract) to Study the Stability and Catabolism of Phenolic Compounds. J. Funct. Food 2015, 14, 529–540. [Google Scholar] [CrossRef]
  10. Correa-Betanzo, J.; Allen-Vercoe, E.; McDonald, J.; Schroeter, K.; Corredig, M.; Paliyath, G. Stability and Biological Activity of Wild Blueberry (Vaccinium Angustifolium) Polyphenols during Simulated in Vitro Gastrointestinal Digestion. Food Chem. 2014, 165, 522–531. [Google Scholar] [CrossRef] [PubMed]
  11. Martillanes, S.; Rocha-Pimienta, J.; Cabrera-Bañegil, M.; Martín-Vertedor, D.; Delgado-Adámez, J. Application of Phenolic Compounds for Food Preservation: Food Additive and Active Packaging. In Phenolic Compounds-Biological Activity; InTech: London, UK, 2017. [Google Scholar] [Green Version]
  12. Maqsood, S.; Benjakul, S.; Shahidi, F. Emerging Role of Phenolic Compounds as Natural Food Additives in Fish and Fish Products. Crit. Rev. Food Sci. Nutr. 2013, 53, 162–179. [Google Scholar] [CrossRef] [PubMed]
  13. Maestre, R.; Micol, V.; Funes, L.; Medina, I. Incorporation and Interaction of Grape Seed Extract in Membranes and Relation with Efficacy in Muscle Foods. J. Agric. Food Chem. 2010, 58, 8365–8374. [Google Scholar] [CrossRef] [PubMed]
  14. Kennedy, E.T. Evidence for Nutritional Benefits in Prolonging Wellness. Am. J. Clin. Nutr. 2006, 8, 16470004. [Google Scholar] [CrossRef] [PubMed]
  15. Bengmark, S. Acute and “Chronic” Phase Reaction-a Mother of Disease. Clin. Nutr. 2004, 23, 1256–1266. [Google Scholar] [CrossRef] [PubMed]
  16. Visioli, F.; Galli, C. The Effect of Minor Constituents of Olive Oil on Cardiovascular Disease: New Findings. Nutr. Rev. 1998, 56, 142–147. [Google Scholar] [CrossRef] [PubMed]
  17. Visioli, F.; Galli, C. The Role of Antioxidants in the Mediterranean Diet. Lipids 2001, 36, S49–S52. [Google Scholar] [CrossRef] [PubMed]
  18. Middleton, E., Jr.; Kandaswami, C.; Theoharides, T.C. The Effects of Plant Flavonoids on Mammalian Cells: Implications for Inflammation, Heart Disease, and Cancer. Pharmacol. Rev. 2000, 52, 673–751. [Google Scholar] [PubMed]
  19. Urquiaga, J.; Leighton, F. Plant Polyphenol Antioxidants and Oxidative Stress. Biol. Res. 2000, 33, 55–64. [Google Scholar] [CrossRef] [PubMed]
  20. Scalbert, A.; Manach, C.; Morand, C.; Rémésy, C.; Jiménez, L. Dietary Polyphenols and the Prevention of Diseases. Crit. Rev. Food Sci. Nutr. 2005, 45, 287–306. [Google Scholar] [CrossRef] [PubMed]
  21. Yoon, J.H.; Baek, S.J. Molecular Targets of Dietary Polyphenols with Anti-Inflammatory Properties. Yonsei Med. J. 2005, 46, 585–596. [Google Scholar] [CrossRef] [PubMed]
  22. Malireddy, S.; Kotha, S.R.; Secor, J.D.; Gurney, T.O.; Abbott, J.L.; Maulik, G.; Maddipati, K.R.; Parinandi, N.L. Phytochemical Antioxidants Modulate Mammalian Cellular Epigenome: Implications in Health and Disease. Antioxid. Redox Signal. 2012, 17, 327–339. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Santangelo, C.; Varì, R.; Scazzocchio, B.; Di Benedetto, R.; Filesi, C.; Masella, R. Polyphenols, Intracellular Signalling and Inflammation. Ann. Ist. Super. Sanita 2007, 43, 394–405. [Google Scholar] [PubMed]
  24. Karasawa, K.; Uzuhashi, Y.; Hirota, M.; Otani, H. A Matured Fruit Extract of Date Palm Tree (Phoenix dactylifera L.) Stimulates the Cellular Immune System in Mice. J. Agric. Food Chem. 2011, 59, 11287–11293. [Google Scholar] [CrossRef] [PubMed]
  25. John, C.M.; Sandrasaigaran, P.; Tong, C.K.; Adam, A.; Ramasamy, R. Immunomodulatory Activity of Polyphenols Derived from Cassia Auriculata Flowers in Aged Rats. Cell. Immunol. 2011, 271, 474–479. [Google Scholar] [CrossRef] [PubMed]
  26. Mohar, D.; Malik, S. The Sirtuin System: The Holy Grail of Resveratrol? J. Clin. Exp. Cardiol. 2012, 3, 216. [Google Scholar] [CrossRef] [PubMed]
  27. Speciale, A.; Chirafisi, J.; Saija, A.; Cimino, F. Nutritional Antioxidants and Adaptive Cell Responses: An Update. Curr. Mol. Med. 2011, 11, 770–789. [Google Scholar] [CrossRef] [PubMed]
  28. Biasutto, L.; Mattarei, A.; Zoratti, M. Resveratrol and Health: The Starting Point. ChemBioChem 2012, 13, 1256–1259. [Google Scholar] [CrossRef] [PubMed]
  29. Capiralla, H.; Vingtdeux, V.; Venkatesh, J.; Dreses-werringloer, U.; Zhao, H.; Davies, P.; Marambaud, P. Identification of Potent Small? Molecule Inhibitors of STAT3 with Anti? Inflammatory Properties in RAW 264.7 Macrophages. FEBS J. 2012, 279, 3791–3799. [Google Scholar] [CrossRef] [PubMed]
  30. Leiherer, A.; Mündlein, A.; Drexel, H. Phytochemicals and Their Impact on Adipose Tissue Inflammation and Diabetes. Vasc. Pharmacol. 2013, 58, 3–20. [Google Scholar] [CrossRef] [PubMed]
  31. Siddiqui, A.M.; Cui, X.; Wu, R.; Dong, W.; Zhou, M.; Hu, M.; Simms, H.H.; Wang, P. The Anti-Inflammatory Effect of Curcumin in an Experimental Model of Sepsis Is Mediated by up-Regulation of Peroxisome Proliferator-Activated Receptor-γ. Crit. Care Med. 2006, 34, 1874–1882. [Google Scholar] [CrossRef] [PubMed]
  32. Marchiani, A.; Rozzo, C.; Fadda, A.; Delogu, G.; Ruzza, P. Curcumin and Curcumin-like Molecules: From Spice to Drugs. Curr. Med. Chem. 2014, 21, 204–222. [Google Scholar] [CrossRef] [PubMed]
  33. Noorafshan, A.; Ashkani-Esfahani, S. A Review of Therapeutic Effects of Curcumin. Curr. Pharm. Des. 2013, 19, 2032–2046. [Google Scholar] [PubMed]
  34. Gupta, S.C.; Prasad, S.; Kim, J.H.; Patchva, S.; Webb, L.J.; Priyadarsini, I.K.; Aggarwal, B.B. Multitargeting by Curcumin as Revealed by Molecular Interaction Studies. Nat. Prod. Rep. 2011, 28, 1937–1955. [Google Scholar] [CrossRef] [PubMed]
  35. Bae, J. Role of High Mobility Group Box 1 in Inflammatory Disease: Focus on Sepsis. Arch. Pharm. Res. 2012, 35, 1511–1523. [Google Scholar] [CrossRef] [PubMed]
  36. Tsuda, S.; Egawa, T.; Ma, X.; Oshima, R.; Kurogi, E.; Hayashi, T. Coffee Polyphenol Caffeic Acid but Not Chlorogenic Acid Increases 5’AMP-Activated Protein Kinase and Insulin-Independent Glucose Transport in Rat Skeletal Muscle. J. Nutr. Biochem. 2012, 23, 1403–1409. [Google Scholar] [CrossRef] [PubMed]
  37. Akyol, S.; Ozturk, G.; Ginis, Z.; Amutcu, F.; Yigitoglu, M.; Akyol, O. In Vivo and in Vitro Antıneoplastic Actions of Caffeic Acid Phenethyl Ester (CAPE): Therapeutic Perspectives. Nutr. Cancer 2013, 65, 1515–1526. [Google Scholar] [CrossRef] [PubMed]
  38. Kanwar, J. Recent Advances on Tea Polyphenols. Front. Biosci. 2012, E4, 111–131. [Google Scholar] [CrossRef]
  39. Domitrovic, R. The Molecular Basis for the Pharmacological Activity of Anthocyans. Curr. Med. Chem. 2011, 18, 4454–4469. [Google Scholar] [CrossRef] [PubMed]
  40. Singh, B.; Shankar, S.; Sriivastava, R. Green Tea Catechin, Epigallocatechin-3-Gallate (EGCG): Mechanisms, Perspectives and Clinical. Biochem. Pharmacol. 2011, 82, 1807–1821. [Google Scholar] [CrossRef] [PubMed]
  41. Landis-Piwowar, K.; Chen, D.; Foldes, R.; Chan, T.-H.; Dou, Q.P. Novel Epigallocatechin Gallate Analogs as Potential Anticancer Agents: A Patent Review (2009–Present). Expert Opin. Ther. Pat. 2013, 23, 189–202. [Google Scholar] [CrossRef] [PubMed]
  42. Sakaguchi, S.; Miyara, M.; Costantino, C.M.; Hafler, D.A. FOXP3 + Regulatory T Cells in the Human Immune System. Nat. Rev. Immunol. 2010, 10, 490–500. [Google Scholar] [CrossRef] [PubMed]
  43. Boissier, M.C.; Assier, E.; Biton, J.; Denys, A.; Falgarone, G.; Bessis, N. Regulatory T Cells (Treg) in Rheumatoid Arthritis. J. Bone Spine 2009, 76, 10–14. [Google Scholar] [CrossRef] [PubMed]
  44. Robinson, D.S.; Larché, M.; Durham, S.R. Tregs and Allergic Disease. J. Clin. Investig. 2004, 114, 1389–1397. [Google Scholar] [CrossRef] [PubMed]
  45. Wong, C.P.; Nguyen, L.P.; Noh, S.K.; Bray, T.M.; Bruno, R.S.; Ho, E. Induction of Regulatory T Cells by Green Tea Polyphenol EGCG. Immunol. Lett. 2011, 139, 7–13. [Google Scholar] [CrossRef] [PubMed]
  46. Yang, J.; Yang, X.; Li, M. Baicalin, a Natural Compound, Promotes Regulatory T Cell Differentiation. IBMC Complement. Altern. Med. 2012, 16, 64. [Google Scholar] [CrossRef] [PubMed]
  47. Wang, H.K.; Yeh, C.H.; Iwamoto, T.; Satsu, H.; Shimizu, M.; Totsuka, M. Dietary Flavonoid Naringenin Induces Regulatory T Cells via an Aryl Hydrocarbon Receptor Mediated Pathway. J. Agric. Food Chem. 2012, 60, 2171–2178. [Google Scholar] [CrossRef] [PubMed]
  48. Wang, J.; Pae, M.; Meydani, S.N.; Wu, D. Green Tea Epigallocatechin-3-Gallate Modulates Differentiation of Naïve CD4+T Cells into Specific Lineage Effector Cells. J. Mol. Med. 2013, 91, 485–495. [Google Scholar] [CrossRef] [PubMed]
  49. Yang, J.; Yang, X.; Chu, Y.; Li, M. Identification of Baicalin as an Immunoregulatory Compound by Controlling TH17 Cell Differentiation. PLoS ONE 2011, 6, e21359178. [Google Scholar] [CrossRef] [PubMed]
  50. Murray, P.J.; Wynn, T.A. Protective and Pathogenic Functions of Macrophage Subsets. Nat. Rev. Immunol. 2011, 11, 723–737. [Google Scholar] [CrossRef] [PubMed]
  51. González, R.; Ballester, I.; López-Posadas, R.; Suárez, M.D.; Zarzuelo, A.; Martínez-Augustin, O.; Sánchez de Medina, F. Effects of Flavonoids and Other Polyphenols on Inflammation. Crit. Rev. Food Sci. Nutr. 2011, 51, 331–362. [Google Scholar] [CrossRef] [PubMed]
  52. Wang, K.; Ping, S.; Huang, S.; Hu, L.; Xuan, H.; Zhang, C.; Hu, F. Molecular Mechanisms Underlying the In Vitro Anti-Inflammatory Effects of a Fla Vonoid -Rich Ethanol Extract from Chinese Propolis (Poplar Type). Cell 2013, 2013, 127672. [Google Scholar]
  53. Park, K.I.; Kang, S.R.; Park, H.S.; Lee, D.H.; Nagappan, A.; Kim, J.A.; Shin, S.C.; Kim, E.H.; Lee, W.S.; Chung, H.J.; et al. Regulation of Proinflammatory Mediators via NF-ΚB and P38 MAPK-Dependent Mechanisms in RAW 264.7 Macrophages by Polyphenol Components Isolated from Korea Lonicera Japonica THUNB. Evid.-Based Complement. Altern. Med. 2012, 2012, 22611435. [Google Scholar] [CrossRef] [PubMed]
  54. Lai, Z.-R.; Ho, Y.-L.; Huang, S.-C.; Huang, T.-H.; Lai, S.-C.; Tsai, J.-C.; Wang, C.-Y.; Huang, G.-J.; Chang, Y.-S. Antioxidant, Anti-Inflammatory and Antiproliferative Activities of Kalanchoe gracilis (L.) DC Stem. Am. J. Chin. Med. 2011, 39, 1275–1290. [Google Scholar] [CrossRef] [PubMed]
  55. Bohstam, M.; Asgary, S.; Kouhpayeh, S.; Shariati, L.; Khanhamad, H. Aptamers Against Pro- and Anti-Inflammatory Cytokines: A Review. Inflamm. Febr. 2017, 40, 340–349. [Google Scholar] [CrossRef] [PubMed]
  56. Kolehmainen, M.; Mykkänen, O.; Kirjavainen, P.V.; Leppänen, T.; Moilanen, E.; Adriaens, M.; Laaksonen, D.E.; Hallikainen, M.; Puupponen-Pimiä, R.; Pulkkinen, L.; et al. Bilberries Reduce Low-Grade Inflammation in Individuals with Features of Metabolic Syndrome. Mol. Nutr. Food Res. 2012, 56, 1501–1510. [Google Scholar] [CrossRef] [PubMed]
  57. Fitó, M.; Cladellas, M.; de la Torre, R.; Martí, J.; Muñoz, D.; Schröder, H.; Alcántara, M.; Pujadas-Bastardes, M.; Marrugat, J.; Ló-Sabater, M.C.; et al. Anti-Inflammatory Effect of Virgin Olive Oil in Stable Coronary Disease Patients: A Randomized, Crossover, Controlled Trial. Eur. J. Clin. Nutr. 2008, 62, 570–574. [Google Scholar] [CrossRef] [PubMed]
  58. Bitler, C.M.; Viale, T.M.; Damaj, B.; Crea, R. Hydrolyzed Olive Vegetation Water in Mice Has Anti-Inflammatory Activity. J. Nutr. 2005, 135, 1475–1479. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  59. Comalada, M.; Ballester, I.; Bailon, E.; Sierra, S.; Xaus, J.; de Medina, F.; Zarzuelo, A. Inhibition of pro-Inflammatory Markers in Primary Bone Marrow-Derived Mouse Macrophages by Naturally Occurring Flavonoids: Analysis of the Structure-Activity Relationship. Biochem. Pharmacol. 2006, 72, 1010–1021. [Google Scholar] [CrossRef] [PubMed]
  60. Blonska, M.; Czuba, Z.P.; Krol, W. Effect of Flavone Derivatives on Interleukin-1beta (IL-1beta) MRNA Expression and IL-1beta Protein Synthesis in Stimulated RAW 264.7 Macrophages. Scand. J. Immunol. 2003, 57, 162–166. [Google Scholar] [CrossRef] [PubMed]
  61. Sharma, V.; Mishra, M.; Ghosh, S.; Tewari, R.; Basu, A.; Seth, P.; Sen, E. Modulation of Interleukin-1beta Mediated Inflammatory Response in Human Astrocytes by Flavonoids: Implications in Neuroprotection. Brain Res. Bull. 2007, 73, 55–63. [Google Scholar] [CrossRef] [PubMed]
  62. Sato, M.; Miyazaki, T.; Kambe, F.; Maeda, K.; Seo, H. Quercetin, a Bioflavonoid, Inhibits the Induction of Interleukin 8 and Monocyte Chemoattractant Protein-1 Expression by Tumor Necrosis Factor-Alpha in Cultured Human Synovial Cells. J. Rheumatol. 1997, 24, 1680–1684. [Google Scholar] [PubMed]
  63. Min, Y.; Choi, C.; Bark, H.; Son, H.; Park, H.; Lee, S.; Park, J.; Park, E.; Shin, H.; Kim, S. Quercetin Inhibits Expression of Inflammatory Cytokines through Attenuation of NFkappaB and P38 MAPK in HMC-1 Human Mast Cell Line. Inflamm. Res. 2007, 56, 210–215. [Google Scholar] [CrossRef] [PubMed]
  64. Lyu, S.Y.; Park, W.B. Production of Cytokine and NO by RAW 264.7 Macrophages and PBMC in Vitro Incubation with Flavonoids. Arch. Pharm. Res. 2005, 28, 573–581. [Google Scholar] [CrossRef] [PubMed]
  65. Olivera, A.; Moore, T.W.; Hu, F.; Brown, A.P.; Sun, A.; Liotta, D.C.; Snyder, J.P.; Yoon, Y.; Shim, H.; Marcus, A.I.; et al. Inhibition of the NF-ΚB Signaling Pathway by the Curcumin Analog, 3,5-Bis(2-Pyridinylmethylidene)-4-Piperidone (EF31): Anti-Inflammatory and Anti-Cancer Properties. Int. Immunopharmacol. 2012, 12, 368–377. [Google Scholar] [CrossRef] [PubMed]
  66. Drummond, E.M.; Harbourne, N.; Marete, E.; Martyn, D.; Jacquier, J.C.; O’Riordan, D.; Gibney, E.R. Inhibition of Proinflammatory Biomarkers in THP1 Macrophages by Polyphenols Derived from Chamomile, Meadowsweet and Willow Bark. Phyther. Res. 2013, 27, 588–594. [Google Scholar] [CrossRef] [PubMed]
  67. Schindler, R.; Mancilla, J.; Endres, S.; Ghorbani, R.; Clark, S.C.; Dinarello, C.A. Correlations and Interactions in the Production of Interleukin-6 (IL-6), IL-1, and Tumor Necrosis Factor (TNF) in Human Blood Mononuclear Cells: IL-6 Suppresses IL-1 and TNF. Blood 1990, 75, 40–47. [Google Scholar] [PubMed]
  68. Essafi-Benkhadir, K.; Refai, A.; Riahi, I.; Fattouch, S.; Karoui, H.; Essafi, M. Quince (Cydonia oblonga Miller) Peel Polyphenols Modulate LPS-Induced Inflammation in Human THP-1-Derived Macrophages through NF-ΚB, P38MAPK and Akt Inhibition. Biochem. Biophys. Res. Commun. 2012, 418, 180–185. [Google Scholar] [CrossRef] [PubMed]
  69. Okamoto, I.; Iwaki, K.; Koya-Miyata, S.; Tanimoto, T.; Kohno, K.; Ikeda, M.; Kurimoto, M. The Flavonoid Kaempferol Suppresses the Graft-versus-Host Reaction by Inhibiting Type 1 Cytokine Production and CD8+T Cell Engraftment. Clin. Immunol. 2002, 103, 132–144. [Google Scholar] [CrossRef] [PubMed]
  70. Crouvezier, S.; Powell, B.; Keir, D.; Yaqoob, P. The Effects of Phenolic Components of Tea on the Production of Pro- and Anti-Inflammatory Cytokines by Human Leukocytes in Vitro. Cytokine 2001, 13, 280–286. [Google Scholar] [CrossRef] [PubMed]
  71. Nam, N. Naturally Occurring NF-kappa B Inhibitors. Mini Rev. Med. Chem. 2006, 6, 945–951. [Google Scholar] [CrossRef] [PubMed]
  72. Hayden, M.S.; Ghosh, S. Signaling to NF-KappaB. Genes Dev. 2004, 18, 2195–2224. [Google Scholar] [CrossRef] [PubMed]
  73. Haddad, J.J. Redox Regulation of pro-Inflammatory Cytokines and IkappaB-Alpha/NF-KappaB Nuclear Translocation And. Biochem. Biophys. Res. Commun. 2002, 296, 847–856. [Google Scholar] [CrossRef]
  74. Karin, M.; Ben-Neriah, Y. Phosphorylation Meets Ubiquitination: The Control of NF-[Kappa]B Activity. Annu. Rev. Immunol. 2000, 18, 621–663. [Google Scholar] [CrossRef] [PubMed]
  75. Perkins, N.D. Integrating Cell-Signalling Pathways with NF-ΚB and IKK Function. Nat. Rev. Mol. Cell Biol. 2007, 8, 49–62. [Google Scholar] [CrossRef] [PubMed]
  76. Karin, M.; Yamamoto, Y.; Wang, Q.M. The IKK NF-ΚB System: A Treasure Trove for Drug Development. Nat. Rev. Drug Discov. 2004, 3, 17–26. [Google Scholar] [CrossRef] [PubMed]
  77. Rahman, I.; Biswas, S.; Kirkham, P. Regulation of Inflammation and Redox Signaling by Dietary Polyphenols. Biochem. Pharmacol. 2006, 72, 1439–1452. [Google Scholar] [CrossRef] [PubMed]
  78. Rahman, I.; Marwick, J.; Kirkham, P. Redox Modulation of Chromatin Remodeling: Impact on Histone Acetylation and Deacetylation, NF-KappaB and pro-Inflammatory Gene Expression. Biochem. Pharmacol. 2004, 68, 1255–1267. [Google Scholar] [CrossRef] [PubMed]
  79. De Stefano, D.; Maiuri, M.C.; Simeon, V.; Grassia, G.; Soscia, A.; Cinelli, M.P.; Carnuccio, R. Lycopene, Quercetin and Tyrosol Prevent Macrophage Activation Induced by Gliadin and IFN-γ. Eur. J. Pharmacol. 2007, 566, 192–199. [Google Scholar] [CrossRef] [PubMed]
  80. Comalada, M.; Camuesco, D.; Sierra, S.; Ballester, I.; Xaus, J.; Gálvez, J.; Zarzuelo, A. In Vivo Quercitrin Anti-Inflammatory Effect Involves Release of Quercetin, Which Inhibits Inflammation through down-Regulation of the NF-ΚB Pathway. Eur. J. Immunol. 2005, 35, 584–592. [Google Scholar] [CrossRef] [PubMed]
  81. Ruiz, P.A.; Braune, A.; HÖlzlwimmer, G.; Quintanilla-Fend, L.; Haller, D. Quercetin Inhibits TNF-Induced NF-ΚB Transcription Factor Recruitment to Proinflammatory Gene Promoters in Murine Intestinal Epithelial Cells. J. Nutr. 2007, 137, 1208–1215. [Google Scholar] [CrossRef] [PubMed]
  82. Chen, J.C.; Ho, F.M.; Chao, P.D.L.; Chen, C.P.; Jeng, K.C.G.; Hsu, H.B.; Lee, S.T.; Wen, T.W.; Lin, W.W. Inhibition of INOS Gene Expression by Quercetin Is Mediated by the Inhibition of IκB Kinase, Nuclear Factor-Kappa B and STAT1, and Depends on Heme Oxygenase-1 Induction in Mouse BV-2 Microglia. Eur. J. Pharmacol. 2005, 521, 9–20. [Google Scholar] [CrossRef] [PubMed]
  83. Gracia-Lafuente, A.; Guillamon, E.; Villares, A.; Rostagno, M.; Martinez, J. Flavonoids as Anti-Inflammatory Agents: Implications in Cancer and Cardiovascular Disease. Inflamm. Res. 2009, 58, 537–552. [Google Scholar] [CrossRef] [PubMed]
  84. Nishitani, Y.; Yamamoto, K.; Yoshida, M.; Azuma, T.; Kanazawa, K.; Hashimoto, T.; Mizuno, M. Intestinal Anti-Inflammatory Activity of Luteolin: Role of the Aglycone in NF-ΚB Inactivation in Macrophages Co-Cultured with Intestinal Epithelial Cells. Biofactors 2013, 39, 522–533. [Google Scholar] [CrossRef] [PubMed]
  85. Ji, G.; Zhang, Y.; Yang, Q.; Cheng, S.; Hao, J.; Zhao, X.; Jiang, Z. Genistein Suppresses LPS-Induced Inflammatory Response through Inhibiting NF-ΚB Following AMP Kinase Activation in RAW 264.7 Macrophages. PLoS ONE 2012, 7, e23300870. [Google Scholar] [CrossRef] [PubMed]
  86. Kim, H.H.; Bae, Y.; Kim, S.H. Galangin Attenuates Mast Cell-Mediated Allergic Inflammation. Food Chem. Toxicol. 2013, 57, 209–216. [Google Scholar] [CrossRef] [PubMed]
  87. Wheeler, D.S.; Catravas, J.D.; Odoms, K.; Denenberg, A.; Malhotra, V.; Wong, H.R. Epigallocatechin-3-Gallate, a Green Tea-Derived Polyphenol, Inhibits IL-1 Beta-Dependent Proinflammatory Signal Transduction in Cultured Respiratory Epithelial Cells. J. Nutr. 2004, 134, 1039–1044. [Google Scholar] [CrossRef] [PubMed]
  88. Aneja, R.; Hake, P.W.; Burroughs, T.J.; Denenberg, A.G.; Wong, H.R.; Zingarelli, B. Epigallocatechin, a Green Tea Polyphenol, Attenuates Myocardial Ischemia Reperfusion Injury in Rats. Mol. Med. 2004, 10, 55–62. [Google Scholar] [CrossRef] [PubMed]
  89. Ichikawa, D.; Matsui, A.; Imai, M.; Sonoda, Y.; Kasahara, T. Effect of Various Catechins on the IL-12 p40 Production by Murine Peritoneal Macrophages and A. Biol. Pharm. Bull. 2004, 27, 1353–1358. [Google Scholar] [CrossRef] [PubMed]
  90. Lin, Y.; Lin, J. Epigallocatechin-3-Gallate Blocks the Induction of Nitric Oxide Synthase by Down-Regulating Lipopolysaccharide-Induced Activity of Transcription Factor Nuclear Factor-κB. Mol. Pharmacol. 1997, 472, 465–472. [Google Scholar] [CrossRef]
  91. Mackenzie, G.; Carrasquedo, F.; Delfino, J.; Keen, C.; Fraga, C.; Oteiza, P. Epicatechin, Catechin, and Dimeric Procyanidins Inhibit PMA? Induced NF? KappaB Activation at Multiple Steps in Jurkat T Cells. FASEB J. 2004, 18, 167–169. [Google Scholar] [CrossRef] [PubMed]
  92. Carluccio, M.A.; Siculella, L.; Ancora, M.A.; Massaro, M.; Scoditti, E.; Storelli, C.; Visioli, F.; Distante, A.; De Caterina, R. Olive Oil and Red Wine Antioxidant Polyphenols Inhibit Endothelial Activation: Antiatherogenic Properties of Mediterranean Diet Phytochemicals. Arterioscler. Thromb. Vasc. Biol. 2003, 23, 622–629. [Google Scholar] [CrossRef] [PubMed]
  93. Chang, L.; Karin, M. Mammalian MAP Kinase Signalling Cascades. Nature 2001, 410, 37–40. [Google Scholar] [CrossRef] [PubMed]
  94. Khan, N.; Afaq, F.; Saleem, M.; Ahmad, N.; Mukhtar, H. Targeting Multiple Signaling Pathways by Green Tea Polyphenol (−)-Epigallocatechin-3-Gallate. 1 Khan N, Afaq F, Saleem M, Ahmad N, Mukhtar H. Author Information Full. Cancer Res. 2006, 66, 2500–2505. [Google Scholar] [CrossRef] [PubMed]
  95. Kolch, W. Coordinating ERK/MAPK Signalling through Scaffolds and Inhibitors. Nat. Rev. Mol. Cell Biol. 2005, 6, 827–837. [Google Scholar] [CrossRef] [PubMed]
  96. Lu, Z.; Xu, S. ERK1/2 MAP Kinases in Cell Survival and Apoptosis. IUBMB Life 2006, 58, 621–631. [Google Scholar] [CrossRef] [PubMed]
  97. Mayor, F.; Jurado-Pueyo, M.; Campos, P.M.; Murga, C. Interfering with MAP Kinase Docking Interactions: Implications and Perspective for the P38 Route. Cell Cycle 2007, 6, 528–533. [Google Scholar] [CrossRef] [PubMed]
  98. Kaminska, B. MAPK Signalling Pathways as Molecular Targets for Anti-Inflammatory Therapy—From Molecular Mechanisms to Therapeutic Benefits. Biochim. Biophys. Acta 2005, 1754, 253–262. [Google Scholar] [CrossRef] [PubMed]
  99. Karin, M. Inflammation-Activated Protein Kinases as Targets for Drug Development. Proc. Am. Thorac. Soc. 2005, 2, 386–390. [Google Scholar] [CrossRef] [PubMed]
  100. Xagorari, A.; Roussos, C.; Papapetropoulos, A. Inhibition of LPS-Stimulated Pathways in Macrophages by the Flavonoid Luteolin. Br. J. Pharmacol. 2002, 136, 1058–1064. [Google Scholar] [CrossRef] [PubMed]
  101. Chen, C.; Chow, M.; Huang, W.; Lin, Y.; Chang, Y. Flavonoids Inhibit Tumor Necrosis Factor-Alpha-Induced up-Regulation of Intercellular Adhesion Molecule-1 (ICAM-1) in Respiratory Epithelial Cells through Activator Protein-1 and Nuclear Factor-KappaB: Structure-Activity Relationships. Mol. Pharmacol. 2004, 66, 683–693. [Google Scholar] [PubMed]
  102. Wadsworth, T.L.; McDonald, T.L.; Koop, D.R. Effects of Ginkgo Biloba Extract (EGb 761) and Quercetin on Lipopolysaccharide-Induced Signaling Pathways Involved in the Release of Tumor Necrosis Factor-Alpha. Biochem. Pharmacol. 2001, 62, 963–974. [Google Scholar] [CrossRef]
  103. Cho, S.; Park, S.; Kwon, M.; Jeong, T.; Bok, S.; Choi, W.; Jeong, W.; Ryu, S.; Do, S.; Song, C.; et al. Quercetin Suppresses Proinflammatory Cytokines Production through MAP Kinases AndNF-Kappa B Pathway in Lipopolysaccharide-Stimulated Macrophage. Mol. Cell. Biochem. 2003, 243, 153–160. [Google Scholar] [CrossRef] [PubMed]
  104. Kundu, J.K.; Surh, Y.J. Epigallocatechin Gallate Inhibits Phorbol Ester-Induced Activation of NF-ΚB and CREB in Mouse Skin Role of P38 MAPK. Ann. N. Y. Acad. Sci. 2007, 1095, 504–512. [Google Scholar] [CrossRef] [PubMed]
  105. Pasten, C.; Olave, N.; Zhou, L.; Tabengwa, E.; Wolkowicz, P.; Grenett, H. Polyphenols Downregulate PAI-1 Gene Expression in Cultured Human Coronary Artery Endothelial Cells: Molecular Contributor to Cardiovascular Protection. Thromb. Res. 2007, 121, 59–65. [Google Scholar] [CrossRef] [PubMed]
  106. Chandrasekharan, N.V.; Dai, H.; Roos, K.L.T.; Evanson, N.K.; Tomsik, J.; Elton, T.S.; Simmons, D.L. COX-3, a Cyclooxygenase-1 Variant Inhibited by Acetaminophen and Other Analgesic/Antipyretic Drugs: Cloning, Structure, and Expression. Proc. Natl. Acad. Sci. USA 2002, 99, 13926–13931. [Google Scholar] [CrossRef] [PubMed]
  107. Needleman, P.; Isakson, P. The Discovery and Function of COX-2. J. Rheumatol. Suppl. 2018, 49, 6–8. [Google Scholar]
  108. Kim, H.P.; Son, K.H.; Chang, H.W.; Kang, S.S. Anti-Inflammatory Plant Flavonoids and Cellular Action Mechanisms. J. Pharmacol. Sci. 2004, 96, 229–245. [Google Scholar] [CrossRef] [PubMed]
  109. Welton, A.F.; Tobias, L.D.; Fiedler-Nagy, C.; Anderson, W.; Hope, W.; Meyers, K.; Coffey, J.W. Effect of Flavonoids on Arachidonic Acid Metabolism. Prog. Clin. Biol. Res. 1986, 213, 231–242. [Google Scholar] [PubMed]
  110. Laughton, M.; Evans, P.; Moroney, M.; Hoult, J.; Halliwell, B. Inhibition of Mammalian 5-Lipoxygenase and Cyclo-Oxygenase by Flavonoids and Phenolic Dietary Additives. Relationship to Antioxidant Activity and to Iron Ion-Reducing Ability. Biochem. Pharmacol. 1991, 42, 1673–1681. [Google Scholar] [CrossRef]
  111. Aviram, M.; Fuhrman, B. Polyphenolic Flavonoids Inhibit Macrophage-Mediated Oxidation of LDL and Attenuate Atherogenesis. Atherosclerosis 1998, 137, 9694541. [Google Scholar] [CrossRef]
  112. Ferrandiz, M.L.; Alcaraz, M.J. Ferrandiz 1991-Anti-Inflammatory Activity and Inhibition of Arachidonic Acid Metabolism by Flavonoids. Agent Action 1991, 32, 283–288. [Google Scholar] [CrossRef]
  113. Kim, H.; Mani, I.; Iversen, L.; Ziboh, V. Effects of Naturally-Occurring Flavonoids and Biflavonoids on Epidermal Cyclooxygenase and Lipoxygenase from Guinea-Pigs. Prostaglandin Leukot. Essent. Fat. Acid. 1998, 58, 17–24. [Google Scholar] [CrossRef]
  114. Luceri, C.; Caderni, G.; Sanna, A.; Dolara, P. Red Wine and Black Tea Polyphenols Modulate the Expression of Cycloxygenase-2, Inducible Nitric Oxide Synthase and Glutathione-Related Enzymes in Azoxymethane-Induced F344 Rat Colon Tumors. J. Nutr. 2002, 132, 1376–1379. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  115. Hou, D.X.; Luo, D.; Tanigawa, S.; Hashimoto, F.; Uto, T.; Masuzaki, S.; Fujii, M.; Sakata, Y. Prodelphinidin B-4 3′-O-Gallate, a Tea Polyphenol, Is Involved in the Inhibition of COX-2 and INOS via the Downregulation of TAK1-NF-ΚB Pathway. Biochem. Pharmacol. 2007, 74, 742–751. [Google Scholar] [CrossRef] [PubMed]
  116. Hou, D.; Masuzaki, S.; Hashimoto, F.; Uto, T.; Tanigawa, S.; Fujii, M.; Sakata, Y. Green Tea Proanthocyanidins Inhibit Cyclooxygenase-2 Expression in LPS-Activated Mouse Macrophages: Molecular Mechanisms and Structure? Activity Relationship. Arch. Biochem. Biophys. 2007, 460, 67–74. [Google Scholar] [CrossRef] [PubMed]
  117. Miles, E.A.; Zoubouli, P.; Calder, P.C. Differential Anti-Inflammatory Effects of Phenolic Compounds from Extra Virgin Olive Oil Identified in Human Whole Blood Cultures. Nutrition 2005, 21, 389–394. [Google Scholar] [CrossRef] [PubMed]
  118. Tuck, K.L.; Hayball, P.J. Major Phenolic Compounds in Olive Oil: Metabolism and Health Effects. J. Nutr. Biochem. 2002, 13, 636–644. [Google Scholar] [CrossRef]
  119. De la Puerta, R.; Gutierrez, V.R.; Hoult, J. Inhibition of Leukocyte 5 Lipoxygenase by Phenolics from Virgin Olive Oil. Biochem. Pharmacol. 1999, 57, 445–449. [Google Scholar] [CrossRef]
  120. Beauchamp, G.K.; Keast, R.S.J.; Morel, D.; Lin, J.; Pika, J.; Han, Q.; Lee, C.H.; Smith, A.B.; Breslin, P.A.S. Ibuprofen-like Activity in Extra-Virgin Olive Oil. Nature 2005, 437, 45–46. [Google Scholar] [CrossRef] [PubMed]
  121. Berlett, B.S.; Stadtman, E.R.; Berlett, B.S.; Stadtman, E.R. Protein Oxidation in Aging, Disease, and Oxidative Stress. J. Biol. Chem. 1997, 272, 20313–20316. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  122. Salzano, S.; Checconi, P.; Hanschmann, E.-M.; Lillig, C.H.; Bowler, L.D.; Chan, P.; Vaudry, D.; Mengozzi, M.; Coppo, L.; Sacre, S.; et al. Linkage of Inflammation and Oxidative Stress via Release of Glutathionylated Peroxiredoxin-2, Which Acts as a Danger Signal. Proc. Natl. Acad. Sci. USA 2014, 111, 12157–12162. [Google Scholar] [CrossRef] [PubMed]
  123. Willcox, J.K.; Ash, S.L.; Catignani, G.L. Antioxidants and Prevention of Chronic Disease. Crit. Rev. Food Sci. Nutr. 2004, 44, 275–295. [Google Scholar] [CrossRef] [PubMed]
  124. Bryan, N.; Ahswin, H.; Smart, N.; Bayon, Y.; Wohlert, S.; Hunt, J.A. Reactive Oxygen Species (ROS)-A Family of Fate Deciding Molecules Pivotal in Constructive Inflammation and Wound Healing. Eur. Cells Mater. 2012, 24, 249–265. [Google Scholar] [CrossRef]
  125. Naik, E.; Dixit, V.M. Mitochondrial Reactive Oxygen Species Drive Proinflammatory Cytokine Production: Figure 1. J. Exp. Med. 2011, 208, 417–420. [Google Scholar] [CrossRef] [PubMed]
  126. Clark, R.A.; Valente, A.J. Nuclear Factor Kappa B Activation by NADPH Oxidases. Mech. Ageing Dev. 2004, 125, 799–810. [Google Scholar] [CrossRef] [PubMed]
  127. Geiszt, M.; Leto, T.L. The Nox Family of NAD(P)H Oxidases: Host Defense and Beyond. J. Biol. Chem. 2004, 279, 51715–51718. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  128. Heim, K.E.; Tagliaferro, A.R.; Bobilya, D.J. Flavonoid Antioxidants: Chemistry, Metabolism and Structure-Activity Relationships. J. Nutr. Biochem. 2002, 13, 572–584. [Google Scholar] [CrossRef]
  129. Mishra, A.; Sharma, A.K.; Kumar, S.; Saxena, A.K.; Pandey, A.K. Bauhinia Variegata Leaf Extracts Exhibit Considerable Antibacterial, Antioxidant, and Anticancer Activities. Biomed. Res. Int. 2013, 2013, 915436. [Google Scholar] [CrossRef] [PubMed]
  130. Mishra, A.; Kumar, S.; Pandey, A.K. Scientific Validation of the Medicinal Efficacy of Tinospora Cordifolia. Sci. World J. 2013, 2013, 292934. [Google Scholar] [CrossRef] [PubMed]
  131. Marnett, L.J.; Riggins, J.N.; West, J.D. Endogenous Generation of Reactive Oxidants and Electrophiles and Their Reactions with DNA and Protein. J. Clin. Investig. 2003, 111, 583–593. [Google Scholar] [CrossRef] [PubMed]
  132. Prousek, J. Fenton Chemistry in Biology and Medicine. Pure Appl. Chem. 2007, 79, 2007–2010. [Google Scholar] [CrossRef]
  133. Deby-Dupont, G.; Mouithys-Mickalad, A.; Serteyn, D.; Lamy, M.; Deby, C. Resveratrol and Curcumin Reduce the Respiratory Burst of Chlamydia-Primed THP-1 Cells. Biochem. Biophys. Res. Commun. 2005, 333, 21–27. [Google Scholar] [CrossRef] [PubMed]
  134. Chow, S.E.; Hshu, Y.C.; Wang, J.S.; Chen, J.K. Resveratrol Attenuates OxLDL-Stimulated NADPH Oxidase Activity and Protects Endothelial Cells from Oxidative Functional Damages. J. Appl. Physiol. 2007, 102, 1520–1527. [Google Scholar] [CrossRef] [PubMed]
  135. Petrônio, M.S.; Zeraik, M.L.; Da Fonseca, L.M.; Ximenes, V.F. Apocynin: Chemical and Biophysical Properties of a NADPH Oxidase Inhibitor. Molecules 2013, 18, 2821–2839. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  136. Shen, L.; Ji, H.F. Insights into the Inhibition of Xanthine Oxidase by Curcumin. Bioorg. Med. Chem. Lett. 2009, 19, 5990–5993. [Google Scholar] [CrossRef] [PubMed]
  137. Aucamp, J. Inhibition of Xanthine Oxidase by Tea Catechins (Camellia Sinensis). Method Mol. Biol. 1997, 702, 47–60. [Google Scholar]
  138. Schmidt, A.; Böhmer, A.E.; Antunes, C.; Schallenberger, C.; Porciuncula, L.; Elisabetsky, E.; Lara, D.; Souza, D. Anti-Nociceptive Properties of the Xanthine Oxidase Inhibitor Allopurinol in Mice: Role of A1 Adenosine Receptors. Br. J. Pharmacol. 2009, 156, 163–172. [Google Scholar] [CrossRef] [PubMed]
  139. Nguyen, M.T.T.; Nguyen, N.T. Xanthine Oxidase Inhibitors from Vietnamese Blume balsamifer L. Phyther. Res. 2012, 26, 1178–1181. [Google Scholar] [CrossRef] [PubMed]
  140. Bräunlich, M.; Slimestad, R.; Wangensteen, H.; Brede, C.; Malterud, K.E.; Barsett, H. Extracts, Anthocyanins and Procyanidins from Aronia Melanocarpa as Radical Scavengers and Enzyme Inhibitors. Nutrients 2013, 5, 663–678. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  141. Huang, X.F.; Li, H.Q.; Shi, L.; Xue, J.Y.; Ruan, B.F.; Zhu, H.L. Synthesis of Resveratrol Analogues, and Evaluation of Their Cytotoxic and Xanthine Oxidase Inhibitory Activities. Chem. Biodivers. 2008, 5, 636–642. [Google Scholar] [CrossRef] [PubMed]
  142. Cheon, B.S.; Kim, Y.H.; Son, K.S.; Chang, H.W.; Kang, S.S.; Kim, H.P. Effects of Prenylated Flavonoids and Biflavonoids on Lipopolysaccharide-Induced Nitric Oxide Production from the Mouse Macrophage Cell Line RAW 264.7. Planta Med. 2000, 66, 596–600. [Google Scholar] [CrossRef] [PubMed]
  143. Sarkar, A.; Bhaduri, A. Black Tea Is a Powerful Chemopreventor of Reactive Oxygen and Nitrogen Species: Comparison with Its Individual Catechin Constituents and Green Tea. Biochem. Biophys. Res. Commun. 2001, 284, 173–178. [Google Scholar] [CrossRef] [PubMed]
  144. Sporn, M.B.; Liby, K.T. NRF2 and Cancer: The Good, the Bad and the Importance of Context. Nat. Rev. Cancer 2012, 12, 564–571. [Google Scholar] [CrossRef] [PubMed]
  145. Chu, A. Antagonism by Bioactive Polyphenols Against Inflammation: A Systematic View. Inflamm. Allergy Drug Targets 2014, 13, 34–64. [Google Scholar] [CrossRef] [PubMed]
  146. Meydani, M.; Hasan, S.T. Dietary Polyphenols and Obesity. Nutrients 2010, 2, 737–751. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  147. Yahfoufi, N.; Mallet, J.F.; Graham, E.; Matar, C. Role of Probiotics and Prebiotics in Immunomodulation. Curr. Opin. Food Sci. 2018, 20, 82–91. [Google Scholar] [CrossRef]
  148. Roy, D.; Perreault, M.; Marette, A. Insulin Stimulation of Glucose Uptake in Skeletal Muscles and Adipose Tissues in Vivo Is NO Dependent. Am. J. Physiol. Endocrinol. Metab. 1998, 274, E692–E699. [Google Scholar] [CrossRef]
  149. Fryer, L.G.; Hajduch, E.; Rencurel, F.; Salt, I.P.; Hundal, H.S.; Hardie, D.G.; Carling, D. Activation of Glucose Transport by AMP-Activated Protein Kinase via Stimulation of Nitric Oxide Synthase. Diabetes 2000, 49, 1978–1985. [Google Scholar] [CrossRef] [PubMed]
  150. Roberts, C.K.; Barnard, R.J.; Scheck, S.H.; Balon, T.W. Exercise-Stimulated Glucose Transport in Skeletal Muscle Is Nitric Oxide Dependent. Am. J. Physiol. 1997, 273, E220–E225. [Google Scholar] [PubMed]
  151. Peters, U.; Poole, C.; Arab, L. Does Tea Affect Cardiovascular Disease? A Meta-Analysis. Am. J. Epidemiol. 2001, 154, 495–503. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  152. Lindsay, J.; Laurin, D.; Verreault, R.; Hébert, R.; Helliwell, B.; Hill, G.; McDowell, I. Risk Factors for Alzheimer’s Disease: A Prospective Analysis from the Canadian Study of Health and Aging. Am. J. Epidemiol. 2002, 156, 445–453. [Google Scholar] [CrossRef] [PubMed]
  153. Truelsen, T.; Thudium, D.; Grønbaek, M.; Copenhagen City Heart Study. Amount and Type of Alcohol and Risk of Dementia: The Copenhagen City Heart Study. Neurology 2002, 59, 1313–1319. [Google Scholar] [CrossRef] [PubMed]
  154. Hadi, S.M.; Asad, S.F.; Singh, S.; Ahmad, A. Putative Mechanism for Anticancer and Apoptosis-Inducing Properties of Plant-Derived Polyphenolic Compounds. IUBMB Life 2000, 50, 167–171. [Google Scholar] [PubMed] [Green Version]
  155. Park, S.; Ahmad, F.; Philip, A.; Baar, K.; William, T.; Luo, H.; Ke, H.; Rehmann, H.; Taussing, R.; Brown, A.; et al. Resveratrol Ameliorates Aging-Related Metabolic Phenotypes by Inhibiting CAMP Phosphodiesterases. Cell 2012, 148, 421–433. [Google Scholar] [CrossRef] [PubMed]
  156. Wallerath, T.; Deckert, G.; Ternes, T.; Anderson, H.; Li, H.; Witte, K.; Forstermann, U. Resveratrol, a Polyphenolic Phytoalexin Present in Red Wine, Enhances Expression and Activity of Endothelial Nitric Oxide Synthase. Circulation 2002, 106, 1652–1658. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  157. Kumar, S.; Narwal, S.; Kumar, V.; Prakash, O. α-Glucosidase Inhibitors from Plants: A Natural Approach to Treat Diabetes. Pharmacogn. Rev. 2011, 5, 19–29. [Google Scholar] [CrossRef] [PubMed]
  158. Di Castelnuovo, A.; Rotondo, S.; Iacoviello, L.; Donati, M.B.; De Gaetano, G. Meta-Analysis of Wine and Beer Consumption in Relation to Vascular Risk. Circulation 2002, 105, 2836–2844. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  159. Hooper, L.; Kroon, P.A.; Rimm, E.B.; Cohn, J.S.; Harvey, I.; Cornu, K.A.; Le Ryder, J.J.; Hall, W.L.; Cassidy, A. Flavonoids, Flavonoid-Rich Foods, and Cardiovascular Risk: A Meta-Analysis of Randomized Controlled Trials 1, 2. Am. J. Clin. Nutr. 2008, 88, 38–50. [Google Scholar] [CrossRef] [PubMed]
  160. Shen, M.; Zhao, L.; Wu, R.X.; Yue, S.Q.; Pei, J.M. The Vasorelaxing Effect of Resveratrol on Abdominal Aorta from Rats and Its Underlying Mechanisms. Vasc. Pharmacol. 2013, 58, 64–70. [Google Scholar] [CrossRef] [PubMed]
  161. Peppa, M.; Raptis, S.A. Advanced Glycation End Products and Cardiovascular Disease. Curr. Diabete Rev. 2008, 4, 92–100. [Google Scholar] [CrossRef]
  162. Huang, S.M.; Wu, C.H.; Yen, G.C. Effects of Flavonoids on the Expression of the Pro-Inflammatory Response in Human Monocytes Induced by Ligation of the Receptor for AGEs. Mol. Nutr. Food Res. 2006, 50, 1129–1139. [Google Scholar] [CrossRef] [PubMed]
  163. Kim, J.M.; Lee, E.K.; Kim, D.H.; Yu, B.P.; Chung, H.Y. Kaempferol Modulates Pro-Inflammatory NF-ΚB Activation by Suppressing Advanced Glycation Endproducts-Induced NADPH Oxidase. Age 2010, 32, 197–208. [Google Scholar] [CrossRef] [PubMed]
  164. Wilkinson-Berka, J.L.; Rana, I.; Armani, R.; Agrotis, A. Reactive Oxygen Species, Nox and Angiotensin II in Angiogenesis: Implications for Retinopathy. Clin. Sci. 2013, 124, 597–615. [Google Scholar] [CrossRef] [PubMed]
  165. Thomasset, S.; Teller, N.; Cai, H.; Marko, D.; Berry, D.; Steward, W.; Gescher, A. Do Anthocyanins and Anthocyanidins, Cancer Chemopreventive Pigments in the Diet, Merit Development as Potential Drugs? Cancer Chemother. Pharmacol. 2009, 64, 201–211. [Google Scholar] [CrossRef] [PubMed]
  166. Aviram, M.; Fuhrman, B. Wine Flavonoids Protect against LDL Oxidation and Atherosclerosis. Ann. N. Y. Acad. Sci. 2002, 957, 146–161. [Google Scholar] [CrossRef] [PubMed]
  167. Commenges, D.; Scotet, V.; Renaud, S.; Jacqmin-Gadda, H.; Barberger-Gateau, P.; Dartigues, J.F. Intake of Flavonoids and Risk of Dementia. Eur. J. Epidemiol. 2000, 16, 357–363. [Google Scholar] [CrossRef] [PubMed]
  168. Dai, Q.; Borenstein, A.R.; Wu, Y.; Jackson, J.C.; Larson, E.B. Fruit and Vegetable Juices and Alzheimer’s Disease: The Kame Project. Am. J. Med. 2006, 119, 751–759. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  169. Morris, M.C.; Evans, D.A.; Tangney, C.C.; Bienias, J.L.; Wilson, R.S. Associations of Vegetable and Fruit Consumption with Age-Related Cognitive Change. Neurology 2006, 67, 1370–1376. [Google Scholar] [CrossRef] [PubMed]
  170. Checkoway, H.; Powers, K.; Smith-Weller, T.; Franklin, G.M.; Longstreth, W.T.; Swanson, P.D. Parkinson’s Disease Risks Associated with Cigarette Smoking, Alcohol Consumption, and Caffeine Intake. Am. J. Epidemiol. 2002, 155, 732–738. [Google Scholar] [CrossRef] [PubMed]
  171. Shehzad, A.; Lee, Y.S. Molecular Mechanisms of Curcumin Action: Signal Transduction. Biofactors 2013, 39, 27–36. [Google Scholar] [CrossRef] [PubMed]
  172. Gomez-Pinilla, F.; Nguyen, T.T.J. Natural Mood Foods: The Actions of Polyphenols against Psychiatric and Cognitive Disorders. Nutr. Neurosci. 2012, 15, 127–133. [Google Scholar] [CrossRef] [PubMed]
  173. Vauzour, D.; Vafeiadou, K.; Rice-Evans, C.; Williams, R.J.; Spencer, J.P.E. Activation of Pro-Survival Akt and ERK1/2 Signalling Pathways Underlie the Anti-Apoptotic Effects of Flavanones in Cortical Neurons. J. Neurochem. 2007, 103, 1355–1367. [Google Scholar] [CrossRef] [PubMed]
  174. Vafeiadou, K.; Vauzour, D.; Lee, H.Y.; Rodriguez-Mateos, A.; Williams, R.J.; Spencer, J.P.E. The Citrus Flavanone Naringenin Inhibits Inflammatory Signalling in Glial Cells and Protects against Neuroinflammatory Injury. Arch. Biochem. Biophys. 2009, 484, 100–109. [Google Scholar] [CrossRef] [PubMed]
  175. Wang, X.; Chen, S.; Ma, G.; Ye, M.; Lu, G. Genistein Protects Dopaminergic Neurons by Inhibiting Microglial Activation. Neuroreport 2005, 16, 267–270. [Google Scholar] [CrossRef] [PubMed]
  176. Bhat, N.R.; Feinstein, D.L.; Shen, Q.; Bhat, A.N. P38 MAPK-Mediated Transcriptional Activation of Inducible Nitric-Oxide Synthase in Glial Cells: Roles of Nuclear Factors, Nuclear Factor ΚB, CAMP Response Element-Binding Protein, CCAAT/Enhancer-Binding Protein-β, and Activating Transcription Factor-2. J. Biol. Chem. 2002, 277, 29584–29592. [Google Scholar] [CrossRef] [PubMed]
  177. Whiting, S.; Derbyshire, E.; Tiwari, B.K. Capsaicinoids and Capsinoids. A Potential Role for Weight Management? A Systematic Review of the Evidence. Appetite 2012, 59, 341–348. [Google Scholar] [CrossRef] [PubMed]
  178. Saito, M.; Yoneshiro, T. Capsinoids and Related Food Ingredients Activating Brown Fat Thermogenesis and Reducing Body Fat in Humans. Curr. Opin. Lipidol. 2013, 24, 71–77. [Google Scholar] [CrossRef] [PubMed]
  179. Higuchi, M.; Dusting, G.J.; Peshavariya, H.; Jiang, F.; Hsiao, S.T.-F.; Chan, E.C.; Liu, G.-S. Differentiation of Human Adipose-Derived Stem Cells into Fat Involves Reactive Oxygen Species and Forkhead Box O1 Mediated Upregulation of Antioxidant Enzymes. Stem Cell Dev. 2013, 22, 878–888. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  180. Okamoto, M.; Irii, H.; Tahara, Y.; Ishii, H.; Hirao, A.; Udagawa, H.; Hiramoto, M.; Yasuda, K.; Takanishi, A.; Shibata, S.; et al. Synthesis of a New [6]-Gingerol Analogue and Its Protective Effect with Respect to the Development of Metabolic Syndrome in Mice Fed a High-Fat Diet. J. Med. Chem. 2011, 54, 6295–6304. [Google Scholar] [CrossRef] [PubMed]
  181. Panahi, Y.; Hosseini, M.S.; Khalili, N.; Naimi, E.; Soflaei, S.S.; Majeed, M.; Sahebkar, A. Effects of Supplementation with Curcumin on Serum Adipokine Concentrations: A Randomized Controlled Trial. Nutrition 2016, 32, 1116–1122. [Google Scholar] [CrossRef] [PubMed]
  182. Yang, C.S.; Landau, J.M.; Huang, M.T.; Newmark, H.L. Inhibition of Carcinogenesis by Dietary Polyphenolic Compounds. Annu. Rev. Nutr. 2001, 21, 381–406. [Google Scholar] [CrossRef] [PubMed]
  183. Wenzel, U.; Kuntz, S.; Brendel, M.D.; Daniel, H. Dietary Flavone Is a Potent Apoptosis Inducer in Human Colon Carcinoma Cells. Cancer Res. 2000, 60, 3823–3831. [Google Scholar] [PubMed]
  184. Turrini, E.; Ferruzzi, L.; Fimognari, C. Potential Effects of Pomegranate Polyphenols in Cancer Prevention and Therapy. Oxid. Med. Cell. Longev. 2015, 2015, 938475. [Google Scholar] [CrossRef] [PubMed]
  185. Wessner, B.; Strasser, E.-M.; Koitz, N.; Schmuckenschlager, C.; Unger-Manhart, N.; Roth, E. Green Tea Polyphenol Administration Partly Ameliorates Chemotherapy-Induced Side Effects in the Small Intestine of Mice. J. Nutr. 2007, 137, 634–640. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  186. Harper, C.E.; Patel, B.B.; Wang, J.; Eltoum, I.A.; Lamartiniere, C.A. Epigallocatechin-3-Gallate Suppresses Early Stage, but Not Late Stage Prostate Cancer in TRAMP Mice: Mechanisms of Action. Prostate 2007, 67, 1576–1589. [Google Scholar] [CrossRef] [PubMed]
  187. Chuang, S.E.; Cheng, A.L.; Lin, J.K.; Kuo, M.L. Inhibition by Curcumin of Diethylnitrosamine-Induced Hepatic Hyperplasia, Inflammation, Cellular Gene Products and Cell-Cycle-Related Proteins in Rats. Food Chem. Toxicol. 2000, 38, 991–995. [Google Scholar] [CrossRef]
  188. Link, A.; Balaguer, F.; Goel, A. Cancer Chemoprevention by Dietary Polyphenols: Promising Role for Epigenetics. Biochem. Pharmacol. 2010, 80, 1771–1792. [Google Scholar] [CrossRef] [PubMed]
  189. Brenner, D.E.; Gescher, A.J. Cancer Chemoprevention: Lessons Learned and Future Directions. Br. J. Cancer 2005, 93, 735–739. [Google Scholar] [CrossRef] [PubMed]
  190. Weng, C.-J.; Yen, G.-C. Chemopreventive Effects of Dietary Phytochemicals against Cancer Invasion and Metastasis: Phenolic Acids, Monophenol, Polyphenol, and Their Derivatives. Cancer Treat. Rev. 2012, 38, 76–87. [Google Scholar] [CrossRef] [PubMed]
  191. Liou, G.-Y.; Storz, P. Reactive Oxygen Species in Cancer. Free Radic. Res. 2010, 44, 479–496. [Google Scholar] [CrossRef] [PubMed]
  192. Wang, C.; Schuller Levis, G.B.; Lee, E.B.; Levis, W.R.; Lee, D.W.; Kim, B.S.; Park, S.Y.; Park, E. Platycodin D and D3 Isolated from the Root of Platycodon Grandiflorum Modulate the Production of Nitric Oxide and Secretion of TNF-Alpha in Activated RAW 264.7 Cells. Int. Immunopharmacol. 2004, 4, 1039–1049. [Google Scholar] [CrossRef] [PubMed]
  193. Amararathna, M.; Johnston, M.R.; Rupasinghe, H.P.V. Plant Polyphenols as Chemopreventive Agents for Lung Cancer. Int. J. Mol. Sci. 2016, 17, 1352. [Google Scholar] [CrossRef] [PubMed]
  194. Tsuji, P.A.; Walle, T. Inhibition of Benzo[a]Pyrene-Activating Enzymes and DNA Binding in Human Bronchial Epithelial BEAS-2B Cells by Methoxylated Flavonoids. Carcinogenesis 2006, 27, 1579–1585. [Google Scholar] [CrossRef] [PubMed]
  195. Zhai, X.; Lin, M.; Zhang, F.; Hu, Y.; Xu, X.; Li, Y.; Liu, K.; Ma, X.; Tian, X.; Yao, J. Dietary Flavonoid Genistein Induces Nrf2 and Phase II Detoxification Gene Expression via ERKs and PKC Pathways and Protects against Oxidative Stress in Caco-2 Cells. Mol. Nutr. Food Res. 2013, 57, 249–259. [Google Scholar] [CrossRef] [PubMed]
  196. Lambert, J.D.; Elias, R.J. The Antioxidant and Pro-Oxidant Activities of Green Tea Polyphenols: A Role in Cancer Prevention. Arch. Biochem. Biophys. 2010, 501, 65–72. [Google Scholar] [CrossRef] [PubMed]
  197. Nakazato, T.; Ito, K.; Ikeda, Y.; Kizaki, M. Green Tea Component, Catechin, Induces Apoptosis of Human Malignant B Cells via Production of Reactive Oxygen Species. Clin. Cancer Res. 2005, 11, 6040–6049. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  198. Howells, L.M.; Mitra, A.; Manson, M.M. Comparison of Oxaliplatin- and Curcumin-Mediated Antiproliferative Effects in Colorectal Cell Lines. Int. J. Cancer 2007, 121, 175–183. [Google Scholar] [CrossRef] [PubMed]
  199. Balasubramanian, S.; Efimova, T.; Eckert, R.L. Green Tea Polyphenol Stimulates a Ras, MEKK1, MEK3, and P38 Cascade to Increase Activator Protein 1 Factor-Dependent Involucrin Gene Expression in Normal Human Keratinocytes. J. Biol. Chem. 2002, 277, 1828–1836. [Google Scholar] [CrossRef] [PubMed]
  200. Kao, Y.-L.; Kuo, Y.-M.; Lee, Y.-R.; Yang, S.-F.; Chen, W.-R.; Lee, H.-J. Apple Polyphenol Induces Cell Apoptosis, Cell Cycle Arrest at G2/M Phase, and Mitotic Catastrophe in Human Bladder Transitional Carcinoma Cells. J. Funct. Food 2015, 14, 384–394. [Google Scholar] [CrossRef]
  201. Singh, M.; Singh, R.; Bhui, K.; Tyagi, S.; Mahmood, Z.; Shukla, Y. Tea Polyphenols Induce Apoptosis through Mitochondrial Pathway and by Inhibiting Nuclear Factor-KappaB and Akt Activation in Human Cervical Cancer Cells. Oncol. Res. 2011, 19, 245–257. [Google Scholar] [CrossRef] [PubMed]
  202. Monasterio, A.; Urdaci, M.C.; Pinchuk, I.V.; López-Moratalla, N.; Martínez-Irujo, J.J. Flavonoids Induce Apoptosis in Human Leukemia U937 Cells through Caspase- and Caspase-Calpain-Dependent Pathways. Nutr. Cancer 2004, 50, 90–100. [Google Scholar] [CrossRef] [PubMed]
  203. Brusselmans, K.; Vrolix, R.; Verhoeven, G.; Swinnen, J.V. Induction of Cancer Cell Apoptosis by Flavonoids Is Associated with Their Ability to Inhibit Fatty Acid Synthase Activity. J. Biol. Chem. 2005, 280, 5636–5645. [Google Scholar] [CrossRef] [PubMed]
  204. Lee, S.H.; Yumnam, S.; Hong, G.E.; Raha, S.; Saralamma, V.V.G.; Lee, H.J.; Heo, J.D.; Lee, S.J.; Lee, W.-S.; Kim, E.-H.; et al. Flavonoids of Korean Citrus Aurantium L. Induce Apoptosis via Intrinsic Pathway in Human Hepatoblastoma HepG2 Cells. Phyther. Res. PTR 2015, 29, 1940–1949. [Google Scholar] [CrossRef] [PubMed]
  205. Castillo-Pichardo, L.; Dharmawardhane, S.F. Grape Polyphenols Inhibit Akt/Mammalian Target of Rapamycin Signaling and Potentiate the Effects of Gefitinib in Breast Cancer. Nutr. Cancer 2012, 64, 1058–1069. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  206. Sepporta, M.V.; Fuccelli, R.; Rosignoli, P.; Ricci, G.; Servili, M.; Morozzi, G.; Fabiani, R. Oleuropein Inhibits Tumour Growth and Metastases Dissemination in Ovariectomised Nude Mice with MCF-7 Human Breast Tumour Xenografts. J. Funct. Food 2014, 8, 269–273. [Google Scholar] [CrossRef]
  207. Rivera, A.R.; Castillo-Pichardo, L.; Gerena, Y.; Dharmawardhane, S. Anti-Breast Cancer Potential of Quercetin via the Akt/AMPK/Mammalian Target of Rapamycin (MTOR) Signaling Cascade. PLoS ONE 2016, 11, e0157251. [Google Scholar] [CrossRef] [PubMed]
  208. Xia, Y.; Shen, S.; Verma, I.M. NF-ΚB, an Active Player in Human Cancers. Cancer Immunol. Res. 2014, 2, 823–830. [Google Scholar] [CrossRef] [PubMed]
  209. Kim, J.-M.; Noh, E.-M.; Kwon, K.-B.; Kim, J.-S.; You, Y.-O.; Hwang, J.-K.; Hwang, B.-M.; Kim, B.-S.; Lee, S.-H.; Lee, S.J.; et al. Curcumin Suppresses the TPA-Induced Invasion through Inhibition of PKCα-Dependent MMP-Expression in MCF-7 Human Breast Cancer Cells. Phytomed. Int. J. Phyther. Phytopharm. 2012, 19, 1085–1092. [Google Scholar] [CrossRef] [PubMed]
  210. Sarkar, F.H.; Li, Y.; Wang, Z.; Kong, D. The Role of Nutraceuticals in the Regulation of Wnt and Hedgehog Signaling in Cancer. Cancer Metastasis Rev. 2010, 29, 383–394. [Google Scholar] [CrossRef] [PubMed]
  211. Aggarwal, B.B. Nuclear Factor-KappaB: The Enemy Within. Cancer Cell 2004, 6, 203–208. [Google Scholar] [CrossRef] [PubMed]
  212. Bachmeier, B.; Nerlich, A.G.; Iancu, C.M.; Cilli, M.; Schleicher, E.; Vené, R.; Dell’Eva, R.; Jochum, M.; Albini, A.; Pfeffer, U. The Chemopreventive Polyphenol Curcumin Prevents Hematogenous Breast Cancer Metastases in Immunodeficient Mice. Cell. Physiol. Biochem. 2007, 19, 137–152. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  213. Farhangi, B.; Alizadeh, A.M.; Khodayari, H.; Khodayari, S.; Dehghan, M.J.; Khori, V.; Heidarzadeh, A.; Khaniki, M.; Sadeghiezadeh, M.; Najafi, F. Protective Effects of Dendrosomal Curcumin on an Animal Metastatic Breast Tumor. Eur. J. Pharmacol. 2015, 758, 188–196. [Google Scholar] [CrossRef] [PubMed]
  214. Tsai, J.H.; Yang, J. Epithelial–Mesenchymal Plasticity in Carcinoma Metastasis. Gene Dev. 2013, 27, 2192–2206. [Google Scholar] [CrossRef] [PubMed]
  215. Kang, J.; Kim, E.; Kim, W.; Seong, K.M.; Youn, H.; Kim, J.W.; Kim, J.; Youn, B. Rhamnetin and Cirsiliol Induce Radiosensitization and Inhibition of Epithelial-Mesenchymal Transition (EMT) by MiR-34a-Mediated Suppression of Notch-1 Expression in Non-Small Cell Lung Cancer Cell Lines. J. Biol. Chem. 2013, 288, 27343–27357. [Google Scholar] [CrossRef] [PubMed]
  216. Lin, C.-H.; Shen, Y.-A.; Hung, P.-H.; Yu, Y.-B.; Chen, Y.-J. Epigallocathechin Gallate, Polyphenol Present in Green Tea, Inhibits Stem-like Characteristics and Epithelial-Mesenchymal Transition in Nasopharyngeal Cancer Cell Lines. BMC Complement. Altern. Med. 2012, 12, 201. [Google Scholar] [CrossRef] [PubMed]
  217. Lin, Y.-S.; Tsai, P.-H.; Kandaswami, C.C.; Cheng, C.-H.; Ke, F.-C.; Lee, P.-P.; Hwang, J.-J.; Lee, M.-T. Effects of Dietary Flavonoids, Luteolin, and Quercetin on the Reversal of Epithelial-Mesenchymal Transition in A431 Epidermal Cancer Cells. Cancer Sci. 2011, 102, 1829–1839. [Google Scholar] [CrossRef] [PubMed]
  218. Hara, Y. Tea Catechins and Their Applications as Supplements and Pharmaceutics. Pharmacol. Res. 2011, 64, 100–104. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Potential points of action of polyphenols within inflammatory cascade. NF-κ B: nuclear factor kappa-light-chain-enhancer of activated B cells; IKK: IkB-kinase; ERK: extracellular signal-related kinases; JNK: c-Jun amino-terminal kinases; p38 (or p38-MAPK): p38-mitogen-activated protein kinase; COX: cyclooxygenase; LOX: lipoxygenase; AA: arachidonic acid; PLA2: phospholipase A2; PGs: prostaglandins; LTs: leukotriens. For references see the text.
Figure 1. Potential points of action of polyphenols within inflammatory cascade. NF-κ B: nuclear factor kappa-light-chain-enhancer of activated B cells; IKK: IkB-kinase; ERK: extracellular signal-related kinases; JNK: c-Jun amino-terminal kinases; p38 (or p38-MAPK): p38-mitogen-activated protein kinase; COX: cyclooxygenase; LOX: lipoxygenase; AA: arachidonic acid; PLA2: phospholipase A2; PGs: prostaglandins; LTs: leukotriens. For references see the text.
Nutrients 10 01618 g001
Figure 2. Key polyphenolic anti-oxidant actions in relation to anti-inflammation. Polyphenols scavenge radicals, chelate metal ions, inhibit ROS production and promote ROS detoxification. On the right panel ROS contribution to inflammation. ROS: reactive oxygen species; RNS: reactive nitrogen species; NOX: NADPH oxidase; SOD: superoxide dismutase; GSH-PX: glutathione peroxidase; ERK: extra-cellular signal regulated kinases; PI3K/AkT: phosphatidylinositide 3-kinases/protein kinase B; EGCG: epigallactocatechine gallate.
Figure 2. Key polyphenolic anti-oxidant actions in relation to anti-inflammation. Polyphenols scavenge radicals, chelate metal ions, inhibit ROS production and promote ROS detoxification. On the right panel ROS contribution to inflammation. ROS: reactive oxygen species; RNS: reactive nitrogen species; NOX: NADPH oxidase; SOD: superoxide dismutase; GSH-PX: glutathione peroxidase; ERK: extra-cellular signal regulated kinases; PI3K/AkT: phosphatidylinositide 3-kinases/protein kinase B; EGCG: epigallactocatechine gallate.
Nutrients 10 01618 g002
Figure 3. Anti-tumorigenic activities of polyphenols. MAPK: mitogen-activated protein kinase; NFκB: nuclear factor kappa-light-chain-enhancer of activated B cells; PI3K: phosphatidylinositide 3-kinase; ERK: extracellular signal-related kinases; ROS: reactive oxygen species; COX: cyclooxygenase; EMT: epithelial mesenchymal transition; HIF-1α: hypoxia-inducible factor 1-aplha.
Figure 3. Anti-tumorigenic activities of polyphenols. MAPK: mitogen-activated protein kinase; NFκB: nuclear factor kappa-light-chain-enhancer of activated B cells; PI3K: phosphatidylinositide 3-kinase; ERK: extracellular signal-related kinases; ROS: reactive oxygen species; COX: cyclooxygenase; EMT: epithelial mesenchymal transition; HIF-1α: hypoxia-inducible factor 1-aplha.
Nutrients 10 01618 g003

Share and Cite

MDPI and ACS Style

Yahfoufi, N.; Alsadi, N.; Jambi, M.; Matar, C. The Immunomodulatory and Anti-Inflammatory Role of Polyphenols. Nutrients 2018, 10, 1618. https://doi.org/10.3390/nu10111618

AMA Style

Yahfoufi N, Alsadi N, Jambi M, Matar C. The Immunomodulatory and Anti-Inflammatory Role of Polyphenols. Nutrients. 2018; 10(11):1618. https://doi.org/10.3390/nu10111618

Chicago/Turabian Style

Yahfoufi, Nour, Nawal Alsadi, Majed Jambi, and Chantal Matar. 2018. "The Immunomodulatory and Anti-Inflammatory Role of Polyphenols" Nutrients 10, no. 11: 1618. https://doi.org/10.3390/nu10111618

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop