The Immunomodulatory and Anti-Inflammatory Role of Polyphenols

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.


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 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].
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.

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].
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-k B activation and TNF-α secretion [84]. Likewise, Genistein represses LPS-induced activation of NF-k B in monocytes and reduces the inflammation by inhibiting NF-k 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 Ik Bα and the translocation of p65 NF-k 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). 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 proinflammatory 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 NFĸ 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).

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

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.

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].

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 Fe 2+ , Cu 2+ , and free radicals which lead to a reduction of highly oxidizing free radicals [130]. inflammatory drug). Oleocanthal-like ibuprofen-inhibits COX-1 and COX-2 activities in a dosedependent manner [120].

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 Fe 2+ , Cu 2+ , and free radicals which lead to a reduction of highly oxidizing free radicals [130]. Transition metal ions, like Fe +2 , Cu 2+ , Co 2+ , Ti 3+ , or Cr 5+ , results in OH• formation from H2O2 [131,132]. Curcumin is able to chelate transition metal (Cu 2+ and Fe 2+ ) ions. Alike, EGCG and quercetin chelate Fe 2+ (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   [131,132]. Curcumin is able to chelate transition metal (Cu 2+ and Fe 2+ ) ions. Alike, EGCG and quercetin chelate Fe 2+ (iron ion) [128]. Polyphenols like apocynin, reservatol, and curcumin can inhibit NOX (NADPH oxidase) causing a reduction in the generation of O 2 • 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.

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.

Polyphenols and Insulin Resistance
Polyphenols reduce insulin resistance. They promote glycolysis by activation of AMPK (AMPactivated 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].

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].

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].

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].

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-kB) [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). 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 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.

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.  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.