Immunomodulatory; Anti-inflammatory/antioxidant Effects of Polyphenols: A Comparative Review on the Parental Compounds and Their Metabolites

Polyphenols are a big family of phytochemicals that includes a wide range of natural substances with various biological activities. Amongst these activities, the immunomodulatory property has significant importance due to the central and vital roles of the immune system in the human body. The biological activities of polyphenols depend crucially on the chemical structure and the biotransformation undergone in the body. The glycosylation state of polyphenols and its diversity have a significant impact on the immunomodulatory activity, while there is a lack of a comprehensive review paper in this concept. Hence, we aimed to review the body of literature to light the way for effective modulation of the immune system function using dietary polyphenols. However, due to the significant diversity in the structure and biotransformation of polyphenols, it is hard to draw a general pattern in this regard. The sugar moiety, type, position, and extent of glycosylation determine the antioxidant, anti-inflammatory, and generally the immunomodulatory activities of polyphenols. In conclusion, this study provides a new comparative approach regarding the immunomodulatory activities of polyphenols versus their metabolites. Moreover, we conclude that polyphenols can modulate the immune system, while each polyphenol has its structural relevance and should be assessed case by case.Abbreviations: BBC: brush border cell; GI: gastrointestinal tract; LPH: lactase-phlorizin hydrolase; CBG: cytosolic beta-glucosidase; CYP: cytochrome p450 enzymes; COMT: catechol-O-methyltransferases; SULT: sulphotransferases; UDPGT: uridine-5′-diphosphate glucuronosyl-transferases; ABC: ATP-binding cassette; ET: transporters, ellagitannin; EA: ellagic acid; EGCG: epigallocatechin-3- gallate; DC: dendritic cell; Th: T helper; NK: natural killer; Treg: cells, regulatory T cells; TGFβ: transforming growth factor β; Foxp3: forkhead box P3; T-bet: T-box transcription factor; RORγt: Retineic-acid-receptor-related orphan nuclear receptor gamma; STAT: Signal transducer and activator of transcription; AhR: aryl hydrocarbon receptor; XRE: xenobiotic-responsive elements; PWM: pokeweed mitogen; Igs: immunoglobulins; PGE2: prostaglandin E2; TNF-α: tumor necrosis factor α; COX-2: cyclooxygenase-2; iNOS: inducible nitric oxide synthase; LPS: lipopolysaccharide; ApoE: apolipoprotein E; NF-κB: nuclear factor kappa light chain enhancer of activated B cells; JNK: c-Jun N-terminal kinases; IκBα: IκB alpha; IKK: IκB kinase; hsCRP: high sensitivity C reactive protein; ICAM-1: Intracellular adhesion molecule-1; MCP-1: Monocyte chemoattractant protein-1; VCAM-1: vascular cellular adhesion molecule-1; M3Gal: myricetin 3-O-β-D-galactopyranoside; Q3Glc: quercetin 3-O-β-D-glucopyranoside; Q3Rut: quercetin 3-O-β-D-rutinoside; and Q3Gal: quercetin 3-O-β-D-galactopyranoside; ISR, 3-methyl metabolite of quercetin: isorhamnetin; TAM, 4ʹ-O-methyl quercetin: tamarixetin; ConA: Concanavalin A; ROS: Reactive oxygen species; ROS: Reactive oxygen species; THC: tetrahydrocurcumin; DHC: dihydrocurcumin; OHC: octahydrocurcumin; HHC: hexahydrocurcumin; NaC: sodium curcuminate; TEC: triethyl curcumin; DAC: diacetyl curcumin; HHC: hexahydrocurcumin; PLA2: phospholipase A2; TDM: trimethoxydibenzoylmethane; DBM: dibenzoylmethane; cPLA2: cytosolic phospholipase A2; 5-LOX: 5-lipoxygenase; IC50: half maximal inhibitory concentration; PI3K: phosphatidylinositol-3-Kinase; 12-HHT: 12(S)-hydroxy(5Z,8E,10E)-heptadecatrienoic acid; TXB2: thromboxane B2; 12-HETE: 12(S)-hydroxy-(5Z,8Z,10E,14Z)-eicosatetraenoic acid; MIP-1a: macrophage inflammatory protein-1a; DHG: dihydrogenistein; DHD: dihydrodaidzein; O-DMA: O-desmethylangolensin; MnSOD: manganese superoxide dismutase; DP: degree of polymerization; MMPs: matrix metalloproteinases; EC: epicatechin; EGC: epigallocatechin; C3G: cyanidin-3-glucoside; MAPK: mitogen-activated protein kinase; PI3K/PKB: phosphoinositide-3-kinase/protein kinase B; PA: protocatechuic acid; BR: black rice; HHDP: hexahydroxydiphenoyl; AP-1: activator protein 1; TSP: thrombospondin; eNOS: endothelial-nitric oxide synthase; Nrf2: nuclear factor erythroid 2–related factor 2; PAI-1: plasminogen activator inhibitor-1; C–C motif: chemokine; CCL2: ligand 2; miR-155: microRNA-155; M-CSF: macrophage colony-stimulating factor; BMDM: bone marrow-derived macrophage; ORAC: oxygen radical absorbance capacity; PCL: photochemiluminescence; FRAP: ferric reducing antioxidant power; ABTS: 2,2ʹ-azinobis (3-ethylbenzothiazoline-6-sulfonic acid); TEAC: trolox equivalent antioxidant capacity; DPPH: 2,2-diphenyl-1- picrylhydrazyl; ESR: electron spin resonance spectroscopy; CAA: cell-based antioxidant assay; NADPH: nicotinamide adenine dinucleotide phosphate; GST: oxidase, glutathione S-transferase; GPX: glutathione peroxidase; Fe-NTA: ferric nitrilotriacetate; AAPH: 2,2- azobis(2-amidinopropane) dihydrochloride; LP: lipid peroxidation; LOX: lipoxygenase; XO: xanthine oxidase; Q7GA: quercetin-7-O-glucuronide; Q3′GA: quercetin-3′-O-glucuronide; Q4′GA: quercetin-4′-O-glucuronide; Q3S: quercetin-3-O-sulfate; DOPAC: 3,4-dihydroxyphenylacetic acid; protocatechuic acid, PCA: 3,4-dihydroxybenzoic acid; 3-OPAC: 3-hydroxyphenyl acetic acid; CYP1A1: cytoprotective enzyme (cytochrome P450 1A1); HO-1: heme oxygenase 1; QR1: quinone reductase; 1GST: glutathione S-transferase; GCLC: glutamate-cysteine ligase catalytic subunit; 3ʹME7G: 3ʹ-O-methyl-(-)-epicatechin-7-O-glucuronide; E3ʹG: (-)-epicatechin-3ʹ-O-glucuronide; E7G: (-)-epicatechin-7-O-glucuronide; 4ʹME3ʹG: 4ʹ-O-methyl-(-)-epicatechin-3ʹ-O-glucuronide; COPD: chronic obstructive pulmonary disease; LDL: low-density lipoprotein; NBT: nitroblue tetrazolium; PAMPs: pathogen-associated molecular patterns; DAMPs: damage-associated molecular patterns; PRRs: pattern recognition receptors; TLR4: toll-like receptor 4; ERK: extracellular signal-regulated protein kinases; LT: leukotrienes; Pg-3-glc: pelargonidin-3-O-glucoside; PGA: phloroglucinaldehyde; 4-HBA: 4-hydroxybenzoic acid; HUVECs: human umbilical vein endothelial cells; APC: antigen-presenting cells; MHC: major histocompatibility complex; TCR: T cell receptor; PCA: passive cutaneous anaphylaxis; FcεRI: high affinity Immunoglobulin E receptor; EGCG4″Me: (-)-epigallocatechin-3-O-(4-O-methyl)gallate; EGCG3″Me: (-)-epigallocatechin-3-O-(3-O-methyl)gallate; 67LR: 67 kDa laminin receptor; MRLC: myosin II regulatory light chain; CGA: chlorogenic acid; IFN-c: interferon-c; NGC: naringenin chalcone.