[Frontiers in Bioscience 17, 2396-2418, June 1, 2012]

The effects of dietary flavonoids on the regulation of redox inflammatory networks

Valerio Izzi1, Laura Masuelli2, Ilaria Tresoldi3, Pamela Sacchetti2, Andrea Modesti1, Fabio Galvano4, Roberto Bei1

1Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Rome, Italy, 2Department of Experimental Medicine, University of Rome Sapienza, Rome, Italy, 3Department of Public Health and Cell Biology, University of Rome Tor Vergata, Rome, Italy, 4Department of Drug Science, University of Catania, Catania, Italy

TABLES

Table 1. The role of ROS as second messengers: activation of signaling pathways and effects

Stimulus

ROS

Intracellular signaling

Effects

References

EGFR

H2O2

O2.-

Tyrosine phosphorylation, JNK activation, MAPKs activation, PLA2 activation

Cell growth

(39,40)

PDGF-R

H2O2

O2.-

MAPK activation, NOS expression, NF-kB signaling

Mitogenesis

(41,42)

FGF-2, IGF-1, HGF

H2O2

O2.-

c-fos activation, MAPK activation

Mitogenesis, differentiation, apoptosis

(43,44)

TNF-alpha

H2O2

O2.-

MAPK activation, NF-kB signaling

Mitogenesis, cell death, increase of MCP-1, M-CSF, IL-6

(43,45,46)

TNF-alpha +

IL-1/IFN-gamma

H2O2

O2.-

COX-2

Host defense

(47)

IL-1

H2O2

O2.-

MAPK activation, NF-kB signaling

Vascular injury, angiogenesis, activation of inflammation, pathogen killing, fever

(48-51)

IFN-gamma

H2O2

O2.-

COX-2

Pathogen killing, mucosal innate defense, LPO activation

(26)

TGF-beta

H2O2

O2.-

MAPK inhibition, NF-kB signaling perturbation

Immunosuppression, cell growth inhibition, apoptosis, respiratory burst depression, Treg and immature myeloid cells development

(52-59)

Serotonin

O2.-

ERK activation

Muscle cell mitogenesis

(60)

Bradykinin

H2O2

O2.-

COX-dependent and-independent mechanisms

Vascular functions damage

(61)

Thrombin

H2O2

O2.-

MAPKs activation, PLA2 activation

Cell growth

(62,63)

Endothelin

H2O2

O2.-

Ras activity modulation

Myocyte functions regulation

(64)

Abbreviations: EGFR: epidermal growth factor receptor; PDGF-R: platelet-derived growth factor receptor; JNK: c-Jun N-terminal kinases; PLA2: phospholipase A2; FGF-2: fibroblast growth factor-2; IGF-1: insulin growth factor-1; HGF: hepatocyte growth factor; TNF-alpha: tumor necrosis factor-alpha; IL-1: interleukin-1; IFN-gamma: interferon-gamma; TGF-beta: transforming growth factor-beta; COX-2: cyclooxygenase-2; MCP-1: monocyte chemotactic protein-1; M-CSF: macrophage colony-stimulating factor; IL-6: interleukin-6; Tregs: regulatory T-cells.

Table 2. Main classes, forms and sources of dietary flavonoids

Flavonoid class

Main form(s)

Glucide(s)

Main members

Dietary sources

References

Flavonols

Glycosides

Glucose, rhamnose, galactose, arabinose, xylose, glucuronic acid

Quercetin, kaempferol, myricetin

Fruits, plants, wine, tea

(76-79)

Flavones

Glycosides

Glucose, rhamnose, neohesperidose, glucuronic acid

Apigenin, luteolin, tangeretin, nobiletin, baicalein, wogonin, chrysin

Parsley, celery, onion, garlic, pepper, chamomile, bird chili

(76-78,80-82)

Flavan-3-ols

Aglycones

None

(+)-Catechin,

(-)-Epicatechin,

(+)-Gallocatechin,

(-)-Epigallocatechin,

(-)-Epicatechin-3-O-gallate,

(-)- Epigallocatechin-3-O-gallate,

Proanthocyanidins

Fruits, berries, cereals, nuts, chocolate, red wine, tea

(76,77,83,84)

Anthocyanins

Aglycones,

heterosides

Glucose, galactose, arabinose, rhamnose,

xylose

Cyanidin, pelargonidin, delphinidin, peodinin, petunidin, malvidin

Fruits, vegetables, red wine

(76-78,85)

Flavanones

Aglycones,

Monoglycosides,

diglycosides

Neohesperidose,

rhamnose, rutinose

Naringenin, hesperetin,

naringin, neohesperidin, narirutin, hesperidin

Oranges, grapefruit, tomatoes, lemons, mandarins

(76-78,86)

Isoflavones

Aglycones,

glycosides

Glucose

Daidzein, genistein,

glycitein, genistin,

daidzin

Leguminous plants

(76,87-89)

Table 3. Dietary flavonoids as ROS/RNS scavengers and inhibitors

Flavonoids

Target cells and body district

Action(s)

References

Red wine polyphenols

Oral cavity, intestine

Stable antioxidant complexes with microbial flora

(98)

Red wine polyphenols

Stomach

Scavenging of hydroperoxides and aldehydes

(98)

Resveratrol, quercetin, gallic acid, polyphenols

Blood

Synergy with plasmatic low molecular weight antioxidants, blood cells and albumin

(4)

Taxifolin, eriodictyol, hesperetin, luteolin

Activated neutrophils, macrophages

Inhibition of NADPHox, xanthine oxidase and myeloperoxidase

(99)

Quercetin, apigenin, daidzein, genistein, isorhamnetin, kaempferol, naringenin, pelargonidin, chrysin, luteolin

Activated macrophages,

RAW 264.7 cells

iNOS mRNA downregulation

(105,106,113,116)

Soy isoflavones, prenilated flavonoids, biflavonoids

LPS-stimulated macrophages

iNOS activity inhibition

(115)

Apigenin, luteolin, genistein, baicalin, catechin

Mast cells, eosinophils

5-LOX inhibition

(109-112)

Wogonin, genistein, kaempferol, apigenin, quercetin, naringenin, nobiletin, luteolin, EGCG

LPS-stimulated macrophages, fibroblasts, J774A.1, synovial fibroblasts, RAW 264.7 cells, chondrocytes

COX-2 mRNA downregulation

(105-108)

Wogonin, luteolin, galangin, morin

LPS-stimulated macrophages, fibroblasts

COX-2 activity inhibition

(100-104,110-112)

Abbreviations: iNOS: inducible nitric oxide synthase; LPS: lipopolysaccharide;

5-LOX: lipooxygenase-5; EGCG: epigallocatechin-3-gallate.

Table 4. Cytokines, chemokines and signaling pathways inhibition by flavonoids

Flavonoid

Cell type or animal model

Inhibited cytokines and chemokines

Inhibited signaling pathways

References

Flavone derivatives

RAW 264.7

TNF-alpha

AP-1,Nrf2

(121)

Fisetin

Basophils

Th-2 cytokines

AP-1

(122)

Luteolin

Basophils, RAW 264.7 cells

Th-2 cytokines

MAPK/NF-kB

(122,154)

Apigenin

Basophils, THP-1 cells, J774.2 macrophages, BV-2 microglia, head and neck carcinomas

Th-2 cytokines, MCP-1, MDC, CXCL10

IKK, p65, p38 MAPK, JNK, ERK

(119,122,131,134,137,155)

EGCG

Fibroblasts, epithelial cells, mast cells, chondrocytes, endothelial cells, MC3T3-E1 cells, primary osteoblasts, RAW 264.7 cells

IL-8, TNF-alpha, IL-6, IL-1beta, MCP-1

NF-kB-p65, IKK, IkB, NF- kB/DNA-binding, JNK, ERK, p38 MAPK

(123,123,125,131,140-143,154,155)

Quercetin

Mast cells, epithelial cells, HUVEC cells, Chang liver cells, RAW 264.7 cells, A549 cells, LPS-activated macrophages

TNF-alpha, IL-6,

IFN-gamma, IP-10,

MIP-2, VCAM-1, ICAM-1,

E-selectin

IkB, NF-kB/DNA-binding, p38 MAPK, ERK

(118,127,130,138,148-151)

Kaempferol

Mast cells, HUVEC cells,

Chang liver cells, THP-1 cells

TNF-alpha, IL-6,

IFN-gamma, VCAM-1, ICAM-1, E-selectin

IkB, NF-kB/DNA-binding inhibition,

MAPK

(118,127,148,152)

Anthocyanins

Murine asthma model, BV-2 cells

IL-13, IL-6, IL-13R2a, TNF-alpha

NF-kB

(128,145)

Isoflavones

Genistein

Daidzein

3T3-L1 adypocytes,

brain endothelial cells,

In vivo ischemia/reperfusion model

MCP-1

NF-kB

(133,146,147)

Naringenin

Murine asthma model

CCL5, CCL11

NF-kB

(129)

Proanthocyanidins

LPS-stimulated macrophages

COX-2

MAPK/NF-kB

(153)

Chrysin

Caco-2 cells

TNF-alpha, IL -1beta,

IL-4, IL-6

NF-kB

(139,140)

Abbreviations: AP-1: activating protein-1; nuclear factor-erythroid 2-related factor 2; MDC: macrophages-derived chemokine; CXCL10: CXC ligand 10; IP10: interferon-inducible protein 10; MIP-2: macrophage inducible protein-2; VCAM-1: vascular cell adhesion molecule 1; ICAM-1: Inter-Cellular Adhesion Molecule 1; CCL5: CC ligand 5; CCL11: CC ligand 11; IkB: inhibitor of kB; IKK: IkB kinase.

Table 5. Effects of flavonoids on inflammation: human studies and clinical trials

Reference or ClinicalTrial.gov identifier

Flavonoid(s) and dietary sources

Effects and Goals

Subjects

Hanninen et al (158)

Vegan diet

Decrease of joint stiffness and pain

Fibromyalgic and rheumatoid arthritis patients

Jenkins et al. (159)

Soy isoflavones

Increase of IL-6 serum concentrations

Hypercholesterolemic men and postmenopausal women

Phillips et al. (160)

Mixed tocopherols, flavonoids and docosahexaenoate

Decrease of IL-6 and CRP serum levels

Post eccentric exercise-fatigued untrained man

Song et al. (161)

Flavonoid-rich foods

No effects on IL-6 and CRP serum levels

Type-2 diabetes patients

Bogani et al. (162)

Extra vergine olive oil

Decrease of TXB2 and LTB4 levels

Normolipemic healthy subjects

Fanti et al. (163)

Soy isoflavones

Decrease of CRP levels

Haemodialysis patients

Ryan-Borchers et al. (164)

Soy isoflavones

No effects on IFN-gamma, IL-2, TNF-alpha and CRP plasma concentrations and urinary 8-isoprostane

Postmenopausal women

Greany et al. (165)

Soy isoflavones

No effects on CRP, E-selectin, VCAM-1 and ICAM-1 plasma levels

Postmenopausal women

Maskarinec et al. (166)

Soya foods

No effects on leptin, adiponectin, MCP-1, MIP-1alpha, IL-6 and CRP levels

Overweight men

Lyall et al. (167)

Blackcurrant supplementation

TNF-alpha and oxidant production decrease

Exercise-fatigued men

Nieman et al. (168)

Quercetin +/- EGCG +/- isoquercetin +/- eicosapentaenoic acid +/- Q-EGCG

Decrease of GM-CSF, CRP, IL-6 and IL-10 plasma levels

Trained cyclists

Monagas et al. (169)

Cocoa powder

Decrease of VLA-4, CD40 and CD36 in monocytes, decrease of P-selectin serum levels

Atherosclerosis high-risk patients

Heinz et al. (170)

Quercetin

No effects on natural killer cells activity, granulocyte oxidative burst and phagocytosis

Healthy women

Estruch et al. (173)

Red wine

Decreases of major adhesion molecules on monocytes and T-lymphocytes

Healthy men

Schoen et al. (174)

Polyphenol-rich food concentrate

Reduction of ICAM-1 and VCAM-1 blood levels

Healthy men

Zern et al. (175)

Grape polyphenol extract

Decrease of TNF-alpha and IL-6 plasma levels

Pre- and post-menopausal women

Holt et al. (176)

Fruit and vegetables, antioxidants, folate and total flavonoids

Decrease of CRP, TNF-alpha and IL-6 plasma levels and urinary F(2)-isoprostane

Healthy adolescent boys and girls

Karlsen et al. (177)

Blueberries-derived anthocyanin-rich extract

IL-4, IL-8, IL-13, RANTES and IFN-gamma

Healthy adults

NCT00677599

Flavonoid compounds from cocoa and soy

Reduction of cardiovascular disease risk

Type 2 diabetes

NCT01307917

500 mg of flavonoids capsule

Prevention of renal endothelial function

Type 1 or type 2 diabetes mellitus

NCT01003236

Silymarin

Renoprotection

Nephropathy

NCT01001845

Vitamin E + silymarin

Modulation of oxidative stress and inflammation

End-stage renal disease

NCT00331227

OPC-3

Endothelial functions, lipoproteins levels and inflammation

Healthy volunteers

NCT00740077

Phenolic acids and flavonoids

Flavonoid pharmacokinetics

Healthy volunteers

NCT01276951

Cocoa

Oxidative stress and inflammation

Essential arterial hypertension

NCT00559663

Green tea and 70% dark chocolate

Platelet activity, HDL, LDL and CRP levels

Healthy volunteers

NCT00302809

Concord grape juice

Blood pressure and vascular functions

Pre-hypertension and stage 1 hypertension

NCT00512967

Quercetin

Ex vivo LPS-induced cytokine production

Interstitial lung disease

NCT00402623

1000 mg quercetin

Modulation of oxidative stress and inflammation

Pulmonary sarcoidosis

NCT01038362

3 oz of almonds

Lipid profiles and blood markers of inflammation and oxidative stress

Coronary artery disease

NCT00554242

450 mg of grape seed extract + 1500 mg of vitamin C

Hemodynamic parameters and serum markers of inflammation

Coronary artery disease

NCT00538941

80 gr of commercially available dark chocolate

Platelet function, oxidative stress, CRP, 8-Isoprostanes and CD40 ligand levels

Heart failure

NCT01162174

100 or 200 mg Oligonol

Endothelial functions, platelet reactivity and circulating flavonoids

Healthy volunteers

NCT00914576

VITAMAC©

Oxidative stress, endothelial dysfunction and vascular reactivity

100% oxygen and E.Coli LPS-mediated hypoxia and inflammation