Advertisement

The Role of Flavonoids as Modulators of Inflammation and on Cell Signaling Pathways

  • Liliana V. Muschietti
  • Jerónimo L. Ulloa
  • Flavia DC. Redko
Chapter

Abstract

Flavonoids are naturally occurring polyphenolic compounds widely distributed in the plant kingdom. These compounds have long been recognized to possess a broad spectrum of biological activities, such as antioxidant, anti-inflammatory, hepatoprotector, antibacterial, antiviral, antidiabetic, antiproliferative and anticarcinogenic. Although they are not regarded as nutrients, they are important constituents of the human diet. Flavonoids are present in leafy vegetables, apples, onions, broccoli, berries, citrus fruits, grapes and soybeans, also in tea, chocolate and red wine. Many studies have demonstrated that a high intake of flavonoids is associated with a reduced risk of cardiovascular disease, cancer and neurodegenerative disorders. In recent years, there has been an increasing progress in the elucidation of the mechanisms through which flavonoids exert their biological activities. In addition to the already known free radical scavenging effect, flavonoids exert beneficial effects through the interaction with nuclear transcription factor kappa-B, activator protein 1, Janus kinases and phosphatidylinositol-3 kinase signaling pathways. This chapter focuses on recent findings on the role of flavonoids as modulators of inflammation and on cell signaling pathways.

Keywords

Flavonoids Inflammation Inflammatory mediators Signaling pathways 

Abbreviations

4′-HW

4′-hydroxywogonin

5B

(E)-3-(3,4-dimethoxyphenyl)-1-(5-hydroxy-2,2-dimethyl-2H-chromen-6-yl) prop-2-en-1-one

67LR

67-kDa laminin receptor

AA

Arachidonic acid

Afla

Amentoflavone

Akt

Protein kinase B

Alp

Alpinetin

Amp

Ampelopsin

AMPK

Adenosine monophosphate-activated protein kinase

AP-1

Activator protein-1

Api

Apigenin

Ast

Astragalin

BBB

Blood-brain barrier

BMDM

Bone marrow-derived macrophages

C3G

Cyanidin-3-O-glucoside

CAMs

Cell surface adhesion molecules

CAT

Catalase

Cat

Catechin

Chr

Chrysin

CNS

Central nervous system

COMT

Catechol-O-methyltransferase

COX

Cyclooxygenase

Dai

Daidzein

DMH

1,2-dimethyl hydrazine

DNA

Deoxyribonucleic acid

EGCG

Epigallocatechin-3-gallate

EGF

Epidermal growth factor

eNOS

Endothelial nitric oxide synthase

EpRE

Electrophile-responsive element

ERK

Extracellular signal-regulated kinases

Eup

Eupatilin

Fis

Fisetin

FlkA

Flavokawain A

Gen

Genisteína

GEN-27

5-hydroxy-7-[2-hydroxy-3-(piperidin-1-yl) propoxy]-3-{4-[2-hydroxy-3-(piperidin-1-yl) propoxy] phenyl}-4H-chromen-4-one

GPx

Glutathione peroxidase

HaCaT cells

Human keratinocytes

hAs

Human astrocytes

hBMEC

Injured human brain microvascular endothelial cell

HCT116

Human colon tumour

HGF

Human gingival fibroblasts

HIF-1α

Hypoxia-inducible factor 1-α

HMGB

High-mobility group box

HMGB1

High-mobility group box 1 protein

HO-1

Heme oxygenase-1

hPBMCs

Human peripheral blood mononuclear cells

HUVEC

Human umbilical vein endothelial cell

Ibc

Isobavachalcone

Ica

Icariin

ICAM

Intercellular adhesion molecule

ICT

3,5,7-trihydroxy-4′-methoxy-8-(3-hydroxy-3-methylbutyl)-flavone

IFN

Interferon

Ig

Immunoglobulin

IKK

IκB kinase

IL

Interleukin

iNOS

Inducible nitric oxide synthase

IRAK

IL-1 receptor-associated kinase

IκB

Inhibitor of kappa-B

JAK

Janus kinase

JNK

c-Jun N-terminal kinases

L2H17

1-(3,4-Dihydroxyphenyl)-3-(2-methoxyphenyl)prop-2-en-1-one

LicoC

Licochalcone C

LOX

Lypooxygenase

LPH

Lactase phlorizin hydrolase

LPS

Lipopolysaccharide

LT

Leukotriene

Lut

Luteolin

Mal

Malvidin

Mal3OG

Malvidin-3-O-glucoside

MALP-2

Macrophage-activating lipopeptide 2-kDa

MAPK

Mitogen-activated protein kinase

MCAO

Middle cerebral artery occlusion

MCP

Monocyte chemoattractant protein

MIP

Macrophage inflammatory protein

mMEC

Mouse mammary epithelial cell

MMP

Matrix metalloproteinase

MPO

Myeloperoxidase

mRNA

Messenger ribonucleic acid

Nag

Naringin

Nar

Naringenin

NF-κB

Nuclear factor kappa B

nNOS

Neuronal NOS

NO

Nitric oxide

NOS

Nitric oxide synthase

Nrf2

Nuclear factor-erythroid-related factor 2

NSAIDs

Non-steroidal anti-inflammatory drugs

Ono

Ononin

OroA

Oroxylin A

OVA

Ovalbumin

PAI-1

Plasminogen activator inhibitor 1

PCB

Polychlorinated biphenyl

PDGF

Platelet-derived growth factor

Pel

Pelargonidin

Peo

Peonidin

PG

Prostaglandin

Phl

Phloretin

PI3K

Phosphatidylinositol-3 kinase

Pin

Pinocembrin

PKC

Protein kinase C

poly[I:C]

Polyriboinosinic polyribocytidylic acid

PPAR

Peroxisome proliferator-activated receptor

Pru

Prunetin

Pue

Puerarin

Quer

Quercetin

RAGE

Receptor for advanced glycation end products

RANTES

Regulated upon activation normal T-cell expressed and secreted

ROS

Reactive oxygen species

Rut

Rutin

SG

Sophoraflavanone

SIRT

Sirtuin

SOCS

Suppressors of cytokine signaling

SOD

Superoxide dismutase

STATs

Signal transducer and activator of transcription

SULTs

Sulfotransferases

TACR-1

Tachykinin receptor 1

Tax

Taxifolin

TBARS

Thiobarbituric acid reactive substances

TGF

Tumour growth factor

TLR

Toll-like receptor

TNF-α

Tumour necrosis factor-α

Tollip

Toll-interacting protein

Tri

Tricin

TX

Thromboxane

UgoM

Ugonin M

UGTs

Uridine 5′-diphospho-glucuronosyltransferases

UV

Ultraviolet

VCAM

Vascular cell adhesion molecule

VEGF

Vascular endothelial growth factor

Vel

Velutin

Vix

Vitexin

Won

Wogonin

References

  1. Agati G, Azzarello E, Pollastri S et al (2012) Flavonoids as antioxidants in plants: location and functional significance. Plant Sci 196:67–76PubMedCrossRefPubMedCentralGoogle Scholar
  2. Bakhtiari M, Panahi Y, Ameli J et al (2017) Protective effects of flavonoids against Alzheimer’s disease-related neural dysfunctions. Biomed Pharmacother 93:218–229PubMedCrossRefPubMedCentralGoogle Scholar
  3. Bao S, Cao Y, Zhou H et al (2015) Epigallocatechin gallate (EGCG) suppresses lipopolysaccharide-induced toll-like receptor 4 (TLR4) activity via 67 kDa laminin receptor (67LR) in 3T3-L1 adipocytes. J Agric Food Chem 63:2811–2819PubMedCrossRefPubMedCentralGoogle Scholar
  4. Bertics PJ, Koziol-White CJ, Gavala MI et al (2014) Signal transduction. In: Adkinson NF Jr, Bochner BS, Burks AW, Busse WW, Holgate ST, Lemanske RF, O’Hehir RE (eds) Middleton’s allergy: principles and practice, 8th edn. Elsevier Saunders, Philadelphia, pp 184–202Google Scholar
  5. Bode AM, Dong Z (2013) Signal transduction and molecular targets of selected flavonoids. Antioxid Redox Signal 19(2):163–180PubMedCrossRefPubMedCentralGoogle Scholar
  6. Bognar E, Sarszegi Z, Szabo A et al (2013) Antioxidant and anti-inflammatory effects in RAW 264.7 macrophages of malvidin, a major red wine polyphenol. PLoS ONE 8(6):e65355PubMedCrossRefPubMedCentralGoogle Scholar
  7. Byun EB, Sung NY, Byun EH et al (2013) The procyanidin trimer C1 inhibits LPS-induced MAPK and NF-κB signaling through TLR4 in macrophages. Int Immunopharmacol 15(2):450–456PubMedCrossRefPubMedCentralGoogle Scholar
  8. Byun EB, SoYang M, Kim JH et al (2014) Epigallocatechin-3-gallate-mediated Tollip induction through the 67-kDa laminin receptor negatively regulating TLR4 signaling in endothelial cells. Immunobiology 219:866–872.  https://doi.org/10.1016/j.imbio.2014.07.010CrossRefPubMedPubMedCentralGoogle Scholar
  9. Cargnello M, Roux PP (2011) Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev 75(1):50–83PubMedCrossRefPubMedCentralGoogle Scholar
  10. Cassidy A, Rogers G, Peterson JJ et al (2015) Higher dietary anthocyanin and flavonol intakes are associated with anti-inflammatory effects in a population of US adults. Am J Clin Nutr 102(1):172–181PubMedCrossRefPubMedCentralGoogle Scholar
  11. Chen CC, Hung TH, Wang YH (2012) Wogonin improves histological and functional outcomes, and reduces activation of TLR4/NF-κB signaling after experimental traumatic brain injury. PLoS One 7(1):e30294PubMedCrossRefPubMedCentralGoogle Scholar
  12. Chen H, Mo X, Yu J et al (2013) Alpinetin attenuates inflammatory responses by interfering toll-like receptor 4/nuclear factor kappa B signaling pathway in lipopolysaccharide-induced mastitis in mice. Int Immunopharmacol 17(1):26–32PubMedCrossRefPubMedCentralGoogle Scholar
  13. Chen Z, Zheng S, Li L et al (2014) Metabolism of flavonoids in human: a comprehensive review. Curr Drug Metab 15:48–61PubMedCrossRefPubMedCentralGoogle Scholar
  14. Chen Y, Sun T, Wu J et al (2015) Icariin intervenes in cardiac inflammaging through upregulation of sirt6 enzyme activity and inhibition of the NF-kappa B pathway. Biomed Res Int 2015:1–12Google Scholar
  15. Chen L, Teng H, Jia Z et al (2017) Intracellular signaling pathways of inflammation modulated by dietary flavonoids: the most recent evidence. Crit Rev Food Sci Nutr 6:1–17Google Scholar
  16. Chtourou Y, Aouey B, Kebieche M et al (2015) Protective role of naringin against cisplatin induced oxidative stress, inflammatory response and apoptosis in rat striatum via suppressing ROS-mediated NF-κB and P53 signaling pathways. Chem Biol Interact 239:76–86PubMedCrossRefPubMedCentralGoogle Scholar
  17. Chuang JY, Chang PC, Shen YC et al (2014) Regulatory effects of fisetin on microglial activation. Molecules 19:8820–8839PubMedCrossRefPubMedCentralGoogle Scholar
  18. Cines DB, Pollak ES, Buck CA et al (1998) Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood 91(10):3527–3561PubMedPubMedCentralGoogle Scholar
  19. Commenges D, Scotet V, Renaud S et al (2000) Intake of flavonoids and risk of dementia. Eur J Epidemiol 16(4):357–363PubMedCrossRefPubMedCentralGoogle Scholar
  20. Cooper GM (2000) The cell: a molecular approach, 2nd edn. Sinauer Associates, SunderlandGoogle Scholar
  21. Day AJ, Canada FJ, Diaz JC et al (2000) Dietary flavonoid and isoflavone glycosides are hydrolysed by the lactase site of lactase phlorizin hydrolase. FEBS Lett 468(2–3):166–170PubMedCrossRefPubMedCentralGoogle Scholar
  22. Dong L, Yin L, Zhang Y et al (2017) Anti-inflammatory effects of ononin on lipopolysaccharide-stimulated RAW 264.7 cells. Mol Immunol 83:46–51PubMedCrossRefPubMedCentralGoogle Scholar
  23. Dower JI, Geleijnse JM, Gijsbers L et al (2015) Supplementation of the pure flavonoids epicatechin and quercetin affects some biomarkers of endothelial dysfunction and inflammation in (pre)hypertensive adults: a randomized double-blind, placebo-controlled, crossover trial. J Nutr 145(7):1459–1463PubMedCrossRefPubMedCentralGoogle Scholar
  24. During A, Larondelle Y (2013) The O-methylation of chrysin markedly improves its intestinal anti-inflammatory properties: structure-activity relationships of flavones. Biochem Pharmacol 86(12):1739–1746PubMedCrossRefPubMedCentralGoogle Scholar
  25. Fan C, Wu LH, Zhang GF et al (2017) 4′-Hydroxywogonin suppresses lipopolysaccharide-induced inflammatory responses in RAW 264.7 macrophages and acute lung injury mice. PLoS One 12(8):e0181191.  https://doi.org/10.1371/journal.pone.0181191CrossRefPubMedPubMedCentralGoogle Scholar
  26. Fang Q, Deng L, Wang L et al (2015a) Inhibition of mitogen-activated protein kinases/nuclear factor κB-dependent inflammation by a novel chalcone protects the kidney from high fat diet-induced injuries in mice. J Pharmacol Exp Ther 355:235–246PubMedCrossRefPubMedCentralGoogle Scholar
  27. Fang Q, Wang J, Wang L et al (2015b) Attenuation of inflammatory response by a novel chalcone protects kidney and heart from hyperglycemia-induced injuries in type 1 diabetic mice. Toxicol Appl Pharmacol 288:179–191PubMedCrossRefPubMedCentralGoogle Scholar
  28. Feghali CA, Wright TM (1997) Cytokines in acute and chronic inflammation. Front Biosci 2:12–26Google Scholar
  29. Ferrari D, Cimino F, Fratantonio D et al (2017) Cyanidin-3-O-glucoside modulates the in vitro inflammatory crosstalk between intestinal epithelial and endothelial cells. Mediat Inflamm 2017:3454023CrossRefGoogle Scholar
  30. Fink BN, Steck SE, Wolff MS et al (2007) Dietary flavonoid intake and breast cancer risk among women on Long Island. Am J Epidemiol 165(5):514–523CrossRefPubMedGoogle Scholar
  31. Firestein GS (2012) Mechanisms of inflammation and tissue repair. In: Goldman L, Schafer A (eds) Goldman’s Cecil medicine, vol 24. Elsevier Saunders, Philadelphia, pp 230–235CrossRefGoogle Scholar
  32. Formica JV, Regelson W (1995) Review of the biology of quercetin and related bioflavonoids. Food Chem Toxicol 33:1061–1080CrossRefPubMedGoogle Scholar
  33. Franceschelli S, Pesce M, Ferrone A et al (2017). Biological effect of licochalcone C on the regulation of PI3K/Akt/eNOS and NF-κB/iNOS/NO signaling pathways in H9c2 cells in response to LPS stimulation. Int J Mol Sci 18(4):pii:E690.PubMedCrossRefPubMedCentralGoogle Scholar
  34. Frankenfeld CL, Cerhan JR, Cozen W et al (2008) Dietary flavonoid intake and non-Hodgkin lymphoma risk. Am J Clin Nutr 87(5):1439–1445PubMedCrossRefPubMedCentralGoogle Scholar
  35. Fratantonio D, Speciale A, Ferrari D et al (2015) Palmitate-induced endothelial dysfunction is attenuated by cyanidin-3-O-glucoside through modulation of Nrf2/Bach1 and NF-κB pathways. Toxicol Lett 239:152–160CrossRefPubMedGoogle Scholar
  36. García-Lafuente A, Guillamón E, Villares A et al (2009) Flavonoids as anti-inflammatory agents: implications in cancer and cardiovascular disease. Inflamm Res 58(9):537–552CrossRefPubMedGoogle Scholar
  37. Gerd B, Leah BS, Paul SA et al (2008) Dietary flavonoids and colorectal adenoma recurrence in the polyp prevention trial. Cancer Epidemiol Biomark Prev 17(6):1344–1353CrossRefGoogle Scholar
  38. Gleichenhagen M, Schieber A (2016) Current challenges in polyphenol analytical chemistry. Curr Opin Food Sci 7:43–49CrossRefGoogle Scholar
  39. Gutiérrez-Venegas G, Contreras-Sánchez A, Ventura-Arroyo JA (2014) Anti-inflammatory activity of fisetin in human gingival fibroblasts treated with lipopolysaccharide. J Asian Nat Prod Res 16:1009–1017CrossRefPubMedGoogle Scholar
  40. Hämäläinen M, Nieminen R, Vuorela P et al (2007) Anti-inflammatory effects of flavonoids: genistein, kaempferol, quercetin, and daidzein inhibit STAT-1 and NF-kappa B activations, whereas flavone, isorhamnetin, naringenin, and pelargonidin inhibit only NF-kappa B activation along with their inhibitory effect on iNOS expression and NO production in activated macrophages. Mediat Inflamm 2007:45673CrossRefGoogle Scholar
  41. Hara H, Ikeda R, Ninomiya M et al (2014) Newly synthesized “Hidabeni” chalcone derivatives potently suppress LPS-induced NO production via inhibition of STAT1, but not NF-κB, JNK, and p38, pathways in microglia. Biol Pharm Bull 37:1042–1049PubMedCrossRefPubMedCentralGoogle Scholar
  42. Hassan S, Mathesius U (2012) The role of flavonoids in root-rhizosphere signaling: opportunities and challenges for improving plant-microbe interactions. J Exp Bot 63:3429–3444PubMedCrossRefPubMedCentralGoogle Scholar
  43. He Y, Hu Y, Jiang X et al (2017) Cyanidin-3-O-glucoside inhibits the UVB-induced ROS/COX-2 pathway in HaCaT cells. J Photochem Photobiol B 177:24–31PubMedCrossRefPubMedCentralGoogle Scholar
  44. Hollman PCH (2004) Absorption, bioavailability, and metabolism of flavonoids. Pharm Biol 42:74–83CrossRefGoogle Scholar
  45. Hu K, Yang Y, Tu Q et al (2013) Alpinetin inhibits LPS-induced inflammatory mediator response by activating PPAR-γ in THP-1-derived macrophages. Eur J Pharmacol 721(1–3):96–102PubMedCrossRefPubMedCentralGoogle Scholar
  46. Huang WC, Wu SJ, Tu RS et al (2015) Phloretin inhibits interleukin-1β-induced COX-2 and ICAM-1 expression through inhibition of MAPK, Akt, and NF-κB signaling in human lung epithelial cells. Food Funct 6:1960–1967PubMedCrossRefPubMedCentralGoogle Scholar
  47. Huo M, Chen N, Chi G (2012) Traditional medicine alpinetin inhibits the inflammatory response in Raw 264.7 cells and mouse models. Int Immunopharmacol 2(1):241–248CrossRefGoogle Scholar
  48. Hussein SSS, Kamarudin MNA, Kadir HA (2015) (+)-Catechin attenuates NF-κB activation through regulation of Akt, MAPK, and AMPK signaling pathways in LPS-induced BV-2 microglial cells. Am J Chin Med 43:927–952CrossRefGoogle Scholar
  49. Iiyama K, Hajra L, Iiyama M et al (1999) Patterns of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 expression in rabbit and mouse atherosclerotic lesions and at sites predisposed to lesion formation. Circ Res 85(2):199–207PubMedCrossRefPubMedCentralGoogle Scholar
  50. Jaeger BN, Parylak SL, Gage FH (2017) Mechanisms of dietary flavonoid action in neuronal function and neuroinflammation. Mol Asp Med S0098-2997(17):30111–30115Google Scholar
  51. Javadi F, Ahmadzadeh A, Eghtesadi S et al (2017) The effect of quercetin on inflammatory factors and clinical symptoms in women with rheumatoid arthritis: a double-blind, randomized controlled trial. J Am Coll Nutr 36(1):9–15PubMedCrossRefPubMedCentralGoogle Scholar
  52. Jia Z, Nallasamy P, Liu D et al (2015) Luteolin protects against vascular inflammation in mice and TNF-alpha-induced monocyte adhesion to endothelial cells via suppressing IKBα/NF-κB signaling pathway. J Nutr Biochem 26:293–302PubMedCrossRefPubMedCentralGoogle Scholar
  53. Jo IJ, Bae GS, Choi SB et al (2014) Fisetin attenuates cerulein-induced acute pancreatitis through down regulation of JNK and NF-κB signaling pathways. Eur J Pharmacol 737:149–158PubMedCrossRefPubMedCentralGoogle Scholar
  54. Johnson JL, de Mejia EG (2013) Flavonoid apigenin modified gene expression associated with inflammation and cancer and induced apoptosis in human pancreatic cancer cells through inhibition of GSK-3β/NF-κB signaling cascade. Mol Nutr Food Res 57:2112–2127PubMedCrossRefPubMedCentralGoogle Scholar
  55. Jung J, Ko SH, Yoo DY et al (2012) 5,7-Dihydroxy-3,4,6-trimethoxyflavone inhibits intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 via the Akt and nuclear factor-κB-dependent pathway, leading to suppression of adhesion of monocytes and eosinophils to bronchial epithelial cells. Immunology 137(1):98–113PubMedCrossRefPubMedCentralGoogle Scholar
  56. Kaminska B (2005) MAPK signalling pathways as molecular targets for anti-inflammatory therapy—from molecular mechanisms to therapeutic benefits. Biochim Biophys Acta 1754:253–262PubMedCrossRefPubMedCentralGoogle Scholar
  57. Kappelmann M, Bosserhoff A, Kuphal S (2014) AP-1/c-Jun transcription factors: regulation and function in malignant melanoma. Eur J Cell Biol 93(1–2):76–81PubMedCrossRefPubMedCentralGoogle Scholar
  58. Kim HP, Son KH, Chang HW et al (2004) Anti-inflammatory plant flavonoids and cellular action mechanisms. J Pharm Sci 96(3):229–245CrossRefGoogle Scholar
  59. Kim JH, Na HJ, Kim CK et al (2008) The non-provitamin A carotenoid, lutein, inhibits NF-κB-dependent gene expression through redox-based regulation of the phosphatidylinositol 3-kinase/PTEN/Akt and NF-κB-inducing kinase pathway: role of H2O2 in NF-κB activation. Free Radic Biol Med 45(6):885–896PubMedCrossRefPubMedCentralGoogle Scholar
  60. Kim DH, Yun CH, Kim MH et al (2012) 4′-Bromo-5,6,7-trimethoxyflavone represses lipopolysaccharide-induced iNOS and COX-2 expressions by suppressing the NF-kB signaling pathway in RAW 264.7 macrophages. Bioorg Med Chem Lett 22(1):70070–70075Google Scholar
  61. Knekt P, Jarvinen R, Reunanen A et al (1996) Flavonoid intake and coronary mortality in Finland: a cohort study. BMJ 312:478–481PubMedCrossRefPubMedCentralGoogle Scholar
  62. Kokkou E, Siasos G, Georgiopoulos G et al (2016) The impact of dietary flavonoid supplementation on smoking-induced inflammatory process and fibrinolytic impairment. Atherosclerosis 251:266–272PubMedCrossRefPubMedCentralGoogle Scholar
  63. Komatsu W, Itoh K, Akutsu S et al (2017) Nasunin inhibits the lipopolysaccharide-induced pro-inflammatory mediator production in RAW264 mouse macrophages by suppressing ROS-mediated activation of PI3 K/Akt/NF-κB and p38 signaling pathways. Biosci Biotechnol Biochem 81:1956–1966PubMedCrossRefPubMedCentralGoogle Scholar
  64. Kong L, Liu J, Wang J et al (2015) Icariin inhibits TNF-α/IFN-γ induced inflammatory response via inhibition of the substance P and p38-MAPK signaling pathway in human keratinocytes. Int Immunopharmacol 29:401–407PubMedCrossRefPubMedCentralGoogle Scholar
  65. Kretzmann NA, Fillmann H, Mauriz JL et al (2008) Effects of glutamine on pro-inflammatory gene expression and activation of nuclear factor kappa B and signal transducers and activators of transcription in TNBS-induced colitis. Inflamm Bowel Dis 14(11):1504–1513PubMedCrossRefPubMedCentralGoogle Scholar
  66. Kumar S, Pandey AK (2013) Chemistry and biological activities of flavonoids: an overview. Sci World J 2013:162750Google Scholar
  67. Kumar V, Abbas AK, Aster JC (2013) Inflammation and repair. In: Robbins basic pathology, 9th edn. Elsevier Saunders, Philadelphia, pp 29–73Google Scholar
  68. Kuriyama S, Shimazu T, Ohmori K et al (2006) Green tea consumption and mortality due to cardiovascular disease, cancer, and all causes in Japan: the Ohsaki study. JAMA 296(10):1255–1265PubMedCrossRefPubMedCentralGoogle Scholar
  69. Kwon DJ, Ju SM, Youn GS (2013) Suppression of iNOS and COX-2 expression by flavokawain A via blockade of NF-κB and AP-1 activation in RAW 264.7 macrophages. Food Chem Toxicol 58:479–486PubMedCrossRefPubMedCentralGoogle Scholar
  70. Lawrence T (2009) The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol 1(6):a001651PubMedCrossRefPubMedCentralGoogle Scholar
  71. Lee W, Ku SK, Bae JS (2013) Barrier protective effects of rutin in LPS-induced inflammation in vitro and in vivo. Food Chem Toxicol 50(9):3048–3055CrossRefGoogle Scholar
  72. Lee KM, Kim JM, Baik EJ et al (2015) Isobavachalcone attenuates lipopolysaccharide-induced ICAM-1 expression in brain endothelial cells through blockade of toll-like receptor 4 signaling pathways. Eur J Pharmacol 754:11–18PubMedCrossRefPubMedCentralGoogle Scholar
  73. Legeay S, Rodier M, Fillon L et al (2015) Epigallocatechin gallate: a review of its beneficial properties to prevent metabolic syndrome. Nutrients 7:5443–5468PubMedCrossRefPubMedCentralGoogle Scholar
  74. Letenneur L, Proust-Lima C, Le Gouge A et al (2007) Flavonoid intake and cognitive decline over a 10-year period. Am J Epidemiol 165(12):1364–1371PubMedCrossRefPubMedCentralGoogle Scholar
  75. Leyva-López N, Gutierrez-Grijalva EP, Ambriz-Perez DL et al (2016) Flavonoids as cytokine modulators: a possible therapy for inflammation-related diseases. Int J Mol Sci 17(6):921CrossRefPubMedCentralGoogle Scholar
  76. Li X, Peng F, Xie C et al (2013) (E)-3-(3,4-Dimethoxyphenyl)-1-(5-hydroxy-2,2-dimethyl-2H-chromen-6-yl)prop-2-en-1-one ameliorates the collagen-arthritis via blocking ERK/JNK and NF-κB signaling pathway. Int Immunopharmacol 17(4):1125–1133PubMedCrossRefPubMedCentralGoogle Scholar
  77. Li F, Wang W, Cao Y et al (2014a) Inhibitory effects of astragalin on lipopolysaccharide-induced inflammatory response in mouse mammary epithelial cells. J Surg Res 192:573–581PubMedCrossRefPubMedCentralGoogle Scholar
  78. Li J, Li J, Yue Y et al (2014b) Genistein suppresses tumor necrosis factor α-induced inflammation via modulating reactive oxygen species/Akt/nuclear factor κB and adenosine monophosphate-activated protein kinase signal pathways in human synoviocyte MH7A cells. Drug Des Devel Ther 8:315–323PubMedCrossRefPubMedCentralGoogle Scholar
  79. Li W, Sun YN, Yan XT et al (2014c) Anti-inflammatory and antioxidant activities of phenolic compounds from Desmodium caudatum leaves and stems. Arch Pharm Res 37:721–727PubMedCrossRefPubMedCentralGoogle Scholar
  80. Liu Q, Qian Y, Chen F et al (2014a) EGCG attenuates pro-inflammatory cytokines and chemokines production in LPS-stimulated L02 hepatocyte. Acta Biochim Biophys Sin Shanghai 46:31–39PubMedCrossRefPubMedCentralGoogle Scholar
  81. Liu R, Li J, Song J et al (2014b) Pinocembrin protects human brain microvascular endothelial cells against fibrillar amyloid-ß1 40 injury by suppressing the MAPK/NF-κB inflammatory pathways. Biomed Res Int 2014:1–14Google Scholar
  82. Liu B, Xu C, Wu X et al (2015) Icariin exerts an antidepressant effect in an unpredictable chronic mild stress model of depression in rats and is associated with the regulation of hippocampal neuroinflammation. Neuroscience 294:193–205PubMedCrossRefPubMedCentralGoogle Scholar
  83. Liu D, Perkins JT, Hennig B (2016) EGCG prevents PCB 126-induced endothelial cell inflammation via epigenetic modifications of NF-κB target genes in human endothelial cells. J Nutr Biochem 28:164–170PubMedCrossRefPubMedCentralGoogle Scholar
  84. Lu YC, Yeh WC, Ohashi PS (2008) LPS/TLR4 signal transduction pathway. Cytokine 42(2):145–151PubMedCrossRefPubMedCentralGoogle Scholar
  85. Ma MM, Li Y, Liu XY et al (2015) Cyanidin-3-O-Glucoside ameliorates lipopolysaccharide-induced injury both in vivo and in vitro suppression of NF-κB and MAPK pathways. Inflammation 38:1669–1682PubMedCrossRefPubMedCentralGoogle Scholar
  86. Mackert JD, McIntosh MK (2016) Combination of the anthocyanidins malvidin and peonidin attenuates lipopolysaccharide-mediated inflammatory gene expression in primary human adipocytes. Nutr Res 36(12):1353–1360.CrossRefPubMedGoogle Scholar
  87. Maher P (2015) How fisetin reduces the impact of age and disease on CNS function. Front Biosci (Schol Ed) 7:58–82CrossRefGoogle Scholar
  88. Malik S, Suchal K, Khan S et al (2017) Apigenin ameliorates streptozotocin-induced diabetic nephropathy in rats via MAPK-NF-κB-TNF-α and TGF-β1-MAPK-fibronectin pathways. Am J Physiol Renal Physiol 313(2):F414–F422PubMedCrossRefPubMedCentralGoogle Scholar
  89. Manigandan K, Manimaran D, Jayaraj RL et al (2015) Taxifolin curbs NF-κB-mediated Wnt/β-catenin signaling via up-regulating Nrf2 pathway in experimental colon carcinogenesis. Biochimie 119:103–112PubMedCrossRefPubMedCentralGoogle Scholar
  90. Manna K, Das U, Das D et al (2015) Naringin inhibits gamma radiation-induced oxidative DNA damage and inflammation, by modulating p53 and NF-κB signaling pathways in murine splenocytes. Free Radic Res 49:422–439PubMedCrossRefPubMedCentralGoogle Scholar
  91. Marín L, Miguélez EM, Villar CJ et al (2015). Bioavailability of dietary polyphenols and gut microbiota metabolism: antimicrobial properties. Biomed Res Int 2015:905215Google Scholar
  92. Middleton E, Kandaswami CH (1994) The impact of plant flavonoids on mammalian biology: implications for immunity, inflammation and cancer. In: Harbone JB (ed) The flavonoids. Advances in research since 1986. Chapman and Hall, London, p 619Google Scholar
  93. Min G, Ku SK, Park MS et al (2016) Anti-septic effects of pelargonidin in HMGB1-induced inflammatory responses in vitro and in vivo. Arch Pharm Res 39:1726–1738PubMedCrossRefPubMedCentralGoogle Scholar
  94. Nathan C (1992) Nitric oxide as a secretory product of mammalian cells. FASEB J 6(12):3051–3064PubMedCrossRefPubMedCentralGoogle Scholar
  95. Owuor ED, Kong AN (2002) Antioxidants and oxidants regulated signal transduction pathways. Biochem Pharmacol 64(5–6):765–770PubMedCrossRefPubMedCentralGoogle Scholar
  96. Paixão J, Dinis TC, Almeida LM (2012) Malvidin-3-glucoside protects endothelial cells up-regulating endothelial NO synthase and inhibiting peroxynitrite-induced NF-κB activation. Chem Biol Interact 199(3):192–200PubMedCrossRefPubMedCentralGoogle Scholar
  97. Pal HC, Athar M, Elmets CA et al (2015) Fisetin inhibits UVB-induced cutaneous inflammation and activation of PI3K/Akt/NF-κB signaling pathways in SKH-1 hairless mice. Photochem Photobiol 91:225–234PubMedCrossRefPubMedCentralGoogle Scholar
  98. Palmieri D, Perego P, Palombo D (2012) Apigenin inhibits the TNF-α-induced expression of eNOS and MMP-9 via modulating Akt signalling through oestrogen receptor engagement. Mol Cell Biochem 371(1–2):129–136PubMedCrossRefPubMedCentralGoogle Scholar
  99. Park SE, Sapkota K, Kim S et al (2011) Kaempferol acts through mitogen-activated protein kinases and protein kinase B/Akt to elicit protection in a model of neuroinflammation in BV2 microglial cells. Br J Pharmacol 164:1008–1025PubMedCrossRefPubMedCentralGoogle Scholar
  100. Pietta PG (1998) Natural-antioxidants in nutrition, health and disease. Paper presented at the 2nd international conference on natural antioxidants and anticarcinogens, Helsinki, 24–27 June 1998Google Scholar
  101. Pietta PG (2000) Flavonoids as antioxidants. J Nat Prod 63(7):1035–1042PubMedCrossRefPubMedCentralGoogle Scholar
  102. Pratheeshkumar P, Son YO, Divya SP et al (2014) Luteolin inhibits Cr(VI)-induced malignant cell transformation of human lung epithelial cells by targeting ROS mediated multiple cell signaling pathways. Toxicol Appl Pharmacol 281:230–241PubMedCrossRefPubMedCentralGoogle Scholar
  103. Pubchem (2017) Naringin – compound summary. https://pubchem.ncbi.nlm.nih.gov/compound/naringin#section=Top. Accessed 23 Nov 2017
  104. Qi S, Xin Y, Guo Y et al (2012) Ampelopsin reduces endotoxic inflammation via repressing ROS-mediated activation of PI3K/Akt/NF-κB signaling pathways. Int Immunopharmacol 12(1):278–287PubMedCrossRefPubMedCentralGoogle Scholar
  105. Qi Z, Xu Y, Liang Z et al (2015) Naringin ameliorates cognitive deficits via oxidative stress, proinflammatory factors and the PPAR-γ signaling pathway in a type 2 diabetic rat model. Mol Med Rep 12:7093–7101PubMedCrossRefPubMedCentralGoogle Scholar
  106. Rabinovich GA, Zwirner NW, Toscano MA (2011) Regulación de la expresión génica en el sistema inmunitario. In: Fainboim L, Geffner J (eds) Introducción a la inmunología humana, 6th edn. Editorial Médica Panamericana, Buenos Aires, pp 219–239Google Scholar
  107. Rangel-Huerta OD, Pastor-Villaescusa B, Aguilera CM et al (2015) A systematic review of the efficacy of bioactive compounds in cardiovascular disease: phenolic compounds. Nutrients 7(7):5177–5216PubMedCrossRefPubMedCentralGoogle Scholar
  108. Rani N, Bharti S, Bhatia J et al (2016) Chrysin, a PPAR-γ agonist improves myocardial injury in diabetic rats through inhibiting AGE-RAGE mediated oxidative stress and inflammation. Chem Biol Interact 250:59–67PubMedCrossRefPubMedCentralGoogle Scholar
  109. Ren X, Shi Y, Zhao D et al (2016) Naringin protects ultraviolet B-induced skin damage by regulating p38 MAPK signal pathway. J Dermatol Sci 82:106–114PubMedCrossRefPubMedCentralGoogle Scholar
  110. Ribeiro D, Freitas M, Lima JL et al (2015) Proinflammatory pathways: the modulation by flavonoids. Med Res Rev 35(5):877–936PubMedCrossRefPubMedCentralGoogle Scholar
  111. Rücker H, Al-Rifai N, Rascle A et al (2015) Enhancing the anti-inflammatory activity of chalcones by tuning the Michael acceptor site. Org Biomol Chem 13:3040–3047PubMedCrossRefPubMedCentralGoogle Scholar
  112. Sakamoto Y, Kanatsu J, Toh M et al (2016) The dietary isoflavone daidzein reduces expression of pro-inflammatory genes through PPARα/γ and JNK pathways in adipocyte and macrophage co-cultures. PLoS One 11(2):e0149676CrossRefGoogle Scholar
  113. Sakthivel KM, Guruvayoorappan C (2013) Amentoflavone inhibits iNOS, COX-2 expression and modulates cytokine profile, NF-κB signal transduction pathways in rats with ulcerative colitis. Int Immunopharmacol 17(3):907–916PubMedCrossRefPubMedCentralGoogle Scholar
  114. Santangelo C, Varì R, Scazzocchio B et al (2007) Polyphenols, intracellular signalling and inflammation. Ann Inst Super Sanita 43:394–405Google Scholar
  115. Serafini M, Peluso I, Raguzzini A (2010) Flavonoids as anti-inflammatory agents. Proc Nutr Soc 69(3):273–278PubMedCrossRefPubMedCentralGoogle Scholar
  116. Shalini V, Bhaskar S, Kumar KS et al (2012) Molecular mechanisms of anti-inflammatory action of the flavonoid, tricin from Njavara rice (Oryza sativa L.) in human peripheral blood mononuclear cells: possible role in the inflammatory signaling. Int Immunopharmacol 14(1):32–38PubMedCrossRefPubMedCentralGoogle Scholar
  117. Shaulian E, Karin M (2001) AP-1 in cell proliferation and survival. Oncogene 20(19):2390–2400PubMedCrossRefPubMedCentralGoogle Scholar
  118. Shin HJ, Shon DH, Youn HS (2013) Isobavachalcone suppresses expression of inducible nitric oxide synthase induced by Toll-like receptor agonists. Int Immunopharmacol 15(1):38–41PubMedCrossRefPubMedCentralGoogle Scholar
  119. Smith WL, Langenbach R (2001) Why there are two cyclooxygenase isozymes. J Clin Invest 107:1491–1495PubMedCrossRefPubMedCentralGoogle Scholar
  120. Song X, Chen Y, Sun Y et al (2012) Oroxylin A, a classical natural product, shows a novel inhibitory effect on angiogenesis induced by lipopolysaccharide. Pharmacol Rep 64(5):1189–1199PubMedCrossRefPubMedCentralGoogle Scholar
  121. Spencer JP (2010) The impact of fruit flavonoids on memory and cognition. Br J Nutr 104(3):S40–S47PubMedCrossRefPubMedCentralGoogle Scholar
  122. Spencer JPE, Schroeter H, Rechner AR et al (2001) Bioavailability of flavan-3-ols and procyanidins: gastrointestinal flavonoids tract influences and their relevance to bioactive forms in vivo. Antioxid Redox Signal 3:1023–1039PubMedCrossRefPubMedCentralGoogle Scholar
  123. Spencer JPE, Srai SK, Rice-Evans C (2003) Metabolism in the small intestine and gastrointestinal tract. In: Rice-Evans C, Packer L (eds) Flavonoids in health and disease. Marcel Dekker, New York, pp 363–390Google Scholar
  124. Spencer JP, Abd-el-Mohsen MM, Rice-Evans C (2004) Cellular uptake and metabolism of flavonoids and their metabolites: implications for their bioactivity. Arch Biochem Biophys 423:148–161PubMedCrossRefPubMedCentralGoogle Scholar
  125. Tang NP, Zhou B, Wang B et al (2009) Flavonoids intake and risk of lung Cancer: a meta-analysis. Jpn J Clin Oncol 39(6):352–359PubMedCrossRefPubMedCentralGoogle Scholar
  126. Tuñón MJ, García-Mediavilla MV, Sánchez-Campos S et al (2009) Potential of flavonoids as anti-inflammatory agents: modulation of pro-inflammatory gene expression and signal transduction pathways. Curr Drug Metab 10(3):256–271PubMedCrossRefPubMedCentralGoogle Scholar
  127. Vauzour D, Rodriguez-Mateos A, Corona G et al (2010) Polyphenols and human health: prevention of disease and mechanisms of action. Nutrients 2(11):1106–1131PubMedCrossRefPubMedCentralGoogle Scholar
  128. Wagner EF (2001) AP-1 – introductory remarks. Oncogene 20(19):2334–2335PubMedCrossRefPubMedCentralGoogle Scholar
  129. Wang L, Lee IM, Zhang SM et al (2009) Dietary intake of selected flavonols, flavones, and flavonoid-rich foods and risk of cancer in middle-aged and older women. Am J Clin Nutr 89(3):905–912PubMedCrossRefPubMedCentralGoogle Scholar
  130. Wang J, Zhang T, Ma C et al (2015a) Puerarin attenuates airway inflammation by regulation of eotaxin-3. Immunol Lett 163:173–178PubMedCrossRefPubMedCentralGoogle Scholar
  131. Wang Y, Wang B, Du F et al (2015b) Epigallocatechin-3-gallate attenuates oxidative stress and inflammation in obstructive nephropathy via NF-κB and Nrf2/HO-1 signalling pathway regulation. Basic Clin Pharmacol Toxicol 117:164–172PubMedCrossRefPubMedCentralGoogle Scholar
  132. Wang Y, Lu P, Zhang W et al (2016) GEN-27, a newly synthetic isoflavonoid, inhibits the proliferation of colon cancer cells in inflammation microenvironment by suppressing NF-κB pathway. Mediat Inflamm 2016:1–17Google Scholar
  133. Wang F, Yin J, Ma Y, Jiang H, Li Y (2017) Vitexin alleviates lipopolysaccharide‑induced islet cell injury by inhibiting HMGB1 release. Mol Med Rep 15(3):1079–1086.PubMedCrossRefPubMedCentralGoogle Scholar
  134. Wells TN, Power CA, Shaw JP et al (2006) Chemokine blockers-therapeutics in the making? Trends Pharmacol Sci 27:41–47PubMedCrossRefPubMedCentralGoogle Scholar
  135. Williams RJ, Spencer JP, Rice-Evans C (2004) Flavonoids: antioxidants or signalling molecules? Free Radic Biol Med 36(7):838–849PubMedCrossRefPubMedCentralGoogle Scholar
  136. Williamson G (2017) The role of polyphenols in modern nutrition. Nutr Bull 42(3):226–235PubMedCrossRefPubMedCentralGoogle Scholar
  137. Wu J, Zhou J, Chen X et al (2012) Attenuation of LPS-induced inflammation by ICT, a derivate of icariin, via inhibition of the CD14/TLR4 signaling pathway in human monocytes. Int Immunopharmacol 12(1):74–79PubMedCrossRefPubMedCentralGoogle Scholar
  138. Wu LH, Lin C, Lin HY et al (2016) Naringenin suppresses Neuroinflammatory responses through inducing suppressor of cytokine signaling 3 expression. Mol Neurobiol 53:1080–1091PubMedCrossRefPubMedCentralGoogle Scholar
  139. Wu KC, Huang SS, Kuo YH et al (2017) Ugonin M, a Helminthostachys zeylanica constituent, prevents LPS-induced acute lung injury through TLR4-mediated MAPK and NF-κB signaling pathways. Molecules22(4):pii:E573Google Scholar
  140. Wun ZY, Lin CF, Huang WC et al (2013) Anti-inflammatory effect of sophoraflavanone G isolated from Sophora flavescens in lipopolysaccharide-stimulated mouse macrophages. Food Chem Toxico 62:255–261CrossRefGoogle Scholar
  141. Xiao JB (2017) Dietary flavonoid aglycones and their glycosides: what show better biological benefits? Crit Rev Food Sci Nutr 57(9):1874–1905PubMedPubMedCentralGoogle Scholar
  142. Xiao J, Ho CT, Liong EC et al (2014) Epigallocatechin gallate attenuates fibrosis, oxidative stress, and inflammation in non-alcoholic fatty liver disease rat model through TGF/SMAD, PI3 K/Akt/FoxO1, and NF-κB pathways. Eur J Nutr 53:187–199PubMedCrossRefPubMedCentralGoogle Scholar
  143. Xie C, Kang J, Li Z et al (2012) The açaí flavonoid velutin is a potent anti-inflammatory agent: blockade of LPS-mediated TNF-α and IL-6 production through inhibiting NF-κB activation and MAPK pathway. J Nutr Biochem 23(9):1184–1191PubMedCrossRefPubMedCentralGoogle Scholar
  144. Xie H, Sun J, Chen Y et al (2015) Epigallocatechin-3-gallate attenuates uric acid-induced inflammatory responses and oxidative stress by modulating notch pathway. Oxidative Med Cell Longev 2015:1–10CrossRefGoogle Scholar
  145. Xu CQ, Liu BJ, Wu JF et al (2010) Icariin attenuates LPS-induced acute inflammatory responses: involvement of PI3 K/Akt and NF-κB signaling pathway. Eur J Pharmacol 642(1–3):146–153PubMedCrossRefPubMedCentralGoogle Scholar
  146. Yang G, Ham I, Choi HY (2013) Anti-inflammatory effect of prunetin via the suppression of NF-κB pathway. Food Chem Toxicol 58:124–132PubMedCrossRefPubMedCentralGoogle Scholar
  147. Yao Y, Chen L, Xiao J et al (2014) Chrysin protects against focal cerebral ischemia/reperfusion injury in mice through attenuation of oxidative stress and inflammation. Int J Mol Sci 15(11):20913–20926PubMedCrossRefPubMedCentralGoogle Scholar
  148. Yao J, Jiang M, Zhang Y et al (2016) Chrysin alleviates allergic inflammation and airway remodeling in a murine model of chronic asthma. Int Immunopharmacol 32:24–31PubMedCrossRefPubMedCentralGoogle Scholar
  149. Ye T, Zhen J, Du Y et al (2015) Green tea polyphenol (-)-epigallocatechin-3-gallate restores Nrf2 activity and ameliorates crescentic glomerulonephritis. PLoS One 10(2):e0119543PubMedCrossRefPubMedCentralGoogle Scholar
  150. Yoo H, Ku SK, Baek YD (2013) Anti-inflammatory effects of rutin on HMGB1-induced inflammatory responses in vitro and in vivo. Inflamm Res 63(3):197–206PubMedCrossRefPubMedCentralGoogle Scholar
  151. Yoo H, Ku SK, Han MS et al (2014) Anti-septic effects of fisetin in vitro and in vivo. Inflammation 37(5):1560–1574PubMedCrossRefPubMedCentralGoogle Scholar
  152. You OH, Shin EA, Lee H et al (2017) Apoptotic effect of astragalin in melanoma skin cancers via activation of caspases and inhibition of sry-related HMg-Box Gene 10. Phyther Res 31(10):1614–1620CrossRefGoogle Scholar
  153. Yu DH, Ma CH, Yue ZQ et al (2014) Protective effect of naringenin against lipopolysaccharide-induced injury in normal human bronchial epithelium via suppression of MAPK signaling. Inflammation 38(1):195–204CrossRefGoogle Scholar
  154. Zhang X, Liu T, Huang Y et al (2014) Icariin: does it have an osteoinductive potential for bone tissue engineering? Phyther Res 28(4):498–509CrossRefGoogle Scholar
  155. Zhang JX, Xing JG, Wang LL et al (2017) Luteolin inhibits fibrillary β-amyloid1-40-induced inflammation in a human blood-brain barrier model by suppressing the p38 MAPK-mediated NF-κB signaling pathways. Molecules 22(3):pii:E334PubMedCrossRefPubMedCentralGoogle Scholar
  156. Zhou X, Yuan L, Zhao X et al (2014) Genistein antagonizes inflammatory damage induced by β-amyloid peptide in microglia through TLR4 and NF-κB. Nutrition 30(1):90–95CrossRefPubMedGoogle Scholar
  157. Zhou CH, Wang CX, Xie G et al (2015a) Fisetin alleviates early brain injury following experimental subarachnoid hemorrhage in rats possibly by suppressing TLR 4/NF-κB signaling pathway. Brain Res 1629:250–259CrossRefPubMedGoogle Scholar
  158. Zhou LT, Wang KJ, Li L et al (2015b) Pinocembrin inhibits lipopolysaccharide-induced inflammatory mediators production in BV2 microglial cells through suppression of PI3K/Akt/NF-κB pathway. Eur J Pharmacol 761:211–216CrossRefPubMedGoogle Scholar
  159. Zurier RB (2013) Prostaglandins, leukotrienes, and related compounds. In: Firestein GS, Budd RC, Gabriel SE, McInnes IB, O’Dell JR (eds) Kelley’s textbook of rheumatology, 9th edn. Elsevier Saunders, Philadelphia, pp 340–357CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Liliana V. Muschietti
    • 1
    • 2
  • Jerónimo L. Ulloa
    • 1
    • 2
  • Flavia DC. Redko
    • 1
    • 2
  1. 1.Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica: Departamento de Farmacología/ Cátedra de FarmacognosiaBuenos AiresArgentina
  2. 2.Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto de Química y Metabolismo del Fármaco (IQUIMEFA), Facultad de Farmacia y BioquímicaBuenos AiresArgentina

Personalised recommendations