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Anti-inflammatory Nutraceuticals and Chronic Diseases pp 213–244Cite as

Fisetin and Its Role in Chronic Diseases

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Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 928))

Abstract

Chronic inflammation is a prolonged and dysregulated immune response leading to a wide variety of physiological and pathological conditions such as neurological abnormalities, cardiovascular diseases, diabetes, obesity, pulmonary diseases, immunological diseases, cancers, and other life-threatening conditions. Therefore, inhibition of persistent inflammation will reduce the risk of inflammation-associated chronic diseases. Inflammation-related chronic diseases require chronic treatment without side effects. Use of traditional medicines and restricted diet has been utilized by mankind for ages to prevent or treat several chronic diseases. Bioactive dietary agents or “Nutraceuticals” present in several fruits, vegetables, legumes, cereals, fibers, and certain spices have shown potential to inhibit or reverse the inflammatory responses and several chronic diseases related to chronic inflammation. Due to safe, nontoxic, and preventive benefits, the use of nutraceuticals as dietary supplements or functional foods has increased in the Western world. Fisetin (3,3′,4′,7-tetrahydroxyflavone) is a dietary flavonoid found in various fruits (strawberries, apples, mangoes, persimmons, kiwis, and grapes), vegetables (tomatoes, onions, and cucumbers), nuts, and wine that has shown strong anti-inflammatory, anti-oxidant, anti-tumorigenic, anti-invasive, anti-angiogenic, anti-diabetic, neuroprotective, and cardioprotective effects in cell culture and in animal models relevant to human diseases. In this chapter, we discuss the beneficial pharmacological effects of fisetin against different pathological conditions with special emphasis on diseases related to chronic inflammatory conditions.

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Abbreviations

AChE:

Acetylcholinesterase

CAT:

Catalase

COX:

Cyclooxygenase

EMT:

Epithelial-to-mesenchymal transition

EPCR:

Endothelial cell protein C receptor

ERK:

Extracellular signal-regulated kinase

GABAA :

Gamma-aminobutyric acid A

GLUT4:

Glucose transporter type 4

GR:

Glutathione reductase

GSH:

Glutathione

GSH-Px:

Glutathione peroxidase

GST:

Glutathione S-transferase

HDL:

High density lipoprotein

HMGB1:

High mobility group box 1

IL:

Interleukin

iNOS:

Inducible nitrogen oxide synthase

LDL:

Low-density lipoprotein

LOX:

Lipoxygenase

MAPKs:

Mitogen-activated protein kinases

MMP:

Matrix metalloproteinase

MPO:

Myeloperoxidase

mTOR:

Mammalian target of rapamycin

NFκB:

Nuclear factor-kappa B

NO:

Nitric oxide

Nrf2:

Nuclear factor erythroid-2-related factor 2

PECAM-1:

Platelet endothelial cell adhesion molecule 1

PGE2 :

Prostaglandin E2

PI3K:

Phosphatidylinositol 3-kinase

PPARγ:

Peroxisome proliferator-activated receptor gamma

SCD-1:

Stearoyl-CoA desaturase-1

SCEM:

Small Clot Embolism Model

SOD:

Superoxide dismutase

SREBP1C :

Sterol-regulatory-element-binding protein-1c

STAT:

Signal transducer and activator of transcription

TARC:

Thymus and activation regulated chemokine

TLR4:

Toll-like receptor 4

TSLP:

Thymic stromal lymphopoietin

VLDL:

Very-low-density lipoprotein

References

  1. Krishnamoorthy S, Honn KV (2006) Inflammation and disease progression. Cancer Metastasis Rev 25(3):481–491

    Article  PubMed  Google Scholar 

  2. Libby P (2007) Inflammatory mechanisms: the molecular basis of inflammation and disease. Nutr Rev 65(12 Pt 2):S140–S146

    Article  PubMed  Google Scholar 

  3. Aggarwal BB (2004) Nuclear factor-kappaB: the enemy within. Cancer Cell 6(3):203–208

    Article  CAS  PubMed  Google Scholar 

  4. Ahn KS, Aggarwal BB (2005) Transcription factor NF-kappaB: a sensor for smoke and stress signals. Ann N Y Acad Sci 1056:218–233

    Article  CAS  PubMed  Google Scholar 

  5. Tabas I, Glass CK (2013) Anti-inflammatory therapy in chronic disease: challenges and opportunities. Science 339(6116):166–172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lanza FL, Chan FK, Quigley EM (2009) Practice Parameters Committee of the American College of Gastroenterology. Guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol 104(3):728–738

    Article  PubMed  Google Scholar 

  7. Sinha M, Gautam L, Shukla PK, Kaur P, Sharma S, Singh TP (2013) Current perspectives in NSAID-induced gastropathy. Mediators Inflamm 2013:258209

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Prasad S, Aggarwal BB (2014) Chronic diseases caused by chronic inflammation require chronic treatment: anti-inflammatory role of dietary spices. J Clin Cell Immunol 5:4. doi:10.4172/2155-9899.1000238

    Article  CAS  Google Scholar 

  9. Brower V (1998) Nutraceuticals: poised for a healthy slice of the healthcare market? Nat Biotechnol 16(8):728–731

    Article  CAS  PubMed  Google Scholar 

  10. Cencic A, Chingwaru W (2010) The role of functional foods, nutraceuticals, and food supplements in intestinal health. Nutrients 2(6):611–625

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gupta SC, Kim JH, Prasad S, Aggarwal BB (2010) Regulation of survival, proliferation, invasion, angiogenesis, and metastasis of tumor cells through modulation of inflammatory pathways by nutraceuticals. Cancer Metastasis Rev 29(3):405–434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gupta SC, Tyagi AK, Deshmukh-Taskar P, Hinojosa M, Prasad S, Aggarwal BB (2014) Downregulation of tumor necrosis factor and other proinflammatory biomarkers by polyphenols. Arch Biochem Biophys 559:91–99

    Article  CAS  PubMed  Google Scholar 

  13. Arai Y, Watanabe S, Kimira M, Shimoi K, Mochizuki R, Kinae N (2000) Dietary intakes of flavonols, flavones and isoflavones by Japanese women and the inverse correlation between quercetin intake and plasma LDL cholesterol concentration. J Nutr 130(9):2243–2250

    CAS  PubMed  Google Scholar 

  14. Kimira M, Arai Y, Shimoi K, Watanabe S (1998) Japanese intake of flavonoids and isoflavonoids from foods. J Epidemiol 8(3):168–175

    Article  CAS  PubMed  Google Scholar 

  15. Jash SK, Mondal S (2014) Bioactive flavonoid fisetin—a molecule of pharmacological interest. J Org Biomol Chem 2:89–128. Article ID 010314, 40 pp. ISSN:2321- 4163 http://signpostejournals.com

  16. Khan N, Afaq F, Khusro FH, Mustafa Adhami V, Suh Y, Mukhtar H (2012) Dual inhibition of phosphatidylinositol 3-kinase/Akt and mammalian target of rapamycin signaling in human nonsmall cell lung cancer cells by a dietary flavonoid fisetin. Int J Cancer 130(7):1695–1705

    Article  CAS  PubMed  Google Scholar 

  17. Khan N, Afaq F, Mukhtar H (2008) Cancer chemoprevention through dietary antioxidants: progress and promise. Antioxid Redox Signal 10(3):475–510

    Article  CAS  PubMed  Google Scholar 

  18. Pal HC, Athar M, Elmets CA, Afaq F (2015) Fisetin inhibits UVB-induced cutaneous inflammation and activation of PI3 K/AKT/NFκB signaling pathways in SKH-1 hairless mice. Photochem Photobiol 91(1):225–234

    Article  CAS  PubMed  Google Scholar 

  19. Pal HC, Sharma S, Elmets CA, Athar M, Afaq F (2013) Fisetin inhibits growth, induces G2/M arrest and apoptosis of human epidermoid carcinoma A431 cells: role of mitochondrial membrane potential disruption and consequent caspases activation. Exp Dermatol 22(7):470–475

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Suh Y, Afaq F, Khan N, Johnson JJ, Khusro FH, Mukhtar H (2010) Fisetin induces autophagic cell death through suppression of mTOR signaling pathway in prostate cancer cells. Carcinogenesis 31(8):1424–1433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Syed DN, Afaq F, Maddodi N, Johnson JJ, Sarfaraz S, Ahmad A, Setaluri V, Mukhtar H (2011) Inhibition of human melanoma cell growth by the dietary flavonoid fisetin is associated with disruption of Wnt/β-catenin signaling and decreased Mitf levels. J Invest Dermatol 131(6):1291–1299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Pal HC, Baxter RD, Hunt KM, Agarwal J, Elmets CA, Athar M, Afaq F (2015) Fisetin, a phytochemical, potentiates sorafenib-induced apoptosis and abrogates tumor growth in athymic nude mice implanted with BRAF-mutated melanoma cells. Oncotarget. 6(29):28296–28311

    Article  PubMed  PubMed Central  Google Scholar 

  23. Pal HC, Diamond AC, Strickland LR, Kappes JC, Katiyar SK, Elmets CA, Athar M, Afaq F (2016) Fisetin, a dietary flavonoid, augments the anti-invasive and anti-metastatic potential of sorafenib in melanoma. Oncotarget. 7(2):1227–1241.

    Google Scholar 

  24. Pal HC, Sharma S, Strickland LR, Katiyar SK, Ballestas ME, Athar M, Elmets CA, Afaq F (2014) Fisetin inhibits human melanoma cell invasion through promotion of mesenchymal to epithelial transition and by targeting MAPK and NFκB signaling pathways. PLoS ONE 9(1):e86338

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Kim GD, Lee SE, Park YS, Shin DH, Park GG, Park CS (2014) Immunosuppressive effects of fisetin against dinitrofluorobenzene-induced atopic dermatitis-like symptoms in NC/Nga mice. Food Chem Toxicol 66:341–349

    Article  CAS  PubMed  Google Scholar 

  26. Kwak S, Ku SK, Bae JS (2014) Fisetin inhibits high-glucose-induced vascular inflammation in vitro and in vivo. Inflamm Res 63(9):779–787

    Article  CAS  PubMed  Google Scholar 

  27. Lee JD, Huh JE, Jeon G, Yang HR, Woo HS, Choi DY, Park DS (2009) Flavonol-rich RVHxR from Rhus verniciflua Stokes and its major compound fisetin inhibits inflammation-related cytokines and angiogenic factor in rheumatoid arthritic fibroblast-like synovial cells and in vivo models. Int Immunopharmacol 9(3):268–276

    Article  CAS  PubMed  Google Scholar 

  28. Park DK, Lee YG, Park HJ (2013) Extract of Rhus verniciflua bark suppresses 2,4-dinitrofluorobenzene-induced allergic contact dermatitis. Evid Based Complement Alternat 2013:879696

    Google Scholar 

  29. Park HH, Lee S, Oh JM, Lee MS, Yoon KH, Park BH, Kim JW, Song H, Kim SH (2007) Anti-inflammatory activity of fisetin in human mast cells (HMC-1). Pharmacol Res 55(1):31–37

    Article  CAS  PubMed  Google Scholar 

  30. Yoo H, Ku SK, Han MS, Kim KM, Bae JS (2014) Anti-septic effects of fisetin in vitro and in vivo. Inflammation. 37(5):1560–1574

    Article  CAS  PubMed  Google Scholar 

  31. Currais A, Prior M, Dargusch R, Armando A, Ehren J, Schubert D, Quehenberger O, Maher P (2014) Modulation of p25 and inflammatory pathways by fisetin maintains cognitive function in Alzheimer’s disease transgenic mice. Aging Cell 13(2):379–390

    Article  CAS  PubMed  Google Scholar 

  32. Maher P (2006) A comparison of the neurotrophic activities of the flavonoid fisetin and some of its derivatives. Free Radic Res 40(10):1105–1111

    Article  CAS  PubMed  Google Scholar 

  33. Maher P (2008) The flavonoid fisetin promotes nerve cell survival from trophic factor withdrawal by enhancement of proteasome activity. Arch Biochem Biophys 476(2):139–144

    Article  CAS  PubMed  Google Scholar 

  34. Maher P, Akaishi T, Abe K (2006) Flavonoid fisetin promotes ERK-dependent long-term potentiation and enhances memory. Proc Natl Acad Sci USA 103(44):16568–16573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Maher P, Dargusch R, Bodai L, Gerard PE, Purcell JM, Marsh JL (2011) ERK activation by the polyphenols fisetin and resveratrol provides neuroprotection in multiple models of Huntington’s disease. Hum Mol Genet 20(2):261–270

    Article  CAS  PubMed  Google Scholar 

  36. Maher P, Dargusch R, Ehren JL, Okada S, Sharma K, Schubert D (2011) Fisetin lowers methylglyoxal dependent protein glycation and limits the complications of diabetes. PLoS ONE 6(6):e21226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Renoudet VV, Costa-Mallen P, Hopkins E (2012) A diet low in animal fat and rich in N-hexacosanol and fisetin is effective in reducing symptoms of Parkinson’s disease. J Med Food 15(8):758–761

    Article  CAS  PubMed  Google Scholar 

  38. Krasieva TB, Ehren J, O’Sullivan T, Tromberg BJ, Maher P (2015) Cell and brain tissue imaging of the flavonoid fisetin using label-free two-photon microscopy. Neurochem Int 89:243–248

    Article  CAS  PubMed  Google Scholar 

  39. Gollapudi P, Hasegawa LS, Eastmond DA (2014) A comparative study of the aneugenic and polyploidy-inducing effects of fisetin and two model Aurora kinase inhibitors. Mutat Res, Genet Toxicol Environ Mutagen 767:37–43

    Article  CAS  Google Scholar 

  40. Lopez-Lazaro M, Willmore E, Austin CA (2010) The dietary flavonoids myricetin and fisetin act as dual inhibitors of DNA topoisomerases I and II in cells. Mutat Res 696(1):41–47

    Article  CAS  PubMed  Google Scholar 

  41. Olaharski AJ, Mondrala ST, Eastmond DA (2005) Chromosomal malsegregation and micronucleus induction in vitro by the DNA topoisomerase II inhibitor fisetin. Mutat Res 582(1–2):79–86

    Article  CAS  PubMed  Google Scholar 

  42. Salmela AL, Pouwels J, Varis A, Kukkonen AM, Toivonen P, Halonen PK, Perälä M, Kallioniemi O, Gorbsky GJ, Kallio MJ (2009) Dietary flavonoid fisetin induces a forced exit from mitosis by targeting the mitotic spindle checkpoint. Carcinogenesis 30(6):1032–1040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Sung B, Pandey MK, Aggarwal BB (2007) Fisetin, an inhibitor of cyclin-dependent kinase 6, down-regulates nuclear factor-kappaB-regulated cell proliferation, antiapoptotic and metastatic gene products through the suppression of TAK-1 and receptor-interacting protein-regulated IkappaBalpha kinase activation. Mol Pharmacol 71(6):1703–1714

    Article  CAS  PubMed  Google Scholar 

  44. Szliszka E, Helewski KJ, Mizgala E, Krol W (2011) The dietary flavonol fisetin enhances the apoptosis-inducing potential of TRAIL in prostate cancer cells. Int J Oncol 39(4):771–779

    CAS  PubMed  Google Scholar 

  45. Khan N, Asim M, Afaq F, Abu Zaid M, Mukhtar H (2008) A novel dietary flavonoid fisetin inhibits androgen receptor signaling and tumor growth in athymic nude mice. Cancer Res 68(20):8555–8563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Chien CS, Shen KH, Huang JS, Ko SC, Shih YW (2010) Antimetastatic potential of fisetin involves inactivation of the PI3 K/Akt and JNK signaling pathways with downregulation of MMP-2/9 expressions in prostate cancer PC-3 cells. Mol Cell Biochem 333(1–2):169–180

    Article  CAS  PubMed  Google Scholar 

  47. Chuang JY, Chang PC, Shen YC, Lin C, Tsai CF, Chen JH, Yeh WL, Wu LH, Lin HY, Liu YS, Lu DY (2014) Regulatory effects of fisetin on microglial activation. Molecules 19(7):8820–8839

    Article  PubMed  CAS  Google Scholar 

  48. Maher P (2009) Modulation of multiple pathways involved in the maintenance of neuronal function during aging by fisetin. Genes Nutr 4(4):297–307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Dajas F, Rivera F, Blasina F, Arredondo F, Echeverry C, Lafon L, Morquio A, Heinzen H (2003) Cell culture protection and in vivo neuroprotective capacity of flavonoids. Neurotox Res 5(6):425–432

    Article  PubMed  Google Scholar 

  50. Dajas F, Rivera-Megret F, Blasina F, Arredondo F, Abin-Carriquiry JA, Costa G, Echeverry C, Lafon L, Heizen H, Ferreira M, Morquio A (2003) Neuroprotection by flavonoids. Braz J Med Biol Res 36(12):1613–1620

    Article  CAS  PubMed  Google Scholar 

  51. Echeverry C, Arredondo F, Martínez M, Abin-Carriquiry JA, Midiwo J, Dajas F (2015) Antioxidant activity, cellular bioavailability, and iron and calcium management of neuroprotective and nonneuroprotective flavones. Neurotox Res 27(1):31–42

    Article  CAS  PubMed  Google Scholar 

  52. Ishige K, Schubert D, Sagara Y (2001) Flavonoids protect neuronal cells from oxidative stress by three distinct mechanisms. Free Radic Biol Med 30(4):433–446

    Article  CAS  PubMed  Google Scholar 

  53. Hendriks JJ, de Vries HE, van der Pol SM, van den Berg TK, van Tol EA, Dijkstra CD (2003) Flavonoids inhibit myelin phagocytosis by macrophages; a structure–activity relationship study. Biochem Pharmacol 65(5):877–885

    Article  CAS  PubMed  Google Scholar 

  54. Sagara Y, Vanhnasy J, Maher P (2004) Induction of PC12 cell differentiation by flavonoids is dependent upon extracellular signal-regulated kinase activation. J Neurochem 90(5):1144–1155

    Article  CAS  PubMed  Google Scholar 

  55. Maher P, Salgado KF, Zivin JA, Lapchak PA (2007) A novel approach to screening for new neuroprotective compounds for the treatment of stroke. Brain Res 1173:117–125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Rivera F, Urbanavicius J, Gervaz E, Morquio A, Dajas F (2004) Some aspects of the in vivo neuroprotective capacity of flavonoids: bioavailability and structure-activity relationship. Neurotox Res 6(7–8):543–553

    Article  PubMed  Google Scholar 

  57. Joseph JA, Shukitt-Hale B, Denisova NA, Bielinski D, Martin A, McEwen JJ, Bickford PC (1999) Reversals of age-related declines in neuronal signal transduction, cognitive, and motor behavioral deficits with blueberry, spinach, or strawberry dietary supplementation. J Neurosci 19(18):8114–8121

    CAS  PubMed  Google Scholar 

  58. Shukitt-Hale B, Carey AN, Jenkins D, Rabin BM, Joseph JA (2007) Beneficial effects of fruit extracts on neuronal function and behavior in a rodent model of accelerated aging. Neurobiol Aging 28(8):1187–1194

    Article  CAS  PubMed  Google Scholar 

  59. Zheng LT, Ock J, Kwon BM, Suk K (2008) Suppressive effects of flavonoid fisetin on lipopolysaccharide-induced microglial activation and neurotoxicity. Int Immunopharmacol 8(3):484–494

    Article  CAS  PubMed  Google Scholar 

  60. Tahanian E, Sanchez LA, Shiao TC, Roy R, Annabi B (2011) Flavonoids targeting of IκB phosphorylation abrogates carcinogen-induced MMP-9 and COX-2 expression in human brain endothelial cells. Drug Des Devel Ther 5:299–309

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Zhen L, Zhu J, Zhao X, Huang W, An Y, Li S, Du X, Lin M, Wang Q, Xu Y, Pan J (2012) The antidepressant-like effect of fisetin involves the serotonergic and noradrenergic system. Behav Brain Res 228(2):359–366

    Article  CAS  PubMed  Google Scholar 

  62. Inkielewicz-Stepniak I, Radomski MW, Wozniak M (2012) Fisetin prevents fluoride- and dexamethasone-induced oxidative damage in osteoblast and hippocampal cells. Food Chem Toxicol 50(3–4):583–589

    Article  CAS  PubMed  Google Scholar 

  63. Prakash D, Gopinath K, Sudhandiran G (2013) Fisetin enhances behavioral performances and attenuates reactive gliosis and inflammation during aluminum chloride-induced neurotoxicity. NeuroMol Med 15(1):192–208

    Article  CAS  Google Scholar 

  64. Cho N, Choi JH, Yang H, Jeong EJ, Lee KY, Kim YC, Sung SH (2012) Neuroprotective and anti-inflammatory effects of flavonoids isolated from Rhus verniciflua in neuronal HT22 and microglial BV2 cell lines. Food Chem Toxicol 50(6):1940–1945

    Article  CAS  PubMed  Google Scholar 

  65. Cho N, Lee KY, Huh J, Choi JH, Yang H, Jeong EJ, Kim HP, Sung SH (2013) Cognitive-enhancing effects of Rhus verniciflua bark extract and its active flavonoids with neuroprotective and anti-inflammatory activities. Food Chem Toxicol 58:355–361

    Article  CAS  PubMed  Google Scholar 

  66. Cho Y, Chung JH, Do HJ, Jeon HJ, Jin T, Shin MJ (2013) Effects of fisetin supplementation on hepatic lipogenesis and glucose metabolism in Sprague–Dawley rats fed on a high fat diet. Food Chem 139(1–4):720–727

    Article  CAS  PubMed  Google Scholar 

  67. Chen CM, Hsieh YH, Hwang JM, Jan HJ, Hsieh SC, Lin SH, Lai CY (2015) Fisetin suppresses ADAM9 expression and inhibits invasion of glioma cancer cells through increased phosphorylation of ERK1/2. Tumour Biol 36(5):3407–3415

    Article  CAS  PubMed  Google Scholar 

  68. Chen PY, Ho YR, Wu MJ, Huang SP, Chen PK, Tai MH, Ho CT, Yen JH (2015) Cytoprotective effects of fisetin against hypoxia-induced cell death in PC12 cells. Food Funct. 6(1):287–296

    Article  PubMed  CAS  Google Scholar 

  69. Prasath GS, Subramanian SP (2011) Modulatory effects of fisetin, a bioflavonoid, on hyperglycemia by attenuating the key enzymes of carbohydrate metabolism in hepatic and renal tissues in streptozotocin-induced diabetic rats. Eur J Pharmacol 668(3):492–496

    Article  CAS  PubMed  Google Scholar 

  70. Prasath GS, Subramanian SP (2014) Antihyperlipidemic effect of fisetin, a bioflavonoid of strawberries, studied in streptozotocin-induced diabetic rats. J Biochem Mol Toxicol 28(10):442–449

    Article  CAS  PubMed  Google Scholar 

  71. Kim HJ, Kim SH, Yun JM (2012) Fisetin inhibits hyperglycemia-induced proinflammatory cytokine production by epigenetic mechanisms. Evid Based Complement Alternat Med 2012:639469

    PubMed  PubMed Central  Google Scholar 

  72. Kan E, Kiliçkan E, Ayar A, Colak R (2014) Effects of two antioxidants; α-lipoic acid and fisetin against diabetic cataract in mice. Int Ophthalmol [Epub ahead of print] PubMed PMID: 25488016

    Google Scholar 

  73. Zhao X, Li XL, Liu X, Wang C, Zhou DS, Ma Q, Zhou WH, Hu ZY (2015) Antinociceptive effects of fisetin against diabetic neuropathic pain in mice: engagement of antioxidant mechanisms and spinal GABA(A) receptors. Pharmacol Res 102:286–297

    Article  CAS  PubMed  Google Scholar 

  74. Zhao X, Wang C, Cui WG, Ma Q, Zhou WH (2015) Fisetin exerts antihyperalgesic effect in a mouse model of neuropathic pain: engagement of spinal serotonergic system. Sci Rep 5:9043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Jung CH, Kim H, Ahn J, Jeon TI, Lee DH, Ha TY (2013) Fisetin regulates obesity by targeting mTORC1 signaling. J Nutr Biochem 24(8):1547–1554

    Article  CAS  PubMed  Google Scholar 

  76. Lee Y, Bae EJ (2013) Inhibition of mitotic clonal expansion mediates fisetin-exerted prevention of adipocyte differentiation in 3T3-L1 cells. Arch Pharm Res 36(11):1377–1384

    Article  CAS  PubMed  Google Scholar 

  77. Jin T, Kim OY, Shin MJ, Choi EY, Lee SS, Han YS, Chung JH (2014) Fisetin up-regulates the expression of adiponectin in 3T3-L1 adipocytes via the activation of silent mating type information regulation 2 homologue 1 (SIRT1)-deacetylase and peroxisome proliferator-activated receptors (PPARs). J Agric Food Chem 62(43):10468–10474

    Article  CAS  PubMed  Google Scholar 

  78. Kwon O, Eck P, Chen S, Corpe CP, Lee JH, Kruhlak M, Levine M (2007) Inhibition of the intestinal glucose transporter GLUT2 by flavonoids. FASEB J 21(2):366–377

    Article  CAS  PubMed  Google Scholar 

  79. Jeon TI, Park JW, Ahn J, Jung CH, Ha TY (2013) Fisetin protects against hepatosteatosis in mice by inhibiting miR-378. Mol Nutr Food Res 57(11):1931–1937

    Article  CAS  PubMed  Google Scholar 

  80. Lima LCF, Braga VA, do Socorro de França Silva M, Cruz JC, Sousa Santos SH, de Oliveira Monteiro MM, Balarini CM (2015) Adipokines, diabetes and atherosclerosis: an inflammatory association. Front Physiol 6:304

    Article  Google Scholar 

  81. Viola J, Soehnlein O (2015) Atherosclerosis—a matter of unresolved inflammation. Semin Immunol 27(3):184–193

    Article  CAS  PubMed  Google Scholar 

  82. Wong BW, Meredith A, Lin D, McManus BM (2012) The biological role of inflammation in atherosclerosis. Can J Cardiol 28(6):631–641

    Article  PubMed  Google Scholar 

  83. Chistiakov DA, Bobryshev YV, Orekhov AN (2015) Neutrophil’s weapons in atherosclerosis. Exp Mol Pathol 99(3):663–671

    Article  CAS  PubMed  Google Scholar 

  84. Pende A, Artom N, Bertolotto M, Montecucco F, Dallegri F (2015) Role of Neutrophils in atherogenesis: an update. Eur J Clin Invest [Epub ahead of print]. doi:10.1111/eci.12566

    Google Scholar 

  85. Back M, Hansson GK (2015) Anti-inflammatory therapies for atherosclerosis. Nat Rev Cardiol 12(4):199–211

    Article  PubMed  CAS  Google Scholar 

  86. Khan R, Spagnoli V, Tardif JC, L’Allier PL (2015) Novel anti-inflammatory therapies for the treatment of atherosclerosis. Atherosclerosis. 240(2):497–509

    Article  CAS  PubMed  Google Scholar 

  87. Yamashita T, Sasaki N, Kasahara K, Hirata K (2015) Anti-inflammatory and immune-modulatory therapies for preventing atherosclerotic cardiovascular disease. J Cardiol 66(1):1–8

    Article  PubMed  Google Scholar 

  88. de Whalley CV, Rankin SM, Hoult JR, Jessup W, Leake DS (1990) Flavonoids inhibit the oxidative modification of low density lipoproteins by macrophages. Biochem Pharmacol 39(11):1743–1750

    Article  PubMed  Google Scholar 

  89. Podrez EA (2010) Anti-oxidant properties of high-density lipoprotein and atherosclerosis. Clin Exp Pharmacol Physiol 37(7):719–725

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Lian TW, Wang L, Lo YH, Huang IJ, Wu MJ (2008) Fisetin, morin and myricetin attenuate CD36 expression and oxLDL uptake in U937-derived macrophages. Biochim Biophys Acta 1781(10):601–609

    Article  CAS  PubMed  Google Scholar 

  91. Podrez EA, Abu-Soud HM, Hazen SL (2000) Myeloperoxidase-generated oxidants and atherosclerosis. Free Radic Biol Med 28(12):1717–1725

    Article  CAS  PubMed  Google Scholar 

  92. Chiang HM, Chan SY, Chu Y, Wen KC (2015) Fisetin ameliorated photodamage by suppressing the mitogen-activated protein kinase/matrix metalloproteinase pathway and nuclear factor-κB pathways. J Agric Food Chem 63(18):4551–4560

    Article  CAS  PubMed  Google Scholar 

  93. Seo SH, Jeong GS (2015) Fisetin inhibits TNF-α-induced inflammatory action and hydrogen peroxide-induced oxidative damage in human keratinocyte HaCaT cells through PI3 K/AKT/Nrf-2-mediated heme oxygenase-1 expression. Int Immunopharmacol 29(2):246–253

    Article  CAS  PubMed  Google Scholar 

  94. Schadendorf D, Fisher DE, Garbe C, Gershenwald JE, Grob JJ, Halpern A, Herlyn M, Marchetti MA, McArthur G, Ribas A, Roesch A, Hauschild A (2015) Melanoma. Nature Reviews Disease Primers. Article number: 15003, Published online: 23 April 2015

    Google Scholar 

  95. Siegel RL, Miller KD, Jemal A (2015) Cancer statistics, 2015. CA Cancer J Clin 65(1):5–29

    Article  PubMed  Google Scholar 

  96. Melnikova V, Bar-Eli M (2007) Inflammation and melanoma growth and metastasis: the role of platelet-activating factor (PAF) and its receptor. Cancer Metastasis Rev 26(3–4):359–371

    Article  CAS  PubMed  Google Scholar 

  97. Melnikova VO, Bar-Eli M (2009) Inflammation and melanoma metastasis. Pigment Cell Melanoma Res. 22(3):257–267

    Article  CAS  PubMed  Google Scholar 

  98. Richmond A, Yang J, Su Y (2009) The good and the bad of chemokines/chemokine receptors in melanoma. Pigment Cell Melanoma Res 22(2):175–186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Dunn JH, Ellis LZ, Fujita M (2012) Inflammasomes as molecular mediators of inflammation and cancer: potential role in melanoma. Cancer Lett 314(1):24–33

    Article  CAS  PubMed  Google Scholar 

  100. Syed DN, Lall RK, Chamcheu JC, Haidar O, Mukhtar H (2014) Involvement of ER stress and activation of apoptotic pathways in fisetin induced cytotoxicity in human melanoma. Arch Biochem Biophys 563:108–117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Syed DN, Chamcheu JC, Khan MI, Sechi M, Lall RK, Adhami VM, Mukhtar H (2014) Fisetin inhibits human melanoma cell growth through direct binding to p70S6 K and mTOR: findings from 3-D melanoma skin equivalents and computational modeling. Biochem Pharmacol 89(3):349–360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65(2):87–108

    Article  PubMed  Google Scholar 

  103. Haddad AQ, Venkateswaran V, Viswanathan L, Teahan SJ, Fleshner NE, Klotz LH (2006) Novel antiproliferative flavonoids induce cell cycle arrest in human prostate cancer cell lines. Prostate Cancer Prostatic Dis 9(1):68–76

    Article  CAS  PubMed  Google Scholar 

  104. Khan N, Afaq F, Syed DN, Mukhtar H (2008) Fisetin, a novel dietary flavonoid, causes apoptosis and cell cycle arrest in human prostate cancer LNCaP cells. Carcinogenesis 29(5):1049–1056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Mukhtar E, Adhami VM, Sechi M, Mukhtar H (2015) Dietary flavonoid fisetin binds to β-tubulin and disrupts microtubule dynamics in prostate cancer cells. Cancer Lett 367(2):173–183

    Article  CAS  PubMed  Google Scholar 

  106. Khan MI, Adhami VM, Lall RK, Sechi M, Joshi DC, Haidar OM, Syed DN, Siddiqui IA, Chiu SY, Mukhtar H (2014) YB-1 expression promotes epithelial-to-mesenchymal transition in prostate cancer that is inhibited by a small molecule fisetin. Oncotarget. 5(9):2462–2474

    Article  PubMed  PubMed Central  Google Scholar 

  107. Lu X, Ji Jung, Cho HJ, Lim DY, Lee HS, Chun HS, Kwon DY, Park JH (2005) Fisetin inhibits the activities of cyclin-dependent kinases leading to cell cycle arrest in HT-29 human colon cancer cells. J Nutr 135(12):2884–2890

    CAS  PubMed  Google Scholar 

  108. do Lim Y, Park JH (2009) Induction of p53 contributes to apoptosis of HCT-116 human colon cancer cells induced by the dietary compound fisetin. Am J Physiol Gastrointest Liver Physiol 296(5):G1060–G1068

    Article  PubMed  CAS  Google Scholar 

  109. Suh Y, Afaq F, Johnson JJ, Mukhtar H (2009) A plant flavonoid fisetin induces apoptosis in colon cancer cells by inhibition of COX2 and Wnt/EGFR/NF-kappaB-signaling pathways. Carcinogenesis 30(2):300–307

    Article  CAS  PubMed  Google Scholar 

  110. Yu SH, Yang PM, Peng CW, Yu YC, Chiu SJ (2011) Securin depletion sensitizes human colon cancer cells to fisetin-induced apoptosis. Cancer Lett 300(1):96–104

    Article  CAS  PubMed  Google Scholar 

  111. Wu MS, Lien GS, Shen SC, Yang LY, Chen YC (2013) HSP90 inhibitors, geldanamycin and radicicol, enhance fisetin-induced cytotoxicity via induction of apoptosis in human colonic cancer cells. Evid Based Complement Alternat Med 2013:987612

    PubMed  PubMed Central  Google Scholar 

  112. Wu MS, Lien GS, Shen SC, Yang LY, Chen YC (2014) N-Acetyl-l-cysteine enhances fisetin-induced cytotoxicity via induction of ROS-independent apoptosis in human colonic cancer cells. Mol Carcinog 53(Suppl 1):E119–E129

    Article  CAS  PubMed  Google Scholar 

  113. Cho WC, Kwan CK, Yau S, So PP, Poon PC, Au JS (2011) The role of inflammation in the pathogenesis of lung cancer. Expert Opin Ther Targets 15(9):1127–1137

    Article  CAS  PubMed  Google Scholar 

  114. O’Callaghan DS, O’Donnell D, O’Connell F, O’Byrne KJ (2010) The role of inflammation in the pathogenesis of non-small cell lung cancer. J Thorac Oncol 5(12):2024–2036

    Article  PubMed  Google Scholar 

  115. Bremnes RM, Al-Shibli K, Donnem T, Sirera R, Al-Saad S, Andersen S, Stenvold H, Camps C, Busund LT (2011) The role of tumor-infiltrating immune cells and chronic inflammation at the tumor site on cancer development, progression, and prognosis: emphasis on non-small cell lung cancer. J Thorac Oncol 6(4):824–833

    Article  PubMed  Google Scholar 

  116. Gomes M, Teixeira AL, Coelho A, Araújo A, Medeiros R (2014) The role of inflammation in lung cancer. Adv Exp Med Biol 816:1–23

    Article  CAS  PubMed  Google Scholar 

  117. Liao YC, Shih YW, Chao CH, Lee XY, Chiang TA (2009) Involvement of the ERK signaling pathway in fisetin reduces invasion and migration in the human lung cancer cell line A549. J Agric Food Chem 57(19):8933–8941

    Article  CAS  PubMed  Google Scholar 

  118. Kang KA, Piao MJ, Hyun JW (2015) Fisetin induces apoptosis in human nonsmall lung cancer cells via a mitochondria-mediated pathway. Vitro Cell Dev Biol Anim 51(3):300–309

    Article  CAS  Google Scholar 

  119. Ravichandran N, Suresh G, Ramesh B, Siva GV (2011) Fisetin, a novel flavonol attenuates benzo(a)pyrene-induced lung carcinogenesis in Swiss albino mice. Food Chem Toxicol 49(5):1141–1147

    Article  CAS  PubMed  Google Scholar 

  120. Ravichandran N, Suresh G, Ramesh B, Manikandan R, Choi YW, Vijaiyan Siva G (2014) Fisetin modulates mitochondrial enzymes and apoptotic signals in benzo(a)pyrene-induced lung cancer. Mol Cell Biochem 390(1–2):225–234

    Article  CAS  PubMed  Google Scholar 

  121. Touil YS, Seguin J, Scherman D, Chabot GG (2011) Improved antiangiogenic and antitumour activity of the combination of the natural flavonoid fisetin and cyclophosphamide in Lewis lung carcinoma-bearing mice. Cancer Chemother Pharmacol 68(2):445–455

    Article  CAS  PubMed  Google Scholar 

  122. Goh FY, Upton N, Guan S, Cheng C, Shanmugam MK, Sethi G, Leung BP, Wong WS (2012) Fisetin, a bioactive flavonol, attenuates allergic airway inflammation through negative regulation of NF-κB. Eur J Pharmacol 679(1–3):109–116

    Article  CAS  PubMed  Google Scholar 

  123. Wu MY, Hung SK, Fu SL (2011) Immunosuppressive effects of fisetin in ovalbumin-induced asthma through inhibition of NF-κB activity. J Agric Food Chem 59(19):10496–10504

    Article  CAS  PubMed  Google Scholar 

  124. Feng G, Jiang ZY, Sun B, Fu J, Li TZ (2015) Fisetin alleviates lipopolysaccharide-induced acute lung injury via TLR4-Mediated NF-κB signaling pathway in rats. Inflammation [Epub ahead of print] PubMed PMID: 26272311

    Google Scholar 

  125. Higa S, Hirano T, Kotani M, Matsumoto M, Fujita A, Suemura M, Kawase I, Tanaka T (2003) Fisetin, a flavonol, inhibits TH2-type cytokine production by activated human basophils. J Allergy Clin Immunol 111(6):1299–1306

    Article  CAS  PubMed  Google Scholar 

  126. Hirano T, Higa S, Arimitsu J, Naka T, Shima Y, Ohshima S, Fujimoto M, Yamadori T, Kawase I, Tanaka T (2004) Flavonoids such as luteolin, fisetin and apigenin areinhibitors of interleukin-4 and interleukin-13 production by activated human basophils. Int Arch Allergy Immunol 134(2):135–140

    Article  CAS  PubMed  Google Scholar 

  127. Morimoto Y, Yasuhara T, Sugimoto A, Inoue A, Hide I, Akiyama M, Nakata Y (2003) Anti-allergic substances contained in the pollen of Cryptomeria japonica possess diverse effects on the degranulation of RBL-2H3 cells. J Pharmacol Sci 92(3):291–295

    Article  CAS  PubMed  Google Scholar 

  128. Park HH, Lee S, Son HY, Park SB, Kim MS, Choi EJ, Singh TS, Ha JH, Lee MG, Kim JE, Hyun MC, Kwon TK, Kim YH, Kim SH (2008) Flavonoids inhibit histamine release and expression of proinflammatory cytokines in mast cells. Arch Pharm Res. 31(10):1303–1311

    Article  CAS  PubMed  Google Scholar 

  129. Nagai K, Takahashi Y, Mikami I, Fukusima T, Oike H, Kobori M (2009) The hydroxyflavone, fisetin, suppresses mast cell activation induced by interaction with activated T cell membranes. Br J Pharmacol 158(3):907–919

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Kim JH, Kim MY, Kim JH, Cho JY (2015) Fisetin suppresses macrophage-mediated inflammatory responses by blockade of Src and Syk. Biomol Ther (Seoul) 23(5):414–420

    Google Scholar 

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Acknowledgments

The work highlighted from the author’s laboratory was supported by NIH Grant R21CA173043.

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Authors and Affiliations

  1. Department of Dermatology, University of Alabama at Birmingham, Volker Hall, Room 501, 1670 University Blvd., Birmingham, AL, 35294, USA

    Harish C. Pal, Ross L. Pearlman & Farrukh Afaq

  2. Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA

    Farrukh Afaq

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  1. Harish C. Pal
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  2. Ross L. Pearlman
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  3. Farrukh Afaq
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Correspondence to Farrukh Afaq .

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Editors and Affiliations

  1. Banaras Hindu University , Varanasi, Uttar Pradesh, India

    Subash Chandra Gupta

  2. MD Anderson Cancer Center, University of Texas, Houston, Texas, USA

    Sahdeo Prasad

  3. Anti-Inflammation Research Institute, San Diego, California, USA

    Bharat B. Aggarwal

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Pal, H.C., Pearlman, R.L., Afaq, F. (2016). Fisetin and Its Role in Chronic Diseases. In: Gupta, S., Prasad, S., Aggarwal, B. (eds) Anti-inflammatory Nutraceuticals and Chronic Diseases. Advances in Experimental Medicine and Biology, vol 928. Springer, Cham. https://doi.org/10.1007/978-3-319-41334-1_10

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