Advertisement

The Journal of Membrane Biology

, Volume 253, Issue 1, pp 57–71 | Cite as

The Interaction of Flavonols with Membrane Components: Potential Effect on Antioxidant Activity

  • Sarmistha SahaEmail author
  • Emiliano Panieri
  • Sibel Suzen
  • Luciano Saso
Article
  • 44 Downloads

Abstract

Flavonols are the most widely distributed class of dietary flavonoids with a wide range of pharmacological properties due to their potent lipid peroxidation inhibition activity. The permeability and orientation of these compounds in lipid bilayers can provide an understanding of their antioxidant and lipid-peroxidation inhibition activity based on their structures at the molecular level. For this purpose, we studied antioxidant activity and atomic-scale molecular dynamics simulations of 3-hydroxyflavone (fisetin), 5-hydroxyflavone (apigenin) and 3,5-hydroxyflavone (morin) in palmitoyloleylphosphatidylcholine (POPC) membrane models with 0 mol% and 40 mol% cholesterol concentration. In pure POPC bilayer with 0 mol% cholesterol concentration, the flavonols penetrated into bilayer with lowest free energy profiles, however, incorporation of 40% cholesterol concentration reduced the permeability of the flavonols. Higher cholesterol concentrations in the POPC lipid bilayer resulted in an increase of the bilayer thickness and corresponding decrease in the area per lipid which rationalizes the reduced partitioning of flavonols due to cholesterol. In the presence of cholesterol, the flavonols reside at the polar interfacial region of the lipid bilayer to form higher H-bonding interactions with cholesterol molecules in addition to water and lipid oxygens. Among all the selected flavonols, morin showed the highest affinity which was driven by the hydrophobic effect as also depicted by ITC (Isothermal titration calorimetry) experiments and thus, more efficient antioxidant in scavenging superoxide, nitric oxide radicals as well as lipid peroxyl radicals. Furthermore, our simulations also confirmed that the permeability of compounds is sensitive towards the cholesterol content in the membrane.

Graphic Abstract

Keywords

Flavonols POPC Cholesterol Lipid peroxidation Molecular dynamics simulations 

Notes

Acknowledgements

We sincerely thank Indian Institute of Technology Delhi HPC facility for computational resources.

Compliance with Ethical Standards

Conflict of interest

The authors state that there are no conflicts of interests.

Research Involving Human and Animal Participants

This article does not contain any studies with human or animal subjects.

Supplementary material

232_2019_105_MOESM1_ESM.jpg (85 kb)
Supplementary material 1 Planar chemical structures of the compounds: (A) fisetin, (B) apigenin and (C) morin. The 2-D chemical structures were obtained by ChemDraw 12.0 and the 3-D structures were obtained by the program PyMOL. (JPEG 85 kb)
232_2019_105_MOESM2_ESM.jpg (334 kb)
Supplementary material 2 Snapshots of MD simulations at 25 and 50 ns in the POPC lipid bilayer characteristic to the location (a, b) fisetin, (c, d) apigenin and (e, f) morin, respectively. (JPEG 333 kb)
232_2019_105_MOESM3_ESM.jpg (326 kb)
Supplementary material 3 Snapshots of MD simulations at 25 and 50 ns in the POPC lipid bilayer with 40% cholesterol characteristic to the location (a, b) fisetin, (c, d) apigenin and (e, f) morin, respectively.(JPEG 325 kb)

References

  1. Aguilera Y, Martin-Cabrejas MA, de Mejia EG (2016) Phenolic compounds in fruits and beverages consumed as part of the mediterranean diet: their role in prevention of chronic diseases. Phytochem Rev 15:405–423Google Scholar
  2. Ahmad A, Ali T, Park HY, Badshah H, Rehman SU, Kim MO (2017) Neuroprotective effect of Fisetin Against amyloid-beta induced cognitive/synaptic dysfunction, neuroinflammation, and neurodegeneration in adult mice. Mol Neurobiol 54:2269–2285PubMedGoogle Scholar
  3. Asgar A (2013) Anti-diabetic potential of phenolic compounds: a review. Int J Food Prop 16:91–103Google Scholar
  4. Banks JL, Beard HS, Cao Y, Cho AE, Damm W, Farid R, Felts AK, Halgren TA, Mainz DT, Maple JR, Murphy R, Philipp DM, Repasky MP, Zhang LY, Berne BJ, Friesner RA, Gallicchio E, Levy RM (2005) Integrated modeling program, applied chemical theory (IMPACT). J Comput Chem 26:1752PubMedPubMedCentralGoogle Scholar
  5. Budhraja A, Gao N, Zhang Z, Son Y, Cheng S, Wang X, Ding S, Hitron A, Chen G, Luo J, Shi X (2012) Apigenin induces apoptosis in human leukemia cells and exhibits anti-leukemic activity in vivo. Mol Cancer Ther 11:132–142PubMedGoogle Scholar
  6. D’Andrea G (2015) Quercetin: a flavonol with multifaceted therapeutic applications? Fitoterapia 106:256–271PubMedGoogle Scholar
  7. Davatgaran-Taghipour Y, Masoomzadeh S, Farzaei MH, Bahramsoltani R, Karimi-Soureh Z, Rahimi R, Abdollahi M (2017) Polyphenol nanoformulations for cancer therapy: experimental evidence and clinical perspective. Int J Nanomed 12:2689–2702Google Scholar
  8. De Young LR, Dill KA (1988) Aggregation and denaturation of apomyoglobin in aqueous urea solutions. Biochemistry 27:5281–5289PubMedGoogle Scholar
  9. Essmann U, Perera L, Berkowitz ML, Darden T, Lee H, Pedersen LG (1995) A smooth particle mesh Ewald method. J Chem Phys 103:8577–8593Google Scholar
  10. Evans DJ, Holian BL (1985) The Nose-Hoover thermostat. J Chem Phys 83:4069–4074Google Scholar
  11. Fu CY, Chen MC, Tseng YS, Chen MC, Zhou Z, Yang JJ, Lin YM, Viswanadha VP, Wang G, Huang CY (2019) Fisetin activates Hippo pathway and JNK/ERK/AP-1 signaling to inhibit proliferation and induce apoptosis of human osteosarcoma cells via ZAK overexpression. Environ Toxicol 34:902–911PubMedGoogle Scholar
  12. Gonçalves S, Romano A (2017) Inhibitory properties of phenolic compounds against enzymes linked with human diseases, Chapter 6. Phenolic compounds-biological activity. IntechOpen, LondonGoogle Scholar
  13. Gurer-Orhan H, Ince E, Konyar D, Saso L, Suzen S (2018) The role of oxidative stress modulators in breast cancer. Curr Med Chem 25:4084–4101PubMedGoogle Scholar
  14. 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 9:68–76PubMedGoogle Scholar
  15. Hanneken A, Lin FF, Johnson J, Maher P (2006) Flavonoids protect human retinal pigment epithelial cells from oxidative-stress-induced death. Invest Ophthalmol Vis Sci 47:3164–3177PubMedGoogle Scholar
  16. 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 111:1299–1306PubMedGoogle Scholar
  17. Ji Y, Jia L, Zhang Y, Xing Y, Wu X, Zhao B, Zhang D, Xu X, Qiao X (2018) Antitumor activity of the plant extract morin in tongue squamous cell carcinoma cells. Oncol Rep 40:3024–3032PubMedGoogle Scholar
  18. Karamia L, Jalili S (2014) Effects of cholesterol concentration on the interaction of cytarabine with lipid membranes: a molecular dynamics simulation study. J Biomol Struct Dyn 33:1254–1268Google Scholar
  19. Kashyap D, Sharma A, Sak K, Tuli HS, Buttar HS, Bishayee A (2018) Fisetin: a bioactive phytochemical with potential for cancer prevention and pharmacotherapy. Life Sci 194:75–87PubMedGoogle Scholar
  20. Kempuraj D, Madhappan B, Chirstodoulou S, Boucher W, Cao J, Papadopoulou N, Cetrulo CL, Theoharides TC (2005) Flavonoids inhibits pro-inflammatory mediator release, intracellular calcium ion levels, and protein kinase C theta phosphorylation in human mast cells. Br J Pharmacol 145:934–944PubMedPubMedCentralGoogle Scholar
  21. Kocábováa J, Kolivoškaa V, Gálb M, Sokolová R (2018) Tuning phospholipid bilayer permeability by flavonoid apigenin: electrochemical and atomic force microscopy study. J Electroanal Chem 221:67–72Google Scholar
  22. Kollman PA, Massova I, Reyes C, Kuhn B, Huo S, Chong L, Cheatham TE (2000) Calculating structures and free energies of complex molecules: combining molecular mechanics and continuum models. Acc Chem Res 33:889–897PubMedGoogle Scholar
  23. Krautler V, Gunsteren WFV, Hunenberger PH (2001) A fast SHAKE: algorithm to solve distance constraint equations for small molecules in molecular dynamics simulations. J Comp Chem 22:501–508Google Scholar
  24. Kumar S, Pandey AK (2013) Chemistry and biological activities of flavonoids: an overview. Sci World J.  https://doi.org/10.1155/2013/162750 CrossRefGoogle Scholar
  25. Liu FF, Dong XY, He L, Middelberg APJ, Sun Y (2011) Molecular insight into conformational transition of amyloid β-peptide 42 inhibited by (−)-epigallocatechin- 3-gallate probed by molecular simulations. J Phys Chem B 115:11879–11887PubMedGoogle Scholar
  26. Lopes D, Jakobtorweihen S, Nunes C, Sarmento B, Reis S (2017) Shedding light on the puzzle of drug-membrane interactions: experimental techniques and molecular dynamics simulations. Prog Lipid Res 65:24–44PubMedGoogle Scholar
  27. Lupanova T, Petkova D, Markovska T, Staneva G, Chakarov S, Skrobanska R, Pankov R, Momchilova A (2012) Effect of cholesterol modulation on the antioxidant potential of quercetin in rat liver plasma membranes. Compt Rend Acad Bulg Sci 65:639–644Google Scholar
  28. Maher P, Akaishi T, Abe K (2006) Flavonoid fisetin promotes ERK-dependent long-term potentiation and enhances memory. Proc Natl Acad Sci USA 103:16568–16573PubMedGoogle Scholar
  29. Mao Z, Gan C, Zhu J, Ma N, Wu L, Wang L, Wang X (2017) Anti-atherosclerotic activities of flavonoids from the flowers of Helichrysum arenarium L. MOENCH through the pathway of anti-inflammation. Bioorg Med Chem Lett 15:2812–2817Google Scholar
  30. Markovic Z, Milenkovic D, Dorovic J, Markovic JMD, Stepanic V, Lucic B, Amic D (2012) Free radical scavenging activity of morin 2′-O(-) phenoxide anion. Food Chem 135:2070–2077PubMedGoogle Scholar
  31. Martyna GJ (1994) Remarks on constant-temperature molecular dynamics with momentum conservation. Phys Rev E 50:3234–3236Google Scholar
  32. Morimoto Y, Baba T, Sasaki T, Hiramatsu K (2015) Apigenin as ananti-quinolone-resistance antibiotic. Int J Antimicrob Agents 46:666–673PubMedGoogle Scholar
  33. Neuvonen M, Manna M, Mokkila S, Javanainen M, Rog T, Liu Z, Bittman R, Vattulainen I, Ikonen E (2014) Enzymatic oxidation of cholesterol: properties and functional effects of cholestenone in cell membranes. PLoS ONE 9:e103743PubMedPubMedCentralGoogle Scholar
  34. Ola MS, Aleisa AM, Al-Rejaie SS, Abuohashish HM, Parmar MY, Alhomida AS, Ahmed MM (2014) Flavonoid, morin inhibits oxidative stress, inflammation and enhances neurotrophic support in the brain of streptozotocin-induced diabetic rats. Neurol Sci 35:1003–1008PubMedGoogle Scholar
  35. Ossman T, Fabre G, Trouillas P (2016) Interaction of wine anthocyanin derivatives with lipid bilayer membranes. Comput Theor Chem 1077:80–86Google Scholar
  36. Pal HC, Sharma S, Elmets CA, Athar M, Afaq F (2013) Fisetin inhibits growth, induces G(2)/M arrest and apoptosis of human epidermoid carcinoma A431 cells: role of mitochondrial membrane potential disruption and consequent caspases activation. Exp Dermatol 22:470–475PubMedPubMedCentralGoogle Scholar
  37. Panche AN, Diwan AD, Chandra SR (2016) Flavonoids: an overview. J Nutr Sci 5:e47PubMedPubMedCentralGoogle Scholar
  38. Pandit SA, Chiu SW, Jakobsson E, Grama A, Scott HL (2008) Cholesterol packing around lipids with saturated and unsaturated chains: a simulation study. Langmuir 24:6858–6865PubMedPubMedCentralGoogle Scholar
  39. Papahadjopoulos D, Nir S, Ohki S (1972) Permeability properties of phospholipid membranes: effect of cholesterol and temperature. Biochim Biophys Acta Biomemb 266:561–583Google Scholar
  40. Papay ZE, Kosa A, Boddi B, Merchant Z, Saleem IY, Zariwala MG, Klebovich I, Somavarapu S, Antal L (2017) Study on the pulmonary delivery system of apigenin-loaded albumin nanocarriers with antioxidant activity. J Aerosol Med Pulm Drug Deliv 30:274–288PubMedGoogle Scholar
  41. Park C, Lee WS, Go SI, Nagappan A, Han MH, Hong SH, Kim GS, Kim GY, Kwon TK, Ryu CH, Shin SC, Choi YH (2014) Morin, a flavonoid from moraceae, induces apoptosis by induction of BAD protein in human leukemic cells. Int J Mol Sci 16:645–659PubMedPubMedCentralGoogle Scholar
  42. Patil RH, Babu RL, Kumar MN, Kumar KMK, Hegde SM, Nagesh R, Ramesh GT, Sharma SC (2016) Anti-Inflammatory effect of Apigenin on LPS-induced pro-inflammatory mediators and AP-1 factors in human lung epithelial cells. Inflammation 39:138–147PubMedGoogle Scholar
  43. Peng HL, Huang WC, Cheng SC, Liou CJ (2018) Fisetin inhibits the generation of inflammatory mediators in interleukin-1β-induced human lung epithelial cells by suppressing the NF-κB and ERK1/2 pathways. Int Immunopharmacol 60:202–210PubMedGoogle Scholar
  44. Prasath GS, Subramanian SP (2013) Fisetin, a tetra hydroxy flavone recuperates antioxidant status and protects hepatocellular ultrastructure from hyperglycemia mediated oxidative stress in streptozotocin induced experimental diabetes in rats. Food Chem Toxicol 59:249–255PubMedGoogle Scholar
  45. Qu Y, Wang C, Liu N, Gao C, Liu F (2018) Morin exhibits anti-inflammatory effects on IL-1β stimulated human osteoarthritis chondrocytes by activating the Nrf2 signaling pathway. Cell Physiol Biochem 51:1830–1838PubMedGoogle Scholar
  46. Reiner GN, Fraceto LF, de Paula E, Perillo MA, Garcia DA (2013) Effects of Gabaergic phenols on phospholipid bilayers as evaluated by 1H-NMR. J Biomat Nanobiot 4:1–7Google Scholar
  47. Roìg T, Pasenkiewicz-Gierula M, Vattulainen I, Karttunen M (2009) Ordering effects of cholesterol and its analogues. Biochim Biophys Acta 1788:7–121Google Scholar
  48. Romano B, Pagano E, Montanaro V, Fortunato AL, Milic N, Borrelli F (2013) Novel insights into the pharmacology of flavonoids. Phytother Res 27:1588–1596PubMedGoogle Scholar
  49. Saija A, Scalese M, Lanza M, Marzullo D, Bonina F, Castelli F (1995) Flavonoids as antioxidant agents: importance of their interaction with biomembranes. Free Radic Biol Med 19:481–486PubMedGoogle Scholar
  50. Sanver D, Murray BS, Sadeghpour A, Rappolt M, Nelson AL (2016) Experimental modeling of flavonoid biomembrane interactions. Langmuir 13:13234–13243Google Scholar
  51. Selvakumar GP, Dhanraj V, Krishnamoorthy M, Tamilarasan M (2012) Morin attenuates haloperidol induced tardive dyskinesia and oxidative stress in mice. J Nat Sci Res 2:153–165Google Scholar
  52. Shinoda W (2016) Permeability across lipid membranes. Biochim et Biophys Acta Biomemb 1858:2254–2265Google Scholar
  53. Shukla S, Gupta S (2010) Apigenin: a promising molecule for cancer prevention. Pharm Res 27:962–978PubMedPubMedCentralGoogle Scholar
  54. Sinha K, Ghosh J, Sil PC (2016) Morin and its role in chronic diseases. Adv Exp Med Biol 928:453–471PubMedGoogle Scholar
  55. Sirk TW, Friedman M, Brown EF (2011) Molecular binding of black tea theaflavins to biological membranes: relationship to bioactivities. J Agric Food Chem 59:3780–3787PubMedGoogle Scholar
  56. Stach M, Maillard N, Kadam RU, Kalbermatter D, Meury M, Page MGP, Fotiadis D, Darbre T, Reymond J (2012) Membrane disrupting antimicrobial peptide dendrimers with multiple amino termini. Med Chem Commun 3:86–89Google Scholar
  57. Subczynski W, Wisniewska A, Yin J, Hyde J, Kusumi A (1994) Hydrophobic barriers of lipid bilayer membranes formed by reduction of water penetration by alkyl chain unsaturation and cholesterol. Biochem 33:7670–7681Google Scholar
  58. Sugihara N, Arakawa T, Ohnishi M, Furuno K (1999) Anti- and pro-oxidative effects of flavonoids on metal-induced lipid hydroperoxide-dependent lipid peroxidation in cultured hepatocytes loaded with alpha-linolenic acid. Free Radic Biol Med 27:1313–1323PubMedGoogle Scholar
  59. Sun X, Ma X, Li Q, Yang Y, Xu X, Sun J, Yu M, Cao K, Yang L, Yang G, Zhang G, Wang X (2018) Anti–cancer effects of fisetin on mammary carcinoma cells via regulation of the PI3K/Akt/mTOR pathway: in vitro and in vivo studies. Int J Mol Med 42:811–820PubMedPubMedCentralGoogle Scholar
  60. Syed DN, Afag 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 131:1291–1299PubMedPubMedCentralGoogle Scholar
  61. Ulmschneider JP, Ulmschneider MB (2018) Molecular dynamics simulations are redefining our view of peptides interacting with biological membranes. Acc Chem Res 51:1106–1116PubMedGoogle Scholar
  62. van Meer G, Voelker DR, Feigenson GW (2008) Membrane lipids: where they are and how they behave. Nat Rev 9:112–125Google Scholar
  63. Verstraeten SV, Fraga CG, Oteiza PI (2015) Interactions of flavan-3-ols and procyanidins with membranes: mechanisms and the physiological relevance. Food Funct 6:32–40PubMedGoogle Scholar
  64. Wennberg CL, van der Spoel D, Hub JS (2012) Large influence of cholesterol on solute partitioning into lipid membranes. J Am Chem Soc 134:5351–5361PubMedGoogle Scholar
  65. Xu Y, Wang RA (2006) computational analysis of the binding affinities of FKBP12 inhibitors using the MM-PB/SA method. Prot Struct Funct Bioinfo 64:1058–1068Google Scholar
  66. Yao D, Cui H, Zhou S, Guo L (2017) Morin inhibited lung cancer cells viability, growth, and migration by suppressing miR-135b and inducing its target CCNG2. Tumour Biol 39:1010428317712443PubMedGoogle Scholar
  67. Youns M, Abdel HHW (2017) The natural flavonoid fisetin inhibits cellular proliferation of hepatic, colorectal, and pancreatic cancer cells through modulation of multiple signaling pathways. PLoS ONE 12:e0169335PubMedPubMedCentralGoogle Scholar
  68. Zhang R, Kang KA, Kang SS, Park JW, Hyun JW (2011) Morin (2′,3,4′,5,7- pentahydroxyflavone) protected cells against c-radiation-induced oxidative stress. Basic Clin Pharmacol Toxicol 108:63–72PubMedGoogle Scholar
  69. Zhang H, Zheng W, Feng X, Yang F, Qin H, Wu S, Hou DX, Chen J (2019) Nrf2ARE signaling acts as master pathway for the cellular antioxidant activity of Fisetin. Molecules 24:E708PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2020

Authors and Affiliations

  1. 1.Materials Science and Engineering, Indian Institute of Technology GandhinagarPalaj, GandhinagarIndia
  2. 2.Department of Physiology and Pharmacology “Vittorio ErspamerSapienza University of RomeRomeItaly
  3. 3.Faculty of PharmacyAnkara UniversityAnkaraTurkey

Personalised recommendations