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Blood–brain barrier transport and neuroprotective potential of blackberry-digested polyphenols: an in vitro study

Abstract

Purpose

Epidemiological and intervention studies have attempted to link the health effects of a diet rich in fruits and vegetables with the consumption of polyphenols and their impact in neurodegenerative diseases. Studies have shown that polyphenols can cross the intestinal barrier and reach concentrations in the bloodstream able to exert effects in vivo. However, the effective uptake of polyphenols into the brain is still regarded with some reservations. Here we describe a combination of approaches to examine the putative transport of blackberry-digested polyphenols (BDP) across the blood–brain barrier (BBB) and ultimate evaluation of their neuroprotective effects.

Methods

BDP was obtained by in vitro digestion of blackberry extract and BDP major aglycones (hBDP) were obtained by enzymatic hydrolysis. Chemical characterization and BBB transport of extracts were evaluated by LC–MSn. BBB transport and cytoprotection of both extracts was assessed in HBMEC monolayers. Neuroprotective potential of BDP was assessed in NT2-derived 3D co-cultures of neurons and astrocytes and in primary mouse cerebellar granule cells. BDP-modulated genes were evaluated by microarray analysis.

Results

Components from BDP and hBDP were shown to be transported across the BBB. Physiologically relevant concentrations of both extracts were cytoprotective at endothelial level and BDP was neuroprotective in primary neurons and in an advanced 3D cell model. The major canonical pathways involved in the neuroprotective effect of BDP were unveiled, including mTOR signaling and the unfolded protein response pathway. Genes such as ASNS and ATF5 emerged as novel BDP-modulated targets.

Conclusions

BBB transport of BDP and hBDP components reinforces the health benefits of a diet rich in polyphenols in neurodegenerative disorders. Our results suggest some novel pathways and genes that may be involved in the neuroprotective mechanism of the BDP polyphenol components.

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References

  1. 1.

    Williams RJ, Spencer JP (2011) Flavonoids, cognition, and dementia: actions, mechanisms, and potential therapeutic utility for Alzheimer disease. Free Radic Biol Med 52(1):35–45. https://doi.org/10.1016/j.freeradbiomed.2011.09.010

    Article  CAS  PubMed  Google Scholar 

  2. 2.

    Miller MG, Shukitt-Hale B (2012) Berry fruit enhances beneficial signaling in the brain. J Agric Food Chem 60(23):5709–5715. https://doi.org/10.1021/jf2036033

    Article  CAS  PubMed  Google Scholar 

  3. 3.

    Garcia G, Nanni S, Figueira I, Ivanov I, McDougall GJ, Stewart D, Ferreira RB, Pinto P, Silva RF, Brites D, Santos CN (2017) Bioaccessible (poly)phenol metabolites from raspberry protect neural cells from oxidative stress and attenuate microglia activation. Food Chem 215:274–283. https://doi.org/10.1016/j.foodchem.2016.07.128

    Article  CAS  PubMed  Google Scholar 

  4. 4.

    Shukitt-Hale B, Cheng V, Joseph JA (2009) Effects of blackberries on motor and cognitive function in aged rats. Nutr Neurosci 12(3):135–140. https://doi.org/10.1179/147683009X423292

    Article  CAS  PubMed  Google Scholar 

  5. 5.

    Ramassamy C (2006) Emerging role of polyphenolic compounds in the treatment of neurodegenerative diseases: a review of their intracellular targets. Eur J Pharmacol 545(1):51–64. https://doi.org/10.1016/j.ejphar.2006.06.025

    Article  CAS  PubMed  Google Scholar 

  6. 6.

    Virgili F, Marino M (2008) Regulation of cellular signals from nutritional molecules: a specific role for phytochemicals, beyond antioxidant activity. Free Radic Biol Med 45(9):1205–1216. https://doi.org/10.1016/j.freeradbiomed.2008.08.001

    Article  CAS  PubMed  Google Scholar 

  7. 7.

    Day AJ, Canada FJ, Diaz JC, Kroon PA, McLauchlan R, Faulds CB, Plumb GW, Morgan MR, Williamson G (2000) Dietary flavonoid and isoflavone glycosides are hydrolysed by the lactase site of lactase phlorizin hydrolase. FEBS Lett 468(2–3):166–170 doi:S0014-5793(00)01211-4

    Article  CAS  PubMed  Google Scholar 

  8. 8.

    Gee JM, DuPont MS, Day AJ, Plumb GW, Williamson G, Johnson IT (2000) Intestinal transport of quercetin glycosides in rats involves both deglycosylation and interaction with the hexose transport pathway. J Nutr 130(11):2765–2771

    Article  CAS  PubMed  Google Scholar 

  9. 9.

    Manach C, Scalbert A, Morand C, Remesy C, Jimenez L (2004) Polyphenols: food sources and bioavailability. Am J Clin Nutr 79(5):727–747

    Article  CAS  Google Scholar 

  10. 10.

    Williamson G, Clifford MN (2010) Colonic metabolites of berry polyphenols: the missing link to biological activity? Br J Nutr 104(Suppl 3):S48–S66. https://doi.org/10.1017/S0007114510003946

    Article  CAS  PubMed  Google Scholar 

  11. 11.

    Rangel-Ordonez L, Noldner M, Schubert-Zsilavecz M, Wurglics M (2010) Plasma levels and distribution of flavonoids in rat brain after single and repeated doses of standardized Ginkgo biloba extract EGb 761®. Planta Med 76(15):1683–1690. https://doi.org/10.1055/s-0030-1249962

    Article  CAS  PubMed  Google Scholar 

  12. 12.

    Ho L, Ferruzzi MG, Janle EM, Wang J, Gong B, Chen TY, Lobo J, Cooper B, Wu QL, Talcott ST, Percival SS, Simon JE, Pasinetti GM (2012) Identification of brain-targeted bioactive dietary quercetin-3-O-glucuronide as a novel intervention for Alzheimer’s disease. FASEB J 27(2):769–781. https://doi.org/10.1096/fj.12-212118

    Article  CAS  PubMed  Google Scholar 

  13. 13.

    Ishisaka A, Mukai R, Terao J, Shibata N, Kawai Y (2014) Specific localization of quercetin-3-O-glucuronide in human brain. Arch Biochem Biophys 557:11–17. https://doi.org/10.1016/j.abb.2014.05.025

    Article  CAS  PubMed  Google Scholar 

  14. 14.

    Gasperotti M, Passamonti S, Tramer F, Masuero D, Guella G, Mattivi F, Vrhovsek U (2015) Fate of microbial metabolites of dietary polyphenols in rats: is the brain their target destination? ACS Chem Neurosci 6(8):1341–1352. https://doi.org/10.1021/acschemneuro.5b00051

    Article  CAS  Google Scholar 

  15. 15.

    Fornasaro S, Ziberna L, Gasperotti M, Tramer F, Vrhovsek U, Mattivi F, Passamonti S (2016) Determination of cyanidin 3-glucoside in rat brain, liver and kidneys by UPLC/MS-MS and its application to a short-term pharmacokinetic study. Sci Rep 6:22815. https://doi.org/10.1038/srep22815

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    McDougall GJ, Fyffe S, Dobson P, Stewart D (2005) Anthocyanins from red wine—their stability under simulated gastrointestinal digestion. Phytochemistry 66(21):2540–2548. https://doi.org/10.1016/j.phytochem.2005.09.003

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    Tavares L, Figueira I, McDougall G, Vieira HA, Stewart D, Alves P, Ferreira R, Santos C (2013) Neuroprotective effects of digested polyphenols from wild blackberry species. Eur J Nutr 52(1):225–236. https://doi.org/10.1007/s00394-012-0307-7

    Article  CAS  PubMed  Google Scholar 

  18. 18.

    Macedo D, Tavares L, McDougall GJ, Vicente Miranda H, Stewart D, Ferreira RB, Tenreiro S, Outeiro TF, Santos CN (2015) Poly)phenols protect from alpha-synuclein toxicity by reducing oxidative stress and promoting autophagy. Hum Mol Genet 24(6):1717–1732. https://doi.org/10.1093/hmg/ddu585

    Article  CAS  PubMed  Google Scholar 

  19. 19.

    Pimpao RC, Dew T, Oliveira PB, Williamson G, Ferreira RB, Santos CN (2013) Analysis of phenolic compounds in Portuguese wild and commercial berries after multienzyme hydrolysis. J Agric Food Chem 61(17):4053–4062. https://doi.org/10.1021/jf305498j

    Article  CAS  PubMed  Google Scholar 

  20. 20.

    Tavares L, Carrilho D, Tyagi M, Barata D, Serra AT, Duarte CM, Duarte RO, Feliciano RP, Bronze MR, Chicau P, Espirito-Santo MD, Ferreira RB, dos Santos CN (2010) Antioxidant capacity of Macaronesian traditional medicinal plants. Molecules 15(4):2576–2592. https://doi.org/10.3390/molecules15042576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Stins MF, Badger J, Sik Kim K (2001) Bacterial invasion and transcytosis in transfected human brain microvascular endothelial cells. Microb Pathog 30(1):19–28. https://doi.org/10.1006/mpat.2000.0406

    Article  CAS  PubMed  Google Scholar 

  22. 22.

    Palmela I, Sasaki H, Cardoso FL, Kim KS, Brites D, Brito MA (2012) Time-dependent dual effects of high levels of unconjugated bilirubin on the human blood–brain barrier lining. Front Cell Neurosci 6. https://doi.org/10.3389/fncel.2012.00022

  23. 23.

    Tavares L, Figueira I, Macedo D, McDougall GJ, Leitão MC, Vieira HLA, Stewart D, Alves PM, Ferreira RB, Santos CN (2012) Neuroprotective effect of blackberry (Rubus sp.) polyphenols is potentiated after simulated gastrointestinal digestion. Food Chem 131(4):1443–1452. https://doi.org/10.1016/j.foodchem.2011.10.025

    Article  CAS  Google Scholar 

  24. 24.

    Gomes A, Pimpão RC, Fortalezas S, Figueira I, Miguel C, Aguiar C, Salgueiro L, Cavaleiro C, Gonçalves MJ, Clemente A, Costa C, Martins-Loução MA, Ferreira RB, Santos CN (2015) Chemical characterization and bioactivity of phytochemicals from Iberian endemic Santolina semidentata and strategies for ex situ propagation. Ind Crops Prod 74:505–513. https://doi.org/10.1016/j.indcrop.2015.04.037

    Article  CAS  Google Scholar 

  25. 25.

    Terrasso AP, Pinto C, Serra M, Filipe A, Almeida S, Ferreira AL, Pedroso P, Brito C, Alves PM (2015) Novel scalable 3D cell based model for in vitro neurotoxicity testing: combining human differentiated neurospheres with gene expression and functional endpoints. J Biotechnol 205:82–92. https://doi.org/10.1016/j.jbiotec.2014.12.011

    Article  CAS  Google Scholar 

  26. 26.

    Terrasso AP, Silva AC, Filipe A, Pedroso P, Ferreira AL, Alves PM, Brito C (2017) Human neuron-astrocyte 3D co-culture-based assay for evaluation of neuroprotective compounds. J Pharmacol Toxicol Methods 83:72–79. https://doi.org/10.1016/j.vascn.2016.10.001

    Article  CAS  PubMed  Google Scholar 

  27. 27.

    Vieira HL, Queiroga CS, Alves PM (2008) Pre-conditioning induced by carbon monoxide provides neuronal protection against apoptosis. J Neurochem 107(2):375–384. https://doi.org/10.1111/j.1471-4159.2008.05610.x

    Article  CAS  PubMed  Google Scholar 

  28. 28.

    Tavares L, Alves PM, Ferreira RB, Santos CN (2011) Comparison of different methods for DNA-free RNA isolation from SK-N-MC neuroblastoma. BMC Res Notes 4:3. https://doi.org/10.1186/1756-0500-4-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Brito C, Simão D, Costa I, Malpique R, Pereira CI, Fernandes P, Serra M, Schwarz SC, Schwarz J, Kremer EJ, Alves PM (2012) Generation and genetic modification of 3D cultures of human dopaminergic neurons derived from neural progenitor cells. Methods 56(3):452–460. https://doi.org/10.1016/j.ymeth.2012.03.005

    Article  CAS  PubMed  Google Scholar 

  30. 30.

    Livak KJ, Schmittgen TD (2001) Analysis of Relative gene expression data using real-time quantitative PCR and the 2–DDCT method. Methods 25(4):402–408. https://doi.org/10.1006/meth.2001.1262

    Article  CAS  Google Scholar 

  31. 31.

    Palmela I, Cardoso FL, Bernas M, Correia L, Vaz AR, Silva RFM, Fernandes A, Kim KS, Brites D, Brito MA (2011) Elevated Levels of bilirubin and long-term exposure impair human brain microvascular endothelial cell integrity. Curr Neurovasc Res 8(2):153–169. https://doi.org/10.2174/156720211795495358

    Article  CAS  PubMed  Google Scholar 

  32. 32.

    Eigenmann DE, Xue G, Kim KS, Moses AV, Hamburger M, Oufir M (2013) Comparative study of four immortalized human brain capillary endothelial cell lines, hCMEC/D3, hBMEC, TY10, and BB19, and optimization of culture conditions, for an in vitro blood–brain barrier model for drug permeability studies. Fluids Barriers CNS 10(1):1–17. https://doi.org/10.1186/2045-8118-10-33

    Article  CAS  Google Scholar 

  33. 33.

    Eigenmann DE, Jähne EA, Smieško M, Hamburger M, Oufir M (2015) Validation of an immortalized human (hBMEC) in vitro blood–brain barrier model. Anal Bioanal Chem 408(8):2095–2107. https://doi.org/10.1007/s00216-016-9313-6

    Article  CAS  Google Scholar 

  34. 34.

    Ishisaka A, Ichikawa S, Sakakibara H, Piskula MK, Nakamura T, Kato Y, Ito M, Miyamoto K-i, Tsuji A, Kawai Y, Terao J (2011) Accumulation of orally administered quercetin in brain tissue and its antioxidative effects in rats. Free Radic Biol Med 51(7):1329–1336. https://doi.org/10.1016/j.freeradbiomed.2011.06.017

    Article  CAS  PubMed  Google Scholar 

  35. 35.

    Bohn T, McDougall GJ, Alegria A, Alminger M, Arrigoni E, Aura AM, Brito C, Cilla A, El SN, Karakaya S, Martinez-Cuesta MC, Santos CN (2015) Mind the gap-deficits in our knowledge of aspects impacting the bioavailability of phytochemicals and their metabolites—a position paper focusing on carotenoids and polyphenols. Mol Nutr Food Res 59(7):1307–1323. https://doi.org/10.1002/mnfr.201400745

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Marques Peixoto F, Fernandes I, Gouvêa ACMS, Santiago MCPA, Galhardo Borguini R, Mateus N, Freitas V, Godoy RLO, Ferreira IMPLVO (2016) Simulation of in vitro digestion coupled to gastric and intestinal transport models to estimate absorption of anthocyanins from peel powder of jabuticaba, jamelão and jambo fruits. J Funct Foods 24:373–381. https://doi.org/10.1016/j.jff.2016.04.021

    Article  CAS  Google Scholar 

  37. 37.

    McDougall GJ, Conner S, Pereira-Caro G, Gonzalez-Barrio R, Brown EM, Verrall S, Stewart D, Moffet T, Ibars M, Lawther R, O’Connor G, Rowland I, Crozier A, Gill CI (2014) Tracking (poly)phenol components from raspberries in ileal fluid. J Agric Food Chem 62(30):7631–7641. https://doi.org/10.1021/jf502259j

    Article  CAS  PubMed  Google Scholar 

  38. 38.

    Figueira I, Menezes R, Macedo D, Costa I, Santos CNd (2017) Polyphenols beyond barriers: a glimpse into the brain. Curr Neuropharmacol 15(4):562–594. https://doi.org/10.2174/1570159X14666161026151545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Figueira I, Garcia G, Pimpao RC, Terrasso AP, Costa I, Almeida AF, Tavares L, Pais TF, Pinto P, Ventura MR, Filipe A, McDougall GJ, Stewart D, Kim KS, Palmela I, Brites D, Brito MA, Brito C, Santos CN (2017) Polyphenols journey through blood–brain barrier towards neuronal protection. Sci Rep 7 (11456). https://doi.org/10.1038/s41598-017-11512-6

  40. 40.

    Ghersi-Egea JF, Leninger-Muller B, Suleman G, Siest G, Minn A (1994) Localization of drug-metabolizing enzyme activities to blood–brain interfaces and circumventricular organs. J Neurochem 62(3):1089–1096. https://doi.org/10.1046/j.1471-4159.1994.62031089.x

    Article  CAS  PubMed  Google Scholar 

  41. 41.

    Shawahna R, Uchida Y, Declèves X, Ohtsuki S, Yousif S, Dauchy S, Jacob A, Chassoux F, Daumas-Duport C, Couraud P-O, Terasaki T, Scherrmann J-M (2011) Transcriptomic and quantitative proteomic analysis of transporters and drug metabolizing enzymes in freshly isolated human brain microvessels. Mol Pharm 8(4):1332–1341. https://doi.org/10.1021/mp200129p

    Article  CAS  PubMed  Google Scholar 

  42. 42.

    Agúndez JAG, Jiménez-Jiménez FJ, Alonso-Navarro H, García-Martín E (2014) Drug and xenobiotic biotransformation in the blood–brain barrier: a neglected issue. Front Cell Neurosci 8:335. https://doi.org/10.3389/fncel.2014.00335

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Chen C, Zhou J, Ji C (2010) Quercetin: a potential drug to reverse multidrug resistance. Life Sci 87(11–12):333–338. https://doi.org/10.1016/j.lfs.2010.07.004

    Article  CAS  PubMed  Google Scholar 

  44. 44.

    Bieger J, Cermak R, Blank R, de Boer VC, Hollman PC, Kamphues J, Wolffram S (2008) Tissue distribution of quercetin in pigs after long-term dietary supplementation. J Nutr 138(8):1417–1420

    Article  CAS  PubMed  Google Scholar 

  45. 45.

    Pogacnik L, Pirc K, Palmela I, Skrt M, Kim KS, Brites D, Brito MA, Ulrih NP, Silva RF (2016) Potential for brain accessibility and analysis of stability of selected flavonoids in relation to neuroprotection in vitro. Brain Res 1651:17–26. https://doi.org/10.1016/j.brainres.2016.09.020

    Article  CAS  PubMed  Google Scholar 

  46. 46.

    Faria A, Meireles M, Fernandes I, Santos-Buelga C, Gonzalez-Manzano S, Duenas M, de Freitas V, Mateus N, Calhau C (2013) Flavonoid metabolites transport across a human BBB model. Food Chem 149:190–196. https://doi.org/10.1016/j.foodchem.2013.10.095

    Article  CAS  PubMed  Google Scholar 

  47. 47.

    Youdim KA, Qaiser MZ, Begley DJ, Rice-Evans CA, Abbott NJ (2004) Flavonoid permeability across an in situ model of the blood–brain barrier. ‎Free Radic Biol Med 36(5):592–604. https://doi.org/10.1016/j.freeradbiomed.2003.11.023

    Article  CAS  PubMed  Google Scholar 

  48. 48.

    Passamonti S, Vrhovsek U, Vanzo A, Mattivi F (2005) Fast access of some grape pigments to the brain. J Agric Food Chem 53(18):7029–7034. https://doi.org/10.1021/jf050565k

    Article  CAS  PubMed  Google Scholar 

  49. 49.

    Nebbia C (2001) Biotransformation enzymes as determinants of xenobiotic toxicity in domestic animals. Vet J 161(3):238–252. https://doi.org/10.1053/tvjl.2000.0561

    Article  CAS  PubMed  Google Scholar 

  50. 50.

    Abbott NJ, Ronnback L, Hansson E (2006) Astrocyte-endothelial interactions at the blood–brain barrier. Nat Rev Neurosci 7(1):41–53. https://doi.org/10.1038/nrn1824

    Article  CAS  Google Scholar 

  51. 51.

    Cardoso FL, Brites D, Brito MA (2010) Looking at the blood–brain barrier: molecular anatomy and possible investigation approaches. Brain Res Rev 64(2):328–363. https://doi.org/10.1016/j.brainresrev.2010.05.003

    Article  CAS  PubMed  Google Scholar 

  52. 52.

    Kim SU, de Vellis J (2005) Microglia in health and disease. J Neurosci Res 81(3):302–313. https://doi.org/10.1002/jnr.20562

    Article  CAS  PubMed  Google Scholar 

  53. 53.

    Vyas P, Kalidindi S, Chibrikova L, Igamberdiev AU, Weber JT (2013) Chemical analysis and effect of blueberry and lingonberry fruits and leaves against glutamate-mediated excitotoxicity. J Agric Food Chem 61(32):7769–7776. https://doi.org/10.1021/jf401158a

    Article  CAS  PubMed  Google Scholar 

  54. 54.

    Sagaya FM, Hurrell RF, Vergeres G (2012) Postprandial blood cell transcriptomics in response to the ingestion of dairy products by healthy individuals. J Nutr Biochem 23(12):1701–1715. https://doi.org/10.1016/j.jnutbio.2012.01.001

    Article  CAS  PubMed  Google Scholar 

  55. 55.

    Siegel D, Gustafson DL, Dehn DL, Han JY, Boonchoong P, Berliner LJ, Ross D (2004) NAD(P)H:quinone oxidoreductase 1: role as a superoxide scavenger. Mol Pharmacol 65(5):1238–1247. https://doi.org/10.1124/mol.65.5.1238

    Article  CAS  Google Scholar 

  56. 56.

    Ross D, Siegel D (2004) NAD(P)H:quinone oxidoreductase 1 (NQO1, DT-diaphorase), functions and pharmacogenetics. Methods Enzymol 382:115–144. https://doi.org/10.1016/S0076-6879(04)82008-1

    Article  CAS  PubMed  Google Scholar 

  57. 57.

    Surget S, Khoury MP, Bourdon JC (2014) Uncovering the role of p53 splice variants in human malignancy: a clinical perspective. Onco Targets Ther 7:57–68. https://doi.org/10.2147/OTT.S53876

    CAS  Article  Google Scholar 

  58. 58.

    DeCoster MA, Schabelman E, Tombran-Tink J, Bazan NG (1999) Neuroprotection by pigment epithelial-derived factor against glutamate toxicity in developing primary hippocampal neurons. J Neurosci Res 56(6):604–610. 10.1002/(SICI)1097-4547(19990615)56:6<604::AID-JNR6>3.0.CO;2-B

    Article  CAS  PubMed  Google Scholar 

  59. 59.

    Amano S, Yamagishi S, Inagaki Y, Nakamura K, Takeuchi M, Inoue H, Imaizumi T (2005) Pigment epithelium-derived factor inhibits oxidative stress-induced apoptosis and dysfunction of cultured retinal pericytes. Microvasc Res 69(1–2):45–55. https://doi.org/10.1016/j.mvr.2004.11.001

    Article  CAS  PubMed  Google Scholar 

  60. 60.

    Tombran-Tink J, Barnstable CJ (2003) PEDF: a multifaceted neurotrophic factor. Nat Rev Neurosci 4(8):628–636. https://doi.org/10.1038/nrn1176

    Article  CAS  PubMed  Google Scholar 

  61. 61.

    Pazoki-Toroudi H, Amani H, Ajami M, Nabavi SF, Braidy N, Kasi PD, Nabavi SM (2016) Targeting mTOR signaling by polyphenols: a new therapeutic target for ageing. Ageing Res Rev 31:55–66. https://doi.org/10.1016/j.arr.2016.07.004

    Article  CAS  PubMed  Google Scholar 

  62. 62.

    Adams LS, Phung S, Yee N, Seeram NP, Li L, Chen S (2010) Blueberry phytochemicals inhibit growth and metastatic potential of MDA-MB-231 breast cancer cells through modulation of the phosphatidylinositol 3-kinase pathway. Cancer Res 70(9):3594–3605. https://doi.org/10.1158/0008-5472.CAN-09-3565

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Ahmad A, Ali T, Park HY, Badshah H, Rehman SU, Kim MO (2016) Neuroprotective effect of fisetin against amyloid-beta-induced cognitive/synaptic dysfunction, neuroinflammation, and neurodegeneration in adult mice. Mol Neurobiol. https://doi.org/10.1007/s12035-016-9795-4

    Article  PubMed  Google Scholar 

  64. 64.

    Zhao W, Wang J, Bi W, Ferruzzi M, Yemul S, Freire D, Mazzola P, Ho L, Dubner L, Pasinetti GM (2015) Novel application of brain-targeting polyphenol compounds in sleep deprivation-induced cognitive dysfunction. Neurochem Int 89:191–197. https://doi.org/10.1016/j.neuint.2015.07.023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    O’Neil BJ, McKeown TR, DeGracia DJ, Alousi SS, Rafols JA, White BC (1999) Cell death, calcium mobilization, and immunostaining for phosphorylated eukaryotic initiation factor 2-alpha (eIF2alpha) in neuronally differentiated NB-104 cells: arachidonate and radical-mediated injury mechanisms. Resuscitation 41(1):71–83

    Article  PubMed  Google Scholar 

  66. 66.

    Hattori K, Naguro I, Runchel C, Ichijo H (2009) The roles of ASK family proteins in stress responses and diseases. Cell Commun Signal 7:9. https://doi.org/10.1186/1478-811X-7-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Han W, Christen P (2004) cis-Effect of DnaJ on DnaK in ternary complexes with chimeric DnaK/DnaJ-binding peptides. FEBS Lett 563(1–3):146–150. https://doi.org/10.1016/S0014-5793(04)00290-X

    Article  CAS  PubMed  Google Scholar 

  68. 68.

    Kampinga HH (1993) Thermotolerance in mammalian cells. Protein denaturation and aggregation, and stress proteins. J Cell Sci 104(Pt 1):11–17

    CAS  PubMed  Google Scholar 

  69. 69.

    Putics A, Vegh EM, Csermely P, Soti C (2008) Resveratrol induces the heat-shock response and protects human cells from severe heat stress. Antioxid Redox Signal 10(1):65–75. https://doi.org/10.1089/ars.2007.1866

    Article  CAS  PubMed  Google Scholar 

  70. 70.

    Thakur VS, Gupta K, Gupta S (2012) Green tea polyphenols increase p53 transcriptional activity and acetylation by suppressing class I histone deacetylases. Int J Oncol 41(1):353–361. https://doi.org/10.3892/ijo.2012.1449

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Lin ST, Tu SH, Yang PS, Hsu SP, Lee WH, Ho CT, Wu CH, Lai YH, Chen MY, Chen LC (2016) Apple polyphenol phloretin inhibits colorectal cancer cell growth via inhibition of the type 2 glucose transporter and activation of p53-mediated signaling. J Agric Food Chem 64(36):6826–6837. https://doi.org/10.1021/acs.jafc.6b02861

    Article  CAS  PubMed  Google Scholar 

  72. 72.

    Sakagami H, Hashimoto K, Suzuki F, Ogiwara T, Satoh K, Ito H, Hatano T, Takashi Y, Fujisawa S-i (2005) Molecular requirements of lignin–carbohydrate complexes for expression of unique biological activities. Phytochemistry 66(17):2108–2120. https://doi.org/10.1016/j.phytochem.2005.05.013

    Article  CAS  PubMed  Google Scholar 

  73. 73.

    Ohkawa H, Sohma H, Sakai R, Kuroki Y, Hashimoto E, Murakami S, Saito T (2002) Ethanol-induced augmentation of annexin IV in cultured cells and the enhancement of cytotoxicity by overexpression of annexin IV by ethanol. BBA Mol Basis Dis 1588(3):217–225. https://doi.org/10.1016/S0925-4439(02)00168-0

    Article  CAS  Google Scholar 

  74. 74.

    Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, Sadri N, Yun C, Popko B, Paules R, Stojdl DF, Bell JC, Hettmann T, Leiden JM, Ron D (2003) An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell 11(3):619–633

    Article  CAS  PubMed  Google Scholar 

  75. 75.

    Rzymski T, Milani M, Singleton DC, Harris AL (2009) Role of ATF4 in regulation of autophagy and resistance to drugs and hypoxia. Cell Cycle 8(23):3838–3847. https://doi.org/10.4161/cc.8.23.10086

    Article  CAS  PubMed  Google Scholar 

  76. 76.

    Teske BF, Fusakio ME, Zhou D, Shan J, McClintick JN, Kilberg MS, Wek RC (2013) CHOP induces activating transcription factor 5 (ATF5) to trigger apoptosis in response to perturbations in protein homeostasis. Mol Biol Cell 24(15):2477–2490. https://doi.org/10.1091/mbc.E13-01-0067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Wang S-Z, Ou J, Zhu LJ, Green MR (2012) Transcription factor ATF5 is required for terminal differentiation and survival of olfactory sensory neurons. Proc Natl Acad Sci USA 109(45):18589–18594. https://doi.org/10.1073/pnas.1210479109

    Article  PubMed  Google Scholar 

  78. 78.

    Dluzen D, Li G, Tacelosky D, Moreau M, Liu DX (2011) BCL-2 is a downstream target of ATF5 that mediates the prosurvival function of ATF5 in a cell type-dependent manner. J Biol Chem 286(9):7705–7713. https://doi.org/10.1074/jbc.M110.207639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Sheng Z, Ma L, Sun JE, Zhu LJ, Green MR (2011) BCR-ABL suppresses autophagy through ATF5-mediated regulation of mTOR transcription. Blood 118(10):2840–2848. https://doi.org/10.1182/blood-2010-12-322537

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Kanakis CD, Tarantilis PA, Polissiou MG, Tajmir-Riahi HA (2006) Interaction of antioxidant flavonoids with tRNA: intercalation or external binding and comparison with flavonoid-DNA adducts. DNA Cell Biol 25(2):116–123. https://doi.org/10.1089/dna.2006.25.116

    Article  CAS  PubMed  Google Scholar 

  81. 81.

    N’Soukpoe-Kossi CN, Bourassa P, Mandeville JS, Bekale L, Bariyanga J, Tajmir-Riahi HA (2015) Locating the binding sites of antioxidants resveratrol, genistein and curcumin with tRNA. Int J Biol Macromol 80:41–47. https://doi.org/10.1016/j.ijbiomac.2015.06.021

    Article  CAS  PubMed  Google Scholar 

  82. 82.

    Cavet ME, Harrington KL, Vollmer TR, Ward KW, Zhang JZ (2011) Anti-inflammatory and anti-oxidative effects of the green tea polyphenol epigallocatechin gallate in human corneal epithelial cells. Mol Vis 17:533–542

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Catalan U, Fernandez-Castillejo S, Angles N, Morello JR, Yebras M, Sola R (2012) Inhibition of the transcription factor c-Jun by the MAPK family, and not the NF-kappaB pathway, suggests that peanut extract has anti-inflammatory properties. Mol Immunol 52(3–4):125–132. https://doi.org/10.1016/j.molimm.2012.05.007

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

iNOVA4Health Research Unit (LISBOA-01-0145-FEDER-007344), which is cofunded by Fundação para a Ciência e Tecnologia / Ministério da Ciência e do Ensino Superior, through national funds, and by FEDER under the PT2020 Partnership Agreement, is acknowledged. Authors would like to acknowledge to COST FA1005–INFOGEST and to FCT for financial support of CNS (IF/01097/2013), IF (SFRH/BD/86584/2012), APT (PD/BD/52473/2014), and DB and MAB (Strategic Project to iMed.ULisboa, UID/DTP/04138/2013). CNS and DS acknowledge funding via BacHBerry (Project No. FP7-613793; http://www.bachberry.eu) and DS and GMcD acknowledge funding from the Scottish Government Rural and Environmental Sciences and Analytical Services (RESAS) Department. Funding from Tecnimede - Sociedade Técnico Medicinal S.A. (Abrunheira, Sintra, Portugal), the European Regional Development Fund (FEDER) and the System of Incentives for the Research and Technological Development (QREN) of the Portuguese Government is also acknowledged. Extensive revising of the English written work by GMcD is also acknowledged.

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Correspondence to Cláudia N. Santos.

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AF is employee of Tecnimede-Sociedade Técnico Medicinal, S.A. The other authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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Supplementary Fig. 1

Representative picture of the isolation of SK-N-MC cells that presented cellular membrane integrity (PI negative) and high mitochondrial transmembrane potential (DiOC6(3) positive) using FACSAria High Speed Cell Sorter. SSC-A – side scatter, FSC-A – forward scatter. Top panels: control cells; Bottom panels: cells incubated with BDP (TIF 332 KB)

Supplementary material 2 (DOCX 13 KB)

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Figueira, I., Tavares, L., Jardim, C. et al. Blood–brain barrier transport and neuroprotective potential of blackberry-digested polyphenols: an in vitro study. Eur J Nutr 58, 113–130 (2019). https://doi.org/10.1007/s00394-017-1576-y

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Keywords

  • Blackberry
  • In vitro digestion
  • Neuronal cells
  • Brain endothelial cells
  • Microarrays