{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T05:24:09Z","timestamp":1778131449080,"version":"3.51.4"},"reference-count":77,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,9,13]],"date-time":"2017-09-13T00:00:00Z","timestamp":1505260800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,9,13]],"date-time":"2017-09-13T00:00:00Z","timestamp":1505260800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Age-related complications such as neurodegenerative disorders are increasing and remain cureless. The possibility of altering the progression or the development of these multifactorial diseases through diet is an emerging and attractive approach with increasing experimental support. We examined the potential of known bioavailable phenolic sulfates, arising from colonic metabolism of berries, to influence hallmarks of neurodegenerative processes. <jats:italic>In silico<\/jats:italic> predictions and <jats:italic>in vitro<\/jats:italic> transport studies across blood-brain barrier (BBB) endothelial cells, at circulating concentrations, provided evidence for differential transport, likely related to chemical structure. Moreover, endothelial metabolism of these phenolic sulfates produced a plethora of novel chemical entities with further potential bioactivies. Pre-conditioning with phenolic sulfates improved cellular responses to oxidative, excitotoxicity and inflammatory injuries and this attenuation of neuroinflammation was achieved <jats:italic>via<\/jats:italic> modulation of NF-\u03baB pathway. Our results support the hypothesis that these small molecules, derived from dietary (poly)phenols may cross the BBB, reach brain cells, modulate microglia-mediated inflammation and exert neuroprotective effects, with potential for alleviation of neurodegenerative diseases.<\/jats:p>","DOI":"10.1038\/s41598-017-11512-6","type":"journal-article","created":{"date-parts":[[2017,9,7]],"date-time":"2017-09-07T13:46:25Z","timestamp":1504791985000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":250,"title":["Polyphenols journey through blood-brain barrier towards neuronal protection"],"prefix":"10.1038","volume":"7","author":[{"given":"I.","family":"Figueira","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5526-5362","authenticated-orcid":false,"given":"G.","family":"Garcia","sequence":"additional","affiliation":[]},{"given":"R. C.","family":"Pimp\u00e3o","sequence":"additional","affiliation":[]},{"given":"A. P.","family":"Terrasso","sequence":"additional","affiliation":[]},{"given":"I.","family":"Costa","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8399-0710","authenticated-orcid":false,"given":"A. F.","family":"Almeida","sequence":"additional","affiliation":[]},{"given":"L.","family":"Tavares","sequence":"additional","affiliation":[]},{"given":"T. F.","family":"Pais","sequence":"additional","affiliation":[]},{"given":"P.","family":"Pinto","sequence":"additional","affiliation":[]},{"given":"M. R.","family":"Ventura","sequence":"additional","affiliation":[]},{"given":"A.","family":"Filipe","sequence":"additional","affiliation":[]},{"given":"G. J.","family":"McDougall","sequence":"additional","affiliation":[]},{"given":"D.","family":"Stewart","sequence":"additional","affiliation":[]},{"given":"K. S.","family":"Kim","sequence":"additional","affiliation":[]},{"given":"I.","family":"Palmela","sequence":"additional","affiliation":[]},{"given":"D.","family":"Brites","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8493-4649","authenticated-orcid":false,"given":"M. A.","family":"Brito","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8926-279X","authenticated-orcid":false,"given":"C.","family":"Brito","sequence":"additional","affiliation":[]},{"given":"C. N.","family":"Santos","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2017,9,13]]},"reference":[{"key":"11512_CR1","unstructured":"Anonymous World report on ageing and health - World Health Organization edited by World Health Organization WHO Press (Geneva, 2015)."},{"issue":"Supplement 1","key":"11512_CR2","doi-asserted-by":"publisher","first-page":"S159","DOI":"10.1016\/j.parkreldis.2015.09.053","volume":"22","author":"AD Korczyn","year":"2016","unstructured":"Korczyn, A. D. Parkinson\u2019s and Alzheimer\u2019s diseases: Focus on mild cognitive impairment. Parkinsonism Relat. Disord. \n22(Supplement 1), S159\u2013S161 (2016).","journal-title":"Parkinsonism Relat. Disord."},{"key":"11512_CR3","doi-asserted-by":"crossref","unstructured":"Deak, F., Freeman, W. M., Ungvari, Z., Csiszar, A., & Sonntag, W. E. Recent Developments in Understanding Brain Aging: Implications for Alzheimer\u2019s Disease and Vascular Cognitive Impairment. J. Gerontol. A Biol. Sci. Med. Sci (2015).","DOI":"10.1093\/gerona\/glv206"},{"key":"11512_CR4","doi-asserted-by":"crossref","unstructured":"Figueira, I. et al. Interventions for age-related diseases: Shifting the paradigm. Mech. Ageing Dev (2016).","DOI":"10.1016\/j.mad.2016.09.009"},{"issue":"5","key":"11512_CR5","doi-asserted-by":"publisher","first-page":"1179","DOI":"10.3945\/ajcn.113.066639","volume":"98","author":"A Rodriguez-Mateos","year":"2013","unstructured":"Rodriguez-Mateos, A. et al. Intake and time dependence of blueberry flavonoid-induced improvements in vascular function: a randomized, controlled, double-blind, crossover intervention study with mechanistic insights into biological activity. Am. J. Clin. Nutr. \n98(5), 1179\u20131191 (2013).","journal-title":"Am. J. Clin. Nutr."},{"issue":"4","key":"11512_CR6","doi-asserted-by":"publisher","first-page":"2499","DOI":"10.3390\/nu7042499","volume":"7","author":"CA Gunn","year":"2015","unstructured":"Gunn, C. A., Weber, J. L., McGill, A.-T. & Kruger, M. C. Increased Intake of Selected Vegetables, Herbs and Fruit may Reduce Bone Turnover in Post-Menopausal Women. Nutrients \n7(4), 2499\u20132517 (2015).","journal-title":"Nutrients"},{"issue":"8","key":"11512_CR7","doi-asserted-by":"publisher","first-page":"1370","DOI":"10.1212\/01.wnl.0000240224.38978.d8","volume":"67","author":"MC Morris","year":"2006","unstructured":"Morris, M. C., Evans, D. A., Tangney, C. C., Bienias, J. L. & Wilson, R. S. Associations of vegetable and fruit consumption with age-related cognitive change. Neurol. \n67(8), 1370\u20131376 (2006).","journal-title":"Neurol."},{"issue":"05","key":"11512_CR8","doi-asserted-by":"publisher","first-page":"752","DOI":"10.1017\/S0007114511001024","volume":"106","author":"ACJ Nooyens","year":"2011","unstructured":"Nooyens, A. C. J. et al. Fruit and vegetable intake and cognitive decline in middle-aged men and women: the Doetinchem Cohort Study. Brit. J. Nutr. \n106(05), 752\u2013761 (2011).","journal-title":"Brit. J. Nutr."},{"issue":"12","key":"11512_CR9","doi-asserted-by":"publisher","first-page":"81","DOI":"10.4103\/0973-7847.99898","volume":"6","author":"GP Kumar","year":"2012","unstructured":"Kumar, G. P. & Khanum, F. Neuroprotective potential of phytochemicals. Pharmacogn. Rev. \n6(12), 81\u201390 (2012).","journal-title":"Pharmacogn. Rev."},{"issue":"2","key":"11512_CR10","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1007\/s12035-014-8722-9","volume":"51","author":"J Lakey-Beitia","year":"2015","unstructured":"Lakey-Beitia, J., Berrocal, R., Rao, K. S. & Durant, A. Polyphenols as Therapeutic Molecules in Alzheimer\u2019s Disease Through Modulating Amyloid Pathways. Mol. Neurobiol. \n51(2), 466\u2013479 (2015).","journal-title":"Mol. Neurobiol."},{"issue":"7","key":"11512_CR11","doi-asserted-by":"publisher","first-page":"3996","DOI":"10.1021\/jf9029332","volume":"58","author":"R Krikorian","year":"2010","unstructured":"Krikorian, R. et al. Blueberry Supplementation Improves Memory in Older Adults. J. Agric. Food Chem. \n58(7), 3996\u20134000 (2010).","journal-title":"J. Agric. Food Chem."},{"issue":"4","key":"11512_CR12","first-page":"464","volume":"32","author":"B Cimrov\u00e1","year":"2011","unstructured":"Cimrov\u00e1, B., Bud\u00e1\u010d, S., Melicherov\u00e1, U., Jergelov\u00e1, M. & Jagla, F. Electrophysiological evidence of the effect of natural polyphenols upon the human higher brain functions. Neuro. Endocrinol. Lett. \n32(4), 464\u2013468 (2011).","journal-title":"Neuro. Endocrinol. Lett."},{"issue":"23","key":"11512_CR13","doi-asserted-by":"publisher","first-page":"5736","DOI":"10.1021\/jf300277g","volume":"60","author":"R Krikorian","year":"2012","unstructured":"Krikorian, R. et al. Concord Grape Juice Supplementation and Neurocognitive Function in Human Aging. J. Agric. Food Chem. \n60(23), 5736\u20135742 (2012).","journal-title":"J. Agric. Food Chem."},{"issue":"23","key":"11512_CR14","doi-asserted-by":"publisher","first-page":"7862","DOI":"10.1523\/JNEUROSCI.0385-14.2014","volume":"34","author":"AV Witte","year":"2014","unstructured":"Witte, A. V., Kerti, L., Margulies, D. S. & Fl\u00f6el, A. Effects of Resveratrol on Memory Performance, Hippocampal Functional Connectivity, and Glucose Metabolism in Healthy Older Adults. J. Neurosci. \n34(23), 7862\u20137870 (2014).","journal-title":"J. Neurosci."},{"issue":"10","key":"11512_CR15","doi-asserted-by":"publisher","first-page":"1049","DOI":"10.1089\/jmf.2013.3004","volume":"17","author":"M-R Choi","year":"2014","unstructured":"Choi, M.-R. et al. Rubus coreanus Miquel Ameliorates Scopolamine-Induced Memory Impairments in ICR Mice. J. Med. Food \n17(10), 1049\u20131056 (2014).","journal-title":"J. Med. Food"},{"issue":"3","key":"11512_CR16","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1179\/147683009X423292","volume":"12","author":"B Shukitt-Hale","year":"2009","unstructured":"Shukitt-Hale, B., Cheng, V. & Joseph, J. A. Effects of blackberries on motor and cognitive function in aged rats. Nutr. Neurosci. \n12(3), 135\u2013140 (2009).","journal-title":"Nutr. Neurosci."},{"issue":"3","key":"11512_CR17","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1016\/j.nut.2010.05.001","volume":"27","author":"DH Malin","year":"2011","unstructured":"Malin, D. H. et al. Short-term blueberry-enriched diet prevents and reverses object recognition memory loss in aging rats. Nutrition \n27(3), 338\u2013342 (2011).","journal-title":"Nutrition"},{"issue":"10","key":"11512_CR18","doi-asserted-by":"publisher","first-page":"1542","DOI":"10.1017\/S0007114515003451","volume":"114","author":"B Shukitt-Hale","year":"2015","unstructured":"Shukitt-Hale, B. et al. The beneficial effects of berries on cognition, motor behaviour and neuronal function in ageing. Brit. J. Nutr. \n114(10), 1542\u20131549 (2015).","journal-title":"Brit. J. Nutr."},{"key":"11512_CR19","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1016\/j.neuint.2015.08.002","volume":"89","author":"C Rendeiro","year":"2015","unstructured":"Rendeiro, C., Rhodes, J. S. & Spencer, J. P. E. The mechanisms of action of flavonoids in the brain: Direct versus indirect effects. Neurochem. Int. \n89, 126\u2013139 (2015).","journal-title":"Neurochem. Int."},{"issue":"S3","key":"11512_CR20","doi-asserted-by":"publisher","first-page":"S48","DOI":"10.1017\/S0007114510003946","volume":"104","author":"G Williamson","year":"2010","unstructured":"Williamson, G. & Clifford, M. N. Colonic metabolites of berry polyphenols: the missing link to biological activity? Brit. J. Nutr. \n104(S3), S48\u2013S66 (2010).","journal-title":"Brit. J. Nutr."},{"issue":"5","key":"11512_CR21","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1039\/c3fo60024f","volume":"4","author":"G Borges","year":"2013","unstructured":"Borges, G., Lean, M. E. J., Roberts, S. A. & Crozier, A. Bioavailability of dietary (poly)phenols: a study with ileostomists to discriminate between absorption in small and large intestine. Food Funct. \n4(5), 754\u2013762 (2013).","journal-title":"Food Funct."},{"issue":"03","key":"11512_CR22","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1017\/S0007114514003511","volume":"113","author":"RC Pimp\u00e3o","year":"2015","unstructured":"Pimp\u00e3o, R. C., Ventura, M. R., Ferreira, R. B., Williamson, G. & Santos, C. N. Phenolic sulfates as new and highly abundant metabolites in human plasma after ingestion of a mixed berry fruit pur\u00e9e. Brit. J. Nutr. \n113(03), 454\u2013463 (2015).","journal-title":"Brit. J. Nutr."},{"issue":"2","key":"11512_CR23","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1016\/j.brainresrev.2010.05.003","volume":"64","author":"FL Cardoso","year":"2010","unstructured":"Cardoso, F. L., Brites, D. & Brito, M. A. Looking at the blood-brain barrier: Molecular anatomy and possible investigation approaches. Brain. Res. Rev. \n64(2), 328\u2013363 (2010).","journal-title":"Brain. Res. Rev."},{"issue":"1","key":"11512_CR24","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/nrn1824","volume":"7","author":"NJ Abbott","year":"2006","unstructured":"Abbott, N. J., Ronnback, L. & Hansson, E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat. Rev. Neurosci. \n7(1), 41\u201353 (2006).","journal-title":"Nat. Rev. Neurosci."},{"issue":"2","key":"11512_CR25","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1096\/fj.12-212118","volume":"27","author":"L Ho","year":"2013","unstructured":"Ho, L. et al. Identification of brain-targeted bioactive dietary quercetin-3-O-glucuronide as a novel intervention for Alzheimer\u2019s disease. FASEB J. \n27(2), 769\u2013781 (2013).","journal-title":"FASEB J."},{"issue":"8","key":"11512_CR26","doi-asserted-by":"publisher","first-page":"1341","DOI":"10.1021\/acschemneuro.5b00051","volume":"6","author":"M Gasperotti","year":"2015","unstructured":"Gasperotti, M. et al. Fate of Microbial Metabolites of Dietary Polyphenols in Rats: Is the Brain Their Target Destination? ACS Chem. Neurosci. \n6(8), 1341\u20131352 (2015).","journal-title":"ACS Chem. Neurosci."},{"issue":"12","key":"11512_CR27","doi-asserted-by":"publisher","first-page":"2432","DOI":"10.1002\/mnfr.201500224","volume":"59","author":"T-Y Chen","year":"2015","unstructured":"Chen, T.-Y. et al. Plasma bioavailability and regional brain distribution of polyphenols from apple\/grape seed and bilberry extracts in a young swine model. Mol. Nutr. Food Res. \n59(12), 2432\u20132447 (2015).","journal-title":"Mol. Nutr. Food Res."},{"issue":"1","key":"11512_CR28","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1046\/j.1471-4159.2003.01652.x","volume":"85","author":"KA Youdim","year":"2003","unstructured":"Youdim, K. A. et al. Interaction between flavonoids and the blood\u2013brain barrier: in vitro studies. J. Neurochem. \n85(1), 180\u2013192 (2003).","journal-title":"J. Neurochem."},{"issue":"5","key":"11512_CR29","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1016\/j.freeradbiomed.2003.11.023","volume":"36","author":"KA Youdim","year":"2004","unstructured":"Youdim, K. A., Qaiser, M. Z., Begley, D. J., Rice-Evans, C. A. & Abbott, N. J. Flavonoid permeability across an in situ model of the blood-brain barrier. Free Radic. Biol. Med. \n36(5), 592\u2013604 (2004).","journal-title":"\u200eFree Radic. Biol. Med."},{"issue":"7","key":"11512_CR30","doi-asserted-by":"publisher","first-page":"1414","DOI":"10.1002\/mnfr.201300822","volume":"58","author":"RC Pimp\u00e3o","year":"2014","unstructured":"Pimp\u00e3o, R. C. et al. Urinary metabolite profiling identifies novel colonic metabolites and conjugates of phenolics in healthy volunteers. Mol. Nutr. Food Res. \n58(7), 1414\u20131425 (2014).","journal-title":"Mol. Nutr. Food Res."},{"issue":"7","key":"11512_CR31","doi-asserted-by":"publisher","first-page":"1265","DOI":"10.1038\/nprot.2010.76","volume":"5","author":"MJ Bernas","year":"2010","unstructured":"Bernas, M. J. et al. Establishment of primary cultures of human brain microvascular endothelial cells to provide an in vitro cellular model of the blood-brain barrier. Nat. Protoc. \n5(7), 1265\u20131272 (2010).","journal-title":"Nat. Protoc."},{"issue":"8","key":"11512_CR32","doi-asserted-by":"publisher","first-page":"2095","DOI":"10.1007\/s00216-016-9313-6","volume":"408","author":"DE Eigenmann","year":"2015","unstructured":"Eigenmann, D. E., J\u00e4hne, E. A., Smie\u0161ko, M., Hamburger, M. & Oufir, M. Validation of an immortalized human (hBMEC) in vitro blood-brain barrier model. Anal. Bioanal. Chem. \n408(8), 2095\u20132107 (2015).","journal-title":"Anal. Bioanal. Chem."},{"key":"11512_CR33","doi-asserted-by":"publisher","unstructured":"Estimation of Blood-Brain Barrier Crossing of Drugs Using Molecular Size and Shape, and H-Bonding Descriptors (distributed by Taylor & Francis; released 1998), doi:10.3109\/10611869808997889.","DOI":"10.3109\/10611869808997889"},{"issue":"3","key":"11512_CR34","first-page":"216","volume":"204","author":"EM Leslie","year":"2005","unstructured":"Leslie, E. M., Deeley, R. G. & Cole, S. P. C. Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. YTAAP \n204(3), 216\u2013237 (2005).","journal-title":"\u200eYTAAP"},{"key":"11512_CR35","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.drup.2016.05.001","volume":"27","author":"W Li","year":"2016","unstructured":"Li, W. et al. Overcoming ABC transporter-mediated multidrug resistance: Molecular mechanisms and novel therapeutic drug strategies. Drug Resist. Updat. \n27, 14\u201329 (2016).","journal-title":"Drug Resist. Updat."},{"issue":"7","key":"11512_CR36","doi-asserted-by":"publisher","first-page":"721","DOI":"10.2174\/0929867013372922","volume":"8","author":"LM Sayre","year":"2001","unstructured":"Sayre, L. M., Smith, M. A. & Perry, G. Chemistry and Biochemistry of Oxidative Stress in Neurodegenerative Disease. Curr. Med. Chem. \n8(7), 721\u2013738 (2001).","journal-title":"Curr. Med. Chem."},{"key":"11512_CR37","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1016\/j.brainres.2015.09.018","volume":"1627","author":"MA Kaisar","year":"2015","unstructured":"Kaisar, M. A., Prasad, S. & Cucullo, L. Protecting the BBB endothelium against cigarette smoke-induced oxidative stress using popular antioxidants: Are they really beneficial? Brain Res. \n1627, 90\u2013100 (2015).","journal-title":"Brain Res."},{"issue":"2","key":"11512_CR38","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1111\/j.1471-4159.2008.05610.x","volume":"107","author":"HLA Vieira","year":"2008","unstructured":"Vieira, H. L. A., Queiroga, C. S. F. & Alves, P. M. Pre-conditioning induced by carbon monoxide provides neuronal protection against apoptosis. J. Neurochem. \n107(2), 375\u2013384 (2008).","journal-title":"\u200eJ. Neurochem."},{"key":"11512_CR39","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1016\/j.vascn.2016.10.001","volume":"83","author":"AP Terrasso","year":"2017","unstructured":"Terrasso, A. P. et al. Human neuron-astrocyte 3D co-culture-based assay for evaluation of neuroprotective compounds. J. Pharmacol. Toxicol. Methods \n83, 72\u201379 (2017).","journal-title":"J. Pharmacol. Toxicol. Methods"},{"issue":"4","key":"11512_CR40","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0036153","volume":"7","author":"M Erb","year":"2012","unstructured":"Erb, M. et al. Features of Idebenone and Related Short-Chain Quinones that Rescue ATP Levels under Conditions of Impaired Mitochondrial Complex I. PLoS One \n7(4), e36153 (2012).","journal-title":"PLoS One"},{"key":"11512_CR41","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1016\/j.jbiotec.2014.12.011","volume":"205","author":"AP Terrasso","year":"2015","unstructured":"Terrasso, A. P. et al. Novel scalable 3D cell based model for in vitro neurotoxicity testing: Combining human differentiated neurospheres with gene expression and functional endpoints. J. Biotechnol. \n205, 82\u201392 (2015).","journal-title":"J. Biotechnol."},{"issue":"40","key":"11512_CR42","doi-asserted-by":"publisher","first-page":"12468","DOI":"10.1073\/pnas.1511003112","volume":"112","author":"CM Sandiego","year":"2015","unstructured":"Sandiego, C. M. et al. Imaging robust microglial activation after lipopolysaccharide administration in humans with PET. Proc. Natl. Acad. Sci. \n112(40), 12468\u201312473 (2015).","journal-title":"Proc. Natl. Acad. Sci."},{"key":"11512_CR43","doi-asserted-by":"crossref","unstructured":"Kaminska, B., Mota, M., & Mota, M. Signal transduction and epigenetic mechanisms in the control of microglia activation during neuroinflammation. BBA - Mol. Basis Dis. 1862 (3), 339\u2013351 (2016).","DOI":"10.1016\/j.bbadis.2015.10.026"},{"issue":"1","key":"11512_CR44","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/2045-8118-10-33","volume":"10","author":"DE Eigenmann","year":"2013","unstructured":"Eigenmann, D. E. et al. 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 \n10(1), 1\u201317 (2013).","journal-title":"Fluids Barriers CNS"},{"issue":"2","key":"11512_CR45","doi-asserted-by":"publisher","first-page":"153","DOI":"10.2174\/156720211795495358","volume":"8","author":"I Palmela","year":"2011","unstructured":"Palmela, I. et al. Elevated Levels of Bilirubin and Long-Term Exposure Impair Human Brain Microvascular Endothelial Cell Integrity. Curr. Neurovasc. Res. \n8(2), 153\u2013169 (2011).","journal-title":"Curr. Neurovasc. Res."},{"key":"11512_CR46","doi-asserted-by":"publisher","first-page":"1883","DOI":"10.1039\/c1mb05008g","volume":"7","author":"J Xiao","year":"2011","unstructured":"Xiao, J., Kai, G., Ni, X., Yang, F. & Chen, X. Interaction of natural polyphenols with \u03b1-amylase in vitro: molecular property\u2013affinity relationship aspect. Mol. Biosyst. \n7, 1883\u20131890 (2011).","journal-title":"Mol. Biosyst."},{"issue":"1","key":"11512_CR47","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1039\/C0FO00100G","volume":"2","author":"A Faria","year":"2011","unstructured":"Faria, A. et al. Insights into the putative catechin and epicatechin transport across blood-brain barrier. Food Funct. \n2(1), 39\u201344 (2011).","journal-title":"Food Funct."},{"issue":"1","key":"11512_CR48","doi-asserted-by":"publisher","first-page":"97","DOI":"10.5455\/jice.20160118062127","volume":"5","author":"SA Hussain","year":"2016","unstructured":"Hussain, S. A., Sulaiman, A. A., Alhaddad, H. & Alhadidi, Q. Natural polyphenols: Influence on membrane transporters. J. Intercult. Ethnopharmacol. \n5(1), 97\u2013104 (2016).","journal-title":"J. Intercult. Ethnopharmacol."},{"issue":"3","key":"11512_CR49","doi-asserted-by":"publisher","first-page":"1089","DOI":"10.1046\/j.1471-4159.1994.62031089.x","volume":"62","author":"JF Ghersi-Egea","year":"1994","unstructured":"Ghersi-Egea, J. F., Leninger-Muller, B., Suleman, G., Siest, G. & Minn, A. Localization of Drug-Metabolizing Enzyme Activities to Blood-Brain Interfaces and Circumventricular Organs. J. Neurochem. \n62(3), 1089\u20131096 (1994).","journal-title":"\u200eJ. Neurochem."},{"issue":"4","key":"11512_CR50","first-page":"1332","volume":"8","author":"R Shawahna","year":"2011","unstructured":"Shawahna, R. et al. Transcriptomic and Quantitative Proteomic Analysis of Transporters and Drug Metabolizing Enzymes in Freshly Isolated Human Brain Microvessels. Mol. Pharm. \n8(4), 1332\u20131341 (2011).","journal-title":"\u200eMol. Pharm."},{"key":"11512_CR51","volume":"8","author":"JAG Ag\u00fandez","year":"2014","unstructured":"Ag\u00fandez, J. A. G., Jim\u00e9nez-Jim\u00e9nez, F. J., Alonso-Navarro, H. & Garc\u00eda-Mart\u00edn, E. Drug and xenobiotic biotransformation in the blood-brain barrier: a neglected issue. Front. Cell Neurosci. \n8, 335 (2014).","journal-title":"Front. Cell Neurosci."},{"issue":"3","key":"11512_CR52","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1002\/bmc.3034","volume":"28","author":"J Liang","year":"2013","unstructured":"Liang, J. et al. The profiling and identification of the metabolites of (+)-catechin and study on their distribution in rats by HPLC-DAD-ESI-IT-TOF-MSn technique. Biomed. Chromatogr. \n28(3), 401\u2013411 (2013).","journal-title":"Biomed. Chromatogr."},{"issue":"8","key":"11512_CR53","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1016\/j.neuropharm.2007.10.003","volume":"53","author":"SM Greenwood","year":"2007","unstructured":"Greenwood, S. M. & Connolly, C. N. Dendritic and mitochondrial changes during glutamate excitotoxicity. Neuropharmacol. \n53(8), 891\u2013898 (2007).","journal-title":"Neuropharmacol."},{"key":"11512_CR54","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.brainres.2016.04.048","volume":"1643","author":"B Wang","year":"2016","unstructured":"Wang, B. et al. Neuroprotective effects of pterostilbene against oxidative stress injury: Involvement of nuclear factor erythroid 2-related factor 2 pathway. Brain Res. \n1643, 70\u201379 (2016).","journal-title":"Brain Res."},{"key":"11512_CR55","doi-asserted-by":"publisher","DOI":"10.1038\/srep33285","volume":"6","author":"D Simao","year":"2016","unstructured":"Simao, D. et al. Functional metabolic interactions of human neuron-astrocyte 3D in vitro networks. Sci. Rep. \n6, 33285 (2016).","journal-title":"Sci. Rep."},{"issue":"1","key":"11512_CR56","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.nbd.2007.07.023","volume":"29","author":"MA Brito","year":"2008","unstructured":"Brito, M. A. et al. Unconjugated bilirubin differentially affects the redox status of neuronal and astroglial cells. Neurobiol. Dis. \n29(1), 30\u201340 (2008).","journal-title":"Neurobiol. Dis."},{"issue":"3","key":"11512_CR57","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1002\/jnr.20562","volume":"81","author":"SU Kim","year":"2005","unstructured":"Kim, S. U. & de Vellis, J. Microglia in health and disease. J. Neurosci. Res. \n81(3), 302\u2013313 (2005).","journal-title":"\u200eJ. Neurosci. Res."},{"key":"11512_CR58","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1111\/j.1749-6632.2010.05857.x","volume":"1215","author":"A Quincozes-Santos","year":"2011","unstructured":"Quincozes-Santos, A. & Gottfried, C. Resveratrol modulates astroglial functions: neuroprotective hypothesis. Ann N Y Acad Sci \n1215, 72\u201378 (2011).","journal-title":"Ann N Y Acad Sci"},{"issue":"6","key":"11512_CR59","doi-asserted-by":"publisher","first-page":"5248","DOI":"10.3892\/mmr.2016.5201","volume":"13","author":"Y Feng","year":"2016","unstructured":"Feng, Y. et al. Neuroprotective effects of resveratrol against traumatic brain injury in rats: Involvement of synaptic proteins and neuronal autophagy. Mol Med Rep \n13(6), 5248\u20135254 (2016).","journal-title":"Mol Med Rep"},{"issue":"1\u20132","key":"11512_CR60","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1007\/s11010-016-2917-5","volume":"428","author":"BA Arus","year":"2017","unstructured":"Arus, B. A. et al. Resveratrol modulates GSH system in C6 astroglial cells through heme oxygenase 1 pathway. Mol Cell Biochem \n428(1\u20132), 67\u201377 (2017).","journal-title":"Mol Cell Biochem"},{"issue":"3","key":"11512_CR61","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1007\/s12017-016-8430-x","volume":"18","author":"P Rangarajan","year":"2016","unstructured":"Rangarajan, P., Karthikeyan, A. & Dheen, S. T. Role of dietary phenols in mitigating microglia-mediated neuroinflammation. Neuromolecular Med. \n18(3), 453\u2013464 (2016).","journal-title":"Neuromolecular Med."},{"key":"11512_CR62","doi-asserted-by":"crossref","unstructured":"Palmela, I. et al. Time-dependent dual effects of high levels of unconjugated bilirubin on the human blood-brain barrier lining. Front. Cell Neurosci. 6 (2012).","DOI":"10.3389\/fncel.2012.00022"},{"issue":"1","key":"11512_CR63","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1006\/mpat.2000.0406","volume":"30","author":"MF Stins","year":"2001","unstructured":"Stins, M. F., Badger, J. & Sik Kim, K. Bacterial invasion and transcytosis in transfected human brain microvascular endothelial cells. Microb. Pathog. \n30(1), 19\u201328 (2001).","journal-title":"Microb. Pathog."},{"key":"11512_CR64","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2014.00152","volume":"8","author":"C Caldeira","year":"2014","unstructured":"Caldeira, C. et al. Microglia change from a reactive to an age-like phenotype with the time in culture. Front. Cell Neurosci. \n8, 152 (2014).","journal-title":"Front. Cell Neurosci."},{"issue":"5","key":"11512_CR65","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0035919","volume":"7","author":"FL Cardoso","year":"2012","unstructured":"Cardoso, F. L. et al. Exposure to Lipopolysaccharide and\/or Unconjugated Bilirubin Impair the Integrity and Function of Brain Microvascular Endothelial Cells. PLoS One \n7(5), e35919 (2012).","journal-title":"PLoS One"},{"key":"11512_CR66","doi-asserted-by":"crossref","unstructured":"Deli, M. A. Potential use of tight junction modulators to reversibly open membranous barriers and improve drug delivery. BBA - Biomembranes \n1788(4), 892\u2013910 (2009).","DOI":"10.1016\/j.bbamem.2008.09.016"},{"issue":"1\u20132","key":"11512_CR67","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1016\/0003-2697(76)90527-3","volume":"72","author":"MM Bradford","year":"1976","unstructured":"Bradford, M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. \n72(1\u20132), 248\u2013254 (1976).","journal-title":"Anal. Biochem."},{"issue":"1","key":"11512_CR68","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1007\/s10571-004-1377-8","volume":"25","author":"MA Deli","year":"2005","unstructured":"Deli, M. A., Abrah\u00e1m, C., Kataoka, Y. & Niwa, M. Permeability Studies on In Vitro Blood-Brain Barrier Models: Physiology, Pathology, and Pharmacology. Cell. Mol. Neurobiol. \n25(1), 59\u2013127 (2005).","journal-title":"Cell. Mol. Neurobiol."},{"issue":"4","key":"11512_CR69","doi-asserted-by":"publisher","first-page":"926","DOI":"10.1089\/jmf.2009.0157","volume":"13","author":"EM Janle","year":"2010","unstructured":"Janle, E. M. et al. Pharmacokinetics and Tissue Distribution of 14C-Labeled Grape Polyphenols in the Periphery and the Central Nervous System Following Oral Administration. J. Med. Food \n13(4), 926\u2013933 (2010).","journal-title":"J. Med. Food"},{"key":"11512_CR70","doi-asserted-by":"crossref","unstructured":"Eigenmann, D. E. et al. In vitro blood-brain barrier permeability predictions for GABAA receptor modulating piperine analogs. Eur. J. Pharm. Biopharm. (2016).","DOI":"10.1016\/j.ejpb.2016.03.029"},{"issue":"4","key":"11512_CR71","doi-asserted-by":"publisher","first-page":"273","DOI":"10.3390\/antiox2040273","volume":"2","author":"A Gomes","year":"2013","unstructured":"Gomes, A. et al. Valuing the Endangered Species Antirrhinum lopesianum: Neuroprotective Activities and Strategies for in vitro Plant Propagation. Antioxidants \n2(4), 273\u2013292 (2013).","journal-title":"Antioxidants"},{"issue":"1","key":"11512_CR72","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1007\/s00394-012-0307-7","volume":"52","author":"L Tavares","year":"2012","unstructured":"Tavares, L. et al. Neuroprotective effects of digested polyphenols from wild blackberry species. Eur. J. Nutr. \n52(1), 225\u2013236 (2012).","journal-title":"Eur. J. Nutr."},{"issue":"1\u20132","key":"11512_CR73","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/0006-8993(96)00156-4","volume":"720","author":"M Ii","year":"1996","unstructured":"Ii, M., Sunamoto, M., Ohnishi, K. & Ichimori, Y. beta-Amyloid protein-dependent nitric oxide production from microglial cells and neurotoxicity. Brain Res. \n720(1\u20132), 93\u2013100 (1996).","journal-title":"Brain Res."},{"issue":"52","key":"11512_CR74","doi-asserted-by":"publisher","first-page":"40714","DOI":"10.1074\/jbc.M110.181255","volume":"285","author":"RT Figueiredo","year":"2010","unstructured":"Figueiredo, R. T. et al. TLR4 recognizes Pseudallescheria boydii conidia and purified rhamnomannans. J. Biol. Chem. \n285(52), 40714\u201340723 (2010).","journal-title":"J. Biol. Chem."},{"issue":"19","key":"11512_CR75","doi-asserted-by":"publisher","first-page":"2603","DOI":"10.1038\/emboj.2013.200","volume":"32","author":"TF Pais","year":"2013","unstructured":"Pais, T. F. et al. The NAD-dependent deacetylase sirtuin 2 is a suppressor of microglial activation and brain inflammation. EMBO J. \n32(19), 2603\u20132616 (2013).","journal-title":"EMBO J."},{"issue":"3","key":"11512_CR76","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1016\/j.ymeth.2012.03.005","volume":"56","author":"C Brito","year":"2012","unstructured":"Brito, C. et al. Generation and genetic modification of 3D cultures of human dopaminergic neurons derived from neural progenitor cells. Methods \n56(3), 452\u2013460 (2012).","journal-title":"Methods"},{"issue":"4","key":"11512_CR77","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1006\/meth.2001.1262","volume":"25","author":"KJ Livak","year":"2001","unstructured":"Livak, K. J. & Schmittgen, T. D. Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2\u2212\u0394\u0394CT Method. Methods \n25(4), 402\u2013408 (2001).","journal-title":"Methods"}],"updated-by":[{"DOI":"10.1038\/s41598-021-96179-w","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2021,8,18]],"date-time":"2021-08-18T00:00:00Z","timestamp":1629244800000}}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-11512-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-11512-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-11512-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T10:52:44Z","timestamp":1671792764000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-11512-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,9,13]]},"references-count":77,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["11512"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-11512-6","relation":{"correction":[{"id-type":"doi","id":"10.1038\/s41598-021-96179-w","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,9,13]]},"assertion":[{"value":"16 January 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 August 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 September 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 August 2021","order":4,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":5,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A Correction to this paper has been published:","order":6,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"https:\/\/doi.org\/10.1038\/s41598-021-96179-w","URL":"https:\/\/doi.org\/10.1038\/s41598-021-96179-w","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A.F. is employee of Tecnimede \u2013 Sociedade T\u00e9cnico Medicinal, S.A. The other authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"11456"}}