emujpharmsci EMU Journal of Pharmaceutical Sciences 2651-3587 Dogu Akdeniz University Pharmacology and Pharmaceutical Sciences Eczacılık ve İlaç Bilimleri The metabolites of ellagitannin metabolism urolithins display various biological activities Yuzugulen Jale EASTERN MEDITARRANEAN UNIVERSITY Noshadi Bahareh EASTERN MEDITARRANEAN UNIVERSITY Shukur Karar EASTERN MEDITARRANEAN UNIVERSITY Sahin Mustafa Fethi EASTERN MEDITARRANEAN UNIVERSITY Gulcan Hayrettin Ozan EASTERN MEDITARRANEAN UNIVERSITY 12 30 2019 2 2 102 110 11 25 2019 12 02 2019 Copyright © 2018, EMU Journal of Pharmaceutical Sciences 2018 EMU Journal of Pharmaceutical Sciences

Dietary consumption to various nuts, berries, and particularlypomegranate is an important source of ellagitannins. These molecules areparticularly subject to gastrointestinal metabolism producing urolithins as theirmetabolites. Urolithins (i.e., hydroxylated benzo[c]chromen-6-one analogues) havea greater absorption than the ellagitannins thus; greater bioavailability is ofgreat significance. Therefore, the biological activities obtained through the useof ellagitannin rich foods are mainly attributed tourolithins. These compoundspossess a good peripheral distribution. In addition, some of their furthermetabolitescan penetrate to the central nervous system which, is of a topic ofinterest for CNS related pathologies. This review has aimed to introduce thestructure and metabolism related formation of different urolithins concomitantto their biological activities discovered so far in the literature.

 Urolithins Ellagitannins Metabolism Cholinesterases Antioxidant Anticancer Antimalarial anti-inflammatory Abe LT, Lajolo FM, Genovese MI (2010). Comparison of phenol content and antioxidant capacity of nuts. Food Science and Technology 30: 254-259. Ahmed AH, Subaiea GM, Eid A, Li L, Seeram NP, Zawia NH (2014). Pomegranate extract modulates processing of amyloid-β precursor protein in an aged Alzheimer’s disease animal model. Curr. Alzheimer Res 11: 834−843. Bialonska D, Kasimsetty SG, Khan SI, Ferreira D (2009). Urolithins, intestinal microbial metabolites of pomegranate ellagitannins, exhibit potent antioxidant activity in a cell-based assay. J Agric Food Chem 57(21): 10181-10186. Bialonska D, Ramnani P, Kasimsetty SG, Muntha KR, Gibson GR, Ferreira D (2010). The influence of pomegranate by-product and punicalagins on selected groups of human intestinal microbiota. Int J Food Microbiol 140(2-3): 175-182. Cerdá B, Espín JC, Parra S, Martínez P, Tomás-Barberán FA (2004) The potent in vitro antioxidant ellagitannins from pomegranate juice are metabolised into bioavailable but poor antioxidant hydroxy-6H-dibenzopyran-6-one derivatives by the colonic microflora of healthy humans. Eur J Nutr 43(4): 205-20. Cerdá, B, Tomás-Barberán FA, Espín JC (2005). Metabolism of antioxidant and chemopreventive ellagitannins from strawberries, raspberries, walnuts, and oak-aged wine in humans: identification of biomarkers and individual variability. J Agric Food Chem 53: 227–235. Clifford MN, Scalbert A (2000). Ellagitannins–nature, occurrence and dietary burden. J Sci Food Agr 80(7): 1118-1125. Dell'Agli M, Galli GV, Bulgari M, Basilico N, Romeo S, Bhattacharya D, Taramelli D, Bosisio E (2010). Ellagitannins of the fruit rind of pomegranate (Punica granatum) antagonize in vitro the host inflammatory response mechanisms involved in the onset of malaria. Malar J 9(1): 208. Eghbaliferiz S and Iranshahi M (2016). Prooxidant activity of polyphenols, flavonoids, anthocyanins and carotenoids: updated review of mechanisms and catalyzing metals. Phytother Res 30(9): 1379-1391. Espín JC, Larrosa M, García-Conesa MT, Tomás-Barberán F (2013). Biological significance of urolithins, the gut microbial ellagic acid-derived metabolites: the evidence so far Evid Based Complement Alternat Med 270418. García-Villalba R, Beltrán D, Espín JC, Selma MV, Tomás-Barberán FA (2013). Time course production of urolithins from ellagic acid by human gut microbiota. J Agric Food Chem 61(37): 8797-8806. Garcia-Villalba R, Espín JC, Aaby K, Alasalvar C, Heinonen M, Jacobs G, Voorspoels S, Koivumäki T, Kroon PA, Pelvan E, Saha S, Barberán FA (2015). Validated method for the characterization and quantification of extractable and nonextractable ellagitannins after acid hydrolysis in pomegranate fruits, juices, and extracts. J Agric Food Chem 63(29): 6555-6566. Giménez-Bastida JA, González-Sarrías A, Larrosa M, Tomás-Barberán F, Espín JC, García-Conesa MT (2012). Ellagitannin metabolites, urolithin A glucuronide and its aglycone urolithin A, ameliorate TNF-α-induced inflammation and associated molecular markers in human aortic endothelial cells. Mol Nutr Food Res 56(5): 784-796. González-Sarrías A, Larrosa M, Tomás-Barberán FA, Dolara P, Espín JC (2010). NF-κB-dependent anti-inflammatory activity of urolithins, gut microbiota ellagic acid-derived metabolites, in human colonic fibroblasts. Br J Nutr 104(4): 503-512. González-Sarrías A, Giménez-Bastida JA, Núñez-Sánchez MÁ, Larrosa M, García-Conesa MT, Tomás-Barberán FA, Espín JC (2014). Phase-II metabolism limits the antiproliferative activity of urolithins in human colon cancer cells. Eur J Nutr 53(3): 853-864. González-Sarrías A, Núñez-Sánchez MÁ, García-Villalba R, Tomás-Barberán FA, Espín JC (2017). Antiproliferative activity of the ellagic acid-derived gut microbiota isourolithin A and comparison with its urolithin A isomer: the role of cell metabolism. Eur J Nutr 56(2): 831-841. González-Barrio R, Borges G, Mullen W, Crozier A (2010). Bioavailability of anthocyanins and ellagitannins following consumption of raspberries by healthy humans and subjects with an ileostomy. J Agric Food Chem 58(7): 3933-3939. Gulcan HO, Unlu S, Esiringu İ, Ercetin T, Sahin Y, Oz D, Sahin MF (2014). Design, synthesis and biological evaluation of novel 6H-benzo [c] chromen-6-one, and 7, 8, 9, 10-tetrahydro-benzo [c] chromen-6-one derivatives as potential cholinesterase inhibitors. Bioorg Med Chem 22(19): 5141-5154. Hadi SM, Bhat SH, Azmi AS, Hanif S, Shamim U, Ullah MF (2007). Oxidative breakage of cellular DNA by plant polyphenols: a putative mechanism for anticancer properties. Semin Cancer Biol 17(5): 370-6. Heleno SA, Martins A, Queiroz MJR, Ferreira IC (2015). Bioactivity of phenolic acids: Metabolites versus parent compounds: A review. Food Chem 173: 501-513. Kallio T, Kallio J, Jaakkola M, Mäki M, Kilpeläinen P, Virtanen V (2013). Urolithins display both antioxidant and pro-oxidant activities depending on assay system and conditions. J Agric Food Chem. 61(45):10720-10729. Landete JM (2011). Ellagitannins, ellagic acid and their derived metabolites: a review about source, metabolism, functions and health. Food Research International 44(5): 1150-1160. Larrosa M, González-Sarrías A, Yáñez-Gascón MJ, Selma MV, Azorín-Ortuño M, Toti S, Tomás-Barberán F, Dolara P, Espín JC (2010). Anti-inflammatory properties of a pomegranate extract and its metabolite urolithin-A in a colitis rat model and the effect of colon inflammation on phenolic metabolism. J Nutr Biochem 21(8): 717-725. Lei F, Xing DM, Xiang L, Zhao YN, Wang W, Zhang LJ, Du LJ (2003). Pharmacokinetic study of ellagic acid in rat after oral administration of pomegranate leaf extract. J Chromatogr B Analyt Technol Biomed Life Sci 796(1): 189-194. Lipińska L, Klewicka E, Sójka M (2014). The structure, occurrence and biological activity of ellagitannins: a general review. Acta Sci Pol Technol Aliment 13(3): 289-299. Manach C, Scalbert A, Morand C, Rémésy C, Jiménez L (2004). Polyphenols: food sources and bioavailability. Am J Clin Nutr 79(5): 727-747. Norouzbahari M, Burgaz EV, Ercetin T, Fallah A, Foroumadi A, Firoozpour L, Sahin MF, Gazi M, Gulcan HO (2018). Design, synthesis and characterization of novel urolithin derivatives as cholinesterase inhibitor agents. Letters in Drug Design & Discovery 15(11): 1131-1140. Okuda T, Yoshida T, Hatano T (1989). Ellagitannins as active constituents of medicinal plants. Planta Medica 55(02): 117-122. Pfundstein B, Haubner R, Würtele G, Gehres N, Ulrich CM, Owen RW (2014). Pilot walnut intervention study of urolithin bioavailability in human volunteers. J Agric Food Chem 62(42): 10264-10273. Piwowarski JP, Stanisławska I, Granica S, Stefańska J, Kiss AK (2017). Phase II conjugates of urolithins isolated from human urine and potential role of β-glucuronidases in their disposition. Drug Metab Dispos 45(6): 657-665. Prato M, Gallo V, Giribaldi G, Arese P (2008). Phagocytosis of haemozoin (malarial pigment) enhances metalloproteinase-9 activity in human adherent monocytes: role of IL-1beta and 15-HETE. Malar J. 7:157. Quideau S, Feldman KS (1996). Ellagitannin chemistry. Chemical Reviews 96(1): 475-504. Sala R, Mena P, Savi M, Brighenti F, Crozier A, Miragoli M, Stilli D, Del Rio D (2015). Urolithins at physiological concentrations affect the levels of pro-inflammatory cytokines and growth factor in cultured cardiac cells in hyperglucidic conditions. J Funct Foods 15: 97-105. Scalbert A, Johnson IT, Saltmarsh M (2005). Polyphenols: antioxidants and beyond. Am J Clin Nutr 81(1): 215S-217S. Seeram NP, Lee R, Heber D (2004). Bioavailability of ellagic acid in human plasma after consumption of ellagitannins from pomegranate (Punica granatum L.) juice. Clin Chim Acta 348(1-2): 63-68. Seeram NP, Zhang Y, Reed JD, Krueger CG, Vaya J (2006). Pomegranate phytochemicals. In Pomegranates (pp. 21-48). CRC Press. Selma MV, Beltrán D, García-Villalba R, Espín JC, Tomás-Barberán FA (2014). Description of urolithin production capacity from ellagic acid of two human intestinal Gordonibacter species. Food Funct 5(8): 1779-1784. Tomas-Barberan FA, García-Villalba R, Gonzalez-Sarrias A, Selma MV, Espin JC (2014). Ellagic acid metabolism by human gut microbiota: consistent observation of three urolithin phenotypes in intervention trials, independent of food source, age, and health status. J Agric Food Chem 62(28): 6535-6538. Tomás-Barberán FA, González-Sarrías A, García-Villalba R, Núñez-Sánchez MA, Selma MV, García-Conesa MT, Espín JC (2017). Urolithins, the rescue of “old” metabolites to understand a “new” concept: Metabotypes as a nexus among phenolic metabolism, microbiota dysbiosis, and host health status. Mol Nutr Food Res 61(1): 1500901. Tomas-Barberan FA, Selma MV, Espín JC (2018). Polyphenols’ gut microbiota metabolites: bioactives or biomarkers?. J Agric Food Chem 66(14): 3593-3594. Yuan T, Ma H, Liu W, Niesen DB, Shah N, Crews R, Rose KN, Vattem DA, Seeram NP (2015). Pomegranate’s neuroprotective effects against Alzheimer’s disease are mediated by urolithins, its ellagitannin-gut microbial derived metabolites. ACS Chem Neurosci 7(1): 26-33. Zhao W, Shi F, Guo Z, Zhao J, Song X, Yang H (2018). Metabolite of ellagitannins, urolithin A induces autophagy and inhibits metastasis in human sw620 colorectal cancer cells. Mol Carcinog 57(2): 193-200.