Ellagic acid in strawberry (Fragaria spp.): Biological, technological, stability, and human health aspects

Selva Muthukumaran; Carole Tranchant; John Shi; Xingqian Ye; Sophia Jun Xue

doi:10.1093/fqsafe/fyx023

Ellagic acid in strawberry (Fragaria spp.): Biological, technological, stability, and human health aspects

Muthukumaran, Selva; Tranchant, Carole; Shi, John; Ye, Xingqian; Xue, Sophia Jun 2017-12-21 00:00:00 Ellagic acid (EA) is one of the plant phenolics associated with human health benefits. It derives from ellagitannins found in some nuts, seeds, and fruits, especially berries. Strawberries are considered a functional food and nutraceutical source, mainly because of their high concentration of EA and its precursors. This review presents the current state of knowledge regarding EA, focusing on its content in strawberry plants, stability during processing and storage of strawberry-based foods, production methods, and relevance to human health. As alternatives to acid-solvent extraction, fermentation-enzymatic bioprocesses hold great promises for more eco-efficient production of EA from plant materials. Strawberry fruits are generally rich in EA, with large variations depending on cultivar, growth conditions and maturity at harvest. High EA contents are also reported in strawberry achenes and leaves, and in wild strawberries. Strawberry postharvest storage, processing and subsequent storage can influence EA content. EA low concentration in strawberry juice and wine can be increased by incorporating pre-treated achenes. Widespread recognition of strawberries as functional foods is substantiated by evidence of EA biological effects, including antioxidant, antiinflammatory, antidiabetic, cardioprotective, neuroprotective, and prebiotic effects. The health benefits attributed to EA-rich foods are thought to involve various protective mechanisms at the cellular level. Dietary EA is converted by the intestinal microbiota to urolithins, which are better absorbed than EA and may contribute significantly to the health effects attributed to EA-rich foods. Based on the evidence available, strawberry EA shows strong promises for functional, nutraceutical, and pharmaceutical applications. Future research should be directed at quantifying EA in different parts of the strawberry plant and in their byproducts; optimizing EA production from byproducts; understanding the biological actions of EA-derived metabolites in vivo, including the interactions between EA metabolites, other substances and food/biological matrices; characterizing the conditions and microorganisms involved in urolithin production; and developing delivery systems that enhance EA functionality and bioactivity. Key words: Strawberry plant; Ellagic acid; Processing; Metabolism; Bioactivity. © The Author(s) 2017. Published by Oxford University Press on behalf of Zhejiang University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 228 Muthukumaran et al., 2017, Vol. 1, No. 4 how stable it is following harvesting and how it can be extracted Introduction from plant materials. Likewise, it is critical to understand EA pos- Ellagic acid (EA) is one of the naturally occurring phenolic acids, sible health effects and fate in the human body. This review aims to a diverse class of bioactive polyphenols produced by plants. It is a present the current state of evidence and its limitations regarding breakdown product of larger and more complex polyphenols, the EA, with specific consideration of (1) EA physicochemical proper - ellagitannins (ETs), and is mostly found in plant cell vacuoles in free ties; (2) EA content in the strawberry plant; (3) its stability post-har- and covalently bound forms, namely EA or EA derivatives and ETs, vest and during processing and storage of strawberry-based foods; respectively (Atkinson et al., 2006; Shahidi and Yeo, 2016). Bound (4) EA production methods from plant materials amenable for use EA predominates in most plants but free EA can be released upon hy- with strawberries and their byproducts; and (5) EA bioactivity and drolysis, which occurs under physiological conditions in the human relevance to human health. While we prioritized evidence that per- gastro-intestinal tract and provides one of the bases for producing tains to strawberry specifically, such evidence is not always available. EA from plant material and for quantifying total EA content (Daniel Therefore, relevant evidence concerning EA from other plant sources et al., 1989). Free EA can also be formed during food processing was included in some sections. (Bakkalbaşi et al., 2009). EA and ET-rich foods and formulations have been shown to exert possible beneficial effects on human health, both in the realm of Chemistry and Physicochemical Properties chronic disease prevention and for the treatment of illnesses or con- of EA ditions such as cancer, diabetes, and diabetic complications, chronic EA (C H O ), also known as 2,3,7,8-tetrahydroxychromeno[5,4,3- 14 6 8 tissue inflammation, metabolic syndrome, obesity-mediated metabolic cde]chromene-5,10-dione (IUPAC nomenclature) and 4,4′,5,5′,6,6′- complications, cardiovascular, gastrointestinal, kidney, liver, and eye hexahydrodiphenic acid 2,6,2′,6′-dilactone, is a polyphenolic com- diseases, depression, Alzheimer’s and other neurodegenerative diseases pound that belongs to the phenolic acid group. Its fused four-ring (Sakthivel et al., 2008; Suzuki et al., 2009; Zhang et al., 2014; García- polyphenol structure (Figure 1a) is a dimeric derivative of gallic Niño and Zazueta, 2015; Ahmed et al., 2016; Anantharaju et al., acid, another phenolic acid, and has a molecular weight of 302.19 g/ 2016; Ayhanci et al., 2016; Derosa et al., 2016; Kang et al., 2016). EA mol (Royal Society of Chemistry, 2011). The four aromatic rings and its derivatives display a wide range of biological and physiological form a lipophilic domain, while the four hydroxyl groups and two activities, most notably antioxidant, antiinflammatory, antiglycative, lactones are hydrophilic and provide hydrogen bonding sites and estrogenic and/or antiestrogenic, antimicrobial as well as prebiotic electron acceptors, respectively. This polycyclic aromatic structure activities, which may contribute to human health (Landete, 2011). enables EA to take part in several reactions, including the formation EA and its precursors are abundant in certain plants and plant parts. of charge-transfer (electron–donor–acceptor) complexes. Those of dietary importance include some nuts, seeds, and fruits, includ- ing berries (Landete, 2011; Ahmed et al., 2016). Dietary intake of EA is Reactivity and interactions thus mainly through these foods either in their fresh or processed forms (Clifford and Scalbert, 2000). Certain berries like strawberries (Fragaria EA chemical reactivity can be divided into three categories, namely: spp.) are notable in that EA is present at high concentrations and can (1) oxidation by reactive free radicals; (2) reactions involving its account for 50% or more of the total phenolic constituents present in nucleophilic hydroxyl groups; and (3) electrophilic aromatic sub- the fruit after hydrolysis of its ET precursors (Häkkinen et al., 1999). stitution of its electron rich aromatic rings (Ahmed et al., 2016). EA is also one of their main antioxidants. As illustrated in Table 1, EA These reactions play a key role in EA antioxidant and other bio- concentration in strawberries is 3–10 times higher than in other fruits logical activities reviewed in the Ellagic Acid, Strawberries, and and nuts of commercial importance (Daniel et al., 1989; Williner et al., Human Health section of this paper. EA can also bind or interact 2003; Landete, 2011). EA is one of the non-nutrient phytochemicals with important biological macromolecules such as DNA, enzymes, supporting the recognition of strawberries as functional foods, health and other proteins, as well as smaller substances including minerals. promoter, and sources of nutraceutical ingredients (Basu et al., 2014; These binding properties are thought to contribute to EA biological Giampieri et al., 2015). Overall, strawberries have an excellent nutri- activities. For example, EA was shown to covalently bind to DNA tional profile (Giampieri et al., 2014) and are widely appreciated as in in vitro studies and this has been suggested as a mechanism for its foods and non-food commodities (e.g. skin products). antimutagenic and anticarcinogenic activities (Zhang et al., 2014). The global strawberry market has been growing, both in terms Similarly, interaction of EA with certain enzymes, such as VEGFR-2 of total revenues (+4.7% compounded annual growth rate from kinase, β-glucosidase, and angiotensin I-converting enzyme (ACE), 2007 to 2015) and in physical terms, reaching 8 476 thousand may exert beneficial effects for preventing breast cancer and manag- tonnes in 2015, a 5% growth from 2014. By 2015, it is expected ing hyperglycaemia and hypertension (da Silva Pinto et al., 2010; to reach 10 million tonnes (IndexBox Marketing, 2017). China Zhang et al., 2014). In vitro studies also showed that EA displays 2+ and the USA are leading the strawberry consuming markets. They an effective ferrous ions (Fe ) chelating activity, contributing to its are also the leading producers, followed by Mexico, Turkey, and antioxidant properties (Kilic et al., 2014), and binds to human serum Egypt, all benefiting from favourable climatic conditions (IndexBox albumin, the major transport protein in blood serum (Pattanayak Marketing, 2017). In the USA, per capita consumption of strawber- et al., 2017). The latter finding opens interesting venues for applica- ries has increased by 58% between 2002 and 2012 (USDA, 2014). tions that require effective transport and release of EA at target sites Strawberries and strawberry-based foods can, therefore, contribute in human physiological systems. a substantial amount of EA to the diet, while their byproducts can Stability and solubility be a valuable source of EA for applications that extend beyond trad- itional foods, thereby further broadening the market opportunities EA is a highly thermostable molecule with a melting point of 450°C and strengthening the strawberry value chain in various countries. and a boiling point of 796.5°C (Royal Society of Chemistry, 2011). To realize the full potential of EA in and from strawberry, it is ne- It is relatively stable under physiological conditions in the stomach cessary to have a good understanding of its distribution in the plant, (Usta et al., 2013), which makes it an interesting phytochemical Ellagic acid in strawberries, 2017, Vol. 1, No. 4 229 Table 1. Total ellagic acid (EA) content of selected fruits and nuts of commercial importance. Fruit or nut Total EA (mg/g DW) Total EA (mg/100 g FW) Reference Blackberries 1.5 – Daniel et al. (1989) Rasperries 1.5 – Daniel et al. (1989) Strawberries, Camarosa 0.70 6.1 Williner et al. (2003) Strawberries 0.63 – Daniel et al. (1989) Strawberries, Honeoye – 77.6 Koponen et al. (2007) Strawberry jam – 24 Koponen et al. (2007) Walnuts 0.59 – Daniel et al. (1989) Pecans 0.33 – Daniel et al. (1989) Green apples 0.07 – Williner et al. (2003) Plums 0.07 – Williner et al. (2003) Pineapples 0.06 – Williner et al. (2003) Pears 0.04 – Williner et al. (2003) Tangerines 0.04 – Williner et al. (2003) Bananas 0.02 – Williner et al. (2003) Brazil nuts ND – Daniel et al. (1989) Kiwi fruits ND – Williner et al. (2003), Daniel et al. (1989) Oranges ND – Williner et al. (2003), Daniel et al. (1989) Peanuts ND – Daniel et al. (1989) Red apples ND – Williner et al. (2003), Daniel et al. (1989) The commodities are ordered by total EA concentration, in descending order. Ripening stage for strawberries (Fragaria × ananassa): commercial ripeness or not specified. Values from Williner et al. (2003) are for strawberries with 50% and 100% red colour combined (fruits with edible value). DW, dry weight; FW, fresh weight; ND, not detected; –, not reported. 1 2 Figure 1. Structures of (a) ellagic acid, (b) a dimethyl derivative of ellagic acid , and two ellagitannins identified in strawberries, namely (c) agrimoniin and (d) 2 1 2 sanguiin H-6 . These compounds were reported, respectively, by Ramírez de Molina et al. (2015), Maas et al. (1991b), Shi et al. (2015), Lipińska et al. (2014), and Vrhovsek et al. (2012). candidate for the development of foods, nutraceuticals, and drugs metabolites called urolithins (Us), which are more water soluble to be taken orally. Pure crystalline EA is sparingly soluble in water and bioavailable than EA (Espín et al., 2013; Tomás-Barberán et al., (9.3 µg/ml at pH 7.4) and in alcohol (O’Neil, 2006; Landete, 2011), 2017). Current research also aims at developing delivery systems which is due in part to the high degree of crystallinity resulting from that enhance EA solubility and bioavailability, as reviewed in the the planar and symmetrical structure of EA and extensive hydrogen- Ellagic Acid, Strawberries, and Human Health section. bonding network formed within the crystal (Li et al., 2013). Low Occurrence water solubility can limit EA bioavailability in humans. However, recent evidence indicates that the metabolism of dietary EA by cer- EA is produced by plants as one of their secondary metabolites. It tain bacteria in the intestine leads to the production of bioactive accumulates in the cell vacuoles in two forms: free EA (i.e. EA and 230 Muthukumaran et al., 2017, Vol. 1, No. 4 EA derivatives, Figure 1a and b) and bound EA, also known as ETs, their content in EA. EA has been shown to contribute to the straw- in which EA is esterified with sugar molecules, commonly glucose berry plant defense system (Amil-Ruiz et al., 2011) and to be dis- (Figure 1c and d). ETs are generally the predominant form. They are tributed in various organs and tissues of the plant. These include the a group of hydrolysable tannins, meaning that they can be fractioned fruits, flowers, leaves, stems, and roots (Figure 2a and b, Table 2), into their constituents, EA in particular, by hydrolysis. Hydrolysable although most of the research to date has focused on the fruit, in tannins are widely distributed in Angiosperms (flowering plants) addition to been primarily concerned with one species. An overview (Ascacio-Valdés et al., 2011), including strawberries, and occur in is provided in the following sections. some algae (Shannon and Abu-Ghannam, 2016). Agrimoniin and It should be noted first that the values of EA content reported in sanguiin H-6 (Figure 1c and d) are two ETs found in strawber- different studies can be difficult to compare and that some discrep- ries (Vrhovsek et al., 2012; Lipińska et al., 2014; Shi et al., 2015). ancies are observed. This is due in part to methodological differences ETs are more water soluble than EA (Landete, 2011). EA and ETs in quantifying the EA (e.g. different hydrolytic, extraction, or de- biosynthesis involves glucose and gallic acid (Ascacio-Valdés et al., tection conditions) and in reporting it (e.g. free vs. total EA), which 2011; Schulenburg et al., 2016). Plant phenols including EA and are not always clearly reported. Moreover, the EA content of fresh ETs have been associated with miscellaneous biological functions in unprocessed strawberries varies considerably depending on multiple plants, such as defense against bacteria, fungi, viruses, and animal factors, including the cultivar (cultivated variety), agricultural prac- herbivores as well as protection against solar radiation, which can tices, growing environment and season, the developmental stage of benefit yields and integrated pest management by increasing plant the fruit, as well as the type of tissue within the fruit and in the resistance to some diseases (Treutter, 2010; Amil-Ruiz et al., 2011; plant. The influence of these factors is relatively well established for Schulenburg et al., 2016). Further details on the sources, chemistry, F. ananassa fruits. In contrast, very little is known about the factors and biology of EA and ETs can be found in the following reviews influencing the EA content of other parts of the plant and of wild (Tsao, 2010; Ascacio-Valdés et al., 2011; Landete, 2011). species of strawberries. Fruits EA Content and Distribution in the EA distribution within the fruit Strawberry Plant Within the strawberry fruit, EA is more concentrated in the achenes Strawberries belong to the genus Fragaria, a member of the Rosaceae (seeds), located on the surface of the fruit, than in the fruit pulp family. This genus includes 20 named wild species, three described or flesh which is devoid of achenes (Figure 2a and b , Table 2). naturally occurring hybrid species, and two cultivated hybrid species Consequently, the whole fruit is richer in EA than the pulp and of commercial importance, namely F. × ananassa (also known as the some of its derived products (e.g. seedless strawberry juices and garden strawberry) and F. vescana, which are cultivated worldwide purées), as illustrated in Table 2. Substantially higher concentra- and in Europe, respectively (Hummer et al., 2011). All of these spe- tions of EA, per fresh weight (FW), in the achenes are partly due to cies are potential sources of EA but very few [F. × ananassa mainly, the lower water content of the achenes. When expressed on a dry followed very distantly by F. vesca (wild or woodland strawberry) weight (DW) basis, EA concentrations in achenes and pulp are gen- and F. chiloensis Chilean white strawberry)] have been studied for erally of the same order of magnitude. A comprehensive study that Figure 2. (a) Cross-section of the strawberry fruit (Fragaria × ananassa) and (b) other plant parts that contain ellagic acid. Ellagic acid in strawberries, 2017, Vol. 1, No. 4 231 Table 2. Total ellagic acid content (mg/100 g of FW, except where indicated) in different parts of the strawberry plant. Country, cultivar Whole fruit ( ) or Achenes Leaves Flowers Roots Juice Reference pulp ( ) Argentina F F P Camarosa 10.1 (18.1 green ) 1.52 – – – – – Williner et al. (9.0 green ) (2003)* USA – 5.22 3.8 – – – ND Daniel et al. (1989) USA Totem 11.8 90.3 – – – – Aaby et al. (2005) Puget Reliance 9.5 35.5 – – – – Spain Camarosa 10.1 146.3 – – – – Ariza et al. (2016)* USA P P Arking 37.1 (64.0 green ) 399 (312 – – – – Maas et al. (1991a)* green) P P Micmac 21.2 (17.7 green ) 613 (721 – – – – green) P P Vesper 19.0 (38.8 green ) 858 (491 – – – – green) P P Tangi 19.1 (30.1 green ) 95.9 (204 – – – – green) P P Tribute 12.3 (25.7 green) 597 (215 807 – – – green) P P Delite 8.9 (22.4 green) 350 (110 501 – – – green) P P Earliglow 6.5 (25.2 green) 1 367 (188 202 – – – green) P P Honeoye 3.4 (19.6 green ) 729 (358 323 – – – green) Finland Jonsok – – 49.1–131 – – – Hukkanen et al. (2007) Czech Republic – – – 21.2– – – – Buřičová et al. 34.5 mg/L (2011) Finland Jonsok – – – Relatively high free – – Hanhineva et al. EA and ET contents (2008) in receptacle** *** USA Blakemore – – – – EA and EAD – Nemec (1973) Howard 17 – – – – previously – Sunrise – – – – found in – Surecrop – – – – fruits and – leaves** Wild strawberries Chile F F F, F. chiloensis EA , EAD and ET ** – EA and ET** – ND – Simirgio- tis and Schmeda– Hirschmann (2010) Portugal F. vesca Dias et al. (2015a,b) Commercial – – 35.3 mg/g**** – 16.1 mg/g – Wild samples – – 69.5 mg/g**** – traces – Cultivars of Fragaria × ananassa, except where indicated (F. chiloensis and F. vesca). Fruits, pulp (fruit without achenes) and achenes were from red strawberries, except where indicated (green). Juice from the fruit was unprocessed. EA, ellagic acid; EAD, ellagic acid derivatives; ET, ellagitannins; ND, not detected; –, not determined. *Values from Williner et al., Ariza et al. and Maas et al. (reported in mg/g of DW by these authors) were converted to mg/100 g of FW by multiplying by 0.08 × 100, i.e. assuming 92% water in strawberries. For achenes and leaves, a water content of 30% and 75% water was assumed, respectively, i.e. conversion factors of 0.7 × 100 and 0.25 × 100. **These compounds were detected but their concentrations were not reported. ***For flowers, five individual flower organs were studied individually, namely the petal, sepal, stamen, pistil, and receptacle that gives rise to the strawberry fruit. Relatively high contents of EA and ET in the receptacle were as in the early stages of the strawberry fruit maturation. ****Leaves and stems were analysed together in the study of Dias et al. (2015a). 232 Muthukumaran et al., 2017, Vol. 1, No. 4 included 36 clones (cultivars and breeding selections) of F. × anana- the pulp, achenes, and leaves from 36 cultivars. The mode of inherit- ssa reported average EA concentrations of 8.46 and 7.24 mg/g of ance of EA content in strawberry remains to be established. DW (about 592 and 506 mg/100 g of FW) in the achenes of red and green strawberries, respectively, and of 1.55 and 3.54 mg/g DW Influence of agricultural practices and growing environment (12.4 and 28.3 mg/100 g FW) in the pulp of red and green fruits Agricultural practices (e.g. cultural system and fertilization) and lo- (Maas et al., 1991a). Superior or high EA concentration in achenes cation (i.e. environmental conditions such as light and temperature) vs. pulp was also found in ripe strawberries of other cultivars (Aaby influence the accumulation of phenols in several crops (Treutter, et al., 2005; Fait et al., 2008; Ariza et al., 2016). Daniel et al. (1989) 2010). Strawberry fruits seem to accumulate higher amounts of reported a relatively low concentration in the achenes (Table 2), but phenolic compounds when they are grown under conditions opti- they did not mention cultivar. It is possible that the pulp in that mized for plant growth and fruit yield. For instance, fruits grown in study was not achene-free. a hill plasticulture (or raised bed) system were found to have higher Strawberry achenes also have superior total phenolic content EA contents and antioxidant capacities than fruits from the con- and antioxidant capacity compared with the pulp. Despite repre- ventional matted-row system (Wang et al., 2002). These research- senting a mere 1% of the whole fruit on a FW basis, achenes were ers showed a significant effect of cultural system and genotype (14 found to contribute 41% of the total phenolic compounds and 45% strawberry cultivars and selections), individually, as well as a signifi- to 81% (depending on the determination method) of the antioxi- cant interaction between the two variables, on the EA content of the dant capacity of the whole ripe fruit (Ariza et al., 2016). Similarly, fruits. Similarly, the use of a compost and full strength NPK fertilizer Aaby et al. (2005) found that the achenes contributed 11% of the almost doubled the free EA content of ripe fruits from Allstar and total phenolics and 14% of antioxidant activity of ripe strawberries. Honeoye cultivars (up to 0.83 and 0.63 mg/100 g FW, respectively) Both studies suggest that, in the achenes, total phenolics and in par- compared with unfertilized controls (Wang and Lin, 2003). In con- ticular EA, EA glycosides, and ETs (Aaby et al., 2005) contributed trast, Anttonen et al. (2006) showed a reduction of total EA (from the most to the antioxidant capacity. The high EA content and anti- 29.29 to 24.79 mg/100 g FW) and flavonol contents in strawberries oxidant capacity of achenes can be used profitably to enrich straw- of the Bounty cv. by increasing the level of fertilization, but there berry juices and purées (see Influence of Processing and Subsequent was no indication about plant growth and yield in their work. They Storage section) as well as other products that would otherwise con- also reported that organically grown fruits from six cultivars tended tain negligible or low amounts of EA. This is a promising strategy to be richer in flavonols than conventionally grown fruits (Anttonen to add value to achene-rich wastes generated during the produc- et al., 2006), but did not assess this effect on EA. Häkkinen and tion of some strawberry-based foods and to turn these wastes into Törrönen (2000) assessed the influence of conventional vs. organic valuable products for food as well as cosmetic and pharmaceutical cultivation technique on the phenolic content of three cultivars applications. (Honeoye, Jonsok, and Polka) and found no significant effect, ex- cept for the Jonsok cv. for which the organically cultivated fruits had Influence of cultivar 12% higher concentrations of total EA and total phenolics. The concentration of EA in ripe strawberry fruits varies considerably Other practices (namely late planting time and use of white vs. among F. ananassa cultivars (genotypes) and studies, ranging from brown mulch) as well as tertiary fruit order in the strawberry in- less than 10 mg/100 g FW to over 100 mg/100 g, as illustrated in florescence were found to significantly increase the contents of EA Table 3. Some studies on the subject (Maas et al., 1991a; Cordenunsi and total phenolics in ripe fruits of the Korona cv., while early forc- et al., 2002; Wang et al., 2002; Williner et al., 2003; Skupień and ing and shading had no significant effect (Anttonen et al., 2006). Oszmiański, 2004; Atkinson et al., 2006; da Silva Pinto et al., 2008; Reflective mulches were also found to significantly increase the total Bojarska et al., 2011; Aaby et al., 2012; Kim et al., 2015) have EA content of fruits of the Flamenco cv., but had no effect in the examined a large number of cultivars, from 5 to 44 depending on Elsanta cv. (Atkinson et al., 2006). These researchers also showed the study. Table 3 provides an overview of some of the studies and that crop load (i.e. number of fruits per plant) had no significant cultivars. It is noteworthy that the cultivars yielding the highest (or effect on the total EA content of fruits of the Elsanta and Florence lowest) levels of EA in ripe fruits generally differ among studies. cultivars, suggesting that EA concentration is relatively tightly regu- This not only reflects methodological differences in quantification lated in strawberry, irrespective of crop load. Last but not least, sig- methods, but also the influence of growing conditions and practices, nificant year-to-year variations in total EA content were reported i.e. the interplay between genotype and environment. For instance, with some cultivars (Atkinson et al., 2006; Kim et al., 2015). The within the following individual studies [Maas et al. (1991a) (36 cv.), influence of location was noted with respect to EA in the fruit pulp Atkinson et al. (2006) (44 cv.), Kim et al. (2015) (14 oriental cv.), and achenes (Maas et al., 1991a) as well as EA and flavonols in the Skupień and Oszmiański (2004) (6 cv.), Bojarska et al. (2011) (11 whole fruit (Häkkinen and Törrönen, 2000; Anttonen et al., 2006). cv.), da Silva Pinto et al. (2008) (7 cv.), Williner et al. (2003) (5 cv.), Aaby et al. (2012) (27 cv.), Cordenunsi et al. (2002) (6 cv.), Wang Influence of fruit maturity et al. (2002) (14 cv.)], the concentration of EA in ripe strawberries EA concentration in strawberry fruits also depends on the devel- varied by a factor of 10, 6, 5, 4, 3, 3, 3, 2, 2, and 2, respectively, be- opmental stage of the fruit. As illustrated in Table 4, the highest tween the cultivars that produced the highest vs. lowest concentra- concentration occurs in the early stages of fruit maturation (green tion. Overall, these findings suggest that the EA content of the fruit strawberries), then gradually declines as the fruit ripens. This trend can be modified through breeding and selecting cultivars that gener - was shown for the whole fruit, that is, pulp and achenes combined ally produce high (or low) EA levels under the growing conditions (Williner et al., 2003; Aaby et al., 2012), as well as for the pulp considered. Fruits with a high EA content can be obtained this way, without achenes (Maas et al., 1991a; Williner et al., 2003; Fait but this may not necessarily translate into high EA concentrations et al., 2008). In whole strawberries, the decrease in the EA content in other parts of the plant, as reported by Maas et al. (1991a). This between green and fully ripe stages ranged from 2.8 to 8.5 times group found no identifiable relationship between the levels of EA in across the five cultivars studied by Williner et al. (2003). In their Ellagic acid in strawberries, 2017, Vol. 1, No. 4 233 Table 3. Total and free ellagic acid (EA) contents of ripe strawberries from selected cultivars grown in different countries. Country, cultivar Total EA (mg/100 g FW) Free EA (mg/100 g FW) Reference Argentina Chandler 6.84 – Williner et al. (2003) Camarosa 6.16 – Sweet Charly 4.86 – Oso Grande 2.85 – Milsei 2.86 – Camarosa 6.67 0.61 Van De Velde et al. (2013) Selva 11.9 0.65 Brazil Oso Grande – 1.87 Cordenunsi et al. (2002) Campineiro – 1.62 Mazi – 1.36 Dover – 1.01 Toyonoka – 0.98 Pajaro – 0.90 Dover 47 2.60 da Silva Pinto et al. (2008) Camarosa 42 2.20 Oso Grande 28 2.22 Sweet Charlie 24.7 0.75 Toyonaka 17.0 1.05 Finland Jonsok 40.3 – Häkkinen et al. (2000) Jonsok 79.9 1.4 Koponen et al. (2007) Honeoye 77.6 2.2 Polka 68.3 0.7 Jonsok 52.2 – Häkkinen and Törrönen (2000) Polka 51.7 – Honeoye 46.7 – Korea Kim et al. (2015) Dahong 15.0 – Keumhyang 8.0 – Seolhyang 3.0 – Norway Aaby et al. (2012) Bounty 17.3 0.7 Honeoye 13.5 1.8 Senga V 11.6 0.6 Polka A 11.2 1.3 Jonsok 10.2 0.8 Poland Camarosa 119.3 – Bojarska et al. (2011) Elsanta 103.4 – Honeoye 63.5 – Senga Sengana 58.0 – Polka 56.1 – Thuriga 55.3 – Kama 54.0 – Onebor 53.4 – Kent 52.8 – Dukat 51.6 – Heros 45.2 – Elsanta 261.0 – Skupień and Oszmiański (2004) Kent 108.8 – Dukat 105.5 – Selva 72.6 – Sweden Määttä-Riihinen et al. (2004) Honeoye 15.5 4.0 Jonsok 14.9 4.1 Polka 11.4 3.5 UK Atkinson et al. (2006) Osmanli (w) 34.1 1.13 Nida 32.2 2.14 Laura 24.3 2.11 EM676WF (w) 20.6 1.17 234 Muthukumaran et al., 2017, Vol. 1, No. 4 Table 3. Continued Country, cultivar Total EA (mg/100 g FW) Free EA (mg/100 g FW) Reference Coral 17.6 2.30 Rosie 15.5 0.64 Ciloe 12.6 0.75 Totem 9.8 1.01 Elsanta 9.4 ND Tango 7.9 0.43 Hapil 6.0 ND USA Arking 37.1 – Maas et al. (1991a)* Micmac 21.2 – Vesper 19.0 – Tangi 11.9 – Oso Grande 9.6 – Allstar 6.6 – Totem 6.6 – Annapolis 3.4 – Honeoye 3.4 – Mohawk – 3.45 Wang et al. (2002) Allstar – 2.57 B244-89 – 1.80 Cultivars of Fragaria × ananassa. Ripening stage: ripe, full maturity, commercial ripeness or not specified, depending on the study. Values from Williner et al. (2003) are for strawberries with 50% and 100% red colour combined (fruits with edible value). FW, fresh weight, except for the values from Atkinson et al. (2006) which are in mg/100 g of frozen weight; ND, not detected; –, not determined; (w), cultivars which produce white fruits. *Values from Maas et al. (1991a) are for pulp without achenes and were reported in mg/g of DW by these authors. They were converted to mg/100 g of FW by multiplying by 0.08 × 100, i.e. assuming 92% water in strawberries. Table 4. Total ellagic acid content (mg/100 g of FW) of strawberries at different stages of ripeness. Country, cultivar Stage of ripeness Reference 0% red (green) 50% red (e) 100% red (e) 50% and 100% red combined (e) Argentina Williner et al. (2003)* Chandler 17.8 9.45 4.13 6.84 Camarosa 12.9 7.82 4.57 6.16 Sweet Charly 11.8 5.87 3.85 4.86 Oso Grande 8.82 4.0 1.69 2.85 Milsei 13.8 4.1 1.63 2.86 USA Maas et al. (1991a)** Arking 64.0 – 37.1 – Micmac 17.7 – 21.2 – Vesper 38.8 – 19.0 – Tangi 30.2 – 11.9 – Oso Grande ND – 9.6 – Annapolis ND – 3.4 – Honeoye 19.7 – 3.4 – Cultivars of Fragaria × ananassa; (e), fruits with edible value; –, not determined. *Values from Williner et al. (2003) are for whole strawberries (pulp with achenes). **Values from Maas et al. (1991a) are for pulp without achenes and were reported in mg/g of DW by these authors. They were converted to mg/100 g of FW by multiplying by 0.08 × 100, i.e. assuming 92% water in strawberries. work, the sharpest decline was for the Milsei cv. in which high EA Based on the evidence available for the Camarosa cv., the decline content in the early developing fruit did not persist during ripening. in EA concentration seems to be less pronounced in the whole fruit Aaby et al. (2012) reported significant decreases in EA conjugates than in the pulp (1.8 and 5.9 time reductions, respectively) (Williner by about 1.6 times between nearly ripe and fully ripe stages (Blink et al., 2003). This finding is consistent with the high EA content of and Polka cv.) and decreases by 1.4 times in agrimoniin content the achenes, which was found to increase or decrease (Maas et al., between nearly ripe and ripe stages (Blink, Polka, and Senga cv.). 1991a), depending on cultivar and possibly other factors to be iden- In the achene-free pulp, the decrease in EA content between green tified, during ripening of the fruit. and fully ripe stages ranged from 1.6 to 4 times across the 31 clones Maas et al. (1991a) showed that the evolution of the EA concen- (cultivars and breeding selections) studied by Maas et al. (1991a). tration in the achenes during ripening is not as consistent as for the Ellagic acid in strawberries, 2017, Vol. 1, No. 4 235 pulp: while it increased by 2–7 times for 17 clones (e.g. Earliglow, amount of free EA in the receptacle was relatively high (Hanhineva Honeoye), it decreased by 1.5–4 times for 13 other clones (e.g. et al., 2008). These findings are consistent with the particularly high Micmac, Tangi), as illustrated in Table 2 for some clones. Lower EA EA content of strawberries in the early stages of maturation (Maas content in the achenes from ripe strawberries was also reported in a et al., 1991a; Funt et al., 2000; Williner et al., 2003). They also con- study of the Herut cv., which indicated that EA, EA derivatives, and cur with the presence of EA in some honeys (Kassim et al., 2010; ETs were less abundant in the achenes during the late stages of fruit Rao et al., 2016), which presumably reflects the ET and EA compos- development (Fait et al., 2008). For the various cultivars studied by ition of the flowers visited by honey bees. It is worth noting that the Maas et al. (1991a), no evident relationship was evidenced between order of the fruit in the strawberry inflorescence, from primary to the EA concentration and its variation during ripening in the achenes tertiary order, seems to increase the amount of EA in the fruit, as evi- and in the pulp. denced in ripe strawberries of the Korona cv. (Anttonen et al., 2006). Fruits from wild species of strawberries Leaves The limited evidence currently available indicates that fruits from The leaves of some berry plants are valuable sources of natural bio- wild strawberry species are rich sources of EA. In a study of fully ma- active compounds, including EA and ETs (Ferlemi and Lamari, 2016). ture F. vesca fruits from 15 wild strawberry accessions (genotypes), Strawberry leaves were found to contain relatively high amounts total EA concentration ranged from 15.18 to 26.36 mg/100 g FW, of EA (Maas et al., 1991a; Hukkanen et al., 2007; Simirgiotis and compared with 18.56 mg/100 g in fruits of the cultivated Camarosa Schmeda-Hirschmann, 2010; Žugić et al., 2014; Dias et al., 2015a), cv. (Yildiz et al., 2014) (Table 5). The high average content found as illustrated in Table 2. The study of Maas et al. (1991a) is the most with accession FV-4 was significantly higher than for Camarosa. comprehensive to date on this subject as it included 36 clones of F. In another study of fully mature F. vesca fruits, values of 37.9 and × ananassa and quantified the EA in the fruit pulp and achenes in 17.5 mg/g of lyophilized extract or infusion were reported for addition to the leaves. Higher EA concentration was found in the total EA derivatives in hydromethanolic fruit extracts and infu- leaves than in the pulp and sometimes achenes. Average EA content sions, respectively (Dias et al., 2016). Consistent with these val- in the leaves, calculated over 13 clones, was 14.71 mg/g DW, with ues, the hydromethamolic extracts showed higher antioxidant and values ranging from 8.08 to 32.30 mg/g depending on clone. This antibacterial activities than the infusions. Another study detected average was about 9, 4, 2, and 2 times higher than for red and green but did not quantify EA, EA derivatives, and ETs in methanolic fruit pulp and achenes from red and green fruits, respectively, which extracts of ripe F. chiloensis ssp. chiloensis f. chiloensis fruits. These were calculated over 36 clones. Large differences in EA content were extracts had higher total phenolic content and antioxidant activity evidenced among clones. All had a superior EA content in the leaves compared with leaf and root extracts (Simirgiotis and Schmeda- compared with fruits, but only eight clones out of 13, including Hirschmann, 2010). Tribute and Delite, had a leaf EA content greater than for red and green achenes. EA content from one tissue did not correlate consist- ently with values of the other tissues (Maas et al., 1991a). A study Flowers of strawberries cv. Jonsok showed that EA, EA derivatives, and ETs There is hardly any information on EA in the strawberry flower. accumulated in the leaves and fruits after treatment with benzothia- A study of secondary metabolites in five individual flower organs diazole (BTH) and inoculation with powdery mildew conidia. This (petal, sepal, pistil, stamen, and receptacle) of F. × ananassa cv. was suggested to play a role in the BTH-induced resistance of the Jonsok revealed that the majority of the metabolites identified were plant to mildew infection (Hukkanen et al., 2007). ETs that accumulated in all five parts of the flower (Hanhineva et al., Leaves of wild species of strawberries have been studied more 2008). The pistil, stamen, and receptacle contained the highest pro- recently in relation to their EA content (Simirgiotis and Schmeda- portion of ETs and ET derivatives, including agrimoniin and galloyl- Hirschmann, 2010; Žugić et al., 2014; Dias et al., 2015a). In F. vesca hexahydroxydiphenic acid (HHDP)-glucose, which also occur in L., EA, EA derivatives, and ETs were found in appreciable amounts in strawberry fruits and leaves. The ETs and ET precursors identified leaves and stems (Dias et al., 2015a), but the results from this study in the receptacle were similar to the ones found in the early develop- are not specific to leaves as mixtures of leaves and stems were used. ing fruit, which derives from the swollen flower receptacle, and the Table 5. Total and free ellagic acid (EA) contents of ripe wild strawberries of different genotypes grown in different countries. Country, genotype Total EA (mg/100 g FW) Free EA (mg/100 g FW) Reference Portugal 37.9 – Dias et al. (2016)* Turkey Yildiz et al. (2014) FV–4 26.4 – FV–1 25.1 – FV–10 23.4 - FV-15 21.2 – FV-14 18.2 – FV-5 17.9 – FV-6 17.1 – FV-7 15.2 – Camarosa cv. 18.6 – Fragaria vesca L., except for the Camarosa cultivar of Fragaria × ananassa included for comparison. FV, Fragaria vesca genotype; FW, fresh weight. *The value from Dias et al. (2016) is for total EA derivatives in mg/g of lyophilized extract. 236 Muthukumaran et al., 2017, Vol. 1, No. 4 They were from commercial and wild samples and three types of to disease and pests. Compiling the values of EA concentrations in extracts were used: hydromethanolic extracts and two water extracts a searchable, peer-reviewed database would be useful. Research in resembling homemade herbal preparations (infusion and decoction). this field should also be extended to lesser studied species and varie- The hydromethanolic extracts showed the highest contents of total EA ties, not only because they are potentially good sources of EA and derivatives (35.31 and 69.49 mg/g for commercial and wild samples, similarly beneficial compounds, but also because they could be bet- respectively). All the extracts displayed antioxidant capacity, particu- ter adapted to grow in certain regions of the world where the cur- larly those from the wild sample, especially the infusion (Dias et al., rent commercial species does not grow as well or as cost-effectively. 2015a). Likewise, Buřičová et al. (2011) reported appreciable contents This could open the way to less input/labour intensive and more of EA (21.2–34.5 mg/l, i.e. 1.1–1.8 mg/g of dry leaves) in water extracts cost-effective and ecological production of EA-rich materials. of F. vesca L. leaves. EA and catechin were found to contribute the most to the total antioxidant capacity of the leaf extracts, which was 62.8% EA Stability in Strawberries During Post- that of green tea. Žugić et al. (2014) reported high contents of total harvest Storage and Processing phenols and total tannins in methanolic extracts of aerial parts of F. vesca L., but it is not clear whether these observations are for extracts Influence of post-harvest storage from leaves or other parts of the plant. For leaves, the extracts had the The total EA content (i.e. bound and free EA) of freshly harvested second highest antioxidant activity of all 10 herbal plants they studied. strawberries of the Jonsok cv. was found to be stable during short- F. chiloensis ssp. chiloensis form chiloensis, a wild species of Fragaria term storage (24 h) at either 5ºC or 22ºC (Häkkinen et al., 2000). endemic to southern Chile, which produces light red or ‘white’ straw- Long-term storage at –20ºC, on the other hand, led to a signifi- berries, was studied by Simirgiotis and Schmeda-Hirschmann (2010). cant reduction of total EA content by 25% and 40% after 6 and They detected EA, EA derivatives, and ETs in methanol extracts from 9 months, respectively (Häkkinen et al., 2000). This reduction was the leaves. Most of these compounds were also detected in the fruit explained by the oxidation of EA and its ability to react with free extracts. The leaf extracts had the second-highest antioxidant activity radicals and chelate metals. After storage at 5ºC for 5 and 10 days, and total phenolic content after the fruit extracts. a 30% increase in the free EA content of the fruits (Selva cv.) was reported in another study (Gil et al., 1997). The increase in free EA Stems can be explained by the hydrolysis of ETs (bound EA) over time, No reports were found on EA in strawberry stems and stolons (run- which releases free EA. These researchers further showed that ners), which are leafless stems growing at or near the surface of the storage for 5 days at 5ºC under modified atmospheres contain- soil. One study used strawberry stems to assess the phenolic com- ing 10–40% CO limited the increase in free EA over time. These position of F. vesca L. vegetative parts (leaves and stems from com- elevated CO concentrations also had a detrimental effect on the mercial and wild samples), but these parts were mixed together (Dias internal colour of the fruits (Gil et al., 1997). Another study found et al., 2015a). Appreciable amounts of EA, EA derivatives, and ETs that the free EA concentration of fresh-cut strawberries (Camarosa were found, but these results are not specific to the stems. cv.) stored at 4ºC under either superatmospheric O , low O , or pas- 2 2 sive atmospheres was stable for 4 days, then rose until Days 9–11 in all samples (Odriozola-Serrano et al., 2010). After that time, the Roots fruits stored under high-O or passive atmosphere exhibited a drop As for flowers and stems, limited information is available on EA in free EA content until the end of the storage period (21 days), while in strawberry roots. An early report revealed that the roots of four free EA continued to rise in the fruits stored under low O atmos- cultivars of F. × ananassa (Blakemore, Howard 17, Sunrise, and pheres. High O atmospheres also promoted the loss of vitamin C. Surecrop) contain a diverse assortment of phenolics, many of which The low O and passive atmospheres were found to best maintain are also present in the leaves and fruits (Nemec, 1973). EA, an EA the antioxidant capacity of the fresh-cut fruits during cold storage derivative, and two hydrolysable tannins were detected in the root (Odriozola-Serrano et al., 2010). Post-harvest treatment of straw- extracts. This researcher noted that the number of phenolic com- berries (Goha cv.) with 15% CO for 3 h prior to storage at 4ºC pounds present in the roots varied during the year and was higher in under regular atmosphere was found to improve the overall quality summer-grown roots. Two subsequent studies looked at the phenolic retention of the fruits for up to 9 days compared with untreated con- composition of roots of wild species of strawberries. The first one, trols and fruits treated with higher concentrations of CO (Chandra with F. chiloensis ssp. chiloensis f. chiloensis, did not detect EA, EA et al., 2015). It remains to be established whether this pre-treatment derivatives, and ETs in root methanol extracts, unlike fruit and leaf could also benefit the retention of EA. extracts. The root extracts had the lowest antioxidant activity, which was attributed to their lower total phenolic content (Simirgiotis and Influence of processing and subsequent storage Schmeda-Hirschmann, 2010). The second study focused on F. vesca L. roots using commercial and wild samples and three types of Jam and purée processing and storage extracts (hydromethanolic extract, infusion, and decoction) (Dias Research into strawberry EA stability in processed foods has focused et al., 2015b). Roots from the commercial sample showed the highest primarily on jams and purées. A few studies looked at the EA content content of total EA derivatives, particularly in the hydromethanolic of strawberry processing byproducts as these are potentially interest- extract (16.06 mg/g). All the extracts possessed antioxidant activity ing sources of EA and of other valuable phytochemicals. Strawberry particularly those from the wild sample, especially the infusion. jam preparation usually involves cooking the slightly mashed fruits In conclusion, the strawberry plant as a whole is a rich source of without completely crushing them. Cooking strawberry fruits with EA. Further research should be directed towards characterizing lesser sugar was found to decrease the total EA content compared with studied parts (e.g. leaves, stems, and roots) for their EA content in re- fresh strawberries. Reductions of 35% and 20% have been reported lation to cultivars, growth conditions and agricultural practices, EA by Flores and del Castillo (2016) (Splendor cv.) and Häkkinen et al. content of other parts of the plant, as well as resistance of the plant (2000) (Jonsok cv.), respectively. These losses in total EA are thought Ellagic acid in strawberries, 2017, Vol. 1, No. 4 237 to be due to increased oxidation of EA when the integrity of the Like strawberry jams, thermally processed strawberry purées, cell wall and membrane is lost upon cooking and mixing (Häkkinen produced by crushing and moderate thermal treatment of the fruits et al., 2000). It is not known whether the addition of antioxidants at 75–80ºC, were found to contain less total EA (Aaby et al., 2007b) may help protect EA and increase its retention in the final products. and more free EA (Aaby et al., 2007b; Truchado et al., 2012) than Other researchers measured free EA (i.e. without hydrolysis) rather fresh strawberries. Storing the purées in the dark at 6ºC improved than total EA (after hydrolysis) to study the effect of jam cooking the retention of total EA compared with storage at 22ºC, especially (Zafrilla et al., 1999). They reported a 150% increase in the content for the purées that had been enriched in EA (Aaby et al., 2007b) of free EA after cooking, both for strawberries and red raspberries, (Table 6). EA content is also influenced by the pH of the product, and suggested that the increase in free EA could be due to ET hy- as shown in a study of pasteurized strawberry purées of different drolysis during cooking as well as superior extractability of EA from pH in the range 2.5–4.5 that were stored at 4ºC or 23ºC (Oliveira the cooked products due to cell-structure disruption. Both trends of et al., 2015). The greater increases in free EA content during storage increased free EA and decreased total EA in strawberry jam com- were observed with the purées that had the lowest pH (3.0 and 2.5). pared with fresh strawberries were also reported by Koponen et al. At both pH, the free EA content of the purées increased by 84% (2007). and 185% after 3 months at 4ºC and 23ºC, respectively, which is Flores and del Castillo (2016) compared the effect of two consistent with ET acid hydrolysis promoted by the combination of jam-making methods, namely, a commercial method (no descrip- thermal treatment, low pH, and storage time. Overall, their findings tion provided) and a homemade method that involved a shorter suggest that pH 2.5 and low storage temperature (4ºC) are the best heating time (60 min) with no addition of sugar or pectin, rely- conditions for preserving both polyphenols and colour in pasteur- ing instead on the pectin naturally occurring in fully ripe straw- ized strawberry purées (Oliveira et al., 2015). berries. Both methods significantly reduced the total EA content As shown by the above studies, the processing of strawberries compared with fresh strawberries, but the reduction was less pro- into jam and purée and their subsequent storage can not only affect nounced in the home-made jam (22% vs. 35%). The homemade the concentration of EA, but also its molecular form (bound vs. free method also reduced the loss of other antioxidant compounds (e.g. EA), which may influence its bioavailability by increasing the amount quercitin) as well as the formation of carcinogenic heat-induced of free EA. The effect of strawberry processing on EA metabolism by volatile compounds. Thus, shorter cooking times seem advisable the intestinal microflora was investigated in healthy human subjects, to enhance the nutritional benefits of strawberry jams and other using thermally processed strawberry purée containing the same heat-processed foods. amount of fruits than the control food (fresh strawberries) and no The effect of storage of the EA content of strawberry jam depends added sugar (Truchado et al., 2012). These researchers found that on the storage temperature, as illustrated in Table 6. Storage at low despite higher amount of free EA in the purée, the microbial metab- temperatures (5ºC and –20ºC) for up to 9 months had no significant olism of EA, assessed by urolithin production (EA bioactive metabo- effect on the total EA content (Häkkinen et al., 2000), while storage lites in humans) and their urinary excretion, was not significantly at 20ºC resulted in a significant decrease in total EA after 3 months different from that of fresh strawberries. (Pineli et al., 2015). Pineli et al. (2015) further showed that the free EA content increased significantly from 1.23 to 2.01 mg/100 g FW Dehydration after storage for 2 months at 20ºC, then decreased to 0.91 mg/100 g Dehydrated strawberries show interesting characteristics and appli- after 4 months. These findings are consistent with ET hydroly- cations for the food industry. The effects of four different drying sis initially, releasing free EA which is then lost to oxidation after methods, namely, convection drying (70ºC), freeze-drying (–60ºC, prolonged times. then +70ºC), vacuum drying (50ºC), and vacuum-microwave (VM) Table 6. Stability of ellagic acid (total content in mg/100 g of FW) during the storage of strawberry jams and strawberry purées at different temperatures. Storage temperature Storage duration Reference Jams 0 day 90 days (3 months) 120 days (4 months) 180 days (6 months) 270 days (9 months) +5ºC 23.8 ± 3.7 24.0 ± 1.8 – 25.4 ± 3.5 21.0 ± 1.7 (1) –20ºC 23.8 ± 3.7 19.6 ± 1.2 – 23.4 ± 0.8 20.2 ± 1.0 (1) +20ºC 27.5 ± 0.7 23.1 ± 1.3 22.3 ± 1.0 – – (2) Purées with variable achene 0 day 8 weeks 16 weeks (3) content +6ºC No achenes 14.0 14.6 14.8 – – Whole berries 22.4 20.5 21.4 – – Achene-enriched 35.5 33.4 32.7 – – +22ºC No achenes 14.0 14.1 13.5 – – Whole berries 22.4 19.5 19.0 – – Achene-enriched 35.5 30.7 30.1 – – Reference (1): Häkkinen et al. (2000), strawberries Jonsok grown in Finland; Reference (2): Pineli et al. (2015), strawberries Camino Real grown in Brazil; Ref- erence (3): Aaby et al. (2007b), strawberries Senga Sengana grown in western Norway, total EA in fresh berries: 25.2 mg/100 g of FW, concentration of achenes in the purées: 0% (purée from achene-free pulp), 1.2% (purée from whole strawberries), and 2.9% (purée from achene-enriched fruits) on a FW basis. –, not determined. 238 Muthukumaran et al., 2017, Vol. 1, No. 4 drying (240, 360, and 480W), on the free EA content of strawberry generated achenes was still high (up to 80 mg/100 g FW depend- fruits were studied with two cultivars (Kent and Elsanta) (Wojdyło ing on the extraction method), indicating that this processing waste et al., 2009). All drying methods significantly reduced the amount could be turned into a valuable source of EA. Sójka et al. (2013) of free EA in the dried products compared with fresh strawberries. studied the phenolic composition of industrial strawberry press With fruits of the Elsanta cv., which were richer in free EA ini- cakes (SPC, comprised of achenes and flesh) and their achene-free tially, the greater retention of free EA was obtained with VM dry- fraction (exhausted strawberry flesh, ESF). SPC were from a modern ing (480W) and vacuum drying, while with the Kent cv., the best fruit transformation plant. High amounts of free and total EA were retention was obtained with VM drying (340W and 480W). This found in dried SPC (99.0 and 985 mg/100 g DW, respectively) and study also showed that convection and vacuum drying led to the freeze-dried ESF (94.2 and 1 046 mg/100 g). Despite the presence of highest decreases in antioxidant activity and vitamin C content in sand in both fractions, which needs to be removed, it was concluded fruits of both cultivars. Freeze-drying and VM drying enabled bet- that SPC and ESF may be used as rich and widely available raw ter retention of antioxidant activity and vitamin C (Wojdyło et al., materials for extracting EA and ETs, especially agrimoniin (Sójka 2009). Other researchers found that VM drying of strawberries (San et al., 2013). In another study, this group found that pesticide residue Andreas cv.) decreased their polyphenol content by half. After stor- contents in strawberry byproducts (SPC, ESF, and a strawberry ET age at 20ºC, the polyphenol content of the vacuum packed straw- preparation) were higher than in fresh strawberries. However, the berries significantly increased after 45 days and remained stable for actual dietary risk to consumers from these byproducts (expressed as 6 months (de Bruijn et al., 2016). per cent of acceptable daily intakes following ingestion of equivalent amounts of ETs contained in strawberries) was comparable to that Juicing from fresh strawberries (Sójka et al., 2015). Strawberry juice contains low amount of EA (Daniel et al., 1989), In conclusion, the stability of EA in strawberries during post- indicating that EA is not well extracted from the fruit during juic- harvest storage and processing is notably influenced by temperature, ing that involves minimal processing. This has prompted research to duration of storage/processing, pH, as well as O concentration in enrich this juice in EA (discussed subsequently). It is worth noting the surrounding atmosphere. These factors influence EA content and that high-intensity pulsed electric fields (HIPEF) may be of value to its molecular form (bound or free). Free EA content was found to inactivate microorganisms in strawberry juices as an alternative to increase temporarily when storage and/or processing conditions pro- pasteurization. HIPEF processing of strawberry juice for short times mote ET hydrolysis and enhance EA extractability. However, free -1 (<2 ms) at electric field strengths from 20 to 35 kV×cm enabled and total EA contents decrease under conditions that promote EA fairly high retention (>80%) of antioxidant activity, anthocyanin, oxidation. Storage below room temperature is one of the strategies and vitamin C (Odriozola-Serrano et al., 2008), but there is no re- that effectively limit the losses in EA. Whether these losses may also port on the possible effect of HIPEF on EA. be delayed by adding antioxidants or using other protection meth- ods (e.g. low O atmospheres and encapsulation of EA) deserves further research. SPC and other byproducts from strawberry pro- EA enrichment strategies cessing hold great promises for recovering the achenes which are rich There are few reports on the enrichment of foods with EA from sources of EA and ETs. The use of pre-treated strawberry achenes is strawberries. Two main strategies have been investigated so far: fer- a promising approach for enriching foods and other products in EA. mentation of plant materials (see Production of Ellagic Acid from Strawberries and Other Plant Materials section) and incorporation of strawberry achenes. Lee and Chen (2016) developed an EA Production of EA from Strawberries and Other enriched strawberry wine by adding micronized ball-milled straw- Plant Materials berry achenes to the must prior to fermentation. This led to a 19.7% and 52.4% increase in EA and total phenol contents, respectively, Free EA can be produced from ET-rich plant materials, including and higher antioxidant capacity of the wine compared with regular edible food sources, some of their byproducts as well as non-edible strawberry wine. They found no significant differences in overall sources. The ETs are hydrolysed by treatment with hot water, acids, quality and acceptance between the enriched strawberry wine and bases, or enzymes (Landete, 2011), which is followed by recovery two commercial strawberry wines. Aaby et al. (2007b) prepared and purification of the EA. Acid–solvent extraction of EA uses con- strawberry purées with varying proportions of achenes (0, 1.2, and centrated HCl or H SO and methanol (Wilson and Hagerman, 2 4 2.9%), using strawberry flesh, whole fruits, and achene-enriched 1990; Lei et al., 2001; Lu and Yuan, 2008). This method has been homogenate, respectively. At production, the achene-enriched purées used for many years but has considerable drawbacks for large-scale contained 1.5 times more total EA than the purées made from whole commercial applications, primarily low yields of EA, high cost, and strawberries. This higher concentration was maintained during stor- limited eco-friendliness. This and other chemical processes often age at 6ºC and 22ºC for 16 weeks (Table 6). Antioxidant activity of suffer from appreciable impurities in addition to low yields, due to the enriched purées was also increased and better retained during variations in plant sources, differences in ET structure, as well as storage. difficulty in purifying the EA (Aguilera-Carbo et al., 2008, 2009). A few studies evaluated the potential of industrial byproducts Consequently, the last decade has seen a quest for alternative meth- from strawberry processing as sources of natural nutraceuticals and ods based on fermentation and hydrolysis of the ETs by microbial antioxidants such as EA. Aaby et al. (2005) studied the achenes enzymes. In these bioprocesses, the use of microbial cultures, primarily generated by industrial production of seedless strawberry purées. fungi, induces the biosynthesis of enzymes such as tannase (tannin Industrial processing was found to markedly reduce the contents acyl hydrolase) and ellagitannase (ET acyl hydrolase), which hydro- of free and total EA as well as the phenolic content and antioxi- lyse the ester bonds present in ETs, and of other enzymes involved dant activity of the achenes compared with achenes separated from in EA bioproduction (Aguilera-Carbo et al., 2008; Ascacio-Valdés freeze-dried strawberries and from non-thermally processed straw- et al., 2016). An overview of the plant sources and microbial strains berry purée. However, the amount of total EA in the industrially that have been studied is provided below. Details can be found in the Ellagic acid in strawberries, 2017, Vol. 1, No. 4 239 following reviews (Aguilera-Carbo et al., 2008; Ascacio-Valdés et al., been studied to produce EA. With aqueous extracts of creosote bush 2011; Sepúlveda et al., 2011). Bioconversion of ETs into EA and their leaves, SSF by A. niger GH1 at 30°C was shown to completely de- derived catabolites by the human gut microbiota will be discussed sep- grade the ETs and a maximum EA concentration of 17 mg/g was arately in the Ellagic Acid, Strawberries, and Human Health section. obtained after 36 h (Aguilera-Carbo et al., 2009). In a similar pro- cess, but with A. niger PSH, EA concentration increased by 92% and 177% after fermentation for 96 h of creosote bush and tar bush Biotechnological production of EA from byproducts leaf extracts, respectively, reaching final concentrations of 4.74 mg/g of edible fruits of creosote bush and 7.56 mg/g of tar bush (Ventura et al., 2008). There is scarce information about fermentation-enhanced EA pro- Another study found that the release of EA was lower with leaves of duction from the strawberry plant. Only one study was found (Dange creosote bush (0.5%) than with pomegranate husk (0.9%) after fer- et al., 2016). This group used raw strawberry fruits unfit for sale, mentation by A. niger GH1 for 96 h (Aguilar et al., 2008). an abundant byproduct often discarded as waste, and performed Bioproduction of EA from oak acorns and tannins has been solid-state fermentation (SSF) with Aspergillus niger NCIM-616 at achieved using SSF with A. niger and Candida utilis (Shi et al., temperatures ranging from 30°C to 40°C. After 96 h, the highest 2005), as well as submerged fermentation with A. SHL6 (Huang concentration of EA (143 ppm, i.e. 1.43 mg/g) was obtained at 35°C. et al., 2005), A. oryzae, Endomyces fibuliger, and Trichoderma ree- Although preliminary, these findings suggest a promising potential of sei (Huang et al., 2007a, 2007b, 2008a, 2008b). With acorn cups, strawberry byproducts as substrates for EA bioproduction. co-culture of A. orizae and T. reesei produced superior yield of EA The feasibility of EA bioproduction from agroindustrial byprod- (23%) compared with the pure cultures (16% and 7%, respectively) ucts was previously established using cranberry (Vaccinium mac- (Huang et al., 2007b). This was attributed to the synergistic action rocarpon) and pomegranate (Punica granatum). One group used of three enzymes in the co-culture, i.e. ET acyl hydrolase, xylase, and SSF with food grade fungi to enrich cranberry pomace in EA. With cellulase. Similar enhancements in EA content were reported with co- Rhizopus oligosporus, they found that the EA content increased cultures of A. oryzae and E. fibuliger or C. utilis grown, respectively, linearly 5-fold by Day 12 to a concentration of 375 µg/g DW of on acorn fringe (Huang et al., 2008a) and valonea oak tannins (Shi pomace (Vattem and Shetty, 2002). A similar level of enrichment was et al., 2005), indicating synergy between ellagitannase, β-glucosidase, obtained using Lentinus edodes (Vattem and Shetty, 2003). These and polyphenol oxidase (PPO) (Huang et al., 2008a), and tannase and relatively high concentrations of EA had not been reported previ- PPO (Shi et al., 2005). With co-cultures of A. oryzae and E. fibuliger ously in cranberries or their pomace. Fermentation of the pomace or T. reesei on acorn fringe, it was further shown that two combi- also increased antioxidant activity (Vattem and Shetty, 2002, 2003). nations of enzymes (ellagitannase–β-glucosidase–PPO and ellagitan- Various parts of the pomegranate fruit were studied to produce nase–cellulase–xylanase) were more effective than ellagitannase alone EA by SSF. With pomegranate husk and A. niger GH1, a maximum for producing EA (Huang et al., 2008b). These findings highlight the concentration of EA of 12.3 mg/g was reached after 96 h (Hernandez- importance of selecting appropriate sources of enzymes for optimizing Rivera, 2008). Another study showed that A. niger strains GH1 EA bioproduction. ET concentration, pH, temperature, carbon and and PSH both grew on the husk at higher growth rates than on the nitrogen sources, and fermentation time were also found to influence seeds, and that yields of 6.3 and 4.6 mg of EA/g of dried husk were EA bioproduction from oak material (Huang et al., 2005, 2007a). obtained with these two strains, respectively (Robledo et al., 2008). The above findings show that bioprocessing is a promising strategy Total hydrolysable polyphenols in the husk were degraded during for producing EA from natural sources using greener and milder condi- the first 72 h of fermentation. Likewise, with an aqueous extract of tions than chemical-based processes. More research is needed to de- pomegranate husk and A. niger GH1, maximum concentration of EA velop new sources and to optimize the bioprocesses for yield and purity was reached after 48 h and ETs degradation was attributed to a new of EA and cost-effectiveness. Characterization of the enzymes respon- tannase, now known as ET acyl hydrolase (or ellagitannase), differ- sible for ETs bioconversion to EA is essential as these biocatalysts must ent from tannin acyl hydrolase (Aguilera-Carbo et al., 2007), as sup- be well-suited to the type of ETs present in the plant material used as ported by other findings (Huang et al., 2008a; Ascacio-Valdés et al., substrate. The development of bioprocesses tailored for use with straw- 2016). Other agroindustrial byproducts such as sugarcane bagasse, berry plant material (e.g. discarded fruits, pomaces, achenes, and other corn cobs, coconut husks, and candelilla stalks were found to be good plant parts) deserves particular consideration in view of the richness of supports for producing ellagitannase by SSF (Buenrostro-Figueroa these materials in ETs/EA and of their relevance to human health. et al., 2013). Submerged fermentation, an alternative to SSF, was also studied to produce EA from pomegranate husk. With A. niger GH1 and the EA, Strawberries, and Human Health best conditions of pH, agitation, and substrate concentration, a max- Biological effects of EA and relevance to imum EA concentration of 21.19 mg/g of husk powder was obtained human health (Sepúlveda et al., 2014). The duration of submerged and solid-state EA and its related compounds (ETs, EA derivatives, and Us) have fermentations also has to be optimized in order to minimize the pos- a wide range of biological and physiological activities, as outlined sible biodegradation of EA by some of the fungal enzymes, which in Table 7. Similarly, their presumed beneficial effects in human may reduce EA content after some time (Aguilera-Carbo et al., 2009; health span across multiple bodily systems, including cardiovascular, Sepúlveda et al., 2014). gastrointestinal, endocrine, and neurocognitive systems, with pos- sible roles both in the prevention and the treatment or management Biotechnological production of EA from bush and of diseases such as cancer, diabetes and its complications, cardio- tree parts vascular, gastrointestinal, kidney, liver, pancreatic and eye diseases, Other plants, mainly oak tree (Quercus spp.) acorns, a forestry depression, Alzheimer’s, and other neurodegenerative diseases byproduct, and some plants from hot semi-desertic areas (Larrea (Table 8 and references therein, and Figures 3 and 4). EA may also tridentata or creosote bush and Fluorensia cernua or tar bush) have confer protection against development of the metabolic syndrome 240 Muthukumaran et al., 2017, Vol. 1, No. 4 and against some microbial, viral, and parasitic diseases or infec- Nevertheless, several studies identified in Tables 7 and 8 were con- tions (Table 8). Some of these effects have been researched exten- ducted with EA extracts from strawberries (e.g. Kosmala et al., 2014; sively over the past decade, principally in vitro and in animal models. Ibrahim and El-Maksoud, 2015; Juśkiewicz et al., 2016) or with An in-depth review is beyond the scope of this section. Instead, we strawberry fruits (reviewed by Basu and Lyons, 2012; Giampieri present the breadth of current research in this field in Tables 7 and et al., 2014, 2015; Vendrame et al., 2016). As indicated in Table 8, 8, along with recent publications supporting the evidence. Reviews several health benefits associated with EA are also associated with and articles published within the last 10 years have been prioritized the consumption of strawberries. Clearly, not all health benefits asso- in both tables whenever available. We refer the reader to these refer- ciated with regular intake of strawberries are attributable to EA as ences for details concerning EA bioactivity and health effects. this fruit is packed with various nutritive substances such as vitamins, Current knowledge on these effects is hardly specific to EA in minerals, dietary fibers, and phytochemicals, many of which (e.g. or from strawberries as various sources of EA have been studied. vitamin C, anthocyanins, and phenolics) are potent antioxidants, Table 7. Overview of the biological activities reported for ellagic acid and its related metabolites. Biological activity EA and related metabolites, when References specified R R Antioxidant or prooxidant EA, EAD, ET, U Tomás-Barberán et al. (2017) , Khodadadi and Nasri (2017) , Bishayee R R R et al. (2016) , de Oliveira (2016) , García-Niño and Zazueta (2015) , R R Espín et al. (2013) , Kallio et al. (2013) , Henning et al. (2010) R R Antiinflammatory EA, EAD, ET, U Tomás-Barberán et al. (2017) , Ahmed et al. (2016) , Derosa et al. R R (2016) , Saha et al. (2016), García-Niño and Zazueta (2015) , Espín et al. (2013) , Giménez-Bastida et al. (2012), Jean-Gilles et al. (2012) Antioedematous EA, ET, U Saha et al. (2016), Mansouri et al. (2015), Jean-Gilles et al. (2012), Rogiero et al. (2006) Analgesic, antinociceptive EA, ET Ahmed et al. (2016) , González-Trujano et al. (2015), Mansouri et al. (2014), Mo et al. (2013) Antiallergic EA García-Niño and Zazueta (2015) Immunomodulator EA Promsong et al. (2015), Balekar et al. (2006) R R Antiglycative EA, ET, U Yeh et al. (2017) , Sadowska-Bartosz and Bartosz (2015) , Espín et al. R R (2013) , Xie and Chen (2013) , Muthenna et al. (2012) Antihyperglycaemic EA, ET Juśkiewicz et al. (2016), Fatima et al. (2015), Malini et al. (2011), da Silva Pinto et al. (2010) R R Antihyperlipidaemic EA, ET, U Kang et al. (2016) , Liu et al. (2015), Usta et al. (2013) Antiatherogenic EA, U Mele et al. (2016), García-Niño and Zazueta (2015) Anti-haemorrhagic EA Gopalakrishnan et al. (2014) Antihypertensive, vasorelaxant EA, ET Usta et al. (2013) , da Silva Pinto et al. (2010) R R Antioestrogenic (antiaromatase) and/ EA, ET, U Espín et al. (2013) , Landete (2011) , Adams et al. (2010) or oestrogenic R R Antimutagenic, antigenotixic EA, EAD, ET Ismail et al. (2016) , García-Niño and Zazueta (2015) , Zahin et al. (2014) Antineoplastic, antimetastatic, anti- EA, EAD, ET, U Ismail et al. (2016) , Ramírez de Molina et al. (2015), Wang et al. proliferative, antiinvasive (2015), Zhang et al. (2014) R R R Antiangiogenic EA, ET Bishayee et al. (2016) , Turrini et al. (2015) , Zhang et al. (2014) R R Antiapoptotic or proapoptotic EA, ET, U Ismail et al. (2016) , García-Niño and Zazueta (2015) , Turrini et al. (2015) , González-Sarrías et al. (2015), Vicinanza et al. (2013), Larrosa et al. (2006) R R Radiosensitizer or radioprotector EA Ahire et al. (2016) , Zhang et al. (2014) , Nemavarkar et al. (2004) R R Neuroregeneration, neuroprotective EA, EAD Ahmed et al. (2016) , Chen et al. (2016), de Oliveira (2016) , Del Rio et al. (2013) R R Antiamyloidogenic EA Ahmed et al. (2016) , Taghavi et al. (2016), Mehan et al. (2015) Anticholestatic, antisteatosic EA García-Niño and Zazueta (2015) Antifibrogenic EA García-Niño and Zazueta (2015) , Suzuki et al. (2009) Antibacterial, antifungal, antiviral EA, ET, U Jurgoński et al. (2017), Ahmed et al. (2016) , García-Niño and Zazueta R R R (2015) , Li et al. (2015), Marín et al. (2015) ; Lipińska (2014) , Espín et al. (2013) , Aguilera-Carbo et al. (2005) Antimalarial, antiparasitic EA, ET, U Espín et al. (2013) , Soh et al. (2012), Ascacio-Valdés et al. (2011), Dell’Agli et al. (2010), Reddy (2007) Prebiotic EA, ET, U Fotschki et al. (2016), Saha et al. (2016), Li et al. (2015), Kosmala et al. R R (2014), Espín et al. (2013) , Landete (2011) Skin-whitening EA Yoshimura et al. (2005) Given the overwhelming number of papers on this subject (mostly in vitro and animal studies, and some clinical studies), recent review articles (R) and articles published over the past 10 years have been prioritized in this table. EA, ellagic acid; EAD, ellagic acid derivatives other than urolithins; ET, ellagitannins; U, urolithins. These compounds were not necessarily from or in straw- berries. Ellagic acid in strawberries, 2017, Vol. 1, No. 4 241 Table 8. Overview of the possible beneficial health effects associated to ellagic acid and to the consumption of strawberries. Disease prevention and/or treatment or EA and related metabolites, when References for EA and related metabolites, or strawberries management specified, or strawberries (when available) Metabolic syndrome (e.g. hypertension, EA, U Kang et al. (2016) , Kang (2015) R R hyperglycaemia), obesity-mediated metabolic strawberries Vandrame et al. (2016) , Giampieri et al. (2015) , Basu and complications Lyons (2012) R R Cardiovascular diseases EA, ET, U Larrosa et al. (2010b) , Del Rio et al. (2013) strawberries Giampieri et al. (2015) Diabetes (types 1 and 2) and diabetic compli- EA, ET, U Derosa et al. (2016) , Kyriakis et al. (2015), Schumacher cations et al. (2015), Goswami et al. (2014), da Silva Pinto et al. (2010) strawberry leaf extract Ibrahim and El-Maksoud (2015) R R Cancer (e.g. bone, brain, breast, cervical, colon, EA, EAD, ET, U Tomás-Barberán et al. (2017) , Derosa et al. (2016) , oral, liver, lung, prostate, skin) González-Sarrías et al. (2016), de Oliveira (2016) , García- R R Niño and Zazueta (2015) , Zhang et al. (2014) , Espín et al. (2013) strawberries Giampieri et al. (2015) Eye diseases (e.g. cataract) EA Muthenna et al. (2012), Sakthivel et al. (2008) Kidney diseases EA Silfeler et al. (2017), Ayhanci et al. (2016), Ahad et al. (2014) strawberry leaf extract Ibrahim and El-Maksoud (2015) R R Liver diseases EA Derosa et al. (2016) , García-Niño and Zazueta (2015) Pancreas fibrosis, chronic pancreatitis EA Suzuki et al. (2009) Gastrointestinal diseases (e.g. ulcers, ulcerative EA Derosa et al. (2016) , Marín et al. (2013), Rosillo et al. colitis, Crohn’s disease) (2012, 2011) strawberries Giampieri et al. (2014) Inflammatory arthritis EA, EAD, ET Allam et al. (2016), Bulani et al. (2014) Depression, anxiety EA Ahmed et al. (2016) strawberries Giampieri et al. (2015) Epilepsy EA Dhingra and Jangra (2014) Cognitive decline, neurological/neurodegenera- EA, ET, U Ahmed et al. (2016) , Chang et al. (2016), Derosa et al. R R R tive diseases (e.g. Alzheimer’s, Hungtington’s, (2016) , de Oliveira (2016) , Del Rio et al. (2013) Parkinson’s diseases) strawberries Giampieri et al. (2015) Infections (bacterial, fungal, parasitic, viral) EA, ET, U Narayan and Rai (2016), García-Niño and Zazueta R R (2015) , Espín et al. (2013) , Soh et al. (2012), Ascacio- Valdés et al. (2011), Dell’Agli et al. (2010), Reddy (2007) Given the overwhelming number of papers on this subject (mostly in vitro and animal studies, and some clinical studies), recent review articles (R) and articles published over the past 10 years have been prioritized in this table. EA, ellagic acid; EAD, ellagic acid derivatives other than urolithins; ET, ellagitannins; U, urolithins. These compounds were not necessarily from or in straw- berries. like EA (Giampieri et al., 2012). While EA and its related com- The antioxidant capacity of EA and of strawberries has been pounds most likely contribute to some of the health benefits associ- researched extensively (Table 7). Strawberries have a 2- to 11-fold ated with strawberry consumption, their specific roles remain to be higher antioxidant capacity than apples, peaches, pears, grapes, toma- ascertained in vivo, including their possible synergistic and cumula- toes, oranges, and kiwi (Giampieri et al., 2012). This high antioxidant tive effects with other bioactive phytochemicals and nutrients found capacity is attributed mainly to vitamin C, anthocyanins, and phen- in strawberries. Indeed, it is not unusual that in vivo findings about olic compounds, with about 40 phenolic compounds identified so far EA bioactivity do not match those from in vitro studies (Landete, including EA and ETs (Giampieri et al., 2012; Aaby et al., 2007a). 2011; Giampieri et al., 2015), which can occur when cells in vivo The pronounced antioxidant action of EA and its related compounds are not in contact with EA or its related metabolites to the same is thought to contribute to some of their other biological activities extent as cultured cells. It is critical, therefore, to better understand outlined in Table 7. This antioxidant action may directly or indir- EA bioactivity under physiologically relevant conditions. Likewise, ectly modify the aetiology of several diseases such as cancer through it is necessary to better comprehend the interactions between EA the inhibition of specific stages of carcinogenesis. Additional modes and its related compounds and the food/biological matrices in which of action of EA, also involved in cellular protection but extending they are contained. A strong emphasis is often placed on the concen- beyond EA antioxidant activity, are becoming recognized (Tsao, 2010; tration of EA in foods and other preparations, but this is not the only Giampieri et al., 2014). These include modulatory actions in cells factor influencing EA bioavailability in humans. Synergies between through the modulation of cell-signalling pathways, enzymatic activ- EA and its coactive constituents as well as EA interaction with car- ity, and epigenetic modifications that regulate gene expression (Tsao, rier (food) matrices may be as important for assessing the strength 2010; Giampieri et al., 2014; Zhang et al., 2014; Kyriakis et al., 2015). and effectiveness of these preparations and for their optimization EA consumption levels and safety aspects (Lansky, 2006). It is known that polyphenols do not always act alone; they can also function as co-antioxidant and can be involved Reliable information on the dietary intakes of EA and ETs is scarce in the regeneration of some vitamins (Tsao, 2010). as these intakes are difficult to estimate with precision (Koponen 242 Muthukumaran et al., 2017, Vol. 1, No. 4 Figure 3. Overview of the suspected protective roles of dietary ellagic acid (EA) and its ellagitannin precursors (ETs) in different types of cancer (adapted from Ismail et al., 2016). et al., 2007; Landete, 2011). The few estimates available indicate or drugs, even if it seems low (Vlachojannis et al., 2015), should be kept in mind. that they vary among countries and regions (Radtke et al., 1998; Ovaskainen et al., 2008; Murphy et al., 2014; Ismail et al., 2016). To our knowledge, no harmful or undesirable side effects from In Western diets, the major contributors to EA and ETs intakes are EA and ETs consumption have been reported in humans in the lit- red fruits, such as strawberries, raspberries, and blackberries, as well erature when these compounds are ingested as part of the diet or as as some nuts and beverages (e.g. pomegranate juice and red wine), nutritional supplement. A small number of individuals experience in variable proportions depending on geographic location and indi- discomfort and adverse reactions after eating strawberries, but these vidual preferences (Landete, 2011; Murphy et al., 2014). are elicited by the presence of histamine (Maintz and Novak, 2007; A recent assessment conducted across geographical regions Ibranji et al., 2015) or allergenic proteins (Zuidmeer et al., 2006) worldwide showed that people in Western Europe have the high- naturally found in strawberries, not by EA or ETs. It is not known est estimated dietary daily intakes of EA in both genders (7.9 mg/ whether EA or ETs may modulate the course of these adverse reac- day in women, 7.6 mg/day in men), followed by the Americas and tions, for instance by interacting with the proteins that trigger the Australia (6.7 mg/day in women, 7.0 mg/day in men) (Murphy et al., allergy to strawberries. Possible undesirable effects of EA and ETs, 2014). Strawberries accounted for over 60% of the daily EA intake documented in animals fed with excessive amounts of ETs, include anti-nutritional effects due to their ability to combine with some in these regions. In contrast, the estimated intakes of EA were low (<1 mg/day) in African, Asian, and South American regions, pre- dietary proteins and fibers, chelate certain minerals (e.g. iron, mag- sumably because of limited availability of berries (Murphy et al., nesium), and inhibit certain digestive enzymes (e.g. β-galactosidase), 2014). The contribution of strawberries to the daily EA intake in which can lead to the malabsorption of essential nutrients (Landete, these regions was 10% or less, 22% and 30%, respectively. Other 2011; Ismail et al., 2016; Saha et al., 2016). EA oxidation into researchers estimated that strawberries contribute 0.2–0.3 mg of EA o-quinone by mushroom PPO, evidenced in vitro by Muñoz-Muñoz per day in France where strawberries are one of the main sources et al. (2009), is of potential concern as quinones have been shown to of EA (Clifford and Scalbert, 2000). Daily ETs intake estimates of induce both cytoprotection and adverse effects (e.g. cytotoxicity and 12 mg/day (15 mg/day in women, 8 mg/day in men) and 5 mg/day carcinogenesis) in vivo (Bolton and Dunlap, 2017). In animals, arte- (5.4 mg/day in women, 4.9 mg/day in men) have been reported in rial blood clots and liver damage have been reported following intra- Finland and Germany, respectively (Radtke et al., 1998; Ovaskainen venous and intraperitoneal injection of EA, respectively (Clifford et al., 2008). The intake of EA may be higher than the above esti- and Scalbert, 2000; Lansky, 2006). These effects are unlikely, and have in fact not been reported, at the doses that characterize typical mates if EA-rich foods other than berries (e.g. pomegranate juice and walnuts) are also part of the regular diet (Tomás-Barberán et al., daily EA intakes and the specific intakes that have been investigated 2009) or if EA supplements are taken. by way of human trials. At these doses, EA is considered safe (Ismail A recent review concluded that, based on ETs daily consump- et al., 2016). tion trends from various dietary sources and on EA NOEL and Additional and well-designed in vivo interventions as well as NOAEL [no observed (adverse) effect levels] currently available, in vitro mechanistic studies are needed to fully understand how these compounds pose negligible risk to human health and safety, EA interacts with human physiological and pathological pro- thus confirming the notion that EA and ETs can be used safely as cesses, so that the benefits from EA, strawberry EA in particular, health-promoting phytonutrients and possibly as therapeutic agents can be enhanced while mitigating any possible undesirable effects. in certain conditions (Ismail et al., 2016). Still, as for all ingested sub- Additional knowledge will be especially valuable if it helps under- stances, the risk of possible undesirable interactions with medications stand the dose and synergistic conditions required for effective Ellagic acid in strawberries, 2017, Vol. 1, No. 4 243 Figure 4. Ellagic acid (filled diamonds) suspected role as (a) radiosensitizer of tumour cells and (b) radioprotector of normal cells (adapted from Ahire and Mishra, 2016). health promotion and disease prevention, and if it is applicable to Gastrointestinal absorption of EA is rapid in humans, with max- complex systems such as strawberries, strawberry-based foods, and imum plasmatic concentration reached within 1 h of the ingestion other products, as well as living organisms, particularly humans of EA/ET-rich foods (Seeram et al., 2004, 2007). EA disappearance and their intestinal microbiota which plays an important role in from plasma was observed 2–6 h after ingestion (Seeram et al., EA metabolism. 2008). The fact that not all studies detected EA in plasma, or in similar concentrations, after the ingestion of foods that were simi- Metabolism and bioavailability of EA larly rich in EA suggests that food matrix characteristics—including Metabolism and bioavailability interactions among specific constituents—may influence EA absorp- The metabolism and bioavailability of EA and ETs in humans have tion (Larrosa et al., 2012). Food characteristics are known to influ- attracted increasing interest due to the possible health effects of these ence the bioavailability of dietary polyphenols in general (Rein et phenolic compounds. Current knowledge is summarized below, al., 2012; Bohn, 2014), but little is known about their effects on highlighting the latest advances and findings relevant to strawberry EA absorption, metabolism, and bioavailability. In humans, inter- EA. Details can be found in earlier reviews (Landete, 2011; Larrosa individual differences in EA absorption and metabolism may be a et al., 2012; Espín et al., 2013). Both ETs and free EA are present in contributing factor. Several animal studies reported EA accumula- EA-rich foods. ETs are generally not absorbed in the human gastro- tion in some organs and tissues (e.g. oesophagus, small intestine, intestinal tract, but they release free EA in the stomach and small in- colon, liver, lung, and prostate) (Boukharta et al., 1992; Larrosa testine. Absorption of free EA can occur in the stomach and, but less et al., 2012). In humans, there is little evidence of EA accumula- importantly, in the small intestine (Espín et al., 2007; Larrosa et al., tion in organs or tissues, except in human intestinal Caco-2 cells 2012). No transporters have been identified to date. Phase I and II in vitro (Whitley et al., 2003). Metabolites derived from EA (Us metabolism of EA in the digestive tract and the liver yields EA deriv- mainly) have been detected in other human tissues (e.g. prostate) atives (mainly EA-methyl and dimethyl ethers and EA-glucuronide (González-Sarrías et al., 2010) but not EA per se. Whitley et al. conjugates), which were detected in peripheral plasma, bile, and (2003) suggested that irreversible binding of EA to macromolecules urine of Iberian pigs fed ET-rich acorns (Espín et al., 2007). Some in intestinal cells may limit its transcellular absorption. EA ioniza- EA-glucuronides undergo enterohepatic circulation. tion, oxidation, and the formation of poorly soluble complexes with 244 Muthukumaran et al., 2017, Vol. 1, No. 4 ions (e.g. calcium, iron, magnesium) under physiological conditions to affect the production and urinary excretion of Us in humans. In may also limit EA bioavailability and modulate its bioactivity. A healthy volunteers, Truchado et al. (2012) found no significant dif- recent study in which strawberries were digested under conditions ferences in the production and excretion of Us between the intake of that simulated chemical digestion in humans found that the antioxi- fresh strawberries and that of thermally processed strawberry purée dant activity of strawberry flesh and achenes was markedly higher (80ºC for 5 min) containing the same amount of strawberries and no in the extracts from the gastric fraction compared with those from added sugar. Thermal processing increased the amount of free EA by the intestinal fraction and undigested fruit (Ariza et al., 2016). 2.5-fold, but had no detectable effect on EA bioconversion into Us Because of their low bioavailability in humans, dietary ETs and EA by the gut microbiota or on the urinary excretion of U metabolites per se are expected to exert their biological activities principally (U-A, U-B, and their glucuronide conjugates) (Truchado et al., 2012). in the digestive tract rather than in the entire body (Cerdá et al., These findings suggest that the release of free EA from ETs does not 2005a, 2005b; Whitley et al., 2006). affect the microbial metabolism of EA in vivo and that moderate In the small intestine, EA is metabolized by the human intestinal thermal treatment does not modify the potential health benefits of microbiota into a series of hydroxydibenzopyran-6-one derivatives, strawberry EA. known as Us. Several Us are produced and absorbed, including U-D Little is known about the gut bacteria and conditions (e.g. pH, and U-C, followed by U-A and U-B (Figure 5) which are the final cata- nutrients/prebiotics, biotic and abiotic interactions) involved in the bolic products before phase I and II metabolism (Tomás-Barberán transformation of EA into Us and their bioavailability in humans. et al., 2017). Recent findings suggest that Us have biologial activities Because U production starts in the small intestine, anaerobic bac- similar to those of EA and ETs (Table 7) but are more bioavailable in teria are thought to be responsible. Two strains of the Gordonibacter humans, being the main EA-derived metabolites detected in plasma, genus able to metabolize EA to Us have been identified in human urine, and some tissues in humans (Tomás-Barberán et al., 2017). faeces (Selma et al., 2014a, 2014b). Higher levels of Gordonibacter For these reasons, it is now thought that Us, U-A, and U-B in par- were reported in individuals that produce only U-A and its conju- ticular, and their derivatives are responsible for most of the in vivo gates compared with individuals that produce both U-A and U-B biological activities and health benefits associated with EA/ET-rich (Selma et al., 2016; González-Sarrías et al., 2017). In rats, the ab- diets, while circulating EA derivatives may contribute to a lesser ex- sorption of EA and ET microbial metabolites (quantified as U-A) tent (Larrosa et al., 2012; Tomás-Barberán et al., 2017). After phase was increased when fructooligosaccharides (which are known prebi- I and II metabolism, U conjugates (mainly glucuronide and methyl otics) were added to the diet (Jurgoński et al., 2017). Both the host ether conjugates) and some EA conjugates circulate in the blood and and its gut microbiota appear to benefit from U production (Selma can reach various tissues and organs, with no accumulation detected et al., 2009; Bialonska et al., 2010; Tomás-Barberán et al., 2017). at these sites in humans so far (Espín et al., 2013). U-A and U-B Prebiotic effects of Us were found in rats (Larrosa et al., 2010a). conjugates are the main EA-derived metabolites detected in human A recent animal and in vitro study showed that the production of plasma and urine. They reach maximum concentrations in plasma U-A limited the non-specific killing of gut bacteria and abolished the 24–48 h after ingestion of EA/ET-rich foods (Espín et al., 2013) and iron-binding property of EA, thus conferring two important com- can be detected for up to 48–72 h in urine (Cerdá et al., 2005a). petitive advantages to the microbiota, in addition to antioxidant and Enterohepatic circulation contributes to their relatively long persist- antiinflammatory effects of U-A (Saha et al., 2016). ence in plasma and urine (Espín et al., 2007). The high interindividual variability in U production and excre- In healthy human subjects who consumed fresh strawberries, tion, which was noted in most human trials, is thought to result U-B conjugated with glucuronide acid was the most abundant U-B from differences in the gut microbiota (González-Sarrías et al., 2010; metabolite detected in urine 48 h and 72 h after intake (Cerdá et al., Tomás-Barberán et al., 2017). Recent evidence supports the existence 2005a). Neither ETs nor EA derivatives (free or conjugated) were of three U phenotypes or metabotypes (UM), namely UM-0 (no urin- detected in urine. This was also the case in three other groups of ary excretion of U-A, U-B, or their conjugates), UM-A (only excretes subjects who consumed other foods rich in ETs/EA (raspberries, U-A and its conjugates), and UM-B (excretes U-B, isoU-A, and their walnuts, and oak-aged red wine, respectively). Higher urinary excre- conjugates in addition to U-A) (Tomás-Barberán et al., 2014). These tion of U-B glucuronide was found in the subjects who ingested a metabotypes were independent of EA amount and food source, vol- double amount of the ET/EA-rich food, but this excretion was not unteer age, gender, BMI, and health status. However, UM-B prevailed proportional to the amount of ETs/EA consumed (Cerdá et al., in patients with illnesses associated with gut dysbiosis (metabolic syn- 2005a). Additionally, strawberry thermal processing does not seem drome and colorectal cancer) and in healthy overweight-obese, while Figure 5. Conversion of dietary ellagic acid into bioactive urolithins by the gastrointestinal microbiota (adapted from García-Villalba et al., 2013; González-Barrio et al., 2011). Ellagic acid in strawberries, 2017, Vol. 1, No. 4 245 UM-A prevailed in healthy subjects, in patients with illnesses not EA encapsulated in chitosan nanoparticles was shown to be more characterized by gut dysbiosis (e.g. prostate cancer) (Tomás-Barberán effective than free EA at inhibiting human oral cancer KB cells in et al., 2014), and in normoweight subjects (Selma et al., 2016). vitro (Arulmozhi et al., 2013) and as an antihaemorrhagic agent, Additionally, an intervention trial with healthy overweight-obese also in vitro (Gopalakrishnan et al., 2014). In AJ/mice treated with subjects found that the UM-B group had a higher baseline for car- nicotine-derived nitrosamine ketone (NNK), a tobacco-specific diovascular risk compared with UM-A subjects and that this baseline nitrosamine involved in lung carcinogenesis, encapsulation of EA in was decreased only in the UM-B group after the ingestion of ET-rich cyclodextrin was found to double the concentration of EA in lung extracts for 6 weeks. This effect was associated with U production tissues following the administration of EA by gavage (Boukharta (González-Sarrías et al., 2017). U-A production has been shown to et al., 1992). In this animal study, EA at a dose of 4 g/kg of diet be inversely correlated with the severity of the metabolic syndrome reduced the multiplicity of NNK-induced lung tumours. EA was in humans (Mora-Cubillos et al., 2015). Certain similitudes between localized preferentially in lung tissues, at levels proportional to the the intestinal metabolism of EA to Us and that of daidzein (an isofla- dose of EA, with a maximum level observed 30 min after gavage. vone found in soybeans and other legumes) to equol raise the possi- Levels in liver tissues were 10-fold lower (Boukharta et al., 1992). bility that U metabotypes may be a useful biomarker for evaluating Further evidence of improved bioavailability and tissue distribution disease risk related to specific gut bacteria involved in EA metabolism of EA-cyclodextrin complexes was presented by Chudasama et al. (Tomás-Barberán et al., 2017). (2011). In their work, plasma and pancreatic levels of EA 30 min These latest advances provide powerful ways of understanding after gavage were 7-fold and 5.8-fold higher, respectively, in rats the interrelations between dietary EA and health, revealing the criti- that received cyclodextrin-encapulated EA in contrast to EA alone. cal role of gut bacteria in EA metabolism. They open new avenues for One hour after gavage, the levels remained high in the experimental personalized nutrition and medicine in relation to EA. One of them group. Bulani et al. (2016) showed in vitro that EA encapsulation in is the development of functional foods and other specialty products β-cyclodextrin enhanced its solubility and dissolution and improved that incorporate the microorganisms (probiotics) responsible for EA its antiinflammatory activity by protecting against protein denatur - bioconversion into specific Us, together with the naturally occur - ation and lysis of the erythrocyte membrane. Dubey et al. (2015) ing ETs and EA. More research is needed to identify the microbial used nano-sized metalla-cages (metalla-prisms) to encapsulate EA communities and the biophysicochemical conditions (including food and reported that these compounds had superior anti-cancer proper- characteristics) that enable or enhance the production of specific Us, ties in vitro compared with free EA. Complex formation between EA so that individuals with different U metabotypes can fully benefit and phospholipids is another promising formulation. In rats exposed from EA intake. The possibility that this variation in EA metabolism to carbon tetrachloride, a liver damaging agent, EA-phospholipid may be associated with differential health outcomes also deserves fur- complexes were shown to enhance EA oral bioavailability and anti- ther research, as do the specific roles of the different Us. oxidant activity, thus providing better hepatoprotection than free EA (Murugan et al., 2009). Amorphous solid dispersion (ASD), i.e. the molecular dispersion Bioavailability enhancement of a poorly water-soluble compound in a polymer matrix, was also Various strategies have been investigated to improve the bioavail- successfully tested to improve EA solubility (Li et al., 2013). These ability of polyphenols in general (Rein et al., 2012; Lewandowska researchers tested several cellulose- and non-cellulose-based poly- et al., 2013). Here, we focus on recent developments regarding the mers for their ability to form ASDs with EA and identified hydroxy- improvement of EA solubility and bioavailability through formu- propylmethylcellulose acetate succinate as the most practical choice lation approaches such as encapsulation, complex formation with for stabilizing EA and improving its solubility. solubilizing agents, and amorphous solid dispersion. These strate- Possible interactions between EA and serum transport pro- gies could be powerful complements to the enrichment strategies teins are of interest in relation to bioavailability as they may play presented in the Ellagic Acid Stability in Strawberries During Post- a role in improving EA solubility in the circulatory system and its harvest Storage and Processing, and Production of Ellagic Acid from delivery to target sites. Non-covalent binding was detected in vitro Strawberries and Other Plant Materials sections. Strategies that between EA and human serum albumin (HSA) (Tang et al., 2013; involve non-oral delivery of EA (e.g. subcutaneous implants for sus- Pattanayak et al., 2017) and bovine serum albumin (BSA) (Labieniec tained systemic delivery of EA) (Vadhanam et al., 2011a, 2011b; and Gabryelak, 2006), as well as between ETs and BSA (Dobreva Gupta et al., 2012) will not be detailed. et al., 2014). Other researchers found that EA and its metabolite U-A EA encapsulation has been achieved using various nanopar- did not bind specifically to sites I and II of HSA which are areas for ticulate systems, mainly poly(D,L-lactic-co-glycolide) (PLGA) and high-affinity binding of certain drugs and other compounds (Nozaki polycaprolactone (PCL) nanoparticles (Bala et al., 2006; Sonaje et al., 2009). et al., 2007), chitosan nanoparticles (Arulmozhi et al., 2013; Collectively, the above findings support the hypothesis that Gopalakrishnan et al., 2014), cyclodextrin derivatives (Boukharta improving EA solubility is a practical way to enhance its oral bio- et al., 1992; Chudasama et al., 2011; Bulani et al., 2016), and nano- availability. These findings can inform the development of dietary sized metalla-cages (Dubey et al., 2015). These systems enable EA and therapeutic applications that require good solubility of EA and to be encapsulated in a water-soluble polymeric matrix (carrier); its effective transport and release at target sites in human physio- some enable a gradual, sustained release of EA at a rate that depends logical systems, while minimizing undesirable interactions with on the carrier composition (Bala et al., 2006; Sonaje et al., 2007; other drugs or food constituents. Gopalakrishnan et al., 2014). Bala et al. (2006) further showed that the in situ intestinal permeability of EA in rats increased from 66% for EA alone to 73% and 87% for EA encapsulated in PLGA Conclusion and Prospects for Further Research nanoparticles of different compositions. Higher in situ intestinal per- meation was also reported for EA encapsulated in PCL or PLGA EA is one of the phytochemicals supporting the recognition of straw- nanoparticles compared with EA alone (Sonaje et al., 2007). berries as functional foods and sources of bioactive molecules with 246 Muthukumaran et al., 2017, Vol. 1, No. 4 Aaby, K., Ekeberg, D., Skrede, G. (2007a). Characterization of phenolic high nutraceutical and therapeutic potential. To help realize the full compounds in strawberry (Fragaria x ananassa) fruits by different HPLC potential of EA in and from strawberries, this review covered four detectors and contribution of individual compounds to total antioxidant areas of practical importance: EA distribution in the strawberry capacity. Journal of Agricultural and Food Chemistry, 55: 4395–4406. plant, its stability during processing, its production from plant mate- Aaby, K., Wrolstad, R. E., Ekeberg, D., Skrede, G. (2007b). Polyphenol compo- rials, and its bioactivity and relevance to human health, highlight- sition and antioxidant activity in strawberry purees; impact of achene level ing current developments, knowledge gaps, as well as opportunities and storage. Journal of Agricultural and Food Chemistry, 55: 5156–5166. for novel applications and products and future research. A number Aaby, K., Mazur, S., Nes, A., Skrede, G. (2012). Phenolic compounds in straw- of these opportunities can add value not only to strawberry prod- berry (Fragaria x ananassa Duch.) fruits: composition in 27 cultivars and ucts, but also to underutilized strawberry byproducts that are rich changes during ripening. Food Chemistry, 132: 86–97. in EA and its ET precursors. The current knowledge and technolo- Adams, L. S., Zhang, Y., Seeram, N. P., Heber, D., Chen, S. (2010). Pomegran- ate ellagitannin-derived compounds exhibit antiproliferative and antiaro- gies presented in this review will be of value for those seeking to matase activity in breast cancer cells in vitro. Cancer Prevention Research enhance the production of EA from strawberry plant materials, (Philadelphia, PA), 3: 108–113. including their processing byproducts, and to develop the functional Aguilar, C. N., et al. (2008). Production of antioxidant nutraceuticals by and therapeutic applications of strawberry EA. The challenges and solid-state cultures of pomegranate (Punica granatum) peel and creosote knowledge gaps that were identified point to a need for research in bush (Larrea tridentata) leaves. Food Technology and Biotechnology, 46: the following areas: 218–222. Aguilera-Carbo, A., Garcia-Agustince, C. A., Belmares, R. E., Aguilar, C. N. 1. Quantification of free and bound EA in different parts of the (2005). 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This will help Technology, Hellenic Association of Food Technologists, Thessaloniki, identify and enhance EA biofortification strategies. Greece, p. 44. 2. Development and optimization of fermentation–enzymatic bio- Aguilera-Carbo, A., Augur, C., Prado-Barragan, L. A., Favela-Torres, E., processes for the efficient and green production of EA from Aguilar, C. N. (2008). Microbial production of ellagic acid and biodeg- strawberry byproducts, whether discarded fruits, achenes, pom- radation of ellagitannins. Applied Microbiology and Biotechnology, 78: aces, or other parts of the plant that contain EA and ETs. 189–199. Aguilera-Carbo, A., Hernandez-Rivera, J. S., Augur, C., Prado-Barragan, L. 3. Development of EA enrichment methods applicable to various A., Favela-Torres, E., Aguilar, C. N. (2009). 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Publisher: Oxford University Press
Copyright: © The Author(s) 2017. Published by Oxford University Press on behalf of Zhejiang University Press.
ISSN: 2399-1399
eISSN: 2399-1402
DOI: 10.1093/fqsafe/fyx023
Publisher site: See Article on Publisher Site

Abstract

Ellagic acid (EA) is one of the plant phenolics associated with human health benefits. It derives from ellagitannins found in some nuts, seeds, and fruits, especially berries. Strawberries are considered a functional food and nutraceutical source, mainly because of their high concentration of EA and its precursors. This review presents the current state of knowledge regarding EA, focusing on its content in strawberry plants, stability during processing and storage of strawberry-based foods, production methods, and relevance to human health. As alternatives to acid-solvent extraction, fermentation-enzymatic bioprocesses hold great promises for more eco-efficient production of EA from plant materials. Strawberry fruits are generally rich in EA, with large variations depending on cultivar, growth conditions and maturity at harvest. High EA contents are also reported in strawberry achenes and leaves, and in wild strawberries. Strawberry postharvest storage, processing and subsequent storage can influence EA content. EA low concentration in strawberry juice and wine can be increased by incorporating pre-treated achenes. Widespread recognition of strawberries as functional foods is substantiated by evidence of EA biological effects, including antioxidant, antiinflammatory, antidiabetic, cardioprotective, neuroprotective, and prebiotic effects. The health benefits attributed to EA-rich foods are thought to involve various protective mechanisms at the cellular level. Dietary EA is converted by the intestinal microbiota to urolithins, which are better absorbed than EA and may contribute significantly to the health effects attributed to EA-rich foods. Based on the evidence available, strawberry EA shows strong promises for functional, nutraceutical, and pharmaceutical applications. Future research should be directed at quantifying EA in different parts of the strawberry plant and in their byproducts; optimizing EA production from byproducts; understanding the biological actions of EA-derived metabolites in vivo, including the interactions between EA metabolites, other substances and food/biological matrices; characterizing the conditions and microorganisms involved in urolithin production; and developing delivery systems that enhance EA functionality and bioactivity. Key words: Strawberry plant; Ellagic acid; Processing; Metabolism; Bioactivity. © The Author(s) 2017. Published by Oxford University Press on behalf of Zhejiang University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 228 Muthukumaran et al., 2017, Vol. 1, No. 4 how stable it is following harvesting and how it can be extracted Introduction from plant materials. Likewise, it is critical to understand EA pos- Ellagic acid (EA) is one of the naturally occurring phenolic acids, sible health effects and fate in the human body. This review aims to a diverse class of bioactive polyphenols produced by plants. It is a present the current state of evidence and its limitations regarding breakdown product of larger and more complex polyphenols, the EA, with specific consideration of (1) EA physicochemical proper - ellagitannins (ETs), and is mostly found in plant cell vacuoles in free ties; (2) EA content in the strawberry plant; (3) its stability post-har- and covalently bound forms, namely EA or EA derivatives and ETs, vest and during processing and storage of strawberry-based foods; respectively (Atkinson et al., 2006; Shahidi and Yeo, 2016). Bound (4) EA production methods from plant materials amenable for use EA predominates in most plants but free EA can be released upon hy- with strawberries and their byproducts; and (5) EA bioactivity and drolysis, which occurs under physiological conditions in the human relevance to human health. While we prioritized evidence that per- gastro-intestinal tract and provides one of the bases for producing tains to strawberry specifically, such evidence is not always available. EA from plant material and for quantifying total EA content (Daniel Therefore, relevant evidence concerning EA from other plant sources et al., 1989). Free EA can also be formed during food processing was included in some sections. (Bakkalbaşi et al., 2009). EA and ET-rich foods and formulations have been shown to exert possible beneficial effects on human health, both in the realm of Chemistry and Physicochemical Properties chronic disease prevention and for the treatment of illnesses or con- of EA ditions such as cancer, diabetes, and diabetic complications, chronic EA (C H O ), also known as 2,3,7,8-tetrahydroxychromeno[5,4,3- 14 6 8 tissue inflammation, metabolic syndrome, obesity-mediated metabolic cde]chromene-5,10-dione (IUPAC nomenclature) and 4,4′,5,5′,6,6′- complications, cardiovascular, gastrointestinal, kidney, liver, and eye hexahydrodiphenic acid 2,6,2′,6′-dilactone, is a polyphenolic com- diseases, depression, Alzheimer’s and other neurodegenerative diseases pound that belongs to the phenolic acid group. Its fused four-ring (Sakthivel et al., 2008; Suzuki et al., 2009; Zhang et al., 2014; García- polyphenol structure (Figure 1a) is a dimeric derivative of gallic Niño and Zazueta, 2015; Ahmed et al., 2016; Anantharaju et al., acid, another phenolic acid, and has a molecular weight of 302.19 g/ 2016; Ayhanci et al., 2016; Derosa et al., 2016; Kang et al., 2016). EA mol (Royal Society of Chemistry, 2011). The four aromatic rings and its derivatives display a wide range of biological and physiological form a lipophilic domain, while the four hydroxyl groups and two activities, most notably antioxidant, antiinflammatory, antiglycative, lactones are hydrophilic and provide hydrogen bonding sites and estrogenic and/or antiestrogenic, antimicrobial as well as prebiotic electron acceptors, respectively. This polycyclic aromatic structure activities, which may contribute to human health (Landete, 2011). enables EA to take part in several reactions, including the formation EA and its precursors are abundant in certain plants and plant parts. of charge-transfer (electron–donor–acceptor) complexes. Those of dietary importance include some nuts, seeds, and fruits, includ- ing berries (Landete, 2011; Ahmed et al., 2016). Dietary intake of EA is Reactivity and interactions thus mainly through these foods either in their fresh or processed forms (Clifford and Scalbert, 2000). Certain berries like strawberries (Fragaria EA chemical reactivity can be divided into three categories, namely: spp.) are notable in that EA is present at high concentrations and can (1) oxidation by reactive free radicals; (2) reactions involving its account for 50% or more of the total phenolic constituents present in nucleophilic hydroxyl groups; and (3) electrophilic aromatic sub- the fruit after hydrolysis of its ET precursors (Häkkinen et al., 1999). stitution of its electron rich aromatic rings (Ahmed et al., 2016). EA is also one of their main antioxidants. As illustrated in Table 1, EA These reactions play a key role in EA antioxidant and other bio- concentration in strawberries is 3–10 times higher than in other fruits logical activities reviewed in the Ellagic Acid, Strawberries, and and nuts of commercial importance (Daniel et al., 1989; Williner et al., Human Health section of this paper. EA can also bind or interact 2003; Landete, 2011). EA is one of the non-nutrient phytochemicals with important biological macromolecules such as DNA, enzymes, supporting the recognition of strawberries as functional foods, health and other proteins, as well as smaller substances including minerals. promoter, and sources of nutraceutical ingredients (Basu et al., 2014; These binding properties are thought to contribute to EA biological Giampieri et al., 2015). Overall, strawberries have an excellent nutri- activities. For example, EA was shown to covalently bind to DNA tional profile (Giampieri et al., 2014) and are widely appreciated as in in vitro studies and this has been suggested as a mechanism for its foods and non-food commodities (e.g. skin products). antimutagenic and anticarcinogenic activities (Zhang et al., 2014). The global strawberry market has been growing, both in terms Similarly, interaction of EA with certain enzymes, such as VEGFR-2 of total revenues (+4.7% compounded annual growth rate from kinase, β-glucosidase, and angiotensin I-converting enzyme (ACE), 2007 to 2015) and in physical terms, reaching 8 476 thousand may exert beneficial effects for preventing breast cancer and manag- tonnes in 2015, a 5% growth from 2014. By 2015, it is expected ing hyperglycaemia and hypertension (da Silva Pinto et al., 2010; to reach 10 million tonnes (IndexBox Marketing, 2017). China Zhang et al., 2014). In vitro studies also showed that EA displays 2+ and the USA are leading the strawberry consuming markets. They an effective ferrous ions (Fe ) chelating activity, contributing to its are also the leading producers, followed by Mexico, Turkey, and antioxidant properties (Kilic et al., 2014), and binds to human serum Egypt, all benefiting from favourable climatic conditions (IndexBox albumin, the major transport protein in blood serum (Pattanayak Marketing, 2017). In the USA, per capita consumption of strawber- et al., 2017). The latter finding opens interesting venues for applica- ries has increased by 58% between 2002 and 2012 (USDA, 2014). tions that require effective transport and release of EA at target sites Strawberries and strawberry-based foods can, therefore, contribute in human physiological systems. a substantial amount of EA to the diet, while their byproducts can Stability and solubility be a valuable source of EA for applications that extend beyond trad- itional foods, thereby further broadening the market opportunities EA is a highly thermostable molecule with a melting point of 450°C and strengthening the strawberry value chain in various countries. and a boiling point of 796.5°C (Royal Society of Chemistry, 2011). To realize the full potential of EA in and from strawberry, it is ne- It is relatively stable under physiological conditions in the stomach cessary to have a good understanding of its distribution in the plant, (Usta et al., 2013), which makes it an interesting phytochemical Ellagic acid in strawberries, 2017, Vol. 1, No. 4 229 Table 1. Total ellagic acid (EA) content of selected fruits and nuts of commercial importance. Fruit or nut Total EA (mg/g DW) Total EA (mg/100 g FW) Reference Blackberries 1.5 – Daniel et al. (1989) Rasperries 1.5 – Daniel et al. (1989) Strawberries, Camarosa 0.70 6.1 Williner et al. (2003) Strawberries 0.63 – Daniel et al. (1989) Strawberries, Honeoye – 77.6 Koponen et al. (2007) Strawberry jam – 24 Koponen et al. (2007) Walnuts 0.59 – Daniel et al. (1989) Pecans 0.33 – Daniel et al. (1989) Green apples 0.07 – Williner et al. (2003) Plums 0.07 – Williner et al. (2003) Pineapples 0.06 – Williner et al. (2003) Pears 0.04 – Williner et al. (2003) Tangerines 0.04 – Williner et al. (2003) Bananas 0.02 – Williner et al. (2003) Brazil nuts ND – Daniel et al. (1989) Kiwi fruits ND – Williner et al. (2003), Daniel et al. (1989) Oranges ND – Williner et al. (2003), Daniel et al. (1989) Peanuts ND – Daniel et al. (1989) Red apples ND – Williner et al. (2003), Daniel et al. (1989) The commodities are ordered by total EA concentration, in descending order. Ripening stage for strawberries (Fragaria × ananassa): commercial ripeness or not specified. Values from Williner et al. (2003) are for strawberries with 50% and 100% red colour combined (fruits with edible value). DW, dry weight; FW, fresh weight; ND, not detected; –, not reported. 1 2 Figure 1. Structures of (a) ellagic acid, (b) a dimethyl derivative of ellagic acid , and two ellagitannins identified in strawberries, namely (c) agrimoniin and (d) 2 1 2 sanguiin H-6 . These compounds were reported, respectively, by Ramírez de Molina et al. (2015), Maas et al. (1991b), Shi et al. (2015), Lipińska et al. (2014), and Vrhovsek et al. (2012). candidate for the development of foods, nutraceuticals, and drugs metabolites called urolithins (Us), which are more water soluble to be taken orally. Pure crystalline EA is sparingly soluble in water and bioavailable than EA (Espín et al., 2013; Tomás-Barberán et al., (9.3 µg/ml at pH 7.4) and in alcohol (O’Neil, 2006; Landete, 2011), 2017). Current research also aims at developing delivery systems which is due in part to the high degree of crystallinity resulting from that enhance EA solubility and bioavailability, as reviewed in the the planar and symmetrical structure of EA and extensive hydrogen- Ellagic Acid, Strawberries, and Human Health section. bonding network formed within the crystal (Li et al., 2013). Low Occurrence water solubility can limit EA bioavailability in humans. However, recent evidence indicates that the metabolism of dietary EA by cer- EA is produced by plants as one of their secondary metabolites. It tain bacteria in the intestine leads to the production of bioactive accumulates in the cell vacuoles in two forms: free EA (i.e. EA and 230 Muthukumaran et al., 2017, Vol. 1, No. 4 EA derivatives, Figure 1a and b) and bound EA, also known as ETs, their content in EA. EA has been shown to contribute to the straw- in which EA is esterified with sugar molecules, commonly glucose berry plant defense system (Amil-Ruiz et al., 2011) and to be dis- (Figure 1c and d). ETs are generally the predominant form. They are tributed in various organs and tissues of the plant. These include the a group of hydrolysable tannins, meaning that they can be fractioned fruits, flowers, leaves, stems, and roots (Figure 2a and b, Table 2), into their constituents, EA in particular, by hydrolysis. Hydrolysable although most of the research to date has focused on the fruit, in tannins are widely distributed in Angiosperms (flowering plants) addition to been primarily concerned with one species. An overview (Ascacio-Valdés et al., 2011), including strawberries, and occur in is provided in the following sections. some algae (Shannon and Abu-Ghannam, 2016). Agrimoniin and It should be noted first that the values of EA content reported in sanguiin H-6 (Figure 1c and d) are two ETs found in strawber- different studies can be difficult to compare and that some discrep- ries (Vrhovsek et al., 2012; Lipińska et al., 2014; Shi et al., 2015). ancies are observed. This is due in part to methodological differences ETs are more water soluble than EA (Landete, 2011). EA and ETs in quantifying the EA (e.g. different hydrolytic, extraction, or de- biosynthesis involves glucose and gallic acid (Ascacio-Valdés et al., tection conditions) and in reporting it (e.g. free vs. total EA), which 2011; Schulenburg et al., 2016). Plant phenols including EA and are not always clearly reported. Moreover, the EA content of fresh ETs have been associated with miscellaneous biological functions in unprocessed strawberries varies considerably depending on multiple plants, such as defense against bacteria, fungi, viruses, and animal factors, including the cultivar (cultivated variety), agricultural prac- herbivores as well as protection against solar radiation, which can tices, growing environment and season, the developmental stage of benefit yields and integrated pest management by increasing plant the fruit, as well as the type of tissue within the fruit and in the resistance to some diseases (Treutter, 2010; Amil-Ruiz et al., 2011; plant. The influence of these factors is relatively well established for Schulenburg et al., 2016). Further details on the sources, chemistry, F. ananassa fruits. In contrast, very little is known about the factors and biology of EA and ETs can be found in the following reviews influencing the EA content of other parts of the plant and of wild (Tsao, 2010; Ascacio-Valdés et al., 2011; Landete, 2011). species of strawberries. Fruits EA Content and Distribution in the EA distribution within the fruit Strawberry Plant Within the strawberry fruit, EA is more concentrated in the achenes Strawberries belong to the genus Fragaria, a member of the Rosaceae (seeds), located on the surface of the fruit, than in the fruit pulp family. This genus includes 20 named wild species, three described or flesh which is devoid of achenes (Figure 2a and b , Table 2). naturally occurring hybrid species, and two cultivated hybrid species Consequently, the whole fruit is richer in EA than the pulp and of commercial importance, namely F. × ananassa (also known as the some of its derived products (e.g. seedless strawberry juices and garden strawberry) and F. vescana, which are cultivated worldwide purées), as illustrated in Table 2. Substantially higher concentra- and in Europe, respectively (Hummer et al., 2011). All of these spe- tions of EA, per fresh weight (FW), in the achenes are partly due to cies are potential sources of EA but very few [F. × ananassa mainly, the lower water content of the achenes. When expressed on a dry followed very distantly by F. vesca (wild or woodland strawberry) weight (DW) basis, EA concentrations in achenes and pulp are gen- and F. chiloensis Chilean white strawberry)] have been studied for erally of the same order of magnitude. A comprehensive study that Figure 2. (a) Cross-section of the strawberry fruit (Fragaria × ananassa) and (b) other plant parts that contain ellagic acid. Ellagic acid in strawberries, 2017, Vol. 1, No. 4 231 Table 2. Total ellagic acid content (mg/100 g of FW, except where indicated) in different parts of the strawberry plant. Country, cultivar Whole fruit ( ) or Achenes Leaves Flowers Roots Juice Reference pulp ( ) Argentina F F P Camarosa 10.1 (18.1 green ) 1.52 – – – – – Williner et al. (9.0 green ) (2003)* USA – 5.22 3.8 – – – ND Daniel et al. (1989) USA Totem 11.8 90.3 – – – – Aaby et al. (2005) Puget Reliance 9.5 35.5 – – – – Spain Camarosa 10.1 146.3 – – – – Ariza et al. (2016)* USA P P Arking 37.1 (64.0 green ) 399 (312 – – – – Maas et al. (1991a)* green) P P Micmac 21.2 (17.7 green ) 613 (721 – – – – green) P P Vesper 19.0 (38.8 green ) 858 (491 – – – – green) P P Tangi 19.1 (30.1 green ) 95.9 (204 – – – – green) P P Tribute 12.3 (25.7 green) 597 (215 807 – – – green) P P Delite 8.9 (22.4 green) 350 (110 501 – – – green) P P Earliglow 6.5 (25.2 green) 1 367 (188 202 – – – green) P P Honeoye 3.4 (19.6 green ) 729 (358 323 – – – green) Finland Jonsok – – 49.1–131 – – – Hukkanen et al. (2007) Czech Republic – – – 21.2– – – – Buřičová et al. 34.5 mg/L (2011) Finland Jonsok – – – Relatively high free – – Hanhineva et al. EA and ET contents (2008) in receptacle** *** USA Blakemore – – – – EA and EAD – Nemec (1973) Howard 17 – – – – previously – Sunrise – – – – found in – Surecrop – – – – fruits and – leaves** Wild strawberries Chile F F F, F. chiloensis EA , EAD and ET ** – EA and ET** – ND – Simirgio- tis and Schmeda– Hirschmann (2010) Portugal F. vesca Dias et al. (2015a,b) Commercial – – 35.3 mg/g**** – 16.1 mg/g – Wild samples – – 69.5 mg/g**** – traces – Cultivars of Fragaria × ananassa, except where indicated (F. chiloensis and F. vesca). Fruits, pulp (fruit without achenes) and achenes were from red strawberries, except where indicated (green). Juice from the fruit was unprocessed. EA, ellagic acid; EAD, ellagic acid derivatives; ET, ellagitannins; ND, not detected; –, not determined. *Values from Williner et al., Ariza et al. and Maas et al. (reported in mg/g of DW by these authors) were converted to mg/100 g of FW by multiplying by 0.08 × 100, i.e. assuming 92% water in strawberries. For achenes and leaves, a water content of 30% and 75% water was assumed, respectively, i.e. conversion factors of 0.7 × 100 and 0.25 × 100. **These compounds were detected but their concentrations were not reported. ***For flowers, five individual flower organs were studied individually, namely the petal, sepal, stamen, pistil, and receptacle that gives rise to the strawberry fruit. Relatively high contents of EA and ET in the receptacle were as in the early stages of the strawberry fruit maturation. ****Leaves and stems were analysed together in the study of Dias et al. (2015a). 232 Muthukumaran et al., 2017, Vol. 1, No. 4 included 36 clones (cultivars and breeding selections) of F. × anana- the pulp, achenes, and leaves from 36 cultivars. The mode of inherit- ssa reported average EA concentrations of 8.46 and 7.24 mg/g of ance of EA content in strawberry remains to be established. DW (about 592 and 506 mg/100 g of FW) in the achenes of red and green strawberries, respectively, and of 1.55 and 3.54 mg/g DW Influence of agricultural practices and growing environment (12.4 and 28.3 mg/100 g FW) in the pulp of red and green fruits Agricultural practices (e.g. cultural system and fertilization) and lo- (Maas et al., 1991a). Superior or high EA concentration in achenes cation (i.e. environmental conditions such as light and temperature) vs. pulp was also found in ripe strawberries of other cultivars (Aaby influence the accumulation of phenols in several crops (Treutter, et al., 2005; Fait et al., 2008; Ariza et al., 2016). Daniel et al. (1989) 2010). Strawberry fruits seem to accumulate higher amounts of reported a relatively low concentration in the achenes (Table 2), but phenolic compounds when they are grown under conditions opti- they did not mention cultivar. It is possible that the pulp in that mized for plant growth and fruit yield. For instance, fruits grown in study was not achene-free. a hill plasticulture (or raised bed) system were found to have higher Strawberry achenes also have superior total phenolic content EA contents and antioxidant capacities than fruits from the con- and antioxidant capacity compared with the pulp. Despite repre- ventional matted-row system (Wang et al., 2002). These research- senting a mere 1% of the whole fruit on a FW basis, achenes were ers showed a significant effect of cultural system and genotype (14 found to contribute 41% of the total phenolic compounds and 45% strawberry cultivars and selections), individually, as well as a signifi- to 81% (depending on the determination method) of the antioxi- cant interaction between the two variables, on the EA content of the dant capacity of the whole ripe fruit (Ariza et al., 2016). Similarly, fruits. Similarly, the use of a compost and full strength NPK fertilizer Aaby et al. (2005) found that the achenes contributed 11% of the almost doubled the free EA content of ripe fruits from Allstar and total phenolics and 14% of antioxidant activity of ripe strawberries. Honeoye cultivars (up to 0.83 and 0.63 mg/100 g FW, respectively) Both studies suggest that, in the achenes, total phenolics and in par- compared with unfertilized controls (Wang and Lin, 2003). In con- ticular EA, EA glycosides, and ETs (Aaby et al., 2005) contributed trast, Anttonen et al. (2006) showed a reduction of total EA (from the most to the antioxidant capacity. The high EA content and anti- 29.29 to 24.79 mg/100 g FW) and flavonol contents in strawberries oxidant capacity of achenes can be used profitably to enrich straw- of the Bounty cv. by increasing the level of fertilization, but there berry juices and purées (see Influence of Processing and Subsequent was no indication about plant growth and yield in their work. They Storage section) as well as other products that would otherwise con- also reported that organically grown fruits from six cultivars tended tain negligible or low amounts of EA. This is a promising strategy to be richer in flavonols than conventionally grown fruits (Anttonen to add value to achene-rich wastes generated during the produc- et al., 2006), but did not assess this effect on EA. Häkkinen and tion of some strawberry-based foods and to turn these wastes into Törrönen (2000) assessed the influence of conventional vs. organic valuable products for food as well as cosmetic and pharmaceutical cultivation technique on the phenolic content of three cultivars applications. (Honeoye, Jonsok, and Polka) and found no significant effect, ex- cept for the Jonsok cv. for which the organically cultivated fruits had Influence of cultivar 12% higher concentrations of total EA and total phenolics. The concentration of EA in ripe strawberry fruits varies considerably Other practices (namely late planting time and use of white vs. among F. ananassa cultivars (genotypes) and studies, ranging from brown mulch) as well as tertiary fruit order in the strawberry in- less than 10 mg/100 g FW to over 100 mg/100 g, as illustrated in florescence were found to significantly increase the contents of EA Table 3. Some studies on the subject (Maas et al., 1991a; Cordenunsi and total phenolics in ripe fruits of the Korona cv., while early forc- et al., 2002; Wang et al., 2002; Williner et al., 2003; Skupień and ing and shading had no significant effect (Anttonen et al., 2006). Oszmiański, 2004; Atkinson et al., 2006; da Silva Pinto et al., 2008; Reflective mulches were also found to significantly increase the total Bojarska et al., 2011; Aaby et al., 2012; Kim et al., 2015) have EA content of fruits of the Flamenco cv., but had no effect in the examined a large number of cultivars, from 5 to 44 depending on Elsanta cv. (Atkinson et al., 2006). These researchers also showed the study. Table 3 provides an overview of some of the studies and that crop load (i.e. number of fruits per plant) had no significant cultivars. It is noteworthy that the cultivars yielding the highest (or effect on the total EA content of fruits of the Elsanta and Florence lowest) levels of EA in ripe fruits generally differ among studies. cultivars, suggesting that EA concentration is relatively tightly regu- This not only reflects methodological differences in quantification lated in strawberry, irrespective of crop load. Last but not least, sig- methods, but also the influence of growing conditions and practices, nificant year-to-year variations in total EA content were reported i.e. the interplay between genotype and environment. For instance, with some cultivars (Atkinson et al., 2006; Kim et al., 2015). The within the following individual studies [Maas et al. (1991a) (36 cv.), influence of location was noted with respect to EA in the fruit pulp Atkinson et al. (2006) (44 cv.), Kim et al. (2015) (14 oriental cv.), and achenes (Maas et al., 1991a) as well as EA and flavonols in the Skupień and Oszmiański (2004) (6 cv.), Bojarska et al. (2011) (11 whole fruit (Häkkinen and Törrönen, 2000; Anttonen et al., 2006). cv.), da Silva Pinto et al. (2008) (7 cv.), Williner et al. (2003) (5 cv.), Aaby et al. (2012) (27 cv.), Cordenunsi et al. (2002) (6 cv.), Wang Influence of fruit maturity et al. (2002) (14 cv.)], the concentration of EA in ripe strawberries EA concentration in strawberry fruits also depends on the devel- varied by a factor of 10, 6, 5, 4, 3, 3, 3, 2, 2, and 2, respectively, be- opmental stage of the fruit. As illustrated in Table 4, the highest tween the cultivars that produced the highest vs. lowest concentra- concentration occurs in the early stages of fruit maturation (green tion. Overall, these findings suggest that the EA content of the fruit strawberries), then gradually declines as the fruit ripens. This trend can be modified through breeding and selecting cultivars that gener - was shown for the whole fruit, that is, pulp and achenes combined ally produce high (or low) EA levels under the growing conditions (Williner et al., 2003; Aaby et al., 2012), as well as for the pulp considered. Fruits with a high EA content can be obtained this way, without achenes (Maas et al., 1991a; Williner et al., 2003; Fait but this may not necessarily translate into high EA concentrations et al., 2008). In whole strawberries, the decrease in the EA content in other parts of the plant, as reported by Maas et al. (1991a). This between green and fully ripe stages ranged from 2.8 to 8.5 times group found no identifiable relationship between the levels of EA in across the five cultivars studied by Williner et al. (2003). In their Ellagic acid in strawberries, 2017, Vol. 1, No. 4 233 Table 3. Total and free ellagic acid (EA) contents of ripe strawberries from selected cultivars grown in different countries. Country, cultivar Total EA (mg/100 g FW) Free EA (mg/100 g FW) Reference Argentina Chandler 6.84 – Williner et al. (2003) Camarosa 6.16 – Sweet Charly 4.86 – Oso Grande 2.85 – Milsei 2.86 – Camarosa 6.67 0.61 Van De Velde et al. (2013) Selva 11.9 0.65 Brazil Oso Grande – 1.87 Cordenunsi et al. (2002) Campineiro – 1.62 Mazi – 1.36 Dover – 1.01 Toyonoka – 0.98 Pajaro – 0.90 Dover 47 2.60 da Silva Pinto et al. (2008) Camarosa 42 2.20 Oso Grande 28 2.22 Sweet Charlie 24.7 0.75 Toyonaka 17.0 1.05 Finland Jonsok 40.3 – Häkkinen et al. (2000) Jonsok 79.9 1.4 Koponen et al. (2007) Honeoye 77.6 2.2 Polka 68.3 0.7 Jonsok 52.2 – Häkkinen and Törrönen (2000) Polka 51.7 – Honeoye 46.7 – Korea Kim et al. (2015) Dahong 15.0 – Keumhyang 8.0 – Seolhyang 3.0 – Norway Aaby et al. (2012) Bounty 17.3 0.7 Honeoye 13.5 1.8 Senga V 11.6 0.6 Polka A 11.2 1.3 Jonsok 10.2 0.8 Poland Camarosa 119.3 – Bojarska et al. (2011) Elsanta 103.4 – Honeoye 63.5 – Senga Sengana 58.0 – Polka 56.1 – Thuriga 55.3 – Kama 54.0 – Onebor 53.4 – Kent 52.8 – Dukat 51.6 – Heros 45.2 – Elsanta 261.0 – Skupień and Oszmiański (2004) Kent 108.8 – Dukat 105.5 – Selva 72.6 – Sweden Määttä-Riihinen et al. (2004) Honeoye 15.5 4.0 Jonsok 14.9 4.1 Polka 11.4 3.5 UK Atkinson et al. (2006) Osmanli (w) 34.1 1.13 Nida 32.2 2.14 Laura 24.3 2.11 EM676WF (w) 20.6 1.17 234 Muthukumaran et al., 2017, Vol. 1, No. 4 Table 3. Continued Country, cultivar Total EA (mg/100 g FW) Free EA (mg/100 g FW) Reference Coral 17.6 2.30 Rosie 15.5 0.64 Ciloe 12.6 0.75 Totem 9.8 1.01 Elsanta 9.4 ND Tango 7.9 0.43 Hapil 6.0 ND USA Arking 37.1 – Maas et al. (1991a)* Micmac 21.2 – Vesper 19.0 – Tangi 11.9 – Oso Grande 9.6 – Allstar 6.6 – Totem 6.6 – Annapolis 3.4 – Honeoye 3.4 – Mohawk – 3.45 Wang et al. (2002) Allstar – 2.57 B244-89 – 1.80 Cultivars of Fragaria × ananassa. Ripening stage: ripe, full maturity, commercial ripeness or not specified, depending on the study. Values from Williner et al. (2003) are for strawberries with 50% and 100% red colour combined (fruits with edible value). FW, fresh weight, except for the values from Atkinson et al. (2006) which are in mg/100 g of frozen weight; ND, not detected; –, not determined; (w), cultivars which produce white fruits. *Values from Maas et al. (1991a) are for pulp without achenes and were reported in mg/g of DW by these authors. They were converted to mg/100 g of FW by multiplying by 0.08 × 100, i.e. assuming 92% water in strawberries. Table 4. Total ellagic acid content (mg/100 g of FW) of strawberries at different stages of ripeness. Country, cultivar Stage of ripeness Reference 0% red (green) 50% red (e) 100% red (e) 50% and 100% red combined (e) Argentina Williner et al. (2003)* Chandler 17.8 9.45 4.13 6.84 Camarosa 12.9 7.82 4.57 6.16 Sweet Charly 11.8 5.87 3.85 4.86 Oso Grande 8.82 4.0 1.69 2.85 Milsei 13.8 4.1 1.63 2.86 USA Maas et al. (1991a)** Arking 64.0 – 37.1 – Micmac 17.7 – 21.2 – Vesper 38.8 – 19.0 – Tangi 30.2 – 11.9 – Oso Grande ND – 9.6 – Annapolis ND – 3.4 – Honeoye 19.7 – 3.4 – Cultivars of Fragaria × ananassa; (e), fruits with edible value; –, not determined. *Values from Williner et al. (2003) are for whole strawberries (pulp with achenes). **Values from Maas et al. (1991a) are for pulp without achenes and were reported in mg/g of DW by these authors. They were converted to mg/100 g of FW by multiplying by 0.08 × 100, i.e. assuming 92% water in strawberries. work, the sharpest decline was for the Milsei cv. in which high EA Based on the evidence available for the Camarosa cv., the decline content in the early developing fruit did not persist during ripening. in EA concentration seems to be less pronounced in the whole fruit Aaby et al. (2012) reported significant decreases in EA conjugates than in the pulp (1.8 and 5.9 time reductions, respectively) (Williner by about 1.6 times between nearly ripe and fully ripe stages (Blink et al., 2003). This finding is consistent with the high EA content of and Polka cv.) and decreases by 1.4 times in agrimoniin content the achenes, which was found to increase or decrease (Maas et al., between nearly ripe and ripe stages (Blink, Polka, and Senga cv.). 1991a), depending on cultivar and possibly other factors to be iden- In the achene-free pulp, the decrease in EA content between green tified, during ripening of the fruit. and fully ripe stages ranged from 1.6 to 4 times across the 31 clones Maas et al. (1991a) showed that the evolution of the EA concen- (cultivars and breeding selections) studied by Maas et al. (1991a). tration in the achenes during ripening is not as consistent as for the Ellagic acid in strawberries, 2017, Vol. 1, No. 4 235 pulp: while it increased by 2–7 times for 17 clones (e.g. Earliglow, amount of free EA in the receptacle was relatively high (Hanhineva Honeoye), it decreased by 1.5–4 times for 13 other clones (e.g. et al., 2008). These findings are consistent with the particularly high Micmac, Tangi), as illustrated in Table 2 for some clones. Lower EA EA content of strawberries in the early stages of maturation (Maas content in the achenes from ripe strawberries was also reported in a et al., 1991a; Funt et al., 2000; Williner et al., 2003). They also con- study of the Herut cv., which indicated that EA, EA derivatives, and cur with the presence of EA in some honeys (Kassim et al., 2010; ETs were less abundant in the achenes during the late stages of fruit Rao et al., 2016), which presumably reflects the ET and EA compos- development (Fait et al., 2008). For the various cultivars studied by ition of the flowers visited by honey bees. It is worth noting that the Maas et al. (1991a), no evident relationship was evidenced between order of the fruit in the strawberry inflorescence, from primary to the EA concentration and its variation during ripening in the achenes tertiary order, seems to increase the amount of EA in the fruit, as evi- and in the pulp. denced in ripe strawberries of the Korona cv. (Anttonen et al., 2006). Fruits from wild species of strawberries Leaves The limited evidence currently available indicates that fruits from The leaves of some berry plants are valuable sources of natural bio- wild strawberry species are rich sources of EA. In a study of fully ma- active compounds, including EA and ETs (Ferlemi and Lamari, 2016). ture F. vesca fruits from 15 wild strawberry accessions (genotypes), Strawberry leaves were found to contain relatively high amounts total EA concentration ranged from 15.18 to 26.36 mg/100 g FW, of EA (Maas et al., 1991a; Hukkanen et al., 2007; Simirgiotis and compared with 18.56 mg/100 g in fruits of the cultivated Camarosa Schmeda-Hirschmann, 2010; Žugić et al., 2014; Dias et al., 2015a), cv. (Yildiz et al., 2014) (Table 5). The high average content found as illustrated in Table 2. The study of Maas et al. (1991a) is the most with accession FV-4 was significantly higher than for Camarosa. comprehensive to date on this subject as it included 36 clones of F. In another study of fully mature F. vesca fruits, values of 37.9 and × ananassa and quantified the EA in the fruit pulp and achenes in 17.5 mg/g of lyophilized extract or infusion were reported for addition to the leaves. Higher EA concentration was found in the total EA derivatives in hydromethanolic fruit extracts and infu- leaves than in the pulp and sometimes achenes. Average EA content sions, respectively (Dias et al., 2016). Consistent with these val- in the leaves, calculated over 13 clones, was 14.71 mg/g DW, with ues, the hydromethamolic extracts showed higher antioxidant and values ranging from 8.08 to 32.30 mg/g depending on clone. This antibacterial activities than the infusions. Another study detected average was about 9, 4, 2, and 2 times higher than for red and green but did not quantify EA, EA derivatives, and ETs in methanolic fruit pulp and achenes from red and green fruits, respectively, which extracts of ripe F. chiloensis ssp. chiloensis f. chiloensis fruits. These were calculated over 36 clones. Large differences in EA content were extracts had higher total phenolic content and antioxidant activity evidenced among clones. All had a superior EA content in the leaves compared with leaf and root extracts (Simirgiotis and Schmeda- compared with fruits, but only eight clones out of 13, including Hirschmann, 2010). Tribute and Delite, had a leaf EA content greater than for red and green achenes. EA content from one tissue did not correlate consist- ently with values of the other tissues (Maas et al., 1991a). A study Flowers of strawberries cv. Jonsok showed that EA, EA derivatives, and ETs There is hardly any information on EA in the strawberry flower. accumulated in the leaves and fruits after treatment with benzothia- A study of secondary metabolites in five individual flower organs diazole (BTH) and inoculation with powdery mildew conidia. This (petal, sepal, pistil, stamen, and receptacle) of F. × ananassa cv. was suggested to play a role in the BTH-induced resistance of the Jonsok revealed that the majority of the metabolites identified were plant to mildew infection (Hukkanen et al., 2007). ETs that accumulated in all five parts of the flower (Hanhineva et al., Leaves of wild species of strawberries have been studied more 2008). The pistil, stamen, and receptacle contained the highest pro- recently in relation to their EA content (Simirgiotis and Schmeda- portion of ETs and ET derivatives, including agrimoniin and galloyl- Hirschmann, 2010; Žugić et al., 2014; Dias et al., 2015a). In F. vesca hexahydroxydiphenic acid (HHDP)-glucose, which also occur in L., EA, EA derivatives, and ETs were found in appreciable amounts in strawberry fruits and leaves. The ETs and ET precursors identified leaves and stems (Dias et al., 2015a), but the results from this study in the receptacle were similar to the ones found in the early develop- are not specific to leaves as mixtures of leaves and stems were used. ing fruit, which derives from the swollen flower receptacle, and the Table 5. Total and free ellagic acid (EA) contents of ripe wild strawberries of different genotypes grown in different countries. Country, genotype Total EA (mg/100 g FW) Free EA (mg/100 g FW) Reference Portugal 37.9 – Dias et al. (2016)* Turkey Yildiz et al. (2014) FV–4 26.4 – FV–1 25.1 – FV–10 23.4 - FV-15 21.2 – FV-14 18.2 – FV-5 17.9 – FV-6 17.1 – FV-7 15.2 – Camarosa cv. 18.6 – Fragaria vesca L., except for the Camarosa cultivar of Fragaria × ananassa included for comparison. FV, Fragaria vesca genotype; FW, fresh weight. *The value from Dias et al. (2016) is for total EA derivatives in mg/g of lyophilized extract. 236 Muthukumaran et al., 2017, Vol. 1, No. 4 They were from commercial and wild samples and three types of to disease and pests. Compiling the values of EA concentrations in extracts were used: hydromethanolic extracts and two water extracts a searchable, peer-reviewed database would be useful. Research in resembling homemade herbal preparations (infusion and decoction). this field should also be extended to lesser studied species and varie- The hydromethanolic extracts showed the highest contents of total EA ties, not only because they are potentially good sources of EA and derivatives (35.31 and 69.49 mg/g for commercial and wild samples, similarly beneficial compounds, but also because they could be bet- respectively). All the extracts displayed antioxidant capacity, particu- ter adapted to grow in certain regions of the world where the cur- larly those from the wild sample, especially the infusion (Dias et al., rent commercial species does not grow as well or as cost-effectively. 2015a). Likewise, Buřičová et al. (2011) reported appreciable contents This could open the way to less input/labour intensive and more of EA (21.2–34.5 mg/l, i.e. 1.1–1.8 mg/g of dry leaves) in water extracts cost-effective and ecological production of EA-rich materials. of F. vesca L. leaves. EA and catechin were found to contribute the most to the total antioxidant capacity of the leaf extracts, which was 62.8% EA Stability in Strawberries During Post- that of green tea. Žugić et al. (2014) reported high contents of total harvest Storage and Processing phenols and total tannins in methanolic extracts of aerial parts of F. vesca L., but it is not clear whether these observations are for extracts Influence of post-harvest storage from leaves or other parts of the plant. For leaves, the extracts had the The total EA content (i.e. bound and free EA) of freshly harvested second highest antioxidant activity of all 10 herbal plants they studied. strawberries of the Jonsok cv. was found to be stable during short- F. chiloensis ssp. chiloensis form chiloensis, a wild species of Fragaria term storage (24 h) at either 5ºC or 22ºC (Häkkinen et al., 2000). endemic to southern Chile, which produces light red or ‘white’ straw- Long-term storage at –20ºC, on the other hand, led to a signifi- berries, was studied by Simirgiotis and Schmeda-Hirschmann (2010). cant reduction of total EA content by 25% and 40% after 6 and They detected EA, EA derivatives, and ETs in methanol extracts from 9 months, respectively (Häkkinen et al., 2000). This reduction was the leaves. Most of these compounds were also detected in the fruit explained by the oxidation of EA and its ability to react with free extracts. The leaf extracts had the second-highest antioxidant activity radicals and chelate metals. After storage at 5ºC for 5 and 10 days, and total phenolic content after the fruit extracts. a 30% increase in the free EA content of the fruits (Selva cv.) was reported in another study (Gil et al., 1997). The increase in free EA Stems can be explained by the hydrolysis of ETs (bound EA) over time, No reports were found on EA in strawberry stems and stolons (run- which releases free EA. These researchers further showed that ners), which are leafless stems growing at or near the surface of the storage for 5 days at 5ºC under modified atmospheres contain- soil. One study used strawberry stems to assess the phenolic com- ing 10–40% CO limited the increase in free EA over time. These position of F. vesca L. vegetative parts (leaves and stems from com- elevated CO concentrations also had a detrimental effect on the mercial and wild samples), but these parts were mixed together (Dias internal colour of the fruits (Gil et al., 1997). Another study found et al., 2015a). Appreciable amounts of EA, EA derivatives, and ETs that the free EA concentration of fresh-cut strawberries (Camarosa were found, but these results are not specific to the stems. cv.) stored at 4ºC under either superatmospheric O , low O , or pas- 2 2 sive atmospheres was stable for 4 days, then rose until Days 9–11 in all samples (Odriozola-Serrano et al., 2010). After that time, the Roots fruits stored under high-O or passive atmosphere exhibited a drop As for flowers and stems, limited information is available on EA in free EA content until the end of the storage period (21 days), while in strawberry roots. An early report revealed that the roots of four free EA continued to rise in the fruits stored under low O atmos- cultivars of F. × ananassa (Blakemore, Howard 17, Sunrise, and pheres. High O atmospheres also promoted the loss of vitamin C. Surecrop) contain a diverse assortment of phenolics, many of which The low O and passive atmospheres were found to best maintain are also present in the leaves and fruits (Nemec, 1973). EA, an EA the antioxidant capacity of the fresh-cut fruits during cold storage derivative, and two hydrolysable tannins were detected in the root (Odriozola-Serrano et al., 2010). Post-harvest treatment of straw- extracts. This researcher noted that the number of phenolic com- berries (Goha cv.) with 15% CO for 3 h prior to storage at 4ºC pounds present in the roots varied during the year and was higher in under regular atmosphere was found to improve the overall quality summer-grown roots. Two subsequent studies looked at the phenolic retention of the fruits for up to 9 days compared with untreated con- composition of roots of wild species of strawberries. The first one, trols and fruits treated with higher concentrations of CO (Chandra with F. chiloensis ssp. chiloensis f. chiloensis, did not detect EA, EA et al., 2015). It remains to be established whether this pre-treatment derivatives, and ETs in root methanol extracts, unlike fruit and leaf could also benefit the retention of EA. extracts. The root extracts had the lowest antioxidant activity, which was attributed to their lower total phenolic content (Simirgiotis and Influence of processing and subsequent storage Schmeda-Hirschmann, 2010). The second study focused on F. vesca L. roots using commercial and wild samples and three types of Jam and purée processing and storage extracts (hydromethanolic extract, infusion, and decoction) (Dias Research into strawberry EA stability in processed foods has focused et al., 2015b). Roots from the commercial sample showed the highest primarily on jams and purées. A few studies looked at the EA content content of total EA derivatives, particularly in the hydromethanolic of strawberry processing byproducts as these are potentially interest- extract (16.06 mg/g). All the extracts possessed antioxidant activity ing sources of EA and of other valuable phytochemicals. Strawberry particularly those from the wild sample, especially the infusion. jam preparation usually involves cooking the slightly mashed fruits In conclusion, the strawberry plant as a whole is a rich source of without completely crushing them. Cooking strawberry fruits with EA. Further research should be directed towards characterizing lesser sugar was found to decrease the total EA content compared with studied parts (e.g. leaves, stems, and roots) for their EA content in re- fresh strawberries. Reductions of 35% and 20% have been reported lation to cultivars, growth conditions and agricultural practices, EA by Flores and del Castillo (2016) (Splendor cv.) and Häkkinen et al. content of other parts of the plant, as well as resistance of the plant (2000) (Jonsok cv.), respectively. These losses in total EA are thought Ellagic acid in strawberries, 2017, Vol. 1, No. 4 237 to be due to increased oxidation of EA when the integrity of the Like strawberry jams, thermally processed strawberry purées, cell wall and membrane is lost upon cooking and mixing (Häkkinen produced by crushing and moderate thermal treatment of the fruits et al., 2000). It is not known whether the addition of antioxidants at 75–80ºC, were found to contain less total EA (Aaby et al., 2007b) may help protect EA and increase its retention in the final products. and more free EA (Aaby et al., 2007b; Truchado et al., 2012) than Other researchers measured free EA (i.e. without hydrolysis) rather fresh strawberries. Storing the purées in the dark at 6ºC improved than total EA (after hydrolysis) to study the effect of jam cooking the retention of total EA compared with storage at 22ºC, especially (Zafrilla et al., 1999). They reported a 150% increase in the content for the purées that had been enriched in EA (Aaby et al., 2007b) of free EA after cooking, both for strawberries and red raspberries, (Table 6). EA content is also influenced by the pH of the product, and suggested that the increase in free EA could be due to ET hy- as shown in a study of pasteurized strawberry purées of different drolysis during cooking as well as superior extractability of EA from pH in the range 2.5–4.5 that were stored at 4ºC or 23ºC (Oliveira the cooked products due to cell-structure disruption. Both trends of et al., 2015). The greater increases in free EA content during storage increased free EA and decreased total EA in strawberry jam com- were observed with the purées that had the lowest pH (3.0 and 2.5). pared with fresh strawberries were also reported by Koponen et al. At both pH, the free EA content of the purées increased by 84% (2007). and 185% after 3 months at 4ºC and 23ºC, respectively, which is Flores and del Castillo (2016) compared the effect of two consistent with ET acid hydrolysis promoted by the combination of jam-making methods, namely, a commercial method (no descrip- thermal treatment, low pH, and storage time. Overall, their findings tion provided) and a homemade method that involved a shorter suggest that pH 2.5 and low storage temperature (4ºC) are the best heating time (60 min) with no addition of sugar or pectin, rely- conditions for preserving both polyphenols and colour in pasteur- ing instead on the pectin naturally occurring in fully ripe straw- ized strawberry purées (Oliveira et al., 2015). berries. Both methods significantly reduced the total EA content As shown by the above studies, the processing of strawberries compared with fresh strawberries, but the reduction was less pro- into jam and purée and their subsequent storage can not only affect nounced in the home-made jam (22% vs. 35%). The homemade the concentration of EA, but also its molecular form (bound vs. free method also reduced the loss of other antioxidant compounds (e.g. EA), which may influence its bioavailability by increasing the amount quercitin) as well as the formation of carcinogenic heat-induced of free EA. The effect of strawberry processing on EA metabolism by volatile compounds. Thus, shorter cooking times seem advisable the intestinal microflora was investigated in healthy human subjects, to enhance the nutritional benefits of strawberry jams and other using thermally processed strawberry purée containing the same heat-processed foods. amount of fruits than the control food (fresh strawberries) and no The effect of storage of the EA content of strawberry jam depends added sugar (Truchado et al., 2012). These researchers found that on the storage temperature, as illustrated in Table 6. Storage at low despite higher amount of free EA in the purée, the microbial metab- temperatures (5ºC and –20ºC) for up to 9 months had no significant olism of EA, assessed by urolithin production (EA bioactive metabo- effect on the total EA content (Häkkinen et al., 2000), while storage lites in humans) and their urinary excretion, was not significantly at 20ºC resulted in a significant decrease in total EA after 3 months different from that of fresh strawberries. (Pineli et al., 2015). Pineli et al. (2015) further showed that the free EA content increased significantly from 1.23 to 2.01 mg/100 g FW Dehydration after storage for 2 months at 20ºC, then decreased to 0.91 mg/100 g Dehydrated strawberries show interesting characteristics and appli- after 4 months. These findings are consistent with ET hydroly- cations for the food industry. The effects of four different drying sis initially, releasing free EA which is then lost to oxidation after methods, namely, convection drying (70ºC), freeze-drying (–60ºC, prolonged times. then +70ºC), vacuum drying (50ºC), and vacuum-microwave (VM) Table 6. Stability of ellagic acid (total content in mg/100 g of FW) during the storage of strawberry jams and strawberry purées at different temperatures. Storage temperature Storage duration Reference Jams 0 day 90 days (3 months) 120 days (4 months) 180 days (6 months) 270 days (9 months) +5ºC 23.8 ± 3.7 24.0 ± 1.8 – 25.4 ± 3.5 21.0 ± 1.7 (1) –20ºC 23.8 ± 3.7 19.6 ± 1.2 – 23.4 ± 0.8 20.2 ± 1.0 (1) +20ºC 27.5 ± 0.7 23.1 ± 1.3 22.3 ± 1.0 – – (2) Purées with variable achene 0 day 8 weeks 16 weeks (3) content +6ºC No achenes 14.0 14.6 14.8 – – Whole berries 22.4 20.5 21.4 – – Achene-enriched 35.5 33.4 32.7 – – +22ºC No achenes 14.0 14.1 13.5 – – Whole berries 22.4 19.5 19.0 – – Achene-enriched 35.5 30.7 30.1 – – Reference (1): Häkkinen et al. (2000), strawberries Jonsok grown in Finland; Reference (2): Pineli et al. (2015), strawberries Camino Real grown in Brazil; Ref- erence (3): Aaby et al. (2007b), strawberries Senga Sengana grown in western Norway, total EA in fresh berries: 25.2 mg/100 g of FW, concentration of achenes in the purées: 0% (purée from achene-free pulp), 1.2% (purée from whole strawberries), and 2.9% (purée from achene-enriched fruits) on a FW basis. –, not determined. 238 Muthukumaran et al., 2017, Vol. 1, No. 4 drying (240, 360, and 480W), on the free EA content of strawberry generated achenes was still high (up to 80 mg/100 g FW depend- fruits were studied with two cultivars (Kent and Elsanta) (Wojdyło ing on the extraction method), indicating that this processing waste et al., 2009). All drying methods significantly reduced the amount could be turned into a valuable source of EA. Sójka et al. (2013) of free EA in the dried products compared with fresh strawberries. studied the phenolic composition of industrial strawberry press With fruits of the Elsanta cv., which were richer in free EA ini- cakes (SPC, comprised of achenes and flesh) and their achene-free tially, the greater retention of free EA was obtained with VM dry- fraction (exhausted strawberry flesh, ESF). SPC were from a modern ing (480W) and vacuum drying, while with the Kent cv., the best fruit transformation plant. High amounts of free and total EA were retention was obtained with VM drying (340W and 480W). This found in dried SPC (99.0 and 985 mg/100 g DW, respectively) and study also showed that convection and vacuum drying led to the freeze-dried ESF (94.2 and 1 046 mg/100 g). Despite the presence of highest decreases in antioxidant activity and vitamin C content in sand in both fractions, which needs to be removed, it was concluded fruits of both cultivars. Freeze-drying and VM drying enabled bet- that SPC and ESF may be used as rich and widely available raw ter retention of antioxidant activity and vitamin C (Wojdyło et al., materials for extracting EA and ETs, especially agrimoniin (Sójka 2009). Other researchers found that VM drying of strawberries (San et al., 2013). In another study, this group found that pesticide residue Andreas cv.) decreased their polyphenol content by half. After stor- contents in strawberry byproducts (SPC, ESF, and a strawberry ET age at 20ºC, the polyphenol content of the vacuum packed straw- preparation) were higher than in fresh strawberries. However, the berries significantly increased after 45 days and remained stable for actual dietary risk to consumers from these byproducts (expressed as 6 months (de Bruijn et al., 2016). per cent of acceptable daily intakes following ingestion of equivalent amounts of ETs contained in strawberries) was comparable to that Juicing from fresh strawberries (Sójka et al., 2015). Strawberry juice contains low amount of EA (Daniel et al., 1989), In conclusion, the stability of EA in strawberries during post- indicating that EA is not well extracted from the fruit during juic- harvest storage and processing is notably influenced by temperature, ing that involves minimal processing. This has prompted research to duration of storage/processing, pH, as well as O concentration in enrich this juice in EA (discussed subsequently). It is worth noting the surrounding atmosphere. These factors influence EA content and that high-intensity pulsed electric fields (HIPEF) may be of value to its molecular form (bound or free). Free EA content was found to inactivate microorganisms in strawberry juices as an alternative to increase temporarily when storage and/or processing conditions pro- pasteurization. HIPEF processing of strawberry juice for short times mote ET hydrolysis and enhance EA extractability. However, free -1 (<2 ms) at electric field strengths from 20 to 35 kV×cm enabled and total EA contents decrease under conditions that promote EA fairly high retention (>80%) of antioxidant activity, anthocyanin, oxidation. Storage below room temperature is one of the strategies and vitamin C (Odriozola-Serrano et al., 2008), but there is no re- that effectively limit the losses in EA. Whether these losses may also port on the possible effect of HIPEF on EA. be delayed by adding antioxidants or using other protection meth- ods (e.g. low O atmospheres and encapsulation of EA) deserves further research. SPC and other byproducts from strawberry pro- EA enrichment strategies cessing hold great promises for recovering the achenes which are rich There are few reports on the enrichment of foods with EA from sources of EA and ETs. The use of pre-treated strawberry achenes is strawberries. Two main strategies have been investigated so far: fer- a promising approach for enriching foods and other products in EA. mentation of plant materials (see Production of Ellagic Acid from Strawberries and Other Plant Materials section) and incorporation of strawberry achenes. Lee and Chen (2016) developed an EA Production of EA from Strawberries and Other enriched strawberry wine by adding micronized ball-milled straw- Plant Materials berry achenes to the must prior to fermentation. This led to a 19.7% and 52.4% increase in EA and total phenol contents, respectively, Free EA can be produced from ET-rich plant materials, including and higher antioxidant capacity of the wine compared with regular edible food sources, some of their byproducts as well as non-edible strawberry wine. They found no significant differences in overall sources. The ETs are hydrolysed by treatment with hot water, acids, quality and acceptance between the enriched strawberry wine and bases, or enzymes (Landete, 2011), which is followed by recovery two commercial strawberry wines. Aaby et al. (2007b) prepared and purification of the EA. Acid–solvent extraction of EA uses con- strawberry purées with varying proportions of achenes (0, 1.2, and centrated HCl or H SO and methanol (Wilson and Hagerman, 2 4 2.9%), using strawberry flesh, whole fruits, and achene-enriched 1990; Lei et al., 2001; Lu and Yuan, 2008). This method has been homogenate, respectively. At production, the achene-enriched purées used for many years but has considerable drawbacks for large-scale contained 1.5 times more total EA than the purées made from whole commercial applications, primarily low yields of EA, high cost, and strawberries. This higher concentration was maintained during stor- limited eco-friendliness. This and other chemical processes often age at 6ºC and 22ºC for 16 weeks (Table 6). Antioxidant activity of suffer from appreciable impurities in addition to low yields, due to the enriched purées was also increased and better retained during variations in plant sources, differences in ET structure, as well as storage. difficulty in purifying the EA (Aguilera-Carbo et al., 2008, 2009). A few studies evaluated the potential of industrial byproducts Consequently, the last decade has seen a quest for alternative meth- from strawberry processing as sources of natural nutraceuticals and ods based on fermentation and hydrolysis of the ETs by microbial antioxidants such as EA. Aaby et al. (2005) studied the achenes enzymes. In these bioprocesses, the use of microbial cultures, primarily generated by industrial production of seedless strawberry purées. fungi, induces the biosynthesis of enzymes such as tannase (tannin Industrial processing was found to markedly reduce the contents acyl hydrolase) and ellagitannase (ET acyl hydrolase), which hydro- of free and total EA as well as the phenolic content and antioxi- lyse the ester bonds present in ETs, and of other enzymes involved dant activity of the achenes compared with achenes separated from in EA bioproduction (Aguilera-Carbo et al., 2008; Ascacio-Valdés freeze-dried strawberries and from non-thermally processed straw- et al., 2016). An overview of the plant sources and microbial strains berry purée. However, the amount of total EA in the industrially that have been studied is provided below. Details can be found in the Ellagic acid in strawberries, 2017, Vol. 1, No. 4 239 following reviews (Aguilera-Carbo et al., 2008; Ascacio-Valdés et al., been studied to produce EA. With aqueous extracts of creosote bush 2011; Sepúlveda et al., 2011). Bioconversion of ETs into EA and their leaves, SSF by A. niger GH1 at 30°C was shown to completely de- derived catabolites by the human gut microbiota will be discussed sep- grade the ETs and a maximum EA concentration of 17 mg/g was arately in the Ellagic Acid, Strawberries, and Human Health section. obtained after 36 h (Aguilera-Carbo et al., 2009). In a similar pro- cess, but with A. niger PSH, EA concentration increased by 92% and 177% after fermentation for 96 h of creosote bush and tar bush Biotechnological production of EA from byproducts leaf extracts, respectively, reaching final concentrations of 4.74 mg/g of edible fruits of creosote bush and 7.56 mg/g of tar bush (Ventura et al., 2008). There is scarce information about fermentation-enhanced EA pro- Another study found that the release of EA was lower with leaves of duction from the strawberry plant. Only one study was found (Dange creosote bush (0.5%) than with pomegranate husk (0.9%) after fer- et al., 2016). This group used raw strawberry fruits unfit for sale, mentation by A. niger GH1 for 96 h (Aguilar et al., 2008). an abundant byproduct often discarded as waste, and performed Bioproduction of EA from oak acorns and tannins has been solid-state fermentation (SSF) with Aspergillus niger NCIM-616 at achieved using SSF with A. niger and Candida utilis (Shi et al., temperatures ranging from 30°C to 40°C. After 96 h, the highest 2005), as well as submerged fermentation with A. SHL6 (Huang concentration of EA (143 ppm, i.e. 1.43 mg/g) was obtained at 35°C. et al., 2005), A. oryzae, Endomyces fibuliger, and Trichoderma ree- Although preliminary, these findings suggest a promising potential of sei (Huang et al., 2007a, 2007b, 2008a, 2008b). With acorn cups, strawberry byproducts as substrates for EA bioproduction. co-culture of A. orizae and T. reesei produced superior yield of EA The feasibility of EA bioproduction from agroindustrial byprod- (23%) compared with the pure cultures (16% and 7%, respectively) ucts was previously established using cranberry (Vaccinium mac- (Huang et al., 2007b). This was attributed to the synergistic action rocarpon) and pomegranate (Punica granatum). One group used of three enzymes in the co-culture, i.e. ET acyl hydrolase, xylase, and SSF with food grade fungi to enrich cranberry pomace in EA. With cellulase. Similar enhancements in EA content were reported with co- Rhizopus oligosporus, they found that the EA content increased cultures of A. oryzae and E. fibuliger or C. utilis grown, respectively, linearly 5-fold by Day 12 to a concentration of 375 µg/g DW of on acorn fringe (Huang et al., 2008a) and valonea oak tannins (Shi pomace (Vattem and Shetty, 2002). A similar level of enrichment was et al., 2005), indicating synergy between ellagitannase, β-glucosidase, obtained using Lentinus edodes (Vattem and Shetty, 2003). These and polyphenol oxidase (PPO) (Huang et al., 2008a), and tannase and relatively high concentrations of EA had not been reported previ- PPO (Shi et al., 2005). With co-cultures of A. oryzae and E. fibuliger ously in cranberries or their pomace. Fermentation of the pomace or T. reesei on acorn fringe, it was further shown that two combi- also increased antioxidant activity (Vattem and Shetty, 2002, 2003). nations of enzymes (ellagitannase–β-glucosidase–PPO and ellagitan- Various parts of the pomegranate fruit were studied to produce nase–cellulase–xylanase) were more effective than ellagitannase alone EA by SSF. With pomegranate husk and A. niger GH1, a maximum for producing EA (Huang et al., 2008b). These findings highlight the concentration of EA of 12.3 mg/g was reached after 96 h (Hernandez- importance of selecting appropriate sources of enzymes for optimizing Rivera, 2008). Another study showed that A. niger strains GH1 EA bioproduction. ET concentration, pH, temperature, carbon and and PSH both grew on the husk at higher growth rates than on the nitrogen sources, and fermentation time were also found to influence seeds, and that yields of 6.3 and 4.6 mg of EA/g of dried husk were EA bioproduction from oak material (Huang et al., 2005, 2007a). obtained with these two strains, respectively (Robledo et al., 2008). The above findings show that bioprocessing is a promising strategy Total hydrolysable polyphenols in the husk were degraded during for producing EA from natural sources using greener and milder condi- the first 72 h of fermentation. Likewise, with an aqueous extract of tions than chemical-based processes. More research is needed to de- pomegranate husk and A. niger GH1, maximum concentration of EA velop new sources and to optimize the bioprocesses for yield and purity was reached after 48 h and ETs degradation was attributed to a new of EA and cost-effectiveness. Characterization of the enzymes respon- tannase, now known as ET acyl hydrolase (or ellagitannase), differ- sible for ETs bioconversion to EA is essential as these biocatalysts must ent from tannin acyl hydrolase (Aguilera-Carbo et al., 2007), as sup- be well-suited to the type of ETs present in the plant material used as ported by other findings (Huang et al., 2008a; Ascacio-Valdés et al., substrate. The development of bioprocesses tailored for use with straw- 2016). Other agroindustrial byproducts such as sugarcane bagasse, berry plant material (e.g. discarded fruits, pomaces, achenes, and other corn cobs, coconut husks, and candelilla stalks were found to be good plant parts) deserves particular consideration in view of the richness of supports for producing ellagitannase by SSF (Buenrostro-Figueroa these materials in ETs/EA and of their relevance to human health. et al., 2013). Submerged fermentation, an alternative to SSF, was also studied to produce EA from pomegranate husk. With A. niger GH1 and the EA, Strawberries, and Human Health best conditions of pH, agitation, and substrate concentration, a max- Biological effects of EA and relevance to imum EA concentration of 21.19 mg/g of husk powder was obtained human health (Sepúlveda et al., 2014). The duration of submerged and solid-state EA and its related compounds (ETs, EA derivatives, and Us) have fermentations also has to be optimized in order to minimize the pos- a wide range of biological and physiological activities, as outlined sible biodegradation of EA by some of the fungal enzymes, which in Table 7. Similarly, their presumed beneficial effects in human may reduce EA content after some time (Aguilera-Carbo et al., 2009; health span across multiple bodily systems, including cardiovascular, Sepúlveda et al., 2014). gastrointestinal, endocrine, and neurocognitive systems, with pos- sible roles both in the prevention and the treatment or management Biotechnological production of EA from bush and of diseases such as cancer, diabetes and its complications, cardio- tree parts vascular, gastrointestinal, kidney, liver, pancreatic and eye diseases, Other plants, mainly oak tree (Quercus spp.) acorns, a forestry depression, Alzheimer’s, and other neurodegenerative diseases byproduct, and some plants from hot semi-desertic areas (Larrea (Table 8 and references therein, and Figures 3 and 4). EA may also tridentata or creosote bush and Fluorensia cernua or tar bush) have confer protection against development of the metabolic syndrome 240 Muthukumaran et al., 2017, Vol. 1, No. 4 and against some microbial, viral, and parasitic diseases or infec- Nevertheless, several studies identified in Tables 7 and 8 were con- tions (Table 8). Some of these effects have been researched exten- ducted with EA extracts from strawberries (e.g. Kosmala et al., 2014; sively over the past decade, principally in vitro and in animal models. Ibrahim and El-Maksoud, 2015; Juśkiewicz et al., 2016) or with An in-depth review is beyond the scope of this section. Instead, we strawberry fruits (reviewed by Basu and Lyons, 2012; Giampieri present the breadth of current research in this field in Tables 7 and et al., 2014, 2015; Vendrame et al., 2016). As indicated in Table 8, 8, along with recent publications supporting the evidence. Reviews several health benefits associated with EA are also associated with and articles published within the last 10 years have been prioritized the consumption of strawberries. Clearly, not all health benefits asso- in both tables whenever available. We refer the reader to these refer- ciated with regular intake of strawberries are attributable to EA as ences for details concerning EA bioactivity and health effects. this fruit is packed with various nutritive substances such as vitamins, Current knowledge on these effects is hardly specific to EA in minerals, dietary fibers, and phytochemicals, many of which (e.g. or from strawberries as various sources of EA have been studied. vitamin C, anthocyanins, and phenolics) are potent antioxidants, Table 7. Overview of the biological activities reported for ellagic acid and its related metabolites. Biological activity EA and related metabolites, when References specified R R Antioxidant or prooxidant EA, EAD, ET, U Tomás-Barberán et al. (2017) , Khodadadi and Nasri (2017) , Bishayee R R R et al. (2016) , de Oliveira (2016) , García-Niño and Zazueta (2015) , R R Espín et al. (2013) , Kallio et al. (2013) , Henning et al. (2010) R R Antiinflammatory EA, EAD, ET, U Tomás-Barberán et al. (2017) , Ahmed et al. (2016) , Derosa et al. R R (2016) , Saha et al. (2016), García-Niño and Zazueta (2015) , Espín et al. (2013) , Giménez-Bastida et al. (2012), Jean-Gilles et al. (2012) Antioedematous EA, ET, U Saha et al. (2016), Mansouri et al. (2015), Jean-Gilles et al. (2012), Rogiero et al. (2006) Analgesic, antinociceptive EA, ET Ahmed et al. (2016) , González-Trujano et al. (2015), Mansouri et al. (2014), Mo et al. (2013) Antiallergic EA García-Niño and Zazueta (2015) Immunomodulator EA Promsong et al. (2015), Balekar et al. (2006) R R Antiglycative EA, ET, U Yeh et al. (2017) , Sadowska-Bartosz and Bartosz (2015) , Espín et al. R R (2013) , Xie and Chen (2013) , Muthenna et al. (2012) Antihyperglycaemic EA, ET Juśkiewicz et al. (2016), Fatima et al. (2015), Malini et al. (2011), da Silva Pinto et al. (2010) R R Antihyperlipidaemic EA, ET, U Kang et al. (2016) , Liu et al. (2015), Usta et al. (2013) Antiatherogenic EA, U Mele et al. (2016), García-Niño and Zazueta (2015) Anti-haemorrhagic EA Gopalakrishnan et al. (2014) Antihypertensive, vasorelaxant EA, ET Usta et al. (2013) , da Silva Pinto et al. (2010) R R Antioestrogenic (antiaromatase) and/ EA, ET, U Espín et al. (2013) , Landete (2011) , Adams et al. (2010) or oestrogenic R R Antimutagenic, antigenotixic EA, EAD, ET Ismail et al. (2016) , García-Niño and Zazueta (2015) , Zahin et al. (2014) Antineoplastic, antimetastatic, anti- EA, EAD, ET, U Ismail et al. (2016) , Ramírez de Molina et al. (2015), Wang et al. proliferative, antiinvasive (2015), Zhang et al. (2014) R R R Antiangiogenic EA, ET Bishayee et al. (2016) , Turrini et al. (2015) , Zhang et al. (2014) R R Antiapoptotic or proapoptotic EA, ET, U Ismail et al. (2016) , García-Niño and Zazueta (2015) , Turrini et al. (2015) , González-Sarrías et al. (2015), Vicinanza et al. (2013), Larrosa et al. (2006) R R Radiosensitizer or radioprotector EA Ahire et al. (2016) , Zhang et al. (2014) , Nemavarkar et al. (2004) R R Neuroregeneration, neuroprotective EA, EAD Ahmed et al. (2016) , Chen et al. (2016), de Oliveira (2016) , Del Rio et al. (2013) R R Antiamyloidogenic EA Ahmed et al. (2016) , Taghavi et al. (2016), Mehan et al. (2015) Anticholestatic, antisteatosic EA García-Niño and Zazueta (2015) Antifibrogenic EA García-Niño and Zazueta (2015) , Suzuki et al. (2009) Antibacterial, antifungal, antiviral EA, ET, U Jurgoński et al. (2017), Ahmed et al. (2016) , García-Niño and Zazueta R R R (2015) , Li et al. (2015), Marín et al. (2015) ; Lipińska (2014) , Espín et al. (2013) , Aguilera-Carbo et al. (2005) Antimalarial, antiparasitic EA, ET, U Espín et al. (2013) , Soh et al. (2012), Ascacio-Valdés et al. (2011), Dell’Agli et al. (2010), Reddy (2007) Prebiotic EA, ET, U Fotschki et al. (2016), Saha et al. (2016), Li et al. (2015), Kosmala et al. R R (2014), Espín et al. (2013) , Landete (2011) Skin-whitening EA Yoshimura et al. (2005) Given the overwhelming number of papers on this subject (mostly in vitro and animal studies, and some clinical studies), recent review articles (R) and articles published over the past 10 years have been prioritized in this table. EA, ellagic acid; EAD, ellagic acid derivatives other than urolithins; ET, ellagitannins; U, urolithins. These compounds were not necessarily from or in straw- berries. Ellagic acid in strawberries, 2017, Vol. 1, No. 4 241 Table 8. Overview of the possible beneficial health effects associated to ellagic acid and to the consumption of strawberries. Disease prevention and/or treatment or EA and related metabolites, when References for EA and related metabolites, or strawberries management specified, or strawberries (when available) Metabolic syndrome (e.g. hypertension, EA, U Kang et al. (2016) , Kang (2015) R R hyperglycaemia), obesity-mediated metabolic strawberries Vandrame et al. (2016) , Giampieri et al. (2015) , Basu and complications Lyons (2012) R R Cardiovascular diseases EA, ET, U Larrosa et al. (2010b) , Del Rio et al. (2013) strawberries Giampieri et al. (2015) Diabetes (types 1 and 2) and diabetic compli- EA, ET, U Derosa et al. (2016) , Kyriakis et al. (2015), Schumacher cations et al. (2015), Goswami et al. (2014), da Silva Pinto et al. (2010) strawberry leaf extract Ibrahim and El-Maksoud (2015) R R Cancer (e.g. bone, brain, breast, cervical, colon, EA, EAD, ET, U Tomás-Barberán et al. (2017) , Derosa et al. (2016) , oral, liver, lung, prostate, skin) González-Sarrías et al. (2016), de Oliveira (2016) , García- R R Niño and Zazueta (2015) , Zhang et al. (2014) , Espín et al. (2013) strawberries Giampieri et al. (2015) Eye diseases (e.g. cataract) EA Muthenna et al. (2012), Sakthivel et al. (2008) Kidney diseases EA Silfeler et al. (2017), Ayhanci et al. (2016), Ahad et al. (2014) strawberry leaf extract Ibrahim and El-Maksoud (2015) R R Liver diseases EA Derosa et al. (2016) , García-Niño and Zazueta (2015) Pancreas fibrosis, chronic pancreatitis EA Suzuki et al. (2009) Gastrointestinal diseases (e.g. ulcers, ulcerative EA Derosa et al. (2016) , Marín et al. (2013), Rosillo et al. colitis, Crohn’s disease) (2012, 2011) strawberries Giampieri et al. (2014) Inflammatory arthritis EA, EAD, ET Allam et al. (2016), Bulani et al. (2014) Depression, anxiety EA Ahmed et al. (2016) strawberries Giampieri et al. (2015) Epilepsy EA Dhingra and Jangra (2014) Cognitive decline, neurological/neurodegenera- EA, ET, U Ahmed et al. (2016) , Chang et al. (2016), Derosa et al. R R R tive diseases (e.g. Alzheimer’s, Hungtington’s, (2016) , de Oliveira (2016) , Del Rio et al. (2013) Parkinson’s diseases) strawberries Giampieri et al. (2015) Infections (bacterial, fungal, parasitic, viral) EA, ET, U Narayan and Rai (2016), García-Niño and Zazueta R R (2015) , Espín et al. (2013) , Soh et al. (2012), Ascacio- Valdés et al. (2011), Dell’Agli et al. (2010), Reddy (2007) Given the overwhelming number of papers on this subject (mostly in vitro and animal studies, and some clinical studies), recent review articles (R) and articles published over the past 10 years have been prioritized in this table. EA, ellagic acid; EAD, ellagic acid derivatives other than urolithins; ET, ellagitannins; U, urolithins. These compounds were not necessarily from or in straw- berries. like EA (Giampieri et al., 2012). While EA and its related com- The antioxidant capacity of EA and of strawberries has been pounds most likely contribute to some of the health benefits associ- researched extensively (Table 7). Strawberries have a 2- to 11-fold ated with strawberry consumption, their specific roles remain to be higher antioxidant capacity than apples, peaches, pears, grapes, toma- ascertained in vivo, including their possible synergistic and cumula- toes, oranges, and kiwi (Giampieri et al., 2012). This high antioxidant tive effects with other bioactive phytochemicals and nutrients found capacity is attributed mainly to vitamin C, anthocyanins, and phen- in strawberries. Indeed, it is not unusual that in vivo findings about olic compounds, with about 40 phenolic compounds identified so far EA bioactivity do not match those from in vitro studies (Landete, including EA and ETs (Giampieri et al., 2012; Aaby et al., 2007a). 2011; Giampieri et al., 2015), which can occur when cells in vivo The pronounced antioxidant action of EA and its related compounds are not in contact with EA or its related metabolites to the same is thought to contribute to some of their other biological activities extent as cultured cells. It is critical, therefore, to better understand outlined in Table 7. This antioxidant action may directly or indir- EA bioactivity under physiologically relevant conditions. Likewise, ectly modify the aetiology of several diseases such as cancer through it is necessary to better comprehend the interactions between EA the inhibition of specific stages of carcinogenesis. Additional modes and its related compounds and the food/biological matrices in which of action of EA, also involved in cellular protection but extending they are contained. A strong emphasis is often placed on the concen- beyond EA antioxidant activity, are becoming recognized (Tsao, 2010; tration of EA in foods and other preparations, but this is not the only Giampieri et al., 2014). These include modulatory actions in cells factor influencing EA bioavailability in humans. Synergies between through the modulation of cell-signalling pathways, enzymatic activ- EA and its coactive constituents as well as EA interaction with car- ity, and epigenetic modifications that regulate gene expression (Tsao, rier (food) matrices may be as important for assessing the strength 2010; Giampieri et al., 2014; Zhang et al., 2014; Kyriakis et al., 2015). and effectiveness of these preparations and for their optimization EA consumption levels and safety aspects (Lansky, 2006). It is known that polyphenols do not always act alone; they can also function as co-antioxidant and can be involved Reliable information on the dietary intakes of EA and ETs is scarce in the regeneration of some vitamins (Tsao, 2010). as these intakes are difficult to estimate with precision (Koponen 242 Muthukumaran et al., 2017, Vol. 1, No. 4 Figure 3. Overview of the suspected protective roles of dietary ellagic acid (EA) and its ellagitannin precursors (ETs) in different types of cancer (adapted from Ismail et al., 2016). et al., 2007; Landete, 2011). The few estimates available indicate or drugs, even if it seems low (Vlachojannis et al., 2015), should be kept in mind. that they vary among countries and regions (Radtke et al., 1998; Ovaskainen et al., 2008; Murphy et al., 2014; Ismail et al., 2016). To our knowledge, no harmful or undesirable side effects from In Western diets, the major contributors to EA and ETs intakes are EA and ETs consumption have been reported in humans in the lit- red fruits, such as strawberries, raspberries, and blackberries, as well erature when these compounds are ingested as part of the diet or as as some nuts and beverages (e.g. pomegranate juice and red wine), nutritional supplement. A small number of individuals experience in variable proportions depending on geographic location and indi- discomfort and adverse reactions after eating strawberries, but these vidual preferences (Landete, 2011; Murphy et al., 2014). are elicited by the presence of histamine (Maintz and Novak, 2007; A recent assessment conducted across geographical regions Ibranji et al., 2015) or allergenic proteins (Zuidmeer et al., 2006) worldwide showed that people in Western Europe have the high- naturally found in strawberries, not by EA or ETs. It is not known est estimated dietary daily intakes of EA in both genders (7.9 mg/ whether EA or ETs may modulate the course of these adverse reac- day in women, 7.6 mg/day in men), followed by the Americas and tions, for instance by interacting with the proteins that trigger the Australia (6.7 mg/day in women, 7.0 mg/day in men) (Murphy et al., allergy to strawberries. Possible undesirable effects of EA and ETs, 2014). Strawberries accounted for over 60% of the daily EA intake documented in animals fed with excessive amounts of ETs, include anti-nutritional effects due to their ability to combine with some in these regions. In contrast, the estimated intakes of EA were low (<1 mg/day) in African, Asian, and South American regions, pre- dietary proteins and fibers, chelate certain minerals (e.g. iron, mag- sumably because of limited availability of berries (Murphy et al., nesium), and inhibit certain digestive enzymes (e.g. β-galactosidase), 2014). The contribution of strawberries to the daily EA intake in which can lead to the malabsorption of essential nutrients (Landete, these regions was 10% or less, 22% and 30%, respectively. Other 2011; Ismail et al., 2016; Saha et al., 2016). EA oxidation into researchers estimated that strawberries contribute 0.2–0.3 mg of EA o-quinone by mushroom PPO, evidenced in vitro by Muñoz-Muñoz per day in France where strawberries are one of the main sources et al. (2009), is of potential concern as quinones have been shown to of EA (Clifford and Scalbert, 2000). Daily ETs intake estimates of induce both cytoprotection and adverse effects (e.g. cytotoxicity and 12 mg/day (15 mg/day in women, 8 mg/day in men) and 5 mg/day carcinogenesis) in vivo (Bolton and Dunlap, 2017). In animals, arte- (5.4 mg/day in women, 4.9 mg/day in men) have been reported in rial blood clots and liver damage have been reported following intra- Finland and Germany, respectively (Radtke et al., 1998; Ovaskainen venous and intraperitoneal injection of EA, respectively (Clifford et al., 2008). The intake of EA may be higher than the above esti- and Scalbert, 2000; Lansky, 2006). These effects are unlikely, and have in fact not been reported, at the doses that characterize typical mates if EA-rich foods other than berries (e.g. pomegranate juice and walnuts) are also part of the regular diet (Tomás-Barberán et al., daily EA intakes and the specific intakes that have been investigated 2009) or if EA supplements are taken. by way of human trials. At these doses, EA is considered safe (Ismail A recent review concluded that, based on ETs daily consump- et al., 2016). tion trends from various dietary sources and on EA NOEL and Additional and well-designed in vivo interventions as well as NOAEL [no observed (adverse) effect levels] currently available, in vitro mechanistic studies are needed to fully understand how these compounds pose negligible risk to human health and safety, EA interacts with human physiological and pathological pro- thus confirming the notion that EA and ETs can be used safely as cesses, so that the benefits from EA, strawberry EA in particular, health-promoting phytonutrients and possibly as therapeutic agents can be enhanced while mitigating any possible undesirable effects. in certain conditions (Ismail et al., 2016). Still, as for all ingested sub- Additional knowledge will be especially valuable if it helps under- stances, the risk of possible undesirable interactions with medications stand the dose and synergistic conditions required for effective Ellagic acid in strawberries, 2017, Vol. 1, No. 4 243 Figure 4. Ellagic acid (filled diamonds) suspected role as (a) radiosensitizer of tumour cells and (b) radioprotector of normal cells (adapted from Ahire and Mishra, 2016). health promotion and disease prevention, and if it is applicable to Gastrointestinal absorption of EA is rapid in humans, with max- complex systems such as strawberries, strawberry-based foods, and imum plasmatic concentration reached within 1 h of the ingestion other products, as well as living organisms, particularly humans of EA/ET-rich foods (Seeram et al., 2004, 2007). EA disappearance and their intestinal microbiota which plays an important role in from plasma was observed 2–6 h after ingestion (Seeram et al., EA metabolism. 2008). The fact that not all studies detected EA in plasma, or in similar concentrations, after the ingestion of foods that were simi- Metabolism and bioavailability of EA larly rich in EA suggests that food matrix characteristics—including Metabolism and bioavailability interactions among specific constituents—may influence EA absorp- The metabolism and bioavailability of EA and ETs in humans have tion (Larrosa et al., 2012). Food characteristics are known to influ- attracted increasing interest due to the possible health effects of these ence the bioavailability of dietary polyphenols in general (Rein et phenolic compounds. Current knowledge is summarized below, al., 2012; Bohn, 2014), but little is known about their effects on highlighting the latest advances and findings relevant to strawberry EA absorption, metabolism, and bioavailability. In humans, inter- EA. Details can be found in earlier reviews (Landete, 2011; Larrosa individual differences in EA absorption and metabolism may be a et al., 2012; Espín et al., 2013). Both ETs and free EA are present in contributing factor. Several animal studies reported EA accumula- EA-rich foods. ETs are generally not absorbed in the human gastro- tion in some organs and tissues (e.g. oesophagus, small intestine, intestinal tract, but they release free EA in the stomach and small in- colon, liver, lung, and prostate) (Boukharta et al., 1992; Larrosa testine. Absorption of free EA can occur in the stomach and, but less et al., 2012). In humans, there is little evidence of EA accumula- importantly, in the small intestine (Espín et al., 2007; Larrosa et al., tion in organs or tissues, except in human intestinal Caco-2 cells 2012). No transporters have been identified to date. Phase I and II in vitro (Whitley et al., 2003). Metabolites derived from EA (Us metabolism of EA in the digestive tract and the liver yields EA deriv- mainly) have been detected in other human tissues (e.g. prostate) atives (mainly EA-methyl and dimethyl ethers and EA-glucuronide (González-Sarrías et al., 2010) but not EA per se. Whitley et al. conjugates), which were detected in peripheral plasma, bile, and (2003) suggested that irreversible binding of EA to macromolecules urine of Iberian pigs fed ET-rich acorns (Espín et al., 2007). Some in intestinal cells may limit its transcellular absorption. EA ioniza- EA-glucuronides undergo enterohepatic circulation. tion, oxidation, and the formation of poorly soluble complexes with 244 Muthukumaran et al., 2017, Vol. 1, No. 4 ions (e.g. calcium, iron, magnesium) under physiological conditions to affect the production and urinary excretion of Us in humans. In may also limit EA bioavailability and modulate its bioactivity. A healthy volunteers, Truchado et al. (2012) found no significant dif- recent study in which strawberries were digested under conditions ferences in the production and excretion of Us between the intake of that simulated chemical digestion in humans found that the antioxi- fresh strawberries and that of thermally processed strawberry purée dant activity of strawberry flesh and achenes was markedly higher (80ºC for 5 min) containing the same amount of strawberries and no in the extracts from the gastric fraction compared with those from added sugar. Thermal processing increased the amount of free EA by the intestinal fraction and undigested fruit (Ariza et al., 2016). 2.5-fold, but had no detectable effect on EA bioconversion into Us Because of their low bioavailability in humans, dietary ETs and EA by the gut microbiota or on the urinary excretion of U metabolites per se are expected to exert their biological activities principally (U-A, U-B, and their glucuronide conjugates) (Truchado et al., 2012). in the digestive tract rather than in the entire body (Cerdá et al., These findings suggest that the release of free EA from ETs does not 2005a, 2005b; Whitley et al., 2006). affect the microbial metabolism of EA in vivo and that moderate In the small intestine, EA is metabolized by the human intestinal thermal treatment does not modify the potential health benefits of microbiota into a series of hydroxydibenzopyran-6-one derivatives, strawberry EA. known as Us. Several Us are produced and absorbed, including U-D Little is known about the gut bacteria and conditions (e.g. pH, and U-C, followed by U-A and U-B (Figure 5) which are the final cata- nutrients/prebiotics, biotic and abiotic interactions) involved in the bolic products before phase I and II metabolism (Tomás-Barberán transformation of EA into Us and their bioavailability in humans. et al., 2017). Recent findings suggest that Us have biologial activities Because U production starts in the small intestine, anaerobic bac- similar to those of EA and ETs (Table 7) but are more bioavailable in teria are thought to be responsible. Two strains of the Gordonibacter humans, being the main EA-derived metabolites detected in plasma, genus able to metabolize EA to Us have been identified in human urine, and some tissues in humans (Tomás-Barberán et al., 2017). faeces (Selma et al., 2014a, 2014b). Higher levels of Gordonibacter For these reasons, it is now thought that Us, U-A, and U-B in par- were reported in individuals that produce only U-A and its conju- ticular, and their derivatives are responsible for most of the in vivo gates compared with individuals that produce both U-A and U-B biological activities and health benefits associated with EA/ET-rich (Selma et al., 2016; González-Sarrías et al., 2017). In rats, the ab- diets, while circulating EA derivatives may contribute to a lesser ex- sorption of EA and ET microbial metabolites (quantified as U-A) tent (Larrosa et al., 2012; Tomás-Barberán et al., 2017). After phase was increased when fructooligosaccharides (which are known prebi- I and II metabolism, U conjugates (mainly glucuronide and methyl otics) were added to the diet (Jurgoński et al., 2017). Both the host ether conjugates) and some EA conjugates circulate in the blood and and its gut microbiota appear to benefit from U production (Selma can reach various tissues and organs, with no accumulation detected et al., 2009; Bialonska et al., 2010; Tomás-Barberán et al., 2017). at these sites in humans so far (Espín et al., 2013). U-A and U-B Prebiotic effects of Us were found in rats (Larrosa et al., 2010a). conjugates are the main EA-derived metabolites detected in human A recent animal and in vitro study showed that the production of plasma and urine. They reach maximum concentrations in plasma U-A limited the non-specific killing of gut bacteria and abolished the 24–48 h after ingestion of EA/ET-rich foods (Espín et al., 2013) and iron-binding property of EA, thus conferring two important com- can be detected for up to 48–72 h in urine (Cerdá et al., 2005a). petitive advantages to the microbiota, in addition to antioxidant and Enterohepatic circulation contributes to their relatively long persist- antiinflammatory effects of U-A (Saha et al., 2016). ence in plasma and urine (Espín et al., 2007). The high interindividual variability in U production and excre- In healthy human subjects who consumed fresh strawberries, tion, which was noted in most human trials, is thought to result U-B conjugated with glucuronide acid was the most abundant U-B from differences in the gut microbiota (González-Sarrías et al., 2010; metabolite detected in urine 48 h and 72 h after intake (Cerdá et al., Tomás-Barberán et al., 2017). Recent evidence supports the existence 2005a). Neither ETs nor EA derivatives (free or conjugated) were of three U phenotypes or metabotypes (UM), namely UM-0 (no urin- detected in urine. This was also the case in three other groups of ary excretion of U-A, U-B, or their conjugates), UM-A (only excretes subjects who consumed other foods rich in ETs/EA (raspberries, U-A and its conjugates), and UM-B (excretes U-B, isoU-A, and their walnuts, and oak-aged red wine, respectively). Higher urinary excre- conjugates in addition to U-A) (Tomás-Barberán et al., 2014). These tion of U-B glucuronide was found in the subjects who ingested a metabotypes were independent of EA amount and food source, vol- double amount of the ET/EA-rich food, but this excretion was not unteer age, gender, BMI, and health status. However, UM-B prevailed proportional to the amount of ETs/EA consumed (Cerdá et al., in patients with illnesses associated with gut dysbiosis (metabolic syn- 2005a). Additionally, strawberry thermal processing does not seem drome and colorectal cancer) and in healthy overweight-obese, while Figure 5. Conversion of dietary ellagic acid into bioactive urolithins by the gastrointestinal microbiota (adapted from García-Villalba et al., 2013; González-Barrio et al., 2011). Ellagic acid in strawberries, 2017, Vol. 1, No. 4 245 UM-A prevailed in healthy subjects, in patients with illnesses not EA encapsulated in chitosan nanoparticles was shown to be more characterized by gut dysbiosis (e.g. prostate cancer) (Tomás-Barberán effective than free EA at inhibiting human oral cancer KB cells in et al., 2014), and in normoweight subjects (Selma et al., 2016). vitro (Arulmozhi et al., 2013) and as an antihaemorrhagic agent, Additionally, an intervention trial with healthy overweight-obese also in vitro (Gopalakrishnan et al., 2014). In AJ/mice treated with subjects found that the UM-B group had a higher baseline for car- nicotine-derived nitrosamine ketone (NNK), a tobacco-specific diovascular risk compared with UM-A subjects and that this baseline nitrosamine involved in lung carcinogenesis, encapsulation of EA in was decreased only in the UM-B group after the ingestion of ET-rich cyclodextrin was found to double the concentration of EA in lung extracts for 6 weeks. This effect was associated with U production tissues following the administration of EA by gavage (Boukharta (González-Sarrías et al., 2017). U-A production has been shown to et al., 1992). In this animal study, EA at a dose of 4 g/kg of diet be inversely correlated with the severity of the metabolic syndrome reduced the multiplicity of NNK-induced lung tumours. EA was in humans (Mora-Cubillos et al., 2015). Certain similitudes between localized preferentially in lung tissues, at levels proportional to the the intestinal metabolism of EA to Us and that of daidzein (an isofla- dose of EA, with a maximum level observed 30 min after gavage. vone found in soybeans and other legumes) to equol raise the possi- Levels in liver tissues were 10-fold lower (Boukharta et al., 1992). bility that U metabotypes may be a useful biomarker for evaluating Further evidence of improved bioavailability and tissue distribution disease risk related to specific gut bacteria involved in EA metabolism of EA-cyclodextrin complexes was presented by Chudasama et al. (Tomás-Barberán et al., 2017). (2011). In their work, plasma and pancreatic levels of EA 30 min These latest advances provide powerful ways of understanding after gavage were 7-fold and 5.8-fold higher, respectively, in rats the interrelations between dietary EA and health, revealing the criti- that received cyclodextrin-encapulated EA in contrast to EA alone. cal role of gut bacteria in EA metabolism. They open new avenues for One hour after gavage, the levels remained high in the experimental personalized nutrition and medicine in relation to EA. One of them group. Bulani et al. (2016) showed in vitro that EA encapsulation in is the development of functional foods and other specialty products β-cyclodextrin enhanced its solubility and dissolution and improved that incorporate the microorganisms (probiotics) responsible for EA its antiinflammatory activity by protecting against protein denatur - bioconversion into specific Us, together with the naturally occur - ation and lysis of the erythrocyte membrane. Dubey et al. (2015) ing ETs and EA. More research is needed to identify the microbial used nano-sized metalla-cages (metalla-prisms) to encapsulate EA communities and the biophysicochemical conditions (including food and reported that these compounds had superior anti-cancer proper- characteristics) that enable or enhance the production of specific Us, ties in vitro compared with free EA. Complex formation between EA so that individuals with different U metabotypes can fully benefit and phospholipids is another promising formulation. In rats exposed from EA intake. The possibility that this variation in EA metabolism to carbon tetrachloride, a liver damaging agent, EA-phospholipid may be associated with differential health outcomes also deserves fur- complexes were shown to enhance EA oral bioavailability and anti- ther research, as do the specific roles of the different Us. oxidant activity, thus providing better hepatoprotection than free EA (Murugan et al., 2009). Amorphous solid dispersion (ASD), i.e. the molecular dispersion Bioavailability enhancement of a poorly water-soluble compound in a polymer matrix, was also Various strategies have been investigated to improve the bioavail- successfully tested to improve EA solubility (Li et al., 2013). These ability of polyphenols in general (Rein et al., 2012; Lewandowska researchers tested several cellulose- and non-cellulose-based poly- et al., 2013). Here, we focus on recent developments regarding the mers for their ability to form ASDs with EA and identified hydroxy- improvement of EA solubility and bioavailability through formu- propylmethylcellulose acetate succinate as the most practical choice lation approaches such as encapsulation, complex formation with for stabilizing EA and improving its solubility. solubilizing agents, and amorphous solid dispersion. These strate- Possible interactions between EA and serum transport pro- gies could be powerful complements to the enrichment strategies teins are of interest in relation to bioavailability as they may play presented in the Ellagic Acid Stability in Strawberries During Post- a role in improving EA solubility in the circulatory system and its harvest Storage and Processing, and Production of Ellagic Acid from delivery to target sites. Non-covalent binding was detected in vitro Strawberries and Other Plant Materials sections. Strategies that between EA and human serum albumin (HSA) (Tang et al., 2013; involve non-oral delivery of EA (e.g. subcutaneous implants for sus- Pattanayak et al., 2017) and bovine serum albumin (BSA) (Labieniec tained systemic delivery of EA) (Vadhanam et al., 2011a, 2011b; and Gabryelak, 2006), as well as between ETs and BSA (Dobreva Gupta et al., 2012) will not be detailed. et al., 2014). Other researchers found that EA and its metabolite U-A EA encapsulation has been achieved using various nanopar- did not bind specifically to sites I and II of HSA which are areas for ticulate systems, mainly poly(D,L-lactic-co-glycolide) (PLGA) and high-affinity binding of certain drugs and other compounds (Nozaki polycaprolactone (PCL) nanoparticles (Bala et al., 2006; Sonaje et al., 2009). et al., 2007), chitosan nanoparticles (Arulmozhi et al., 2013; Collectively, the above findings support the hypothesis that Gopalakrishnan et al., 2014), cyclodextrin derivatives (Boukharta improving EA solubility is a practical way to enhance its oral bio- et al., 1992; Chudasama et al., 2011; Bulani et al., 2016), and nano- availability. These findings can inform the development of dietary sized metalla-cages (Dubey et al., 2015). These systems enable EA and therapeutic applications that require good solubility of EA and to be encapsulated in a water-soluble polymeric matrix (carrier); its effective transport and release at target sites in human physio- some enable a gradual, sustained release of EA at a rate that depends logical systems, while minimizing undesirable interactions with on the carrier composition (Bala et al., 2006; Sonaje et al., 2007; other drugs or food constituents. Gopalakrishnan et al., 2014). Bala et al. (2006) further showed that the in situ intestinal permeability of EA in rats increased from 66% for EA alone to 73% and 87% for EA encapsulated in PLGA Conclusion and Prospects for Further Research nanoparticles of different compositions. Higher in situ intestinal per- meation was also reported for EA encapsulated in PCL or PLGA EA is one of the phytochemicals supporting the recognition of straw- nanoparticles compared with EA alone (Sonaje et al., 2007). berries as functional foods and sources of bioactive molecules with 246 Muthukumaran et al., 2017, Vol. 1, No. 4 Aaby, K., Ekeberg, D., Skrede, G. (2007a). Characterization of phenolic high nutraceutical and therapeutic potential. To help realize the full compounds in strawberry (Fragaria x ananassa) fruits by different HPLC potential of EA in and from strawberries, this review covered four detectors and contribution of individual compounds to total antioxidant areas of practical importance: EA distribution in the strawberry capacity. Journal of Agricultural and Food Chemistry, 55: 4395–4406. plant, its stability during processing, its production from plant mate- Aaby, K., Wrolstad, R. E., Ekeberg, D., Skrede, G. (2007b). Polyphenol compo- rials, and its bioactivity and relevance to human health, highlight- sition and antioxidant activity in strawberry purees; impact of achene level ing current developments, knowledge gaps, as well as opportunities and storage. Journal of Agricultural and Food Chemistry, 55: 5156–5166. for novel applications and products and future research. A number Aaby, K., Mazur, S., Nes, A., Skrede, G. (2012). Phenolic compounds in straw- of these opportunities can add value not only to strawberry prod- berry (Fragaria x ananassa Duch.) fruits: composition in 27 cultivars and ucts, but also to underutilized strawberry byproducts that are rich changes during ripening. Food Chemistry, 132: 86–97. in EA and its ET precursors. The current knowledge and technolo- Adams, L. S., Zhang, Y., Seeram, N. P., Heber, D., Chen, S. (2010). Pomegran- ate ellagitannin-derived compounds exhibit antiproliferative and antiaro- gies presented in this review will be of value for those seeking to matase activity in breast cancer cells in vitro. Cancer Prevention Research enhance the production of EA from strawberry plant materials, (Philadelphia, PA), 3: 108–113. including their processing byproducts, and to develop the functional Aguilar, C. N., et al. (2008). Production of antioxidant nutraceuticals by and therapeutic applications of strawberry EA. The challenges and solid-state cultures of pomegranate (Punica granatum) peel and creosote knowledge gaps that were identified point to a need for research in bush (Larrea tridentata) leaves. Food Technology and Biotechnology, 46: the following areas: 218–222. Aguilera-Carbo, A., Garcia-Agustince, C. A., Belmares, R. E., Aguilar, C. N. 1. Quantification of free and bound EA in different parts of the (2005). Inhibitory effect of ellagic acid from pomegranate husk (Punica strawberry plant and in strawberry-based foods and byproducts, granatum) on different food-borne pathogens. In: Proceedings of the extending this characterization to lesser studied species/varie- International Congress on Food Safety, FAO, San José, Costa Rica, pp. 1–5. ties of strawberries and compiling the standardized results in a Aguilera-Carbo, A., Hernandez-Rivera, J. S., Prado-Barragan, L. A., Augur, peer-reviewed database. Research in this area should also aim to C., Favela-Torres, E., Aguilar, C. N. (2007). Ellagic acid production by identify the mode of inheritance of EA traits in strawberry and solid-state culture using a Punicata granatum husk aqueous extract as to better understand the influence of agricultural practices, grow- culture broth. In: Proceedings of the 5th International Congress on Food ing environment, and processing on EA content. This will help Technology, Hellenic Association of Food Technologists, Thessaloniki, identify and enhance EA biofortification strategies. Greece, p. 44. 2. Development and optimization of fermentation–enzymatic bio- Aguilera-Carbo, A., Augur, C., Prado-Barragan, L. A., Favela-Torres, E., processes for the efficient and green production of EA from Aguilar, C. N. (2008). Microbial production of ellagic acid and biodeg- strawberry byproducts, whether discarded fruits, achenes, pom- radation of ellagitannins. Applied Microbiology and Biotechnology, 78: aces, or other parts of the plant that contain EA and ETs. 189–199. Aguilera-Carbo, A., Hernandez-Rivera, J. S., Augur, C., Prado-Barragan, L. 3. Development of EA enrichment methods applicable to various A., Favela-Torres, E., Aguilar, C. N. (2009). Ellagic acid production from foods and specialty products, and development of formulations biodegradation of creosote bush ellagitannins by Aspergillus niger in solid that enhance EA solubility, stability, and bioavailability. state culture. Food and Bioprocess Technology, 2: 208–212. 4. Understanding EA metabolism in humans, including the role of Ahad, A., Ganai, A. A., Mujeeb, M., Siddiqui, W. A. (2014). Ellagic acid, an the intestinal microbiota, and the modes of action of EA and NF-κB inhibitor, ameliorates renal function in experimental diabetic its metabolites in physiological and pathological processes. To nephropathy. Chemico-Biological Interactions, 219: 64–75. this end, more precise data on its circulating metabolites, well- Ahire, V. R., Mishra, K. P. (2016). Ellagic acid radiosensitizes tumor cells by designed in vivo interventions, and in vitro mechanistic studies evoking apoptotic pathway. Journal of Radiation and Cancer Research, are needed. 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Ellagic acid in strawberry (Fragaria spp.): Biological, technological, stability, and human health aspects

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Ellagic acid in strawberry (Fragaria spp.): Biological, technological, stability, and human health aspects

Ellagic acid in strawberry (Fragaria spp.): Biological, technological, stability, and human health aspects

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