Fragaria Genus: Chemical Composition and Biological Activities

The strawberries represent in our days one of the main fresh fruits consumed globally, inevitably leading to large amounts of by-products and wastes. Usually appreciated because of their specific flavor, the strawberries also possess biological properties, including antioxidant, antimicrobial, or anti-inflammatory effects. In spite of the wide spread of the Fragaria genus, few species represent the subject of the last decade scientific research. The main components identified in the Fragaria species are presented, as well as several biological properties, as emerging from the scientific papers published in the last decade.


Introduction
The production of different fruits all around the world exceeds millions of tons, depending on geographical zones, consumption, and growing traditions, inevitably leading to large amounts of by-products and wastes. Fragaria genus (Rosaceae), commonly known as strawberry, represents one of the most important food plants all over the world, with a double global production compared with all other fruit berries combined [1]. Their widespread use, primarily because of their flavor, can also lead to considerable benefits to human health. Among other characteristics, nonvisual properties like taste, nutritional values, or aroma make these fruits to be in the top of consumer preferences [2].
Known and consumed for thousands of years, Fragaria species are encountered throughout the northern hemisphere, as well as in some areas of South America [1]. Several authors present the historical consumption of strawberries in pre-Columbian sites, Picunche and Mapuche people (Chile), Romans or ancient China. [1,[3][4][5] The exact number of accepted species of the genus remains a subject of debate, ranging from 22 [6] to 16 [7]. In addition, there are many hybrids and cultivars representing ploidy levels ranging from diploid (2n = 2x = 14) to decaploid (2n = 10x = 70), influencing the size of the fruits. Most of the research regarding the genus can be traced to the extraordinary work of Antoine Nicolas Duchesne, that offered botanical description, details on the history, cultivation, sex, and polyploidy of different species [5]. Generally speaking, all Fragaria species share some common characteristics: are low-growing perennials, with usually evergreen and trifoliolate leaves, insect-pollinated, with white actinomorphic flowers (usually 5-petalled). The main difference between species is represented by the animal-dispersed accessory aggregate fruits, in terms of color, shape, and achene (the 1-seeded simple fruits) and calyx positions at maturity. From the different composition and other characteristics of those fruits, also arise the potential commercial value of the species. Many cultivars are perennials that vary in their photoperiod needs, leading to varying harvesting times (June-bearers, ever-bearers, day-neutral) [8].
Among the 247 varieties known and listed, only few present commercial interest: Fragaria x ananassa Duchesne (octoploid hybrid-containing 56 chromosomes, known as garden strawberry, native to northern America, cultivated all over the world), and, to a lesser extent, Fragaria vesca L. (diploid species, known as wild strawberry, native to Northern hemisphere) and Fragaria chiloensis (L.) Mill. (octoploid species, known as Chilean strawberry, native to northern, pacific and southern America) [1].
As previously mentioned, the strawberries represent one of the most important fruit plants. Their production reached 9.22 million tones (world level) in 2017, the major producers being China (40.3% of total world production), United States (15.7%), Mexico (7.14%), Egypt (4.42%), Turkey (4.34%), Spain (3.9%), Republic of Korea (2.28%), Poland, Russian Federation, Morocco, Japan, Germany, United Kingdom, and Italy (between 1 and 2%) [9]. This mass-production invariably leads to large amounts of wastes, that can be further exploited in multiple areas, including medicine, cosmetics, and food industry [10]. The wastes are generated throughout the growth cycle (maturation, multiplication, and expansion), while the large-scale methods of cultivation (e.g., in fields, plastic tunnels., etc.) leads to large amounts of wastes from leaves, stolons, fruits, etc.
The present review paper aims to present the identified components in different species of the Fragaria genus, as well as their potential biological activities, as emerging from the scientific papers published in the past decade. The selection of the articles to be included in the present review was performed using the well-known data-bases (Scopus, Web of Science, ScienceDirect, and PubMed), using specific keywords ("composition", "therapeutic", "cytotoxic", "anti*"-returning results for "antimicrobial", "antifungal", "anti-inflammatory", etc.). The validation of the articles was performed manually (by reading the entire article) and in the present review were inserted only articles with significant contribution to the field of research.

Composition of Fragaria L. Genus
Giampieri et al. [11] reviewed the composition of the strawberry (Fragaria x ananassa), while Morales-Quintana and Ramos [12] reviewed the composition and potential applications of the Chilean strawberry (Fragaria chiloensis (L.) Mill.), while the functional properties of the berries, in general, and of the strawberries, in particular, were reviewed by Jimenez-Garcia et al. [13]. As resulting from various literature studies [11][12][13][14][15], the general composition of the strawberries (in terms of major components) can be summarized in Table 1 (with a general image provided in Figure 1). Table 1. Major (common) components in Fragaria L. aggregate fruits (adapted from [11][12][13][14][15]).

Class
Compound Ref.
As the primary economic importance of the Fragaria genus is related to their fruits, it must be stated that, besides the previously presented factors, their composition (and finally, their health benefits) is correlated with the applied processing methods. The most encountered forms of products (besides fresh fruits) are represented by the dried fruits and puree. Méndez-Lagunas et al. [56] studied the influence of the thermal drying on the anthocyanins and total phenolic content of Fragaria × ananassa Duch. fruits. The study revealed a 26% loss of anthocyanins content when drying at 50 • C, respectively a 45% loss upon drying at 60 • C. The total phenolic content was even more seriously affected by the thermal process, with 60.9% loss associated with 50 • C, and 78.1% for the 60 • C treatment, respectively. Thus, the importance of fresh fruits consumption and when not possible, application of appropriate drying methods was emphasized; the authors propose the 50 • C treatment as suitable for preserving the bioactive compounds found in the strawberries (particularly anthocyanins). Álvarez-Fernández et al. [57] evaluated the variation in non-anthocyanin phenolic composition (hydrolyzed tannins, flavanols and condensed tannins, ellagic acid and derivatives, hydroxycinnamic acids, flavonol glycosides and stilbenes) of strawberry puree in different production stages. If mashing process affected the content of some phenolics (gallic acid, monogalloylglucoside and ellagic acid), the pasteurization process induced the decrease of all the compounds' concentration. However, the non-anthocyanin phenolic profile was not significantly affected, suggesting that the strawberry puree represents a good source of phenolic compounds.
The strawberry "seeds" (achenes) were proven to be a valuable source of unsaturated fatty acids. Thus, several studies revealed that commercially available achenes oil contained high amounts of linoleic and α-linoleic acids (over 70%), with a total content of over 90% unsaturated fatty acids (also including oleic and traces of palmitoleic acid), while the saturated fatty acids were mainly represented by palmitic and stearic acids [58,59]. In the same time, the seeds could also be considered a source of dietary fibers, proteins, polyphenols (mainly ellagitannins), and vitamins [60]. Figure 1 summarizes the main classes of constituents found in Fragaria genus.

Antioxidant Properties
Traditionally consumed in the form of fruits (as previously presented), Fragaria species have also found application in traditional medicine. For example, Fragaria vesca leaves and fruits were traditionally used for the treatment of external rashes, as well as internally, as blood purification and roborontarium, for the treatment of diarrhea [61], as macerate for renal stones, or as tea (together with other medicinal plants) for treating stomach inflammations, sedation, or regulation of digestion [62]. The following paragraphs presents the main biological properties of different Fragaria species, as emerging from the literature data published in the past decade. Particularly, the anthocyanins family represent the subject of several review papers published in the last years, dealing with their bioavailability and potential health benefits [63][64][65]. The following chapters includes only the studies regarding the biological activity of compounds or extracts obtained from Fragaria species (not studies presenting the activity of compounds that are found in those plants).
The major classes of compounds found in the Fragaria species (anthocyanins and non-anthocyanin phenolic compounds) are known for their antioxidant properties [65,66]. As can be expected, the vast majority of the literature presenting the biological activities of species belonging to Fragaria genus present their antioxidant activity. However, the studies that will be presented should be carefully considered, as many are performed using assays predisposed to positive results in the presence of oxygenated functions on aromatic rings (thus being considered more "class-related" than as specific molecular targeting) [67]. Thus, those studies, although useful as screening tools, should be confirmed by more specific assays, such as in vivo or cell-based models [66,67].
Pineli et al. [28] performed a study on two Fragaria × ananassa Duch. cultivars (Osogrande and Camino Real), regarding the correlation between composition and the antioxidant activity (established using 2,2-Diphenyl-1-picrylhydrazyl radical-scavenging activity-DPPH and ferric reducing antioxidant power-FRAP assays) of acetone extracts obtained from fruits at different ripening stages. Very interestingly, although, as expected, the anthocyanins levels were higher in the red fruits (full ripe), the best antioxidant activities, for both cultivars and both assays were obtained for the pink fruits. The only exception is represented by the DPPH assay results for Osogrande cultivar (for which the best results were obtained for the red fruits); however, the differences between the results of the DPPH assay for the cultivar at the three ripening stages were not statistically significant. The differences between the results can be explained by the different mechanisms of the assays (as previously described by our group) [66]. A much better correlation was observed by the authors with the total phenolic and vitamin C content. Finally, the Osogrande cultivar presented superior antioxidant properties (associated with higher levels of the total phenolic and total ellagic acid content, especially in pink and red fruits). Zhu et al. [35] evaluated the influence of the solvent used for room-temperature extraction (water/ethanol) and of the extracted Fragaria × ananassa var. Amaou parts (red fruit, green fruit, red calyx, green calyx, flower, leaf, stolon, stolon leaf, stem, crown, and root) on the antioxidant properties of the extract. Their conclusion was that the ethanol was the solvent of choice (because of different polarities of the phenolic compounds found in the plant) and, among the plant parts, best results (presented as Trolox equivalents-TE per gram or extract and per 100 g of plant fresh weight-FW) were obtained for flower extracts (1460.1 µMol TE/g extract), respectively for crown (6212.3 µMol TE/100g FW), when reported to a fresh weight basis. Stolon leaves (1456.7 µMol TE/g extract, respectively 5244.2 µMol TE/100g FW) also exhibited a very good antioxidant activity.
Individual compounds (including phenolic glucosides, flavone glucuronides, and lignan glycosides) were isolated from the Fragaria x ananassa Duch. cv. Falandi fruits by Yang et al. [20] and tested for antioxidant properties. The best results were obtained for flavone glucuronides (in the ABTS and DPPH assays), and a lignan glycoside (in the FRAP assay), respectively. Considering the results obtained for the positive control used in the antioxidant assays (ascorbic acid), the authors suggested that the investigated phenolic compounds play an important role in the overall antioxidant property of the plant. Contrary to other studies, Chaves et al. [39] demonstrated a correlation between the total anthocyanin content and the antioxidant potential of strawberry fruits, in a study over seven cultivars. The antioxidant potential of plants, as it results from literature studies, seems to be correlated with total anthocyanins and not with total phenolic content.
In 2019, Nowicka et al. [43] published a study regarding the variation in composition and antioxidant properties of 90 cultivars of Fragaria × ananassa Duch. fruits over two years of production. The results (average values presented in Table 3) revealed not only that some cultivars can be considered as having superior antioxidant properties (Roxana, Gigaline, Selvik, Thuriga ISK, Eratina, Siria, Dagol, Plarionfre, Grenadier, and Kimberly), but also, considering the phytochemical profile, that the main compounds responsible for the activity are the tannins, especially ellagitannins and procyanidins.
As previously stated, because of the increasing request, strawberries are often commercialized as processed products. The effect of fruit drying on the antioxidant potential of the Fragaria × ananassa Duch., Diamante var. fruits was presented by Méndez-Lagunas et al. [56]. The antioxidant assay performed on the processed fruits (DPPH) revealed 74.7% loss of antioxidant activity for the thermal treatment at 50 • C, while the 60 • C treatment led to a 66.2% loss of the activity. The results suggested that, beyond temperature, heat treatment time has a stronger effect on the antioxidant activity (as at higher temperature, shorter periods are necessary). Similar, several researches were performed regarding the changes of antioxidant activity (determined using ORAC and DPPH assays) during different stages of puree production [57]. Although slight reduction of the antioxidant properties was recorded (statistically significant only for the pasteurization step), the authors recommended the strawberry puree as an excellent source of antioxidants. The same group [68] observed no effect of the gluconic fermentation of strawberry puree (applied for the production of beverages) on the antioxidant activity (determined using the DPPH assay); the authors even reported an increase of the antioxidant potential after the pasteurization step, which was correlated with an increase in the gallic acid and hydroxycinnamic derivatives content. The results would suggest that the gluconic fermentation could maintain the antioxidant potential of the fresh products upon processing.
The antioxidant potential of strawberries could rapidly find industrial applications, as was the case for other plant-derived antioxidants [69,70] in, for example, meat industry, as recently reviewed by Lorenzo et al. [71], for increasing the shelf-life of different products (as sausages or raw, cooked, and cooked-chilled porcine patties). Table 3 summarizes the main findings regarding the antioxidant potential of Fragaria species, as well as the responsible classes of compounds (as presented by the authors).
As a general remark, it can be observed that most authors assign the antioxidant potential to the total phenolic content in general, and in particular to some classes of compounds, such as anthocyanins, flavan-3-ols or tannins. Considering the individual species, Fragaria x ananassa fruits presented antioxidant properties in the DPPH assay (the assays with the widest application) between 76.73-100 mg/mL (IC 50 ) for various cultivars (the best results being obtained for the Camarosa cultivar) [39] or between 300 and 1300 µMol trolox/100 g fresh weight, for a larger survey (comprising 90 cultivars) [43]. Also, regarding the differences between the antioxidant potential of different plant parts, for F. chiloensis methanolic extracts the best activity was observed for fruits [26], while for Fragaria × ananassa for the crown ethanolic extract (6213.3 µMol trolox/100 g fresh weight). Fragaria vesca was mainly evaluated in terms of leaves, roots, or vegetative parts antioxidant activity, with antioxidant potential ranging from 13.46 mg/L to approx. 140 mg/L (IC 50 ), strongly dependent on the source of vegetal material and applied extraction technique [72,73]. where: ABTS-2,2 -azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) assay; BHT-butylated hydroxytoluene; DPPH-reduction of 2,2-diphenyl-1-picrylhydrazyl; DW-dry weight; eq.-equivalents; FRAP-ferric reducing ability of plasma; FS-ferrous sulphate; FW-fresh weight; IC 50 -half maximal inhibitory concentration; ORAC-oxygen radical absorbance capacity; SAS-superoxide anion assay; TBARS-thiobarbituric acid reactive substances assay; TEAC-Trolox equivalent antioxidant capacity.

Anti-Inflammatory Properties
As previously stated, one of the traditional uses of Fragaria is as an anti-inflammatory agent [61,62]. Most of the authors assign the anti-inflammatory properties to the presence of anthocyanins (the most representative being pelargonidin and cyanidin derivates) [75], molecules with known anti-inflammatory potential [76,77], demonstrated both in vitro and in vivo [78,79]. Similar to the other biomedical potential, the anti-inflammatory action is also correlated with the composition of different Fragaria species. The traditional use of F. vesca as an anti-inflammatory agent was supported by the study of Liberal et al. [80]. The authors observed the decrease of a relevant mediator of the inflammatory response (nitric oxide) produced by macrophages, cultured in the presence of a NO-production inducing bacterial endotoxin (LPS). The ethanolic extract obtained from Fragaria vesca leaves, used at non-cytotoxic concentrations (80 and 160 mg/L), induced a 31%, and 40% inhibition, respectively. The authors assigned the NO decrease to a direct scavenging effect (as demonstrated by a 23% inhibition of the nitrite content in the culture media, correlated with the absence of a significant effect when quantifying the inducible nitric oxide synthase-iNOS and the pro-inflammatory cytokine IL-1β). The authors also observed a statistically insignificant increase in the phosphorylated IκBα (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha) content, suggesting either an increase of its expression or a decrease in its degradation. More than that, the authors observed an increased conversion of the microtubule-associated protein light chain LC3-I to LC3-II (a marker of autophagy), suggesting further anti-cancer properties. Methanolic extracts of Fragaria x ananassa, var. Alba fruits were also confirmed by Gasparrini et al. [81] to lower the intracellular levels of reactive oxygen species (ROS), decrease apoptotic rate and improve antioxidant defenses and mitochondria functionality in E. Coli induced inflammation in human dermal fibroblast cells. Their results showed significant decrease of TNF-α (tumor necrosis factor alpha), IL-1β and IL-6 (interleukin 6) levels. The authors proposed as responsible mechanism the action on AMPK (5 AMP-activated protein kinase) related pathways (increment in phosphorylated AMPK expression). Between the two presented studies there are several experimental design/inputs differences that can explain the different obtained results (including the species and the solvent used for extraction). Thus, the higher levels of bioactive molecules in the Fragaria x ananassa fruits (compared with the F. vesca leaves, as previously presented) can explain the differences observed by the authors in terms of anti-inflammatory action. Similar observations were made by Molinett et al. [82] who proved the anti-inflammatory and hepatoprotective effect of aqueous F. chiloensis fruits extracts on LPS-inducted liver injury on rats. The anti-inflammatory effect of the Fragaria x ananassa var. Camarosa fruits was also in vivo evaluated on female mice by Duarte et al. [83], who assigned the activity to the presence of anthocyanins. Moreover, the authors performed in vitro experiments using pelargonidin-3-O-glucoside (the major anthocyanin in Fragaria) in order to establish its molecular mechanism of action. Regarding the in vivo experiments the authors noticed the inhibition of the carrageenan-induced leukocyte influx to the pleural cavity upon crude extract treatment, due to the reduction in neutrophil migration. The extract also induced a reduction of myeloperoxidase activity and reduced the exudate concentration in the pleural cavity and NO levels. The pure compound pelargonidin-3-O-glucoside produced similar results, inhibiting IkBα, also reducing the phosphorylation of p65 NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells) subunit. The authors proposed as mechanism of the anthocyanin the mitogen-activated protein kinase (MAPK) pathways, leading to the decrease in NF-kB and activated protein 1 (AP-1) translocation. In 2019, Van de Velde et al. [84] supported the previously reported anti-inflammation properties of strawberry extracts, also proposing another possible application, by evaluating the wound-healing effects. The extract and polyphenolics/anthocyanins-enriched fractions influenced the skin fibroblast migration (45% of the migration registered for the positive control-fetal bovine serum, for the crude extract, 50% of the positive control for the anthocyanins enriched fraction at 1 mg/L, 30% of the positive control for the polyphenolics enriched fraction), suggesting that the wound-healing properties are strongly associated with the anthocyanins presence. The dietary use of strawberry achenes commercial oil has also been proven to reduce the activity of superoxide dismutase (SOD) and glutathione peroxidase (cGPx) in rats (38.73, respectively 10.5 international units/gram of hemoglobin-U/g Hb, compared with the control group-67.33, and 22.9 U/g Hb, respectively), thus being qualified as a potential nutraceutical reducing oxidative stress [58].

Other Potential Applications
The anti-microbial properties were evaluated within the reviewed time period, especially for F. vesca. Hydromethanolic extracts obtained from leaves and roots of Fragaria vesca L. were evaluated by Gomes et al. [85] as antimicrobial agents a series of S. aureus strains. The results suggested a weak antimicrobial potential of the extracts (5-9 mm inhibition halos in the qualitative assays), which did not qualify the extracts for quantitative determinations. Superior results in terms of antimicrobial properties were obtained by Cardoso et al. [86]. Using hydroalcoholic extracts, the authors observed good antimicrobial properties of the crude extract against a series of Helicobacter pylori isolates (inhibition zones ≥ 15 mm) at a 25 mg/mL concentration. The ellagitannin-enriched fraction was efficient against all isolates at lower concentrations (7.5 mg/mL), which led the authors to assume that the ellagitannins were the main class of compounds responsible for the anti-microbial properties. As the H. pylori represents a pathogen involved in several gastric pathologies (including gastritis, gastroduodenal ulcer disease, gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma), the authors proposed the wild strawberry extract as a potential candidate for human health applications.
The anti-allergenic potential of several compounds (linocinnamarin, 1-O-trans-cinnamoyl-b-d-glucopyranose, p-coumaric acid, cinnamic acid, chrysin, kaempferol, catechin, and trans-tiliroside) isolated from Fragaria x ananassa var. Minomusume fruits were evaluated by Ninomiya et al. [87], through the determination of their inhibitory effects on antigen-stimulated degranulation in rat basophilic leukemia RBL-2H3 cells. Among the studied compounds, linocinnamarin (95% inhibition of control at 100 µM) and cinnamic acid (approx. 80% of control at 100 µM) were the most efficient in degranulation suppression (through direct inactivation of spleen tyrosine kinase), being proposed as promising tools for alleviating symptoms of type I allergy.
Another interesting study is represented by the one performed by Zhu et al. [35]. Besides the phytochemical and anti-oxidant studies (previously presented), the authors also evaluated the anti-obesity, anti-allergy, and skin-lightening effects of extracts obtained from different parts of strawberry in different ripening stages. The extracts exhibited anti-obesity activity (the water extract of unripe fruit and the ethanol extracts of the stem, stolon leaf, and crown ripe fruits exhibiting anti-lipase activity, as well as inhibitory effect on adipocyte differentiation), anti-allergy function (the ethanol extracts of flower, stolon leaf and red calyx showing strong suppression effect on the release of β-hexosaminidase), and skin-lightening potential (ethanol extracts of ripe fruits, unripe fruit and the crown exhibiting melanogenesis inhibitory action, correlated with the tyrosinase-inhibitory activities).
The cytotoxic potential of the Fragaria species was demonstrated in several studies. Somasagara et al. [89] evaluated the potential application of methanolic strawberry extract in leukemia (CEM) and breast cancer (T47D) cell lines ex vivo, as well as its therapeutic and chemopreventive potential in vivo. The MTT, trypan blue and LDH assays revealed the cytotoxicity of the extract on cancer cells, in a concentration-dependent manner, while the in vivo studies revealed the anti-proliferative action on tumor cells. Forni et al. [90] investigated the antiproliferative and differentiation potential of an anthocyanin-rich strawberry fruit extract on B16-F10 murine melanoma cells. Their results showed the reduction of cell proliferation (30% after 48 h), accompanied by the lowering of the intracellular levels of polyamines (63.8% decrease of spermidine, 52.9% decrease of spermine, after 72 h), and the enhancement of tissue transglutaminase (172% increase after 48 h). The used extract also down-regulated p53 and p21 expression (47.2%, and 32.6%, respectively). Liberal et al. [33] presented the cytotoxic potential of an ellagitannin-enriched fraction from Fragaria vesca leaves on human hepatic carcinoma cell line (HepG2). Their results showed that the crude extract and, more pronounced, the ellagitannin-enriched fraction, were able to interfere with cell cycle distribution. The ellagitannin-enriched fraction also induced necrosis and apoptosis in the threated cells, decreased chymotrypsin-like activity of the 26S proteasome, impaired autophagic flux, promoted the accumulation of ubiquitinated proteins, and decreased the expression of several proteasome subunits. Lucioli et al. [91] evaluated the influence of hydroalcoholic extracts (methanol, ethanol, isopropanol) from in vitro cell suspension on the proliferation of several cancer cells (neuroblastoma, colon, and cervix carcinoma cell lines). The extracts induced a statistically significant reduction of cell growth but did not affect the human fibroblasts from healthy donors. The chemoprotective action of strawberries was also studied by Casto et al. [92] (results not presented in Table 4 as authors used commercial strawberry powder). The chemoprotective role of strawberries on colorectal cancer in inflammatory bowel disease was recently reviewed by Chen et al. [93], who proposed a mechanism of action involving the suppression of cytokines release, decrease of oxidative stress, reduction of genomic instability, and inhibition of NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) and related signalling pathways. Table 4 summarizes the main biological activities (except anti-oxidant properties, presented in Table 3), as emerging from the literature survey, considering the main constituents of the tested extracts.

Current Limitations and Future Perspectives
In spite of the wide spread of the Fragaria genus, few species represent the subject of the last decade scientific research, with many works focused on the composition and bioactivities of wild and garden species. Although those species, with certain commercial value, represent a very valuable source of different classes of polyphenols (including proanthocyanidins, anthocyanins, ellagitannins, flavonoids, phenylpropanoids, stilbenes, phenol glycosides, and dihydrochalcones) and thus possessing important nutritional value [96], the researchers should also focus on less-studied species, native to different parts of the world. This could represent an important opportunity for future studies. Also, the evaluation of other possible application (such as cosmetic products) could represent an interesting area of research. As an example, Sikora et al. [59] used supercritical CO 2 extraction for obtaining strawberry seeds (achenes) oil and applied it (in varying concentration from 0.5-2%) for the development of shower/bath cosmetics with good skin-moisturizing properties, without influencing the stability of the products.
A drawback that limits the potential beneficial effects of the strawberries' consumption is represented by their processing. As previously mentioned, the thermal treatment reduces both the bioactive compounds and their biological activities. In this area, new protective coatings obtained using nanotechnological approaches were proposed for increasing their shelf-lives [97], or as post-harvest treatments, alternatives to the classical thermal treatments currently applied [98,99].
As emerging from the literature study, most of the research is performed via classical extraction methods in order to align with traditional uses of the species (infusion, decoction), and only few are including modern extraction and separation techniques (such as countercurrent chromatography). In this area, would be beneficial to evaluate the use of modern methods of extraction/separation of biological active compounds [100].
The rich anthocyanin content of the genus seems to offer promising compounds for very important applications, such as anti-cancer or chemoprotective agents. Another surprising aspect emerging from the reviewed works is the relatively few studies concerning the potential of Fragaria species towards anti-microbial applications. Although the literature abounds in examples regarding the anti-microbial potential of different plants extracts, it appears that the Fragaria could still offer some surprising results in this domain (considering its rich composition). Also, the application of Fragaria extracts in other areas, such as nanotechnology, is only "surface-scratched" at this moment. For example, Demirbas et al. [101] evaluated anthocyanins-rich berry extracts (including strawberry) for the phytosynthesis of silver nanoparticles and evaluated their antioxidant and anti-microbial potential. Although the results of the phytosynthesis process were promising (smallest dimensions, compared with the blackberry or raspberry extracts (35 nm), and with less aggregation, the antimicrobial effect was relatively poor (and only on B. cereus). The field of nanotechnology in general, and of nanoparticles phytosynthesis in special, represents a continuously increasing domain, so the extracts obtained from different species of the genus could demonstrate their usefulness in this area [102]. Other different nanoparticles could be obtained using the extracts, as well with tuned properties, using enrichment of the extracts [103]. Correlated with the anti-microbial properties, the potential toward nanotechnology could also lead to the development of other materials (such as polymeric encapsulated nanoparticles or even natural extracts) for different anti-microbial applications or for wider applications in increasing the quality of food products [104,105].
Finally, as a more general remark, the absence of standardized methods for the evaluation of different potential applications represents a major draw-back in the comparison of the results presented by different authors.

Conclusions
Fragaria represents a widely spread genus, with species encountered all over the world. The current study aimed to present the progress made in the last decade in the study of the composition and potential applications of the species belonging to the Fragaria genus. However, in spite the wide spread of its species, only a few represents the subject of current research. The literature study revealed that three species represent the major subject of research, respectively the wild, garden and beach strawberry.
Used in traditional medicine especially as an anti-inflammatory adjuvant, the scientific research supports this application, as well as several other potentially important uses, for example as a chemoprotective agent.
The composition of the genus, rich in polyphenolic compounds in general, and in anthocyanins in particular, suggests its possible application in multiple other areas. The relatively under-study of the genus (and the severe lack of literature for some of the species) offers in turn an opportunity for future research. At the same time, elucidation of the composition and properties of the commercially valuable products represents a very important aspect, as the characteristics of such a widely consumed product should be thoroughly elucidated.
Author Contributions: R.C.F., A.O., N.E.B., G.T., and I.F. contributed to data collection and analysis, and manuscript design. R.C.F., G.T., and I.F. prepared and revised the manuscript, and are the main authors of the study. All authors have read and agreed to the published version of the manuscript.

Funding:
The authors gratefully acknowledge the support obtained through the project SusMAPWaste, SMIS 104323, Contract No. 89/09.09.2016, from the Operational Program Competitiveness 2014-2020, project co-financed from the European Regional Development Fund.

Conflicts of Interest:
The authors declare no conflict of interest.