Chemical Composition and Biological Activities of Fragaria Genus

Chemical Composition and Biological Activities of Fragaria Genus: Comparison

Please note this is a comparison between Version 2 by Peter Tang and Version 4 by Peter Tang.

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. Usually appreciated because of their specific flavor, the strawberries also possess biological properties, including antioxidant, antimicrobial, or anti-inflammatory effects.

Fragaria genus
chemical composition
biological properties

1. 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].

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].

2. Composition of Fragaria L. Genus

Giampieri et al. ^[3] reviewed the composition of the strawberry (Fragaria x ananassa), while Morales-Quintana and Ramos ^[4] 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. ^[5]. As resulting from various literature studies ^{[3][4][5][6][7]}, 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).

Figure 1. Main components Fragaria species identified according literature data.

Table 1. Major (common) components in Fragaria L. aggregate fruits (adapted from ^{[3][4][5][6][7]}).

Class

species (as presented by original works published in the reviewed period; references presented in chronological order).

Species	Compound	Plant Part, Other Variables Ref.
Anthocyanins	Pelargonidin 3-glucoside, cyanidin 3-glucoside, cyanidin 3-rutinoside, pelargonidin 3-galactoside, pelargonidin 3-rutinoside, pelargonidin 3-arabinoside, pelargonidin 3-malylglucoside

Species

Compound

Plant Part, Other Variables

Ref.

Identified Compounds and Main Findings

Identification Method

Ref.

Anthocyanins

Pelargonidin 3-glucoside, cyanidin 3-glucoside, cyanidin 3-rutinoside, pelargonidin 3-galactoside, pelargonidin 3-rutinoside, pelargonidin 3-arabinoside, pelargonidin 3-malylglucoside

^[35][36]. 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 antioxidant properties (Table 3) are among the most studied effects of Fragaria extracts.

Table 3. Antioxidant properties of different extracts obtained from Fragaria species (references presented in chronological order).

Species	Extraction Method	Antioxidant Assay	Antioxidant Potential	Responsible Compounds	Ref.
^[	³	^]^[
F. chiloensis	⁴	^]^[^5]
	Ripe fruits	Anthocyanins (cyanidin 3-O-glucoside, pelargonidin 3-O-glucoside cyanidin-malonyl-glucoside and pelargonidin-malonyl-glucoside); procyanidins, ellagitannins, ellagic acid and flavonol derivatives	HPLC-DAD, LC-ESI-MS	^[9]	^[10]	Flavonols
F. chiloensis	Quercetin, kaempferol, fisetin, their glucuronides, and glycosides	Leaves
Fragaria chiloensis spp. chiloensis form chiloensis fruits	Methanol: formic acid (99:1 v/v	^[3]^[4]^[5]^[8]
	Procyanidins, ellagitannins, ellagic acid and flavonol derivatives		HPLC-DAD, LC-ESI-MS	) extraction ^[9]	Flavanols	Catechin, proanthocyanidin B1, proanthocyanidin trimer, proanthocyanidin B3
F. chiloensis
Fragaria × ananassa, Camarosa var. fruits	Anthocyanins isolated using CCC
	DPPH, SAS
Rhizomes		^[3]
		ORAC, FRAP	ORAC: 2.7–24.46 mmol Trolox/g; FRAP: 2.75–12.5 mmol Fe²⁺/g (depending on the fraction)	Anthocyanins	DPPH assay: IC₅₀ = 38.7 mg/L; SAS: 79.3%)	Aglycone and glycosylated ellagic acid and flavonoids	^[9]
Fragaria chiloensis spp. chiloensis form chiloensis leaves	Methanol: formic acid (99:1 v/v) extraction	Procyanidins, ellagitannins, ellagic acid and flavonol derivatives	DPPH, SAS HPLC-DAD, LC-ESI-MS		DPPH assay: IC₅₀ = 49.4 mg/L; SAS: 67.60% ^[9]	Aglycone and glycosylated ellagic acid and flavonoids	^[9]	Ellagitannins	Sanguiin H-6, ellagitannin, ellagic acid, lambertianin C, galloylbis-hexahydroxydiphenoyl-glucose
Fragaria × ananassa
Fragaria chiloensis spp. chiloensis form chiloensis rhizomes	Fruits	Methanol: formic acid (99:1 v/v) extraction^[3]
		Anthocyanins (pelargonidin-3-glucoside, pelargonidin-3-rutinoside, cyanidin-3-rutinoside, pelargonidin-3,5-diglucoside, pelargonidin-3-(6-acetyl)-glucoside, 5-carboxypyranopelargonidin-3-glucoside, delphinidin-3-glucoside, peonidin-3-glucoside, cyanidin-3-galactoside), p-hydroxybenzoic acid, (+)-catechin, ellagic acid, p-coumaric acid, quercetin glucoside	DPPH, SAS LC-MS/MS, HPLC-UV/Vis	DPPH assay: IC₅₀ = 64.8 mg/L; SAS: 55% ^[10]	Aglycone and glycosylated ellagic acid and flavonoids	^[9]	Phenolic acids	4-coumaric acid, p-hydroxybenzoic acid, ferulic acid, vanillic acid, sinapic acid	^[
Fragaria × ananassa	Fruits, cultivar and seasonal variations	^7]

Fragaria x ananassa Osogrande var. frozen fruits	Acetone (80%) extraction	Vitamin C, β-carotene, total phenolics, total anthocyanins; genotype influence is stronger than the environmental influence	DPPH, FRAP Colorimetric	DPPH: 11.91–12.83 μmol BHT eq./g FW; best results for ripe fruits FRAP: 27.37–36.75 μmol FS eq./g FW; best results for green fruits ^[11]	Total phenolic content, vitamin C	^[12]	Vitamins	Vitamin C, vitamin B9	^[
Fragaria × ananassa	Fruits, different cultivars on different ripeness stage	^6]
	Total vitamin C, total phenolics, total anthocyanins, total ellagic acid/pelargonidin-3-glucoside and cyanidin-3-glucoside; higher amounts in pink fruits compared with fully ripped fruits
Fragaria x ananassa Camino Real var. frozen fruits	Acetone (80%) extraction	DPPH, FRAP	Colorimetric/HPLC-DAD	^[12]	DPPH: 9.75–12.01 μmol BHT eq./g FW, FRAP: 24.13–28.49 μmol FS eq./g FW (best results for pink fruits)	Minerals	Mn, K, Mg, P, Ca	^[
Fragaria × ananassa	Fruits, different farming methods	^3]
Others	Sugars (glucose, fructose, and sucrose), fibers	^[3]

The presented composition varies with a series of factors, including the value of the cultivar, seasonal variation, and the degree of fruit ripeness. In the reviewed time period, several studies presented the evaluation of species belonging to Fragaria genus. Their main findings are presented in Table 2, while relevant studies are presented in the following paragraphs.

Table 2. Composition of Fragaria


Total phenolic content, vitamin C


Total phenolics/pelargonidin-3-glucoside and cyanidin-3-glucoside, vitamin C, higher in organic farming fruits
		Colorimetric/HPLC-DAD		^[13]
	^[	¹²	Fragaria × ananassa	Fruits, different cultivars (27) and ripening stages	Phenolic compounds (multiple classes, including anthocyanins, flavanols and ellagitannins); composition dependent on cultivar, cinnamic acid conjugates and anthocyanins levels increased with the ripening stage	HPLC-DAD-MS	^[14]
Fragaria × ananassa, F. vesca	Fruits	Quercetin and isorhamnetin glycosides (higher levels in wild strawberry)	HPLC-DAD, LC-ESI-MS	^[15]
Fragaria × ananassa, F. vesca	Fruits, different cultivars	Volatile esters (including ethyl acetate, hexyl acetate, methyl butanoate, ethyl butanoate, hexyl butanoate, methyl hexanoate, ethyl hexanoate, hexyl hexanoate); higher levels in cultivated strawberries.	GC-MS	^[16]
	F. vesca	Fruits, two different cultivars	Anthocyanins (cyanidin 3-O-glucoside, pelargonidin 3-O-glucoside, peonidin 3-O-glucoside, cyanidin 3-O-malonylglucoside, pelargonidin 3-O-malonylglucoside, peonidin 3-O-malonylglucoside), dihydroflavonol and flavonols (taxifolin 3-O-arabinoside, kaempferol 3-O-glucoside, quercetin 3-O-glucoside, quercetin-acetylhexoside, kaempferol 3-O-acetylhexosides), flavan-3-ols and proanthocyanidins (catechin, B type proanthocyanidin dimers, trimers, and tetramers), ellagic acid and derivatives (glycosylated, methyl pentoside, methylellagic acid methyl pentoside, ellagitannins), other compounds (benzoic acid, ferulic acid hexose derivative, citric acid, furaneol glucoside)	HPLC-DAD	^[17]
	Anti-lipase assay, adipocyte differentiation inhibition assay, melanogenesis inhibition assay, β-hexosaminidase inhibition assay, tyrosinase inhibition assay			Crown, stolon leaf and flowers extracts exhibited the highest effects	Total phenolic content	^[21]	Fragaria × ananassa, F. vesca	Fruits	Anthocyanins (cyanidin, pelargonidin), cyanidin glycosides (cyanidin 3-glucoside, cyanidin 3-arabinoside, cyanidin 3-sambubioside, delphinidin 3-galactoside, delphinidin 3-glucoside, delphinidin 3-malonylglucoside); higher levels of cyanidin glycosides in wild species
Antihyperuricemic	Fragaria x ananassa cv. Tochiotome leaves	Supercritical CO₂ extraction with different entrainers	HPLC-DAD	Uric acid production in AML12 hepatocytes ^[18]
	Reduction of uric acid at 100 mg/mL (96 mmol/2 h/mg protein), compared with the control (16,096 mmol/2 h/mg protein)			Kaempferol, quercetin		^[40]	F. vesca	Leaves
Cytotoxic, anti-proliferative	Fragaria x ananassa fruits	Ellagitannins (sanguiin H-2 isomer, sanguiin H-10 isomer, sanguiin H-6/agrimoniin/lambertianin A isomer, castalagin/vescalagin isomer, sanguiin H-10 isomer, sanguiin H-2 isomer, casuarictin/potentillin isomer)	LC-PDA-ESI-MS	^[	Meth. extraction ^19]
	Ex vivo: cell viability assay; in vivo: developing tumor size determination			Cytotoxic on cancer cells, blocked the proliferation of tumor cells	Phenolic compounds	^[56]	Fragaria × ananassa
Antineoplastic	Fruits, different cultivars and production years	Vitamin C, anthocyanins (pelargonidin 3-glucoside, cyanidin 3-glucoside, pelargonidin 3-rutinoside), ellagic acid; strongly dependent on the cultivar and production year	Fragaria x ananassa var. Pajaro HPLC-UV/Vis	fruits	Acidified hydro-eth. extraction	Transglutaminase assay and polyamine detection, immunoblot analysis ^[20]
	reduction of cell proliferation, lowering of the intracellular levels of polyamine, enhancement of tissue transglutaminase activity			Anthocyanins		^[57]	Fragaria × ananassa	Fruits, at different ripening stage	Vitamin C, pelargonidin-3-rutinoside, ellagic acid, cyanidin-3-glucoside, quercetin (red fruits), neochlorogenic, pelargonidin-3-glucoside, pelargonidin-3-rutinoside, epicatechin, quercetin-3-β-d-glucoside, ellagic acid (green fruits)	LC-ESI-TOF	^[21]
Cytotoxic	Fragaria vesca L. leaves	Hydroalcoholic extract at room temperature, ellagitannins-enriched fraction	Effects on HepG2 cells—cell viability assessment, cell proliferation, cell cycle and cell death analysis, Western blot analysis, proteasome chymotrypsin-like activity	Inhibition of HepG2 cell viability IC₅₀ = 690 mg/L (extract)/113 mg/L (fraction); fraction induced necrosis and apoptosis, influenced the cellular proteolytic mechanisms	Ellagitannins	^[19]	Fragaria × ananassa
Chemopreventive	Calyx (red and green)	Lyophilized Fragaria x ananassa fruits Quercetin-3-β-d-glucoside, ellagic acid, kaempferol-3-O-glucoside, vitamin C (red), catechin, quercetin-3-β-d-glucoside, ellagic acid (green)	Ultrasound-assisted extraction with acidified acetone LC-ESI-TOF	Histological studies, Western blot analysis, PGE₂ ^[21]
measurement, and nitrate/nitrite colorimetric assay			Decreased tumor incidence, decreased levels of TNF-α, IL-1β, IL-6, COX-2 and iNOS, inhibition of the phosphorylation of PI3K, Akt, ERK, and NFκB		anthocyanins, ellagitannin/ellagic acid/ellagic acid derivatives flavonols	^[58]	Fragaria × ananassa	Flower	Catechin, quercetin-3-β-d-glucoside, ellagic acid, kaempferol-3-O-glucoside, vitamin C
Cytotoxic	Fragaria x ananassa leaves		LC-ESI-TOF	^[21]
	Hydroalcoholic extracts (meth., eth., isopropanol) from in vitro cell suspension		Cell proliferation, cell viability	Under 50% viable cells for colorectal adenocarcinoma and colon adenocarcinoma upon treatment with extracts containing 0.29 mM ethoxy-dihydrofuro-furan	Polyphenols	^[59]	Fragaria × ananassa	Leaf	Procyanidin dimer and trimer, catechin, quercetin-3-β-d-glucoside, vitamin C, ellagic acid	LC-ESI-TOF	^[21]
Fragaria × ananassa	Stolon	Neochlorogenic, procyanidin dimer, catechin, quercetin-3-β-d-glucoside, ellagic acid, vitamin C, kaempferol-3-O-glucoside	LC-ESI-TOF	^[21]
Fragaria × ananassa	Stem	Procyanidin dimer, catechin, ferulic acid, quercetin-3-β-d-glucoside, ellagic acid	LC-ESI-TOF	^[21]
Fragaria × ananassa	Crown	Procyanidin dimer and trimer, catechin, propelargonidin dimer, ellagic acid	LC-ESI-TOF	IC₅₀ (mg/mL) ranging from 76.73 (Camarosa)—100 (Camino Real) ^[21]
	Total anthocyanin content			^[	^26]	Fragaria × ananassa	Root	Procyanidin dimer and trimer, catechin, neochlorogenic, propelargonidin dimer	LC-ESI-TOF
F. vesca leaves native to Italy	Ultrasonic extraction with ethanol: water solvent (70:30, v/v)	TEAC		^[	0.34–0.35 mg/mL Trolox eq., compared with quercetin (0.40)^21]
		Condensed tannins and flavonoid derivatives			^[28]	Fragaria × ananassa	Fruits, different novel cultivars	Phenolic acids (p-coumaric acid, ellagic acid, ferulic acid derivative, p-coumaric acid derivatives), monomeric flavanols ((+)-catechin), flavonols (quercetin 3-O-glucoside, fisetin, quercetin 3-O-glucoside derivative), anthocyanins (cyanidin 3-glucoside, cyanidin 3-rutinoside, cyanidin pentoside, pelargonidin 3-galactoside, pelargonidin 3,5-diglucoside, pelargonidin 3-glucoside, pelargonidin 3-rutinoside, cyanidin 3-Oacetylglucoside, cyanidin hexoside, pelargonidin 3-O-monoglucuronide, pelargonidin derivatives)
Fragaria x ananassa cv. Tochiotome	HPLC-DAD, LC-ESI-QTOF			^[22]
leaves	Supercritical CO₂ extraction with different entrainers	DPPH	0.07 (simple supercritical extraction)—5.82 μmol BHT/g sample (with ethanol, dried at 40 °C)	Phenolic compounds	^[40]	Fragaria × ananassa
Fragaria × ananassa fruits (90 cultivars)	Fruits, grown on different altitudes, on consecutive years	Ultrasonic aqueous methanol (70%) acidified with 1.5% formic acid, at room temperature	DPPH, ABTS	Average values (μmol Trolox/100 g):765.06 (DPPH), 1637.96 (ABTS)	Tannin-based compounds.	^[31]

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; IC₅₀—half maximal inhibitory concentration; ORAC—oxygen radical absorbance capacity; SAS—superoxide anion assay; TBARS—thiobarbituric acid reactive substances assay; TEAC—Trolox equivalent antioxidant capacity.

3.2. Anti-Inflammatory Properties

As previously stated, one of the traditional uses of Fragaria is as an anti-inflammatory agent ^[32][33]. Most of the authors assign the anti-inflammatory properties to the presence of anthocyanins (the most representative being pelargonidin and cyanidin derivates) ^[41], molecules with known anti-inflammatory potential ^[42][43], demonstrated both in vitro and in vivo ^[44][45]. 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. ^[46]. 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.

3.3. 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. ^[47] 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. ^[48]. 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. ^[49], 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.

The commercially-available strawberry freeze-dried powder was demonstrated by Abdulazeez ^[50] to reverse alloxan-induced diabetes (results not presented in Table 4 as authors used commercial powder product); in a similar study, Yang et al. ^[4] evaluated the potential anti-diabetic application of new and known compounds isolated from strawberry fruits (as presented in Section 2) by determining the α-glucosidase inhibitory activity. The best results were obtained for cupressoside A (IC₅₀ = 25.39 μM), kaempferol 3-(6-methylglucuronide) (IC₅₀ = 65.22 μM), and 2-p-hydroxybenzoyl-2,4,6-tri hydroxyphenylacetate (IC₅₀ = 97.81 μM), with very good results obtained for a newly proposed structure (kaempferol 3-(6-butylglucuronide)-IC₅₀ = 107.52 μM); results superior to the positive control (acarbose-IC₅₀ = 619.94 μM) were also obtained for five other compounds.

Table 4. Main biological activities presented in the literature (references listed in chronological order).

Action	Plant	Extraction Method	Assay	Results	Responsible Compounds	Ref.
Anti-inflammatory on inflammatory bowel disease	Fragaria vesca leaves	Eth. extraction	MPO activity; GSH, SOD and CAT levels	Prevention of increase in colon weight and disease activity index, decrease in macroscopic and microscopic lesion score; significant improvement of MPO, CAT and SOD levels at 500 mg/kg 5 days oral treatment	Phenolic acids, flavonoids	^[51]
Anti-inflammatory	Fragaria vesca leaves	Eth. extraction at room temperature, infusion	Nitric oxide production, western blot analysis (expression of pro-inflammatory proteins in lipopolysaccharide-triggered macrophages); nitric oxide scavenger activity	Inhibition of nitrite production on pre-treated cells (at 80 and 160 mg/L—31%/40%); 23% inhibition in culture media, at 160 mg/L	Phenolic content	^[46]
Anti-inflammatory	Fragaria x ananassa, var. Alba fruits	Meth. extraction at room temperature, infusion	Determination of ROS intracellular levels, apoptosis detection, antioxidant enzyme activities, immunoblotting analysis, determination of mitochondrial respiration and extracellular acidification rate in cells	Reduction of intracellular ROS levels (significant at 100 mg/L), decreased apoptotic rate (significant at 50 and 100 mg/L); Increased ARE-antioxidant enzymes expression, reduced NO and inflammatory cytokines production (at 50 and 100 mg/L) to control levels	Vitamin C, anthocyanins, flavonoids	^[52]
Anti-inflammatory, hepatoprotective	Fragaria chiloensisssp. Chiloensis fruits	Aq. extracts	Histological analyses, determination of transaminases, cytokines, F2-isoprostanes, and glutathione assays	maintained hepatocellular membrane, structural integrity, attenuated hepatic oxidative stress, and inhibited inflammatory response in LPS-induced liver injury; downregulation of cytokines (TNFa, IL-1β, and IL-6)	Phenolic content	^[53]
Anti-inflammatory	Fragaria x ananassa var. Camarosa fruits	Ultrasonic-assisted, acidified meth. extraction, separation	In vivo: quantification of the leukocyte content, exudate concentration, MPO and ADA activities, nitric oxide products, TNF-α and IL-6 levels; in vitro: MTT assay, measurement of nitric oxide products, TNF-α and IL-6 levels, western blot analysis	Inhibition of the carrageenan-induced leukocyte influx to the pleural cavity; reduction of myeloperoxidase activity, exudate concentration, NO levels.	Phenolic compounds, anthocyanins (particularly pelargonidin-3-O-glucoside)	^[54]
Anti-inflammatory, wound healing	Fragaria x ananassa var. San Andreas fruits	^]
	Ultrasound-assisted extraction, acidified meth.: aq. (80:20); separation of different fractions		MTT assay, ROS, NO levels, effects on inflammatory markers and on skin fibroblast migration	ROS reduction, suppression of IL-1β, IL-6 and iNOS gene expressions; enhanced skin fibroblast migration	Polyphenolic compounds, especially anthocyanins	^[55]	F. vesca leaves	Methanol, ultrasounds extraction	DPPH, FRAP
Anti-microbial		DPPH: IC	₅₀ = 13.46 mg/L; FRAP: 0.878 mmol Fe²⁺/g DW	Total phenols, total tannins	^[	Fragaria vesca leaves and roots	Centrifugation extraction with meth.: aq. (80:20) ³⁷	Disc diffusion assay	6–9 mm inhibition zones for leaves, 5–9 mm for roots (depending on S. aureus strain) ^]
	Phenolic compounds			^[	⁴⁷	^]	F. vesca roots, wild-growing	Hydromethanolic extraction, infusion, decoction	DPPH, FRAP, β-Carotene bleaching inhibition, TBARS	IC₅₀, mg/L: DPPH—50.03/50.56/50.62; FRAP—40.98/44.78/49.23; β-C bleaching—116.26/44.88/66.10; TBARS—35.76/4.76/6.14	Total phenolics, total flavan-3-ols, total dihydroflavonols,
Anti-microbial	Fragaria vesca leaves	Hydroalcoholic extraction, separation	^[	Disc diffusion assay	^38]
	Good inhibition potential at 25 mg/mL, better effect for the ellagitannin-enriched fraction			Ellagitannins		^[48]	F. vesca roots, commercial
Anti-allergenic	Hydromethanolic extraction, infusion, decoction	DPPH, FRAP, β-Carotene bleaching inhibition, TBARS	IC₅₀, mg/L: DPPH—68.89/255.81/51.32; FRAP—327.75/78.99/67.92; β-C bleaching—68.34/23.44/114.67; TBARS—6.69/24.25/10.62	Total phenolics, total flavan-3-ols, total dihydroflavonols,	^[	Fragaria x ananassa var. Minomusume^38]
fruits		Methanol fraction of fruits juice (obtained by squeezing)	Antigen-stimulated degranulation in RBL-2H3 cells	degranulation suppression (95–60% inhibition for linocinnamarin, cinnamic acid, chrysin, kaempferol, trans-tiliroside)	Best results - phenylpropanoid glycoside	^[49]	Fragaria × ananassa var. Amaou, fruits, at different ripening stage	Ethanol or water room temperature extraction	Modified ABTS assay
Anti-diabetic		Ethanol: 150.5/151.9; water: 227.2/189.4 (red/green fruits) μmol TE/100 g FW		Fragaria x ananassa var. Falandi fruits Total phenolic content		Compounds isolated from eth. extracts	α-glucosidase inhibitory activity	IC₅₀^[21]
values better than the positive control (acarbose) for nine compounds (537.43 to 25.39 μM)			Individual compounds			^[24]	Fragaria × ananassa var. Amaou calyx (red and green)
Anti-obesity, anti-allergy, skin-lightening	Ethanol or water room temperature extraction	Fragaria ×ananassa var. Amaou, entire plant (red fruit, green fruit, red calyx, green calyx, flower, leaf, stolon, stolon leaf, stem, crown and root) Modified ABTS assay	Ethanol: 241.1/1239.9; water: 1716.6/577.7 μmol TE/100 g FW (red/green calyx)	Total phenolic content	^[21]
	Fragaria × ananassa var. Amaou flower	Ethanol or water room temperature extraction	Modified ABTS assay	4234.4/387.5 μmol TE/100 g FW (ethanol/water)	Total phenolic content	^[21]
Fragaria × ananassa var. Amaou leaves	Ethanol or water room temperature extraction	Modified ABTS assay	2401.7/241.1 μmol TE/100 g FW (ethanol/water)	Total phenolic content	^[21]
Eth. or aq. room temperature extraction		Fragaria × ananassa var. Amaou stolon	Ethanol or water room temperature extraction	Modified ABTS assay	1089.4/1856.7 μmol TE/100 g FW (ethanol/water)	Total phenolic content	^[21]
Fragaria × ananassa var. Amaou stem	Ethanol or water room temperature extraction	Modified ABTS assay	1338.6/1123.1 μmol TE/100 g FW (ethanol/water)	Total phenolic content	^[21]
Fragaria × ananassa var. Amaou crown	Ethanol or water room temperature extraction	Modified ABTS assay	6213.3/128.7 μmol TE/100 g FW (ethanol/water)	Total phenolic content	^[21]
Fragaria × ananassa var. Amaou root	Ethanol or water room temperature extraction	Modified ABTS assay	253.1/69.2 μmol TE/100 g FW (ethanol/water)	Total phenolic content	^[21]
F. vesca vegetative parts (leaves and stems), wild-growing	Hydromethanolic and aqueous extracts; wild-growing infusion microencapsulated in alginate and incorporated in k-carrageenan gelatine	DPPH, FRAP, β-Carotene bleaching inhibition, TBARS	IC₅₀, mg/L: DPPH—123.67/86.17/109.10; FRAP—81.40/62.36/77.28; β-C bleaching—56.71/12.34/13.40; TBARS—12.63/3.12/5.03 (hydromethanolic/infusion/decoction); Final formulation (mg/mL)—DPPH—2.74; FRAP = 1.23	Total phenolics, total flavan-3-ols, total dihydroflavonols,	^[39]
		Hydroxybenzoic acid, p-coumaric acid, other hydroxycinnamic acids, (+)-catechin, (−)-epicatechin, procyanidins, flavonols, anthocyanins (cyanidin 3-glucoside, pelargonidin 3-glucoside, pelargonidin derivative); higher levels recorded at lower altitudes.	HPLC-DAD	^[23]
Fragaria × ananassa	Fruits	Kaempferol 3-(6-methylglucuronide), quercetin 3-(6-methylglucuronide), isorhamnetin 3-(6-methylglucuronide), trichocarpin, 2-p-hydroxybenzoyl-2,4,6-tri hydroxyphenylacetate, 2-p-hydroxyphene thyl-6-caffeoylglucoside, zingerone 4-glucoside, b-hydroxypropiovanillone 3-glucoside, (+)-isolariciresinol 90-glucoside, (−)-isolariciresinol 90-glucoside, aviculin, (−)-secoisolariciresinol 4-glucoside, cupressoside A, cedrusin, icariside E4, dihydrodehydrodiconiferyl alcohol 90-glucoside, massonianoside A, urolignoside, (−)-pinoresinol 4-glucoside, 2,3”-epoxy-4-(butan-2-one-3-yl)-5,7,40-trihydroxy flavane 3-glucoside, kaempferol 3-(6-butylglucuronide), benzyl 2-glucosyl-6-rhamnosylbenzoate
F. vesca vegetative parts (leaves and stems), commercial	Hydromethanolic and aqueous extracts	DPPH, FRAP, β-Carotene bleaching inhibition, TBARS	IC₅₀, mg/L: DPPH—139.33/121.94/118.89; FRAP—324.49/91.88/88.20; β-C bleaching—388.90/76.41/69.98; TBARS—24.36/23.07/17.52 (hydromethanolic/infusion/decoction).	Total phenolics, total flavan-3-ols, total dihydroflavonols,	^[39]
Fragaria x ananassa cv. Falandi fruit	22 compounds isolated from ethanolic extracts	ABTS, DPPH, FRAP	Best results (IC₅₀): ABTS—4.42 μM kaempferol 3-(6-methylglucuronide); DPPH—32.12 μM quercetin 3-(6-methylglucuronide); FRAP—0.05 mmol/g—urolignoside.	Individual compounds	^[24]
Fragaria x ananassa cv. Albion, Aromas, Camarosa, Camino Real, Monte Rey, Portola, and San Andreas fruits	Ultrasonic extraction with acidified methanol	DPPH		¹H NMR, ¹³C NMR, HMBC, HPLC-UV/Vis, LC-MS/MS, HR-ESI-MS,	^[24]
F. vesca	Fruits, wild and cultivated, from different geographical areas	39 phenolic compounds (including cyanidin 3-O-glucoside, delphinidin-3-O-glucoside, pelargonidin-3-O-glucoside, pelargonidin-3-O-rutinoside, (+) catechin, (−) epicatechin, procyanidin B1 and B2, isoquercetin, gallic acid, p-coumaric acid, phloridzin); composition dependent on the geographical area	LC-ESI-Orbitrap-MS, LC-ESI-QTrap-MS, LC-ESI-QTrap-MS/MS	^[25]
Fragaria × ananassa	Fruits, different cultivars	Cyanidin 3-O-glucoside, pelargonidin-3-O-glucoside, pelargonidin-O-rutinoside, total anthocyanins content, dependent on the cultivar	UPLC-PDA-ESI-MS, HPLC-DAD	^[26]
F. vesca	Fruits	Volatile composition—one hundred compounds (including esters, aldehydes, ketones, alcohols, terpenoids, furans and lactones).	GS-MS	^[27]
F. vesca	Leaves	27 metabolites (organic acids, flavonoids, catechin and its oligomers, ellagitannins), including quinic acid, chelidonic acid, quercetin derivatives, catechin and procyanidins, phloridzin, pedunculagin, methyl ellagic acid glucuronide.	LC-ESI-Orbitrap-MS	^[28]
Fragaria × ananassa, F. vesca	White-fruited mutants, different genotypes	Anthocyanins, flavonols, flavan-3-ols, hydroxycinnamic acids, and ellagic acid—derived compounds, dependent on genotype	LC-ESI-MS/MS	^[29]
F. chiloensis	Fruits	Anthocyanins (cyanidin-3-O-glucoside, pelargonidin hexoside, cyanidin manlonyl hexoside, pelargonidin-malonyl hexoside), ellagitannins (ellagic acid hexoside, pentoside, rhamnoside), proanthocyanidin dimers, epicatechin, flavonols (quercetin pentoside, glucuronide)	HPLC-DAD, LC-ESI-MS	^[30]
Fragaria × ananassa	Fruits, different cultivars	Anthocyanins, flavonoids, cinnamic acid derivatives, tannins and related compounds, triterpenoids; concentration dependent on the cultivar	UPLC-ESI-QTOF-MS/MS, HPLC-DAD	^[31]

where:¹³C NMR—Carbon-13 nuclear magnetic resonance; GC-MS—gas chromatography–mass spectrometry; ¹H NMR—proton nuclear magnetic resonance; HMBC —heteronuclear multiple bond correlation; HPLC-DAD—high-performance liquid chromatography with diode array detector; HPLC-UV/Vis—high-performance liquid chromatography equipped with UV/vis detector; HR-ESI-MS—high-resolution electrospray ionization mass spectrometry analysis; LC-ESI-MS(/MS)—liquid chromatography electrospray ionization (tandem) mass spectrometry analysis; LC-ESI-Orbitrap-MS—liquid chromatography electrospray ionization Orbitrap mass spectrometry; LC-ESI-QTrap-MS(/MS)—liquid chromatography electrospray ionization quadrupole ion trap mass spectrometry; LC–ESI–(Q)TOF—liquid chromatography electrospray ionization with (quadrupole) time-of-flight; LC-MS/MS—liquid chromatography–tandem mass spectrometry; LC-PDA-ESI-MS—liquid chromatography equipped with photodiode array detector coupled to mass spectrometry using the electrospray ionization interface; UPLC-ESI-QTOF-MS/MS—ultra-performance liquid chromatography equipped quadrupole time of flight coupled to tandem mass spectrometry using the electrospray ionization interface; UPLC-PDA-ESI-MS—ultra-performance liquid chromatography equipped with photodiode array detector coupled to mass spectrometry using the electrospray ionization interface.

3. Biological Activities of Fragaria Genus

3.1. 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 ^[32], as macerate for renal stones, or as tea (together with other medicinal plants) for treating stomach inflammations, sedation, or regulation of digestion ^[33]. 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 ^[34]

where: ADA—adenosine-deaminase; Akt—Protein Kinase B; aq.—water (aqueous); CAT—catalase; COX-2—cyclooxygenase-2 enzyme; ERK—extracellular signal-regulated kinase; eth—ethanol; GSH—glutathione; HepG2—human liver cancer cell line; IC_50—half maximal inhibitory concentration; IL-1β—Interleukin 1 beta cytokine protein; IL-6—interleukin 6; iNOS—inducible nitric oxide synthase; meth.—methanol; MPO—myeloperoxidase; MTT—3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NFκB—nuclear factor kappa-light-chain-enhancer of activated B cells; NO—nitric oxide; PGE₂—Prostaglandin E₂; PI3K—phosphatidylinositol 3-kinase; RBL—rat basophilic leukemia cells; ROS—reactive oxygen species; SOD—superoxide dismutase; TNF-α—tumor necrosis factor alpha;.

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