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 3 by Radu Claudiu Fierascu 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

^[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		Ref.
	Extraction Method		Identified Compounds and Main Findings				Antioxidant Assay		Identification Method			Antioxidant Potential		Ref.
		Responsible Compounds			Ref.
	Anthocyanins			Pelargonidin 3-glucoside, cyanidin 3-glucoside, cyanidin 3-rutinoside, pelargonidin 3-galactoside, pelargonidin 3-rutinoside, pelargonidin 3-arabinoside, pelargonidin 3-malylglucoside			^[3]^[
	F. chiloensis		⁴^]^[5]
	Ripe fruits
	Fragaria × ananassa, Camarosa		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
	Fragaria chiloensis spp. chiloensis form chiloensis fruits		Quercetin, kaempferol, fisetin, their glucuronides, and glycosides			Leaves		^[3]^[4		Methanol: formic acid (99:1 v/v) extraction		^]^[^5]^[8]
	Procyanidins, ellagitannins, ellagic acid and flavonol derivatives			HPLC-DAD, LC-ESI-MS			^[9]			Flavanols			Catechin, proanthocyanidin B1, proanthocyanidin trimer, proanthocyanidin B3
var. fruits			Anthocyanins isolated using CCC			ORAC, FRAP			ORAC: 2.7–24.46 mmol Trolox/g; FRAP: 2.75–12.5 mmol Fe²⁺/g (depending on the fraction)			Anthocyanins			DPPH, SAS			DPPH assay: IC₅₀ = 38.7 mg/L; SAS: 79.3%)		Aglycone and glycosylated ellagic acid and flavonoids		^[9]		F. chiloensis
	Fragaria chiloensis spp. chiloensis form chiloensis leaves		Rhizomes		^[3]
	Methanol: formic acid (99:1 v/v		Procyanidins, ellagitannins, ellagic acid and flavonol derivatives		) extraction		HPLC-DAD, LC-ESI-MS				DPPH, SAS			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			Fruits		^[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			LC-MS/MS, HPLC-UV/Vis			^[10]			Phenolic acids			4-coumaric acid, p-hydroxybenzoic acid, ferulic acid, vanillic acid, sinapic acid			^[
	Fragaria × ananassa			Fruits, cultivar and seasonal variations		^7]
	Vitamin C, β-carotene, total phenolics, total anthocyanins; genotype influence is stronger than the environmental influence			Colorimetric			^[11]			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			Colorimetric/HPLC-DAD			^[12]			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 phenolics/pelargonidin-3-glucoside and cyanidin-3-glucoside, vitamin C, higher in organic farming fruits

Colorimetric/HPLC-DAD

Fragaria chiloensis spp. chiloensis form chiloensis rhizomes

Methanol: formic acid (99:1 v/v) extraction

DPPH, SAS

DPPH assay: IC₅₀ = 64.8 mg/L; SAS: 55%

Aglycone and glycosylated ellagic acid and flavonoids

^[9]

Fragaria x ananassa Osogrande var. frozen fruits

Acetone (80%) extraction

^[13]

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]

DPPH, FRAP

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

Total phenolic content, vitamin C

^[12]

Fragaria x ananassa Camino Real var. frozen fruits

Acetone (80%) extraction

DPPH, FRAP

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)

Total phenolic content, vitamin C

^[12]

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

Anti-lipase assay, adipocyte differentiation inhibition assay, melanogenesis inhibition assay, β-hexosaminidase inhibition assay, tyrosinase inhibition assay

^[17]

Crown, stolon leaf and flowers extracts exhibited the highest effects

Total phenolic content

^[21]

Fragaria × ananassa, F. vesca

Antihyperuricemic

Fruits

Fragaria x ananassa cv. Tochiotome leaves

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

HPLC-DAD

Supercritical CO₂ extraction with different entrainers

^[18]

Uric acid production in AML12 hepatocytes

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

Cytotoxic, anti-proliferative

Leaves

Fragaria x ananassa

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)

fruits

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

Fragaria x ananassa var. Pajaro fruits

Vitamin C, anthocyanins (pelargonidin 3-glucoside, cyanidin 3-glucoside, pelargonidin 3-rutinoside), ellagic acid; strongly dependent on the cultivar and production year

Acidified hydro-eth. extraction

HPLC-UV/Vis

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

Cytotoxic

Fragaria vesca L. leaves

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)

Hydroalcoholic extract at room temperature, ellagitannins-enriched fraction

LC-ESI-TOF

^[21]

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)

LC-ESI-TOF

Ultrasound-assisted extraction with acidified acetone

Histological studies, Western blot analysis, PGE₂ measurement, and nitrate/nitrite colorimetric assay

^21]

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

Cytotoxic

Flower

Catechin, quercetin-3-β-

Fragaria x ananassad-glucoside, ellagic acid, kaempferol-3-O-glucoside, vitamin C

LC-ESI-TOF

^[21]

leaves

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

Fragaria × ananassa

Leaf

Procyanidin dimer and trimer, catechin, quercetin-3-β-d-glucoside, vitamin C, ellagic acid

LC-ESI-TOF

^[21]

⁵⁹

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

₅₀

(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

F. vesca leaves native to Italy

LC-ESI-TOF

Ultrasonic extraction with ethanol: water solvent (70:30, v/v)

TEAC

²¹

0.34–0.35 mg/mL Trolox eq., compared with quercetin (0.40)

Condensed tannins and flavonoid derivatives

^28]

Fragaria × ananassa

Fragaria x ananassa cv. Tochiotome leavesFruits, different novel cultivars

Supercritical CO₂ extraction with different entrainers

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)

HPLC-DAD, LC-ESI-QTOF

^[22]

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)

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
	Anti-microbial		Methanol, ultrasounds extraction		DPPH, FRAP				Fragaria vesca leaves and rootsDPPH: IC₅₀ = 13.46 mg/L; FRAP: 0.878 mmol Fe²⁺/g DW			Total phenols, total tannins			Centrifugation extraction with meth.: aq. (80:20)		Disc diffusion assay		6–9 mm inhibition zones for leaves, 5–9 mm for roots (depending on S. aureus^[37]
strain)			Phenolic compounds		^[47]			F. vesca roots, wild-growing
	Anti-microbial		Hydromethanolic extraction, infusion, decoction		Fragaria vesca leaves		DPPH, FRAP, β-Carotene bleaching inhibition, TBARS			Hydroalcoholic extraction, separation		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,		^[38]
	Disc diffusion assay			Good inhibition potential at 25 mg/mL, better effect for the ellagitannin-enriched fraction		Ellagitannins			^[48]			F. vesca roots, commercial		Hydromethanolic extraction, infusion, decoction

Fruits, grown on different altitudes, on consecutive years


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
	Anti-allergenic			Fragaria x ananassa var. Minomusume fruits	DPPH, FRAP, β-Carotene bleaching inhibition, TBARS			IC₅₀		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		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]
, 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,		Methanol fraction of fruits juice (obtained by squeezing)		^[38]
	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
	Anti-diabetic		Ethanol or water room temperature extraction		Fragaria x ananassa var. Falandi fruits		Modified ABTS assay				Compounds isolated from eth. extracts		Ethanol: 150.5/151.9; water: 227.2/189.4 (red/green fruits) μmol TE/100 g FW		Total phenolic content		^[21]
	α-glucosidase inhibitory activity			IC₅₀ 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)		Ethanol or water room temperature extraction		Modified ABTS assay
	Anti-obesity, anti-allergy, skin-lightening		Ethanol: 241.1/1239.9; water: 1716.6/577.7 μmol TE/100 g FW (red/green calyx)		Total phenolic content			Fragaria ×ananassa var. Amaou, entire plant (red fruit, green fruit, red calyx, green calyx, flower, leaf, stolon, stolon leaf, stem, crown and root)		^[21]
	Eth. or aq. room temperature extraction			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]
	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]
	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 × ananassa		Fruits, different cultivars
	Fragaria x ananassa cv. Albion, Aromas, Camarosa, Camino Real, Monte Rey, Portola, and San Andreas fruits			Ultrasonic extraction with acidified methanol		DPPH			IC			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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