Psidium cattleianum fruit extracts are efficient in vitro scavengers of
Transcription
Psidium cattleianum fruit extracts are efficient in vitro scavengers of
Food Chemistry 165 (2014) 140–148 Contents lists available at ScienceDirect Food Chemistry journal homepage: www.elsevier.com/locate/foodchem Psidium cattleianum fruit extracts are efficient in vitro scavengers of physiologically relevant reactive oxygen and nitrogen species Alessandra Braga Ribeiro a, Renan Campos Chisté b, Marisa Freitas b, Alex Fiori da Silva c, Jesuí Vergílio Visentainer a, Eduarda Fernandes b,⇑ a b c Center for Agricultural Sciences, PostGraduate Program of Food Science, State University of Maringá, 87020-900 Maringá, Paraná, Brazil REQUIMTE, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal PostGraduate Program of Health Sciences, State University of Maringá, 87020-900 Maringá, Paraná, Brazil a r t i c l e i n f o Article history: Received 14 February 2014 Received in revised form 31 March 2014 Accepted 14 May 2014 Available online 22 May 2014 Keywords: Strawberry guava Phenolic compounds Carotenoids LC–MS ROS RNS Antioxidant capacity a b s t r a c t Psidium cattleianum, an unexploited Brazilian native fruit, is considered a potential source of bioactive compounds. In the present study, the in vitro scavenging capacity of skin and pulp extracts from P. cattleianum fruits against reactive oxygen species (ROS) and reactive nitrogen species (RNS) was evaluated by in vitro screening assays. Additionally, the composition of phenolic compounds and carotenoids in both extracts was determined by LC–MS/MS. The major phenolic compounds identified and quantified (dry matter) in the skin and pulp extracts of P. cattleianum were ellagic acid (2213–3818 lg/g extracts), ellagic acid deoxyhexoside (1475–2070 lg/g extracts) and epicatechin gallate (885–1603 lg/g extracts); while all-trans-lutein (2–10 lg/g extracts), all-trans-antheraxanthin (1.6–9 lg/g extracts) and all-transb-carotene (4–6 lg/g extracts) were the major carotenoids identified in both extracts. P. cattleianum pulp extract showed higher scavenging capacity than skin extract for all tested ROS and RNS. Considering the potential beneficial effects to human health, P. cattleianum may be considered as a good source of natural antioxidants and may be useful for the food and phytopharmaceutical industry. Ó 2014 Elsevier Ltd. All rights reserved. 1. Introduction Psidium cattleianum Sabine, commonly known as strawberry guava or araçá vermelho (Brazilian name), is a tropical plant belonging to Myrtaceae family. This plant is native to the Atlantic coast of Brazil and its unexplored fruits possess high potential to be commercialised. P. cattleianum can easily adapt to a variety of climates and has been cultivated in many countries with tropical climates, such as Hawaii and many Caribbean islands (Biegelmeyer et al., 2011; Patel, 2012). The fruits from P. cattleianum have a firm and sweet-acidulous pulp, noted by an excellent strawberry-like flavour and it is described as being more aromatic than common guava, which belongs to the same botanical family (Mccook-Russell, Muraleedharan, Facey, & Bowen-Forbes, 2012). Additionally, P. cattleianum possess three to four times more ascorbic acid than ⇑ Corresponding author. Address: REQUIMTE, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal. Tel.: +351 220428675; fax: +351 226093483. E-mail address: [email protected] (E. Fernandes). http://dx.doi.org/10.1016/j.foodchem.2014.05.079 0308-8146/Ó 2014 Elsevier Ltd. All rights reserved. citrus fruits and possess potentially important biological properties, as the plant is extensively used in Brazilian traditional medicine to treat several diseases including painful disorders, diarrhoea, dental caries, diabetes and also as a prophylactic hepatoprotective agent (Alvarenga et al., 2013; Im et al., 2012; Menezes, Delbem, Brighenti, Okamoto, & Gaetti-Jardim, 2010). In this sense, P. cattleianum may be considered a plant with latent prospects in food and pharmaceutical industry for its potential application as functional food and phytotherapeutics (Patel, 2012), most probably due to the presence of bioactive compounds, such as phenolic compounds and carotenoids (Im et al., 2012; Medina et al., 2011). Phenolic compounds and carotenoids present in plant extracts are known to contribute for its scavenging capacity against reactive oxygen species (ROS) and reactive nitrogen species (RNS) (Almeida, Fernandes, Lima, Costa, & Bahia, 2008a; Chisté, Freitas, Mercadante, & Fernandes, 2012; Chisté et al., 2011), although this may vary extensively, according to their inherent antioxidant potency, the chemical interaction among each other, and the interaction with endogenous antioxidants. In vitro studies showed that P. cattleianum has higher antioxidant activity [as determined by ABTS [2,20 -azino-bis(3-ethylbenzothiazoline6-sulfonic acid)] and Ferric Reducing Antioxidant Power (FRAP) A.B. Ribeiro et al. / Food Chemistry 165 (2014) 140–148 assays] and also higher phenolic contents than many fruits (Luximon-Ramma, Bahorun, & Crozier, 2003). The antioxidant activity, antimicrobial and antiproliferative effects of aqueous and acetone extracts of P. cattleianum were previously correlated to the high levels of phenolic compounds in the extracts (Medina et al., 2011). Moreover, Im et al. (2012) showed that the extract of P. cattleianum leaves, which is rich in phenolic compounds, with major compound identified as quercetin-3-glucuronide, could reduce the proliferation of lung cancer cells and be used to control the metastatic process. Despite the potential beneficial effects of P. cattleianum, there are only few data about the antioxidant capacity of its extracts and these studies were mostly performed by using stable and non-physiological radicals, such as ABTS and DPPH (2,2-diphenyl1-picrylhydrazyl) (Luximon-Ramma et al., 2003; Mccook-Russell et al., 2012; Medina et al., 2011). To the best of our knowledge, data related to the scavenging capacity of P. cattleianum extracts against physiologically relevant ROS and RNS are not available in the literature. Additionally, its phenolic and carotenoid profiles, as determined by high performance liquid chromatography coupled to diode array detector and tandem mass spectrometry (HPLC-DAD–MS/MS), were not reported so far in the literature. Considering the above, this study aimed to identify and quantify the phenolic compounds and carotenoids of two extracts of P. cattleianum (skin and pulp) by HPLC-DAD–MS/MS, as well as to determine the scavenging capacity of these extracts against the most common ROS and RNS in biological systems: superoxide radical (O2), hydrogen peroxide (H2O2), hypochlorous acid (HOCl), singlet oxygen (1O2), nitric oxide (NO) and peroxynitrite (ONOO). 2. Materials and methods 2.1. Chemicals Dihydrorhodamine 123 (DHR), 4,5-diaminofluorescein (DAF-2), 30% hydrogen peroxide, sodium hypochlorite solution, with 4% available chlorine, 3-(aminopropyl)-1-hydroxy-3-isopropyl-2-oxo1-triazene (NOC-5), b-nicotinamide adenine dinucleotide (NADH), phenazine methosulphate (PMS), nitroblue tetrazolium chloride (NBT), lucigenin, quercetin, gallic acid, L-ascorbic acid, catechin, chlorogenic acid, epicatechin, p-coumaric acid, ellagic acid, ferulic acid, myricetin, quercetin, kaempferol, all-trans-lutein, alltrans-zeaxanthin, all-trans-b-cryptoxanthin, all-trans-b-carotene, methanol, methyl tert-butyl ether (MTBE), acetonitrile and all other chemical salts and solvents of analytical grade were obtained from Sigma–Aldrich (St. Louis, USA). Ultrapure water was obtained from the ariumÒ pro system (Sartorius, Germany). All phenolic compounds and carotenoids standards showed at least 95% of purity, as determined by HPLC-DAD. 2.2. P. cattleianum samples and extract preparation The fruits of P. cattleianum Sabine (5 kg) were collected from a farm (Sítio Frutas Raras) located in Monte Alegre city, São Paulo State, Brazil (23°350 3100 S and 48°380 3800 W). The fresh and ripe fruits were washed with distilled water; the pulp and skin were manually separated and ground. Approximately 10 g of the pulp or skin was weighed and absolute ethanol was added in mass:solvent ratio of 1:10 (w/v) and the extraction was performed under magnetic stirring, for 4 h, at room temperature (25 °C), and protected against luminosity. The mixture was filtered and the solvent was evaporated under reduced pressure at 40 °C. The concentrated material was stored under light-free conditions at 20 °C prior to analysis. 141 2.3. HPLC-DAD–MS/MS analysis of phenolic compounds and carotenoids HPLC-DAD analysis of phenolic compounds and carotenoids was performed in an Accela LC system (Thermo Fisher Scientific, San Jose, CA) equipped with quaternary pumps (Accela 600), a DAD detector and an auto-sampler cooled to 5 °C. The equipment was also connected in series to a LTQ Obritrap™ XL mass spectrometer (Thermo Fisher Scientific, San Jose, CA) with electrospray ionisation source (ESI), and a hybrid system combining a linear ion-trap and the Orbitrap mass analyzer. For chromatographic analysis, samples and solvents were filtered using, respectively, membranes of 0.22 lm (OlimPeak, TeknokromaÒ, Spain) and 0.45 lm (Billerica, MA, USA). The contents of carotenoids and phenolic compounds determined by HPLC-DAD, were expressed as lg/g of extract (dry matter), considering three independent extraction procedures (n = 3). 2.3.1. Phenolic compounds The phenolic compounds of both extracts of skin and pulp from P. cattleianum fruit were analysed after solubilising 10 mg of each extract in 500 lL of methanol/water (8:2, v/v) and filtered using membranes of 0.22 lm. Both identification and quantification of phenolic compounds by HPLC-DAD–ESI-MS/MS were carried out on a C18 Synergi Hydro column (4 lm, 250 4.6 mm, Phenomenex) at 0.9 mL/min, column temperature at 29 °C, with a mobile phase in a linear gradient of water/formic acid (99.5:0.5, v/v) and acetonitrile/formic acid (99.5:0.5, v/v) (Chisté & Mercadante, 2012). The mass spectra were acquired with a scan range from m/z 100 to 1000; the MS parameters were set as follows: ESI source in negative ion mode; the capillary temperature was 275 °C and the capillary voltage of was set at 2.5 kV. The sheath gas and the auxiliary gas flow rate were set to 40 and 10, respectively, (arbitrary unit as provided by the software settings) and normalised collision energy for MS/MS experiments of 35%. The phenolic compounds were tentatively identified based on the following information: elution order, retention time of peaks, and UV–Visible and mass spectra features as compared to authentic standards (data not shown) analysed under the same conditions and data available in the literature (Chisté & Mercadante, 2012; Gordon, Jungfer, Silva, Maia, & Marx, 2011; Ho et al., 2012; Im et al., 2012; Santos, Vilela, Freire, Neto, & Silvestre, 2013). The phenolic compounds were quantified by comparison to external standards using seven-point analytical curves (in duplicate) for gallic acid, chlorogenic acid, quercetin (0.5–49.5 lg/mL) and ellagic acid (0.5–33 lg/mL). 2.3.2. Carotenoids The carotenoids of both extracts of skin and pulp from P. cattleianum fruit were extracted according to an adaptation of the procedure described by Chisté et al. (2012) for carotenoids from extracts of Caryocar villosum fruit. Briefly, 15 mg of each extract were solubilised in 500 lL of methanol and directed to liquid–liquid partition in a separation funnel with petroleum ether/diethyl ether (1:2, v/v) and washed with distilled water. After partition, the carotenoid extract was saponified overnight with 10% KOH in methanol (1:0.5, v/v), re-partitioned, evaporated under N2 flow, re-dissolved in methanol/MTBE (70:30, v/v) and injected into the chromatographic system. The carotenoids were separated on a C30 YMC column (5 lm, 250 mm 4.6 mm) using as mobile phase a linear gradient of methanol/MTBE, with flow rate of 0.9 mL/min and the column temperature set at 29 °C (Chisté & Mercadante, 2012). The MS parameters were set as follows: ESI source in positive ion mode; the capillary temperature was 350 °C and the capillary voltage of was set at 3.1 kV. The sheath gas and the auxiliary gas flow rate were set to 40 and 10, respectively, (arbitrary unit as provided by the software settings) and 142 A.B. Ribeiro et al. / Food Chemistry 165 (2014) 140–148 normalised collision energy for MS/MS experiments of 35%. The carotenoids were tentatively identified according to the following combined information: elution order on C30 column, co-chromatography with authentic standards, and UV–Vis spectrum [(kmax, spectral fine structure (%III/II), peak cis intensity (%AB/AII)] compared with data available in the literature (Britton, Liaaen-Jensen, & Pfander, 2004; Chisté & Mercadante, 2012; Rodrigues, Mariutti, & Mercadante, 2013). The carotenoids were quantified by HPLC-DAD, using external seven-point analytical curves (in duplicate) all-trans-lutein, all-trans-zeaxanthin, alltrans-b-cryptoxanthin and all-trans-b-carotene (0.4–30 lg/mL). All other carotenoids (including epoxy and cis isomers) were estimated using the curve of its all-trans-carotenoid. The NAS-IOM (2001) conversion factor was used to calculate the vitamin A value, with 12 lg of dietary all-trans-b-carotene or 24 lg of all-trans-bcryptoxanthin corresponding to 1 lg of retinol activity equivalent (RAE), and the activity used was 100% for all-trans-b-carotene and 50% for all-trans-b-cryptoxanthin. 2.4. ROS- and RNS-scavenging assays All ROS- and RNS-scavenging assays were performed using a microplate reader (Synergy HT, Biotek, Vermont, USA), for fluorescence, UV/Vis and chemiluminescence measurements, equipped with a thermostat. Pulp and skin extracts of P. cattleianum fruit were dissolved in DMSO for all ROS- and RNS-scavenging assays, except for the extracts in the HOCl assay (dissolved in ethanol). The standards, quercetin, gallic acid and ascorbic acid, were dissolved in ethanol (0.03 lg/mL to 2000 mg/mL). Each IC50 value (inhibitory concentration, in vitro, to decrease in 50% the amount of reactive species in the tested media) corresponds to four experiments using five to seven concentrations in duplicate, calculated from the curves of percentage of inhibition versus antioxidant concentration, using the GraphPad Prism 5 software, and the comparison graphs were plotted using OriginPro 8 software. Quercetin, gallic acid and ascorbic acid were used as positive controls in the scavenging assays of 1O2, HOCl, H2O2, O and its 2 , NO, ONOO values were similar to those previously reported by others authors (Chisté et al., 2012; Gomes et al., 2007). To ensure the results are not flawed by any interference of solvents or fluorescence/ chemiluminescence/absorbance response of extracts, additional experiments were performed using P. cattleianum extracts and the tested standard compounds (data not shown). 2.4.1. Singlet oxygen-scavenging assay The 1O2-scavenging capacity was measured by monitoring the oxidation of the non-fluorescent DHR to the fluorescent rhodamine 123 by the reaction with 1O2, generated by thermal decomposition (37 °C) of a previously synthesised water-soluble endoperoxide (disodium 3,30 -(1,4-naphthalene) bispropionate, NDPO2) (Costa et al., 2007). The results were expressed in percentage as the inhibition of 1O2-induced oxidation of DHR. 2.4.2. Hypochlorous acid-scavenging assay The HOCl-scavenging capacity was measured as previously described by Rezk, Haenen, van der Vijgh, and Bast (2004) adapted to a microplate reader (Gomes et al., 2007). The assay verifies the effect of the extracts and standards on HOCl-induced oxidation of DHR to rhodamine 123. HOCl was prepared by adjusting the pH of a 1% (w/v) solution of NaOCl to 6.2 with dropwise addition of 10% (v/v) H2SO4. The concentration of HOCl was further determined spectrophotometrically at 235 nm, using the molar absorption coefficient of 100 M1 cm1. The results were expressed, in percentage, as inhibition of HOCl-induced oxidation of DHR. 2.4.3. Hydrogen peroxide-scavenging assay The H2O2 scavenging activity was measured using a chemiluminescence methodology, by monitoring the effect of the extracts and standards on the H2O2-induced oxidation of lucigenin (Chisté et al., 2011). The results were expressed as the inhibition, in percentage, of the H2O2-induced oxidation of lucigenin. 2.4.4. Superoxide radical-scavenging assay The O 2 was generated by a non-enzymatic system NADH/PMS/ O2 and this radical reduces NBT into a purple coloured formazan (Gomes et al., 2007). The O 2 scavenging capacity was determined spectrophotometrically, by monitoring the effect of the extracts and standards on the O 2 -induced reduction of NBT at 560 nm, after 2 min. The effects were expressed as the inhibition, in percentage, of the NBT reduction to formazan. 2.4.5. Nitric oxide-scavenging assay The NO-scavenging capacity was measured by monitoring the effect of the extracts and standards on NO-induced oxidation of non-fluorescent DAF-2 to the fluorescent triazolofluorescein (DAF-2T) (Almeida, Fernandes, Lima, Costa, & Bahia, 2008b). NO was generated by decomposition of NOC-5. The results were expressed as the percentage of inhibition of NO-induced oxidation of DAF-2. 2.4.6. Peroxynitrite-scavenging assay The ONOO-scavenging capacity was measured by monitoring the effect of the extracts and standards on ONOO-induced oxidation of non-fluorescent DHR to the fluorescent rhodamine 123 (Almeida et al., 2008a). In a parallel set of experiments, the assays were performed in the presence of 25 mM NaHCO3, in order to simulate the physiological CO2 concentrations. The results were expressed, in percentage, as the inhibition of ONOO induced oxidation of DHR. 3. Results and discussion 3.1. Phenolic compounds and carotenoids in the extracts of P. cattleianum fruit Ethanol was the chosen solvent for obtaining extracts of skin and pulp from P. cattleianum fruits, this solvent is favourably chosen to extract bioactive compounds, such as phenolic compounds and carotenoids from fruit matrix. Moreover, after comparing the most frequent solvents used for antioxidant activity research (ethanol, water and methanol), the water has a disadvantage over ethanol, hence it needs a freeze drying step after extraction and methanol has its use limited by the highest toxicity (Alam, Bristi, & Rafiquzzaman, 2013). Some data are available concerning the identification of phenolic compounds from Psidium guineense (Gordon et al., 2011), another fruit from the same family (Myrtaceae) and from the same genus (Psidium). It is also possible to find two studies in the literature related to the identification, by nuclear magnetic resonance (NMR), of seven flavonoids isolated from leaves of P. cattleianum (Ho et al., 2012) or by LC–MS (Im et al., 2012). In addition, six phenolic compounds from extracts of P. cattleianum pulp were identified based only on the retention time (LC with UV detector) (Medina et al., 2011). In relation to the carotenoid composition, only one study was found that reported the carotenoids profile to the same fruit, in which the identification was based on the UV–Vis spectra and retention times (Pereira et al., 2012). Another study reported the conclusive identification of 16 carotenoids isolated from the flesh of Brazilian red guavas (Psidium guajava L.) and their structures were established by means of UV–Vis, 143 A.B. Ribeiro et al. / Food Chemistry 165 (2014) 140–148 NMR, mass and circular dichroism spectra (Mercadante, Steck, & Pfander, 1999). The applied HPLC-DAD–ESI-MS/MS method allowed the separation, quantification and tentative identification of 21 phenolic compounds (Fig. 1) and 7 carotenoids (Fig. 2). For phenolic compounds, ESI in the negative ion mode and the hybrid m/z analyzer (linear ion-trap with Orbitrap) provided a very sensitive, selective method and produced by far the most characteristic data for the identification of each compound in these extracts. On the other hand, although ESI in positive ion mode have been used to carry out the tentative identification of carotenoids (Crupi, Milella, & Antonacci, 2010; Pop et al., 2014), in our study the ionisation was not able to allow the observation of protonated molecule ([M+H]+) nor the sodiated molecular ion [M+Na]+. However, since only seven peaks of carotenoids were observed after HPLC-DAD analysis, and most of these compounds presented the same chromatographic behaviour and UV–Vis spectra of the authentic standards, the tentative identification was performed only based on the elution order on C30 column, co-chromatography with authentic standards and UV–Vis spectrum characteristics [(kmax, spectral fine structure (%III/II) and peak cis intensity (%AB/AII)]. Phenolic compounds, in nature, generally occur as conjugates of sugars, especially in the form of O-glycosides, although in the present study, the identification of the sugar moiety was not be determined by the applied methodology, for simplification. According to Table 1, peak 1 was assigned as chlorogenic acid hexoside with m/z at 515 [MH], and the loss of a hexose moiety (162 u) exhibited the chlorogenic acid (caffeoylquinic acid) molecule (m/z 353). Peak 2 presented deprotonated molecule at m/z 647 and three consecutive losses of galloyl moieties (152 u) (m/z 495, 343, 191). Peaks 3, 6, 11 and 20 were positively identified as gallic acid, chlorogenic acid, ellagic acid and quercetin, on the basis of coelution and comparison of UV–Vis and mass spectra with authentic standards. Peaks 4 and 5 were assigned as two ellagitannins-like compounds, in which the MS/MS fragments match with those already reported to P. guineense fruits (Gordon et al., 2011). Peaks 7, 8, 9, 16, 17 and 19 were tentatively identified ellagic acid derivatives since MS/MS analysis indicated that cleavage of the glycosidic linkage with concomitant H rearrangement leads to elimination of the sugar residue as neutral losses: 162 u (hexose), 132 u (pentose) and 146 u (deoxyhexose) (Chisté & Mercadante, 2012). Peak 10 presented deprotonated molecule at m/z 441 and was tentatively identified as epicatechin gallate with MS/MS 50 1 2 Absorbance at 450 nm (mAU) 25 6 5 4 3 7 0 skin 50 25 2 1 3 6 5 4 7 0 1000 pulp Lut Zea 500 β-Cry β-Car standards 0 5 10 15 20 25 30 35 40 45 50 Time (min) Fig. 2. Chromatogram of carotenoids from extracts of Psidium cattleianum fruit (skin and pulp) and authentic standard of all-trans-lutein (Lut), all-trans-zeaxanthin (Zea), all-trans-b-cryptoxanthin (b-Cry) and all-trans-b-carotene (b-Car), obtained by HPLC-DAD. Chromatographic conditions: see text. Peak characterization is given in Table 2. fragment at m/z 289 (epicatechin) after losing a galloyl group ([MH152]). Peaks 12, 13, 14, 15 and 21 were assigned as quercetin derivatives due to the neutral losses of a glucuronide moiety (176 u, peak 12), hexose (162 u, peak 13), pentose (132 u, peak 14), deoxyhexose (146 u, peak 15), coumaroyl deoxyhexose (292 u, peak 21) and after noticing the same fragmentation pattern given by quercetin (peak 20), which was positively confirmed with authentic standard. The identification of quercetin 3-glucuronide was already carried out in a butanol fraction of P. cattleianum leaf extract by HPLC–ESI-MS/MS (Im et al., 2012), which reinforces the identification of this compound in our study. Finally, peak 18 was tentatively identified as cinnamoyl–galloyl hexoside with deprotonated molecule at m/z 461 [MH] and MS/MS fragments at m/z 313 (loss of a cinnamoyl moiety) and m/z 169 ([gallic acidH]), which MS pattern matches with those previously described in the literature (Santos et al., 2013). Therefore, the major phenolic compounds identified in both extracts were ellagic acid (varying from 2213 to 3818 lg/g extract), ellagic acid deoxyhexoside (from 1475 to 2070 lg/g extract) and epicatechin gallate (from 885 to 1603 lg/g extract) and the total 9 11 800 13 Absorbance at 280 nm (mAU) 12 10 15 400 21 14 16 1 2 3 4 5 6 7 8 18 19 17 20 skin 0 5 10 15 20 25 30 1400 35 40 45 50 11 9 12 700 13 15 10 3 1 4 5 7 6 8 14 16 2 18 17 19 20 21 pulp 0 5 10 15 20 25 30 35 40 45 50 Time (min) Fig. 1. Chromatogram of phenolic compounds from extracts of Psidium cattleianum fruit (skin and pulp), obtained by HPLC-DAD. Chromatographic conditions: see text. Peak characterisation is given in Table 1. 144 A.B. Ribeiro et al. / Food Chemistry 165 (2014) 140–148 Table 1 Chromatographic and spectroscopic characteristics of phenolic compounds from extracts of Psidium cattleianum fruit (skin and pulp). Peaks tR range (min)a kmax (nm)b MS/MS () (m/z)c [MH](m/z) Concentration (lg/g extract)d Compound Skin 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 7.0–7.1 8.8–9.0 10.4–10.7 14.5–14.7 16.4–16.6 18.5–18.9 21.9–22.1 24.9–25.8 25.7–25.9 26.5–26.6 27.3–27.5 27.9–28.0 28.1–28.3 29.1–29.2 29.8–30.0 30.7–30.8 32.9–33.1 34.9–35.1 35.9–36.1 38.5–38.6 40.2–40.4 264, 300 (sh) 270 272 280 272 283 (sh), 325 345 (sh), 361 300, 345 (sh), 300, 345 (sh), 280 300, 350 (sh), 280, 343 280, 352 271, 349 265 (sh), 300, 300, 350 (sh), 300, 350 (sh), 280 270 (sh), 352, 300 (sh), 371 276, 338, 363 361 361 368 346 365 363 366 515.1242 647.1880 169.0141 933.0624 783.0679 353.0869 463.0504 433.0399 447.0558 441.0818 301.9982 477.0920 463.0870 433.0766 447.0925 461.1074 461.1078 461.0716 503.0821 301.0344 593.2468 353, 495, 125 783, 481, 335, 301, 301, 301, 331, 283, 301, 301, 301, 301, 315, 315, 401, 443, 273, 447, Chlorogenic acid hexoside1 29 ± 15 Trigalloylquinic acid2 9±2 2 Gallic acid 464 ± 155 2 675, 631, 451, 301, 273 Ellagitannin-like 77 ± 27 301, 275 Di-HHDP-hexoside2 222 ± 64 263, 245, 233, 205, 191 Chlorogenic acid1 69 ± 42 273, 257, 198 Ellagic acid hexoside3 136 ± 5 283, 257, 195, 143 Ellagic acid pentoside3 164 ± 4 283, 257, 245 Ellagic acid deoxyhexoside3 1475 ± 138 2 315, 289, 169 Epicatechin gallate 885 ± 26 273, 257, 229, 185 Ellagic acid3 2213 ± 101 20 ± 9 273, 257, 179, 151 Quercetin glucuronide4 273, 257, 179, 151 Quercetin hexoside4 17.5 ± 0.5 273, 257, 179, 151 Quercetin pentoside4 39 ± 13 273, 257, 179, 151 Quercetin deoxyhexoside4 53 ± 14 3 300, 283, 269 Methyl ellagic acid deoxyhexoside 475 ± 23 3 300, 235, 169 Methyl ellagic acid deoxyhexoside 34 ± 2 573 ± 17 313, 211, 169, 151 Cinnamoyl–galloyl hexoside2 315, 300, 283 Methyl ellagic acid acetyl-deoxyhexoside3 10 ± 1 257, 179, 151 Quercetin4 115 ± 2 301, 273, 257, 193 Quercetin coumaroyl deoxyhexoside4 15 ± 1 Total phenolic (lg/g extract) 7098 ± 280 191, 173, 111 475, 343, 191 Pulp 26 ± 14 85 ± 5 1510 ± 37 1022 ± 13 150 ± 66 121 ± 8 346 ± 15 412 ± 19 2070 ± 216 1603 ± 37 3818 ± 94 18 ± 7 11.4 ± 0.3 27 ± 1 11.2 ± 0.5 646 ± 38 20 ± 1 880 ± 115 2±1 32 ± 5 8.5 ± 0.5 12821 ± 540 a Retention time on the C18 Synergi Hydro (4 lm) column. Solvent: gradient of water/formic acid (99.5:0.5, v/v) and acetonitrile/formic acid (99.5:0.5, v/v). c In the MS/MS, the most abundant ion is shown in boldface. d Mean ± standard deviation (n = 3, dry matter). HHDP = Hexahydroxydiphenoyl. The peaks were quantified as equivalent of chlorogenic acid1, gallic acid2, ellagic acid3 and quercetin4. b phenolic contents found in the pulp extract were almost 2-fold higher than that found in skin extract. The major phenolic compounds identified and quantified (HPLC-DAD) by Medina et al. (2011) in water and acetone extracts of 6 different genotypes of P. cattleianum Sabine were ()-epicatechin and gallic acid in a similar concentration range reported in this study for epicatechin gallate and gallic acid. Although these fruits are from the same species that we evaluated in this work, the difference in phenolic composition is not surprising, since the extraction procedure was not the same and the identification carried out by Medina et al. (2011) was based only on the retention time and UV–Vis spectra in comparison with standards. Considering the total phenolic contents found in our study, both extracts from skin and pulp presented higher values than freeze-dried extracts of C. villosum fruit pulp obtained with water (1745 lg/g) or ethanol/water (5163 lg/g) (Chisté et al., 2012) and methanol/water extract of Solanum sessiliflorum fruit (1718 lg/g) (Rodrigues et al., 2013). In relation to the carotenoids composition of P. cattleianum extracts (Table 2), peaks 2, 3, 5 and 6 were tentatively identified as all-trans-lutein, all-trans-zeaxanthin, all-trans-b-cryptoxanthin and all-trans-b-carotene, respectively, after positive confirmation with authentic standards. These compounds were previously reported in the literature for P. cattleianum Sabine fruit (Pereira et al., 2012). Peaks 1, 4 and 7 were tentatively identified as alltrans-antheraxanthin, 5,6-epoxy-b-cryptoxanthin and 9-cis-b-carotene, respectively, due to the comparison with the same kmax, spectral fine structure and retention time reported to these compounds at identical HPLC-DAD conditions (Chisté & Mercadante, 2012; Faria et al., 2009; Rodrigues et al., 2013). Peak 4 was assigned as 5,6-epoxy-b-cryptoxanthin due to 6 nm hypsochromic shift compared to the kmax of b-cryptoxanthin, indicating the presence of one epoxide group at 5,6 position (Britton et al., 2004; Faria et al., 2009). The 9-cis isomer of b-carotene (peak 7) was identified considering that the spectral fine structure (%III/II) decreases and intensity of the cis-peak (%AB/AII) increases as the cis-double bond is getting closer to the centre of the molecule (Faria et al., 2009). Therefore, the major carotenoids identified in both P. cattleianum extracts were all-trans-lutein, followed by all-trans-antheraxanthin Table 2 Chromatographic, UV–Vis characteristics (HPLC-DAD) and contents of carotenoids from Psidium cattleianum extracts. Peak tR range (min)a Carotenoid 1 1 All-trans-antheraxanthin 2 All-trans-lutein1 3 All-trans-zeaxanthin2 4 5,6-Epoxy-b-cryptoxanthin3 5 All-trans-b-cryptoxanthin3 6 All-trans-b-carotene4 7 9-cis-b-carotene4 Total carotenoids (lg/g) Vitamin A value (lg RAE/g extract) a 10.2–10.6 12.1–12.3 14.3–14.6 17.5–17.8 22.4–22.9 32.3–32.6 34.1–34.5 kmax (nm)b 420, 420, 425, 420, 420, 425, 331, 445, 445, 450, 445, 451, 451, 420, 472 471 476 471 476 477 446, 472 %III/II 61 61 25 58 25 25 20 %AB/AII 0 0 0 0 0 0 9 Concentration (lg/g extract)c Skin Pulp 9±1 10 ± 3 <LOQ 7±1 6 ± 0.7 5.9 ± 0.3 3.9 ± 0.3 42 ± 5 1.19 1.6 ± 0.1 1.9 ± 0.1 <LOQ 2.4 ± 0.4 3.4 ± 0.2 3.7 ± 0.5 0.95 ± 0.01 14 ± 1 0.58 Retention time on the C30 column. Linear gradient of methanol/MTBE. c Mean ± standard deviation (n = 3, dry matter). The peaks were quantified as equivalent to lutein1, zeaxanthin2, b-cryptoxanthin3 and b-carotene4. RAE = retinol activity equivalent. <LOQ, value lower than the limit of quantification. b 145 A.B. Ribeiro et al. / Food Chemistry 165 (2014) 140–148 and all-trans-b-carotene; and the total carotenoid contents were 3 times higher in skin (42 lg/g) than in pulp extracts (12 lg/g) (Table 2). The values found for the pulp extracts were similar to that reported to another Brazilian fruits (Chisté & Mercadante, 2012; Rodrigues et al., 2013). Regarding vitamin A activity, both extracts presented values lower than those reported for Amazonian fruits (3.44–36.4 lg RAE/g pulp), which are known good pro-vitamin A sources (De Rosso & Mercadante, 2007). Thus, the extracts of P. cattleianum fruits obtained in this study should not be considered as a good pro-vitamin A sources. 3.2. Scavenging of ROS and RNS by P. cattleianum extracts The endogenous formation of ROS and RNS is involved in important physiological roles, namely during the inflammatory response and to defend the organism against a microbe invasion (Costa et al., 2007). However, in the event of a sustained overproduction of prooxidant reactive species, a redox unbalance is generated, which can lead to cell and/or tissue damage. Additionally, ROS and RNS may rapidly be interconverted. For example, O2 may be converted to O 2 by several enzymatic and chemical systems, which is then converted into H2O2, both spontaneously and catalysed by superoxide dismutases. H2O2 may then be converted into hydroxyl radicals (OH) by the Fenton or Haber–Weiss reactions and these free radicals may react with Cl to produce hypochlorite or HOCl (Cannizzo, Clementa, Sahua, Follo, & Santambrogio, 2011). The lethal consequence of NO increases significantly upon reaction with O 2 resulting in the formation of ONOO, a highly reactive specie with reactivity similar to OH. This reactive specie leads to serious toxic reactions with biomolecules; thus, the production of NO may be tightly regulated to minimise the damage (Luo, Sun, Mao, Lu, & Tan 2004; Matsuda et al., 2000). The pulp and skin extracts of P. cattleianum showed a notable capacity to scavenge all the tested ROS and RNS in a concentration-dependent manner, and all IC50 values were found at a low lg/mL range (Table 3), with special emphasis for the low concentration required for scavenging NO. In all cases, the pulp extract of P. cattleianum showed higher scavenging capacity against all tested ROS and RNS than skin extract (Fig. 3), probably due to the highest content of phenolic compounds (Table 1) found in the extract obtained from the pulp fruit. Data are noteworthy, since pulp is the most important edible part of this fruit. The content of phenolic compounds in skin and pulp extracts were, respectively, about 170 and 916 times higher than the content of total carotenoids, indicating a close relation between the scavenging capacity of P. cattleianum extracts and their phenolic compounds content. Ellagic acid, the major phenolic compound identified in both extracts, has been shown to elicit interesting biological properties such as anti-proliferative, and antimicrobial activity. Additionally, this compound is able to induce apoptosis of some carcinogenic cells (Puupponen-Pimia et al., 2005; Whitley, Stoner, Darby, & Walle, 2003). The pulp extract presented high efficiency in quenching 1O2 with IC50 values being lower than that of lipoic acid (46.15 lg/mL), an essential cofactor for mitochondrial enzymes and a naturally occurring antioxidant (Hazra, Sarkar, Biswas, & Mandal, 2010). Furthermore, the skin extract of P. cattleianum showed lower activity than aqueous extracts of C. villosum fruit pulp (156 lg/mL) (Chisté et al., 2012), Terminalia chebula, Terminalia belerica and Emblica officinalis fruit extracts (IC50 from 233.12 to 490.42 lg/mL) (Hazra et al., 2010). Fig. 3 shows the behaviour related to HOCl scavenging activity of pulp and peel of P. cattleianum extracts. For this reactive specie, the pulp extract exhibited an IC50 similar to that obtained for S. sessiliflorum, an Amazonian fruit (13 lg/mL), and higher efficiency activity than trolox (134 lg/mL) and 5-caffeoylquinic acid (56 lg/mL), the major compound of S. sessiliflorum, possibly responsible for its excellent scavenging capacity against ROS (Rodrigues et al., 2013). H2O2 scavenging activities of both extract of P. cattleianum were higher than quercetin and lower than gallic acid and ascorbic acid (Table 1), and the scavenging capacity found for the pulp extract was higher than that found for the skin. In addition, the H2O2 scavenging capacity of P. cattleianum pulp extract was superior to that described for leaf extracts of Castanea sativa (410 lg/mL) (Almeida et al., 2008a). Regarding to O 2 scavenging capacity of both extracts, they inhibited the formation of formazan in a concentration-dependent manner (Fig. 3) and the pulp extract showed lower IC50 value (20.6 ± 0.6 lg/mL) than quercetin (14 ± 1 lg/mL); however, similarly to the most effective extract of Monotheca buxifolia fruit (22.3 lg/mL) and ascorbic acid (21.1 lg/mL) (Jan, Khan, Rashid, & Bokhari, 2013). The IC50 value found for skin extract of P. cattleianum (84 ± 2 lg/mL) was lower than the IC50 value previously found for extracts of Cynodon dactylon (IC50 = 430.06 lg/mL), a plant traditionally used to heal several disorders (Jananie, Priya, & Vijayalakshmi, 2011). The ability of P. cattleianum extracts and standards to scavenge NO is shown in Table 3. The skin extract showed to be three times less effective than pulp, even though, both parts can be considered as good scavengers compared with previous results reported by Hazra et al. (2010) for curcumin (90.82 lg/mL) and fruits used in traditional Indian medicine (maximum activity of 33.28 lg/mL) (Hazra et al., 2010). Table 3 Scavenging activities of extracts of skin and pulp from Psidium cattleianum for superoxide radical (O2), hydrogen peroxide (H2O2), hypochlorous acid (HOCl), nitric oxide (NO), peroxynitrite (ONOO) and singlet oxygen (1O2). IC50 (lg/mL) (n = 4) Reactive species P. cattleianum extracts Positive controls Skin Pulp Gallic acid Quercetin Ascorbic acid ROS 1 O2 HOCl H2O2 O 2 83 ± 1 32 ± 1 431 ± 2 84 ± 2 22.8 ± 0.3 18.7 ± 0.6 378 ± 2 20.6 ± 0.6 1.6 ± 0.1 1.1 ± 0.1 214.8 ± 0.1 3.9 ± 0.1 1.20 ± 0.03 0.12 ± 0.02 526.35 ± 0.04 14 ± 1 5.6 ± 0.4 0.5 ± 0.1 116.50 ± 0.05 NA RNS NO ONOO8 ONOO⁄ 6.8 ± 0.2 12.1 ± 0.3 55 ± 1 2.2 ± 0.1 5.6 ± 0.1 26 ± 1 0.1 ± 0.01 0.10 ± 0.06 0.10 ± 0.06 0.27 ± 0.02 0.78 ± 0.05 1.7 ± 0.1 0.20 ± 0.03 0.15 ± 0.09 0.16 ± 0.07 IC50 = inhibitory concentration, in vitro, to decrease in 50% the amount of reactive species in the tested media (mean ± standard error). NA = IC50 no activity was found up to the highest tested concentration (1 mg/mL). * In the presence of 25 mM NaHCO3. 146 A.B. Ribeiro et al. / Food Chemistry 165 (2014) 140–148 75 50 25 Skin Pulp (a) 0 0 50 100 150 200 H2 O2 scavenging capacity (%) 100 1 O2 scavenging capacity (%) 100 75 50 25 Skin Pulp 0 Psidium cattleianum extract concentration ( μg/mL) 500 1000 1500 2000 Psidium cattleianum extract concentration ( μg/mL) 100 80 60 40 20 (c) 0 0 60 120 75 50 25 Skin Pulp .- Skin Pulp O2 scavenging capacity (%) 100 HOCl scavenging capacity (%) (b) 0 250 (d) 0 0 180 60 120 180 Psidium cattleianum extract concentration (μg/mL) Psidium cattleianum extract concentration (μg/mL) .NO scavenging capacity (%) 100 75 50 25 Skin Pulp (e) 0 0 10 20 30 100 100 ONOO- scavenging capacity (%) ONOO- scavenging capacity (%) with2Na HCO3 Psidium cattleianum extract concentration ( μg/mL) 75 50 25 Skin Pulp 0 0 30 (f) 60 90 Psidium cattleianum extract concentration (μg/mL) 75 50 25 Skin Pulp (g) 0 0 60 120 180 Psidium cattleianum extract concentration ( μg/mL) Fig. 3. Scavenging capacity of skin and pulp extracts of P. cattleianum against (a) singlet oxygen (1O2), (b) hydrogen peroxide (H2O2), (c) hypochlorous acid (HOCl), (d) superoxide radical (O2), (e) nitric oxide (NO) and (f, g) peroxynitrite (ONOO) in the absence and presence of NaHCO3. Each point shows the standard error bars and represents the values obtained from four experiments, performed in duplicate, in five to seven concentrations. In relation to ONOO-scavenging capacity, both extracts of P. cattleianum exhibited a reduction in its scavenging efficiency (almost 5 times) when this assay was carried out in the presence of 25 mM NaHCO3 (Fig. 3), which is a disadvantage, since under physiological conditions the reaction between ONOO and CO2 is predominant, with a very fast rate constant (k = 3–5.8 104 M1 s1) (Whiteman, Ketsawatsakul, & Halliwell, 2002). However, gallic acid and quercetin presented very low IC50 values, both in the absence A.B. Ribeiro et al. / Food Chemistry 165 (2014) 140–148 or presence of NaHCO3 and a slight increase of IC50 was observed for ascorbic acid in the presence of NaHCO3, as also described by Almeida et al. (2008a). 4. Conclusion The skin and pulp extracts of P. cattleianum showed to be potent scavengers of ROS and RNS, though more effectively of the latter, especially NO. Furthermore, the pulp presented to be a potent scavenger of O2, HOCl and 1O2, which may associated to the high content of phenolic compounds, especially ellagic acid and epicatechin, well described as potent antioxidants. Noteworthy, this is the first time that the composition of phenolic compounds in P. cattleianum extracts (skin and pulp) was reported. Furthermore, not only the major phenolic compounds were determined by HPLC–ESI-MS/MS, but more than 15 minor phenolic compounds were also identified. Thus, P. cattleianum may be considered as a promising source of bioactive compounds with efficient antioxidant properties and great prospect to commercial growers for the application in the food and phytopharmaceutical industry. Acknowledgements Alessandra Braga Ribeiro acknowledges CAPES Foundation (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior), Ministry of Education of Brazil, the financial support for the PDSE grant. This work received financial support from the European Union (FEDER funds through COMPETE) and National Funds (FCT, Fundação para a Ciência e Tecnologia, Portugal) through project Pest-C/EQB/LA0006/2013. The work also received financial support from the European Union (FEDER funds) under the framework of QREN through Project NORTE-07-0124-FEDER-000066. Marisa Freitas acknowledges FCT the financial support for the Post-doc grant (SFRH/BPD/76909/2011) in the ambit of ‘‘POPH-QREN – Tipologia 4.1-Formação Avançada’’ co-sponsored by FSE and national funds of MCTES. The authors also thank the Mr. Helton J.T. Muniz, Sítio Frutas Raras/Campina do Monte Alegre-SP for providing P. cattleianum fruits. References Alam, M. N., Bristi, N. J., & Rafiquzzaman, M. (2013). Review on in vivo and in vitro methods evaluation of antioxidant activity. Saudi Pharmaceutical Journal, 21, 143–152. Almeida, I. F., Fernandes, E., Lima, J. L. F. C., Costa, P. C., & Bahia, M. F. (2008a). Walnut (Juglans regia) leaf extracts are strong scavengers of pro-oxidant reactive species. Food Chemistry, 106, 1014–1020. Almeida, I. F., Fernandes, E., Lima, J. L. F. C., Costa, P. C., & Bahia, M. F. (2008b). Protective effect of Castanea sativa and Quercus robur leaf extracts against oxygen and nitrogen reactive species. 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