Extraction of essential oils of Ferulago angulata with microwave-assisted hydrodistillation

Industrial Crops & Products 137 (2019) 43–51

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Extraction of essential oils of Ferulago angulata with microwave-assisted hydrodistillation

T

⁎

Saeed Mollaeia, , Farzaneh Sedighia, Biuck Habibib, Saeid Hazratic, Parina Asghariand a

Phytochemical laboratory, Department of Chemistry, Faculty of Sciences, Azarbaijan Shahid Madani University, Tabriz, Iran Department of Chemistry, Faculty of Sciences, Azarbaijan Shahid Madani University, Tabriz, Iran c Department of Agronomy, Faculty of Agriculture, Azarbaijan Shahid Madani University, Tabriz, Iran d Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran b

A R T I C LE I N FO

A B S T R A C T

Keywords: Antioxidant Cytotoxic Ferulago angulate MAHD RSM

Ferulago angulata (Apiaceae), an important medicinal plant of Iran, has been considered to have different therapeutical effects and are widely used in the perfume and pharmacological industries. Considering capability of F. angulata essential oils, the present study was conducted to optimized microwave-assisted hydrodistillation (MAHD) method for F. angulata fruit in order to improve the yield and biological activities of essential oils. Optimization of the yield was done through central composite design (CCD) of the response surface methodology (RSM) using three variable factors (hydrodistillation time, irradiation power and plant/liquid ratio). Based on the RSM results, the maximum essential oil yield was obtained with the microwave power of 980 W and plant/ liquid ratio of 2 (g/100 mL) at 72 min. The results revealed that MAHD of F. angulata produced the highest essential oil yield (6.50%) as compared with essential oil prepared with hydrodistillation (HD) (2.65%). The essential oils extracted by MAHD and HD were analyzed by gas chromatography–mass spectroscopy (GC–MS) and indicated the main constituents of them were limonene, α-Pinene, ß-Phellandrene, α-Phellandrene, and Terpinolene. The antioxidant study revealed that MAHD essential oil had higher antioxidant activity than the HD essential oil. Furthermore, the essential oil obtained by MAHD demonstrated potent anti-proliferative activity against MCF-7 with IC50 8.51 μg/mL. This research revealed that MAHD could be an effective method for hydrodistillation of essential oil in F. angulata in terms of shortening hydrodistillation time, reduction of energy consumption and increasing biological activities compared with the HD method.

1. Introduction Ferulago angulata (Schlecht.) Boiss. belonged to Apiaceae family, is an endemic medicinal plant in western and southwestern of Iran, which known as “chavil” (Mozaffarian, 2008). This plant is a perennial and glabrous herb, which grows 1.5–1.6 m height; its stem is thick, erect and single, sulcate or deeply significant channel. Its leaves are basal, pale, glabrous and bluish. Its flowers are small, yellowish and virtually unspecific and flowering occurs between May and July, and the seeds ripen in September (Lorigooini et al., 2017). The different parts of F. angulata have found various uses in the food industry such as for flavoring cheese and meat (Sefidkon and Omidbaigi, 2004). In food industries, the essential oil of F. angulata is used to increase the shelf life of soybean oil, the mixture of sunflower seed oil and palm olein, vegetable oil, and dairy products (Rustaiyan et al., 2002; Khanahmadi and Janfeshan, 2006; Sadeghi et al., 2016). Also, this plant is widely used in

traditional medicine as anti-diabetics, sedative, digestive, aphrodisiac, tonic, anti-hemorrhoids, anti-ulcer, anti-parasitic, and also the treatment for snake bites, spleen and headache (Amirghofran et al., 2009; Sodeifian et al., 2011). The previous studies showed that the essential oil F. angulata was characterized by large amounts of monoterpene hydrocarbon. Research on the seed essential oil of F. angulata showed that the major constituents were α-pinene, sabinene, (Z)-β-ocimene, p-cymene, α-phellandrene and β-phellandrene (Moghaddam et al., 2018). Components of essential oils extracted from different parts of F. angulata subsp. Carduchorum (flower, stem and leave) demonstrated that α-phellandrene, α-pinene β-phellandrene and p-cymene were the major essential oils components (Akhlaghi et al., 2008). These different findings on the composition of essential oil of F. angulata could be concluded from the difference in geographic and parts of plant. Essential oils are secondary metabolites that have attracted

⁎ Corresponding author at: Phytochemical Laboratory, Department of Chemistry, Faculty of Sciences, Azarbaijan Shahid Madani University, Tabriz 53714-161, Iran. E-mail address: [email protected] (S. Mollaei).

https://doi.org/10.1016/j.indcrop.2019.05.015 Received 29 December 2018; Received in revised form 4 May 2019; Accepted 6 May 2019 Available online 10 May 2019 0926-6690/ © 2019 Elsevier B.V. All rights reserved.

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University Herbarium (ASMUH) (Tabriz, Iran).

attention, because of their biological activities, such as anti-microbial, anti-oxidant, anti-cancer, insecticidal, and anti-parasitic properties (Sharifi-Rad et al., 2017). The potential anti-oxidant, anti-bacterial, and anti-fungal activities of F. angulata essential oil were proved in many reported researches in the literature (Taran et al., 2010; Bagci et al., 2016; Moghaddam et al., 2018). Moghaddam et al. (2018) illustrated the anti-microbial potential of essential oil from F. angulata against different plant pathogenic microorganisms. In another study, the essential oil of seeds and aerial parts of F. angulata indicated anti-microbial activity against different infectious microbes (Taran et al., 2010). Bagci et al. (2016) studied the effects of inhaled F. angulata essential oil on spatial memory and the findings showed that the multiple exposures to F. angulata essential oil ameliorate scopolamine-induced spatial memory impairment. Moreover, the study on the antioxidant activity of F. angulata essential oil showed that F. angulata essential oil could be as anti-oxidant agents (Bagci et al., 2016). Until now, many methods such as solvent extraction, supercritical fluid extraction and hydrodistillation (HD) were applied to extract essential oils from natural sources (Conde-Hernández et al., 2017; Zhuang et al., 2018; Moon et al., 2019). Therefore, the disadvantages of these methods were long time consumption, high operating temperature, degradation of target compounds, low yield, and large energy consumption. Due to these disadvantages, scientists are challenged to find technologies which can reduce the consumption of time and energy, and increased the yield of extraction. Recently, microwave-assisted hydrodistillation (MAHD) method has been defined as an alternative method for the essential oil extraction from plants due to its shorter extraction time, its lower energy consumption, low costs of extraction, the decrease of CO2 emissions, and higher yields of essential oils (Asghari et al., 2012; Mohamadi et al., 2013; Moradi et al., 2018). Up to our knowledge, the hydrodistallation of essential oil from F. angulate fruit has not been reported yet. So, for the first time, we used a central composite design to maximize the hydrodistallation yields of essential oils from F. angulata by optimizing MAHD conditions such as hydrodistallation time, microwave power, and ratio of plant/liquid using response surface methodology (RSM). RSM, a powerful mathematical technique, is a method which has been used for optimizing complex extraction procedures, when many factors and their interactions affect the response. Compared with traditional methods, the advantage of this method is that it generally reduces the number of experimental runs, time, and cost, and applied to optimize the process of MAHD of essential oil from plants (Bagheri et al., 2014; Belhachat et al., 2018; Palconite et al., 2018). Moreover, in this study, antioxidant and cytotoxic activities as well as total phenolic and flavonoids compounds of the essential oil obtained by MAHD were compared with HD methods. The results of the present study might be help to finding highquality essential oil with antioxidant and cytotoxic activities.

2.3. Hydro-distillation (HD) The essential oil of F. angulata fruit was extracted by hydrodistillation method under the optimum conditions (dried fruit weight, 15 g; hydro-distillation time, 3 h; distilled water volume, 100 mL). Briefly, 15 g of the dried fruit powder (mesh size of 1–2 mm) was put into a 250 mL round-bottom flask with a Clevenger apparatus and distillated with 100 mL of distilled water for 3 h. The essential oils obtained were collected, weighed, dehydrated with anhydrous Na2SO4 and then stored in an amber glass vial (−20 °C in a freezer) for further analysis. 2.4. Microwave-Assisted Hydro-distillation (MAHD) MAHD was performed using the microwave-accelerated reaction system (Shanghai, China) operating at 0–1000 W microwave output delivered in 10 w increments with microwave irradiation frequency of 2450 MHz. This system was equipped with an electromagnetic stirrer, an infrared temperature sensor, a circulating water-cooling system, and a timing controller. In the MAHD procedure, different amount of the dried plant/liquid ratio were subjected to round-bottom flask and the hydrodistillation of essential oils were done at different microwave power and time. Subsequently, the essential oils obtained were collected, dehydrated with anhydrous Na2SO4 and then stored in an amber glass vial (−20 °C in a freezer) until the analysis. Each hydrodistillation was performed at least three times. The essential oil yield (%) was calculated according to below equation:

Essential oil yield (%) =

Amount of essential oil (g) × 100 Amount of plant (g)

2.5. Experimental design for RSM and statistical analysis

2. Materials and methods

Design Expert software (Version 7.0.0; Stat-Ease, Inc., Minneapolis, MN, USA) was used to design the experiments and analyze the results of essential oil hydrodistillation stage. A three-factor-five-level CCD followed by RSM was applied in order to optimization of MAHD method for obtaining the maximum essential oil yield of F. angulata fruits. Three independent variables were irradiation power (X1= 20, 200, 500, 800, and 980 W), hydrodistillation time (X2= 8, 20, 40, 60, and 72 min), and plant/liquid ratio (X3= 2, 5, 10, 15, and 18 g/100 mL), and the essential oil yield was selected as responses. According to CCD, twenty randomized experiments including six replicates at the center points were proposed. The replicates at the center point can provide an estimate of the pure error. The general full second-order polynomial equation is:

2.1. Chemicals

Y= β0 +

Gallic acid, quercetin, and 3-(4,5-dimethylthiazol2-yl)-2,5-diphenyltetrazolium bromide reagent (MTT) were purchased from Merck (Darmstadt, Germany). Folin–Ciocalteu and 2,2′-diphenyl-1-picrylhydrazyl (DPPH) radical were obtained from Sigma–Aldrich (St Louis, MO, USA). All other organic solvents and chemicals used for analysis were purchased from Merck (Darmstadt, Germany) by high purity.

Where Y is the predicted essential oil yield, β0 is constant coefficient; and βi, βii and βij are the linear, quadratic and interaction regression coefficients of the RSM model, respectively. Experimental results are expressed as mean ± standard error (n = 3). Analysis of variance (ANOVA) was done to test significance and fit. Significance was analyzed and evaluated by calculating F at where probability (p) equaled 0.05.

n

n

n

∑i=1 βi Xi+ ∑i=1 βii X 2i + ∑i < j βijXiXj

2.2. Plant materials 2.6. Gas chromatography–mass spectroscopy (GC–MS) Fruits of Ferula angulata were collected from Sepidan, Fars province, Iran, at the ripping stage in September 2016. The taxonomic identification of this plant was done, in Faculty of science, Azarbaijan Shahid Madani University, Tabriz-Iran. The voucher specimen has been deposited at the Ecology Laboratory of Azarbaijan Shahid Madani

The analysis of essential oil was done using GC–MS (Shimadzu GCMS QP 5050A) with a fused capillary column DB-1 (60 m ×0.25 mm id, 0.25 μm film thickness). The oven temperature was constant at 50 °C for 3 min, increased to 260 °C by a ramp-up of 3 °C/min and then held 44

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for 5 min. Nitrogen was as a carrier gas with a flow rate of 1.3 ml/min. The splitting ratio was 1:29 and the injector and detector temperatures were adjusted at 240 and 270 °C, respectively. The solvent delay, ionization voltage, scan time, and mass range were 2 min, 70 eV, 0.4 s, and 30–600 m/z, respectively. The identification of essential oil constituents was performed by comparison of the Kovats retention index (RI), Wiley and NIST 11.0 mass-spectral libraries, and previous literature. To obtain the percentage of compounds, FID peak area was used without the usage of correction factors (Hazrati et al., 2018).

determined spectrophotometrically at 570 nm in a micro-titer plate reader. The cell viability (%) was calculated based on the following equation:

Cell viability (%) =

Atest × 100 A control

2.11. Statistical analysis All data were analyzed statistically using a one-way analysis of variance (ANOVA) of a completely randomized design and differences among the means were determined for significance at P = 0.01 using Tukey test (by SAS software version 9.2). In the cause of cytotoxicity assay, a factorial experiment was laid out in a completely randomized design with three replications. The factorial combination of two methods (HD, and MAHD) and seven concentration of essential oil (control, 5, 10, 20, 30, 40, and 50 μg/mL) were considered as main factors. Interaction effects of experimental factors were determined from analysis of variance (ANOVA) using the general linear model (GLM) procedure. The data are presented as mean ± standard error of the three replications.

2.7. Total phenolic content The total phenolic content was determined by the method described by Haghighi et al. (2012) with a minor modification. Briefly, 50 μL of the essential oil (2 mg/mL) was mixed with 550 μL of Folin–Ciocalteu reagent (10% v/v) for 5 min, followed by the addition of 250 μL of Na2CO3 (7% w/v). After incubation for 2 h, the absorbance was measured at λmax =765 nm. Then, the total phenolic content was expressed as mg Gallic acid equivalent per gram of the essential oil using the standard curve. 2.8. Total flavonoid content

3. Results and discussion

Total flavonoid content was determined according to the aluminum chloride colorimetric assay with a minor modification (Haghighi et al., 2012). Briefly, 100 μL of the essential oil (2 mg/ml) was mixed with 50 μL of the AlCl3 (2% w/v) solution and 100 μL of sodium acetate (1 M). After 10 min of incubation, the absorbance of the sample was measured at 426 nm. Then, total flavonoid contents were expressed as mg Quercetin equivalents per gram of the essential oil using the standard curve.

3.1. Single-factor investigation According to previous studies, microwave power, hydrodistillation time, and plant/liquid ratio could influence the hydrodistillation yield of essential oils obtained by MAHD (Jeyaratnam et al., 2016; FrancoVega et al., 2019). So, preliminary experiments, via single-factor experiments, were studied to determine the levels and range of these dependent variables which were eventually used during the optimization of essential oil yield of F. angulata fruit. The eff ;ect of hydrodistillation time was evaluated in the range of 10–60 min at microwave power of 500 W and plant/liquid ratio of 10 (g/100 mL). The yield of essential oil was gradually elevated from 10 to 40 min, maximized to 3.24% at 40 min (Fig. 1). As the hydrodistillation time was increased further than 40 min, the yield of essential oil reduced. Increasing the absorption of microwave energy can be achieved by increasing the hydrodistillation time which this action improves the dissolution process of essential oil into the water (Hosseini et al., 2016). Furthermore, a decrease in the essential oil yield after 40 min hydrodistillation time may be due to the degradation of the plant essential oils (Chen et al., 2007). Microwave power was another dependent variable which could influence on the yield of essential oil. So, different microwave power (300, 400, 500, 600, and 700 W) was evaluated with extraction time of 40 min and plant/liquid ratio of 10 (g/100 mL). The essential oils yield was increased with the increase of microwave power from 300 to 500 W, maximized to 3.24% at 500 W, and then declined (Fig. 2).

2.9. Free radical scavenging activity using DPPH The antioxidant activity of the essential oil of F. angulata fruit was evaluated by the method previously described by Asgharian et al. (2015) with some modifications. This method is based on the ability of the essential oil to trap the free DPPH radical. The stock solution of the essential oil was prepared at 2 mg per 1 mL of ethanol. Then a serial dilution of 50 percent was made to obtain 8 concentration ranges (1000 - 7.8 μg/mL). Then, 550 μL of the DPPH solution (1 mg/10 mL) was mixed with 50 μL of the essential oil solution. After 30 min of incubation in the dark, at room temperature, the absorbance of the mixture was read at 517 nm using a spectrophotometer. The percentage of inhibition of DPPH radical was calculated based on the following equation:

Radical scavenging activity (%) =

A control − A sample A control

× 100

2.10. Cytotoxicity assay The essential oil of F. angulata fruit was tested for in vitro cytotoxicity; against human breast adenocarcinoma (MCF-7) cells by MTT assay (Goodarzi et al., 2017). Briefly, the human breast adenocarcinoma (MCF-7) cell lines were cultured in RPMI 1640 (Roswell Park Memorial Institute) medium containing 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin. The cells were cultured in a humidified incubator and, then were plated in 96-well plates at a density of 1 × 104 cells/well (100 μL). Following incubation, the medium of each well was changed by 100 μL fresh medium containing different concentrations of essential oil of F. angulata (5, 10, 20, 30, 40, and 50 μg/ mL). The cells were incubated for 72 h at 37 °C in a humidified 5% CO2 incubator. After 72 h of incubation, 20 μL of MTT (5 mg/mL in phosphate- buffered saline) was added into each well and the cells incubated at 37 °C for 4 h. Finally, the quantification of MTT reduction was

Fig. 1. Effect of hydrodistillation time on the essential oil yield of F. angulata fruit. Data shown are mean of ± SD (n = 3). 45

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Table 1 Experimental levels of independent variables. Variables

Symbol

Microwave power (w) Plant/liquid ratio (g/ 100 mL) Time (min)

Variable levels -α (-1.6)

−1

0

+1

+ α (+1.6)

X1 X2

20 2

200 5

500 10

800 15

980 18

X3

8

20

40

60

72

independent variables for maximum essential oil yield from fruit of F. angulata. Table 1 shows the range of independent variables and their coded levels that were derived after preliminary runs and were used in the experimental design.

Fig. 2. Effect of microwave power on the essential oil yield of F. angulata fruit. Data shown are mean of ± SD (n = 3).

Increased temperature, created by microwave-induced movement of molecules, could decrease the essential oil yield through two mechanisms: 1) Magnetic wave of microwave heats water within the plant cells, and caused breaking down plant cell walls. This process increases the essential oil release from the plant material to water, 2) High temperature decreases the viscosity of water which facilitates faster penetration of heat into the cells (Zhang et al., 2011; Soran et al., 2014). In this condition, some temperature-sensitive metabolites could decompose, and then affect on the yield and quality of essential oil. Therefore, according to the results, the microwave power of 500 W, and hydrodistillation time of 40 min were chosen as the optimum conditions. Moreover, diff ;erent plant/liquid ratio was set at 5, 10, 15, and 20 (g/100 mL) at constant microwave power (500 W) and hydrodistillation time (40 min). The finding results (Fig. 3) showed the essential oil yield increased significantly within plant/liquid ratio of 5 and 10 and then subsequently started to drop. This finding result was in agreement with the research done by Peng et al. (2012), who studied extraction of essential oil Zingiber Cassumunar. At the low ratio of plant/liquid, the interaction between water and plant improve, which will cause reducing the mass transfer resistance and accelerate desorption of essential oil from the cells. Therefore, this process increases the essential oil yield (Zhu and Liu, 2013; Kusuma and Mahfud, 2015). At the high ratio of plant/liquid, the amount of water is less which causing overheating of the plant, resulting in a low essential oil extraction yield. When the ratio of plant/liquid is high, the effectiveness of liquid to extract the essential oil is relatively low due to the problem of diffusivity (Pinelo et al., 2005; Lau et al., 2015). Moreover, the hydrolytic effect might have contributed to the lower yield (Desai et al., 2014). Therefore, plant/liquid ratio of 10 (g/100 mL) was selected for the best result of 2.34% yield. Thus, based on the preliminary experiments, microwave power of 500 W, hydrodistillation time of 40 min, and plant/liquid ratio of 10 (g/ 100 mL) were chosen as the central conditions for the optimization study. Then, optimization study investigated the effects of the

3.2. Optimization of experimental conditions using RSM Microwave-assisted hydrodistillation of essential oil from F. angulata fruit was optimized using RSM. To examine the combined effect of three different independent variables (hydrodistillation time, microwave power, and plant/liquid ratio) on the essential oil yield, 20 experiments were done. The experimental design, along with experimental data and predicted responses, was given in Table 2. According to Table 2, the essential oil yields ranged from 0.20 to 5.30%, and the maximum yield was obtained at hydrodistillation time: 60 min, microwave power: 800 W, and plant/liquid ratio of 5 g/100 mL (run number 6). The different models such as linear, 2Fl, quadratic and cubic can be evaluated based on scores obtained from the sequential model sum of squares. In choosing the right model, if the p-value of the model was less than 0.05 then it should be the best model. The model suggested by the Design Expert was calculated using the statistical software and the result was shown in Table 3. In the Quadratic Model, the larger amount of F (9.46) and the smaller value of p (≤ 2.90 × 10−3) confirmed the significance of this model (Cheng et al., 2017; Cui et al., 2018). The model P–value observed was < 2.90 × 10−3, which indicated that the model was significant. Furthermore, the non-significant value of lack of fit (P–value of 0.07) for the Quadratic model showed that this model is valid (Tran et al., 2018). In addition, a good model fit was achieved for essential oil yield, with "R-Squared" of 0.96, and "Adj RTable 2 Central composite design (CCD) matrix with the actual responses and predicted values for yield of essential oil hydrodistillation. Run

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Fig. 3. Effect of plant/liquid ratio on essential oil yield of F. angulata fruit. Data shown are mean of ± SD (n = 3). 46

Independent variable

Response (yield; %)

X1(W)

X2 (g/100 mL)

X3 (min)

Experimental

Predicted

200 (-1) 800 (+1) 200 (-1) 800 (+1) 200 (-1) 800 (+1) 200 (-1) 800 (+1) 20 (-1.6) 980 (+1.6) 500 (0) 500 (0) 500 (0) 500 (0) 500 (0) 500 (0) 500 (0) 500 (0) 500 (0) 500 (0)

5 (-1) 5 (-1) 15 (+1) 15 (+1) 5 (-1) 5 (-1) 15 (+1) 15 (+1) 10 (0) 10 (0) 2 (-1.6) 18 (+1.6) 10 (0) 10 (0) 10 (0) 10 (0) 10 (0) 10 (0) 10 (0) 10 (0)

20 (-1) 20 (-1) 20 (-1) 20 (-1) 60 (+1) 60 (+1) 60 (+1) 60 (+1) 40 (0) 40 (0) 40 (0) 40 (0) 8 (-1.6) 72 (+1.6) 40 (0) 40 (0) 40 (0) 40 (0) 40 (0) 40 (0)

1.60 3.90 1.60 2.60 1.40 5.30 1.30 3.50 0.20 3.10 3.30 2.00 2.10 3.70 3.10 3.10 3.40 3.00 2.90 3.40

1.42 3.61 1.51 2.20 1.53 5.12 1.33 3.42 0.14 3.57 3.50 2.21 2.57 3.64 3.12 3.12 3.12 3.12 3.12 3.12

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the yield of essential oil increased with increase in microwave power at constant hydrodistillation time (40 min). The increase of the microwave power facilitates the rate of hydrodistillation and so increases the essential oil yield. The study reported elsewhere with essential oil hydrodistillation from the plant showed that the microwave power had a positive effect on the yield of essential oil (Ranitha et al., 2014). Also, at a constant microwave power (980 W), the yield of essential oil decrease with increase in plant/liquid ratio, which this result was similar to Kusuma et al. report (Kusuma and Mahfud, 2015). Thus, the maximum essential oil yield achieved at a low plant/liquid ratio and high microwave power. Fig. 4b indicates the interaction between microwave power and hydrodistillation time on the essential oil yield. It could be noticed that the yield of essential oil was positively influenced by the microwave power. So, high microwave power was more suitable for the essential oil yield. The obtained result is in accordance with Ranitha et al. finding on the effect of microwave power on essential oil hydrodistillation of Cymbopogon citratus using MAHD (Ranitha et al., 2014). Furthermore, at a constant microwave power (980 w), the hydrodistillation time had a positive effect on the essential oil yield and increasing the hydrodistillation time led to an increase in the essential oil yield. So, the maximum essential oil yield of F. angulata fruit was obtained at high level of microwave power and the hydrodistillation time. Briefly, the most important factors which could influence the yield of essential oil were the microwave power and the hydrodistillation time. In this concept, figures which contain these factors presented a linear increase of essential oil yield when the values of them, increase due to the positive terms of X1 and X3.

Table 3 Sequential model sum of squares for percentage essential oil yield from F. angulata fruit. SOV

SS

df

F-value

P-value

Linear 2Fl uadratic Cubic

18.60 2.15 3.11 0.48

3 3 3 4

15.60 2.21 9.46 1.17

1.00 × 10−4 0.13 2.90 × 10−3 0.41

Suggested

SS: Sum of squares. 2Fl: Simpler factorial model.

Squared" of 0.92, showing good representation of the variability of the parameters by the models (Tan et al., 2012). The "Pred R-Squared" of 0.72 was in agreement with the "Adj R-Squared" (Chan et al., 2009). The adequate precision ratio of 22.26 shows an appropriated signal to noise ratio (Table 4). The significance of each model term was studied by p-value (Table 4). The p-value less than 0.05 had significant effects on the yield of essential oil, while values greater than 0.05 indicated that the model terms were not significant. Thus, Based on ANOVA results, X1, X2, X3, X12, X1X2, and X1X3 had significant effects on the yield of essential oil (p-value less than 0.05). Hence, after removing the effect of non-significant factors, the final predicted second-order polynomial equation obtained is described as follows: Y = 3.12 + 1.07X1 - 0.40X2 + 0.33X3 - 0.37X1X2 + 0.35X1X3 - 0.49X12 (1) Where Y is the essential oil yield, X1 is the microwave power, X2 is the hydrodistillation time, and X3 is plant/liquid ratio. Based on the RSM results, the optimum conditions for all parameters combined were X1 = 980 (W), X2 = 2 (g/100 mL), and X3 = 72 (min), and the predicted essential oil yield was 6.50% with 100% desirability. The Eq. (1) indicates that hydrodistillation time, and microwave power, as well as the interaction between the microwave power with the hydrodistillation time, had a positive effect on the yield of essential oil, while the interactions between the microwave power with plant/ liquid ratio had a negative effect on the yield of essential oil. In order to visualize influence of the independent variables and their mutual interactions on the yield of essential oil, three-dimensional response surface graphs were plotted (Fig. 4a, b). These were generated by plotting two independent factors against response while keeping the other factor at zero level. Fig. 4a showed the response surface plot between microwave power and plant/liquid ratio on the yield of essential oil. According to Fig. 4a,

3.3. Optimization and model validation Considering the above results and using Design Expert, optimum conditions were as follows: 980 (W) microwave power (X1), plant/liquid ratio of 2 (g/100 mL) (X2), and 72 min of hydrodistillation time (X3). Furthermore, RSM predicted a maximum essential oil yield of 6.5%. Furthermore, the validity of the model was checked; and the experimental value (6.30%) was closed with the predicted values. Therefore, the extraction conditions obtained by RSM may be considered accurate and reliable. 3.4. Comparison of MAHD and HD method At the optimum condition of MAHD and HD methods, the essential oil of them were compared in terms of yield and components, total phenol and flavonoid content, antioxidant, and cytotoxicity activities.

Table 4 The analysis of variance of response surface reduced quadratic model for percentage essential oil yield from F. angulata fruit and fitness of quadratic model. Source

SS

df

F-value

P-value

Model X1 X2 X3 X1X2 X1X3 X2X3 X12 X22 X32 Residual Lack of fit Pure error Total R-Squared Adj R-Squared Pred R-Squared

23.86 15.02 2.12 1.45 1.13 0.98 0.04 3.03 0.13 3.00 × 10−4 1.10 0.88 0.22 24.96 0.96 0.92 0.72

9 1 1 1 1 1 1 1 1 1 10 5 5 19

24.17 136.98 19.37 13.21 10.26 8.93 0.41 27.62 1.20 3.00 × 10−3

1.00 × 10−4 1.00 × 10−4 1.30 × 10−3 4.60 × 10−3 9.40 × 10−3 1.36 × 10−2 0.54 4.00 × 10−4 0.30 0.96

significant

4.10

0.07

not significant

SS: Sum of squares. 47

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Fig. 4. Response surface plot showing the (a) 3D effect and contour plot of microwave power and plant/liquid ratio; (b) 3D effect and contour plot of microwave power and hydrodistillation time.

Cymene. The study on the F. angulata gathered from Khorasan (northeast of Iran) showed that α-Pinen, Limonene and ß-Myrcene were the main constituents of essential oil (Akhlaghi, 2008). Moreover, Taran et al. (2010) reported the major constituents of F. angulata essential oil were Z-ß-Ocimene, α-Pinene, Bornyl acetate, Germacrene D and transOcimene. Difference in the yield and the major constituents of F. angulata essential oil could conclude from the difference in geographic of plant, environmental and agronomic condition, and phenological plants stage harvest time as well as extraction methods. Also, the essential oils were divided into hydrocarbon monoterpenes, oxygenated monoterpenes, hydrocarbon sesquiterpenes, and oxygenated sesquiterpenes groups. Using HD method considerably decreased the percentage of oxygenated compounds compared with MAHD method. When the HD method was used, the oxygenated compounds may be decomposed by thermal and hydrolytic reactions and this process reduce the percentage of oxygenated compounds (Lucchesi et al., 2007). As a result, the total oxygenated compounds of essential oil obtained by MAHD method were found to be higher than obtained by HD method. In addition, the essential oils with higher amounts of the oxygenated compounds could be considered as agents with higher antioxidant activity.

3.4.1. Essential oil yield The analysis of variance showed that the effect of the extraction method was significant on the yield of essential oil and the maximum essential oil yield (6.30%) was related to the MAHD method and the essential oil yield of HD method was 2.65%. Moreover, a higher yield of F. angulata essential oil was obtained in our study compared with Akhlaghi report which got the yields of 0.66%, 0.54%, and 0.43% (w/ w) from flowers, stems, and leaves of this plant, respectively (Akhlaghi, 2008). In another study, air-dried aerial part of F. angulata was subjected to HD to produce essential oil in 2.5% yield (Rustaiyan et al., 2002). These results confirmed that MAHD is more effective method for hydrodistillation of volatile oil from F. angulata fruit.

3.4.2. Essential oil components The essential oil components of F. angulata was analyzed and identified by comparing their retention times and retention indices as well as mass spectra in GCeMS. Table 5 shows the identified compounds in the extracted F. angulata essential oils by MAHD and HD methods. In the essential oils obtained by MAHD and HD methods, 22 and 29 compounds were identified, yielding 97.49% and 97.86% of the essential oils, respectively (Table 5). The results showed that the main compounds were Limonene, α-Pinene, ß-Phellandrene, α-Phellandrene, and Terpinolene. Limonene was the main constituent with 38.08% and 34.93% obtained by HD and MAHD methods, respectively. Moreover, the HD method significantly affected on the percentage of compounds and the most considerable changes were observed in the case of Limonene, α-Pinene, and Bornyl acetate. The results of the previous research on the essential oils of F. angulata aerial part indicated that the most abundant compounds were α-Pinene, Z-β-ocimene, Bornyl acetate, Germacrene D, Myrcene, gama-Terpinene, Limonene and p-

3.4.3. Total phenols and flavonoids assay The result of total phenol contents of F. angulata essential oil is given in Table 6. The results indicated the total phenolic content of essential oil obtained by HD and MAHD methods were found to be 1.10 and 1.96 (mg GAE/g), respectively. These observations clearly indicated that MAHD method could recover a higher concentration of phenolic compounds in comparison to the HD method. MAHD is an efficient technology to the hydrodistillation of volatile phenolic compounds such as Coumarin,7-methoxy-6-(3-methyl-2-butenyl) from F. angulata fruit. 48

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essential oil obtained by MAHD method showed the lowest IC50 (222 ± 12 μg/mL) compared with IC50 of HD (478 ± 8 μg/mL) (Table 6). These observations confirmed that MAHD essential oil was largely more effective than HD against DPPH radical-scavenging. Djouahri et al. (2013) showed that antioxidant activities of Tetraclinis articulata essential oils, obtained by MAHD and HD methods, were 191.72 and 517.65 μg/mL, respectively. These results suggest that the antioxidant activity was due to higher amounts of the oxygenated compounds that MAHD essential oils contained (Djouahri et al., 2013). Also, according to previous studies, phenolic and flavonoid compounds have shown to be powerful antioxidants compounds (Huyut et al., 2017; Lin et al., 2018). Thus, the essential oil obtained by MAHD had higher antioxidant activity which could be mainly due to the action of phenolic and oxygenated compounds existing in the essential oil studied.

Table 5 Essential oil composition of F. angulata obtained by HD, and MAHD methods. No.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29

Compound

α-Thujene α-Pinene Camphene Sabinene β-Pinene Myrcene α-Phellandrene δ-3-Carene ρ-Cymene β-Phellandrene Limonene (E)-β-Ocimene γ-Terpinene α-Pinene oxide Terpinolene Linalool cis-Verbenol Terpinen-4-ol (E)-2-Caren-4-ol 2,6-dimethyl-3,5,7octatriene-2-ol Citronellol Bornyl acetate Germacrene A Germacrene D γ-Elemene β-Sesquiphellandrene Spathulenol Caryophyllene oxide Coumarin,7-methoxy6-(3-methyl-2butenyl) Monoterpene hydrocarbons Oxygenated monoterpenes Sesquiterpene hydrocarbons Oxygenated Sesquiterpene Total

a

Retention index

b

Retention index

Method HD (%)

MAHD (%)

899 911 918 935 941 952 966 970 978 984 990 998 1010 1016 1032 1035 1067 1092 1109 1114

902 911 919 938 942 951 964 970 976 985 994 999 1008 1017 1032 1035 1071 1097 1107 1114

0.24 18.16 1.01 4.55 1.68 3.48 4.72 1.84 3.29 7.29 38.08 2.62 0.80 0.68 4.01 0.38 0.74 0.48 0.08 0.80

0.25 13.93 0.99 4.18 1.77 3.65 4.87 1.99 2.48 6.61 34.93 1.89 1.43 0.38 4.75 0.32 1.48 1.06 0.96 1.01

1137 1177 1260 1339 1347 1365 1404 1443 1819

1133 1180 1268 1335 1346 1365 1399 1442 1813

0.83 1.73 – – – – – – –

1.07 3.41 0.20 1.24 0.51 0.21 0.98 0.32 0.99

92.15

84.04

5.34

9.37

0.00

2.16

0.00

2.29

97.49

97.86

3.4.5. Cytotoxicity assay Up to now, the cytotoxic activity of the genus Ferula and their important compounds were discussed (Iranshahi et al., 2018; Sharopov et al., 2019). However, this study was the first report concerning the cytotoxic activity of the essential oil of F. angulata fruit. Cytotoxicity of essential oils obtained by HD and MAHD from F. angulata fruit was evaluated against the human breast adenocarcinoma (MCF-7) cell lines by MTT assay. The results demonstrated that both of them exhibited potent cytotoxic effects on MCF-7 cell lines (Fig. 5). Also, the essential oil obtained by MAHD method showed the lowest IC50 (8.51 μg/mL) compared with IC50 of HD (22.20 μg/mL) against MCF-7 cell lines. It was obvious that the essential oil of MAHD was more potent than HD as an anti-proliferative agent. The anti-proliferative effects of the essential oil may be due to their potential antioxidant activity, which further attributes to the collective contribution of phenolic and oxygenated compounds (Nakagawa and Suzuki, 2003; Rabi and Bishayee, 2009). Nakagawa and Suzuki (2003) showed that the cytotoxicity of the Foeniculum vulgare essential oils was due to the major oxygenated monoterpene such as (E)-Anethole. Also, Limonene, one of the major compounds found at the Bidens sulphurea essential oil, significantly enhanced the cytotoxicity to normal prostate epithelial cells (DU-145) (Rabi and Bishayee, 2009). The finding results indicated that the F. angulata fruit obtained by MAHD are enriched with phenolic and oxygenated compounds compared with the essential oil obtained by HD, which could be the reason of the cytotoxicity activities. The criteria of cytotoxic activity for the essential oil is an IC50 value of 20 μg/mL and below in the preliminary assay (Suffness and Pezzuto, 1990). Based on these criteria, the essential oil obtained by MAHD method demonstrated potent cytotoxic activities against MCF-7.

HD: Hydrodistillation. MAHD: Microwave-assisted hydrodistillation. a Retention indices of each compound calculated in DB-1 column by retention time with that of n-alkanes (C8–C26). b Retention indices that refers to NIST Chemical Web Book.

The total flavonoid content of the essential oils showed that there is no significant (p < 0.05) difference between the total flavonoids in the MAHD and HD methods. On the other hand, both the MAHD and HD methods contain a similar amount of total flavonoids, which were found to be 0.938 and 0.936 (mg quercetin/g), respectively.

4. Conclusions Herein, optimization of the essential oil yield from F. angulata fruit was done through central composite design (CCD). The optimal conditions suggested by design expert to obtain the highest yield of essential oil, as well as the highest antioxidant and cytotoxic activities were at hydrodistillation time of 72 min, microwave power of 980 W, and plant/liquid ratio of 2 (g/ 100 mL). The finding results suggest that

3.4.4. Antioxidant activity The antioxidant activity of essential oil obtained by HD and MAHD from F. angulata fruit was studied. The results indicated that the Table 6 Comparison of HD, and MAHD methods. Hydrodistillation method

X1 W

X2 min

X3 g/100 mL

Y1 %

Y2 mg GAE/g

Y3 mg QE/g

MAHD HD

980 –

72 180

2 15

6.50a 2.65b

1.96 a 1.10b

0.94 0.94

a a

Y4 %

Y5 %

222b 478 a

8.51b 22.20a

HD: Hydrodistillation; MAHD: Microwave-assisted hydrodistillation. X1: Microwave power; X2: Hydrodistillation time; X3: Plant/liquid ratio; Y1: Essential oil yield; Y2: Total phenol content; Y3: Total flavonoid content; Y4: DPPH radical scavenging activity; Y5: Cytotoxic activity. GAE: Gallic acid; QE: Quercetin. Values with different superscripts within each individual response were significant different (P ≤ 0.01) (Tukey test). 49

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Fig. 5. Cytotoxic effect of hydrodistillation (HD) and microwave-assisted hydrodistillation (MAHD) essential oils of F. angulata against the human breast adenocarcinoma (MCF-7) cell lines at different concentration (μg/mL). Cell proliferation was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Data shown are mean of ± SE (n = 3). Means within a column followed by the same letter are not significantly different at the level of 1%.

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