Pomegranate as a promising opportunity in medicine and nanotechnology

Trends in Food Science & Technology 69 (2017) 59e73

Contents lists available at ScienceDirect

Trends in Food Science & Technology journal homepage: http://www.journals.elsevier.com/trends-in-food-scienceand-technology

Review

Pomegranate as a promising opportunity in medicine and nanotechnology Mahsan Karimi a, *, Rohollah Sadeghi a, **, Jozef Kokini b a b

Department of Food Science and Technology, Islamic Azad University, Kermanshah Branch, Kermanshah, Iran Department of Food Science, Purdue University, West Lafayette, IN, USA

a r t i c l e i n f o

a b s t r a c t

Article history: Received 2 October 2016 Received in revised form 17 June 2017 Accepted 30 August 2017

Pomegranate tree is one of the oldest fruit trees known to humans (4000 and 3000 BCE). Pomegranate blooms as a symbol of life, permanence, wellbeing, femaleness, fertility, knowledge, immortality, and holiness. In efforts to figure out the best source of phenolic compounds in human diet, pomegranate receives a great amount of popularity owing to the biological effects that exerts through free radical scavenging capabilities by its phenolic compounds. Pomegranate has risen to fame for its medical applications since ancient times. Antioxidant, immunity-boosting, and anti-carcinogenic properties are the major virtues of the pomegranate as a fruit that can be applied as an herbal cure. Unique antimicrobial, antihelminthic, and antioxidant effects seen in pomegranate extracts encourage scientists to employ them as cancer preventative agents. Present review is aimed to study the different parts of the pomegranate along with their characteristics and components, chemical compositions, antibacterial effects and the mechanisms of its bactericidal behavior, medicinal applications and its anticancer properties. Then, nanotechnology applications of pomegranate including its use in biosynthesizing different nanoparticles (NPs) and developing drug delivery systems like nanoemulsion, nanoparticles, nanoliposomes, phytosomes, nanovesicles and niosomes will be discussed in detail. © 2017 Elsevier Ltd. All rights reserved.

Keywords: Pomegranate Anticancer Antimicrobial agent Nanoparticles Nanodelivery system

1. Introduction Human has been familiar with pomegranate since ancient times (4000 and 3000 BCE). Pomegranate blooms as a symbol of life, permanence, wellbeing, femaleness, fertility, knowledge, immortality, and holiness (Mahdihassan, 1984). Pomegranate belongs to the Punicaceae family and can grow up to 6e10 m and live for a long time (Morton, 1987) and to the best of our knowledge it is originally native to Iran (Kulkarni & Aradhya, 2005). Pomegranate is now harvested in many counties like India, Pakistan, Israel, Afghanistan, Egypt, China, Japan, the USA, Russia, Australia, South Africa, and Saudi Arabia, and also in the subtropical areas of South America (Holland, Hatib, & Bar-Ya’akov, 2009). Annual worldwide production of this remedial fruit is around 2,000,000 Metric Tons; 50% of which is produced in India. Iran is the second producer of pomegranate with an estimated 55,000 ha in production (Lye, 2008). Iran

* Corresponding author. ** Corresponding author. E-mail addresses: [email protected] (M. Karimi), [email protected] (R. Sadeghi), [email protected] (J. Kokini). http://dx.doi.org/10.1016/j.tifs.2017.08.019 0924-2244/© 2017 Elsevier Ltd. All rights reserved.

has been the capital of pomegranate cultivation, with a total production of 910,000 tons in 2013 (Iran Statistical Yearbook, 2013), consisting of more than 800 genotypes which are collected and retained in the Yazd and Saveh germplasm facilities (Behzadi Shahrebabaki, 1998). Pomegranate ranked 18th according to the annual global fruit consumption statistics (Brodie, 2009), and its health-promoting properties promotes its popularity, particularly in the developed countries (Lansky & Newman, 2007). It can survive through dry and harsh conditions. Fruit harvesting time is when a waxy shining layer is formed and the fruit is fully ripe (Biale, 1981). During maturation, physiological, biochemical, and structural changes develop the size, color and taste of the fruit that eventually make the fruit palatable (Al-Maiman & Ahmad, 2002). Internal factors like color, total soluble solids and acidity play important roles in determining the extent of the ripeness (Kader, 2006; Holland et al., 2009). Pomegranate is used in different forms like fresh juice, fresh fruit, concentrated juice, arils, and products such as teas, pharmaceutical and medicinal products, dyes and decoration (Lye, 2008). Pomegranate is used in producing jellies, wine, jam, paste and coloring beverages, pomegranate salad dressing and seed oils in industry (Holland et al., 2009). Present

60

M. Karimi et al. / Trends in Food Science & Technology 69 (2017) 59e73

review is aimed to study the different parts of the pomegranate along with their characteristics and components, chemical compositions, antibacterial effect and the mechanism of its bactericidal behavior, medicinal applications and its anticancer properties. Then, nanotechnology applications of pomegranate including its use in biosynthesizing different nanoparticles (NPs) and developing drug delivery systems like nanoemulsions, NPs, nanoliposomes, phytosomes, nanovesicles and niosomes will be discussed in detail.

such as bark (Tanaka, Nonaka, & Nishioka, 1986b), leaf (Nawwar, Hussein, & Merfort, 1994b; Tanaka, Nonaka, & Nishioka, 1985), and husk contain ellagitannins and gallotannins. Furthermore, apigenin and luteolin glycosides could be detected in pomegranate leaves (Nawwar et al., 1994a) while, hydrolysable tannins like punicalagins and punicalin are found in pomegranate husk (Tanaka et al., 1986a). 1.2. Chemical compositions of a pomegranate

1.1. Different parts of the pomegranate Pomegranate is composed of three parts: 1) Seeds constitute about 30% of the fruit weight which is mainly made of sugars, vitamins, polysaccharides, polyphenols, minerals (Melgarejo and Artes, 2000) and a small amount of oil that contains polyunsaturated (n-3) fatty acids (Singh, Murthy, & Jayaprakasha, 2002). Seeds are covered by a thin white membrane and its high tannic acid content makes it bitter. Seeds open new avenues in beauty and productiveness businesses (Aslama, Lansky, & Varani, 2006). 2) About 30% of the fruit's weight is the juice, which is a good source of potassium, phosphorous, calcium, iron, manganese, zinc and copper. Pomegranate juice (PJ) is produced through squeezing the whole fruit; thus major of the water soluble ingredients such as ellagitannins and punicalagins are found in juice rather than pulp. PJ is rich in anthocyanins, 3-glucosides and 3, 5diglucosides of delphinidin, cyanidin, pelargonidin, citric and ascorbic acids (El-Nemr, Ismail, & Ragab, 1990). About 90% of the antioxidant activity of pomegranate is assigned to ellagitannin. Punicalagin is the most dominant ellagitannins in PJ (Gil, TomasBarberan, Hess-Pierce, Holcroft, & Kader, 2000; Tzulker et al., 2007). Punicalagin concentration may vary (from 0.017 to 1.5 g/L of PJ) depending on the fruit cultivar, maturity index, seasonal changes, processing and storage conditions (Gil et al., 2000; Seeram, Lee, & Heber, 2004a). PJ possesses the highest amounts of antioxidants (Aviram, 2002) that should be about 3 times higher than antioxidant levels in red wine, and green tea (Gil et al., 2000; Schubert, Lansky, & Neeman, 1999). PJ is a popular beverage especially in Iran, which is used in health promoting studies (Aviram, 2002) and is well regarded as a perfect candidate for healthy products and nutraceuticals manufacturers (Singh et al., 2002). 3) Peels comprise 26e30% of the total fruit weight and encompass the inner membranes (Lansky & Newman, 2007). Astringency is attributed to the peel (pericarp) (Aslama et al., 2006). Despite the high amount of polyphenol compounds and beneficial biological activities of pomegranate peel (PP) (Al-Said, Opara, & Al-Yahyai, 2009) unfortunately it is frequently treated as waste and disposed (Li et al., 2006). Phenolic compounds like anthocyanins, ellagic acid glycosides, free ellagic acid, ellagitannins, punicalagin, punicalin and gallotannins are profoundly found in PP (Cristofori et al., 2011; Saad et al., 2012; Seeram, Schulman, & Heber, 2006). Pomegranate peel extract (PPE) is profuse of phenolics, flavonoids and tannins, thus has found an important place in food industry to provide the co-products of PJ-related preparations (Viuda-Martos, Perez-Alvarez, Sendra, & Fernandez-Lopez, 2013). As an example, adding about 0.5% of dried PPE to tomato and orange juice could elevate their antioxidant levels (Salgado et al., 2012). Ibrahim has suggested food preservative role for PPE (Ibrahim, 2010). Pomegranate parts fit for human consumption are aril, which is about 52% of the total weight of fruit and is mainly composed of 78% juice and 22% seeds. Analysis of the data acquired by researchers showed that each 100 g of aril contains 72 kcal of energy, 1.0 g protein, 16.6 g carbohydrate, 1 mg Na, 379 mg K, 13 mg Ca, 12 mg Mg, 0.7 mg Fe, 0.17 mg Cu, 0.3 mg niacin, and 7 mg acid ascorbic (Grove & Grove, 2008). Other parts of the pomegranate

Adverse health effects that synthetic compounds leave in human body, encourage the consumers to use the natural ingredients from the fruit origin (Negi, Jayaprakasha, & Jena, 2003; Poyrazoglu, Gokmen, & Artak, 2002; Singh et al., 2002). Pomegranate is gaining growing attention owing to its phenolics, anthocyanins, and vitamin C contents, which provide its nutritional and therapeutic €rez-Vicente et al., 2002). Pomegranate is an extremely effects (Pea nutritious fruit, mainly composed of acids, sugars, vitamins, polysaccharides, polyphenols and minerals (Al-Maiman & Ahmad, 2002). Proteins, sugars and minerals are the main constituents of the pomegranate (Elfalleh et al., 2012). About 85.4% of the fresh juice is water, other than that, total soluble solids (TSS), total sugars, reducing sugars, anthocyanins, phenolics, ascorbic acid, proteins (El-Nemr et al., 1990), and antioxidants (Gil et al., 2000; Kulkarni, Aradhya, & Divakar, 2004) exist. Pomegranate owes its health promoting properties to the beneficial compounds like tannins, flavonoids, alkaloids, organic acids, triterpenes and steroids, found in all over the plant. Zarei and colleagues studied six cultivars of Iranian pomegranate and showed that the variety could influence all the chemical factors of pomegranate. Total soluble solids ranged from 15.77 to 19.56, pH was between 3.06 and 3.74, titrable acidity was from 0.51 to 1.35 (g/100 g), total sugar content was between 16.88 and 22.76 (g/100 g), anthocyanins ranged between 7.93 and 27.73 (g/100 g). Ascorbic acid and total phenolics were measured to be 8.68 to 15.07 (g/100 g) and 526.40 to 797.49 (mg tannic/100 g) while, total tannins expanded between 18.77 and 38.21 (mg tannic/ 100 g). Antioxidant activity was 46.51e52.71% and extremely dependent on the total phenolics (r ¼ 0.912) (Zarei, Azizi, & BashiriSadr, 2010). A brief description about the main constituents of pomegranate could be seen below. 1.2.1. Sugars Cui and coworkers reported glucose and fructose as the main sugars in pomegranate (Cui, Sasada, Sato, & Nii, 2004). Tezcan and colleagues reported glucose and fructose content of the PJ as 0.36 and 3.6 mg/ml, respectively (Tezcan, Gultekin-Ozguven, Diken, Ozcelik, & Bedia Erim, 2009). 1.2.2. Acids Citric acid, malic acid, tartaric acid, fumaric acid, succinic acid and ascorbic acid, are the aliphatic organic acids of pomegranate (Poyrazoglu et al., 2002) from which malic and citric acid had the highest levels in the commercial PJs detected by capillary electrophoretic separation method (Tezcan et al., 2009). 1.2.3. Minerals Minerals like Fe, Ca, Ce, Cl, Co, Cr, Cs, Cu, K, Mg, Mn, Mo, Na, Rb, Sc, Se, Sn, Sr, and Zn exist in the PJ and seeds of a pomegranate (Waheed, Siddique, Rahman, Zaidi, & Ahmad, 2004). Ripening stage of a pomegranate is an important factor to determine the minerals contents of a fruit. The highest detected minerals were K, Ca and Na followed by Mg, P, Zn, Fe, and Co (Al-Maiman & Ahmad, 2002). During maturation the concentrations of the most of the minerals decrease in the following order in aril and peel: K > N > Ca > P > Mg > Na (Mirdehghan & Rahemi, 2007).

M. Karimi et al. / Trends in Food Science & Technology 69 (2017) 59e73

1.2.4. Polyphenols In effort to figure out the best source of phenolic compounds in human diet, pomegranate receives a great amount of popularity which is due to the biological effects it exerts through free radical scavenging capabilities by its phenolic compounds (Lansky, Shubert, & Neeman, 1998). Functional and nutritional properties of pomegranate results from the high levels of tannin and other beneficial biochemicals like phenolics, which make it a vital part of the human diet (Jaiswal, DerMarderosian, & Porter, 2010; Martınez, Melgarejo, Hernandez, Salazar, & Martınez, 2006). About 153 different phytochemicals with the ability to combat diseases have been detected in pomegranate with polyphenols being the most abundant compounds found in all parts of the tree, especially the peels (Jyotsana & Maity, 2010). Antioxidants activity of a pomegranate is related to the polyphenols concentration (Aviram et al., 2000; Gil et al., 2000; Seeram, Lee, Hardy, & Heber, 2005a; Tzulker et al., 2007), but it must be taken into consideration that phenolic compounds cause astringency when present in very high amounts (Kader, 2006). In maturation process, astringent compounds reduce and as a result, palatability and quality characteristics of a pomegranate increase (Borochov-Neori et al., 2009; Weerakkody, Jobling, Maria, & Rogers, 2010). Pomegranate is rich in polyphenols like flavonoids (anthocyanins, catechins and other complex flavanoids) and hydrolyzable tannins (punicalin, pedunculagin, punicalagin, gallagic and ellagic acid esters of glucose), which are responsible for its antioxidant activity (Afaq, Saleem, Krueger, Reed, & Mukhtar, 2005; Aviram, 2002). Akhavan and coworkers in 2015 conducted a study to assay the phenolic compounds and antioxidant activities of ten juices from the arils and whole pomegranate harvested in Iran. They showed that juices squeezed from the whole fruit possessed considerably higher levels of phenolics and thus showed higher antioxidant activities than juices gained just from the arils, although the variety was the determining factor. Punicalagins A (5.40e285 mg/L), punicalagins B (25.9e884 mg/L), and ellagic acid (17.4e928 mg/L) were reported as the key phenolic compounds. Detected anthocyanins were cyanidin 3,5-diglucoside (0.7e94.7 mg/L), cyanidin 3-glucoside (0.5e52.5 mg/L), pelargonidin 3,5-diglucoside delphinidin 3-glucoside (0e10.3 mg/L), delphinidin 3,5-diglucoside (0e7.68 mg/L), pelargonidin 3-glucoside (0e9.40 mg/L), and cyanidin-pentoside (0e1.13 mg/L) (Akhavan, Barzegar, Weidlich, & Zimmermann, 2015). The beneficial properties of PP are due to the presence of polyphenol compounds like ellagic, tannins, flavonols, anthocyanins, catechin, procyanidins, ellagic acid and gallic acid (Lansky & Newman, 2007; Viuda-Martos, Fernandez-Lopez, & Perez-Alvarez, 2010). The amounts of the abovementioned compounds along with the pomegranate varieties, determine the bioactivities of a pomegranate (Holland et al., 2009). Comparison between the bioactive contents of different parts of a pomegranate shows that peel possesses the highest amounts of the phenolic compounds (Li et al., 2006). Similarly, scavenging and reducing activities of DPPH (a-diphenyl-b-picrylhydrazyl) were significantly higher than those seen in juice or seed extracts. The results achieved by the investigations of Orak and coworkers in 2012 showed that most of polyphenols, flavonoids and tannins are present in PP, while most of anthocyanins, tannins and acids are found in PJ. Phenolic compounds of PP include anthocyanins, gallotannins, ellagitannins, gallagylesters, hydroxyl benzoic acids, hydroxyl cinnamic acids and dihydro flavonol (Cerda, Ceron, Tomas-Barberan, & Espin, 2003; Larrosa, Gonzalez-Sarrias, Garcia-Conesa, Tomas-Barberan, & Espin, 2006). Fig. 1 shows the structure of the polyphenols present in pomegranate. Ellagitannins is present in 3 forms: ellagic acid (either free or bound forms), gallic acid and punicalagins (Cerda et al., 2003; Larrosa et al., 2006). Punicalagins and other ellagitannins play

61

Fig. 1. Structure of the polyphenols present in pomegranate.

their roles through hydrolyzing into ellagic acid and other smaller polyphenols (Larrosa, Tomas-Barberan, & Espin, 2005; Seeram et al., 2004b), which cause the high concentrations of ellagic acid in the pomegranate extracts (PE) (Seeram et al., 2005b; Lee and Talcott, 2002). Ellagic acid content varies in the different parts of the fruit; from 10 to 50 mg/100 g in peel to 1e2.38 mg/100 ml in PJ (Akbarpour, Hemmati, & Sharifani, 2009; Seeram et al., 2004a). Punicalagin is responsible for the major antioxidant, antifungal, anti-proliferative and antibacterial functionalities. Alpha and beta punicalagin are hydrolysable tannins and isomers of 2, 3-(S)-hexa hydroxyl diphenoyl-4, 6-(S, S)-gallagyl-D-glucose. Punicalagin is water soluble and hydrolyzes into smaller polyphenolic compounds in the small intestine. About 11e20 g/kg of the ellagitannins in peel powder is punicalagin (Fischer, Carle, & Kammerer, 2011; Seeram et al., 2005a). Anthocyanidin contents include delphinidin, cyanidin and pelargonidin (Borochov-Neori et al., 2011; Gil, Garcia-Viguera, Artes, & Tomas-Barberan, 1995; Hernandez, Melgarejo, TomasBarberran, & Artes, 1999) all with the ability to inhibit lipid peroxidation caused by H2O2 in rat brain homogenates (Halvorsen et al., 2002). Six anthocyanin pigments are involved in red-purple color of PJ; the absence or the reduced concentration of which will cause pale color of the juice (Zhang et al., 2009). Mousavinejad and coworkers detected these six anthocyanins, phytoestrogen, flavonoids and ellagic acid content of eight Iranian pomegranate cultivars. Detected anthocyanins from the highest to the lowest levels were delphinidin 3, 5-diglucoside (372e5301 mg/L), cyanidin 3, 5-diglucoside (242e2361 mg/L), delphinidin 3-glucoside (49e1042 mg/L) and pelargonidin 3, 5-diglucoside (7e90 mg/L), respectively. Sweet Arak cultivar contained the highest amounts of total tannins (3 mg/L), while the highest levels of ellagic acid (160 mg/L) were seen in Saveh Black Leather (Mousavinejad, Emam-Djomeh, Rezaei, & Haddad Khodaparast, 2009). Pomegranate bark tannins (punicacortein) (Kashiwada, Nonaka, Nishioka, Chang, & Lee, 1992) and the fermented PJ (Schubert et al., 1999) show antioxidant and antitumor properties. Antioxidant activity varied among the cultivars depending on the total phenolic compounds (Mousavinejad et al., 2009). Antioxidants activity of PP which is assigned to its ellagitannins and flavonoids contents has been emphasized in many studies. PP contains 3.5% ellagic acid (Lu & Yuan, 2008) and 4.23% (42.36 mg

62

M. Karimi et al. / Trends in Food Science & Technology 69 (2017) 59e73

rutin equivalent/g) of total flavonoids (Viuda-Martos, PerezAlvarez, Sendra, & Fernandez-Lopez, 2013). Ferric reducing antioxidant assay (FRAP) regarded PPE as the most powerful antioxidants compared to PE of other fruits (Okonogi, Duangrat, Anuchpreeda, Tachakittirungrod, & Chowwanapoonpohn, 2007; Tehranifar, Selahvarzi, Kharrazi, & Bakhsh, 2011) which could increase up to 400 mg/g (Negi & Jayaprakasha, 2003). 1.2.5. Pomegranate seed oil (PSO) PSO is obtained by crushing and drying of the pomegranate seeds and could be up to 66e193 g/kg of the fruit weight in some of Iranian varieties (Fadavi, Barzegar, & Azizi, 2006). PSO forms 12e20% of the total seed weight of pomegranate. The main constituents of PSO are fatty acids (about 95%) from which about 99% is triacylglycerol. Other important components are conjugated octadecatrienoic fatty acids, with a high content of cis 9, trans 11, cis 13 acid (punicic acid) (Hornung, Pernstich, & Feussner, 2002). Minor parts of the PSO are cerebroside (Tsuyuki, Ito, & Nakatsukasa, 1981), isoflavone genistein, the phytoestrogen coumestrol and the sex steroid estrone at 17 mg/kg dry seed weight and non-steroidal estrogens like daidzein (a glucoside), genistein (a glycone), and coumestrol (Alekperov, 2002; Moneam et al., 1988). 2. Pomegranate medicinal applications Pomegranate has risen to fame for its medical applications since ancient times. Pomegranate has been regarded as the most significant medication even in the writings of Hippocrates, Pliny, Soranus and Dioscorides. Health beneficial properties of pomegranate especially PPE was known to ancient civilizations. In Egypt, it was used for curing inflammation, diarrhea, intestinal worms, cough and infertility (Lansky & Newman, 2007). It was known as superfood or youth elixir because of its health promoting and prebiotic properties (Penalver-Mellado, Lopez-Mas, Streitenberger, & Martinez-Ortiz, 2011), and today it is gaining growing attention for treating diseases like obesity and so forth (Al-Muammar & Khan, 2012; Rahimi, Arastoo, & Ostad, 2012). PPE was traditionally applied to combat diarrhea, dysentery, and dental plaque. Also, its ethno pharmacological profile turned it to a valuable traditional asset as a douche and enema agent (Lansky, Shubert, & Neeman, 2004). Old Indian used dried PPE, pomegranate bark and flower infusions to treat diarrhea, intestinal worms, bleeding noses and ulcers. It was also gargled in a liquid form to release sore throat. In dentistry field, it was used to treat bleeding gums and plaque in patients with periodontitis (Amrutesh, 2011). Nowadays natural antioxidants have opened new perspectives to counter oxidative stress induced diseases like Alzheimer's and aging (Gil et al., 2000; Singh et al., 2002). Antioxidant, immunityboosting, and anti-carcinogenic properties are the major virtues of the pomegranate as a fruit that can be applied as an herbal cure (Kaplan et al., 2001). Pomegranate possesses great amounts of phenolic compounds which is effective in decreasing cardio- and cerebrovascular diseases (Hertog, van Poppel, & Verhoeven, 1997a,b). Antioxidant and antitumor properties of pomegranate bark tannins (punicacortein) (Kashiwada et al., 1992; Su, Osawa, Kawakishi, & Namili, 1988) and also the antioxidant activity of the fermented PJ have been reported by Schubert and colleagues (Schubert et al., 1999). Its antiatherogenic effect in healthy humans and in mice affected by atherosclerotic has been reported (Aviram et al., 2000). Punicalagin, punicalin, strictinin A and granatin B are important constitutes of PP, which are in charge of constraining the expression of pro-inflammatory proteins (Romier, Van De Walle, During, Larondelle, & Schneider, 2008). High amount of bioflavonoids present in pomegranate is considered as a remedy to cure acquired

immune deficiency syndrome (AIDS) owing to its free radical scavenging and lipoxygenase inhibitory effects (Lee & Watson, 1998; Nonaka et al., 1990). Health promoting compounds present in pomegranate contribute to its remedial properties like hypolipidemic, antiviral, anti-neoplastic, helminthic, digestive protection, and immunomodulation activities (Borochov-Neori et al., 2009; Chandra, Jadhav, & Sharma, 2010; Miguel, Neves, & Antunes, 2010; Syed, Afaq, & Mukhtar, 2007; Tehranifar, Zarei, Nemati, Esfandiyari, & Vazifeshenas, 2010; Wang, Ding, Liu, Xiang, & Du, 2010). They also act efficiently in combatting diseases like blood pressure, dysentery (Aviram & Dornfeld, 2001), leprosy, haemorrhages, bronchitis and dyspepsia (Adams et al., 2006; Adhami, Siddiqui, Syed, Lall, & Mukhtar, 2012; Akbarpour, Hemmati, Sharifari, & Sadr, 2010; Al-Said et al., 2009; Holland et al., 2009; Julie, 2008; Lansky & Newman, 2007; Pantuck et al., 2006; Stover & Mercure, 2007), also could be used to resolve allergic signs (Damiani, Aloia, Priore, Nardulli, & Ferrannini, 2009; Watanabe & Hatakoshi, 2002), anti-plasmodial (Dell’Agli et al., 2009), anti-diabetes (Althunibat et al., 2010; Julie, 2008; Olapour, Mousavi, Sheikhzade, Hoseininezhad, & Najafzadeh, 2009), as a replacer in hormone therapy (Lansky, 2000), agent for oral hygiene (Kim & Kim, 2002), as ophthalmic ointment (Bruijn, Christ, & Dziabo, 2003), weight loss soap (Guojian, 1995), and as an additional treatment to enhance the bioavailability of radioactive dyes (Amorim et al., 2003). It has been evident that punicic acid and polyphenol compounds have the ability to impede prostaglandin biosynthesis (Nugteren & Christ-Hazelhof, 1987). Phenolic compounds present in PSO inhibit lipoxygenase and cyclooxygenase enzymes (Schubert et al., 1999; Wallace, 2002). Pomegranate is also prominent for the anti-parasitic properties in Ayurveda and also has been well applied as a blood tonic and an active agent to amend ulcers and metabolic syndromes (Medjakovic & Jungbauer, 2012). PPE is rich in antioxidant compounds, thus has been quite successful in combatting superoxide anion, hydroxyl and proxy radicals and preventing LDL oxidation related to CuSO4 (Li et al., 2006). PPE has been beneficial for better function of kidney and liver (Hayrapetyan, Hazeleger, & Beumer, 2012; Ibrahim, 2010). Different parts of pomegranate containing a wide range of phytochemicals effective to cure diseases, have been reviewed by da Silva et al in 2013. Active phytochemicals found in different parts of the pomegranate are briefly presented in Table 1. Not only polyphenolic compounds possess anti-inflammatory and immunomodulatory activities, but also reduce the previously increased inflammation biomarker such as IL-1, IL-6, and TNF-alpha (Rogers et al., 2005). Ellagic acid is effective in preventing IL-1betaand TNF-alpha initiated stimulation of activator protein-1 and mitogen-activated protein kinases in activated pancreatic stellate cells in vitro (Masamune et al., 2005). Secretion of cytokines IL-2 and IL-4 are beneficial host immune responses, provoked by polyphenols (Bub et al., 2003; Chen et al., 2005). Mertens-Talcott and his colleagues conducted oxygen radical absorbance capacity (ORAC) test in PE and their findings indicated that the inflammation marker interleukin-6 (IL-6) remained intact after the consumption of the extract up to 4 h (Mertens-Talcott et al., 2006). Fawole and coworkers also showed the radical scavenging ability, ferrous ion chelating (FIC) and ferric ion reducing antioxidant power (FRAP) of pomegranate to be cultivar and dose dependent, respectively (Fawole, Opara, & Theron, 2012). As a way to address erectile dysfunction issues, (Azadzoi, Schulman, Aviram, & Siroky, 2005; Loren, Seeram, Schulman, & Holtzman, 2005), carotid occlusion (Aviram et al., 2004) and neonatal ischemia (Loren et al., 2005) using pomegranate is suggested. Aslama and coworkers observed PSO induced keratinocyte propagation reactions and slight thickening of the epidermis in monolayer skin organ culture. Besides, PPE encouraged type I procollagen production and prevented

M. Karimi et al. / Trends in Food Science & Technology 69 (2017) 59e73

63

Table 1 Active phytochemicals found in different parts of pomegranate. Pomegranate part

Active phytochemicals

Reference

Seed, bark and leaves bark and leaves seed oil Leaves juice rind fruit bark and leaves juice and rind PJ, seeds, and peel extracts seeds

lignins, sterols and terpenoids alkaloids fatty acids and triglycerides simple gallyol derivatives organic acids flavonols flavonols flavonols anthocyanins and anthocyanidins, catechin and procyanidins estrogens Essential oils

(Lansky & Newman, 2007) (Lansky & Newman, 2007) (Lansky & Newman, 2007) (Ender, Vural, & Nevzat, 2002); (Ender et al., 2002); (Kim et al., 2002; van Elswijk et al., 2004), (Mirdehghan & Rahemi, 2007), (Jaiswal et al., 2010; Kashiwada et al., 1992; Lansky & Newman, 2007); (Jaiswal et al., 2010; Kashiwada et al., 1992; Lansky & Newman, 2007); (Kho, Jung, Kwon, & Kim, 2010); (Abbasi, Rezaei, Emamdjomeh, & Mousavi, 2008).

matrix metalloproteinase-1 (MMP-1; interstitial collagenase) fabrication by dermal fibroblasts, which shows the facilitated skin repairing and dermis regeneration abilities of the pomegranate (Aslama et al., 2006). Pomegranate cures coronary heart diseases and cardiac disorders, hypoxia, ischemia, brain and liver impairments (Adhami et al., 2012; Jyotsana & Maity, 2010; Pantuck et al., 2006; Rahman & Megeid, 2006; Seeram et al., 2006). Pomegranate possesses estrogens (estradiol, estrone, and estriol), and Mori-Okamoto and colleagues showed that adding PE to ovariectomized mice inhibited the loss of uterus weight, increased the bone bulk and the trabecular amount while decreased the trabecular separation, suggesting that pomegranate is clinically operational on depressive state and bone loss in women with menopausal syndrome (Mori-Okamoto, Otawara-Hamamoto, Yamato, & Yoshimura, 2004). TavassoliHojjati and coworkers employed PJ as a storage media for avulsed teeth and confirmed the role of 7.5% solution of PJ in keeping the viability of PDL cell through neutral red uptake test. In the light of the previous findings, PJ was approved as a suitable transport medium for avulsed teeth (Tavassoli-Hojjati et al., 2014). To perceive the importance of daily intake of PJ, the clinical symptoms of patients afflicted with stable chronic obstructive pulmonary disease (COPD) as the fifth deadly disease with the predicted globally growing occurrence in the next decades, were evaluated (Murray & Lopez, 1997) although the results of the experiments of Cerda and colleagues did not approve PJ role in curing COPD (Cerda et al., 2006). The main formulation developed to cure malaria is composed of the dried PP powder, which can fight with Plasmodium falciparum and Plasmodium vivax (Dell’Agli et al., 2010). The wound healing characteristic of pomegranate relies on its epithelialization, antioxidant immunity and biochemical properties (Adiga, Tomar, & Rajput, 2010). Ellagitanin from PP powder could be efficiently used as dietary fiber source to combat the hypercholesterolemia and atherosclerosis, since its daily consumption seems to be quite helpful in reducing the serum total cholesterol, triglycerides, LDL and lipid peroxidation levels in hypercholesterolemia rats (Hossin, 2009). 3. Anticancer properties of pomegranate Today, natural antioxidants are preferred to the widely found synthetic ones since they do not raise safety issues when high amounts are consumed (Ismail, Sestili, & Akhtar, 2012). Unique antimicrobial, antihelminthic, and antioxidant effects seen in the PE encouraged the scientists to employ them as a cancer preventative agent (Ackland, Van DeWaarsenburg, & Jones, 2005; Brusselmans, Vrolix, Verhoeven, & Swinnen, 2005; Kowalski, Samojedny, Paul, Pietsz, & Wilczok, 2005). This high value fruit is also prominent for its anti-apoptotic and anti-genotoxic effects (Lin, Hsu, & Lin, 1999; Seeram et al., 2005a), and anti-mutagen

activities (Lansky & Newman, 2007). Polyphenols were found effective in controlling several kinds of cancer and cardiovascular disease through improving antioxidant levels (Mertens-Talcott et al., 2006) and reducing creatine kinase-MB, lactate dehydrogenase and glutathione in plasma (de Nigris et al., 2005). Cancer is a destructive disease with the ability to metastasize to other organs of the body through triple step reactions called carcinogenesis which includes: 1) initiation, in which contact with a carcinogen cause genotoxic mutilation. 2) Tumor promotion, in which the affected cells dynamically propagate. 3) Progression stage in which the resulted tumor grow (Syed et al., 2007). Reactive oxygen species (ROS) are regarded as an essential cancer initiation factor. ROS damages DNA, which in turn provokes somatic mutations and organ malignancies (Chevion, 1988; Sies, 1997). Polyphenolic compounds of PJ can reduce the oxidative stress induced atherogenesis, act as anti-proliferative, anti-invasive and pro-apoptotic agents in in vitro and in vivo systems (Alekperov, 2002). Ellagic acid is known as an effective chemo preventive agent for cancer treatment (Kelloff et al., 1994) with the ability to reduce white fat deposits and triglycerides concentrations (Lei et al., 2007). Taking high amounts of flavonoids, frequently called phytoestrogens, decreases the occurrence of hormonally involved cancer (van Elswijk, Schobel, Lansky, Irth, & van der Greef, 2004). In order to find the naturally occurring herbs with the ability to prevent tumor development without leaving any toxic influence, the effects of pomegranate phytochemicals on four most common cancers including prostate, breast, colon and lung along with prevalent skin cancer are reviewed. 3.1. Prostate cancer Prostate cancer is the most prevalent cancer in American men. With the intension of investigating the effect of pomegranate on prostate cancer, the inhibitory effect of ellagic acid, caffeic acid, luteolin and punicic acid on the propagation and invasion of human PC-3 prostate cancer cells were proved in in vitro systems (Lansky, Harrison, Froom, & Jiang, 2005a,b). PJ gains lots of attractions due to its remedial and preventative roles against prostate cancer. Its ability in inhibiting cell growth and inducing apoptosis has been confirmed (Koyama et al., 2010). Findings of Komaya showed that applying PE along with IGFBP-3 actively decrease the cell growth promoters (Akt and mTOR) conducting as a pro-apoptotic inhibiting agent in cancer cells growth (Koyama et al., 2010). In vitro studies confirmed the suppressive effect of PPE and PSO on human PC-3 prostate cancer cells. Results of the prostate cancer risk analysis showed that beneficial phytochemicals of pomegranate like hydrolysable tannins, condensed tannins, anthocyanins, and other flavonoids could actively decrease the incidence of prostate cancer (Block, Patterson, & Subar, 1992). PE hindered the progress of androgen-responsive CWR22Rv1 tumor cell, captured G1-phase

64

M. Karimi et al. / Trends in Food Science & Technology 69 (2017) 59e73

and tempted PC3 cell apoptosis (Malik et al., 2005). Other investigations conducted by Rettig and colleagues confirmed the ability of PE to retard the prostate cancer cell growth (Rettig et al., 2008). Androgen-based lesion provokes prostate cancer. PE decreased the expressions of genes of the enzyme involved in the synthesizing androgen and at the same time downregulate the hypoxia-inducible factor 1-a (HIF-1a) to constrain angiogenesis in prostate cancer (Sartippour et al., 2008). Human prostate cancer DU145 cells stop the propagation and start to undergo apoptosis in the presence of PJ. Using 2 DE-based proteomics, nine pairs of the proteome maps from untreated and treated DU145 cells were compared and the results showed that 11 proteins were deregulated, 3 were upregulated and 8 were downregulated in affected DU145 cells while dys-regulated proteins were active in cytoskeletal tasks, anti-apoptosis, proteasome activity, NF-kB signaling, cancer cell propagation, invasion, and angiogenesis (Lee et al., 2012). In vitro and in vivo studies on human PCa cell growth after treatment with different pomegranate biocompounds revealed their ability to hinder the growth of human PCa LNCaP, PC-3, and DU 145 cells (Albrecht et al., 2004). Result of a clinical trial on men affected by prostate cancer, approved the inhibitory effects of PJ on progression of prostate cancer as well as its role on increasing adhesion and decreasing migration of the live cells (Wang, Ho, Glackin, & Martins-Green, 2012). 3.2. Breast cancer Findings of Toi and colleagues on the anti-angiogenic activity of PSO on breast cancer offered hope as its therapeutic interventions were approved by the results of their anti-proliferative effect on angiogenic cells, human umbilical vein endothelial cell (HUVEC) in myometrial and amniotic fluid fibroblasts, inhibitory effect on forming HUVEC tubule in an in vitro model (Toi et al., 2003). PE was recognized as an apoptosis inducer agent in breast cancer cells (MCF-7). MCF-7 inhibitory and cytotoxicity effects are greatly provoked in breast cancer cells treated with PPE (Khan et al., 2009). Researchers exposed human breast cancer cell lines MCF-7 and MB-MDA-231 cells to PSO, fermented and fresh PJ and showed that polyphenols from fermented juice, fresh PJ and PSO hinder cancer cells devision, although the former was found twice more effective (Kim et al., 2002). Human breast cancer cells MCF-7 were exposed to PE and genistein and the findings indicated that applying both at the same time could meaningfully improve their cytotoxic, inhibition and apoptosis inductor activities (Jeune, Kumi-Diaka, & Brown, 2005). In vitro studies conducted by Kim et al., ascertained the antiproliferative effects of pomegranate on human breast cancer cells (Kim et al., 2002). Anti-proliferative activity of PP homogenates against breast (MCF7 and MDA-MB-453) and prostate (LNCaP and PC-3) cancer cells were evaluated using MTT method. Antiproliferative activity was seen against MCF7, MDA-MB-453 and LNCaP (androgen-dependent) cell line, while it was not really effective on the androgen-independent prostate cancer cell line PC3 (Orgil, Spector, Holland, Mahajna, & Amir, 2016). The effect of Iranian pomegranate seed extract (PSE) on A549 (lung non-small cell carcinoma), MCF-7 (breast adenocarcinoma), SKOV3 (ovarian cancer cells), and PC-3 (prostate adenocarcinoma) cells were examined using MTT assays. PSE effectively decreased the cell viability. In case of SKOV3 ovarian cancer cells, maximum IC50 was observed while its antiproliferative effects on different human cancer cells were proved (Seidi, Jahanban-Esfahlan, & Abasi, 2016). 3.3. Colon cancer The role of pomegranate chemo preventive agents to inhibit multiplication and apoptosis in colon cancer cell, was confirmed by

Adams and coworkers through changing the cellular transcription factors and signaling proteins (Adams et al., 2006). Outcomes of the research of Koyama and coworkers in 2010 again approved the anti-tumorigenic and preventative effects of PE since it could retard the multiplication of LAPC4 human prostate cancer cells and trigger the apoptosis in HT-29 and HCT116 human colon cancer cells (Koyama et al., 2010). 3.4. Lung cancer PE showed higher antioxidant activity on human lung carcinoma A549 cells than green tea PE (Khan, Hadi et al., 2007). Acetone extract of pomegranate exerted apoptosis on human lung cancer A549 cells through downregulating the cell-cycle regulatory proteins, suppressing NF-kB and Map kinase pathway (Khan, Hadi et al., 2007). In another study by the same researchers, it was revealed that pomegranate compounds retard the growth and angiogenesis of lung tumor through the above mentioned strategies (Khan, Afaq, Kweon, Kim, & Mukhtar, 2007). In the effort to find an anticancer with the least side effects, non-small cell lung carcinoma cell line A549, H1299 and mouse Lewis lung carcinoma cell line LL/2 were exposed to pomegranate leaves extract (PLE), which showed concentration/time-dependent anti-proliferative action of PLE on non-small cell lung carcinoma cell line. Not only ROS but also mitochondrial membrane potential (DYm) decreased, cell migration weakened and matrix metalloproteinase (MMP) MMP-2 and MMP-9 expression reduced in the presence of PLE, which reveal that PLE play a key role in apoptosis induction (Li et al., 2016). 3.5. Skin cancer Ellagic acid and punicalagins are considered as efficient natural anti-carcinogenic that successfully initiate apoptosis to suppress cancer cell growth. Feeding PE to mice exposed to UVB irradiation prevented skin edema, hyperplasia, lipid peroxidation, penetration of leukocytes, and hydrogen peroxide production while supported against DNA damage (Afaq, Hafeez, Syed, Kweon, & Mukhtar, 2010). Role of PSO in combatting skin cancer has been reported by Hora and coworkers (Hora, Maydew, Lansky, & Dwivedi, 2003). Ellagitannins from PPE (500e10,000 mg/L) were found effective in combatting free radical synthesis in human skin exposed to UVA and UVB irradiations, which prevents DNA strands breakage, skin burns and depigmentation (Kasai et al., 2006). PE suppresses the melanocyte and melanin synthesis through inhibiting tyrosinase activity (Yoshimura, Watanabe, Kasai, Yamakoshi, & Koga, 2005). Recent literature have proved the photo chemo preventive effects of pomegranate against UVA and UVB irradiations in normal human epidermal keratinocytes (NHEK) as a test system (Syed et al., 2006). Chemo preventive effect of PE on the skin tumor was studied and the results of 2-stage mouse skin tumorigenesis model showed 55% decrease in tumor prevalence. Examining the combined effects of PE and diallyl sulfide showed that their inhibitory effects on cellular propagation and apoptosis inducing activity increases when they are used together (George, Singh, Srivastava, Bhui, & Shukla, 2011). 4. Antimicrobial behavior of pomegranate Antimicrobial behavior of pomegranate plant against lots of bacteria has been proved by using disc diffusion assays or minimum inhibitory concentration (MIC). Methanol extracts of pomegranate possess the highest antibacterial activity since they contain lots of hydrolysable tannins, ellagic and gallic acids (Howell and D'Souza, 2013). Fawole and his collaborators in 2012 assayed the

M. Karimi et al. / Trends in Food Science & Technology 69 (2017) 59e73

antibacterial activities of the methanolic PPE and concluded that it could hinder the growth of Gram-positive and Gram-negative bacteria, with the MIC between 0.2 and 0.78 mg/ml. Chitinase is a newly found component in PJ with the ability to hydrolyze colloidal chitin to its oligomers with no antifungal activity (Kopparapu, Liu, Yan, Jian, & Zhang, 2010). In a study conducted to assay the bactericidal effect of PPE (rind), seed extract, PJ and the whole fruit, it was revealed that extracts containing tannin, were more successful in fighting with the pathogens (Parseh, Hassanpour, Emam-Djome, & Lavasani, 2012). PPE acted more efficiently on microbes and fungi compared to seed extract, PLE, PJ and whole fruit extracts, with the Staphylococcus aureus and Aspergillus niger (Dahham, Ali, Tabassum, & Khan, 2010; Hegde et al., 2012; Tehranifar et al., 2011), and Pseodomonas stutzeri (Devatkal, Jaiswal, Jha, Bharadwaj, & Viswas, 2011) being the most sensitive species. PPE also affected gut bacteria in fat mice and decreased tissue inflammation and hypercholesterolemia (Neyrinck et al., 2013). Not only the methanol extract of a pomegranate influences the biofilms forming ability of Staphylococcus aureus, methicillin resistant S. aureus, Escherichia coli, and Candida albicans, but also damages pre-formed biofilms and prevents germ tube formation. Ellagic acid was found effective in constraining the growth of all the species in suspension with the concentration of >75 mgml1 (Bakkiyaraj, Nandhini, Malathy, & Pandian, 2013). The hydroalcoholic extract of PP could inhibit the growth of the fungi Trichophyton mentagrophytes, T. rubrum, Microsporum canis and M. gypseum at the conidial and hyphal stages, with MIC values of 125 mg/ml and 250 mg/ml, respectively for each genus (Foss et al., 2014). Gallic acid, ellagic acid and punicalagin, have all been recognized as strong weapons against enteric pathogens like Escherichia coli, Salmonella spp. Shigella spp. and Vibrio cholerae (Aviram et al., 2008). Research conducted by Al-Zokery revealed anti-microbial effect of PP on Listeria monocytogenes, Staphylococcus aureus, Escherichia coli and Yersinia enterocolitica with MIC values of 4 mg/ ml for Salmonella enteritidis (Al-Zoreky, 2009). Salmonella typhi (causes a very serious enteric infection called Typhoid fever) sensitivity toward pomegranate was comparable to that of ampicillin (Perez & Anesini, 1994). Dahham and coworkers reported antifungal activities for methanol extracts of pomegranate; A. niger was the most affected one followed by P. citrinum, R. oryzae, T. reesei and M. indicus, respectively (Dahham et al., 2010). ndez and Capriles, antibacterial In another study conducted by Mele effects of pomegranate against E. coli, Enterobacter cloacae, P. fluorescens, Proteus vulgaris, Alcaligenes faecalis, Serratia marcescens, E. aerogenes, S. aureus, Arthrobacter globiformis, M. luteus, B. cereus, B. subtilis, B. coagulans, Micrococcus roseus, M. phlei, M. rodochrus and M. smegmatis were approved by inhibition zones of 11e31 mm ndez & Capriles, 2006). (Mele 4.1. Mechanism of bactericidal effect of pomegranate Anti-viral activities (against respiratory infections and influenza) of punicalin, punicalagin, gallic acid and ellagic acid are based on their abilities to hydrolyze tannins (Gil et al., 2000; Nonaka et al., 1990). Cyto protective effects of ellagic acid from PPE on oxidative induced damages in cells and DNA and also depletion of the nonprotein sulfhydryl pool, have been reported. PP phenolic compounds can precipitate membrane proteins which induce microbial cell lysis (Sestili et al., 2007). Phenolic compounds can precipitate microbial cell membrane proteins and/or protein sulfhydryl groups and at the same time inhibit enzymes such as glycosyltransferases which finally break down bacterial cells (Naz, Siddiqi, Ahmad, Rasool, & Sayeed, 2007; Vasconcelos, Sampaio, Sampaio, & Higino, 2003). Anti-viral effect of pomegranate is assigned to the

65

ability of the phenolic compounds to inhibit RNA replication (Haidari, Ali, WardCasscells, & Madjid, 2009). It has been shown that phenolic compounds of the peel could directly damage the virus structure or indirectly inhibit virus replication (Kotwal, 2008). Pomegranate encompasses oligomeric ellagitannin with a degree of polymerization of up to 5 core glucose units which is responsible for the antibacterial activity of the pomegranate, although anthocyanins and flavonols may play synergistic role as well (Howell and D'Souza, 2013). 5. Pomegranate application in nanotechnology Bioactive compounds present in pomegranate have recently attracted the attention of nano scientists. They use pomegranate biocompounds to develop new nano structures like nanoemulsion, NPs, nanoliposomes, phytosomes, nanovesicles and niosomes which are widely used in drug delivery systems (Fig. 2). 5.1. Role of pomegranate in NPs biosynthesize NPs are smaller and have higher surface area than conventional particles which explain their high reactivity and ability to cross the cellular barriers (Maynard et al., 2006). Many researchers have reported the applications of PJ bioactive compounds for the synthesis of metal nanostructures. NPs have been synthesized through several methods. Chemical reduction reaction occurs between nanoparticle's precursor and a reducing agent that is replaced by a natural capping agent in green synthesis approach. Green method confers several benefits like using harmless and ecofriendly chemicals, and applicability in mild temperature and pressure thus does not waste energy (Meena Kumari, Jacob, & Philip, 2015). Researchers also found that by adjusting juice concentration, different shapes could be synthesized (Byranvand & Nemati Kharat, 2014). Application of pomegranate biocompounds in synthesizing different NPs has been summarized in Table 2. 5.2. Role of pomegranate in developing drug delivery systems Novel drug delivery process is based on introducing a drug molecule to the target organ and according to the amount required by the diseased tissue (Jain, Jain, & Mahajan, 2014). Different nanovehicles with diverse structures and biological activities have been developed and assayed for this purpose (Suri, Fenniri, & Singh, 2007). Below you could find some of the nanodelivery systems that have been applied in loading and transporting bioactive compounds of pomegranate: 5.2.1. Nanoemulsions Nanoemulsions are nanostructured delivery systems with nano size droplets and more bioavailability for the nutrients than conventional emulsions (Fryd & Mason, 2012). They are colloidal, solid, spherical, biphasic and thermodynamically unstable systems requiring emulsifier for stabilization (Bouchemal, Briancon, Perrier, & Fessi, 2004). Three types of nanoemulsion exist: (a) oil in water, (b) water in oil and (c) bi-continuous nanoemulsions (Jaiswal, Dudhe, & Sharma, 2015). Nanoemulsion properties like the droplet size depend significantly on the oily phase, thus choosing the appropriate oil phase is of critical importance (Bouchemal et al., 2004). High amounts of conjugated fatty acids, polyphenols and estrogen compounds in PSO contributing to its anti-inflammatory, antioxidant and antitumor properties (Lansky & Newman, 2007) have encouraged researchers to take a deeper insight into these health promoting properties. Thereby, Ferreira and coworkers decided to employ PSO and ketoprofen in nanoemulsion systems to improve their antinociceptive effect. They achieved higher stability

M. Karimi et al. / Trends in Food Science & Technology 69 (2017) 59e73

66

Fig. 2. a) nanoemulsion (modified from McClements, 2012), b) liposome (captured from Bozzuto & Molinari, 2015), c) phytosome (captured from Li et al., 2014). d) NPs (captured from Karimi et al., 2014), e) Nanovesicle (modified from Hwang et al., 2015), f) niosome (captured from Muzzalupo & Tavano, 2015).

Table 2 Application of pomegranate in synthesizing different NPs. PPa

Nano structure

PPEb Silver NPs (15e35 nm) PSOc PLEd Gold nanowire, Gold PE PSO NPs (5e20 nm) PPE PLE PJe

PJ P

P PLE PE PJ PEP PPEf

Au/GrO nanocomposite Silverestearate NPs bimetallic of Au-Ag NPs trigonal nanostructures flowerlike CuI microstructure Sulfur NPs iron NPs (<60. nm)

ZnO NPs (~60 nm) Polyethylenimine dextran sulfate NPs (~500 nm) PJ Dye sensitized nano solar cell PPEsg PPE-gelatin NPs (149.3 nm) a b c d e f g

Application

References

bactericidal effect against gram positive and gram negative bacteria, antibacterial activity toward Escherichia coli (E. coli), bacteriocide for different multi drug resistant human pathogens antibacterial activity against Candida albicans, Aspergillus flavus, Staphylococcus aureus, Salmonella typhi and Vibrio cholera, imaging and drug delivery applications in the human body, active against Streptobacillus sp. and Escherichia coli, targeted drug delivery for cancer, Arsenate sensing small containers in drug delivery and catalysis

(Boroumand et al., 2015; Chauhan, Upadhyay, Rishi, & Lokwani, 2012; Sadrolhosseini, Rashid, Noor, Kharazmi, & Mehdipour, 2015; Yang, Ren, Wang, & Wang, 2016). (Basavegowda, Sobczak-Kupiec, Fenn, & Dinakar, 2013; Byranvand & Nemati Kharat, 2014; Elia et al., 2014; Ganeshkumar, Sathishkumar, Ponrasu, Dinesh, & Suguna, 2013; Lokina et al., 2014; Rao et al., 2013; Sadrolhosseini, Noor, Husin, & Sairi, 2014) (Mohammadi, Ranjbar, & Targholizadeh, 2016)

catalysts in the reduction of 2, 3, 4 nitrophenols to the corresponding amines and in the degradation of methyl orange

(Bakirdere et al., 2015) (Meena Kumari et al., 2015) (Tavakoli, Salavati-Niasari, & Mohandes, 2013)

antibacterial agent against Group A Streptococcus local oral mucosa delivery

(Salem et al., 2016; Machado, Pacheco, Nouws, Albergaria, & Delerue-Matos, 2015; Mystrioti, Xanthopoulou, Tsakiridis, Papassiopi, & Xenidis, 2016; Mystrioti et al., 2015). (Akash, Shantha Kumar, & Dhamodhar, 2015) (Tiyaboonchai et al., 2015)

apoptotic effects on leukemia cells HL60

(Behjat et al., 2015; Adithi et al., 2013) (Li, Percival, Bonard, & Gu, 2011)

Cr(VI) reduction, hexavalent chromium removal from contaminated waters

PP: Pomegranate Part. PPE: Pomegranate Peel Extract. PSO: Pomegranate Seed Oil. PLE: Pomegranate Leave Extract. PJ: Pomegranate Juice. PEP: Pomegranate epicarp. PPEs: Purified Pomegranate Ellagitannins.

M. Karimi et al. / Trends in Food Science & Technology 69 (2017) 59e73

of ketoprofen's against UVC radiation, drug releasing efficiency of 100% and the ability to reduce abdominal constrictions (Ferreira et al., 2016). Evaluating antitumor activity of ketoprofen-loaded PSO nanoemulsion against glioma cells in vitro indicated that they successfully delayed the UVC radiation-induced ketoprofen degradation, while achieved the controlled release of about 95.0% of ketoprofen in 5 h. The results of fibroblasts viability tests confirmed that these nanostructures could hold promise for the treatment of glioma cells (Ferreira et al., 2015). PSO nanoemulsion (Nano PSO) with the average size of 135 nm was prepared according to the sonication method mentioned by Mizrahi and colleagues. PSO was used to treat TgMHu2ME199K mice in the natural form and in the form of water soluble nanoemulsion to study its preventative and curative effects on neurodegenerative diseases. Results of this study confirmed the neuroprotective effect of nano-PSO to postpone disease symptoms (Mizrahi et al., 2014). PSO contains great amounts of very strong antioxidants called punicic acid, which is assumed to overcome sensitivity to oxidative stress as a main reason of progressive irreparable brain injury. Thus young and asymptomatic mice, along with older and already sick TgMHu2ME199K mice, were treated with either natural PSO or nano-PSO as model of Creutzfeldt-Jacob disease (gCJD) for several months. It was revealed that deferring the disease onset in young Tgs is only achieved by feeding large amounts of PSO while the same results were gained by lower doses of nano-PSO. Nano-PSO treatments showed strong neuroprotective effect since it could lessen lipid oxidation and neuronal loss and restore neurogenesis (Gabizon et al., 2014). In another study conducted by Binyamin and colleagues and under the light of the previous findings, both natural PSO and nanoPSO were introduced to experimentally autoimmune encephalomyelitis (EAE) -afflicted mice (as a model of Multiple Sclerosis (MS)). While both PSO and nano-PSO offered hope as a remedy to reduce the presentations of the EAE, nano-PSO was not only much more effective in controlling EAE but also were successful in lessening the demyelination and lipids oxidation rates in the brains of the EAE-afflicted animals (Binyamin et al., 2015). In another study PSO nanoemulsions were loaded with polyphenol-rich ethyl acetate and their anti-hemolytic effect on the oxidative damage in human red blood cells were proved. Their photosafety effects were approved through the reduced degradation of the membrane proteins, lessened oxidative damage and disruption of the membranes which make them a protective weapon against adverse effects of sunlight on skin (Baccarin, Mitjans, Ramos, Lemos-Senna, & Vinardell, 2015a). PE, punicalagin and ellagic acid were encapsulated in poly (d,l-lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) NPs to increase the bioavailability and half-life of pomegranate polyphenols. They were then labeled by Alexa Fluor-488 NPs and traced in MCF-7 breast cancer cells up to 24-h to see their effects on the progression profile of the cancer. Their effects on proliferation were surprising since they retarded the spreading rate of breast cancer cells in dimensions much bigger than free compounds (Shirode et al., 2015). In another study on the healing compounds of pomegranate, nanostructure lipid carriers (NLCs) were loaded with ellagic acid rich (EPP) compounds with anti-tyrosinase activity using warm microemulsion method. This delivery vehicle with the enhanced bioavailability and penetrability of the active compounds could be used in beauty products. Controlled release of ellagic acid from the EPP loaded NLCs were achieved after 12 h following the Higuchi's model. The penetration efficiency of NLCs improved significantly compared to the products containing free EPP (Tokton, Ounaroon, Panichayupakaranant, & Tiyaboonchai, 2014). In a study conducted by Lu and colleagues in 2015, transresveratrol-loaded self-nanoemulsifying drug delivery system

67

containing PSO (RES SNEDDS-PSO) was developed. Comparing anticancer efficiency of SNEDDS containing PSO versus SNEDDS containing other types of oily phase in battle with MCF-7 breast cancer cells showed that PSO synergistically acts with resveratrol and exponentially increase the anti-inflammatory and anticancer activities of RES SNEDDS-PSO. Dilution of these drug vehicle systems with water yields nanoemulsions (44 nm) which could improve water solubility and thus stability of intestinal fluid of resveratrol (Lu et al., 2015). It is assumed that PSO nanoemulsion loaded with the polyphenol-rich ethyl acetate provide protection against sunlight; thus keratinocyte HaCaT cell line were exposed to UVB (90e200 mJ/ cm2) rays after treating with the aforementioned nanoemulsions and they were well regarded as photoprotective agents (Baccarin et al., 2015b). 5.2.2. NPs NPs are particles with less than 100 nm magnitude in at least one dimension and their small size facilitate their adsorption by cells thus; they could be an appropriate vehicle for drug delivery purposes. Drugs could be transported via adhering to the surface of the NPs or assimilating with the NPs (Yokoyama, 2005). In a study conducted by Golbashy and colleagues, polyphenol from PP were loaded into montmorillonite (MMT) clay to increase the bioavailability, half-life, and solubility, and decrease the high oxidation rate (in pH 7 and more) of polyphenols. These polyphenol-loaded NPs could be used for drug delivery purposes, although the hydrophilic nature of montmorillonite made it more applicable in cosmetic applications (Golbashy, Sabahi, Allahdadi, Nazokdast, & Hosseini, 2016). Mucoadhesive polyethylenimine-dextran sulfate NPs (PDNPs) were loaded with PPE to form a mucoadhesive drug delivery system against oral bacteria with the extended release property and long-term efficacy (Tiyaboonchai, Rodleang, & Ounaroon, 2015). Gold NPs with a narrow particle size were fabricated through green method using PPE, then, functionalized with folic acid to be employed as drug delivery system to target cancer cells with high affinity. In vitro cytotoxicity of 5-Fu was assayed versus 5Fu@PAuNPs-Fa in MCF-7 cells (breast cancer). The result showed that IC50 of 5Fu@PAuNPs-Fa was much lower than that of free 5-Fu (Ganeshkumar et al., 2013). 5.2.3. Phytosomes This novel drug delivery system is formed by binding polyphenol with phospholipids like phosphatidylcholine (PC), in fact in this complex one or more molecules of PC encompass one polyphenol molecule. The amphipathic nature of this phytosome allows its penetration to the cell membranes, and ushering the polyphenol into the cell (Kidd, 2009) while bioactive components remain intact and do not break down by intestinal enzymes and gut bacteria. Pande and coworkers fabricated phytosomes from polyphenols of PP and PC and approved the higher bioavailability of these drug delivery systems (Pande, Wagh, Bhagure, Patil, & Deshmukh, 2015). 5.2.4. Nanovesicles Vesicles are well-organized complexes made of one or more concentric bilayers. They are fabricated when amphiphilic precursors self-accumulate in aquatic environment. When using vesicles as drug delivery vehicles, much lower levels are required to traditional drug delivery systems owing to transportation of the drug to its desired site of action. These newly developed targeted delivery systems offer advantages like: enabling to encapsulate both hydrophilic and hydrophobic drugs, enhancing the bioavailability of drugs, slowing the rate of drug break down, extend the drug half-life, stabilizing sensitive drugs, lessening the toxic and side effects of drugs (Jain et al., 2014).

68

M. Karimi et al. / Trends in Food Science & Technology 69 (2017) 59e73

In a study conducted by Kaur and Saraf, nanovesicles were loaded with PE to benefit from photo protecting, antioxidant, and anti-carcinogenic properties of PE. These PE loaded nanovesicles were combined in cream and compared with conventional cream formulations in in vivo assays and the result confirmed that skin properties and biochemical parameters improved in newly formulated creams (Kaur & Saraf, 2011). 5.2.5. Nanoliposomes Concentric bilayer vesicles are called liposomes. They are mainly composed of phosphatidylcholine and cholesterol (fluidity buffer agent). Liposomes have been regarded as targeted drug carrier systems (Jain et al., 2014). Altunkaya made liposome from L-aphosphatidylcholine and used as a natural model system to assay the antioxidant activity of PPE, PSE, and also their combinations with a-tocopherol (TOH), quercetin (QC) and ascorbic acid (AA). Pomegranate derived extracts could extend the lag phase especially when used with TOH or QC (Altunkaya, 2014). Aldose reductase inhibitory effect of PSE and pomegranate hull extracts (PHE) were compared in in vitro systems and IC50 of PHE was found much less than that of PSE. Besides, their antioxidant activities were compared by DPPH test and showed that PHE was more successful and could more effectively protect the peroxidase induced injuries in liposomal membrane compared to the other studied biocompounds (Karasu et al., 2012). In another study, the antioxidant activity of punicalagin and the methanol extract was approved using a liposome model system (Kulkarni et al., 2004). Gallocatechin, gallocatechin-(4e8)-catechin, gallocatechin-(4e8)-gallocatechin and catechin-(4e8)-gallocatechin from PP were assayed in terms of their capability to induce peroxidation of phosphatidylcholine liposomes and free radical scavenging. Results indicated that prodelphinidin had the highest antioxidant ability compared to the other compounds (Plumb, De Pascual-Teresa, Santos-Buelga, Rivas-Gonzalo, & Williamson, 2002). 5.2.6. Niosome Drawbacks coming along with liposome like loose structure, inefficiency for encapsulating hydrophilic drug, high costs and low circulation time in body accompanied by the need to cryogenic liquids for their transportation (Altunkaya, 2014) have encouraged scientists to design new structures for drug delivery purposes with improved entrapment efficiency and bioavailability that do not suffer from the above mentioned issues. Niosomes are lamellar vesicles which are formed by interacting non-ionic surfactants (mainly of alkyl or dialkyl polyglycerol ether class) and cholesterol in aqueous solution (Jain et al., 2014). In effort to use the maximum healing effects of pomegranate bioactive compounds and provide the most protection against hydrolysis, punicalagin from PPE was encapsulated with the varying ratios of non-ionic surfactant to cholesterol. Niosome F7 formula containing the surfactant: cholesterol: drug ratio of 7:1:1 was the smallest niosome and possessed the maximum entrapment efficiency (Hanu & Harmanpreet, 2012). 6. Conclusions Evidences on the health beneficial properties of pomegranate are so abundant that cannot be neglected, but still the need to conduct more comprehensive studies to completely find its importance to human health is deeply felt. Suggesting its use on a daily basis should be based on prolonged studies on human. In vitro digestion study of PJ revealed that oppose to anthocyanins, phenolics do not change during digestion, which necessities complementary studies before establishing the chemo preventive ability of pomegranate against different kinds of cancer. Although using

pomegranate has been widespread for a long time in several nations and without any unpleasant consequences but still safety verification, clinical trials, considering the chemical profile and establishing the toxicological limit, before its vast use in current medication, seems inevitable. However, consuming the decoction of the tree bark, and pericarps of the fruit, may leave some toxic effects, thus more remains to be discovered. Lots of studies presenting the antibacterial and antiviral activities of pomegranate have been the results of in vitro cell-based assays, which require in vivo assays as well to be more reliable. Pomegranate application in nanotechnology is still a very new field of science and only a few of this road has been walked. Finding more applications especially in medicine and cancer treatment needs so much more studies on the safety and applicability issues. References Abbasi, H., Rezaei, K., Emamdjomeh, Z., & Mousavi, S. M. E. (2008). Effect of various extraction conditions on the phenolic contents of pomegranate seed oil. European Journal of Lipid Science and Technology, 110, 668. Ackland, M. L., Van DeWaarsenburg, S., & Jones, R. (2005). Synergistic antiproliferative action of the flavonols quercetin and kaempferol in cultured human cancer cell lines. In Vivo, 19, 69e76. Adams, L. S., Seeram, N. P., Aggarwal, B. B., Takada, Y., Sand, D., & Heber, D. (2006). Pomegranate juice, total pomegranate ellagitannins, and punicalagin suppress inflammatory cell signaling in colon cancer cells. Journal of Agricultural and Food Chemistry, 54, 980e985. Adhami, V. M., Siddiqui, I. A., Syed, D. N., Lall, R. K., & Mukhtar, H. (2012). Oral infusion of pomegranate fruit extract inhibits prostrate carcinogenesis in the TRAMP model. Carcinogenesis, 33, 644e651. Adiga, S., Tomar, P., & Rajput, R. R. (2010). Effect of Punica granatum peel aqueous extraction normal and dexamethasone suppressed wound healing in wistar rats. International Journal of Pharmaceutical Sciences Review and Research, 5, 134e140. Adithi, U., Thomas, S., Uma, V., & Pradeep, N.. (2013). Electrical characterization of dye sensitized nano solar cell using natural pomegranate juice as photosensitizer. Paper presented at the AIP Conference Proceedings, 1512, 208e209. Afaq, F., Hafeez, B., Syed, D. N., Kweon, M. H., & Mukhtar, H. (2010). Oral feeding of pomegranate fruit extract inhibits early biomarkers of UVB radiation induced carcinogenesis in SKH-1 hairless mouse epidermis. Photochemistry and Photobiology, 86(6), 1318e1326. Afaq, F., Saleem, M., Krueger, C. G., Reed, J. D., & Mukhtar, H. (2005). Anthocyaninand hydrolyzable tannin-rich pomegranate fruit extract modulates MAPK and NF-kappaB pathways and inhibits skin tumorigenesis in CD-1 mice. International Journal of Cancer, 113, 423e433. Akash, S., Shantha Kumar, S. S., & Dhamodhar, P. (2015). Inhibition of group a streptococcus by green synthesized zinc oxide nanoparticles. International Journal of Pharma and Bio Sciences, 6(2), P85eP98. Akbarpour, V., Hemmati, K., & Sharifani, M. (2009). Physicaland chemical properties of pomegranate (Punica granatum L.) fruit in maturation stage. AmericanEurasian Journal of Agricultural & Environmental Sciences, 6, 411e416. Akbarpour, V., Hemmati, K., Sharifari, M., & Sadr, Z. B. (2010). Multivariate analysis of physical and chemical characteristics in some pomegranate (Punica granatum L.) cultivars of Iran. Journal of Food, Agriculture and Environment, 8, 244e248. Akhavan, H., Barzegar, M., Weidlich, H., & Zimmermann, B. F. (2015). Phenolic compounds and antioxidant activity of juices from ten Iranian pomegranate cultivars depend on extraction. Hindawi Publishing Corporation Journal of Chemistry, 7, 1e7. Al-Maiman, S. A., & Ahmad, D. (2002). Changes in physical and chemical properties during pomegranate (Punica granatum L.) fruit maturation. Food Chemistry, 76, 437e441. Al-Muammar, M. N., & Khan, F. (2012). Obesity, the preventive role of the pomegranate (Punica granatum). Nutrition, 28, 595e604. Al-Said, F. A., Opara, L. U., & Al-Yahyai, R. A. (2009). Physico-chemical and textural quality attributes of pomegranate cultivars (Punica granatum L.) grown in the Sultanate of Oman. Journal of Food Engineering, 90, 129e134. Al-Zoreky, N. S. (2009). Antimicrobial activity of pomegranate (Punica granatum L.) fruit peels. International Journal of Food Microbiology, 134, 244e248. Albrecht, M., Jiang, W., Kumi-Diaka, J., Lansky, E. P., Gommersall, L. M., Patel, A., et al. (2004). Pomegranate extracts potently suppress proliferation, xenograft growth, and invasion of human prostate cancer cells. Journal of Medicinal Food, 7(3), 274e283. Alekperov, U. K. (2002). Plant antimutagens and their mixtures in inhibition of genotoxic effects of xenobiotics and aging processes. European Journal of Cancer Prevention, 2, 8e11. Althunibat, O. Y., Al-Mustafa, A. H., Tarawneh, K., Khleifat, K. M., Ridzwan, B. H., & Qaralleh, H. N. (2010). Protective role of Punica granatum L peel extract against oxidative damage in experimental diabetic rats. Process Biochemistry, 45, 581e585. Altunkaya, A. (2014). Potential antioxidant activity of pomegranate peel and seed

M. Karimi et al. / Trends in Food Science & Technology 69 (2017) 59e73 extracts and synergism with added phenolic antioxidants in a liposome system: A preliminary study. Irish Journal of Agricultural and Food Research, 53(2), 121e131. Amorim, L. F., Catanho, M. T. J. A., Terra, D. A., Brandao, K. C., Holanda, C. M. C. X., Jales-Junior, L. H., et al. (2003). Assessment of the effect of Punica granatum (pomegranate) on the bioavailability of the radiopharmaceutical sodium pertechnetate (99mTc) in wistar rats. Cellular and Molecular Biology, 49, 501e507. Amrutesh, S. (2011). Dentistry & Ayurveda Van evidence based approach. International Journal of Clinical Dental Science, 2(1), 3e9. Aslama, M. N., Lansky, E. P., & Varani, J. (2006). Pomegranate as a cosmeceutical source, Pomegranate fractions promote proliferation and procollagen synthesis and inhibit matrix metalloproteinase-1 production in human skin cells. Journal of Ethnopharmacology, 103, 311e318. Aviram, M. (2002). In Pomegranate juice as a major source for polyphenolic flaVonoids and it is most potent antioxidant against LDL oxidation and atherosclerosis. In Proceedings of the 11th biennal meeting of the society for free radical research international, Paris, France (pp. 523e528). Paris, France: Medimond Inc. Aviram, M., & Dornfeld, L. (2001). Pomegranate juice consumption inhibits serum angiotensis converting enzyme activity and reduces systolic blood pressure. Atherosclerosis, 158, 195e198. Aviram, M., Dornfeld, L., Rosenblat, M., Volkova, N., Kaplan, M., Coleman, R., et al. (2000). Pomegranate juice consumption reduces oxidative stress, atherogenic modifications to LDL, and platelet aggregation, studies in humans and in atherosclerotic apolipoprotein E-deficient mice. American Journal of Clinical Nutrition, 71, 1062e1076. Aviram, M., Rosenblat, M., Gaitini, D., Nitecki, S., Hoffman, A., Dornfeld, L., et al. (2004). Pomegranate juice consumption for 3 years by patients with carotid artery stenosis reduces common carotid intima-media thickness, blood pressure and LDL oxidation. Clinical Nutrition, 23, 423e433. Aviram, M., Volkova, N., Coleman, R., Dreher, M., Reddy, M. K., Ferreira, D., et al. (2008). Pomegranate phenolics from the peels, arils, and flowers are antiatherogenic: Studies in vivo in atherosclerotic apolipoproteine-deficient (E0) mice and in vitro incultured macrophages and lipoproteins. Journal of Agricultural and Food Chemistry, 56, 1148e1157. Azadzoi, K. M., Schulman, R. N., Aviram, M., & Siroky, M. B. (2005). Oxidative stress in arteriogenic erectile dysfunction, prophylactic role of antioxidants. Journal of Urology, 174, 386e393. Baccarin, T., Mitjans, M., Lemos-Senna, E., & Vinardell, M. P. (2015). Protection against oxidative damage in human erythrocytes and preliminary photosafety assessment of Punica granatum seed oil nanoemulsions entrapping polyphenolrich ethyl acetate fraction. Toxicology in Vitro, 30(1), 421e428. Baccarin, T., Mitjans, M., Ramos, D., Lemos-Senna, E., & Vinardell, M. P. (2015). Photoprotection by Punica granatum seed oil nanoemulsion entrapping polyphenol-rich ethyl acetate fraction against UVB-induced DNA damage in human keratinocyte (HaCaT) cell line. Journal of Photochemistry and Photobiology B: Biology, 153, 127e136. Bakirdere, S., Yilmaz, M. T., Tornuk, F., Keyf, S., Yilmaz, A., Sagdic, O., et al. (2015). Molecular characterization of silver-stearate nanoparticles (AgStNPs): A hydrophobic and antimicrobial material against foodborne pathogens. Food Research International, 76, 439e448. Bakkiyaraj, D., Nandhini, J. R., Malathy, B., & Pandian, S. K. (2013). The anti-biofilm potential of pomegranate (Punica granatum L.) extract against human bacterial and fungal pathogens. Biofouling, 29(8), 929e937. Basavegowda, N., Sobczak-Kupiec, A., Fenn, R. I., & Dinakar, S. (2013). Bioreduction of chloroaurate ions using fruit extract Punica granatum (pomegranate) for synthesis of highly stable gold nanoparticles and assessment of its antibacterial activity. Micro & Nano Letters, 8(8), 400e404. Behjat, A., Jafari Nodoushan, F., Khoshroo, A., & Ghoshani, M. (2015). Study of the effect of titanium dioxide nano particle size on efficiency of the dye-sensitized solar cell using natural pomegranate juice. Iranian Journal of Physics Research, 14(4), 361e367. Behzadi Shahrbabaki, H. (1998). Genetic diversity of pomegranate genotypes in Iran. Nashr Amoozesh Keshavarzi (p. 265). Biale, J. B. (1981). Respiration and ripening in fruits-retrospect and prospect. In J. Friend, & M. J. Rhodes (Eds.), Recent advances in the biochemistry of fruits and vegetables (pp. 1e39). London: Academic Press. Binyamin, O., Larush, L., Frid, K., Keller, G., Friedman-Levi, Y., Ovadia, H., et al. (2015). Treatment of a multiple sclerosis animal model by a novel nanodrop formulation of a natural antioxidant. International Journal of Nanomedicine, 10, 7165e7174. Block, G., Patterson, B., & Subar, A. (1992). Fruit, vegetables and cancer prevention: A review of the epidemiological evidence. Nutrition and Cancer, 18, 1e29. Borochov-Neori, H., Judeinstein, S., Harari, M., Bar-Ya’akov, I., Patil, B. S., Lurie, S., et al. (2011). Climate effects on anthocyanin accumulation and composition in the pomegranate (Punica granatum L.) fruit arils. Journal of Agricultural and Food Chemistry, 59, 5325e5334. Borochov-Neori, H., Judeinstein, S., Tripler, E., Harari, M., Greenberg, A., Shomer, I., et al. (2009). Seasonal and cultivar variations in antioxidant and sensory quality of pomegranate (Punica granatum L.) fruit. Journal of Food Composition and Analysis, 22, 189e195.  Boroumand, M. N., Montazer, M., Simon, F., Liesiene, J., Saponjic, Z., & Dutschk, V. (2015). Novel method for synthesis of silver nanoparticles and their application on wool. Applied Surface Science, 346, 477e483. Bouchemal, K., Briancon, S., Perrier, E., & Fessi, H. (2004). Nano-emulsion formulation using spontaneous emulsification: Solvent, oil and surfactant

69

optimisation. International Journal of Pharmaceutics, 280, 241e251. Bozzuto, G., & Molinari, A. (2015). Liposomes as nanomedical devices. International Journal of Nanomedicine, 10, 975e999. Brodie, L. (2009). Pomegranate production in South Africa. South African Fruit Journal, 8, 30e35. Bruijn, C. D., Christ, F. R., Dziabo, A. J. (2003) Ophthalmic, pharmaceutical and other healthcare preparations with naturally occurring plant compounds, extracts and derivatives. US Patent Application 20030086986. Brusselmans, K., Vrolix, R., Verhoeven, G., & Swinnen, J. V. (2005). Induction of cancer cell apoptosis by flavonoids is associated with their ability to inhibit fatty acid synthase activity. Journal of Biological Chemistry, 280, 5636e5645. Bub, A., Watzl, B., Blockhaus, M., Briviba, K., Liegibel, U., Muller, H., et al. (2003). Fruit juice consumption modulates antioxidative status, immune status and DNA damage. The Journal of Nutritional Biochemistry, 14(2), 90e98. Byranvand, M. M., & Nemati Kharat, A. (2014). One pot green synthesis of gold nanowires using pomegranate juice. Materials Letters, 13464e13466. Cerda, B., Ceron, J. J., Tomas-Barberan, F. A., & Espin, J. C. (2003). Repeated oral administration of high doses of the pomegranate ellagitannin punicalagin to rats for 37 day is not toxic. Journal of Agricultural and Food Chemistry, 51, 3493e3501. nchez-Gasco n, F., Tom Cerda, B.1, Soto, C., Albaladejo, M. D., Martínez, P., Sa asn, F., et al. (2006). Pomegranate juice supplementation in chronic Barbera obstructive pulmonary disease: A 5-week randomized, double-blind, placebocontrolled trial. European Journal of Clinical Nutrition, 60(2), 245e253. Chandra, R., Jadhav, V. T., & Sharma, J. (2010). Global scenario of pomegranate (Punica granatum L.) culture with special reference to India. In R. Chandra (Ed.), Pomegranate. Fruit, Vegetable and Cereal Science and Biotechnology (Vol. 4, pp. 7e18), 2. Chauhan, S., Upadhyay, M. K., Rishi, S., & Lokwani, P. (2012). Phytofabrication of silver nanoparticles through leaf extract of pomegranate fruit. International Journal of Pharmaceutical Sciences Review and Research, 12(1), 61e63. Chen, C. M., Li, S. C., Lin, Y. L., Hsu, C. Y., Shieh, M. J., & Liu, J. F. (2005). Consumption of purple sweet potato leaves modulates human immune response, Tlymphocyte functions, lytic activity of natural killer cell and antibody production. World Journal of Gastroenterology, 11(37), 5777e5781. Chevion, M. (1988). A site-specific mechanism for free radical induced biological damage: The essential role of redox-active transition metals. Free Radical Biology and Medicine, 5(1), 27e37. Cristofori, V., Caruso, D., Latini, G., Dell'Agli, M., Cammilli, C., Rugini, E., et al. (2011). Fruit quality of Italian pomegranate (Punica Punica granatum L.) autochthonous varieties. European Food Research and Technology, 232, 397e403. Cui, S. M., Sasada, Y., Sato, H., & Nii, N. (2004). Cell structure and sugar and acid contents in the arils of developing pomegranate fruit. Journal of the Japanese Society for Horticultural Science, 73, 241e243. Dahham, S. S., Ali, M. N., Tabassum, H., & Khan, M. (2010). Studies on antibacterial and antifungal activity of pomegranate (Punica granatum L.). American-Eurasian Journal of Agricultural & Environmental Sciences, 9(3), 273e281. Damiani, E., Aloia, A. M., Priore, M. G., Nardulli, S., & Ferrannini, A. (2009). Pomegranate (Punica granatum) allergy, clinical and immunological findings. Annals of Allergy, Asthma & Immunology, 103, 178e180. da Silva, J. A. T., Singh, R. T., Narzaryd, D., Vermae, N., Meshramf, D. T., & Ranade, S. A. (2013). Pomegranate biology and biotechnology, a review. Scientia Horticulturae, 160, 85e107. Dell'Agli, M., Galli, G. V., Bulgari, M., Basilico, N., Romeo, S., Bhattacharya, D., et al. (2010). Ellagitannins of the fruitrind of pomegranate (Punica granatum) antagonize in vitro the host inflammatory response mechanisms involved in the onset of malaria. Malaria Journal, 9, 208. Dell'Agli, M., Galli, G. V., Corbett, Y., Taramelli, D., Lucantoni, L., Habluetzel, A., et al. (2009). Antiplasmodial activity of Punica granatum L. fruit rind. Journal of Ethnopharmacology, 125, 279e285. de Nigris, F., Williams-Ignarro, S., Lerman, L. O., Crimi, E., Botti, C., Mansueto, G., et al. (2005). Beneficial effects of pomegranate juice on oxidation-sensitive genes and endothelial nitric oxide synthase activity at sites of perturbed shear stress. Proceedings of the National Academy of Sciences of the United States of America, 102(13), 4896e4901. Devatkal, S. K., Jaiswal, P., Jha, S. N., Bharadwaj, R., & Viswas, K. N. (2011). Antibacterial activity of aqueous extract of pomegranate peel against Pseudomonas stutzeri isolated from poultry meat. Journal of Food Science and Technology, 48, 1e6. Elfalleh, W., Hannachi, H., Guetat, A., Tlili, N., Guasmi, F., Ferchichi, A., et al. (2012). Storage protein and amino acid contents of Tunisian and Chinese pomegranate (Punica granatum L.) cultivars. Genetic Resources and Crop Evolution, 59, 999e1014. Elia, P., Zach, R., Hazan, S., Kolusheva, S., Porat, Z., & Zeiri, Y. (2014). Green synthesis of gold nanoparticles using plant extracts as reducing agents. International Journal of Nanomedicine, 9(1), 4007e4021. El-Nemr, S. E., Ismail, I. A., & Ragab, M. (1990). Chemical composition of juice and seeds of pomegranate fruit. Die Nahrung, 34, 601e606. van Elswijk, D. A., Schobel, U. P., Lansky, E. P., Irth, H., & van der Greef, J. (2004). Rapid dereplication of estrogenic compounds in pomegranate (Punica granatum) using on-line biochemical detection coupled to mass spectrometry. Phytochemistry, 65, 233e241. Ender, P., Vural, G., & Nevzat, A. (2002). Organic acids and phenolic compounds inpomegranates (Punica granatum L.) grown in Turkey. Journal of Food Composition and Analysis, 15, 567e575.

70

M. Karimi et al. / Trends in Food Science & Technology 69 (2017) 59e73

Fadavi, A., Barzegar, M., & Azizi, M. H. (2006). Determination of fatty acids and total lipid content in oilseed of 25 pomegranates varieties grown in Iran. Journal of Food Composition and Analysis, 19, 676e680. Fawole, O. A., Opara, U. L., & Theron, K. I. (2012). Chemical and phytochemical properties and antioxidant activities of three pomegranate cultivars grown in South Africa. Food and Bioprocess Technology, 5, 425e444. Ferreira, L. M., Cervi, V. F., Gehrcke, M., da Silveira, E. F., Azambuja, J. H., Braganhol, E., et al. (2015). Ketoprofen-loaded pomegranate seed oil nanoemulsion stabilized by pullulan: Selective antiglioma formulation for intravenous administration. Colloids and Surfaces B: Biointerfaces, 130, 272e277. Ferreira, L. M., Sari, M. H. M., Cervi, V. F., Gehrcke, M., Barbieri, A. V., Zborowski, V. A., et al. (2016). Pomegranate seed oil nanoemulsions improve the photostability and in vivo antinociceptive effect of a non-steroidal anti-inflammatory drug. Colloids and Surfaces B: Biointerfaces, 144, 214e221. Fischer, U. A., Carle, R., & Kammerer, D. R. (2011). Identification and quantification of phenolic compounds from pomegranate (Punica granatum L.) peel, mesocarp, aril and differently produced juices by HPLC-DADeESI/MS. Food Chemistry, 127, 807e821. Foss, S. R., Nakamura, C. V., Ueda-Nakamura, T., Cortez, D. A. G., Endo, E. H., & Dias Filho, B. P. (2014). Antifungal activity of pomegranate peel extract and isolated compound punicalagin against dermatophytes. Annals of Clinical Microbiology and Antimicrobials, 13, 32. Fryd, M. M., & Mason, T. G. (2012). Advanced nanoemulsions. Annual Review of Physical Chemistry, 63, 493e518. Gabizon, R., Mizrahi, M., Friedman-Levy, Y., Larush, L., Frid, K., Binyamin, O., et al. (2014). Novel pomegranate oil nano-emulsions for the prevention and treatment of neurodegenerative diseases: The case of genetic CJD. Neurology, 82, 236e235. Ganeshkumar, M., Sathishkumar, M., Ponrasu, T., Dinesh, M. G., & Suguna, L. (2013). Spontaneous ultra fast synthesis of gold nanoparticles using punica granatum for cancer targeted drug delivery. Colloids and Surfaces B: Biointerfaces, 106, 208e216. George, J., Singh, M., Srivastava, A. K., Bhui, K., & Shukla, Y. (2011). Synergistic growth inhibition of mouse skin tumors by pomegranate fruit extract and diallyl sulfide: Evidence for inhibition of activated MAPKs/NF-kB and reduced cell proliferation. Food and Chemical Toxicology, 49(7), 1511e1520. Gil, M., Garcia-Viguera, C., Artes, F., & Tomas-Barberan, F. (1995). Changes in pomegranate juice pigmentation during ripening. Journal of the Science of Food and Agriculture, 68, 77e81. Gil, M. I., Tomas-Barberan, F. A., Hess-Pierce, B., Holcroft, D. M., & Kader, A. A. (2000). Antioxidant activity of pomegranate juice and its relationship with phenolic composition and processing. Journal of Agricultural and Food Chemistry, 48, 4581e4589. Golbashy, M., Sabahi, H., Allahdadi, I., Nazokdast, H., & Hosseini, M. (2016). Synthesis the montmorillonite- pomegranate (punicagranatum l.) peel polyphenols nanostructure as a drug delivery vehicle. Biomedical and Pharmacology Journal, 9(1), 385e392. Grove, P., & Grove, C. (2008). Curry, spice and all things nice e the what, where and when. Surrey, UK: Grove Publications. http//www.menumagazine.co.uk/book/ azpomegranate.htm. Guojian, L. (1995) Body weight-reducing soaps containing algae and plant extracts. Chinese Patent CN 1, 104, 246. Haidari, M., Ali, M., WardCasscells, S., 3rd, & Madjid, M. (2009). Pomegranate (Punica granatum) purified polyphenol extract inhibits influenza virus and has a synergistic effect with oseltamivir. Phytomedicine: International Journal of Phytotherapy and Phytopharmacology, 16, 1127e1136. Halvorsen, B. L., Holte, K., Myhrstad, M. C., Barikmo, I., Hvattum, E., Remberg, S. F., et al. (2002). A systematic screening of total antioxidants in dietary plants. Journal of Nutrition, 132, 461e471. Hanu, P., & Harmanpreet, S. (2012). Formulation and evaluation of niosomes containing punicalagin from peels of punica granatum. Journal of Drug Delivery & Therapeutics, 2(6), 56e67. Hayrapetyan, H., Hazeleger, W. C., & Beumer, R. R. (2012). Inhibition of Literis monocytogenes by pomegranate (Punica granatum L.) peel extract in meat pate ate different temperatures. Food Control, 23, 66e72. Hegde, C. R., Madhuri, M., Swaroop, T. N., Das, A., Bhattacharya, S., & Rohit, K. C. (2012). Evaluation of antimicrobial properties, phytochemical contents and antioxidant capacities of leaf extracts of Punica granatum L. ISCA Journal of Biological Science, 1, 32e37. Hernandez, F., Melgarejo, P., Tomas-Barberran, F. A., & Artes, F. (1999). Evolution of juice anthocyanins during ripening of new selected pomegranate (Punica granatum) clones. European Food Research and Technology, 210, 39e42. Hertog, M. L. G., Sweetnam, P. M., Fehily, A. M., Elwood, P. C., & Kromhout, D. (1997). Antioxidant flavonols and ischaemic heart disease in Welsh population of men. The Caerphilly study. The American Journal of Clinical Nutrition, 65, 1489e1494. Hertog, M. L. G., van Poppel, G., & Verhoeven, D. (1997). Potentially anticarcinogenic s-Barbera n, & secondary metabolites from fruit and vegetables. In F. A. Toma R. J. Robins (Eds.), Phytochemistry of fruit and vegetables (pp. 13e329). Oxford, U.K.: Clarendon Press. Holland, D., Hatib, K., & Bar-Ya’akov, I. (2009). Pomegranate, botany, horticulture, breeding. Horticultural Reviews, 35, 127e191. Hora, J. J., Maydew, E. R., Lansky, E. P., & Dwivedi, C. (2003). Chemopreventive effect of pomegranate seed oil on skin tumor development in CD1 mice. Journal of Medicinal Food, 6, 157e161. Hornung, E., Pernstich, C., & Feussner, I. (2002). Formation of conjugated _11_13-

double bonds by _12-linoleic acid (1,4)-acyl-lipid-desaturase in pomegranate seeds. European Journal of Biochemistry, 269, 4852e4859. Hossin, F. L. A. (2009). Effect of Pomegranate (Punica granatum) peels and it's extract on obese hypercholesterolemic rats. Pakistan Journal of Nutrition, 8, 1251e1257. Howell, A. B., & D'Souza, D. H. (2013). The pomegranate: Effects on bacteria and viruses that influence human health, evidence-based complementary and alternative medicine (Vol. 2013, pp. 1e11). Hwang, D. W., Choi, H., Jang, S. C., Yoo, M. Y., Park, J. Y., Choi, N. E., et al. (2015). Noninvasive imaging of radiolabeled exosome-mimetic nanovesicle using 99m tc-HMPAO. Scientific Reports, 5. http://dx.doi.org/10.1038/srep15636. Ibrahim, M. I. (2010). Efficiency of pomegranate peel extract as antimicrobial, antioxidant and protective agents. World Journal of Agricultural Research Science, 6, 338e344. Iran Statistical Yearbook 1392 [March 2013-March 2014] (pp. 23e24). (2013). Presidency, Management and Planning Organization, Statistical Centre of Iran, Tehran, Statistical Centre of Iran. Ismail, T., Sestili, P., & Akhtar, S. (2012). Pomegranate peel and fruit extracts: A review of potential anti-inflammatory and anti-infective effects. Journal of Ethnopharmacology, 143, 397e405. Jain, S., Jain, V., & Mahajan, S. C. (2014). Lipid based vesicular drug delivery systems. Article ID 574673 Advances in Pharmaceutics, 2014, 12. http://dx.doi.org/10.1155/ 2014/574673. Jaiswal, V., DerMarderosian, A., & Porter, J. R. (2010). Anthocyanins and polyphenol oxidase from dried arils of pomegranate (Punica granatum L.). Food Chemistry, 118, 11e16. Jaiswal, M., Dudhe, R., & Sharma, P. K. (2015). Nanoemulsion: An advanced mode of drug delivery system. Biotechnology, 5(2), 123e127. Jeune, M. A., Kumi-Diaka, J., & Brown, J. (2005). Anticancer activities of pomegranate extracts and genistein in human breast cancer cells. Journal of Medicinal Food, 8, 469e475. Julie, J. M. T. (2008). Theraupatic applications of pomegranate (Punica granatum L.). Alternative Medicine Review, 13, 123e144. Jyotsana, S., & Maity, A. (2010). Pomegranate phytochemicals, nutraceutical and therapeutical values. In R. Chandra (Ed.), Pomegranate. Fruit, Vegetable and Cereal Science and Biotechnology (Vol. 4, pp. 56e76). Kader, A. A. (2006). Postharvest biology and technology of pomegranates. In N. P. Seeram, et al. (Eds.), Pomegranates, ancient roots to modern medicine (pp. 211e220). Boca Raton, FL: CRC Press. Kaplan, M., Hayek, T., Raz, A., Coleman, R., Dornfeld, L., Vaya, J., et al. (2001). Pomegranate juice supplementation to atherosclerotic mice reduces macrophage lipid peroxidation, cellular cholesterol accumulation and development of atherosclerosis. Journal of Nutrition, 131(8), 2082e2089. Karasu, C., Cumaoǧlu, A., Gúrpinar, A. R., Kartal, M., Kovacikova, L., Milackova, I., et al. (2012). Aldose reductase inhibitory activity and antioxidant capacity of pomegranate extracts. Interdisciplinary Toxicology, 5(1), 15e20. Karimi, M., Habibi-Rezaei, M., Safari, M., Chaudhury, I., Jianjun, C., & Kokini, J. (2014). Immobilization of endo-inulinase on non-porous aminofunctionalized silica nanoparticles. Journal of Molecular Catalysis B Enzymatic, 104, 48e55. Kashiwada, Y., Nonaka, G. I., Nishioka, I., Chang, J. J., & Lee, K. H. (1992). Antitumor agents, 129. Tannins and related compounds as selective cytotoxic agents. Journal of Natural Products, 55, 1033e1043. Kaur, C. D., & Saraf, S. (2011). Photoprotective herbal extract loaded nanovesicular creams inhibiting ultraviolet radiations induced photoaging. International Journal of Drug Delivery, 3(4), 699e711. Kelloff, G. J., Boone, C. W., Crowell, J. A., Steele, V. E., Lubet, R., & Sigman, C. C. (1994). Chemopreventive drug development: perspectives and progress. Cancer Epidemiology, Biomarkers & Prevention: A Publication of the American Association for Cancer Research (Cosponsored by the American Society of Preventive Oncology), 3, 85e98. Khan, N., Afaq, F., Kweon, M. H., Kim, K., et al. (2007b). Oral consumption of pomegranate fruit extract inhibits growth and progression of primary lung tumors in mice. Cancer Research, 67, 3475e3482. Khan, N., Hadi, N., Afaq, F., Syed, D. N., et al. (2007a). Pomegranate fruit extract inhibits prosurvival pathways in human A549 lung carcinoma cells and tumor growth in athymic nude mice. Carcinogenesis, 28, 163e173. Khan, G. N., Gorin, M. A., Rosenthal, D., Pan, Q., Bao, L. W., Wu, Z. F., et al. (2009). Pomegranate fruit extract impairs invasion and motility in human breast cancer. Integrative Cancer Therapies, 8, 242e253. Kho, Y. L., Jung, W., Kwon, D., & Kim, J. H. (2010). Identification of estrone in pomegranate (punica granatum) extracts by liquid chromatography-tandem mass spectrometry. Food Science and Biotechnology, 19(3), 809e813. Kidd, P. M. (2009). Bioavailability and activity of phytosome complexes from botanical polyphenols: The silymarin, curcumin, green tea, and grape seed extracts. Alternative Medicine Review, 14(3), 226e246. Kim, M. M., Kim, S. (2002) Composition for improving oral hygiene containing Punica granatum L. extract. Korean Patent: KR 2002066042. Kim, N. D., Mehta, R., Yu, W. P., Neeman, I., Livney, T., Amichay, A., et al. (2002). Chemopreventive and adjuvant therapeutic potential of pomegranate (Punica granatum) for human breast cancer. Breast Cancer Research and Treatment, 71, 203e217. Kopparapu, N. K., Liu, Z., Yan, Q., Jian, Z., & Zhang, S. (2010). A novel thermostable chitinase (PJC) from pomegranate (Punica granatum L.). Food Chemistry, 127, 1569e1575. Kotwal, G. J. (2008). Genetic diversity-independent neutralization of pandemic viruses (e.g., HIV), potentially pandemic (e.g., H5N1 strain of influenza) and

M. Karimi et al. / Trends in Food Science & Technology 69 (2017) 59e73 carcinogenic (e.g., HBV and HCV) viruses and possible agents of bioterrorism (variola) by enveloped virus neutralizing compounds (EVNCs). Vaccine, 26, 3055e3058. Kowalski, I., Samojedny, A., Paul, M., Pietsz, G., & Wilczok, T. (2005). Effect of kaempferol on the production and gene expression of monocyte chemoattractant protein-1 in J7742 macrophages. Pharmacological Reports, 57, 107e112. Koyama, S., Cobb, L. J., Mehta, H. H., Seeram, N. P., Heber, D., Pantuck, A. J., et al. (2010). Pomegranate extract induces apoptosis in human prostate cancer cells by modulation of the IGFeIGFBP axis. Growth Hormone & IGF Research, 20, 55e62. Kulkarni, A. P., & Aradhya, S. M. (2005). Chemical change and antioxidant activity in pomegranate arils during fruit development. Food Chemistry, 93, 319e324. Kulkarni, A. P., Aradhya, S. M., & Divakar, S. (2004). Isolation and identification of a radical scavenging antioxidant - punicalagin from pith and carpellary membrane of pomegranate fruit. Food Chemistry, 87(4), 551e557. Lansky, E. P. (2000) Pomegranate supplements prepared from pomegranate material including pomegranate seeds. US Patent 6,060,063. Lansky, E. P., Harrison, G., Froom, P., & Jiang, W. G. (2005). Pomegranate (Punica granatum) pure chemicals show possible synergistic inhibition of human PC-3 prostate cancer cell invasion across Matrigel. Investigational New Drugs, 23, 121e122. Lansky, E. P., Jiang, W., Mo, H., Bravo, L., Froom, P., Yu, W., et al. (2005). Possible synergistic prostate cancer suppression by anatomically discrete pomegranate fractions. Investigational New Drugs, 23, 11e20. Lansky, E. P., & Newman, R. A. (2007). Punica granatum (pomegranate) and its potential for prevention and treatment of inflammation and cancer. Journal of Ethnopharmacology, 109, 177e206. Lansky, E., Shubert, S., & Neeman, I. (1998). Pharmacological and therapeutical properties of pomegranate. In P. Megarejo, J. J. Martínez, & J. Martínez (Eds.), Proceedings 1st international symposium on pomegranate. Orihuela, Spain: CIHEAM. Pr-07. Lansky, E., Shubert, S., & Neeman, I. (2004). Pharmacological and therapeutic properties of pomegranate. CIHEAMeOptions Mediterraneennes. Larrosa, M., Gonzalez-Sarrias, A., Garcia-Conesa, M. T., Tomas-Barberan, F. A., & Espin, J. C. (2006). Urolithins, ellagic acid-derived metabolites produced by human colonic microflora, exhibit estrogenic and antiestrogenic activities. Journal of Agricultural and Food Chemistry, 54, 1611e1620. Larrosa, M., Tomas-Barberan, F. A., & Espin, J. C. (2005). The dietary hydrolysable tannin punicalagin releases ellagic acid that induces apoptosis in human colon adenocarcinoma Caco-2 cells by using the mitochondrial pathway. The Journal of Nutritional Biochemistry, 17(9), 611e625. Lee, J. H., & Talcott, S. T. (2002). Ellagic acid and ellagitannins affect on sedimentation in muscadine juice and wine. Journal of Agricultural and Food Chemistry, 50(14), 3971e3976. Lee, J., & Watson, R. R. (1998). Pomegranate, a role in health promotion and AIDS? In R. R. Watson (Ed.), Nutrition food and AIDS (pp. 179e192). Boca Raton, FL: CRC Press. Lee, S. T., Wu, Y. L., Chien, L. H., Chen, S. T., Tzeng, Y. K., & Wu, T. F. (2012). Proteomic exploration of the impacts of pomegranate fruit juice on the global gene expression of prostate cancer cell. Proteomics, 12(21), 3251e3262. Lei, F., Zhang, X. N., Wang, W., Xing, D. M., Xie, W. D., Su, H., et al. (2007). Evidence of anti-obesity effects of the pomegranate leaf extract in high-fat diet induced obese mice. International Journal of Obesity (London), 31, 1023e1029. Li, Y., Guo, C., Yang, J., Wei, J., Xu, J., & Cheng, S. (2006). Evaluation of antioxidant properties of pomegranate peel extract in comparison with pomegranate pulp extract. Food Chemistry, 96, 254e260. Lin, C. C., Hsu, Y. F., & Lin, T. C. (1999). Effects of punicalagin on arrageenan-induced inflammation in rats. The American Journal of Chinese Medicine, 27, 371e376. Li, Z., Percival, S. S., Bonard, S., & Gu, L. (2011). Fabrication of nanoparticles using partially purified pomegranate ellagitannins and gelatin and their apoptotic effects. Molecular Nutrition and Food Research, 55(7), 1096e1103. Li, J., Wang, X., Zhang, T., Wang, C., Huang, Z., Luo, X., et al. (2014). A review on phospholipids and their main applications in drug delivery systems. Asian Journal of Pharmaceutical Sciences, 10(2), 81e98. Li, Y., Yang, Zheng, W., Hu, M., Wang, J., Ma, S., et al. (2016). Punica granatum (pomegranate) leaves extract induces apoptosis through mitochondrial intrinsic pathway and inhibits migration and invasion in non-small cell lung cancer in vitro. Biomedicine & Pharmacotherapy, 80, 227e235. Lokina, S., Suresh, R., Giribabu, K., Stephen, A., Lakshmi Sundaram, R., & Narayanan, V. (2014). Spectroscopic investigations, antimicrobial, and cytotoxic activity of green synthesized gold nanoparticles. Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 129, 484e490. Loren, D. J., Seeram, N. P., Schulman, R. N., & Holtzman, D. M. (2005). Maternal dietary supplementation with pomegranate juice is neuroprotective in an animal model of neonatal hypoxic-ischemic brain injury. Pediatric Research, 57, 858e864. Lu, L., Liu, Y., Zhang, Z., Gou, X., Jiang, J., Zhang, J., & Yao, Q. (2015). Pomegranate seed oil exerts synergistic effects with trans-resveratrol in a self-nanoemulsifying drug delivery system. Biological and Pharmaceutical Bulletin, 38(10), 1658e1662. Lu, J., & Yuan, Q. (2008). A new method for ellagic acid production from pomegranate husk. Journal of Food Process Engineering, 31, 443e454. Lye, C. (2008). Pomegranate Preliminary assessment of the potential for an Australian industry. RIRDC Publication No 08/153 RIRDC Project No GPI-1A. Machado, S., Pacheco, J. G., Nouws, H. P. A., Albergaria, J. T., & Delerue-Matos, C.

71

(2015). Characterization of green zero-valent iron nanoparticles produced with tree leaf extracts. Science of the Total Environment, 533, 76e81. Mahdihassan, S. (1984). Outline of the beginnings of alchemy and its antecedents. American Journal of Chinese Medicine, 12, 32e42. Malik, A., Afaq, F., Sarfaraz, S., Adhami, V. M., Syed, D. N., & Mukhtar, H. (2005). Pomegranate fruit juice for chemoprevention and chemotherapy of prostate cancer. Proceedings of the National Academy of Sciences of the United States of America, 102, 14813e14818. Martınez, J. J., Melgarejo, P., Hernandez, F., Salazar, D. M., & Martınez, R. (2006). Seed characterization of five new pomegranate varieties. Scientia Horticulturae, 110, 241e246. Masamune, A., Satoh, M., Kikuta, K., Suzuki, N., Satoh, K., & Shimosegawa, T. (2005). Ellagic acid blocks activation of pancreatic stellate cells. Biochemical Pharmacology, 70(6), 869e878. €rster, G., et al. Maynard, A. D., Aitken, R. J., Butz, T., Colvin, V., Donaldson, K., Oberdo (2006). Safe handling of nanotechnology. Nature, 444, 267e269. McClements, D. J. (2012). Nanoemulsions versus microemulsions: Terminology, differences, and similarities. Soft Matter, 8(6), 1719e1729. Medjakovic, S., & Jungbauer, A. (2012). Pomegranate, a fruit that ameliorates metabolic syndrome. Food Function, 4, 19e39. Meena Kumari, M., Jacob, J., & Philip, D. (2015). Green synthesis and applications of au-ag bimetallic nanoparticles. Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 137, 185e192. ndez, P. A., & Capriles, V. A. (2006). Antibacterial properties of tropical plants Mele from Puerto Rico. Phytomedicine, 13(4), 272e276. s, F. (2000). Total lipid content and fatty acid composition of Melgarejo, P., & Arte oilseed from lesser known sweet pomegranate clones. Journal of the Science of Food and Agriculture, 80(10), 1452e1454. Mertens-Talcott, S. U., Jilma-Stohlawetz, P., Rios, J., Hingorani, L., & Derendorf, H. (2006). Absorption, metabolism, and antioxidant effects of pomegranate (Punica granatum L.) polyphenols after ingestion of a standardized extract in healthy human volunteers. Journal of Agricultural and Food Chemistry, 54, 8956e8961. Miguel, M. G., Neves, M. A., & Antunes, M. D. (2010). Pomegranate (Punica granatum L.), a medicinal plant with myriad biological properties. Journal of Medicinal Plants Research, 4, 2836e2847. Mirdehghan, S. H., & Rahemi, M. (2007). Seasonal changes of mineral nutrients and phenolics in pomegranate(Punica granatum L.). Scientia Horticulturae, Fruit, 111, 120e127. Mizrahi, M., Friedman-Levi, Y., Larush, L., Frid, K., Binyamin, O., Dori, D., et al. (2014). Pomegranate seed oil nanoemulsions for the prevention and treatment of neurodegenerative diseases: The case of genetic CJD. Nanomedicine: Nanotechnology, Biology, and Medicine, 10(6), 1353e1363. Mohammadi, K., Ranjbar, M., & Targholizadeh, H. (2016). Synthesis and characterization photoluminescence properties of Au/GrO nanocomposites by microwave method. Journal of Materials Science: Materials in Electronics,, 1e5. http:// dx.doi.org/10.1007/s10854-016-4772-2. Moneam, N. M. A., El Sharaky, A. S., & Badreldin, M. M. (1988). Oestrogen content of pomegranate of seeds. Journal of Chromatography A, 438, 438e442. Mori-Okamoto, J., Otawara-Hamamoto, Y., Yamato, H., & Yoshimura, H. (2004). Pomegranate extract improves a depressive state and bone properties in menopausal syndrome model ovariectomized mice. Journal of Ethnopharmacology, 92, 93e101. Morton, J. F. (1987). Pomegranate. In J. F. Morton (Ed.), Fruits of warm climates (pp. 352e355). Miami, FL. Mousavinejad, G., Emam-Djomeh, Z., Rezaei, K., & Haddad Khodaparast, M. H. (2009). Identification and quantification of phenolic compounds and their effects on antioxidant activity in pomegranate juices of eight Iranian cultivars. Food Chemistry, 115, 1274e1278. Murray, C. J., & Lopez, A. D. (1997). Alternative projections of mortality and disability by cause 1990e2020, global burden of disease study. Lancet, 349, 1498e1504. Muzzalupo R., Tavano L. (2015) Niosomal drug delivery for transdermal targeting: recent advances, Dove press, 2015(4), 23e33. Mystrioti, C., Sparis, D., Papasiopi, N., Xenidis, A., Dermatas, D., & Chrysochoou, M. (2015). Assessment of polyphenol coated nano zero valent iron for hexavalent chromium removal from contaminated waters. Bulletin of Environmental Contamination and Toxicology, 94(3), 302e307. Mystrioti, C., Xanthopoulou, T. D., Tsakiridis, P. E., Papassiopi, N., & Xenidis, A. (2016). Comparative evaluation of five plant extracts and juices for nanoiron synthesis and application for hexavalent chromium reduction. Science of the Total Environment, 539, 105e113. Nawwar, M. A. M., Hussein, S. A. M., & Merfort, I. (1994). Leaf phenolics of Punica granatum. Phytochemistry, 37, 1175e1177. Nawwar, M. A. M., Hussein, S. A. M., & Merfort, I. (1994). NMR Spectral analysis of polyphenols from Punica granatum. Phytochemistry, 36, 793e798. Naz, S., Siddiqi, R., Ahmad, S., Rasool, S. A., & Sayeed, S. A. (2007). Antibacterial activity directed isolation of compounds from Punica granatum. Journal of Food Science, 72, 341e345. Negi, P. S., & Jayaprakasha, G. K. (2003). Antioxidant and antibacterial activities of Punica granatum peel extracts. Food Microbiology and Safety, 68, 1473e1477. Negi, P. S., Jayaprakasha, G. K., & Jena, B. S. (2003). Antioxidant and antimutagenic activities of pomegranate peel extracts. Food Chemistry, 80, 393e397. Neyrinck, A. M., Van Hee, V. F., Bindels, L. B., De Backer, F., Cani, P. D., & Delzenne, N. M. (2013). Polyphenol-rich extract of pomegranate peel alleviates

72

M. Karimi et al. / Trends in Food Science & Technology 69 (2017) 59e73

tissue inflammation and hypercholesterolaemia in high-fat diet-induced obese mice, potential implication of the gut microbiota. British Journal of Nutrition, 109, 802e809. Nonaka, G., Nishioka, I., Nishizawa, M., Yamagishi, T., Kashiwada, Y., Dutschman, G. E., et al. (1990). Anti-AIDS agents, 2: Inhibitory effects of tannins on HIV reverse transcriptase and HIV replica- tion in H9 lymphocyte cells. Journal of Natural Products, 53, 587e595. Nugteren, D. H., & Christ-Hazelhof, E. (1987). Naturally occurring conjugated octadecatrienoic acids are strong inhibitors of prostaglandin biosynthesis. Prostaglandins, 33, 403e417. Okonogi, S., Duangrat, C., Anuchpreeda, S., Tachakittirungrod, S., & Chowwanapoonpohn, S. (2007). Comparison of antioxidant capacities and cytotoxicities of certain fruit peels. Food Chemistry, 103, 839e846. Olapour, S., Mousavi, E., Sheikhzade, M., Hoseininezhad, O., & Najafzadeh, H. (2009). Evaluation anti-diarrheal effects of pomegranate peel extract. Journal of the Iranian Chemical Society, 6, 115e143. Orak, H. H., Yagar, H., & Isbilir, S. S. (2012). Comparison of antioxidant activities of juice, peel, and seed of pomegranate (Punica granatum L.) and interrelationships with total phenolic, tannin, anthocyanin, and flavonoid contents. Food Science and Biotechnology, 21, 373e387. Orgil, O., Spector, L., Holland, D., Mahajna, J., & Amir, R. (2016). The anti-proliferative and anti-androgenic activity of different pomegranate accessions. Journal of Functional Foods, 26, 517e528. Pande, S. D., Wagh, A. S., Bhagure, L. B., Patil, S. G., & Deshmukh, A. R. (2015). Preparation and evaluation of phytosomes of pomegrane peels. Research Journal of Pharmacy and Technology, 8(4), 416e422. Pantuck, A. J., Leppert, J. T., Zomorodian, N., Aronson, W., Hong, J., Barnard, R. J., et al. (2006). Phase II study of pomegranate juice for Men with rising prostatespecific antigen following surgery or radiation for prostate cancer. Clinical Cancer Research, 12, 4018e4026. Parseh, H., Hassanpour, S., Emam-Djome, Z., Lavasani, A. S. (2012) Antimicrobial properties of pomegranate (Punica granatum L.) as a tannin rich fruit, In, The 1st International and the 4th National Congress on Recycling of Organic Waste in Agriculture, 26e27 April 2012, Isfahan, Iran http//crowa.khuisf.ac.ir/DorsaPax/ userfiles/file/pazhohesh/crowa91/34.pdf (last accessed on 10.05.13). €a-Viguera, C. (2002). In vitro Pearez-Vicente, A. P., Gil-Izquierdo, A., & Garcia gastrointestinal digestion study of pomegranate juice phenolic compounds, anthocyanins, and vitamin C. Journal of Agricultural and Food Chemistry, 50, 2308e2312. Penalver-Mellado M., Lopez-Mas J. A., Streitenberger S. A., Martinez-Ortiz, P. (2011) Use of plant extracts as prebiotics, compostions and foods containing such extracts. Patent Number, WO2011036316. http//patentscope.wipo.int/search/ en/WO2011036316 (last accessed on 10.05.13). Perez, C., & Anesini, C. (1994). In vitro antibacterial activity of Argentine folk medicinal plants against Salmonella typhi. Journal of Ethnopharmacology, 44(1), 41e46. Plumb, G. W., De Pascual-Teresa, S., Santos-Buelga, C., Rivas-Gonzalo, J. C., & Williamson, G. (2002). Antioxidant properties of gallocatechin and prodelphinidins from pomegranate peel. Redox Report, 7(1), 41e46. Poyrazoglu, E., Gokmen, V., & Artak, N. (2002). Organic acid and phenolic compounds in pomegranates (Punica granatum L.) grown in Turkey. Journal of Food Composition and Analysis, 15, 567e575. Rahimi, H. R., Arastoo, M., & Ostad, S. N. (2012). A comprehensive review of Punica granatum (pomegranate) properties in toxicological, pharmacological, cellular and molecular biology researches. Iran Journal of Pharmaceutical Research, 11, 385e400. Rahman, M. K. A., & Megeid, A. A. A. (2006). Hepatoprotective effect of soapworts (Saponaria officinalis), pomegranate peel (Punica granatum L.) and cloves (Syzygium aromaticum Linn) on mice with CCL4 hepatic intoxication. World Journal of Chemistry, 1, 41e46. Rao, A., Mahajan, K., Bankar, A., Srikanth, R., Kumar, A. R., Gosavi, S., et al. (2013). Facile synthesis of size-tunable gold nanoparticles by pomegranate (Punica granatum leaf extract: Applications in arsenate sensing. Materials Research Bulletin, 48(3), 1166e1173. Rettig, M. B., Heber, D., An, J., Seeram, N. P., Rao, J. Y., & Liu, H. (2008). Pomegranate extract inhibits androgen-independent prostate cancer growth through a nuclear factor-kappaB dependent mechanism. Molecular Cancer Therapeutics, 7, 2662e2671. Rogers, J., Perkins, I., van Olphen, A., Burdash, N., Klein, T. W., & Friedman, H. (2005). Epigallocatechin gallate modulates cytokine production by bone marrowderived dendritic cells stimulated with lipopolysaccharide or muramyl dipeptide, or infected with Legionella pneumophila. Experimental Biology and Medicine (Maywood), 230(9), 645e651. Romier, B., Van De Walle, J., During, A., Larondelle, Y., & Schneider, Y. J. (2008). Modulation of signalling nuclear factor-kappa B activation pathway by polyphenols in human intestinal Caco-2 cells. The British Journal of Nutrition, 100, 542e551. Saad, H., Charrier-El Bouhtoury, F., Pizzi, A., Rode, K., Charrier, B., & Ayed, N. (2012). Characterization of pomegranate peels tannin extractives. Industrial Crops and Products, 40, 239e246. Sadrolhosseini, A. R., Noor, A. S. M., Husin, M. S., & Sairi, N. A. (2014). Green synthesis of gold nanoparticles in pomegranate seed oil stabilized using laser ablation. Journal of Inorganic and Organometallic Polymers and Materials, 24(6), 1009e1013. Sadrolhosseini, A. R., Rashid, S. A., Noor, A. S. M., Kharazmi, A., & Mehdipour, L. A.

(2015). Fabrication of silver nanoparticles in pomegranate seed oil with thermal properties by laser ablation technique. Digest Journal of Nanomaterials and Biostructures, 10(3), 1009e1018. Salem, N. M., Albanna, L. S., & Awwad, A. M. (2016). Green synthesis of sulfur nanoparticles using Punica granatum peels and the effects on the growth of tomato by foliar spray applications. Environmental Nanotechnology, Monitoring and Management, 6, 83e87. Salgado, J. M., Ferreira, T. R. B., Biazotto, F., de, O., Dias, C. T., & dos, S. (2012). Increased antioxidant content in juice enriched with dried extract of pomegranate (Punica granatum) peel. Plant Foods for Human Nutrition, 67, 39e43. Sartippour, M. R., Seeram, N. P., Rao, J. Y., Moro, A., Harris, D. M., Henning, S. M., et al. (2008). Ellagitannin-rich pomegranate extract inhibits angiogenesis in prostate cancer in vitro and in vivo. International Journal of Oncology, 32, 475e480. Schubert, S. Y., Lansky, E. P., & Neeman, I. (1999). Antioxidant and eicosanoid enzyme inhibition properties of pomegranate seed oil and fermented juice flavonoids. Journal of Ethnopharmacology, 66, 11e17. Seeram, N. P., Adams, L. S., Henning, S. M., Niu, Y., Zhang, Y., Nair, M. G., et al. (2005). In vitro anti-proliferative, apoptotic and antioxidant activities of punicalagin, ellagic acid and a total pomegranate tannin extract are enhanced in combination with other polyphenols as found in pomegranate juice. The Journal of Nutritional Biochemistry, 16(6), 360e367. Seeram, N. P., Lee, R., Hardy, M. L., & Heber, D. (2005). Rapid large scale purification of ellagitannins from pomegranate husk, a byproduct of the commercial juice industry. Separation and Purification Technology, 41, 49e55. Seeram, N. P., Schulman, R. N., & Heber, D. (2006). Pomegranates, ancient roots to modern medicine. Boca Raton, FL: CRC Press Taylor and Francis Group. Seeram, N. P. A. M., Volkova, N., Zhang, Y., Henning, S. M., Nair, M., & Heber, D. (2004a). Dietary polyphenols derived from pomegranates are potent antioxidants, evaluation in various in vitro models of antioxidation. In 228th national meeting of the American Chemical Society. Philadelphia, PA: American Chemical Society. Seeram, N. P., Lee, R., & Heber, D. (2004b). Bioavailability of ellagic acid in human plasma after consumption of ellagitannins from pomegranate (Punica granatum L.) juice. Clinica Chimica Acta, 348(1e2), 63e68. Seidi, K., Jahanban-Esfahlan, R., & Abasi, M. (2016). Anti-tumoral Properties of Punica granatum (pomegranate) seed extract in different human cancer cells. Asian Pacific Journal of Cancer Prevention, 17(3), 1119e1122. Sestili, P., Martinelli, C., Ricci, D., Fraternale, D., Bucchini, A., Giamperi, L., Curcio, R., et al. (2007). Cytoprotective effect of preparations from various parts of Punica granatum L. fruits in oxidatively injured mammalian cells in comparison with their antioxidant capacity in cell free systems. Pharmacolo- Gical Research: The Official Journal of the Italian Pharmacological Society, 56, 18e26. Shirode, A. B., Bharali, D. J., Nallanthighal, S., Coon, J. K., Mousa, S. A., & Reliene, R. (2015). Nanoencapsulation of pomegranate bioactive compounds for breast cancer chemoprevention. International Journal of Nanomedicine, 10, 475e484. Sies, H. (1997). Physiological society symposium: Impaired endothelial and smooth muscle cell function in oxidative stress oxidative stress: Oxidants and antioxidants. Experimental Physiology, 82, 291e295. Singh, R. P., Murthy, K. N. C., & Jayaprakasha, G. H. (2002). Studies on the antioxidant activity of pomegranate (Punica granatum) peel and seed extraction using in vitro model. Journal of Agricultural and Food Chemistry, 50, 81e86. Stover, E., & Mercure, E. W. (2007). The pomegranate, a new look at the fruit of paradise. HortScience, 42, 1088e1092. Su, J. D., Osawa, T., Kawakishi, S., & Namili, M. (1988). Tannin antioxidants from Osbeckia Chinensis. Phytochemistry, 27, 1315e1319. Suri, S. S., Fenniri, H., & Singh, B. (2007). Nanotechnology-based drug delivery systems. Journal of Occupational Medicine and Toxicology (London, England), 2, 16. Syed, D. N., Afaq, F., & Mukhtar, H. (2007). Pomegranate derived products for cancer chemoprevention. Seminars in Cancer Biology, 17, 377e385. Syed, D. N., Malik, A., Hadi, N., Sarfaraz, S., Afaq, F., & Mukhtar, H. (2006). Photochemo preventive effect of pomegranate fruit extract on UVA-mediated activation of cellular pathways in normal human epidermal keratinocytes. Photochemistry and Photobiology, 82, 398e405. Tanaka, T., Nonaka, G. I., & Nishioka, I. (1985). Punicafolin, and ellagitannin from the leaves of Punicagranatum. Phytochemistry, 24, 2075e2078. Tanaka, T., Nonaka, G. I., & Nishioka, I. (1986). Tannins and related compounds. XL. Revision of the structures of Punicalin and Punicalagin, and isolation and characterization of 2-Galloylpunicalin from the bark of Punica granatum L. Chemical and Pharmaceutical Bulletin, 34, 650e655. Tanaka, T., Nonaka, G. I., & Nishioka, I. (1986). Tannins and related compounds. XLI. Isolation and characterization of novel ellagitannins, punicacorteins A, B, C and D and punigluconin from the bark of Punica granatum L. Chemical and Pharmaceutical Bulletin, 34, 656e663. Tavakoli, F., Salavati-Niasari, M., & Mohandes, F. (2013). Green synthesis of flowerlike CuI microstructures composed of trigonal nanostructures using pomegranate juice. Materials Letters, 100, 133e136. Tavassoli-Hojjati, S., Aliasghar, E., Ahmadian Babaki, F., Emadi, F., Parsa, M., Tavajohi, S., et al. (2014). Pomegranate juice (Punica granatum), a new storage medium for avulsed teeth. Journal of Dentistry of Tehran University of Medical Sciences, 11(2), 225e232. Tehranifar, A., Selahvarzi, Y., Kharrazi, M., & Bakhsh, V. J. (2011). High potential of agroindustrial by products of pomegranate (Punica granatum L.) as the powerful antifungal and antioxidant substances. Industrial Crops and Products, 34, 1523e1527.

M. Karimi et al. / Trends in Food Science & Technology 69 (2017) 59e73 Tehranifar, A., Zarei, M., Nemati, Z., Esfandiyari, B., & Vazifeshenas, M. R. (2010). Investigation of physic-chemical properties and antioxidant activity of twenty Iranian pomegranate (Punica granatum L.). Scientia Horticulturae, 126, 180e185. Tezcan, F., Gultekin-Ozguven, M., Diken, T., Ozcelik, B., & Bedia Erim, F. (2009). Antioxidant activity and total phenolic, organic acid and sugar content in commercial pomegranate juices. Food Chemistry, 115, 873e877. Tiyaboonchai, W., Rodleang, I., & Ounaroon, A. (2015). Mucoadhesive polyethylenimine-dextran sulfate nanoparticles containing punica granatum peel extract as a novel sustained-release antimicrobial. Pharmaceutical Development and Technology, 20(4), 426e432. Toi, M., Bando, H., Ramachandran, C., Melnick, S. J., Imai, A., Fife, R. S., et al. (2003). Preliminary studies on the anti-angiogenic potential of pomegranate fractions in vitro and in vivo. Angiogenesis, 6(2), 121e128. Tokton, N., Ounaroon, A., Panichayupakaranant, P., & Tiyaboonchai, W. (2014). Development of ellagic acid rich pomegranate peel extract loaded nanostructured lipid carriers (NLCs). International Journal of Pharmacy and Pharmaceutical Sciences, 6(4), 259e265. Tsuyuki, H., Ito, S., & Nakatsukasa, Y. (1981). Lipids in pomegranate seeds. Nihon Daigaku No-Juigakubu Gakujutsu Kenkyu Hokoku, 38, 141e148. Tzulker, R., Glazer, I., Bar-Ilan, I., Holland, D., Aviram, M., & Amir, R. (2007). Antioxidant activity, polyphenol content and related compounds in different fruit juices and homogenates prepared from 29 different pomegranate accessions. Journal of Agricultural and Food Chemistry, 55, 9559e9570. Vasconcelos, L. C., Sampaio, M. C., Sampaio, F. C., & Higino, J. S. (2003). Use of Punica granatum as an antifungal agent against candidosis associated with denture stomatitis. Mycoses, 46, 192e196. Viuda-Martos, M., Fernandez-Lopez, J., & Perez-Alvarez, J. A. (2010). Pomegranate and its many functional components as related to human health, a review. Comprehensive Reviews in Food Science and Food Safety, 9, 635e654. Viuda-Martos, M., Perez-Alvarez, J. A., Sendra, E., & Fernandez-Lopez, J. (2013). In vitro antioxidant properties of pomegranate (Punica granatum) peel powder extract obtained as co-product in the juice extraction process. Journal of Food Processing and Preservation, 37(5), 772e776. Waheed, S., Siddique, N., Rahman, A., Zaidi, J. H., & Ahmad, S. (2004). INAA for

73

dietary assessment of essential and other trace elements in 14 fruits harvested and consumed in Pakistan. Journal of Radioanalytical and Nuclear Chemistry, 260, 523e531. Wallace, J. M. (2002). Nutritional and botanical modulation of the inflammatory cascade eicosanoids, cyclooxygenases, and lipoxygenases e as an adjunct in cancer therapy. Integrative Cancer Therapies, 1, 7e37. Wang, L., Ho, J., Glackin, C., & Martins-Green, M. (2012). Specific pomegranate juice components as potential inhibitors of prostate cancer metastasis. Translational Oncology, 5(5), 344e355. Wang, R.-F., Ding, Y., Liu, R.-N., Xiang, L., & Du, L.-J. (2010). Pomegranate, Constituents, bioactivities and pharmacokinetics. In R. Chandra (Ed.), Pomegranate. Fruit, Vegetable and Cereal Science and Biotechnology (Vol. 4, pp. 77e87). Watanabe, K., Hatakoshi, M.. (2002) Punica granatum leaf extracts for inactivation of allergen. Japan Kokai TokkyoKoho (Japanese patent) JP 2002370996 A2 20021224, 5 pp. Weerakkody, P., Jobling, J. I., Maria, M. V., & Rogers, G. (2010). The effect of maturity, sunburn and the application of sunscreens on the internal and external qualities of pomegranate fruit grown in Australia. Scientia Horticulturae, 124, 57e61. Yang, H., Ren, Y., Wang, T., & Wang, C. (2016). Preparation and antibacterial activities of Ag/Agþ/Ag3þ nanoparticle composites made by pomegranate (punica granatum) rind extract. Results in Physics, 6, 299e304. Yokoyama, M. (2005). Drug targeting with nano-sized carrier systems. Journal of Artificial Organs, 8, 77e84. Yoshimura, M., Watanabe, Y., Kasai, K., Yamakoshi, J., & Koga, T. (2005). Inhibitory effect of an ellagic acid-rich pomegranate extracts on tyrosinase activity and ultraviolet-induced pigmentation. Bioscience, Biotechnology, and Biochemistry, 69, 2368e2373. Zarei, M., Azizi, M., & Bashiri-Sadr, Z. (2010). Studies on physico-chemical properties and bioactive compounds of six pomegranate cultivars grown in Iran. Journal of Food Technology, 8(3), 112e117. Zhang, Y., Krueger, D., Durst, R., Lee, R., Wang, D., Seeram, N., et al. (2009). Specification (IMAS) algorithm for detection of commercial pomegranate juice adulteration, international multidimensional authenticity. Journal of Agricultural and Food Chemistry, 57, 2550e2557.