Rutin: A review on extraction, identification and

Trends in Food Science & Technology 67 (2017) 220e235

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Review

Rutin: A review on extraction, identification and purification methods, biological activities and approaches to enhance its bioavailability n, Thelmo A. Lú-Chau, María Teresa Moreira, Juan M. Lema, Gemma Eibes* Beatriz Gullo Dept. of Chemical Engineering, Institute of Technology, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain

a r t i c l e i n f o

a b s t r a c t

Article history: Received 5 December 2016 Received in revised form 1 June 2017 Accepted 10 July 2017 Available online 11 July 2017

Background: Rutin is a common dietary flavonoid which has received great attention in literature, due to their pharmacological properties, including antimicrobial, anti-inflammatory, anticancer, antidiabetic, inter alia. Over 860 products containing rutin are currently marketed in the US. The major disadvantage associated with rutin is its constrained bioavailability, mainly caused by its low aqueous solubility, poor stability and limited membrane permeability. Scope and approach: The aim of this contribution is to give an overview of the current methods (conventional and innovative) for the extraction, identification and purification of rutin. Furthermore, recent findings regarding its pharmacological activities and the different approaches to increase rutin solubility in both aqueous and lipid phases will be discussed. Key findings and conclusions: Current trends on extraction process have been focused on the discovery and design of green and sustainable extraction techniques to optimize the recovery of rutin. Despite the bioactivity expressed in different in vitro systems, its biological effects in vivo are limited by the poor bioavailability of the flavonoid. The utilization of delivery systems for rutin or its enzymatic or chemical transformation towards highly soluble derivatives have the potential to improve rutin bioavailability, as well as its stability and/or specific biological properties. These novel rutin formulations may bring this promising flavonoid to the forefront of nutraceuticals for the prevention and/or treatment of various chronic human diseases. © 2017 Elsevier Ltd. All rights reserved.

Keywords: Rutin Extraction methods Biological activity Bioavailability Drug delivery Rutin derivatives

1. Introduction Flavonoids and their glycosides constitute one of the major classes of plant secondary metabolites. They are widely distributed natural compounds of special interest due to their antioxidant properties as well as their role in the prevention of various diseases such as cancer, cardiovascular diseases, neurodegenerative diseases, diabetes or osteoporosis (Scalbert, Manach, Morand, & Remesy, 2005). Rutin (30 ,40 ,5,7-tetrahydroxy-flavone-3-rutinoside) is a flavonol glycoside (Table 1), which has been reported to present clinically relevant functions, potentially beneficial in preventing diseases and protecting genome stability (Sharma, Ali, Ali, Sahni, & Baboota, 2013a). The Dietary Supplement Label Database lists over 860 products containing rutin that are currently marketed in the US (DSLD, 2016). Rutin prescription is specially recommended for the

* Corresponding author. E-mail address: [email protected] (G. Eibes). http://dx.doi.org/10.1016/j.tifs.2017.07.008 0924-2244/© 2017 Elsevier Ltd. All rights reserved.

treatment of various diseased conditions such as varicose veins, internal bleeding or hemorrhoids. Common oral doses range from 500 mg to 2000 mg per day and can be safely continued for long periods, up to 6 months (Incandela et al., 2002). To date, it is reported that more than 70 plant species contain rutin. Buckwheat (Fagopyrum esculentum Moench) from the family Polygonaceae is reported as a major source of natural rutin (Kim et al., 2005). Buckwheat of Chinese origin has a long cultivation history due to its interest in traditional medicine. It was recorded in various old agricultural books and medicinal works (Lin, Zhou, Wang, & Li, 2001). In Japan, buckwheat is cultivated, not only to be used in traditional foods, but also as an ingredient for health foods (Suzuki et al., 2015). In the United States, the interest in rutin from buckwheat can date back to 1940s, when buckwheat was cultivated as a source of rutin for medicinal use (Ohsawa & Tsutsumi, 1995). Other major commercial sources of rutin include Ruta graveolens L. (Rutaceae), Sophora japonica L. (Fabaceae) and Eucalyptus spp. (Myrtaceae) (Chua, 2013). The major disadvantage associated with rutin is its poor

n et al. / Trends in Food Science & Technology 67 (2017) 220e235 B. Gullo

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Table 1 Physico-chemical properties of rutin. CAS No Other names Molecular weight Structure

153-18-4 Rutoside; Quercetin 3-rutinoside; Birutan; Eldrin; Vitamin P 610.518 g/mol

Appearance Melting point Solubilitya

Yellow crystalline powder 195 C water 0.13 g/L pyridine 37.3 g/L methanol 55 g/L ethanol 5.5 g/L 0.64b; 0.21c 14.7 mm/h, in vitro skin penetrationc (0e1.34)$106 cm/s, intestinal epithelial cells (Caco-2)d,e 5.8$104 s1, UV-photodegradationf (10.3e23.3)$105 s1, thermal degradation under oxidative conditionsg (8.06e88.6)$105 s1, UV-photodegradation and thermal degradation in presence of H2O2, NaOH or HClh

log P permeability coefficient decay rate

a b c d e f g h

Krewson & Naghski, 1952. Rothwell, Day, & Morgan, 2005. Lin et al., 2012. Tian, Yang, Yang, & Wang, 2009. Rastogi & Jana, 2016. Almeida et al., 2010. Makris & Rossiter, 2000. Paczkowska et al., 2015b.

bioavailability, mainly caused by its low aqueous solubility, poor stability and limited membrane permeability (Table 1). This is a determinant factor that hinders the in vivo biological effects of rutin despite it may show detectable bioactivity in different in vitro systems. Additionally, the low liposolubility of rutin limits its practical use for topical applications. Since the demand for natural rutin has an increasing trend, it is important to review the most recent extraction and purification methods of this flavonoid. Furthermore, significant research efforts have been recently devoted to produce more specific and efficient flavonoid derivatives with minimum side effects, high bioavailability and therapeutic benefit for use in the food and pharmaceutical fields (Lee, Kang, & Cho, 2007). The aim of this article is to give an overview of the current methods for the extraction, identification and purification of rutin, as well as the recent findings regarding its pharmacological activities and the different approaches carried out to increase rutin solubility in both aqueous and lipid phases. 2. Methods for the extraction of rutin In the recovery of bioactive compounds from natural sources, the extraction step plays a very important role. This step must meet a series of requirements such as versatility, ease of use, efficiency, cost-effective as well as it should extract and preserve the major fraction of the natural bioactive substances contained in the plant materials (Thoo et al., 2013). Over the last years, intensive research has been focused on the extraction of valuable compounds using both conventional and innovative technologies, including the use of green solvents (Chua, 2013). Some works that summarize the extraction methods of rutin from various bioresources are detailed in Table 2. Extraction methods include different conventional techniques such as Soxhlet extraction, which has been widely used for the

extraction of bioactive compounds (Chua, 2013; Uppugundla et al., 2009). Nevertheless, this method presents some major drawbacks related with the thermal degradation of target compounds due to the high temperature maintained for prolonged extraction periods, as well as for its potential effect on human health and environment associated to the large use of hazardous organic solvents (Chua, 2013; Singh, Ahmad, & Ahmad, 2015). To overcome these inconveniences and with the development of the ‘‘Green Chemistry’’ concept in the last two decades, the use of more environment friendly techniques has gained great attention by researchers (Ameer, Shahbaz, & Kwon, 2017). Thus, emerging extraction technologies based on ultrasonics (Ameer et al., 2017), microwave (Angiolillo, Del Nobile, & Conte, 2015), infrared irradiation (Duan, lez, & Chen, & Chen, 2010), pressurized liquid (Carro, Gonza Lorenzo, 2013), enzymes (Puri, Sharma, & Barrow, 2012), mechanochemical method (Xie et al., 2011a) and supercritical fluids (Liza et al., 2010), have been identified as green extraction techniques for the separation of high-added value compounds such as rutin. Regarding conventional extraction, several types of solvents have been evaluated for the efficient extraction of rutin from plant matrices. Among the different types of extraction solvents, the most suitable ones are ethanol, methanol, acetone, diethyl ether, isopropanol, ethyl acetate, and their mixtures with water (Stalikas, 2007). Kim et al. (2005) reported that the yields of rutin extraction from buckwheat varies with the solvent used, obtaining the highest extraction yield with 50% ethanol. Uppugundla et al. (2009) attained the highest titers of rutin from switchgrass with 60% methanol solution. In this line, several studies have informed that aqueous mixtures containing organic solvents enhance the efficiency of extraction of bioactive compounds (Chua, 2013). As it is stated above, although these conventional organic solvents are extensively used for the recovery of plant extracts, their use can cause potential problems of environmental pollution and health risk provided that solvent traces remain in the extracts (Mojzer,


222

Table 2 Different technologies used for the extraction of rutin from various bioresources. Sample

Treatment conditions

Yield

Reference

1.21 mg/g extract 620 mg/g sample, d.b. 1.6 mg/g sample, d.b. 4.6 mg/g sample, d.b. 0.54 mg/g sample, d.b.

Thoo et al., 2013

Solvent extraction Morinda citrifolia Ethanol at solid-to-solvent ratio of 1:10 in a temperature-controlled water bath shaker. The fruit optimal conditions were 75% ethanol for 40 min at 57 C Panicum virgatum L. 60% MeOH at solid-to-solvent ratio of 1:30 (g/mL), 80 C in a water bath for 20 min Valeriana officinalis L. Verbena officinalis L. Flowers of Smallanthus sonchifolius. Ultrasound assisted Verbena officinalis L. Betonica officinalis L. Flos Sophorae Immaturus Sophora japonica Fresh olives Aronia melanocarpa Urtica dioica L.

Microwave assisted Forsythia suspensa

Pure methanol at solid-to-solvent ratio of 1:50 (g/mL) in Soxhlet extractor for 1 h Pure methanol at solid-to-solvent ratio of 1:50 (g/mL) in Soxhlet extractor for 1 h Pure methanol at solid-to solvent ratio of 1:150 (g/mL) in Soxhlet extractor for 72 h

extraction (UAE) 30% acetonitrile, room temperature, 25 min and solid-to-solvent ratio of 1:53 (g/mL)

5.13 mg/g sample, d.b. 30% acetonitrile, room temperature, 25 min and solid-to-solvent ratio of 1:53 (g/mL) 3.8 mg/g sample, d.b. frequency of 40 kHz, power of 498 W, room temperature, 60 min, 82% methanol and a solid-to- 0.288 mg/g solvent ratio of 1:56 (g/mL) extract frequency of 60e62 kHz, power of 150 W, 20 C, 15 min, 70% ethanol and a solid-to-solvent ratio of 182.25 mg/g sample, d.b. 1:25 (g/mL) 61.9 mg/g power of 240 W, 47 C, 30 min, 80% methanol and a solid-to-solvent ratio of 1:22 (g/mL) frequency of 20 kHz,63 W/L, 40 C, 40 min, 50% ethanol and a solid-to-solvent ratio of 1:40 (g/mL) sample, d.b. frequency of 35 kHz, power of 60 W, room temperature, 30 min, 54% methanol and a solid-to- 616 mg/g solvent ratio of 1:20 (g/mL) sample, d.b. 48.4 mg/mL extraction (MAE) frequency of 40 kHz, power of 400 W, 70 C, 1 min, 70% methanol and solid-to-solvent ratio of 1:30 1.73 mg/g (g/mL) sample, d.b. frequency of 2.45 GHz, power of 420 W under 0.08 MPa of vacuum, 19 min and solid-to-solvent 0.71 mg/g ratio of 1:15 (g/mL), ionic liquid 1 M [C6mim][BF4] as extracting agent sample, d.b. pressure under 300 kPa, power of 170 W, 6 min, 50% ethanol and solid-to-solvent ratio of 1:40 (g/ 0.26 mg/g sample, d.b. mL) 0.86 mg/L power of 30 W, 50 s, 50% ethanol and solid-to-solvent ratio of 1:10 (g/mL)

Sorbus tianschanica leaves Stalks Euonymus alatus (Thunb.) Sieb Physalis angulata Infrared assisted solvent extraction (IRAE) Flos Sophorae Extracted with methanol for 6 min with infrared power of 418.4 W, solid-to-solvent ratio of 1:20 Immaturus (g/mL) Flos Sophorae Extracted with 70% methanol for 4.80 min and infrared power 205 W, with solid-to-solvent ratio of Immaturus 1:30 (g/mL) Pressurized Liquid Extraction (PLE) Flos sophorae Extracted with 1.0 mol/L [C4mim][Cl at 120 C for 5 min with pressure of 10.3 MPa Immaturus Hypericum japonicum Thunb Folium Mori

Extracted with 30% ethanol, at 188 C for 20 min and a pressure of 10 MPa Amaranthus paniculatus Extracted with 50% ethanol, at 65 C for 10 min and a pressure of 10 MPa Asparagus officinalis L Mechanochemical-assisted extraction (MCAE) Hibiscus mutabilis L. Grinding with 15% of Na2CO3 and 1.5% of Na2B4O7$10H2O for 4 min. Then it is extracted with water at 25 C for 15 min (two cycles of 10 min and 5 min), solid-to-solvent ratio of 1:25 (g/mL) and adjusted to pH 5.0 with 6 M HCl Supercritical fluid extraction (SFE) Strobilanthes crispus SFE system: CO2 þ EtOH, dynamic extraction time of 60 min at 50 C and 200 bar (Pecah Kaca) Mentha spicata L.) SFE system: CO2 þ EtOH, dynamic extraction time of 60 min at 60 C and 200 bar leaves Date seeds SFE system: CO2 þ EtOH, dynamic extraction time of 240 min (two repeated extractions) at 50 C and 350 bar. Asparagus officinalis SFE system: CO2 þ EtOH: Water (1:1), dynamic extraction time of 10 min at 65 C and 15 MPa L.

Hrn ci c, Skerget, Knez, & Bren, 2016). Taking into account these considerations, other solvents including ionic liquids (ILs) and deep eutectic solvents (DEEs) have been suggested as a new class of sustainable and safe solvents for the extraction of target compounds (Nam, Zhao, Lee, Jeong, & Lee, 2015a). For instance, Nam et al. (2015a) evaluated the potential of different DEEs as extracting agents of flavonoids from Flos sophorae.

202 mg/g sample, d.b. 251.4 mg/g sample, d.b. 196 mg/g sample, d.b. 2.35 mg/g sample, d.b. 1.05 mg/g sample, d.b. 14.3 mg/g sample, d.b. 2.17 mg/g sample, d.b

Uppugundla et al., 2009 , Adam, Bajer, & Bajerova Ventura, 2014 et al., 2014 Bajerova de Andrade, de Souza Leone, Ellendersen, & Masson, 2014

et al., 2014 Bajerova et al., 2014 Bajerova Xie et al., 2014 Liao et al., 2015 Deng et al., 2017 Tao et al., 2017 Vaji c et al., 2015

Fang, Wang, Wang, Zhang, & Wang, 2013 Gu, Chen, Zhang, & Zang, 2016 Zhang, Yang, Su, & Guo, 2009 Carniel et al., 2017

Gan, Chen, Fu, & Chen, 2012 Li et al., 2012

Wu et al., 2012

Kraujalis et al., 2015 Solana, Boschiero, Dall’Acqua, & Bertucco, 2015

5.44 mg/g sample, d.b.

Xie et al., 2011a

8.47 mg/g sample, d.b. 0.148 mg/g sample, d.b. not specified

Liza et al., 2010

2.28 mg/g sample, d.b.

Solana et al., 2015

Bimakr et al., 2011 Liu et al., 2013

In the same line, Zhao et al. (2015) also applied these solvents to extract rutin from the flower buds of Sophora japonica. They observed that the higher solubility of rutin in choline chloridebased DEEs resulted in enhanced extraction efficiency, reaching 194.17 mg/g. More recently, Huang et al. (2017) also obtained a significant improvement in rutin extraction yield from tartary buckwheat hull using DEEs compared to 80% methanol under the


same extraction conditions. Qin, Zhou, Peng, Li, and Chen (2015) have reported the extraction of rutin from Ficus carica L. by means of ILs. Although the number of reports on the use of these “green” solvents for the extraction of bioactive compounds such as rutin is scarce, it is expected that they will be widely used for this purpose in the near future. As aforementioned, current trends on extraction process have been focused in the use of innovative technologies that allow to optimize the recovery of bioactive compounds and enhance the quality of extracts (Ameer et al., 2017). In this line, Ultrasound Assisted Extraction (UAE) has been recently utilized for the extraction of bioactive compounds. This technique offers several advantages in contrast to conventional extraction such as symplicity, rapidity, low required solvent volume, inexpensive, and ecofriendliness among others (Ameer et al., 2017). The mechanism of UAE is ascribed to the phenomenon of acoustic cavitation that causes the rupture of sample matrix, and facilitates the diffusion of the solvent into the cellular material, that consequently enhances the extraction efficiency (Ameer et al., 2017; Chua, 2013). According to the reviewed literature, there are a number of parameters that affect the extraction efficiency of UAE, such as power, temperature and frequency (Ameer et al., 2017). In this context, Liao, Qu, Liu, and Zheng (2015) studied the UAE operational conditions to enhance the rutin extraction from Sophora japonica. In order to evaluate the efficiency of the UAE, several studies have compared this technique with convectional extraction. In this line, Deng et al. (2017) compared both procedures for the extraction of different bioactive compounds (including hydroxytyrosol, oleuropein and rutin) from fresh olives. The authors found that UAE resulted in higher extraction yields of all target compounds than those obtained by conventional extraction processes. Another promising approach is the Microwave-Assisted Extraction (MAE). This method is based on the use of microwave energy causing molecular motion by ionic conduction and dipole rotation (Chen et al., 2008). The process induces an increase of temperature and pressure that causes changes in the cell structure, improving the penetration of solvent across the sample matrix (Angiolillo et al., 2015). The main interest of this technique is the reduction of the extraction time and volume of solvent in comparison to conventional methods such as Soxhlet extraction and maceration (Angiolillo et al., 2015; Chua, 2013). Due to these advantages, MAE has gained wide reputation as a green extraction method for the recovery of phytochemicals from natural sources and industrial by-products (Ameer et al., 2017). Different operating parameters such as microwave irradiation, power or extraction temperature can affect the recovery yield in MAE processes (Ameer et al., 2017). This method was applied successfully for the extraction of rutin, quercetin, genistein, kaempferol and isorhamnetin from Flos Sophorae Immaturus (Liu, Li, & Hu, 2016). In this study, several variables (methanol and ethanol concentrations, particle size, extraction frequency, liquid-to-solid ratio, microwave power, and extraction time) were optimized to maximize the recovery of the molecules of interest. Similarly, Carniel et al. (2017) also evaluated the influence of MAE parameters on the selective recovery of phenolic acids (gallic acid, ellagic acid and caffeic acid) and flavonoids (rutin and mangiferin) from Physalis Angulata. It is important to note that the extraction of active compounds using MAE has already been implemented at industrial scale and various companies manufacture extracts obtained by this technology (Ciriminna et al., 2016). Nowadays, Infrared-Assisted Extraction (IRAE) is considered as an alternative to conventional technique to extract natural flavonoids from different bioresources (Huang, Chen, Wang, & Lai, 2014). This technique involves the use of infrared energy to get a high efficiency heating of the solvent to obtain partition analytes from

223

the cell wall into the surrounding medium (Huang et al., 2014). In the last few years, Pressurized Liquid Extraction (PLE), also known as accelerated solvent extraction, has been widely utilized for the extraction of natural products. PLE uses solvents at high pressure (up to 200 bar) and temperature (up to 200 C) and hence, it improves the solubility of the target analytes (Ameer et al., 2017; Carro et al., 2013). Wu, Chen, Fan, Elsebaei, and Zhu (2012) reported the extraction of rutin and quercetin from Chinese medicine plants using Ionic Liquid-based Pressurized Liquid Extraction (IL-PLE). In ~ ez, and Herrero (2015) this line, Kraujalis, Venskutonisa, Iban developed a procedure based on PLE to recover rutin from Amaranthus paniculatus leaves. In recent years, Enzyme-Assisted Extraction (EAE) is considered a promising and alternative ecofriendly technique for the extraction of bioactive compounds from plant sources (Puri et al., 2012). This method is based on the degradation and rupturing of the cell walls catalyzed by enzymes; thus, improving the yield of the target compounds (Puri et al., 2012). Different enzymes such as pectinases, cellulases and hemicellulases have been successfully used for the extraction of flavonoids (Xu, Chen, Wang, & Liu, 2013). Despite the growing interest of enzymatic extraction of bioactive compounds from plant sources, its use for rutin extraction has not yet been explored. Due to the benefits of this technique and the continued research on this topic (Puri et al., 2012), it can be expected that EAE will be applied for rutin extraction in the next few years. Among the innovative technologies available for flavonoids extraction, the Mechanochemical-Assisted Extraction (MCAE) is also considered. MCAE is based on the combination of chemical and mechanical energy as a pretreatment alternative to solvent extraction (Zhu, Lin, Chen, Xie, & Wang, 2011). Limited information exists on the application of MCAE for the isolation of flavonoids such as rutin, although their use is envisioned as a novel tool to improve the extraction yield of rutin (Chua, 2013; Xie et al., 2011a). Supercritical Fluid Extraction (SFE) is advantageously positioned as a green extraction technology and has been widely applied to isolate high value compounds (Ameer et al., 2017). Most research works on SFE use CO2 as supercritical fluid due to a number of advantages: non-flammable, nontoxic, inexpensive and recyclable (Liu et al., 2013). Nonetheless, due to lack of polarity of CO2, it is necessary to use cosolvents (modifiers) like ethanol to enhance the extraction efficiency of the polar bioactive compounds (Bimakr et al., 2011). 3. Chemical identification and purification of rutin in extracts The identification and quantification of flavonoids in several natural sources is a key point for researchers (Marston & Hostettmann, 2006). In this context, a colorimetric method is widely used for the quantification of the total flavonoid content. This method is based on the formation of flavonoid-aluminum chloride (AlCl3) complex and it is used to determine the total flavonoid content in methanolic or ethanolic extracts of plants (Naczk & Shahidi, 2006). Thin-layer chromatography (TLC) is another technique extensively used for the qualitative analysis of flavonoids, and it is suitable as a quick screening of these compounds in plant extracts (Stalikas, 2007). However, the identification and quantification of specific flavonoid compounds cannot be performed with the foregoing methods (Ignat, Volf, & Popa, 2011). To achieve this purpose, techniques like high-performance liquid chromatography (HPLC), gas chromatography (GC), capillary electrophoresis (CE), capillary zone electrophoresis (CZE), and micellar electrokinetic chromatography (MEKC) are commonly applied due to their high efficiency to separate and characterize flavonoids. Other interesting alternatives for the analysis of flavonoid


224

compounds include the hydrophilic interaction liquid chromatography (HILIC), high-speed counter current chromatography (HSCCC), ultrahigh-pressure liquid chromatography (UHPLC), supercritical fluid chromatography (SFC) or near infrared reflectance spectroscopy (NIRS) (Ignat et al., 2011; Liu et al., 2008). Different detection systems can be used for the analysis of flavonoids in complex extracts, being the most extensively utilized UV-Vis, photodiode array (DAD) and UV-fluorescence (UV-FL) for HPLC, UV-Vis and IR for capillary electrophoresis and flame ionization detector (FID) for GC (Liu et al., 2008). More recently, the introduction of mass spectrometry (MS) or nuclear magnetic resonance (NMR) has achieved growing importance and, nowadays, they are widespread as tools for the structural elucidation of flavonoid r-Perl & Füzfai, 2005). In this line, chromatogcompounds (Molna raphy techniques coupled to different MS detectors such as HPLCMS, HPLC-ESI-MS, HPLC-MALDIeMS or GC-MS are suitable for the characterization of complex flavonoids compounds in natural r-Perl & Füzfai, products (Marston & Hostettmann, 2006; Molna 2005; Stalikas, 2007). Amongst the different methods available, HPLC is the most extended analytical technique for the identification and quantification of several flavonoids like rutin (Ignat et al., 2011). The HPLC conditions mainly include the use of C18 reverse phased column, a binary solvent gradient, and different detection systems such as DAD, MS or NMR (Marston & Hostettmann, 2006). Examples of HPLC applications for the determination of rutin in various natural sources are compiled in Table 3. GC is another chromatographic technique that can also be applied for the analysis of flavonoid compounds, and in combination with mass spectrometry (GC-MS), it provides excellent separation capacity as well as high sensitivity and selectivity (Ignat et al., 2011). However, the analysis of bioactive compounds by GC requires troublesome chemical modification steps, such as the

derivatization to volatile compounds (Ignat et al., 2011). It should be noted that the analysis of flavonoid glycosides by GCeMS may be problematic, because derivatization may form several derivatives from a single flavonoid (Rijke et al., 2006). For this reason, scarce information concerning the identification of rutin by GC is found in the literature. In this context, Proestos, Boziaris, Nychas, and Komaitis (2006) carried out silylation as derivatization procedure for sample analysis of rutin by GC-MS. Capillary electrophoresis (CE) has been gaining attention for the separation and quantification of flavonoids. This technique offers high separation efficiency, good resolution, short analysis time and minimal sample volume requirement as well as low consumption of chemicals. It is, therefore, an excellent alternative to HPLC for the analysis of this type of compounds (Ignat et al., 2011). Table 4 summarizes some reports on the application of CE for the analysis of rutin in natural sources. In those cases, where deeper structural information of certain compounds is required, NMR is an excellent alternative. However, despite the utility of this technique for unambiguous identification of flavonoids, there are only a limited number of references, possibly due to the need of expensive deuterated solvents or the high cost of the equipment (Ignat et al., 2011; Stalikas, 2007). Lommen, Godejohann, Venema, Hollman, and Spraul (2000) confirmed the presence of flavonoid glycosides like rutin in apple peel using HPLC-NMR-MS. Recently, Forino, Tartaglione, Dell'Aversano, and Ciminiello (2016), used 1H and 13C NMR for identifying various bioactive compounds, among these, the rutin present in goji berries. Another approach is based on the use of near infrared reflectance spectroscopy (NIRS) that is a useful tool used widely to determine different bioactive compounds in a wide range of raw ~es, & Lopes, 2013). This materials and foodstuffs (P ascoa, Magalha technique offers significant improvements over traditional

Table 3 Selected publications on HPLC analysis of rutin from plant-based extracts. Sample

Method

Eluents

Column

Apricot fruits

HPLC-UV-ED

A: citric acid (75 mM); B: ammonium acetate (25 mM)

Phenomenex Gemini C18; Zitka et al., 2011 150 4.6; 3 mm Xie et al., 2011b Agilent Eclipse Plus C18; 150 mm 2.1 mm, 1.8 mm Diphenyl; 150 mm 3 mm, 5 mm Jaiswal et al., 2013

Gynostemma pentaphyllum HPLC-DAD-MS A: water containing 0.1% formic acid; B: acetonitrile Makino containing 0.1% formic acid Prunus salicina L. and HPLC-DAD-MS A: water/formic acid (1000:0.05 v/v); B: methanol Prunus domestica L. Morinda citrifolia fruit HPLC-DAD A: deionised water containing 0.1% formic acid; B Hypersil Gold C18; acetonitrile containing 0.1% formic acid 150 mm 2.1 mm, 3 mm Forsythia suspensa RP-HPLC-DAD A: acetonitrile; B: water containing 0.04% phosphoric (v/v) Agilent ZORBAX SB-C18; 4.6 mm 250 mm, 5 mm Medicago sativa L./Thymus HPLCUV A: water with acetic acid (pH 2.94), B: acetonitrile LiChrospher® RP-18e; 250 mm 3 mm, 5 mm vulgaris L. Fig leaves LC-DAD-MS/ A: 2% acetic acid; B 0.5% acetic acid/acetonitrile (1/1) Synergi Hydro-RP; MS 100 mm 3 mm, 2.5 mm Banana fruits HPLCeESI-HR- A: water with 0.1% formic acid; B: acetonitrile with 0.1% Waters XSelect CSH C18; MS formic acid 100 3 mm, 2.5 mm A: water containing 0.1% formic acid; B: acetonitrile ProntoSIL 120-5-C18-ace-EPS; Buckwheat sprouts HPLCeESI containing 0.1% formic acid 4.6 250 mm, 5 mm eMS/MS 1 H-NMR and 13 C-NMR Flos sophorae UHPLC-Q-TOF- A: 0.1% formic acid in water: B: 0.1% formic acid in Acquity UPLC BEH C18; MS acetonitrile 50 mm 2.1 mm, 1.7 mm ED: electrochemical detector. DAD: photodiode array. MS: mass spectrometry. ESI-MS: electrospray ionization mass spectrometry. UHPLC: Ultra high performance liquid chromatography. Q-TOF-MS: quadrupole-time-of flight mass spectrometry. HPLC: high performance liquid chromatography. HR: high-resolution. NMR: nuclear magnetic resonance. UV: ultraviolet detection.

Reference

Thoo et al., 2013 Fang et al., 2013 Bajerov a et al., 2014 Takahashi, Okiura, Saito, & Kohno, 2014 Passo et al., 2015 Nam et al., 2015b

Nam et al., 2015a


225

Table 4 Representative examples of capillary electrophoresis for the analysis of rutin. Sample

Method

Eluents

Capillary

Reference

Grapefruit Chamomilla recutita L. Buckwheat

CEeED CEC-UV-Vis MEKC-UV-Vis

Fused silica SCX/C18 CElest FS75

Wu, Guan, & Ye, 2007 th, 2007 Fonseca, Tavares, & Horva & Kalinova , 2010 Dad akova

Flos Sophorae Immaturus Traditional chinese medicines

CEeAD CEeAD

Borate buffer (pH 9.0, 60 mM) Phosphate buffer (pH 2.8, 50 mM) containing 50% acetonitrile Sodium tetra-borate:boric acid: SDS (pH 9.2, 10:10:20 mM) containing 5% methanol Borate buffer (pH 9.2, 50 mM) Borax buffer (pH 10.2, 18 mM)

Not specified Not specified

Gan et al., 2012 Wang, Lin, Ma, Xu, & Lin, 2016

CEC: Capillary electrochromatography. ED: electrochemical detector. CE-AD: capillary electrophoresiseamperometric detection. MECK: Micellar Electrokinetic Chromatography.

chemical analysis, since it is considered rapid, cost -effective, nondestructive and accurate (Ferrer-Gallego, Hern andez-Hierro, n, 2011). Despite that the literaRivas-Gonzalo, & Escribano-Bailo ture shows that NIRS is appropriate for the assessment of flavonoids in food and natural products, only a few research studies have applied this technique for the quantification of rutin. In this context, Yang and Ren (2008) used NIRS to determine rutin content in samples of tartary buckwheat. Mao, Shan, Wang, Cai, and Shao (2014) also reported the utilization of this technique for quantitative determination of rutin in tobacco plants. More recently, Cirilli et al. (2016) considered the application of NIRS for the determination of specific metabolites (like chlorophyll, anthocyanins, carotenoids and rutin) during the olive fruit ripening. Other spectroscopic methods such as Fourier transform infrared spectroscopy (FT-IR) and Raman spectroscopy have been used to obtain structural information and the molecular geometry of different flavonoids. These methods have also been successfully used to study the relationship between molecular structure and biological activity of metal complexes of flavonoids (Samsonowicz & Regulska, 2017). FT-IR and Raman spectroscopy have been reported by Paczkowska et al. (2015a) in a recent paper for the identification of rutin obtained from Ruta officinalis. FT-IR has also been applied to analyze the possible alterations of rutin after a supercritical antisolvent process used for the synthesis of submicron particles based on this flavonoid (Montes, Wehner, Pereyra, & Martínez de la Ossa, 2016). Independently on the methodology used for the identification and quantification of bioactive compounds, additional stages of clean-up and fractionation are usually necessary to remove undesirable compounds present in the crude extract (Zitka et al., 2011). Several procedures and strategies have been developed for the purification of flavonoids: liquid-liquid extraction, solid phase extraction (SPE) using styrene-based resin cartridges, a Sephadex LH-20 column, ion exchange resins such as Amberlite XAD-2 and Amberlite XAD-7, or counter-current chromatography (CCC) (Chua, 2013; Marston & Hostettmann, 2006; Stalikas, 2007). Liquid-liquid extraction is a classical technology widely used in the purification of natural products after extraction (Ma et al., 2013). Aqueous two-phase systems (ATPS) are ideal for this purpose and have gained great attention over the last few decades because they allow achieving a product with high purity and at a high yield (Ma et al., 2013). He, Li, Wang, and Deng (2016) proposed an ATPS composed of ethanol and NaH2PO4 for the extraction and purification of quercitrin, hyperoside, rutin, and afzelin from Zanthoxylum bungeanum leaves. Furthermore, scale-up experiments showed that the larger scale purification was feasible. Despite the limited studies regarding rutin purification, CCC has been successfully applied to purify this compound from natural extracts (Dai et al., 2013). This technique offers numerous advantages such as high recovery and efficiency, low cost, and easy scaling (Chen, Wu, & Pan, 2013a). In this line of work, Chen et al.

(2013a) used CCC to fractionate five compounds such as hyperoside, isoquercitrin, rutin, kaempferol-3-rutinoside, and quercetin from Ampelopsis heterophylla extracts. Likewise, Dai et al. (2013) applied the High Speed CCC (HSCCC) to purify seven antioxidants from aqueous extract of Eucommia ulmoides Oliv. The isolated compounds included an iridoid (geniposidic acid), three phenylpropanoids (caffeic acid, chlorogenic acid and ferulic acid) and three flavonoids (quercetin-3-O-sambubioside, rutin and isoquercitrin) which were identified by MS and NMR. Rutin has also been successfully purified from crude extracts obtained Flos Sophorae Immaturus using HSCCC (Xie et al., 2014). The application of macroporous resins is another suitable alternative for the separation and purification of different types of bioactive ingredients. This technology is characterized by its high adsorption capacity, low cost, feasible regeneration, low environmental impact and that is suitable for industrial applications (Li, Liu, Cao, Deng, & Lu, 2013). The D101 macroporous resin has been effectively applied for the separation of three target analytes (salicin, hyperin and rutin) from ionic liquid extraction solution using Populus bark as raw material (Chen et al., 2013b). Sephadex LH-20 column has also been used in the purification of rutin from ethyl acetate extracts obtained from litchi leaf (Wen et al., 2014). Recently, Kumaran, Ho, & Hwang, 2017 used this same resin for the purification of different flavonoids (including rutin) from Nelumbo nucifera seed embryo extracts. SPE is the most widely used technique for the separation and purification of compounds from complex samples because of its simple preparation, low cost and environmental friendliness (Li, Ahn, & Row, 2016). A large number of SPE adsorbents are commercially available, such as alkyl-bonded silica, copolymer and new materials including molecularly imprinted polymers (MIPs), graphene (G)-based nanoparticles, and magnetic nanoparticles in, 2016). ter alia (Andrade-Eiroa, Canle, Leroy-Cancellieri, Cerd, & a Kim et al. (2005) applied the SPE procedure for rutin purification from buckwheat extracts obtaining 92% recovery yield with over 95% purity. In another study, the potential of molecularly imprinted solid-phase extraction (MISPE) method for the separation and cleanup of rutin in complex traditional Chinese medicine samples was evaluated (Peng, Wang, Zeng, & Yuan, 2011). More recently, Li, Ahn, & Row, 2016 used DES and ILs as packing agents in SPE for the purification of three target compounds (rutin, scoparone, and quercetin) from Herba Artemisiae Scopariae extracts. Liquid phase microextraction (LPME) is another method applied pez-Mesas, Gonza lez, Mars, & Valiente, for this purpose (Chaieb, Lo 2015). Based on this technique, hollow fiber LPME (HF-LPME) has been used to determine catechin and rutin in ethanolic extracts from faba beans (Chaieb et al., 2015). 4. Biological activities of rutin Rutin has shown a wide range of pharmacological applications

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Free radicals are produced in large amounts due to various reactions going inside our body. The harmful intervention of free radicals in normal metabolic processes leading to pathologic changes is a consequence of their interaction with various biological compounds inside and outside living cells (Sharma et al., 2013a). The ability of flavonoids to scavenge free radicals and chelate metal ions has led to an examination of their activities as antioxidants in lipid peroxidation. Their antioxidant activity is related to its chemical structure, partition coefficients and rate of reaction with the radicals of interest (Boyle et al., 2000). In the case of rutin, most of its biological activities such as anti-inflammatory, antimicrobial, anti-tumor and anti-asthma are mainly attributed to the potent antioxidant property of rutin, particularly as a free radical scavenger (Chua, 2013). It has been demonstrated that rutin has powerful antioxidant capacity against various antioxidant systems in vitro and it has been found that this capacity was concentration dependent (Yang, Guo, & Yuan, 2008). In an in vivo study, the inhibition of lipid peroxidation and the improvement of the antioxidant status in the diabetic liver, kidney and brain of rats by action of rutin was evaluated by Kamalakkannan and Prince (2006). They found that the oral administration of rutin (100 mg/kg) for a period of 45 days has a significant antioxidant effect in streptozotocin (STZ)-induced experimental diabetes. The powerful antioxidant capacity of rutin has been demonstrated by different antioxidant assays. The capacity to neutralize or sequester free radicals has been proved in assays such as hydroxyl radical-scavenging assay, superoxide radical-scavenging assay, 1,1diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging assay, 2,20 azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) radical scavenging and lipid peroxidation assay (Yang et al., 2008). The chelation of transition metals has been proved in assays such as FRAP (Pulido, Bravo, & Saura-Calixto, 2000) and CUPRAC.

Staphylococcus glurance and Eschericia coli (Soni, Malik, Singhai, & Sharma, 2013). Their results led to the conclusion that the rutin hydrogel formulation showed significant antimicrobial activity. In another study, the aqueous methanolic extract of Pteris vittata, that contained high ammounts of rutin, were tested for the growth of eight intestinal microorganisms, by using disc diffusion and micro-dilution methods (Singh, Govindarajan, Rawat, & Khare, 2008). The extract showed potent activity against Pseudomonas aeruginosa and Klebsiella pneumoniae. Rutin has also been used to complement the antibacterial action of other flavonoids. For example, Arima, Ashida, and Danno (2002) described that the antibacterial activities of quercetin, morin, galangin, kaempherol, myricetin and fisetin were enhanced in the presence of rutin when Salmonella enteritidis was used as the test bacterium. Apart from antibacterial and antifungal activity, flavonoids can exert also antiviral activity. It has been reported that different flavonoids, including quercetin and rutin, possess activity against up to seven types of virus, e.g. herpes simplex virus (HSV), respiratory syncytial virus, poliovirus and Sindbis virus (Middleton & Kandaswami, 1994; Selway, 1986). The proposed antiviral mechanisms of action include inhibition of viral polymerase and binding of viral nucleic acid or viral capsid proteins (Selway, 1986). Using a more practical approach, Stojkovi c et al. (2013) tested the antioxidant and antimicrobial properties of rutin and other phenolic compounds in chicken soup and pork meat to obtain information on how these compounds behave in food rather than in microbiological medium. They observed that rutin inhibited the development of the isolated food contaminant Staphylococcus aureus in chicken soup. The antibacterial and antifungal activities of rutin and other five € € plant-derived flavonoids were evaluated by Orhan, Ozçelik, Ozgen, and Ergun (2010) against eight standard strains of bacteria and their drug-resistant isolates, as well as fungi, using the microdilution broth method. They found that rutin and the other flavonoids showed strong antimicrobial and antifungal activities against isolated strains of P. aeruginosa, A. baumanni, S. aureus and C. krusei. In another study, the chemotherapeutic potential of rutin was tested by studying its antibacterial (E. coli, P. auruginosa, S. aureus, K. oxytoca, B. subtilis), antifungal (C. albicans), anthelmintic (A. galli, P. phostuma) and larvicidal (S. aegypti) activity (Dubey, Ganeshpurkar, Bansal, & Dubey, 2013). The authors found that rutin, isolated from tobacco leaves, effectively inhibited fungal and bacterial growth, as well as demonstrated its anthelmintic potential.

4.2. Antimicrobial

4.3. Anti-inflammatory activity

The potentially exploitable activities of flavonoids include direct antibacterial activity, synergism with antibiotics, and suppression of bacterial virulence (Cushnie & Lamb, 2011). These activities may be attributable to up to three mechanisms: cytoplasmic membrane damage (Tsuchiya & Iinuma, 2000), inhibition of nucleic acid synthesis (Plaper et al., 2003), and inhibition of energy metabolism (Haraguchi, Tanimoto, Tamura, Mizutani, & Kinoshita, 1998). In the case of rutin, it has been proposed that it mainly modulates the expression level of proteins involved in general stress response mechanisms and, in particular, induces the activation of protein quality control systems, and affects carbohydrate and amino acid metabolism, protein synthesis and cell wall integrity (Mazzeo et al., 2015). The antimicrobial activity and acute toxicity of natural rutin was first studied by Rym, Eo, Kim, Lee, and Han (1996). More recently, the zone of inhibition of rutin in hydrogel systems was evaluated by a cup plate method against the bacteria Staphylococcus aureus,

The inhibition of some key enzymes involved in inflammation response explains the anti-inflammatory effect of rutin. For et al. (2012) evaluated in vitro and in vivo the example, Rabiskova use of coated pellets intended for rutin colon delivery for treating experimental colitis in rats. They found that rutin was able to promote colonic healing at a dose of 10 mg/kg. As a result, colon/ body-weight ratio decreased and myeloperoxidase activity was significantly suppressed. Based on these results, the authors concluded that the use of rutin delivering systems has numerous advantages in the treatment of inflammatory bowel disease (IBD), and that it could form a promising preparation free of side effects for lifelong therapy of this severe illness. ^go et al. (2016) observed that In a more recent study, Torres-Re rutin significantly inhibited the xilol-induced ear edema and also reduced cell migration in both carrageenan-induced peritonitis and zymosan-induced air pouch models. Reduced levels of cytokines were also observed.

due to its significant antioxidant properties. Patent filing of formulations containing rutin has increased over the past few years as reviewed by Lee et al. (2007) and Sharma, Sahni, Ali, and Baboota (2013b). Conventionally, rutin is used as antimicrobial, antifungal, and antiallergic agent. Current research has shown its pharmacological benefits for the treatment of various chronic diseases such as cancer, diabetes, hypertension and hypercholesterolemia (Sharma et al., 2013b). 4.1. Antioxidant activity


Rutin has also been found to alleviate ROS induced oxidative stress and inflammation in rats via targeting p38-MAPK, NFkB, COX-2, i-NOS and TNF-a, IL-6 (Nafees, Rashid, Ali, Hasan, & Sultana, 2015). It was also observed that rutin could reduce brain damage and improve neurologic dysfunctions partly through its antiinflammatory properties (Hao et al., 2016). Yoo, Ku, Baek, and Bae (2014) found that rutin potently inhibited HMGB1 release, down-regulated HMGB1-dependent inflammatory responses in human endothelial cells, and inhibited HMGB1mediated hyperpermeability and leukocyte migration in mice. High mobility group box 1 (HMGB1) protein acts as a late mediator of severe vascular inflammatory conditions. In addition, treatment with rutin resulted in reduced cecal ligation and puncture-induced release of HMGB1 and sepsis-related mortality. 4.4. Anticancer activity Numerous studies have shown that rutin has anticancer effects. These effects have been evaluated both in vitro and in vivo studies. Many mechanisms of the action of flavonoids as anticancer agents have been identified, including carcinogen inactivation, antiproliferation, cell cycle arrest, induction of apoptosis and differentiation, inhibition of angiogenesis, antioxidation and reversal of multidrug resistance or a combination of these mechanisms (Ren, Qiao, Wang, Zhu, & Zhang, 2003). Rutin has been shown to cause cell cycle arrest and induce apoptosis in many types of human cancer cell lines (Perk et al., 2014). In a recent study, Karakurt (2016) investigated the anti-carcinogen and protective effects of rutin, as well as its modulatory action on cytochrome P450 (CYP) and phase II enzymes in human hepatocellular carcinoma cells. They found that rutin inhibited proliferation of HEPG2 cells in a dose-dependent manner. Rutin was also found to have chemopreventive activity in several animal models. In one of these in vivo studies, Alonso (2013) observed that Castro, Domínguez, and García-Carranca rutin exerts cytotoxic effects on SW480 tumor colon cancer cells, induces in vivo antitumor effects, lacks toxic effects on mice bearing SW480 tumor and exerts antiangiogenic properties. In another study, Gonçalves et al. (2013) evaluated the effect of eight flavonoids on thyroid iodide uptake in Wistar rats. Thyroid iodide uptake through the sodium-iodide symporter is not only an essential step for thyroid hormones biosynthesis, but also fundamental for the diagnosis and treatment of different thyroid diseases. They found that rutin was the only flavonoid able to increase thyroid iodide uptake. Based on these results, they concluded that rutin might be useful as an adjuvant in radioiodine therapy. Chen et al. (2013c) investigated the antineuroblastoma effect of rutin. They found that rutin significantly inhibited the growth of LAN-5 cells and chemotactic ability. Flow cytometric analysis revealed that rutin induced G2/M arrest in the cell cycle progression and induced cell apoptosis. These results support the viability of developing rutin as a novel therapeutic prodrug for neuroblastoma treatment, as well as providing a new path on anticancer effect of a Chinese traditional drug. Most flavonoids have been demonstrated to inhibit proliferation in many kinds of cultured human cancer cell lines, whereas less or no toxic to human normal cells (Kawaii, Tomono, Katase, Ogawa, & Yano, 1999; Pouget et al., 2001). In a more recent study, Srinivasan, Natarajan, and Shivakumar (2016) have tested the anti-proliferative activity of potential extract (ethyl acetate extract), which possess high antioxidant activity, and the isolated rutin compound against U-937 and HT-60 cell lines. Their results showed a dose dependent effect of rutin on both activities. Ben Sghaier et al. (2016) also demonstrated the use of rutin as a multifunctional agent to inhibit proliferation, to reduce the production of ROS, and to decrease cell

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adhesion and migration of human lung and colon cancer cells. Another approach for the use of rutin is its combined treatment with anticancer drugs. Nasiri et al. (2016) demonstrated that the use of rutin with 5-FU and/or oxaliplatin was more effective than the individual treatments of the drugs alone on colon cancer cells. They also found that the combined use of rutin with lower 5-FU and oxaliplatin doses could be useful to reduce the possible adverse effects of anticancer drugs. 4.5. Antidiabetic activity Lee and Jeune (2013) examined the antioxidant activities and anti-inflammatory effects of rutin from streptozotocin (STZ)induced diabetic rats. Their results revealed that the levels of plasma glucose and serum glucose were remarkably higher in the STZ-treated group compared to other groups and were significantly reduced in the STZ þ rutin treated group compared to the STZtreated group. They found that in the STZ-induced diabetic rats, blood glucose level decreased by the antioxidant activities and antiinflammatory effects of rutin. They also observed that pancreas, heart, liver, kidney, and retina tissues that were related to diabetic complications were functionally and protected by rutin. Therefore, these authors suggested to apply rutin clinically for the treatment of diabetes. Diabetic cardiomyopathy (DCM) is a dreadful complication of diabetes responsible for 80% mortality in diabetic patients. Rutin has a long history of use in nutritional supplements for its action against oxidative stress, inflammation, and hyperglycemia, the key players involved in the progression of DCM. In a recent study, Saklani et al. (2016) found out that rutin provided significant protection against diabetes associated oxidative stress, prevented degenerative changes in heart, and improved ECG parameters compared to diabetic control rats. 4.6. Antiallergic Antiallergic activity of rutin was studied by determining its effect on immunoglobulin E-mediated mast cell activation (Chen, Gong, Liu, & Mohammed, 2000). Recently, Kim et al. (2015) demonstrated that rutin had an anti-allergic inflammatory effect, and it might protect against allergic rhinitis. They showed for the first time, that rutin suppresses the levels of chemokines (ICAM-1 and MIP-2) and the precipitation of inflammatory cells by regulating the levels of vascular endothelial growth factor (VEGF). In addition, they observed that rutin reduced the levels of inflammatory cytokines and the activation of caspase-1. Atopic dermatitis (AD) and allergic contact dermatitis (ACD) is a common allergic inflammatory skin disease. Choi and Kim (2013) examined whether rutin modulates AD and ACD symptoms in BALB/c mice ears, used as an atopic dermatitis model. They found that rutin inhibited mast cell infiltration into mice ear and serum histamine level. In addition, rutin suppressed ACD based on ear thickness and lymphocyte proliferation, serum IgG2a levels, and expression of interferon INF-g, and interleukin (IL)-4, IL-5, IL-10, IL17 and tumor necrosis factor-a in ACD ears. Their study showed that rutin inhibits AD and ACD, suggesting that rutin might be a candidate for the treatment of allergic skin diseases. 4.7. Other biological activities Other biological activities of rutin include antihypertensive activity, antithrombogenic activity, treatment of Parkinson disease, Alzheimer's disease, myocardial infarction, antidepressant, chronic venous insufficiency, etc. A major hallmark of Alzheimer's disease (AD) is the

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accumulation of neurotoxic amyloid b (Ab) peptides and their deposition in extracellular plaques. Choi et al. (2015) examined the beneficial effects of the n-butanol fraction and rutin extracted from tartary buckwheat on learning and memory deficits in a mouse model of amyloid b (Ab)-induced Alzheimer's disease. They found that the n-butanol fraction and extracted rutin can protect memory and cognitive function against Ab-induced oxidative stress and have possible therapeutic applications for the treatment of AD. Reactive oxygen species exert toxic effects during ischemiareperfusion (I/R) injury of various organs. Bhandary et al. (2012) tested different isoflavonoids and found that only rutin significantly increased left ventricular developed pressure (LVDP) and increased maximum positive and negative dP/dt (þ/ dP/dtmax). They observed that rutin had consistent protective effects in I/R injury by affecting cardiac dynamic factors as well as by enhancing SOD and DPPH activity. It has also been observed that flavonoids may contribute to the maintenance of normal blood vessel conditions by decreasing capillary permeability and fragility (Mitscher, Telikepalli, McGhee, & Shankel, 1996). Khan et al. (2012) investigated the neuroprotective effects of rutin on 6-hydroxy-dopamine (6-OHDA)-induced Parkinson's disease (PD) in rats. Their results suggest that rutin has antioxidant and anti-inflammatory properties which might delay the onset and slow the progression of PD by protecting 6-OHDA-induced alterations in behavioral, biochemical and histopathological parameters in rats. Thus, rutin may be considered a potential drug candidate for prophylactic treatment in patients prone to PD. Their results suggest that the consumption of rutin may have a protective effect against neurological disorders such as PD. Hydroxyethylrutosides (HR), also known as oxerutins, is a mixture of semi-synthetic flavonoids obtained through the hydroxylation of rutin. HRs are sold as standardized products for the treatment of chronic venous insufficiency (CVI). It has been demonstrated that the most important pharmacologic action of oxerutins is the inhibitory effect on microvascular permeability, with a consequent reduction of the formation of edema following the application of several types of injury (Antignani & Caliumi, 2007). This effect has been demonstrated in controlled, doubleblind clinical trials, both in healthy volunteers and in patients with CVI. In one of these studies, Petruzzellis et al. (2002) carried out a double-blind, randomized, controlled study to determine the efficacy of oxerutin in the treatment of CVI. They concluded that considering both noninvasive tests and clinical evaluation, oxerutins is effective in controlling chronic venous hypertension, without side effect, and with good tolerability. Aziz, Tang, Chong, and Tho (2015) have recently carried out a systematic review of the efficacy and tolerability of HR for improvement of the signs and symptoms of CVI. Their findings showed that HR produced modest improvements in several symptoms of CVI. However, the authors commented that better-quality trials are still required to draw firm conclusions on the usefulness of HR for CVI. 4.8. Toxic effects The toxicity of flavonoids is a controversial matter. It has been argued that flavonoids have low toxicity because they are widely distributed in edible plants and beverages, and have been used in traditional medicine. Its use in dietary supplements or as pure compounds in pharmacological doses does not appear to cause side effects (Dzoyem, Hamamoto, Ngameni, Ngadjui, & Sekimizu, 2013). Even when supplemented at 10% of total caloric intake, the use of flavonoids has been shown non-toxic (Middleton & Kandaswami, 1994). On the other side, results from different studies demonstrated that flavonoids can act as pro-oxidants (Sahu & Gray, 1996) and have been shown to be mutagenic in bacteria and mammalian

test systems (Skibola & Smith, 2000). Their pro-oxidant activity may deplete the nuclear antioxidant defense and lead to oxidative DNA damage, which may be responsible for their mutagenicity. In contrast with these arguments, recent reports indicate that flavonoids, including rutin, seem to be antimutagenic in vivo (Alonso-Castro et al., 2013; Kaur, Arora, & Thukral, 2015). One possible explanation for this contradictory information is that flavonoids are toxic to cancer cells, but are not toxic or less toxic to normal cells (Nijveldt et al., 2001). Furthermore, no side effects have been reported for rutin, which represents an advantage over other aglycones whose use is restricted due to its mutagenic and cytotoxic activity (Sharma et al., 2013a,b). Lin et al. (2001) studied the toxicological safety of the extract of tartary buckwheat, which has high levels of rutin, quercertin and flavonoids. They carried out acute toxicity test and 30-day feeding test on mice, and mutagenic test on bacteria. Their results showed that continuous administration for a long time had no negative effect on the development and the indexes of hematology, biochemistry and pathology. They concluded that the evaluated tartary buckwheat extract was toxicologically safe. 5. Approaches to enhance solubility and biovailability of rutin The main disadvantage related to rutin is its poor bioavailability, caused mainly by its low solubility. Different approaches have been proposed in the last years to increase rutin solubility, not only in the aqueous phase but also in lipid phase (Table 5). These strategies might enhance the bioavailability of the flavonoid when administered orally, but also might widen the field of its application to include different formulations of this bioactive compound. It should be mentioned that most strategies focused on enhancing aqueous solubility. However, both hydrophilicity and lipophilicity could be improved at the same time, as described by Singh, Rawat, Semalty, and Semalty (2012). 5.1. Enhanced aqueous solubility 5.1.1. Nanoparticulate systems In the last decade, an alternative drug delivery approach was developed to overcome the poor water solubility of certain pharmaceuticals by reducing its particle size. The decrease in the drug particle size leads to an increase in the saturation solubility, to an enlarged surface area and to a higher dissolution velocity. Mauludin, Müller, and Keck (2009a,b) prepared lyophilized rutin nanocrystals which could be completely re-dispersed in water. Furthermore, the dissolution velocity of the rutin nanocrystalloaded tablet was superior compared to a marketed tablet. In this sense, rutin was released and dissolved completely from the nanocrystal tablets in water after 30 min. In contrast, only 55% of the total amount of rutin was dissolved from the marketed tablet. Formulating rutin as drug nanocrystals has significant importance to improve its physicochemical properties. Polymeric nanoparticles have been designed to encapsulate lipophilic drugs not only to improve their physicochemical properties but also to avoid drug degradation in the gastrointestinal tract and protection of sensitive materials to chemical degradation induced by UV light. Nanocapsules are polymeric nanoparticles composed of an oily core surrounded by a polymeric wall stabilized by surfactants at the particle/water interface (Fig. 1 A1). Almeida et al. (2010) prepared rutin-loaded nanocapsules and nanoemulsions (Fig. 1 A2), as aqueous intermediate or final systems to the development of nanomedicines containing rutin. Both formulations presented an increase in the rutin photostability and a prolonged in vitro antioxidant activity.


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Table 5 Strategies to increase rutin solubility in aqueous or lipid phase. Enhanced Strategy solubility

Main features

References

Aqueous phase

Completely redispersed in water and higher dissolution velocity Improved physicochemical properties and protection of rutin from adverse conditions

Mauludin et al., 2009a; 2009b Almeida et al., 2010; Babazadeh et al., 2016; Yang et al., 2016; Kumar & Bhopal, 2012; Kamel & Basha, 2013

Lipid phase

Nanoparticulate systems: - Nanocrystals of rutin - Nanocapsules, nanoemulsions, NLCs, SEDDS, SSEDDS Cyclodextrin complex

Co-grinding, kneading and co-evaporation techniques for the formulation of inclusion complexes; increased solubility, dissolution rates and antioxidant activity Derivatization of phenolic hydroxyl groups (mono, di, tri or tetra Chemical reaction hydroxyethylated derivatives). Soluble and stable products commercialized for - Hydroxyethyl the treatment of venous disorders as varicose veins and hemorrhoids under the derivatives - Carboxylate derivatives tradename Venoruton®, Paroven®, Relvene® or Varemoid®. - Sulfonate derivatives Carboxylate and sulfonate groups introduced on rutin sugar moiety; increased water solubility (up to 100-fold) while maintaining antioxidant properties Enzymatic Biocatalyst: laccase oligomerization Increased water solubility (up to 4200 fold) Degree of polymerization depending of laccase source, reaction medium and operational conditions: from dimers to octamers Increased specific biological activities Nanoparticulate systems: Increased solubility in topical formulations; alternative to common synthetic- Gelatin-nanocapsules based sunscreens (enhanced sun protection factor and antioxidant activity) Phospholipid complex Increased solubility (lipophilicity and also hydrophilicity) while maintaining its bioactivity Chemical acylation Not regioselective; derivation of phenolic hydroxyl groups may affect antioxidant activity Enzymatic acylation Biocatalysts: Lipases, subtilisin and esterases Acyl donors: from C2 to C16 Highly regioselective: acylation by lipase on the secondary 4-OH of rhamnose

Sri et al., 2007; Nguyen et al., 2013; Paczkowska et al., 2015b; S¸amlı et al., 2014; Çelik et al., 2015 Favre, 1961; Zyma, 1975; Li, Liang, & Li, 2016 Alluis et al., 2000; Pedriali et al., 2008

Kurisawa et al., 2003; Anthoni et al., 2008; Rhouma et al., 2012; Rhouma et al., 2013; Uzan et al., 2011

de Oliveira et al., 2016; Alexander et al., 2016; Singh et al., 2012; Das & Kalita, 2014 Perrier et al., 2001 Chebil et al., 2006; de Oliveira et al., 2009; Biely et al., 2014; Zheng et al., 2013

NLC: nanostructured lipid carriers. SEDDS: self-emulsifying drug delivery systems. SSEDDS: solid self-emulsifying drug delivery systems.

A novel nanocarrier for stabilization and sustained release of rutin has been formulated by Yang et al. (2016). Epigallocatechin gallate (EGCG) and soybean seed ferritin deprived of iron (apoSSF) were fabricated as a combined double shell material to encapsulate rutin. The ferritin functioned as a spherical wall material for rutin encapsulation in the aqueous phase. On the other hand, EGCG formed complexes with the ferritin cage through hydrophobic or Van der Waals interactions, resulting in an improved protective effect and sustained release of rutin in the simulated gastrointestinal conditions. One of the most popular and commercially viable formulation approaches for solving the problems of low oral bioavailability is self-emulsifying drug delivery systems (SEDDS, Fig. 1 A3). SEDDS, which belong to lipid-based formulations, are isotropic mixtures of drug, oil/lipid, surfactant, and/or co-surfactant, which form fine emulsion/lipid droplets, ranging in size from approximately 100 nm to 12) (Chebil et al., 2006). A recent strategy to increase the productivity of the enzymatic acylation used ultrasound irradiation (Zheng et al., 2013), which reduced mass transfer limitations. Furthermore, less concentration of unsaturated fatty acids was required to saturate the flavonoids under ultrasound irradiation than under stirring condition possibly due to increased emulsification in the former case.

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6. Conclusions and future trends Rutin is a common dietary flavonoid, that is consumed in fruits, vegetables, and plant derived beverages. Additionally, there are hundreds of formulations in the market containing rutin in different dosage forms either alone or in combination with other active ingredients. Both conventional and innovative methods have been reported for the extraction of rutin from natural sources. Accurate comparison between procedures is not straightforward because of the variance in the plant materials. However, current trends on extraction process have been focused on the discovery and design of green and sustainable extraction techniques to optimize the extraction of rutin. Numerous studies have reported diverse pharmacological activities of rutin, including antioxidant, antiinflammatory, anticancer, antidiabetic, antimicrobial and neuroprotection effects. However, the observed effects in vitro do not always translate into the clinic because of rutin poor bioavailability. To overcome this barrier, researchers have focused towards different strategies that, in principle, will enhance bioavailability and ultimately health benefits. The present review provides information about the mechanisms used to increase rutin solubility in both aqueous or lipid phase. Drug delivery systems based on nanoparticle systems, cyclodextrin and phospholipid complexes are some of the rutin formulations with increased bioavailability. Additionally, derivatives of rutin obtained from chemical or enzymatic transformation have been also demonstrated not only to possess increased solubility but also enhanced biological properties. Nevertheless the relevance of these findings to an in vivo setting remains to be determined. One major challenge that food industry faces is to translate basic-applied research and technology innovations (e.g. rutin delivery systems, synthesis of rutin derivatives) into safe products providing health benefits for the consumer. Acknowledgements This work was financially supported by the Spanish Ministry of Economy and Competitiveness (CTQ2014-58879-JIN). The authors belong to the Galician Competitive Research Group GRC2013-032 and to the CRETUS Strategic Partnership (AGRUP2015/02). All n these programmes are co-funded by FEDER (EU). Beatriz Gullo thanks Spanish Ministry of Economy and Competitiveness for her postdoctoral grant (Reference FPDI-2013-17341). References Alexander, A., Ajazuddin, Patel, R. J., Saraf, S., & Saraf, S. (2016). Recent expansion of pharmaceutical nanotechnologies and targeting strategies in the field of phytopharmaceuticals for the delivery of herbal extracts and bioactives. Journal of Controlled Release, 241, 110e124. rol, N., El hajji, H., & Dangles, O. (2000). Water-soluble flavonol (3Alluis, B., Pe hydroxy-2-phenyl-4h-1-benzopyran-4-one) derivatives: Chemical synthesis, colouring, and antioxidant properties. Helvetica Chimica Acta, 83, 428e443. ~ es, L. O. S., de Carvalho, L. M., & Beck, R. C. R. Almeida, J. S., Lima, F., da Ros, S., Bulho (2010). Nanostructured systems containing rutin: In vitro antioxidant activity and photostability studies. Nanoscale Research Letters, 5, 1603e1610. Alonso-Castro, A. J., Domínguez, F., & García-Carranc a, A. (2013). Rutin exerts antitumor effects on nude mice bearing SW480 tumor. Archives of Medical Research, 44, 346e351. Ameer, K., Shahbaz, H. M., & Kwon, J. H. (2017). Green extraction methods for polyphenols from plant matrices and their byproducts: A review. Comprehensive Reviews in Food Science and Food Safety, 16, 295e315. Andrade-Eiroa, A., Canle, M., Leroy-Cancellieri, V., & Cerd a, V. (2016). Solid-phase extraction of organic compounds: A critical review (Part I). Trends in Analytical Chemistry, 80, 641e654. de Andrade, E. F., de Souza Leone, R., Ellendersen, L. N., & Masson, M. L. (2014). Phenolic profile and antioxidant activity of extracts of leaves and flowers of yacon (Smallanthus sonchifolius). Industrial Crops and Products, 62, 499e506. Angiolillo, L., Del Nobile, M. A., & Conte, A. (2015). The extraction of bioactive

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