Plant-Derived Bioactive Compound–Based Nanoemulsions and Their Applications in Food Industries

Plant-derived phytochemicals are produced as secondary metabolites in plants and are categorized depending on their active ingredient component present (Cow'an, 1999; Dhull et ah, 2020c). These bioactive compounds are usually non-nutritive but confer

Major applications of plant bioactive nanoemulsions in food industries

FIGURE 8.1 Major applications of plant bioactive nanoemulsions in food industries.

organoleptic properties and are, therefore, popularly termed “phytochemicals”, being from plant origin. Plants can synthesize limitless compounds with wide array of beneficial advantages in terms of antioxidant, anti-inflammatory, antibacterial, antiviral, and antifungal activities (Dhull et al., 2019b). The use of these compounds in the food industry is still challenging as being sparingly soluble in water which minimizes their stability and shelf life and thus hampers their immense usage in food preparations. Various attempts to remove these undesirable properties is provided by exploring their nanosized structures, mainly by generating their nanoemulsion, which are considered safe for utilization in food formulations. As these nanoemulsions offer added advantages over conventional emulsions, they have become a preferred choice in food industries. The production and accumulation of these bioactive compounds are observed in various plant organs, namely roots, seeds, leaves, and fruits. Phenolic compounds are considered to be the most effective class of phytochemicals where major components are phenols or their oxygen-substituted derivatives (Geissman, 1963). It includes simple phenolic compounds, phenolic acids, flavonoids, quinones, tannins, and coumarins (Cowan, 1999). Apart from this, another essential class termed as essential oils, have been used for food preservation from ancient times. Antimicrobial activity of essential oils has been well summarized by (Donsi, 2018). In addition, alkaloids, lectins, and plant polypeptides are also known to possess antimicrobial activity (Cowan, 1999; Hintz et al., 2015). Specific antimicrobial properties of any particular plant species are generally attributed to the presence of these bioactive molecules. Their antimicrobial activity depends on the concentration, composition, structure, and presence of functional groups (Juneja and Sofos, 2017). In the next section, we briefly summarize various types of phytochemicals as per their classification and their traditional beneficial applications and attempt to list their potential applications as nanoemulsion, including major methods for their synthesis.

Polyphenolic Compounds

Regardless of diversity in the chemical structures, phenolic compounds are usually termed “polyphenols” mainly because of their natural occurrence as conjugates of at least two phenolic rings linked with mono- and polysaccharides and as esters and methyl esters. Phenolic compounds are large group of secondary metabolites in plants, which are characterized by the presence of substituted phenolic ring. They are ubiquitously distributed in the plant kingdom and are the most abundant secondary metabolite in plants. Phenolic compounds play key role in providing defense against insects and plant pathogens. They are helpful in growth and reproduction and impart colour and flavour to fruits and vegetables. The benefits of phenolics include their antimicrobial, antioxidant, anti-inflammatory, antiviral, and anti-allergenic properties, among others, which have been reviewed in detail by Cowan (1999). Polyphenolic compounds can be broadly grouped into four major categories; flavonoids, phenolic acids, hydroxycinnamic acids, and lignans (Maqsood et al., 2013).

Flavonoids

From plants, more than 5,000 structurally different flavonoids have been isolated and identified. These compounds are ubiquitously distributed in the plant kingdom.

General flavonoid backbone

FIGURE 8.2 General flavonoid backbone.

mainly in photosynthesizing plant cells. Flavonoids are responsible for producing various attractive colours of flowers, fruit, and leaves. Flavonoids are known to exhibit antimicrobial, anti-inflammatory, oestrogenic, enzyme inhibitory, antidiabetic, anti-allergic, antioxidant, and cytotoxic anti-tumourous activity (Cushnie and Lamb, 2005). The basic structure of flavonoid compounds is the flavane nucleus, 15-carbon (C6-C3-C6) skeleton, which consists of two benzene rings linked through a heterocyclic pyrane ring (Figure 8.2). Based on various substitution pattern, flavonoids can be categorized in six major subgroups, viz. flavonols, flavanones, is of lavonoids, flavones, flavan-3-ol, and anthocyanins (Cushnie and Lamb, 2005; Hossain et al., 2016).

Flavonols

Flavonols are known as 3-hydroxyflavones since they have a hydroxyl group attached to position 3 of the flavones. Flavonols are extensively concentrated in the outer parts (skin of fruits) as well as in the leaves of the higher plants. In higher plants, nearly 450 different flavone aglycones have been documented so far. The major dietetical flavonols include quercetin, kaempferol. myricetin. isorhamnetin, and fisetin. The recent work done utilizing them for nanoemulsion preparation and its method of preparation is briefly summarized.

Quercetin is biologically significant flavonoids in human dietary nutrition in plentiful amount and forms the skeletons of many other flavonoids, such as hesperidin, naringenin, and rutin. It is found in various fruits and vegetables such as apples, grapes, red wine, cherries, cranberries, red onions, green leafy vegetables, broccoli, pepper, coriander, buckwheat citrus fruits, tea, and blueberries. Quercetin shows numerous health benefits, including lowering of blood pressure, anti-tumour, cardiovascular protection, an immunomodulatory effect, an antiviral property, gastroprotec- tive effects, and antimicrobial activity (Hossain et al., 2016). Quercetin also demonstrates high free radical scavenging activities towards hydroxyl ions, peroxyl ions, and superoxide anions (Karadag et al., 2013). Antibacterial properties exhibited by quercetin majorly employs inhibitory activity on FabZ in Helicobacter pylori, the inhibition of d-alanine:d-alanine ligase in H. pylori and Escherichia coli, the inhibition of DNA gyrase in E. coli, the inhibition of motility due to a disturbed proton motive force, a disturbance of membrane potential, and moderate inhibition of efflux pump in various bacteria (Cushnie and Lamb, 2005; Khameneh et al., 2019). Reports also indicated its antiviral activity due to inhibition of viral integrase and reverse transcriptase in HIV (Cowan, 1999). Moreover, its low solubility in water and gastric juice limit its bioavailability when taken orally. These solubility issues were addressed by utilizing HPH, using a response surface methodology, for the generation of a quercetin-based nanoemulsion with a food-grade emulsifier, were found beneficial for oral uptake (Karadag et al., 2013). As per the available literature, quercetin-based emulsion displayed increased solubility that was found to be 40 times more in medium- chain triglyceride at room temperature. Furthermore, oral pseudo-organogel-based emulsion systems for quercetin had been developed for improved bio accessibility. As compared to quercetin-loaded oil mixture, the bio-accessibility of these pseudo- organogel-based emulsions was found to be enhanced significantly. This may open new avenues for exploring their potential applications in the food, cosmetic, and pharmaceutical industries (Xu, 2014). Another study demonstrated that nanoemulsion of quercetin developed by two-step homogenization process can further be incorporated into edible gelatin films. These films exhibited antimicrobial activity against food- borne pathogens without any reduction in antioxidant activities. These polyphenol- enriched gelatin films, being of plant origin and safe, can be used as active packaging material for reducing the total microbial load of fresh meat and may further extend its shelf life by reducing the risk of foodborne illness (Khan et al., 2020).

Another example of flavonoids is rutin (also known as rutoside, quercetin-3-О- rutinoside, and sophorin), w'hich is a common dietary flavonoid that prevalently exists in the plant kingdom. Rutin exhibits a wider range of pharmacological properties which can exploited as human nutritive medicine. It shows antimicrobial, antifungal, and anti-allergic properties and hence is commonly utilized as vital preventive medicine. The high radical scavenging activity of rutin makes it a suitable candidate that could be utilized as a good source of antioxidants, and due to the several applications, rutin is now categorized among important nutraceutical food product. Rutin shows antibacterial activity against a permeable E. coli strain (a strain into which the envAl allele had been incorporated). Rutin was also shown to inhibit topoisomerase IV-dependent decatenation activity and induce an emergency cellular against extensive DNA damage in the repair pathway SOS response of the E. coli strain, thus leading to growth inhibition (Bernard et al., 1997). Rutin alone or in combination with quercetin, is reported to inhibit the growth of E. coli at 20°C without causing cellular death but was able to display more efficient antibacterial activity at 4°C (Rodriguez Vaquero et al., 2010; Cetin-Karaca and Newman, 2015). Although it shows excellent functional properties, its application in food industries is still hindered due to its poor solubility, low absorption, and poor bioavailability (Dammak et al., 2017; Bazana et al., 2019). To overcome this, rutin O/W nanoemulsions were prepared using a rotor-stator homogenization, using lecithin and chitosan as stabilizers, which remarkably improved their rheological properties, heat stability, kinetic degradation, and release properties when compared to rutin solution (Dammak and do Amaral Sobral, 2018). Rutin was reported as a principle component of Pliysalis peruviana calyx extract for the preparation of a nanoemulsion in which antioxidant stability of the prepared nanoemulsins was compared with free extracts under different storage conditions (7 and 25°C) and with absence of light for an extended time of 4 months. These observed results demonstrated that nanoemulsions were able to retain the antioxidant capacity during preservation, thus resulting in reuse of the extract and thereby avoiding wastage. These findings are of great interest for food industries for the development of new' food products with enhanced shelf life (Bazana et ah. 2019). Similar studies demonstrate that rutin-loaded O/W nanoemulsions incorporated in edible gelatin-based films initiated interactions with the gelatin film matrix, thus inducing a change in the properties of films. Reports exist to ascertain that rutin-loaded nanoemulsions were able to significantly improve the mechanical properties of gelatin films via increasing the films’ resistance towards mechanical stress. Thus, the application of nanoemulsions can be extended as food additives carriers, which allows incorporating a variety of lipophilic bioactive compounds, such as rutin, into the hydrophilic matrices of biopolymers namely gelatins, for the fabrication of films due to their enhanced biodegradability (Dammak et al„ 2017).

In addition, nanoemulsions of other flavonoids, for example kaempferol, isorham- netin, and fisetin, are also reported for their beneficial medicinal activities, namely antiinflammatory, antioxidant, anti-diabetic, and anti-cancerous properties. Kaempferol possesses free radical scavenging activity; anti-aging, anti-inflammation, and anti-diabetic property; and inflammatory pathways suppression and w'as know'n to exhibit antimicrobial, antiviral, anti-tumour, and anti-cancer activities. Myricetin. found in tea, wine, berries, fruits, and vegetables, shows notable antibacterial activity through inhibition of efflux pump (Khameneh et ah, 2019). The scarce solubility of kaempferol was found similar to quercetin and myricetin in the oil phase and requires the addition of amphiphilic molecules in the lipophilic core for the generation of nanoemulsions. Nanoemulsions prepared by the mentioned method resulted in improved thermal and enhanced photo stability (Donsi, 2018).

Flavanones

The flavanones (also called dihydroxyflavones) are structurally different from the rest of flavonoids as they lack a double bond between C-2 and C-3 positions in the C-ring of the flavonoid skeleton, which gives them the presence of a chiral centre at C-2 position. Flavanones are extensively distributed in about 42 larger plant families, especially in Compositae, Leguminosae, and Rutaceae. Flavanones are abundant in citrus fruits and have been reported to exhibit antioxidant, anti-diabetic, lipid-lowering, anti-atherogenic, and anti-inflammatory activities. The main aglycones are nar- ingenin in grapefruit, hesperetin in oranges, and eriodictyol in lemons. Hesperetin, naringenin. and naringin are reported as antibacterial agents, as they inhibited the grow th of methicillin-resistant Staphylococcus aureus and Streptococci by alteration of membrane fluidity (Kumar and Pandey, 2013). Due to their high pharmaceutical values, these compounds are mainly exploited for their medicinal purposes. In a related study, a nanoemulsion was prepared from hesperidin by using high shear- high pressure homogenization bonding technology and surfactant comparison study was carried out (Liao et al., 2020). In another study, pickering nanoemulsions of hesperidin were prepared by homogenization and were applied in a gelatin-based active film, where the encapsulated hesperidin showed a significant antioxidant activity. Hesperidin nanoemulsion was found to improve the emulsifying properties of chitosan nanoparticles in the composite active film used in food packaging (Dammak et ah, 2019). Similarly, another compound taxifolinis categorized under flavanones, which contains basic 3-hydroxyflavanone structure and is naturally found in onion.

citrus fruits, wood of larch, rench maritime bark, tamarind seeds, and milk thistle. Taxifolin is known to exhibit antibacterial, antifungal, anti-inflammatory, antithrombotic, antioxidative, and anti-cancer properties and is utilized as a food supplement. In an associated study, it was found that a nanoemulsion preparation of taxifolin, if consumed by athletes during exercise, can significantly enhance the recovery period from exhaustion to normalcy. O/W nanoemulsions of taxifolin were produced by ultrasonication, which interestingly resulted in minimizing the risk of oxidative stress and provided homeostasis regulation in humans (Kalinina et al„ 2019). Another example of flavanones is silibinin (silybin), which is a natural flavanone compound isolated from milk thistle of Silybum marianum, an important plant. It is structurally similar to quercetin and kaempferol and had historically been used in Chinese medicine; it demonstrates hepato-protective and anti-cancer effects (Li, 2013). Nanoemulsions of silybin from silymarin extract were prepared through a two-stage HPH. Physically stable nanoemulsions were prepared in w'hich antioxidant properties during storage were retained for relatively longer time. This approach of nanoemulsion formation utilizing high medical-value natural plant products represents a suitable tool for the development of next-generation functional foods and pharmaceutical products with enhanced bio-safety (Calligaris et ah, 2015).

Isoflavonoids

Isoflavonoid. nonsteroidal plant compounds, are a broad group of polyphenolic compounds which include structurally similar groups like isoflavones, isoflavonones, and isoflavans. Isoflavones, often found as glycosides, include daidzin, genistin, bio- chanin A, and formononetin. Isoflavones are mainly found in Leguminosae, where soybean is considered to be the richest source. Other sources include kidney, navy, fava, pinto, red. kudzu, lupine, and mung beans and chickpeas, split peas, peanuts, sunflower seeds, and walnut. Genistein is reported to possess anti-diabetic, antiestrogenic, anti-cancer, antioxidant, and anti-helminthic activity (Bultosa, 2016). Genistein exhibits an increased anti-cancer activity and is widely exploited for pharmaceutical purpose rather than food. According to a study, nanoemulsions of genistein were found to be useful in cancer therapy. These prepared nanoemulsions, when incorporated in a small pouch/tablet and placed inside the cheek to let the active ingredient get absorbed directly via oral mucosa, were found to be extremely effective for maintenance therapy of oral cavity and oropharyngeal cancers (Gavin et ah, 2015). Similarly, hydrogel products containing nanoemulsions of isoflavin aglycone rich fraction, containing high amounts of daidzein, genistein, and glycitein (isolated from soybean) w'ere also reported to be effective for dermal applications (Nemitz et ah, 2019). However, very limited studies have been found on the application of nanoemulsions of isoflavonoids in food.

Flavones

Flavones are a subclass of flavonoids characterized by a non-saturated 3-C chain and have a double bond between C-2 and C-3, like flavonols, with which they differ by the absence of hydroxyl in the 3-position, found mainly in celery, parsley, and many related herbs. The major dietary flavones include apigenin, baicalein, and luteolin. Apigenin is found in several plants and vegetables, such as parsley, chamomile, celery, olive, pigeon peas, and chamomile. As per several studies, apigenin possesses antiviral, antibacterial, antioxidant, and strong anti-inflammatory activities and blood pressure reduction properties. It is reported to inhibit the growth of H. pylori and E. coli by inhibiting d-alanine:d-alanine ligase (Wu et al„ 2008). To overcome the issue of poor water solubility, apigenin-loaded W/O/W multiple nanoemulsions w'ere prepared and passed through simulated digestion model; physical properties and digestibility at each stage were recorded which demonstrated in vitro and in vivo bioavailability enhancement in the small intestine (Kim et ah, 2016). For this, O/W emulsions loaded with apigenin was prepared using HPH. The resulting apigenin nanoemulsion, as nutraceutical formulation fortified with hydrophobic flavones, was retained even after storage of 30 days (Abcha et ah, 2019). Another flavone. Baicalein (5,6,7-trihydroxyflavone), present in roots of Scutellaria baicalensis, S. lateriflora, and Oroxylum indicum, is reported to have various pharmacological activities, such as Candida albicans-mediaied biofilm inhibition, anti-cancer, antioxidant, anti-aller- gic, antiviral, and anti-inflammatory activities. It is insoluble in an acidic medium; however, it is said to be highly soluble in alkaline medium, although it is highly unstable. An O/W emulsion, with average size about 300 nm, of baicalein was prepared using HPH, w'hich significantly enhanced its bioavailability and stability. The formulation and stability were also recorded; therefore, it could be utilized for oral delivery of poorly water-soluble compounds at the industrial level (Treesuwan et ah, 2013; Yin et ah, 2017).

Polymethoxy flavone, or PMF, is a general term for flavones bearing two or more methoxy groups on their basic flavane skeleton with a carbonyl group at the C-4 position. PMFs are present in ample amount in citrus fruit peels and are commonly used as a traditional Chinese medicine to relieve stomach upset and cough. PMFs have been of particular interest due to their proven broad-spectrum biological activity, including anti-inflammatory, anti-carcinogenic, and anti-atherogenic properties (Li et ah, 2009). An efficient nanoemulsion-based oral delivery system, with capacity to carry almost 10 times higher concentration required for biological actions, was designed for PMFs to facilitate its application in nutraceutical and pharmaceutical products (Li et ah, 2012). Tangeretin (pentamethoxyflavone) functions as a potential chemo-preventive agent as it possesses anti-inflammatory, anti-proliferative, antiobesity, and anti-diabetic effects and anti-carcinogenic activities. Its low bioavailability when injected orally is due to its poor water solubility. However, the bioavailability of oral delivery of synthesized tangeretin nanoemulsion, prepared by HPH, was significantly enhanced against colorectal cancer (Ting et ah, 2015).

Flavan-3-ol

Flavans-3-ol (also called flavanols) are present in fruits and beverages like tea, chocolate, grapes, lychees, apples, blueberries, gooseberries and red wine. The absence of double bonds between C-2 and C-3 and absence of carbonyl functional group C-4 in ring C of flavanol result in the generation of two chiral centres at C-2 and C-3, thus making four possible diastereoisomers. Due to presence of hydroxyl unit at position 3 of the heterocyclic C-ring they are called flavan-3-ols. The most common flavanols found in fruits and cocoa are catechin and epicatechin, while in grapes, tea, and seeds of certain leguminous plants, the main flavanols present are epicatechingallate.

gallocatechin, epigallocatechin, and epigallocatechin gallate (EGCG). Among them, EGCG is the abundant polyphenol as it composes approximately 50% of total cate- chins in dried green tea leaves. The antioxidant action of catechin. namely antihypertensive, anti-inflammatory, antiviral, anti-proliferative, anti-thrombogenic, and anti-hyperlipidemic, is well established by various in-vitro, in-vivo, and physical methods (Ziaullah et al., 2015; Tsai and Chen, 2016). The highest free radical scavenging activity of EGCG among all types of tea catechins makes it a highly potent molecule, but its larger molecular size and number of hydrogen bonds result in poor bioavailability of EGCG. To enhance the bio-availability of green tea extract, W/O nanoemulsions were prepared using soy, peanut, sunflower, and corn oils that displayed the increased oxidative stability. Thus, the synthesized nanoemulsions could be used as a promising vehicle for delivering green tea bioactive compounds in nutra- ceutical applications (Puligundla et al., 2017). Another study showed the potential of nanoemulsion for development of edible film (Nunes et al., 2020) for p-carotene, which is chemically unstable which hinders its application as a nutraceutical ingredient in foods. The incorporation of (-)-epigallocatechin-3-gallate (EGCG) and alpha- lactalbumin was carried out in the continuous phase to evaluate their efficiency to inhibit p-carotene degradation in nanoemulsions. EGCG was found effective in protecting p-carotene in various emulsion systems without negatively impacting lipid oxidation, signifying its use to support the incorporation of p-carotene into food emulsions (Liu et al., 2016). The study concluded that catechin-containing nanoemulsions could be safely applied in the field of nutraceuticals for enhancing their shelf life (Gadkari and Balaraman, 2015). Recent attempts to replace the petroleum- based packaging, the development of natural polymer-based edible film, such as gelatin, is underway.

Anthocyanins and Anthocyanidins

Anthocyanins, the group of water-soluble pigments found in vegetables like radish and red/purple cabbage, fruits like berries and blackcurrants, flower petals (red rose, blue chicory, and purple passionflower), and certain varieties of grains. These pigments are glycosylated anthocyanidins which contain natural flavylium salts as basic structure termed as anthocyanins. Considerable attention has been paid to anthocyanins because of their potential health benefits of being bactericidal, antiviral, hepato- protective, and anti-inflammatory and having antioxidant, anti-carcinogenic, anti-obesity, and anti-diabetic effects as well as preventive effects on cardiovascular and degenerative diseases (Ziaullah et al., 2015; Rabelo et al., 2018). Anthocyanin shows antimicrobial effects by various possible mechanisms including, cytoplasmic membrane destabilization, permeabilization of plasma membrane, extracellular microbial enzymes inhibition, inhibition of anti-adherence of bacteria to epithelial cells, direct actions on microbial metabolism, and deprivation of the substrates required for microbial growth (Cisowska et al., 2011; Nile and Park, 2014). Anthocyanins are vulnerable to high pH, light, heat, and oxygen during processing and storage. Due to anthocyanins large particle size and low zeta potential, conventional techniques like micro-encapsulation have failed to offer any stability. Therefore, a nanoemulsion of Myrciciria cauliflom peel extract containing 0.8% anthocyanins and 2.56% of total flavonoids was prepared by low-energy methods, thus resulting in reduced economic cost of the process which makes it a feasible option for industrial application (Garcia et al., 2019). In a similar study, anthocyanins and total phenolics were extracted from blueberry pomace, and a food-grade double-nanoemulsion system was successfully developed by using HPH. The findings were useful for designing a co-encapsulation-based system with a high proportion of anthocyanins for the intended application of blueberry pomace in functional foods and other products with enhanced health benefits (Bamba et al., 2018). To overcome the low stability of anthocyanins, a food-grade W/O nanoemulsion for a^ai berry, a type of anthocyanin, was generated by using HPH which resulted in enhanced stability even after long storage. As the acai berry carries a great nutritional profile; its astringency and nutty taste somehow confine its consumption by certain populations. This promising approach of W/O nanoemulsion synthesis may be utilized as a possible application for preparing food product such as sport drinks and pharmaceutical sectors by masking the possible off-taste of this fruit (Rabelo et al., 2018).

Phenolic Acids

Phenolic acids (phenol carboxylic acids) are organic compounds that contain a phenolic ring and an organic carboxylic acid functional group. Phenolic acids, the most widely distributed plant non-flavonoid phenolic compounds, are chemical derivatives of benzoic acid or cinnamic acid (Dhull et al., 2019b, 2020c). They are distributed broadly in fruits like blueberries, kiwi fruit, plums, cherries, and apples, vegetables, and cereal grains. They exert excellent antioxidant activity; their salts are used mainly for antifungal and broad-spectrum antibacterial properties, which make them desirable candidates for the pharmaceutical, cosmetics, and food industries (Dhull and Sandhu, 2018). Phenolic acids are mainly categorized into two major subgroups, namely hydroxybenzoic acid and hydroxycinnamic acid. The four commonly found hydroxybenzoic acids are p-hydroxybenzoic, protocatechuic, vanillic, and syringic acids. The four most common hydroxycinnamic acids are ferulic, caffeic, p-coumaric, and sinapic acids. The antimicrobial action of hydroxybenzoic acids followed the same diffusion pattern like other weak organic acids; it was passed across the membrane by un-dissociated acid exert antimicrobial activity by acidification of cytoplasm, leading to cell death (Almajano et al., 2007). It seems that usually hydroxycinnamic acid (p-coumaric, caffeic, and ferulic acids)-based natural products are capable of exerting antimicrobial action by interfering with membrane integrity; the more lipophilic nature of p-coumaric makes it most powerful among all (Campos et al., 2009).

To further explore their role as nanoemulsions, a novel W/O/W multiphase nanoemulsion of hydrophilic arbutin and hydrophobic coumaric acid was developed by using hydrocolloids. Increased stability of these compounds was recorded even under unfavourable conditions. The outcome of this study suggests that these emulsions could act as a novel delivery method to со-deliver hydrophilic arbutin and hydrophobic coumaric acid for increasing the bio-accessibility of these nutraceutically important phenolic compounds (Huang et al., 2019).

In a related study, nanoemulsions loaded with jaboticaba extract (Plinia peruviana) were found having remarkable antioxidant properties and were able to hold a significant concentration of phenolics, flavonoids, and ellagic acid, thus proving their utility for pharmaceutical and cosmetic applications (Mazzarino et al., 2018).

Generally, ferulic acid (4-hydroxy-3-methoxycinnamic acid), exhibits very low- solubility in the aqueous phase, thereby limiting its application in pharmaceutical and food products. In this regard, a stable nanoemulsion of ferulic acid, by applying the spontaneous emulsification method, was found stable throughout 12 weeks of storage period at 4°C (Ebrahimi et al„ 2013).

Similarly, W/O/W multiple nanoemulsions using gallic acid in the internal aqueous phase were generated w-here more than 50% antioxidant activity was retained after storage of 28 days (Martins et al„ 2020).

Three different acids, viz. vanillic, caffeic, and syringic acid, were individually tested for their ability to provide antioxidant activity for the formulation of virgin olive oil nanoemulsion. These acids were incorporated in the aqueous phase to evaluate their effect on emulsion properties and oxidation stability at various aqueous phase ratios. The crucial role of aqueous phase ratio was elucidated, and caffeic acid was found to be most effective in providing stability against oxidation. Additionally, all the tested phenolic acids were able to reduce the air/water surface tension, thus facilitating an increased emulsion formulation (Katsouli et al., 2017).

In another study, stable trans-cinnamic acid (trans-CA) nanoemulsions were fabricated utilizing low-energy SE methods. It demonstrated enhanced bacteriostatic and bactericidal activity against S. aureus, S. typhimurium, and Pseudomonas aeruginosa at subcellular size as compared to the pure chemical compound. This was found to be very effective in the preservation of freshly chopped lettuce through microbial inhibition in freshly dissected fruits and vegetables (Letsididi et ah, 2018).

Golden spice, turmeric, is another prominent example of polyphenol that is highly utilized since the ancient time of Ayurveda and traditional Chinese medicine contains curcumin. Curcumin (and its two related compounds, the curcuminoids: demetho- xycurcumin and bis-demethoxycurcumin) is derived from the rhizomes of turmeric plant and is widely known for its antioxidant, antimicrobial, anti-cancer, antiinflammatory, anti-Alzheimer’s, psychotic and neurotic activities, anti-diabetic, and wound-healing properties (Jiang et ah, 2020). It exhibits bactericidal activity by damaging the cell membranes of gram-positive and gram-negative bacteria (Khameneh et ah, 2019). However, low water solubility, degradation of structure, and poor bioavailability limit its application. Recently, oil-based nanoemulsion fabrication methods for curcumin have been deeply reviewed, which are categorized as low- and high-energy emulsification methods (Jiang et ah, 2020). Studies highlight that using an oil-water-oil-based phase inversion method can generate curcumin- loaded nanoemulsions, and by optimizing parameters like mechanical stirring, aqueous flow pumping, this could be scalable up to industrial level. Results indicated that after storage of 60 days, 70% of curcumin was retained in emulsion w-hen compared to other systems (Borrin et ah, 2016). Apart from these two, a different nanocarrier system has also been designed which prevents degradation during processing and storage; both systems use same level of surfactant concentration. The release of entrapped curcumin was sustained and both the systems were found to have potential in inhibiting lipid oxidation (Chuacharoen and Sabliov, 2019). Similarly, curcumin nanoemulsions were produced with various surfactant concentrations using HPH, and were applied to a commercial milk system. The nanoemulsion was found stable for a month at room temperature, retaining effective radical scavenging activity, and was also able to inhibit the process of lipid oxidation in milk. In a similar study, preparation of the curcumin nanoemulsion with milk protein named sodium caseinate was carried out for incorporating it in ice cream. The nanoemulsion particle size was found to be influenced by heating, pH, and ionic strength; however, their release kinetics in simulated gastrointestinal digestion suggested their stability against pepsin digestion. The formulation was successfully applied to ice cream, and sensory attributes were evaluated; interestingly, no significant difference was reported as compared to control. The outcomes advocate that ice cream can be an appropriate dairy product for the enhanced delivery of lipophilic bioactive components like curcumin which can be potentially used for therapeutic purposes (Kumar et al., 2016).

Curcumin nanoemulsion, with casein and soy polysaccharide compacted complex, was prepared at an optimized condition and stored for 500 days at lower temperature 4°C. Sustained release was also obtained in simulated gastric and intestinal fluid with rapid and effective absorption in mice model. This study suggests that casein and soy polysaccharide complex nanoemulsion to be an appropriate system for oral delivery of lipophilic nutrients and drugs (Xu et al., 2017). In another study, a uniform curcuminoids-loaded nanoemulsion, for intended oral application, was also prepared with coconut oil by PIT method. These properties make curcumin nanoemulsion as suitable systems for food and beverage industry (Joung et al., 2016).

Tannins

“Tannins” are an important group of complex polymeric phenolic substances originally used in the tanning of leather and animal hides or precipitating gelatin from solutions, a property termed astringency. They are present in almost every part of plant, namely bark, wood, leaves, fruits, and roots, and their occurrence is reported in a wide range of plant families (Dhull et al., 2016, 2020a). Tannins exhibit toxic effect on filamentous fungi, yeasts, some viruses, and bacteria. Their antimicrobial action is attributed to their inhibitory activity against DNA gyrase and the inhibition of other enzymes (Cowan, 1999; Khameneh et al., 2019). Tannin has gained a great deal of attention in recent years due to its excellent antioxidant properties. Tannins are divided into the following three broad classes (Maqsood et al., 2013):

  • 1. Hydrolyzable tannins (gallotannins: gallic acid, quinic acid, tannic acid, ella- gitannins: ellagic acid, castalagin, vescalagin and hydrolysable tannin oligomer: agrimoniin, rugosinD)
  • 2. Condensed tannins also referred to as proanthocyanidins (oligomers of flavan- 3-ols: catechin, epicatechin; flavan-3,4-diol: leucoanthocyanidin)
  • 3. Complex tannins (stenophyllanin A, acutissimin B, mongolicain A, steno- phynin A, etc.).

Tannic acid, an important gallotannin belonging to the hydrolysable class of tannin, is a specific tannin that formally contains 10 galloyl (3,4,5-trihydroxyphenyl) units surrounded with glucose. Tannic acid does not contain carboxyl groups, but its weakly acidic nature is because of the multiple phenolic hydroxyls (Ribeiro et al.. 2018). It exhibits a diverse range of biological activities, including antioxidant, antibacterial, and antiviral activity. Due to its capacity to interact with proteins, polysaccharides.

alkaloids, and metal ions, it is used to enhance emulsifying properties and antioxidant activity. Role of tannic acid as nanoemulsion stabilizer has also been explored by O/W emulsions using a high-pressure microfluidizer by using polyphenol-polysaccharide (tannic acid and (3-glucan) complexes. The results suggest the use of these complex is limited in the range of pH and temperature but definitely increase the application of (3-glucan as a functional ingredient in foods (Li et al„ 2019a). Studies indicated that alginate-based edible films when loaded with tannic acid and quercetien were able to enhance the shelf-life of food items. These alginate-based edible biofilms were analysed on the basis of different parameters, viz. thickness of film, tensile strength, percentage elongation at break, light transmission, film opacity, water vapour permeability, water sorption kinetics, and antioxidant and antimicrobial activity after 11 days storage at 4°C. As per the authors, pork patties wrapped in tannic acid nanosolution-incorporated films showed lower microbial counts (total plate count, yeast and mould count, and psychrophilic count) as compared to control films (Rao, 2020).

The effect of tannic acid and two other plant-based emulsifiers, namely quillaja saponin (QS) and gum arabic (GA), on a nanoemulsion loaded with (3-carotene was also evaluated in a simulated gastrointestinal tract. Emulsifier type and tannic acid addition had no significant effect on p-carotene bio-accessibility but the addition of tannic acid could efficiently inhibited temperature-induced p-carotene degradation which is reported to increase at a higher temperature. These outcomes may facilitate the design of more effective nutraceutical-loaded functional foods and beverages (Li et al., 2019b).

Proanthocyanidins, the condensed tannins, are oligomeric and polymeric products of the flavonoid biosynthetic pathway and are present in flowers, olives, onions, green and black tea, broccoli, nuts, dark chocolate, cocoa, red wine, bark, and seeds of various plants. Berries and fruits like lingonberry, banana, pomegranate, cranberry, oranges, grapefruit, black elderberry, black chokeberry, black currant, blueberry are the greatest sources of proanthocyanidins. They exert antioxidant, cardio-protective, neuro-protective, immunomodulatory, lipid-lowering and antiobesity, anti-cancer, and antimicrobial activity (Rauf et ah, 2019).

In a comparative study, both condensed and hydrolysable tannins were used to generate microcapsules and nanoemulsions and were fabricated by ultrasonic irradiation. The generated nanoemulsions displayed increased stability at slightly alkaline conditions (pH > 8) and were partially disassembled even under acidic conditions (pH < 7). This pH stability of nanoemulsion can be exploited in pH-triggered controlled release nanoemulsions, which can further be explored for food, pharmaceutical, or biomedical applications (Bartzoka et ah, 2017).

Since a limited range of emulsifiers can be used in food and beverage products to get the required functional performance, due to consumer health concerns, in attempt to find suitable food-grade emulsifiers, complex of proteins with other food grade natural products are great deal of concern in recent days. In a recent study, the lotus seedpod proanthocyanidin (LSPC) when incorporated in whey protein, was able to stabilize the (3-carotene-loaded nanoemulsions at various pH and also exhibited better antioxidant activity. Studies suggest that LSPC-whey protein complexes can be used as effective emulsifiers and be useful for developing more efficacious functional foods and beverages for nutraceutical-loaded nanoemulsions (Chen et ah, 2020).

Lignans

Lignans dimers of phenylpropanoid (C6-C3) units joined by the central carbons of their side chains. They are fibre-associated compounds widely dispersed throughout the plant kingdom and found in human common diet, including grains, nuts, seeds, vegetables, and drinks such as tea, coffee, or wine. Grain sources of lignans include oil seeds (flax, rapeseed, and sesame), whole-grain cereals (wheat, oats, rye, barley, and millets), and legumes (soybean). Flaxseed carries the highest concentration of dietary lignans, as secoisolariciresinol diglucoside. Sesamin. matairesinol, pin- oresinol, and lariciresinol are other dietary lignans. Lignan shows various biological activities like anti-cancer, antioxidant, anti-mitotic, anti-hypertensive, antiviral, estrogenic, and insecticidal properties.

Multiple attempts to synthesize nanoemulsion using flaxseed oil, which is a good source of a-linolenic acid (ALA), is reported to inhibit cardiovascular disease, nonalcoholic fatty liver disease, insulin resistance, type 2 diabetes, and neurodegenera- tive disorders. However, a higher concentration of ALA, having a larger surface area of nanoemulsified flaxseed oil, is prone to rapid lipid oxidation in the presence of heat, light and oxygen, which limits their incorporation into functional foods and beverages (Arab-Tehrany et al., 2012). Limited researchers have evaluated flaxseed lignan extract and secoisolariciresinol, secoisolariciresinol diglucoside, and p-cou- maric acid for their antioxidant/pro-oxidant effect in nanoemulsions, and interestingly, these were found to improve the stability of flaxseed oil nanoemulsion, suggesting its application in function for food industries (Cheng et al., 2019). In a similar study, impacts of sesame lignans, natural sesamol (SOH), and sesamin on the stability of flaxseed O/W emulsion were assessed. SOH exhibited higher antioxidant activities, an improved physicochemical property, and a stronger interfacial barrier in flaxseed nanoemulsion (Wang et al., 2019).

Stilbene

The name, stilbene (1,2-diphenylethylene), was originally derived from the Greek word stilbos, which means “shining”. Stilbenoids are hydroxylated derivatives of stilbene, with C6-C,-C6 structure. Stilbenoids are characterized by two phenyl groups linked by a transethane bond. The most famous stilbenoid, resveratrol, has several hydroxyl groups attached to its phenyls. It is present in strongly pigmented vegetables; fruits like some varieties of grapes, berries, and peanuts; and red wine. It is known to provide several health benefits like antioxidant, anti-carcinogenic, chemo- preventive, and cardio-protective effects. Low water solubility accounts for its poor bio-availability. By applying HPH, an O/W nanoemulsion system was developed and tested for oral delivery of resveratrol for its effect on cell viability, cell permeability, and sustained release. Studies revealed a better delivery system with enhanced stability and efficient bioavailability, which can further be explored in nutraceuticals and functional food systems (Sessa et al., 2014). In another study, nanoemulsion was fabricated by the SE method, using grape seed oil and orange oil together in the oil phase. The low-energy nanoemulsion method was successful in the development of stable delivery system (Davidov-pardo and Julian, 2015). Interestingly, in another study, resveratrol nanoemulsion, in tuna fish oil, stabilized by octenyl succinic and hybrid modified starch (OSA-MS) Hi-cap 100, was generated by using a high-energy method and was successfully recommended for application in dairy and beverage products (Shehzad et al., 2020). Other fabrication methods, effect of various oil phase, effect of droplet size, and effect of emulsifiers have been recently deeply reviewed by Choi and McClements (2020).

 
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