Licorice (Glycyrrhiza Glabra, G. Uralensis, And G. Inflata) And Their Constituents As Active Cosmeceutical Ingredients

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Abstract: The interest in plant extracts and natural compounds in cosmetic formulations is growing. Natural products may significantly improve cosmetics performance since they have both cosmetic and therapeutic-like properties, known as cosmeceutical effects. Glycyrrhiza genus, belonging to the Leguminosae family, comprises more than 30 species, widely distributed worldwide. The rhizomes and roots are the most important medicinal parts currently used in pharmaceutical industries and in the production of functional foods and food supplements. In the last few years, the interest in their potential activities in cosmetic formulations has greatly increased. Glycyrrhiza spp. extracts are widely implemented in cosmetic products for their good whitening effect. The biological effects of Glycyrrhiza extracts are especially ascribable to the occurrence of specialized metabolites belonging to the flavonoid class. This review focuses on the botany and the chemistry of the main investigated Glycyrrhiza spp.(G.glabra, G.uralensis, and G. inflata) along with their cosmeceutical activities categorized as skin anti-aging, photoprotective, hair care, and anti-acne. It has been highlighted how, along with Glycyrrhiza extracts, three main flavonoids namely licochalcone A, glabridin, and dehydroglyasperin C are the most investigated compounds. It is noteworthy that other molecules from licorice show potential cosmeceutical effects. These data suggest further investigations to clarify their potential value for cosmetic industries.

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Keywords:Glycyrrhiza; licorice; cosmeceutical;glabridin; skin anti-aging; photoprotective activity;hair care; anti-acne activity

1. Introduction

Plant extracts and natural compounds derived from plants are considered valuable materials for the production of cosmetics. Natural products contained in cosmetic formulations may significantly contribute to an improvement of cosmetics performance. They can also be used as auxiliary substances enhancing the stability or bioavailability of cosmetic formulations [1]. Plants were the primary source of cosmetics before synthetic compounds, and now the trend of the cosmetic industry is to look more and more for natural active ingredients. This is due both to consumers' demand for more natural products and the global attention to environmentally friendly products. This means that new products containing herbs will continue to emerge on the market in the future [2]. The term"cosmeceutical" refers to cosmetics containing active chemicals with drug-like properties. Cosmeceuticals have beneficial local effects, prevent degenerative skin diseases, and improve skin tone. Cosmeceuticals are a growing sector of the personal care industry [2].

Glycyrrhiza genus, belonging to the Leguminosae family (also known as Fabaceae), consists of more than 30 species, widely distributed worldwide. The name"glycyrrhiza" derives from the Grecian words guys and rhiza, which mean sweet and root, respectively [3]. It is also called licorice, licorice, glycyrrhiza, sweet wood, and Liquiritiae radix[4]. Among the Glycyrrhiza spp., G.glabra L., G.uralensis Fisch., and G.inflata Bat. are the most investigated species with nutritional and pharmacological benefits, used as Radix Glycyrrhizae (licorice)[5]. They are also recorded in Chinese Pharmacopoeia as medicinal Glycyrrhiza plants [6]. Rhizomes and roots are the most important medicinal parts of licorice. They have been reported to be used alone or with other herbs to treat many digestive system disorders, respiratory tract disorders, epilepsy, fever, sexual debility, paralysis, rheumatism, leucorrhoea, psoriasis, prostate cancer, malaria, hemorrhagic diseases, and jaundice [3]. The extracts are currently used in pharmaceutical industries and in the manufacture of functional foods and food supplements[4, Moreover, they can be used as a food and beverage flavoring agent [3]. Japan has a wide range of applications for the licorice chemical constituents, which occur 70% in food products(glycyrrhizin),26%in medicinal cosmetics (glabridin), and 4% in tobacco, along with other uses [9].

Researchers focused their attention on exploring mainly G. glabra, G. uralensis, and G. inflata extracts and isolated pure compounds occurring as active ingredients for cosmetic purposes, based on their biological activities. Glycyrrhiza spp. extracts are currently used in cosmetic preparations due to their skin-whitening, anti-sensitizing, and anti-inflammatory properties [10]. Their use was widely implemented in commercial products, especially in cosmetic products, for its good whitening effect [11].

Cistanche can anti-aging

Several formulations containing licorice extracts are present in the market places. They are mostly used daily with SPF (Sun Protection Factor) products containing G.glabra root extract. The extract is incorporated in the internal aqueous phase of water/oleum emulsion in cream and serum formulations, claimed for their anti-aging activities, their effects on wrinkles, hyperpigmentation, and skin lightening. For these effects, the licorice extracts are also used in the formulation of sunscreens and also for personal care products such as facial cleansers, make-up removers, toners, and shampoo. Moreover, make-up products such as foundations, concealers, around-the-eye creams, make-up primers, lipsticks, and BB creams contain licorice extract.

Reviews reported in the literature described the traditional uses, the chemistry, the chemotaxonomy, the pharmacological activities, and the analysis of licorice extracts focusing mainly on G. glabra [3-6,11-13]. Herein, we describe briefly the botany and the chemistry of G.glabra, G.inflata, and G.uralensis focusing on the skin anti-aging, photoprotective, hair care, and anti-acne activities of extracts and bioactive compounds isolated from these species, never summarized before. In light of all the reports, the potential of licorice extracts and their specialized metabolites as constituents of cosmeceutical formulations is confirmed to be very promising.

2. Botanical Description

Glycyrrhiza spp. is an herbaceous plant growing in the subtropical and temperate zone. The plants can reach a maximum height of up to 2m, while the underground stem can grow up to 2m horizontally, generally in the fertile and sandy ground [12]. The plants show pinnate leaves, narrow flowers, and lavender to violet in color. The fruit is an oblong legume containing three-eight brown reniform seeds. The roots are well developed with a brown color. The pieces of roots break with a fibrous fracture and possess a typical aroma and a sweet taste [12,14]. The rhizomes and roots are harvested 3-4 years after the planting, washed to remove buds and rootlets, cut into small pieces, and finally dried [15]. G. glabra, G. inflata, and G.uralensis are significantly explored for nutritional and pharmacological benefits among the known species. Three varieties of G.glabra have been reported, grown in different regions, and designated as G. glabira var. violacea (Persian and Turkish), G. glabra var. gladulifera (Russian), and G. glabra var. typical(Spanish and Italian) [12].

3. Chemistry of Glycyrrhiza

The 50% dry weight of licorice roots is due to water-soluble metabolites and sugars (5-15% glucose, sucrose, and mannitol), starch (25-30%), glycyrrhizin(10-16%), amines (1-2% asparagine, betaine, and choline), and sterols(stigmasterol and β-sitosterol) [12].

Thus far, more than 400 phytochemicals have been isolated from the genus Glycyrrhiza. These molecules can be classified as saponins, flavonoids, chromenes, coumarins, dihy drostilbenes, coumestans, benzofurans, and dihydrophenanthrenes [4,5,12], among which flavonoids and triterpenoid saponins are abundant in the root or rhizome of licorice [5]. Generally, alkaloids and tannins were not detected [12]. Although the roots represent the most used parts, phytochemical investigations were also performed on the leaves, considered an agrochemical waste. These studies demonstrated that certain compounds present in the roots are also identified in the leaves of G.glabra leaves [16]. This section will discuss the flavonoids and triterpenoid saponins isolated in G.glabra, G. inflata, and G.uralensis, the three species investigated for their cosmetic effects, focusing on the main reported compounds and on compounds tested for biological activities. Along with these classes, a coumarin-derivative reported in G.glabra, and G.uralensis, licoarylcoumarin, will also be discussed for its properties.

3.1. Flavonoids

More than 300 compounds belonging to the class of flavonoids have been isolated and identified from licorice [4,11]. Flavonoids, generally formed by two benzene rings(A ring and B ring)through a central tri-carbon chain-generating C ring, are divided into flavonols, flavones, flavanones, flavanols, dihydro-flavones, chalcones, isoflavones, according to the occurrence of the C ring, its oxidation degree, and the connection site of the B ring. Several kinds of flavonoids are representative compounds isolated from G. glabra, G.uralensis, and G. inflata. The more representative flavonoids, tested for their cosmeceutical activities, have been categorized as flavanones, flavonols, flavones, isoflavones, isoflavones, isoflavones, and chalcones. Liquidity is one of the most abundant flavonoids and is used as a quantitative chemical marker in the three official medicinal licorice species in Chinese Pharmacopoeia [5]. It consists of liquiritigenin, a flavanone reported in Glycyrmhiza, linked to a β-D-glucopyranosyl residue at position 4'via a glycosidic linkage. Pinocembrin and liquidity apposite, belonging to the flavanone class, have also been reported (Figure 1).

Flavanols such as kaempferol, pretense, and the flavone chrysoberyl are herein discussed for their activity.

Glabridin is the principal isoflavane identified, ranging between 0.08% and 0.35% of G.glabra root's dry weight [4,17]. Chemically, glabridin is a prenylated isoflavone deemed a typical compound in G.glabra, accounting for 11% of its total flavonoid content [11]. Along with glabridin, licoricidin (also known as licorisoflavan B), hispaglabridin A, glycerin C, Gasperini D, and 3'-hydroxy-4'-O-methylglabridin are mentioned. Isoflavones as glabrate, dehydroglyasperin C, dehydroglyasperin D, isoflavones as glycyrrhisoflavone, semilicoisoflavone B, allolicoisoflavone B, isoangustone A, and formononetin, as well as isoflavones as dihydrodaidzein and glycyrrhisoflavanone were isolated from Glycyrrhiza spp. and tested for cosmeceutical properties. All the reported isoflavonoids, except formononetin, dihydrodaidzein, and pretense are characterized by a prenyl moiety on ring A or ring B, which can be free or involved in the formation of a pyran ring. In the case of glabridin, the prenyl chain at C-8 is involved in the formation of a pyran ring, but this latter can be fused either to the A ring or B ring of the isoflavonoid skeleton. Hispaglabridin A is characterized by a prenyl group cyclized to pyrene on the A ring and an additional prenyl function at the B ring. The isoprenyl groups on the A and B rings make the flavonoid backbone more lipophilic, resulting in increased affinity with cell membrane structures and favorable biological activities (Figure 1) [11].D, licochalcone E, licuraside, and neolicuroside are discussed. The dibenzoyl methane, a structural analog of curcumin (diferuloylmethane)isolated from G.glabra, has also been investigated for its cosmetic properties. Among the flavonoids previously cited, the main representative compounds of Gly-cyrrmhiza are liquidity(4',7-dihydroxyl flavone) and isoliquiritin (2',4',4-trihydroxy chalcone)glycosides (Figure 1).

3.2.Saponins

More than 70 saponins were isolated from Glycyrrhiza roots, and their structures have been shown in a recent review [13].

Among the oleanane triterpenoid saponins, glycyrrhizinic acid (also known as glycyrrhizic acid) or its salt glycyrrhizin has been reported as the major secondary metabolite found in the root of Glycyrrhiza spp.; this monodesmosidic saponin exhibits a 18ß-glycyrrhizic acid skeletal structure, derived from β-amyrin, linked to a disaccharide unit made up of two glucuronic acid moieties at position C-3 [18]. Glycyrrhizin along with its aglycon, and glycyrrhizic acid, is the most studied and abundant compound from the roots of this plant. Glycyrrhizic acid exists as two isomers: 18α-form and 18β-form. As a sweetener, glycyrrhizin is reported to be 30-50 times sweeter than sucrose [18]. Glycyrrhiza saponins, composed of aglycone and sugar moiety, can be classified into several classes, in which glucuronic acid, glucose, and rhamnose are the major characteristic parts of sugar moiety [19]Licorice saponin G2 (also known as 24-hydroxyglycyrrhizin) is shown below(Figure 2).

3.3. Polysaccharides

Among the bioactive ingredients of Glycyrrhiza plants, Glycyrrhiza polysaccharides are receiving more and more attention. A recent review reports their isolation, structural characterization, and biological activities [6]. They are heteropolysaccharides mainly composed of arabinose, glucose, galactose, rhamnose, mannose, xylose, and galacturonic acid in different proportions and types of glycosidic bonds. A preliminary study on the moisture retention of polysaccharides highlighted that their water retention ability was higher than that of glycerol solution, suggesting their potential use as a cosmetic moisturizing additive [6].

3.4. Species-Specific Markers for G. glabra, G.inflata, and G.uralensis

Several analytical methods have been developed to discriminate the chemical differences of G.glabra, G. inflata, and G. uralensis based on the occurrence or amount of specialized metabolites [5,20-23]. These works could provide helpful information to the industry about the choice of Glycyrrhiza species to use. An investigation was performed by a combined approach using GC-MS, LC-MS, and 1D NMR analysis. Compounds responsible for the discrimination among the three species were identified: glycyrrhizin, 4-hydroxyphenyl acetic acid, and glycosidic conjugates of liquiritigenin or isoliquiritigenin along with the amino acid cadaverine were described only in G. inflata [24]. The three species, identified by DNA barcodes, were further analyzed by LC/UV-or LC/MS/MS-based quantitative analysis, revealing 151 bioactive secondary metabolites, of which 27 were discovered able to differentiate the three species [20]. Principal Component Analysis (PCA) performed on 'H NMR spectra, and UHPLC-UV chromatograms highlighted marked chemical differences among the Glycyrrhiza spp. [25]. An NMR-based metabolomics analysis, followed by PCA was also performed [26]. The metabolites licochalcone A and glabridin, which are discussed more in the next paragraphs, were indicated as specific metabolites of G.inflata, and G.glabra, respectively [20,25]. Indeed, G. uralensis and G. inflata roots did not contain glabridin, and therefore, glabridin is considered a unique species-specific marker for G.glabra[12]. Licochalcone A, abundant in G. inflata but present in small amounts in G.uralensis and G.glabra, along with the occurrence of licochalcone C, licochalcone E, and licochalcone D, represent a marker for G.inflata. So far, glycycoumarin, a metabolite reported in higher amounts in G.uralensis, in small amounts in G. inflata, and in trace amounts in G.glabra, is considered a species-specific metabolite for G.uralensis[12]. A detailed report on the species-specific metabolite markers in different licorice species was recently published [12]. In light of all these reports, the metabolomic characterization should be associated with the identification and quantitation of several key markers rather than the only quantitative analysis of a single ubiquitous Glycyrrhiza constituent.

Different extraction methods have been developed for saponins or flavonoids from Glycyrrhiza species. They include maceration, countercurrent extraction, supercritical fluid extraction, extraction by ultrasonics, Soxhlet extraction, and microwave-assisted extraction [5,27]. In this review, most of the cosmeceutical effects described afterward are attributed to the flavonoid constituents of Glycyrrhiza. Literature data revealed how methanol and ethanol aqueous solutions were the most commonly used solvents for the extraction of flavonoids 【28】. Indeed a mixture of ethanol/water （30∶70， v/ø）used for an extraction time of 60 min under 50°C of licorice gave a high recovery of glabridin (72.5%)[28]. To enrich the licorice fractions in licochalcone A, methods including high-speed countercurrent chromatography and treatment by macroporous resin were used [29].

This article is extracted from Cosmetics 2022, 9, 7. https://doi.org/10.3390/cosmetics9010007 https://www.mdpi.com/journal/cosmetics