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The beneficial effects of liquorice in treating chills, colds, and coughs have been fully discussed in Ayurveda, as well as in the texts of ancient Egyptians, Greeks, and Romans. The plant has been prescribed for dropsy during the period of famous Hippocrates. The reason being that it was quite helpful as thirst-quenching drugs (Biondi et al. in J Nat Prod 68:1099–1102, 2005; Mamedov and Egamberdieva in Herbals and human health-phytochemistry. Springer Nature Publishers, 41 pp, 2017). No doubt, the clinical use of liquorice in modern medicine started around 1930; Pedanios Dioscorides of Anazarba (Adana), first century AD-Father of Pharmacists, mentions that it is highly effective in the treatment of stomach and intestinal ulcers. In Ayurveda, people in ancient Hindu culture have used it for improving sexual vigor.
8.1 Traditional Uses
The beneficial effects of liquorice in treating chills, colds, and coughs have been fully discussed in Ayurveda, as well as in the texts of ancient Egyptians, Greeks, and Romans. The plant has been prescribed for dropsy during the period of famous Hippocrates. The reason being that it was quite helpful as thirst-quenching drugs (Biondi et al. 2005; Mamedov and Egamberdieva 2017). Although the clinical use of liquorice in modern medicine started around 1930, its effectiveness in the treatment of stomach and intestinal ulcers has been mentioned in the first century AD by Pedanios Dioscorides of Anazarba from Adana in present day Turkey, who is also regarded as the “Father of Pharmacists”. In Ayurveda, people in ancient Hindu culture have used it for improving sexual vigor. Chinese have been using it as a tea for strength and endurance (Davis and Morris 1991). The liquorice roots have been used in the traditional medicine against treating chest and lung diseases, pneumonia, bronchitis, arthritis, bronchial asthma, kidney diseases, heart diseases, gastric ulcer, mouth ulcers, coughs, swellings, excessive salivation, fluid retention, low blood pressure, allergies, catarrhs of the upper respiratory tract, liver toxicity, hyperglycemia, Addison’s disease, and pancreatic disorders, flatulence, sexual debility, skin diseases, leucorrhoea, hoarseness, and certain viral infections (Blumenthal et al. 2000; Anonymous 2005; Armanini et al. 2002; Sharma et al. 2013; Mamedov and Egamberdieva 2017). In Europe, particularly Britain, France, and Germany, present-day pharmacopeias are in general agreement on the medicinal application of this plant. It is used for the treatment of influenza, eye diseases, uterine complaints, biliousness, liver disease, and arthritis as per the reports published on Indian medicine (Saxena 2005; Mamedov and Egamberdieva 2017). The plant is in use in China since very early times and has been applied to treat acne and pimples, nervous disorders such as hysteria, irritability, epilepsy, as well as reduce the toxic or drastic action of other herbs, and to harmonize herbal formulas (Zhu 1998). The studies undertaken by Kong et al. (1984) reveal that liquorice root extract is used to treat diarrhea in mice, whereas Hong et al. (1988) have demonstrated its strong diuretic activity in rats. G. glabra extract has also been used to treat emotional irritability in adults and stress (Tsuda et al. 1986; Shirinyan et al. 1988). The extract has also been used to treat allergic dermatitis and eczema (Sokolov and Zamotayev 1985; Sheehan and Atherton 1992). According to Yang et al. (2015), liquorice has been used for the treatment of gastro and respiratory diseases in traditional treatments as well as for the alleviation of toxicity to other drugs. In traditional Chinese medicine, it is also honored as the “excellent coordinator” as it harmonizes the activities of other ingredients by promoting their rapid absorption into the bloodstream, organs, and target cells (Yang et al. 2015).
8.2 Industrial Uses
The cultivation areas of this plant in nature extend between Turkey and China together with Southern European countries (Rauchensteiner et al. 2005; Khalesi 2015). One of the major producers is Chinese who use it as plant medicine with yearly trading of US 60 billion dollars (Dubey et al. 2008). Although ginseng is the first herbal medicine in China, liquorice distributed mostly in the northwest of country holds the second place. The species evaluated are as follows: G. uralensis, G. inflata, and G. glabra (Chen et al. 2013). China is expected to become a net importer. Second largest producer on global scale is Iran, where Shiraz, the region located in the southwest of Iran, is the main manufacturer of Iranian liquorice with the variety of G. violacca (Ghahraman 1999; Khalesi 2015). Iran has lately faced severe difficulties in the supply of liquorice to the new customers because of the economic sanctions by Europe and America (Khalesi 2015). In Europe, the main producers are listed as follows: the Netherlands, Spain, and Italy, with a total production of about few hundred tons (Khalesi 2015). The manufacturers of extracts are however, only in China and Iran. The average price for liquorice extract is estimated to lie around 6 Euro per kg, whereas Chinese liquorice is the most expensive due to its high Glycyrrhizic acid content (always above 4.0%) (Cirillo et al. 2011). Main importers of its products on global scale are Japan, Korea, Germany, the Netherlands, and America (Khalesi 2015).
Products containing considerable amounts of glycyrrhizinic acid (De Klerk et al. 1997)
Liquorice sticks, bricks, cakes, toffee, pipes, bars, balls, tubes, Catherine wheels, pastilles and allsorts, Sorbits chewing gum, and Stimorol chewing gum
Liquorice-flavored diet gum, Throat pearls, Liquorice-flavored cough mixtures, Herbal cough mixtures, and Liquorice tea
All types of liquorice root
Russian, Iranian, Chinese, Turkish, Afghan and unknown origin chewing tobacco, and alcoholic drinks
Liquorice is a common and useful ingredient in cosmetic sector. It is used for depigmentation, as an emollient and soothing agent (Nomura et al. 2002). Modern-day herbalist Jeanne Rose recommends making a steam facial with liquorice, comfrey, together with chamomile or lavender. The topical treatment with a gel containing 2% liquorice extract has successfully lead to significant improvement in erythema, edema, and pruritus in a clinical study (Saeedi et al. 2003). Its extracts are also used as skin depigmenting agents and are effective in the treatment of postinflammatory hyperpigmentation, in particular the one caused by chemical peeling and laser therapy (Callender et al. 2011). It helps to open the pores and allows the other cleansing and healing herbs to penetrate the skin. The use of liquorice root as a shampoo ingredient has been reported to suppress the secretion of scalp sebum for a week after shampooing, thereby postponing the oily sheen (Fig. 8.1). It is also used in mouthwash and toothpastes as a sweetening and flavoring agent, sometimes mixed with anise and used in liqueurs as well as in herbal teas.
The liquorice adds flavor, color, and a foamy head when added to the beer and stout preparations. It can at the same time intensify other flavors. The plant has been commercially in use for the preparation of pastries, ice creams, puddings, soy sauce, and soy-based meat substitutes (Rogers 2014). It has been and is used in a number of foods, mainly condiments and confectionery due to its sweet flavor. The soy sauce and sweet chili sauce both contain liquorice powder as a condiment which gives unique sweet flavor, referred to as mellow in English (Kao et al. 2014). In the confectionery products, flavoring with liquorice plant root extract is a common practice; similarly, candies like red vines and London drops are also flavored with it. Tobacco manufacturers use it in considerable amounts in their products. The block, powder, and extract of this plant are used in tobacco for multiple purposes (Kao et al. 2014). According to Carmines et al. (2005), it is added to tobacco to enhance and harmonize the flavor of smoke, reduce mouth and throat dryness, improve the moisture-holding feature of tobacco to increase its stability and shelf life, act as a surface-active agent during the spraying process of the casing ingredients, improve uniformity of the flavor absorption, and minimize the rough smoke character by balancing the overall flavor profile of the tobacco smoke. Although excessive consumption is reported to produce harmful consequences (Rao 1993), it is generally recognized as safe, indicating that it does not represent a hazard to the public when used properly. Liquorice is reported to be the common and useful ingredient in cosmetics (Kao et al. 2014). The extract is also reported to inhibit the rate-limiting first step of the oxidation of tyrosinase (Kim and Uyama 2005). This brings it to the forefront as an effective treatment for melasma (Sheth and Pandya 2011). Moreover, the extract is highly useful in the treatment of aphthous ulcers (Burgess et al. 2008); even its deglycyrrhizinated form (DLG) produces a positive effect (Das et al. 1989).
8.2.1 Liquorice as an Industrial Resource: A Case Study from Japan
According to Hayashi and Sudo (2009) for the production of glycyrrhizin , cosmetics, and food additives, very large quantities of liquorice derived from G. glabra and G. inflata (Xinjiang-Gancao) are imported by Japan as raw materials. Dongbei-Gancao (Tohoku-Kanzo in Japanese) and Xibei-Gancao (Seihoku-Kanzo in Japanese) are also imported from China but are mainly used in the preparation of Japanese Kampo medicines, mainly derived from G. uralensis.
The trade statistics related to liquorice import in Japan reveal that since it is not produced locally in Japan, they import it from China, Afghanistan, Turkmenistan, Uzbekistan, and Pakistan (Hayashi and Sudo 2009). The total amount imported has been 10,723,342 kg in 1987, but in 2007, it has decreased to 1,377,213 kg. At present, the major proportion of glycyrrhizin is extracted. Its purification is done in China and few other countries. In view of this, import for glycyrrhizin production has decreased in Japan (Hayashi and Sudo 2009). A part of it imported from China is the medicinal liquorice, which is more expensive than the one used for glycyrrhizin production as well as few other products. Some are also imported from Australia; 144,710 kg of liquorice has been imported from Australia in 2007, which is quite remarkable. Currently, it is cultivated on a farm owned by a Japanese glycyrrhizin-manufacturing company, namely, Maruzen Pharmaceuticals Co. Ltd., which is used for glycyrrhizin production together with other products (Hayashi and Sudo 2009).
188.8.131.52 Applications of Liquorice and Its Derivatives in Japan (Hayashi and Sudo 2009)
Use in the preparation of Kampo medicines
In Japan, enzymatically modified licorice extract (α-glycosyl-glycyrrhizin) and enzymatically hydrolyzed licorice extract (glycyrrhetinic acid 3-O-glucuronide) are also used as sweeteners (Hayashi and Sudo 2009). The former is produced by treating the extract with cyclodextrin glycosyltransferase, and it is used as a sweetener because of it has higher solubility and better taste than the untreated licorice extract (Liu et al. 2000). The latter is obtained by enzymatic hydrolyzation of the licorice extract. The sweetness of this licorice is attributable to glycyrrhetinic acid 3-O-glucuronide (Kuramoto et al. 1994), which imparts a strong sweetness that is approximately 941 times that of sucrose (Mizutani et al. 1994).
Flavor additives for tobacco
8.3 Other Uses
8.3.1 Liquorice Drinks
The two general forms of liquorice are offered in the markets, these are either roots or the extract. The long brown roots are usually harvested from the field from 3 to 4 years old plants and sun-dried (Cheel et al. 2013). The residual stems and fibrous roots are separated (Ariño et al. 2007b). The extract is prepared by chopping roots followed by their steam extraction (Ariño et al. 2007a), and liquor is filtered and concentrated. The final product may be a solid block or spray-dried powder (Khalesi 2015).
8.3.2 Meyan Balı (the Succus Liquiritiae)
The sun-dried shrinked liquorice roots are treated with boiling water to get a sweet and delicious dark colored extract, with slightly bitter taste in some cases. This is called “liquorice syrup” or “succus liquiritiae”. If this extract is not consumed in short time, it is degraded and to prevent this from happening the extract is concentrated to get a solidified extract, also named as block extract. In succus liquiritiae, glycyrrhizin content varies between 15 and 25%, and it is sold in the market as 5–10 kg blocks (Baytop 1952; İlisulu 1974).
The fresh liquorice roots brought to the factory for the production of succus liquiritiae contain 20–25% water-soluble substance, but the values go up to 30–40% after drying. The former are sugars, glycyrrhizin , resins (small amount), starch (small amount), colorant (small amount), and a small amount of other chemical substances. The remaining pulp is mainly cellulose (Baytop 1952).
The composition of the succus liquiritiae prepared from liquorice roots in the Aegean region of Turkey is as follows: 14–15.9% water, 5–6.9% ash, 4–6% water insoluble portion, 3.5–5.2% glucose, 5.8–6.2% sucrose, 10.9–33% gum and starch, and 23.2–25.4% glycyrrhizin (Baytop 1952; İlisulu 1974; İlisulu and Kolsarıcı 1986).
Cleaning and washing of roots.
Extraction with “reverse current” operation in extraction batteries.
Brewing and reposing.
Separation of the sweet drink in three-stage evaporators.
Repose and filter.
Cake production in moulds.
Transportation to the packaging hall.
8.3.3 Use as Animal Feed
Ozhan and Gol (1975) showed that the leaves of G. glabra can be used to meet the forage requirements of ruminant animals when quality and quantity of forage is limited. Although G. glabra is one of the naturally grown plants used to meet requirements of small ruminants in some semiarid regions of Turkey during the critical periods of the year there are very few studies available to validate the nutritional quality of G. glabra leaves (Kamalak 2006).
Kamalak (2006) has studied the nutritive values of G. glabra leaves, hand harvested at prebud, mid, and late flower stages from three plots. He has evaluated this in terms of chemical composition, in vitro gas production, and in situ dry matter (DM) and crude protein (CP) degradation. As per his observations, the chemical composition is significantly effected together with gas production, metabolizable energy (ME), DM, and CP degradability of the leaves of G. glabra by the maturity stage. Neutral detergent fiber (NDF), acid detergent fiber (ADF), and condensed tannin (CT) contents increase with increase in the maturity stage whereas crude protein decreases. Gas production, DM, CP disappearance, and estimated parameters also decrease with increase in maturity. CP, ADF, and CT contents range between 16.19 and 26.93%, from 20.74 to 29.07% and from 1.57 to 10.83%, respectively (Kamalak 2006). The potential gas production and ME have been recorded to range from 65.34 to 72.12 ml/0.200 g of DM and from 10.14 to 12.12 MJ/kg DM, respectively. The effective DM degradability (EDMD) and effective CP degradability (ECPD) have given the values ranging between 58.70 and 70.59% and from 57.32 to 73.72%. Gas production, DM and CP disappearance, and estimated parameters of G. glabra leaves harvested at prebud stage are significantly higher than those harvested at mid and late flower stages. Gas production, DM and CP disappearance, and estimated parameters are negatively correlated with NDF, ADF, and CT, but show a positive correlation with CP. G. glabra harvested at the proper stage of maturity offers considerable potential as a high-quality forage for ruminants during critical periods in the semiarid and arid regions (Kamalak 2006).
8.3.4 Use as Dye Plant
Different colors have been obtained from liquorice root without using mordant, with the mordant alone, and with potassium bichromate mordant kept constant and the two mordants mixed. These colors include open straw yellow, open henna green, honey color, milky coffee, chick yellow, green yellow, dirty yellow, dry oak leaf, open dirty yellow, open earth, hay yellow, open quince feather, dark quince feather, open dry oak leaf, and dark dry oak leaf colors. These colors are the most used ones in hand weaved carpets and rugs. These are strongly recommended for use in environmentally friendly herbal dyeing of rugs and carpets (Arlı et al. 2002).
Arlı et al. (2002) have conducted a study on the colors obtained from G. glabra root and their fastness values. They recommend that mordants should be used singly; moreover, the colors obtained from the liquorice root in terms of lightfastness are usually medium. For this reason, it is therefore suitable to use these in the dyeing of carpets and rugs (Arlı et al. 2002).
8.3.5 Evaluation of Liquorice Wastes
G. glabra root extracts are commonly used for medicinal purposes as well as a flavoring agent in the food and tobacco industries (Medina et al. 2011). Almost 10,000 tones of liquorice root residues annually accumulate in some countries and must be properly treated, because the untreated residues produce unwanted environmental effects as these are phytotoxic (Medina et al. 2011). Their direct application to the soil is not suitable. No alternative use has been proposed for this waste in recent evaluations. The burning of this waste is strictly forbidden. Landfilling is costly; currently, nearly 40 dollars per ton are required to solve this problem which includes the transportation cost as well. This type of application is regarded as ecologically unfriendly solution, due to extensive production of greenhouse gases, especially methane, under the anaerobic conditions prevailing in landfills (Lou and Nair 2009; Medina et al. 2011).
Medina et al. (2011) have tried to develop a reliable protocol for management of liquorice root wastes and their composting. They suggest that it is possible to use these wastes as a peat substitute in growing media. They have also looked on their suppressiveness against Fusarium oxysporum f. sp. melonis (FOM)—the causal agent of Fusarium wilt of melon. According to Medina et al. (2011), these wastes can be cocomposted. For this purpose, temperature-controlled forced aeration system with the coarse fraction of separated cow manure can be used for an enrichment both its nutrient content as well as microbial population. Thermophilic conditions prevailing in the pile for approximately 3 months allow the compost to get stabilized and reach an ambient temperature 110 days from the beginning. The resulting compost shows physical characteristics which are well comparable to the peat, with a high nutrient content and relatively low salinity, and no phytotoxicity is seen in the extract from compost, according to the cress germination test. They have grown tomato plants as well in compost which have shown enhancement in development when compared to the peat. The number of surviving FOM spores incubated in the compost has declined faster than in peat. Fusarium infected melon plants have survived much better if planted in liquorice compost, as compared to peat. It can be said that liquorice compost can serve as a peat substitute with preferable qualities as proposed by Medina et al. (2011). Latter workers have suggested that the waste can be successfully composted during a reasonable time period, provided enough inoculum and sufficient nutrients are supplied, for example, cattle manure. The composting duration of the chosen mix until full compost maturity (110 days) is reported to be much shorter than that of liquorice waste alone (Hadar and Mandelbaum 1986) and comparable to that of most types of organic matter, in spite of the recalcitrant nature of the waste from these roots (Gagnon et al. 1999; Shi et al. 1999). Medina et al. (2011) have also proposed that resulting compost has adequate chemical and physical characteristics for its use as a component of growth media, and its performance has been clearly demonstrated. The resulted compost has a potential nutritional effect, especially in terms of N and K. The compost negatively affects the survival rate of FOM spores and shows marked suppression against Fusarium wilt of melon. It therefore has a clear potential as an ingredient of growth media (Medina et al. 2011).
8.3.6 Antimicrobial and Antifungal Activity
Lately, several clinical and pharmacological investigations have been undertaken, which demonstrate the antimicrobial activities of liquorice aqueous, ethanol, and supercritical fluid extract (Bodet et al. 2008; Park et al. 2008; Al-Turki et al. 2008; Jain et al. 2013). Such an activity in plant oils and extracts has been recognized since years. It has been indicated that it can be attributed to alkaloids, saponins, flavonoides, tannin, glycosides, and phenols (Shinwari et al. 2009). Antimicrobial activity of ethanolic extract of G. glabra has been tested against Bacillus subtilis MTCC (121), Staphylococcus aureus MTCC (96), Pseudomonas aeruginosa MTCC (429), Escherichia coli MTCC (443), and one fungal strain Candida albicans. Candida albicans and Trichophyton rubrum growth have been reported (Patil et al. 2009). The inhibition by ethanolic extracts of G. glabra and their fractions has been shown by Meghashri (2009) as well. However, G. glabra methanolic extracts seem to show more fungicidal effect against Arthrinium sacchari and Chaetomium funicola (Hojo and Sato 2002). Tharkar et al. (2010) too have recorded the antifungal activity of G. glabra extracts. Similarly, Gupta et al. (2008) have published data related to the antimicrobial activity of G. glabra against Mycobacterium tuberculosis. The liquorice extracts with ethanol, chloroform, and acetone show antibacterial activity against Bacillus subtilis, Stapphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa (Nitalikar et al. 2010). A high antibacterial activity against Staphylococcus epidermidis, Staphylococcus aureus, and Propionibacterium acnes has been recorded with G. glabra extracts (Nand et al. 2012). The antibacterial effect of G. glabra extract against Pseudomonas aeruginosa, Shigella flexneri, Escherichia coli, Staphylococcus epidermidis, S. aureus, and Baillus subtilis has been enlightened by Varsha et al. (2013). According to the results published by Statti et al. (2004), G. glabra methanolic extract also shows antimicrobial activity against various strains of Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212, Micrococcus luteus ATCC 9622, Proteus mirabilis ATCC 29852, Proteus vulgaris ATCC 6361, and Escherichia coli ATCC 4350. An antibacterial activity of G. glabra extracts against Pseudomonas aeruginosa and B. subtilis has also been reported (Shinwari et al. 2009). The upper respiratory tract bacteria such as Streptococcus pyogenes, Haemophilus influenza, and Moraxella catarrhalis studied by Tanaka et al. (2001) reveal that secondary metabolites obtained from Glycyrrhiza species show antibacterial activity against these. Licoricidin and coumarin derivatives like glycyrol, glycyrin, and glycycoumarin too exhibit high activity against all tested microorganisms. Glabridin derived from root of G. glabra has been found to be active against both yeast and filamentous fungi (Fatima et al. 2009). It has shown various biological activities like antimicrobial activity against Helicobacter pylori, Staphylococcus aureus, and inflammation (Hatano et al. 2000; Fukai et al. 2002; Nerya et al. 2003). G. glabra essential oils also show an inhibitory effect against Aspergillus flavus (Ali 2013).
Two new pterocarpenes—glycyrrhizol A (1) and glycyrrhizol B (2)—with structures elucidated by spectroscopic data interpretation along with four known isoflavonoids—5-O-methylglycryol (3), isoglycyrol (4); both identified by comparison of their spectroscopic data with reported values in the literature; 6,8-diisoprenyl-5,7,4′-trihydroxyisoflavone (5), and gancaonin G (6)—have been isolated from the roots of G. uralensis using a bioassay-guided fractionation method. Out of these, compounds 1 and 5 have shown potent antibacterial activity against Streptococcus mutans with minimum inhibitory concentrations of 1 and 2 µg/mL, respectively, while glycyrrhizol B (2) and gancaonin G (6) have shown more moderate activity (He et al. 2006). In all, 12 phenolic compounds have been isolated from the fractions of a supercritical fluid extract of G. uralensis roots (Villinski et al. 2014). Seven of the metabolites from this extract have been reported earlier. Moreover, four known components have been characterized from this material for the first time, namely, 1-methoxyerythrabyssin II (4), 6,8-diprenylgenistein, gancaonin G (5), and isoglycyrol (6), and one new isoflavan, licorisoflavan C (7). When licoricidin (1) was treated by these workers with palladium chloride larger amounts of licorisoflavan C (7) been produced together with two new isoflavans, licorisoflavan D (8); subsequently detected in the liquorice extract; and licorisoflavan E (9). A study on the antibacterial activity of compounds 1–9 against the cariogenic Streptococcus mutans and the periodontopathogenic Porphyromonas gingivalis has revealed that licoricidin (1), licorisoflavan A (2), and 7–9 show antibacterial activity against P. gingivalis (MICs of 1.56–12.5 μg/mL). Most potent activity against S. mutans has been recorded with 7 (MIC of 6.25 μg/mL), followed by 1 and 9 (MIC of 12.5 μg/mL). All these findings support the evidence for the therapeutic potential of liquorice extracts for the treatment and prevention of oral infections (Villinski et al. 2014).
The compounds like 18β-glycyrrhetinic acid, liquiritigenin, glabridin, licochalcone A, licochalcone E, licorisoflavan A, licoricidin, and glycyrrhizol A isolated from liquorice possess antimicrobial effects against S. aureus, C. albicans, Mycobacterium bovis, yeast, and several cariogenic bacteria like S. mutans and Streptococcus sobrinus (Long et al. 2013; Fatima et al. 2009; Messier and Greiner 2011; Zhou et al. 2012a, b; Dai et al. 2013; Kim et al. 2013b; Gafner et al. 2011; Hu et al. 2011).
According to Yang et al. (2015) liquorice has great application prospects as an alternative therapy in treating dental caries, periodontal disease, digestive anabrosis, and tuberculosis. It also has a potential alternative to synthetic fungicides, or as a lead compound for new classes of synthetic fungicides (Yang et al. 2015).
A new prenylated isoflavan, iconisoflavan (1), and a new prenylated isoflav-3-ene, iconisoflaven (2) have been isolated from the roots of G. iconica together with four known earlier (3S)-licoricidin (3), licorisoflavan A (4), topazolin (5), and glycycoumarin (6) (Kırmızıbekmez et al. 2015). Their structures have been elucidated on the basis of extensive spectroscopic analysis including 1D and 2DNMR as well as HR-MS. Kırmızıbekmez et al. (2015) have also established the configurations of compounds 1, 3, and 4 by electronic circular dichroism (ECD). An in vitro evaluation of all the isolated compounds (1–6) has revealed that they show antimicrobial activities against five pathogenic bacteria and one yeast (Candida albicans) using an in vitro microdilution method. Compounds 1 and 3–5 have displayed significant activity against Salmonella typhimurium ATCC 13311 with MIC values ranging from 2 to 8 μg/mL. All compounds have been screened for their in vitro free radical scavenging activities using an in vitro microdilution DPPH assay spectrophotometrically. The tested compounds have exhibited IC50 values in the range of 0.18–0.56 mg/mL. This suggests that they show an activity comparable with that of ascorbic acid (IC50: 0.07 mg/mL). The investigations undertaken by Kırmızıbekmez et al. (2015) are the first phytochemical and bioactivity investigation on G. iconica.
Very important differences have been reported by Karahan et al. (2016) in the antimicrobial and antioxidant activities of root extracts of G. glabra var. glandulifera from different habitats in Hatay (Turkey). The extracts with most potent antioxidant characteristics were those from populations originating from the regions with similar climatic features (rainy Mediterranean climate and low-rain Mediterranean climate). On the other hand, the extracts showing strongest antimicrobial effect have come from the specimens originating from habitats under anthropogenic pressure. This implies that the differences in the biological activities can be attributed partly to the influence of environmental factors (Karahan et al. 2016).
An experimental work has been carried out by Gaur et al. (2016) to explore in vitro as well as in vivo combination effects of liquiritigenin and isoliquiritigenin isolated from G. glabra with β-lactam antibiotics (penicillin, ampicillin, and oxacillin) against mec A-containing strains of methicillin-resistant Staphylococcus aureus. Minimum inhibitory concentration (MIC) of the both components has exhibited significant anti-methicillin-resistant Staphylococcus aureus activity (50–100 μg/mL) against clinical isolates of methicillin-resistant Staphylococcus aureus. In vitro combination study has shown that isoliquiritigenin significantly reduces MIC of β-lactam antibiotics up to 16-folds, while liquiritigenin reduces up to 8-folds. Time-kill kinetics at graded MIC combinations (isoliquiritigenin/liquiritigenin + β-lactam) have indicated 3.27–9.79-fold and 2.59–3.48-fold reduction in the growth of clinical isolates of S. aureus, respectively. In S. aureus-infected Swiss albino mice model, the combination of isoliquiritigenin with oxacillin has significantly lowered the systemic microbial burden in blood, liver, kidney, lung, and spleen tissues in comparison with isoliquiritigenin, oxacillin alone as well as untreated control (Gaur et al. 2016). According to Gaur et al. (2016), considering its synergistic antibacterial effect both isoliquiritigenin and liquiritigenin prove to be the promising compounds for the development of novel antistaphylococcal combinations.
Pandian and Chidambaram (2017) have succeeded in synthesizing “silver nanoparticles” from aqueous extract of G. glabra. The biological reduction of these particles has been carried out in appropriate condition and characterization of synthesized nanoparticles followed by UV-Vis spectroscopy, FT IR, and SEM. The phytochemicals present in the extract of G. glabra have reduced the silver ions into metallic nanoparticles. The synthesized silver nanoparticle has exhibited a strong antibacterial activity against P. aeruginosa and S. aureus. The synthesized SNPs have exhibited potential anticancer activity and are reported to be nontoxic on mammalian Vero cell line. Hence, the SNPs from plant extracts may be used to develop nanomedicine against pathogens (Pandian and Chidambaram 2017).
Several reports clearly depict that liquorice has potent effects in inhibiting the activities of gram-positive and gram-negative bacteria such as Staphylococcus aureus (Long et al. 2013; Snowden et al. 2014; Lau and Plotkin 2013), Porphyromonas gingivalis (Wittschier et al. 2009), Streptococcus mutans (Ahn et al. 2012; Peters et al. 2010), Candida albicans (Irani et al. 2010; Fatima et al. 2009), Escherichia coli (Awandkar et al. 2012), Enterococcus faecalis (Badr et al. 2011), Pseudomonas aeruginosa (Yoshida et al. 2010), Helicobacter pylori (Asha et al. 2013), and Bacillus subtilis (Irani et al. 2010). It also has effects in inhibiting the activities of pathogenic fungi such as Alternaria solani, Botrytis cinerea, and Phytophthora (Treutwein et al. 2010). The liquorice extracts with 80% methanol (oil-based extract of liquorice) have shown great fungicidal effects against Arthrinium sacchari M001 and Chaetomium funicola M002 (Hojo and Sato 2002). An inhibitory effect of the G. glabra extract on Candida albicans and some gram-positive bacteria has also been reported (Irani et al. 2010).
Attempts have been made to evaluate the antifungal activity as well as antitoxin activity of G. glabra extract (Mohseni et al. 2014). Strain American Type Culture Collection 15517 of Aspergillus parasiticus has been used to perform antifungal susceptibility test. The tests have been followed according to clinical and laboratory standards institute document M27-A3, and the rate of aflatoxin production was determined using high-performance liquid chromatography technique after exposure to different concentrations of liquorice extract. Mohseni et al. (2014) have followed the quantitative changes in the expression of the aflR gene, analyzed by measuring the cognate aflR mRNA level with quantitative real-time reverse transcription polymerase chain reaction assay. Their results demonstrate the inhibitory effect of liquorice extract on Aspergillus parasiticus growth at 500 mg/mL. A significant decrease in aflatoxin production has been recorded at the same concentration. The production of aflatoxin B1 has been entirely inhibited in 10 g/mL of the extract. A significant decrease has been observed in the level of aflR gene expression has after exposure of fungal cells to 500 g/mL of extract. The antifungal and antitoxin activities of the extract on Aspergillus parasiticus have revealed its antifungal features together with its effective ability to decrease aflatoxin production (Mohseni et al. 2014).
8.3.7 Antiviral Activity
Several virus diseases including chronic hepatitis B and C, together with human acquired immunodeficiency syndrome (AIDS), have been treated with licorice and glycyrrhizate compounds obtained from the liquorice extract as a potential therapeutic agent (Wang et al. 2000; Chen et al. 2004; Orlent et al. 2006; Tandon et al. 2002). Many reports have indicated antiviral activity of glycyrrhizin and glycyrrhizic acid with the ability to inhibit growth and cytopathology of hepatitis A and C (Crance et al. 1990; Van Rossum et al. 1999), and immunodeficiency virus (HIV) (Hattori et al. 1989; Plyasunova et al. 1992). The glycyrrhizin and its derivatives from G. glabra do reduce the hepatocellular damage in chronic hepatitis B and C, and show antiviral activity against HIV-1, SARS-related coronavirus, respiratory syncytial virus, arboviruses, vaccinia virus, and vesicular stomatitis virus (Fiore et al. 2008). Glycyrrhizin also shows antiviral effect, through an inhibition of viral particle to cell membrane binding, or through cellular signal transduction mechanisms (Crance et al. 2003). 18β-glycyrrhetinic acid is reported as the promising biological alternative for the topical treatment of persistent vulvovaginal candidiasis (Pellatti et al. 2009). In vitro antiviral effects for viruses causing respiratory tract infections like influenza virus and the severe acute respiratory syndrome (SARS) coronavirus, human immunodeficiency virus (HIV) too have been reported (Cinatl et al. 2003)
The potential use G. uralensis for treatment of human infection by enterovirus type 71 (EV71) which can cause life-threatening meningoencephalitis has also been investigated (Kuo et al. 2009). The treatment of viral hepatitis since the late 1970s with liquorice preparations is a well-known fact. Recently, many papers published depict that liquorice extract has significant antiviral activity against HIV, severe acute respiratory syndrome-coronavirus (SARS), HSV, influenza virus (H3N2), rotavirus, respiratory syncytial virus, varicella zoster virus, coxsackievirus, and enterovirus (Booth et al. 2003; Wang et al. 2013a; Kwon et al. 2010; Shebl et al. 2012). As against this, as far as a single compound is concerned, many compounds have been isolated from liquorice but only two triterpenoids, glycyrrhizin and 18β-glycyrrhetinic acid, have been reported to possess antiviral activity, with a significant positive impact on HIV, H3N2, HSV, DHV, HCV, PrV, and IAV (Yang et al. 2015). In addition, other virus types have been worked include the following: H5N1, herpes virus, influenza virus, and rotavirus (Wolkerstorfer et al. 2009; Matsumoto et al. 2013; Huang et al. 2012; Soufy et al. 2012; Michaelis et al. 2010; Sasaki et al. 2002; Kang and Lieberman 2011; Smirnov et al. 2012; Moisy et al. 2012; Sui et al. 2010; Hardy et al. 2012a; Baltina et al. 2012; Yang et al. 2015). The in vitro experiments with glycyrrhizin have shown that it inhibits HCV by suppressing the release of infectious particles (Matsumoto et al. 2013), HSV by depressing the cellular adhesion (Huang et al. 2012), influenza virus by reducing HMGB1 binding to DNA and suppressing interactions between viral macromolecules and host proteins (Moisy et al. 2012), HIV by preventing the virus from replication (Sasaki et al. 2002), and H5N1 not by interfering with H5N1 replication, but by controlling H5N1-induced proinflammatory gene expression (Michaelis et al. 2010). However, does glycyrrhizin inhibit virus replication still needs more research work. It also interacts with the cell membrane and reduces endocytic activity (Wolkerstorfer et al. 2009), and causes deregulation of generating the mature forms of viral mRNA encoding, which is a process important for viral stability (Kang and Lieberman 2011). The glycyrrhetinic acid is reported to show a significant antiviral activity against rotavirus replication by reducing the amounts of viral proteins VP2, VP6, and NSP2 at a step or steps subsequent to virus entry, together with an effective inhibition of HIV-1 by reducing the accumulation of virus antigen p24 and protecting cells from the cytopathogenic action of the virus (Hardy et al. 2012a; Baltina et al. 2012).
In all, 13 new oleanane-type triterpenoid saponins, uralsaponins M-Y (1–13), and 15 known analogues (14–28) have been isolated from the roots of G. uralensis (Song et al. 2014). The structures of 1–13 have been identified on the basis of extensive NMR and MS data analysis. The sugar residues have been identified by gas chromatography and ion chromatography coupled with pulsed amperometric detection after hydrolysis. For the first time, saponins containing a galacturonic acid (1–3) or xylose (5) residue have been reported from Glycyrrhiza species. Compounds 1, 7, 8, and 24 are reported to exhibit good inhibitory activities against the influenza virus A/WSN/33 (H1N1) in MDCK cells with IC50 values of 48.0, 42.7, 39.6, and 49.1 μM, respectively, versus 45.6 μM of the positive control oseltamivir phosphate. Moreover, compounds 24 and 28 have shown anti-HIV activities with IC50 values of 29.5 and 41.7 μM, respectively (Song et al. 2014). Adianti et al. (2014) have reported that glycycoumarin, glycyrin, glycyrol, and liquiritigenin isolated from G. uralensis, as well as isoliquiritigenin, licochalcone A. and glabridin, can be good candidates for seed compounds to develop antivirals against HCV. Glycyrrhizin demonstrates a pronounced lymphocytic proliferation response on white Pekin ducklings and reveals a good immune stimulant and antiviral effect against DHV following in vivo studies (Soufy et al. 2012). A protective effect is exerted by a combination of glutamyl-tryptophan and glycyrrhizin in reducing the death of H3N2 virus-infected mice (Smirnov et al. 2012).
We can conclude that both glycyrrhizin and glycyrrhetinic acid exert antiviral activity mainly by inhibiting the replication and release of the virus. They suppress the interactions between the virus and host cells, activate immune responses in host cells, and attenuate a virus-induced anti-inflammatory response (Yang et al. 2015).
The report published by Matsui et al. (2004) clearly shows that many allergies and other inflammatory diseases have been treated with liquorice species. The anti-inflammatory effects of glycyrol (benzofuran coumarin) isolated from G. uralensis have been investigated at length (Shin et al. 2008). They found that glycerols have potential anti-inflammatory effect. According to Vibha et al. (2009), the steroid-like anti-inflammatory activity of liquorice root constituents is similar to the action of hydrocortisone. The explanation given by them in connection with this finding is that it occurs due to inhibition of phospholipase A2 activity, an enzyme critical to numerous inflammatory processes. The glycyrrhetinic acid (ED 50, 200 mg kg−1) is reported to show an inhibitory effect on carrageenan-induced rat paw edema and anti-allergic activity (Matsui et al. 2004). G. glabra secondary metabolites such as glycyrrhizic acid, glabridin, and licochalcone A also show an anti-inflammatory effect (Furuhashi et al. 2005; Kang et al. 2005).
The liquorice looks like an excellent alternative choice for the treatment of inflammation in the epidemic diseases among populations especially children (Yang et al. 2015). A large number of reports stress the fact that two triterpenoids, glycyrrhizin and 18β-glycyrrhetinic acid, and several flavonoids isolated from liquorice such as glabridin, isoliquiritigenin, licochalcone A, licochalcone B, licochalcone C, licochalcone D, licochalcone E, isoangustone A, dehydroglyasperin C, licoricidin, licorisoflavan A, echinatin, and glyurallin B, possess anti-inflammatory activity (Yang et al. 2015). The effects of these compounds (dehydroglyasperin C, echinatin, glycyrrhizin, 18β-glycyrrhetinic acid, licochalcone A, licochalcone B, licochalcone C, licochalcone D, licochalcone E, licoricidin, licorisoflavan A, isoliquiritigenin, and glabridin) on different inflammatory types have been investigated by different workers (Yang et al. 2015).
The types of inflammations studied are as follows: postischemic brain with middle cerebral artery occlusion (Luo et al. 2013); chronic liver diseases (Imai et al. 2013); mastitis (Fu et al. 2014); acute lung injury (Ni et al. 2011); LPS-induced inflammatory response (Wang et al. 2011; Furusawa et al. 2009); leishmania donovani-infected macrophages (Bhattacharjee et al. 2012); indomethacin-induced small intestinal damage (Ishida et al. 2013); ischemia/reperfusion (Oztanir et al. 2014); LPS-induced J774A.1 murine macrophages (Thiyagarajan et al. 2011); periodontitis (La et al. 2011); lipid peroxidation in rat liver microsomes (Fu et al. 2013); LPS-induced BV-2 microglia (Kim et al. 2013c); glutamate-induced hippocampal HT22 cells (Kim et al. 2012); childhood atopic dermatitis (Wananukul et al. 2013); allergic airway inflammation (Chu et al. 2013); LPS-induced RAW264.7 cell (Fu et al. 2013; Cho et al. 2010); LPS-induced macrophage cells (Fu et al. 2013); in rat liver microsomes (Fu et al. 2013); LPS-induced macrophage cells (Fu et al. 2013); LPS and interferon-gamma-induced inflammatory response (Wang et al. 2013b); allergic inflammation (Tanifuji et al. 2010); and TPA-induced mouse ear edema (Lee et al. 2013a), respectively.
In addition the about studies, Fuhr et al. (2015) have reported that in TNF-α-stimulated colon cells, amorfrutin A (1) (isoprenoid-substituted benzoic acid derivatives, which were found in G. foetida) significantly reduces the expression and secretion of several inflammation mediators, in part due to interaction with PPARγ. Fuhr et al.’s (2015) results support the hypothesis that amorfrutins may have the potential to treat inflammation disorders such as chronic inflammatory bowel diseases.
The glycyrrhizin has also been used in leishmania donovani-infected macrophages as per the in vitro studies published (Bhattacharjee et al. 2012). In lipopolysaccharide-stimulated macrophage models, glycyrrhetinic acid, glabridin, and isoliquiritigenin have been used and in actinobacillus actinomycetemcomitans lipopolysaccharide-treated macrophages, licoricidin and licorisoflavan A have been used (La et al. 2011). Licochalcone A, licochalcone B, and licochalcone E have been used in lipopolysaccharide-induced RAW 264.7 macrophage cells (Fu et al. 2013; Cho et al. 2010), and DGC has been used in lipopolysaccharide-induced BV-2 microglia and mice hippocampal cells (Wang et al. 2011; Thiyagarajan et al. 2011; Kim et al. 2012, 2013c).
Glycyrrhizin has also been used in the postischemic brain with a middle cerebral artery occlusion mouse model both in vivo and clinical studies as well as in a lipopolysaccharide-induced acute lung injury mouse model plus a mastitis mouse model (Ni et al. 2011; Luo et al. 2013; Fu et al. 2014). For the treatment of oxidative and neuronal damage in brain tissue caused by global cerebral ischemia/reperfusion in a C57BL/J6 mouse model also glycyrrhetinic acid has been used (Oztanir et al. 2014). In the childhood atopic dermatitis and in a murine model of asthma licochalcone A has been used, whereas in TPA-induced mice ear edema licochalcone E has been used (Wananukul et al. 2013; Chu et al. 2013; Yang et al. 2013; Lee et al. 2013a). Several studies show that liquorice extracts have benefits in the treatment of acute and chronic inflammatory conditions, indicating that studies on the anti-inflammatory activity of liquorice are very important and meaningful (Nirmala and Selvaraj 2011; Wu et al. 2011; Yang et al. 2015).
The anti-ulcer activity of deglycyrrhizinated liquorice formulations has been demonstrated in Bennett et al. 1980 by Bennett and coworkers. They used a rat model of aspirin-induced gastric mucosal damage. The results have shown that these formulations promote healing by increasing mucous production and blood supply to the damaged stomach mucosa, thus enhancing mucosal healing (Van Marle et al. 1981; Da Nagao et al. 1996). An anti-ulcerogenic effect of carbenoxolone derived from the root of liquorice too has been reported (Masoomeh and Kiarash 2007). This is explained through an inhibition of the secretion of gastrin. The reason is that liquorice compound raises the concentration of prostaglandins in the digestive system and in this way promotes mucus secretion from the stomach. Anti-pepsin effect of liquorice secondary metabolites too has been reported, which prolongs the life span of surface cells in the stomach (Adel et al. 2005).
8.3.10 Anti Tumor
Almost all in vivo and in vitro studies on the liquorice phytochemical constitutes have revealed that it has anticancer effects (Salvi et al. 2003). An inhibition of tumor formation and growth in breast, liver, and skin cancer has been reported (Liu et al. 1998; Shiota et al. 1999; Tamir et al. 2000). In 1998, Fukai and his coworkers reported the inhibitory activity of phenolic compounds such as isoliquiritigenin, semilicoisoflavone B, gancaonin C licoisoflavone B, and licoisoflavanone for the growth of both B. subtilis H17 (wild type) and M45 (recombinationless mutant cells). In in vivo assay, Sheela et al. (2006) have observed that the extract of G. glabra inhibits proliferation of tumor cells and angiogenesis. Antiproliferative effects are displayed by the ethanolic extract and glycyrrhizin against the MCF-7 in dose-dependent manner (Dong et al. 2007). Similar results have been reported by Jo et al. (2005) who used ethanol extract of G. uralensis root which induced apoptosis and G1 cell cycle arrest in MCF-7 human breast cancer cells. The licochalcone E from the roots of G. inflata also exhibits most potent cytotoxic effect compared with the known antitumor agents, licochalcone A, and isoliquiritigenin (Yoon et al. 2005). Many compounds have been derived from G. glabra, namely, glyasperin A, gancaonin P, licochalcone B, topazolin, and gancaonin O by Nomura et al. (2002), which have shown relatively higher cytotoxic activity against human oral squamous cell carcinoma cell line HSC-2. A new retrochalcone derived from the G. inflata by Yoon et al. (2005), during their studies on licochalcone E, has exhibited the potent cytotoxic effect. Isoliquiritigenin has also been reported to inhibit the proliferation of the human non-small cell lung cancer A549 cell line, inducing apoptosis and locking cell cycle progression in the G1 phase (Hsu et al. 2004). Kanazawa et al. (2003) too have reported similar findings, where isoliquiritigenin has inhibited the growth of prostate cancer. It has been suggested as a chemopreventive compound for cancer in humans. In short, the biologically active compound from the liquorice root can be very useful as antiproliferative and antitumor agents (Rahman and Rashid 2008; Hossain et al. 2004).
High mortality due to cancer is one of the leading causes of humans deaths; as such, the use of natural compounds without side effects is currently attracting much attention of researchers. Many studies have proven that various natural compounds in liquorice possess effective antitumor activity, including three triterpenoids, glycyrrhizin , glycyrrhetinic acid, and 11-deoxyglycyrrhetinic acid, and six flavonoids, isoangustone A, glabridin isoliquiritigenin, licochalcone A, licochalcone B, and licochalcone E (Kim et al. 2010, 2013d; Hsu et al. 2011; Li et al. 2012; Kwon et al. 2013; Khan et al. 2013; Lin et al. 2014; Yuan et al. 2014; Huang et al. 2014a; Yang et al. 2015; Park et al. 2016).
The effects of these compounds (glycyrrhizin, 18β-glycyrrhetinic acid, 11- deoxyglycyrrhetinic acid, isoangustone A, licochalcone A, licochalcone B, licochalcone E, isoliquiritigenin, and glabridin) on different cancer types such as colon carcinogenesis, leukemia, prostate cancer, gastric cancer, colorectal cancer, human melanoma, liver cancer, bladder cancer, oral cancer, and breast cancer have been investigated by different investigators (Shetty et al. 2011; Hsu et al. 2011; Xiao et al. 2011; Chueh et al. 2012; Khan et al. 2013; Lee et al. 2013b; Song et al. 2013; Kwon et al. 2013; Wang et al. 2013c; Lin et al. 2014; Huang et al. 2014a; Tsai et al. 2014; Choi et al. 2014; Yuan et al. 2014; Jiang et al. 2014; Kim et al. 2014). Several single compounds isolated from liquorice as well as ethanol extracts and hexane/ethanol extracts of roasted liquorice are reported to show antitumor activity (Seon et al. 2012; Lee et al. 2013c). According to Yang et al. (2015), the liquorice compounds interfere with antitumor activities mainly by attenuating the level of cytokines, blocking cell cycle progression, and inducing cancer cell apoptosis. Isoangustone A has been applied to SW480 human colorectal adenocarcinoma cells during in vitro studies, DU145 to human prostate cancer cells as well as 4T1 murine breast cancer cells; isoliquiritigenin to HeLa human cervical cancer cells and MDA-MB-231 to human breast cancer cells; glycyrrhizin has been applied to WEHI-3 mouse leukemia cells, glycyrrhetinic acid to DU-145 prostate cancer cells, and licochalcone to MKN-28, AGS, MKN-45 gastric cancer cells, HA22T/VGH, SK-Hep-1, HepG2 to human hepatocellular cancer cells, KB human oral cancer cells, and T24 to the bladder cancer cells (Wolkerstorfer et al. 2009; Shetty et al. 2011; Xiao et al. 2011; Chueh et al. 2012; Seon et al. 2012; Wang et al. 2013c; Huang et al. 2014a; Tsai et al. 2014; Jiang et al. 2014; Choi et al. 2014; Kim et al. 2014). Glycyrrhizin has also been applied under in vivo studies and has shown to inhibit 1,2-dimethylhydrazine-induced colon precancerous lesions of Wistar rats (Khan et al. 2013), while glycyrrhetinic acid applied to gastric cancer has inhibited tumor growth in a nude mouse model (Lin et al. 2014). Glabridin has inhibited MDA-MB-231 breast cancer angiogenesis in a nude mouse model; licochalcone B has inhibited MB49 bladder tumor growth in a C57BL/6 mouse model; licochalcone E has suppressed 4T1 mammary tumor growth and lung metastasis in the mammary fat pads in a syngeneic BALB/c mouse model; isoangustone A has significantly suppressed PTEN-deleted human prostate tumor growth and SK-MEL-28 human melanoma tumor growth in xenograft mice models (Hsu et al. 2011; Kwon et al. 2013; Lee et al. 2013b; Song et al. 2013; Yuan et al. 2014). In summary, liquorice embodies interesting and important hits for antitumor drug discovery and development (Yang et al. 2015).
The data published by Siracusa et al. in 2011 clearly depicts the fact that extract of G. glabra leaves shows antioxidant, anti-genotoxic, and anti-inflammatory activities. Many phytochemical constitutes have been found in the roots of Glycyrrhiza. These are considered as a potential source of antioxidants (Singh 2010; Lateef et al. 2012). According to Vaya et al. (1997), isoflavones glabridin and hispaglabridins A and B show significant antioxidant activity. The luteolin, rutin, and apigenin flavonoids found in the G. glabra roots show significant antioxidant characteristics (Hesham and Shgeru 2002). The main compound linked to antioxidant activity is mentioned as phenolic compounds (Škrovánková et al. 2012). The ethanol extract of G. glabra has been reported to possess a cerebroprotective effect in hypoxic rats, which may be mediated by its antioxidant effects (Muralidharan et al. 2009). G. glabra essential oil also exhibits DPPH radical scavenging activity (85.2%) at dose 400 µg/ml (Ali 2013), whereas methanolic extract shows 91.3% scavenging activity at dose of 62.5 µg (Lateef et al. 2012). Licochalcone C is reported to possess antioxidant because it reduces the production of superoxide radicals and consequently reduces the activity of inducible nitric oxide synthase (iNOS) (Franceschelli et al. 2011).
8.3.12 Hepatoprotective Activity
G. glabra is used in the traditional medicine to treat various liver diseases as well (Subramoniam and Pushpangadan 1999). Secondary metabolites derived from liquorice have been observed to lower serum liver enzyme levels and improve tissue pathology in hepatitis patients (Van Rossum et al. 2001).
Isoflavan derivatives, glabridin, hispaglabridin A, hispaglabridin B, 4′-O-methylglabridin, and 3′-hydroxy-4′-O-methylglabridin, isolated from G. glabra have been investigated by Haraguchi et al. (2000) for their ability to protect liver mitochondria against oxidative stresses. These workers have reported that mitochondrial lipid peroxidation linked to respiratory electron transport is induced nonenzymatically and an inhibition of these isoflavans takes place. Hispaglabridin A strongly inhibits both peroxidations and 3′-hydroxy-4′-O-methylglabridin, the most effective at preventing NADH-dependent peroxidation. 3′-Hydroxy-4′-O-methylglabridin protects the mitochondrial respiratory enzyme activity against NADPH-dependent peroxidation injury (Haraguchi et al. 2000). Moreover, dihydroxyfumarate—induced mitochondrial peroxidation is also prevented by this isoflavan. G. glabra isoflavans are highly effective in protecting mitochondrial function against oxidative stresses (Haraguchi et al. 2000). G. glabra root extract also shows radioprotective effect via lipid peroxidation in rat liver microsomes and plasmid pBR322 (Shetty et al. 2002). The extract protects microsomal membranes, which is evident from the reduction in lipid peroxidation, and could also protect plasmid DNA from radiation-induced strand breaks (Shetty et al. 2002).
A significant reduction in serum aminotransferases is induced by glycyrrhizic acid which then improves the liver histology (Curreli et al. 2007). Al-Razzuqi et al. (2012) have demonstrated that G. glabra aqueous extract shows a significant effect in ameliorating liver functions in acute liver diseases if given in a single dose per day of 2 mg/kg body weight. The protective effects of glycyrrhetinic acid against the carbon tetrachloride-induced hepatotoxicity and retrorsine-induced liver damage has also been published by Jeong et al. (2002).
Only three compounds, glycyrrhetinic acid, glycyrrhizin, and dehydroglyasperin C, have been reported until now to possess hepatoprotective activity, especially glycyrrhizin, which according to Yang et al. (2015) is effective in almost the whole process of liver diseases. During the clinical treatment of liver disease, glycyrrhizin preparation has been widely used. After this date, it has been used on a large scale in the treatment of a variety of liver diseases, such as hepatitis B, hepatitis C, liver fibrosis, and cirrhosis of the liver (Yang et al. 2015). Glycyrrhizin has an obvious protective effect in liver injury induced by CCl4 as revealed by different in vivo animal models (Huo et al. 2011; Yin et al. 2011), together with hepatotoxicity induced by xanthium, α-naphthyl isothiocyanates, and liver fibrosis (Zhai et al. 2007; Abe et al. 2008; Sharifzadeh et al. 2008). Moreover, glycyrrhizin , glycyrrhetinic acid, and dehydroglyasperin C have also shown hepatoprotective activity (Abe et al. 2008; Wang et al. 2012; Rasool et al. 2014; Tripathi et al. 2009; Guo et al. 2013; Fujisawa et al. 2000; Chen et al. 2014b; Wu et al. 2008; Hasan et al. 2014; Seo et al. 2014).
Some of the mechanisms that can lead to liver dysfunction are oxidative stress, lipid peroxidation, and transaminase reactions. The downregulation of these factors found recently enlightens the hepatoprotective effect of liquorice. It also exerts its hepatoprotective effect by regulating the expression of CYP enzymes, attenuating oxidative stress, improving the stability of the cell structure as well as biological membrane systems, and inhibiting the cytolytic activity of the complement and apoptosis systems (Yang et al. 2015). Latter also mentions that this extract significantly inhibits the aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase activities, and decreases total protein, albumin, and globulin levels. The liver superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione S-transferase activities are also enhanced by this extract together with glutathione level (Huo et al. 2011; Yin et al. 2011; Rasool et al. 2014; Al-Razzuqi et al. 2012). Liquorice therefore appears to be a highly potent therapeutic agent for the treatment of liver diseases (Yang et al. 2015). The findings of Park et al. (2016) are considered as scientific evidence that isoLQ in liquorice has the function of being a hepatic protectant against oxidative damages through ERK-mediated Nrf2 activation.
8.3.13 Dermatological Effect
As early as 1997 Lee and coworkers have observed many activities like skin whitening, depigmenting, antiaging, anti-acne, and anti-erythemic affiliated to the use of Glycyrrhiza root originating bioactive compounds. Recently, a significant decrease in skin melanin by formulation of G. glabra extracts has been reported by Akhtar et al. (2011). According to Lee et al. (2005), glycyrrhizin derived from the root of G. glabra induces melanin formation; this is probably mediated through an activation of a tyrosinase gene expression.
8.3.14 Antidepressant and Memory-Enhancing Activity
According to Dhingra and Sharma (2005, 2006), the mouse immobility tests have clearly demonstrated that liquorice is highly effective as an antidepressant as well as in the memory-enhancing activity. The studies undertaken by Zhao et al. (2006) have revealed that liquiritin and many other secondary metabolites from G. uralensis show an antidepressant effect on chronic stress following the experiments carried out on the depressed rats. Wang et al. (2008) too have published data related to the antidepressant-like activity of liquiritin and isoliquiritin in the forced swimming test (FST) as well as tail suspension test (TST) in mice. Latter have depicted that an increase in the 5-Hydroxytryptamine and norepinephrine in the mouse hippocampus, hypothalamus, and cortex could be the mechanism of action of these compounds. The sedative and muscle relaxant activities in mice due to another compound in liquorice the carbenoxolone in genetically epilepsy-prone rats (GEPRs) have also been reported by Gareri et al. (2004). The studies on the root extract of G. glabra on learning and memory in another experiment has revealed that 150 and 225 mg/kg doses show an effective enhancement in learning and memory as compared to the control. The reason may be antioxidant and anti-inflammatory action of plant extract. Under these circumstances, the susceptible brain cells get exposed to less oxidative stress resulting in reduced brain damage and improved neuronal function (Chakravarthi et al. 2012).
A large number of workers have investigated the effects of liquorice aqueous extract on learning and memory. One of these is Chakravarthi and Avadhani (2014), who investigated the function of such extract in the dendritic morphology of hippocampal cornu ammonis area three (CA3) neurons. According to these workers, 150 and 225 mg/kg doses show obvious enhancement of dendritic arborization and dendritic intersections in hippocampal pyramidal neurons. This has demonstrated its neuronal dendritic growth stimulating features. These researchers have also found that all doses of such an extract significantly enhances the memory. An application of 150 and 225 mg/kg doses significantly enhance learning as well as memory (Chakravarthi and Avadhani 2013). The nootropic and antiamnestic effects of these extracts are mediated through augmenting monoaminergic transmission in the cortex, hippocampus, and striatum (Michel et al. 2013).
Out of a large number of compounds isolated from liquorice glabridin and 2,2,4-trihydroxychalcone is reported to improve learning and memory. These are commonly used in the treatment of cardiovascular and central nervous system diseases (Yang et al. 2015). The higher doses of former compound effectively antagonize amnesia induced by scopolamine (Cui et al. 2008). According to Hasanein (2011), this compound also prevents the deleterious effects of diabetes on memory and learning as per the experiments carried out on rats. Inhibition of beta-site amyloid precursor protein cleaving enzyme 1 is regarded as an effective strategy for anti-Alzheimerʼs disease drug discovery. As a new beta-site amyloid precursor protein 2,2,4-trihydroxychalcone cleaving enzyme 1 inhibitor has been tested to ameliorate impairment in mice (Zhu et al. 2010). All these findings enlighten the fact that liquorice seems to be a promising drug for improving memory, impaired learning, Alzheimerʼs disease, dementia , and other neurodegenerative disorders (Yu et al. 2007; Cui et al. 2008; Yang et al. 2015).
8.3.15 Immunoregulatory Activity
Most of the research work undertaken during the last decade reveals an immunoregulatory activity of liquorice. Out of the liquorice compounds, glycyrrhiza polysaccharides are believed to play an important role in stimulating the bodyʼs immune ability, by affecting the bodyʼs nonspecific and specific immune functions and through activating immune cells (Hong et al. 2009; Li et al. 2012). In addition, glycyrrhizin , 18β-glycyrrhetinic acid, licochalcone A, liquiritigenin, glycyrol, and glycyrrhiza polysaccharides also showed immunoregulatory activity (Abe et al. 2003; Lee et al. 2009; Li et al. 2010a, 2012; Hendricks et al. 2012; Soufy et al. 2012; Kim et al. 2013a; Ma et al. 2013; Fontes et al. 2014). The compounds isolated from liquorice exert immunoregulatory activity by regulating the production of cytokines and interleukin together with the expression of cell surface molecules and immune responses (Yang et al. 2015). Many in vivo and clinical studies have proved that these compounds produce a protective effect against disseminated candidiasis (Lee et al. 2009). It reduces the severity of experimental autoimmune encephalomyelitis as well (Fontes et al. 2014). It also increases the end point serum antibody titers (Hendricks et al. 2012). The production of IL-10 also increases with Con A-induced hepatitis (Abe et al. 2003). It acts as an immune stimulant against DHV (Soufy et al. 2012). All these reports affirm the immunoregulatory activity of liquorice and indicate that it can be developed as a novel immunomodulatory drug (Yang et al. 2015).
8.3.16 Inhibitory Effect on Diabetes
Liquorice inhibits series of pathological and physiological changes induced by d-galactose, such as insulin resistance and oxidative stress/free radical damage, so as to delay the development of diabetes (Yang et al. 2015). Several compounds isolated from licorice, such as glycyrrhizin, glycyrrhetinic acid, liquiritigenin, isoliquiritigenin, glabridin, licochalcone A, licochalcone E, and some other flavonoids, have been reported to possess an inhibitory effect in diabetes (Choi et al. 2010; Lee et al. 2010; Sen et al. 2011; Yehuda et al. 2011; Park et al. 2012; Alqahtani et al. 2013; Feng et al. 2013; Li et al. 2013; Wu et al. 2013; Gaur et al. 2014; Yao et al. 2014). The liquorice extract can be a highly potent therapeutic agent for the prevention and treatment of diabetes nephropathy led by mesangial fibrosis and glomerulosclerosis through blocking Akt activation and transforming growth factor-β signaling (Li et al. 2010b). It alleviates blood glucose levels, restores renal function, attenuates body weight loss, and modulates the adverse effect of diabetes on renal glutathione and malondialdehyde as well as the activity of catalase and superoxide dismutase. It also restores the total antioxidant capacity of diabetic kidneys, and at the same time has a potential therapeutic effect in diabetes due to its antioxidant and antihyperglycemic features (Kataya et al. 2011; Saleem et al. 2011). All these reports indicate that liquorice is a highly potent therapeutic agent for diabetes treatment (Yang et al. 2015).
The data published by Zhang et al. (2016) indicates that liquiritin has a protective effect against high fructose-induced myocardial fibrosis via suppression of NF-kB and MAPKs signaling pathways. It may be a promising candidate for diabetes-related myocardial fibrosis treatment. Moreover, Xie’s (2017) results indicate that liquiritigenin has a protective role in high fructose feeding-triggered cardiac injury through fibrosis and inflammation response suppression by inactivating NF-kB signaling pathway. Thus, liquiritigenin may be a potential candidate for diabetes-associated cardiac injury (Xie 2017).
8.3.17 Adrenal Cortical Hormone-like Function
Some reports demonstrate that liquorice extracts and compounds show adrenal cortical hormone-like function, increased adrenocorticotropic hormone formation, and stimulated steroidogenesis in adrenal glands. It will also stimulate the secretion of glucocorticoids, mineralocorticoids, and anterior pituitary corticotroph-releasing hormone and vasopressin from the adrenal cortex (Lee et al. 2007; Kratschmar et al. 2011). Out of the compounds isolated from liquorice, 18β-glycyrrhetinic acid, glycyrrhizin , and isoliquiritigenin produce an adrenal cortical hormone-like function (Yang et al. 2015). Isoliquiritigenin has significant estrogenic activities due to its estrogen responsive β selectivity, partial estrogen agonist activity, and the nonenzymatic transformation between isoliquiritigenin and liquiritigenin (Hajirahimkhan et al. 2013). 18β-glycyrrhetinic acid and glycyrrhizin play a very important role in the treatment of glucocorticoid-dependent diseases as a well-known inhibitor of 11β-hydroxysteroid dehydrogenases (Kratschmar et al. 2011; Raikkonen et al. 2010; Sasaki et al. 2010). Glycyrrhetinic acid shows its mineralocorticoid actions by inhibiting the conjugation of deoxycorticosterone and dehydroepiandrosterone at a source within the adrenal cortex (Al-Dujaili et al. 2011). All the abovementioned findings lend support to the reasonable use of liquorice as a promising strategy for the treatment of hormone-dependent diseases (Yang et al. 2015).
8.3.18 Other Effects
A vast number of reports have been published on the pharmacological activities of liquorice extracts and biologically active compounds. The secondary metabolites liquiritigenin and isoliquiritigenin derived from the root of G. glabra have shown dose-related anti-allergic activities (Kakegawa et al. 1992). Moreover, glabridin and glabrene have an estrogen-like effect stimulating the synthesis of epithelial cell DNA. It prevents postmenopausal women from vascular injury and atherosclerosis (Kwon et al. 2008). According to Akasaka et al. (2011), glycyrrhetinic acid is effective in suppressing pain-related behaviors caused by sciatic nerve injury. Isoliquiritigenin has a spasmolytic effect on uterine contraction, an effective function in reducing pain, and an antiangiogenic property (Jhanji et al. 2011; Shi et al. 2012). The traditional compound prescription “gancao wheat jujube soup” has demonstrated a potential antidepressant-like effect by liquiritin treatment in chronic, variable, stress-induced depression; this can be related to the defense of liquiritin against oxidative stress (Zhao et al. 2008). Liquorice is also used to relieve menopausal symptoms in postmenopausal women (Menati et al. 2014; Hajirahimkhan et al. 2015). Nagai et al. (2007) have indicated that licochalcone A may be responsible for the relaxant activity of G. inflata root, which acts through the inhibition of cAMP PDE.
Chen et al.’s (2009) results indicate that isoliquiritigenin plays a dual role in regulating gastrointestinal motility, both spasmogenic and spasmolytic. The spasmogenic effect may involve the activating of muscarinic receptors, while the spasmolytic effect is predominantly due to blockade of the calcium channels. According to Mishra et al. (2011), anti-arthritic activity of G. glabra is due to its significant reduction of paw edema volume and its ability to stabilize lysosomal enzyme activity such as ACP. The results justify the benefit of G. glabra in the treatment of inflammation associated diseases like arthritis. The investigations carried out by Asgary et al. (2007) have revealed that G. glabra extract has an effect of on the blood lipids and atherosclerosis. These workers have found that G. glabra extract significantly decreases total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels and increases high-density lipoprotein cholesterol (HDL-C) and lessens atherosclerotic lesion in aorta. Won et al. (2007) have reported the use of liquorice as a food ingredient for obesity, because licochalcone A derived from G. uralensis reduces the lipase activity as a new inhibitor of pancreatic lipase.
184.108.40.206 Clinical Therapeutics
Many reports about the clinical applications of liquorice ingredients and preparations have been published as the modern pharmacology developed (Yang et al. 2015). The development of glycyrrhizin preparations, mostly used to treat liver diseases, has a long history in Asia among all active compounds isolated from this plant (Li et al. 2014). This preparation has developed four generations so far, from glycyrrhizin tablets to ammonium glycyrrhizinate, diammonium glycyrrhizinate, and magnesium isoglycyrrhizinate. A comparison with its first three preparations, magnesium isoglycyrrhizinate has a better lipotropy, higher targeting, and fewer adverse reactions, because of its use in protecting hepatic L02 cells from ischemia/reperfusion-induced injury (Huang et al. 2014b). It has been successfully used to slow down the process of pulmonary fibrosis (Xiao et al. 2014), inhibiting ethanol-induced testicular injury (He et al. 2010), and restoring hepatic impairments caused by paclitaxel in other cancer treatments (Chen et al. 2014a).
The addition of liquorice and its active compounds to the oral cortisone acetate increases the amount of cortisol available to tissues in Addisonʼs disease (Methlie et al. 2011). A double-blind clinical trial study conducted on patients with allergic rhinitis has shown that the rate of its symptoms including severe rhinorrhea, sneeze, pruritus, and congestion are lowered significantly after using glycyrrhizin nasal drops (Akhavan et al. 2012). According to Agarwal et al. (2009), the liquorice gargle is effective in attenuating the incidence and severity of postoperative sore throat. Jain et al. (2013) have reported that both aqueous and ethanolic extracts of this plant exert cariostatic activities through a clinical trial carried out among 60 pediatric patients aged 7–14. With the discovery of more and more pharmacology activities, liquorice has shown a great potential for acting as a novel drug or complement agent to treat different diseases (Yang et al. 2015).
8.3.19 Side Effects and Toxicity
The toxic effects of liquorice are well documented, but potentially toxic compounds in it have not been confirmed fully. According to Asl and Hosseinzadeh (2008), although deglycyrrhizinated liquorice (DGL) is reported to be free of adverse effects, the large amounts of this plant may result in severe hypertension, hypokalemia, and other signs of mineralocorticoid excess. The doses exceeding 10 times the standard dose when consumed over a long period can lead to a number of dangerous conditions (McGuffin et al. 1997). The use of this plant is contradicted in persons with high blood pressure due to hypertension caused by its overuse, which may be due to its effect on the aldosterone system; however, a treatment with its extract results in dose-dependent increase in plasma renin and sodium with concomitant decrease in plasma cortisol, adrenocorticotropic hormone (ACTH), aldosterone, and potassium levels (Olukoga and Donaldson 2000; Al Qarawi et al. 2002; Sharma and Agrawal 2013). Its prolonged use leads to hypertension, hypokalemia, and edema, since insulin-dependent diabetics appear to be predisposed to hypokalemia and sodium retention, and use of this plant is contradicted by diabetes (McGuffin et al. 1997; De Smet et al. 1997; Asl and Hosseinzadeh 2008; Isbrucker and Burdock, 2006). This plant should not be used with stimulant laxatives or hypotensive diuretics (such as thiazides) because of the potassium loss associated with the laxatives and diuretics (De Smet et al. 1997; Asl and Hosseinzadeh 2008). Glycyrrhizin has been shown to interfere with 5β-reductase breakdown of corticosteroids, thus prolonging the biological half-life of these steroids. The glycyrrhizin or the aglycone, or glycyrrhetinic acid are reported to increase the effect of corticoid treatment (Brinker 1997).
Some studies on liquorice report (ethanol extracts of G. glabra), containing glycyrrhizin and glycyrrhetic acid, negative results in the TA98 and TA100 strains (Mitscher et al. 1986; Zani et al. 1993). Genotoxic potential of G. glabra has been investigated using the Ames IITM, chromosomal aberration, and micronucleus test systems. The results indicate that this plant possesses no mutagenic activities, either with or without metabolic activation (Nakagawa et al. 2008; Chandrasekaran et al. 2011). TA98 has been reported to be more sensitive to the mutagens present in the liquorice water extract (Martinez et al. 1999). The cytotoxic activity of liquorice extract is 63% at 0.24 mg/mL, with greater percentages apparent as its concentrations increase up to 4.8 mg/mL. IC50 values of chloroform, methanol, and water extracts of G. glabra in the breast MCF7 cell line have been reported as 0.45, 0.99, and 1.29 μM, respectively (Rathi et al. 2009). Abudayyak et al. (2015) have reported that G. glabra water extract displays mutagenic activity against the TA100 strain in the presence of metabolic activation, but only at the highest extract concentration. It has been reported that large doses or long-term injections of this plant extract sometimes produce an acquired form of apparent mineralocorticoid excess syndrome, expressed as sodium retention, hypokalemia, and high blood pressure (Wang and Nixon 2001; Shen et al. 2007).
The medical records of patients treated with liquorice herbal complexes from January 1 to December 31, 2010 have revealed changes in the levels of creatinine, potassium, and blood urea nitrogen before and after herbal complex intake and the prevalence of hypokalemia among these patients. A total of 360 patients have not shown significant changes in the levels of potassium and creatinine (p = 0.815 and 0.289, respectively). Hypokalemia has been observed in six patients; however, in five patients, the hypokalemia did not appear to be related to liquorice. The results show that herbal complexes containing liquorice have not significantly influenced the potassium levels in routine clinical herbal therapies (Jung et al. 2014). 4T1 mammary carcinoma cells injected into the mammary fat pads of syngeneic BALB/c mice have revealed that 7 days after the injection, the mice received licochalcone E (7 or 14 mg/kg body weight/day) via oral gavage for 25 days. Licochalcone E suppresses solid tumor growth and lung metastasis, without exhibiting kidney or liver toxicity (Kwon et al. 2013). Russo et al. (2000) have proposed that some people could be susceptible to low doses of glycyrrhizin because of a 11β-hydroxysteroid dehydrogenase deficiency. Harahap et al. (2011) believe that liquorice ingestion and mutations in the HSD11B2 gene, inhibit 11β-hydroxysteroid dehydrogenase type 2 enzyme activity and cause the syndrome of apparent mineral corticoid excess. This supposed that liquorice ingestion is an environmental risk factor for hypertension or an apparent mineral corticoid excess state in patients with a mutation in HSD11B2.
The liquorice is generally recorded as a nontoxic herb in TCM but some health concerns have been reported with its use (Kao et al. 2014). It causes edema and apparent mineralocorticoid excess syndrome as per the clinical studies, because glycyrrhizic acid and glycyrrhetinic acid inhibit the activity of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) which converts biologically active cortisol into the inactive compound cortisone, thereby preventing the overstimulation of the mineralocorticoid receptor by cortisol (Whorwood et al. 1993; Ma et al. 2011; Hardy et al. 2012b). An overdose of the latter can lead to excessive sodium ion levels and the excretion of potassium ions, which end up with water retention and lead to hypertension. Its excessive daily supplementation may cause low potassium levels due to liquorice-induced hyperaldosteronism and finally hypertension and heart disease. The hypertension induced by its use can be reversed by stopping its intake as well as intake of its products (Ruiz-Granados et al. 2012). 11β-Hydroxysteroid dehydrogenase type 2 is inhibited by liquorice and its constituents; this causes hypertonia and hypokalemia because of the associated change in blood potassium levels. Similar concerns are associated with the intake of carbenoxolone because it is a more potent inhibitor of 11βHSD2 (IC50: 20–50 nM) than 11βHSD1 (IC50: 1.8 μM) (Ma et al. 2011). Potassium levels are also affected by digoxin (Bielecka-Dabrowa et al. 2012), which might act synergically with liquorice herbal intake. Some products use deglycyrrhizinated liquorice (DGL) instead of raw extract; this reduces glycyrrhizic acid and glycyrrhetinic acid-induced side effects (Kao et al. 2014).
An overuse of liquorice also influences the effects of other medicines. Glabridin may inhibit human cytochrome P450 (Kent et al. 2002) which metabolizes warfarin (coumadin), an anticoagulant agent, into its inactive form (Cavallari and Limdi 2009), and is an important enzyme in drug metabolism and bioactivation (Guengerich 2008). The liquorice increases warfarin clearance and in case treatment with warfarin is required, consulting a physician is strongly advised before consuming foods containing liquorice (Mu et al. 2006; Kao et al. 2014).
Pregnant females should limit intake of extract from this plant (Kao et al. 2014). Very few investigations have been conducted on the teratogenicity of its extract, but a single study has indicated that it may aggravate cyclophosphamide-induced body weight loss and malformations of fetuses by upregulating cytochrome P450 type 2B (Park et al. 2011). However, Korean researchers have reported that women taking liquorice for the treatment of cough and cold did not have an increased risk of stillbirths (Choi et al. 2013). Its extract also increases estrogen levels in humans (Armanini et al. 2002) and may increase the risk of estrogen-mediated cancer (Boucher et al. 2012). The extract of this herb can potentially cause an antiandrogenic effect, which may lead to erectile dysfunction, therefore to avoid such side effects, careful intake of this herb-related food is highly advised (Armanini et al. 2003; Zamansoltani et al. 2009; Kao et al. 2014).
220.127.116.11 Mycotoxin Contamination in Liquorice Products
The microbial growth on liquorice roots is highly expected because of the effects of the environmental conditions (Khalesi et al. 2013). An exposure to the fungal contamination is seen due to old-style harvesting, processing, and storage conditions. Such a contamination has three main effects: deterioration of the chemical composition, reduction of the medicinal effectiveness, and the risk of mycotoxin production (Khalesi 2015). The presence of aflatoxin B1 (AFB1) has been reported to be much lesser extent than ochratoxin A (OTA) on its roots but the reasons are unknown (Pietri et al. 2010; Wang et al. 2013d). According to a recent report published by Pietri et al. (2010), only 16% of the products from this herb contained AFB1, but majority contained OTA, sometimes up to 990.1 ng/g. In view of this, a large number of papers have been published mainly on the OTA contamination of its products (Khalesi 2015).
The presence of OTA in this herb preparation has been reported for the first time by Bresch et al. (2000) and Majerus et al. (2000). They have reported a high percentage of contaminated samples. The report from the former authors mentions that nearly 50% of the liquorice roots showed OTA contamination in the concentration range of 0.3–216.0 ng/g. The homogeneous brownish samples have been reported to contain higher amounts of OTA than bright yellow ones, which is quite interesting. In another study Majerus et al. (2000) have analyzed 83 liquorice products, as foodstuff or supplements of medicine, all these have indicated low levels of OTA in children’s tea (130–440 ng/g), but quite high levels in supplements (300–64300 ng/g). More than 90% of liquorice tablets have been reported to contain OTA in the range of 700–2600 ng/g. Many more studies have confirmed high amounts of OTA in liquorice products, sometimes with values above 200 ng/g (Kabelitz and Sievers 2004).
The Italian liquorice products too have been reported to contain OTA, while its confectionery contained 0.96 ng OTA/g, dried extracts had 89.6 ng OTA/g with the maximum value of 990.1 ng/g, which represents an extremely high level of contamination. In the light of these reports, OTA intake from dried liquorice extract seems to expose a risk for consumers, especially high consumers, patients, and infants (Pietri et al. 2010; Khalesi 2015).
Ariño et al. (2007a) have also reported high levels of OTA in 30 liquorice products from Spain, including food as well as medicine-based samples. They have reported OTA concentrations up to 252.8 ng/g. Dry liquorice roots contained the highest levels with the mean value of 63.6 ng/g and sweets contained the lowest level with the average value of 3.8 ng/g. The extract of the herb contained 16.0 ng OTA/g and its solid blocks had 39.5 ng OTA/g. These workers have also notified that OTA in dry roots may be shifted to corresponding tea from 1% for infusion tea and up to 5% in the case of decoction tea. Nearly 75% of the liquorice hard candies purchased from public markets in Spain are reported to show OTA contamination, with a mean value of 2.96 ng/g, while for the soft candies, contamination is only 39%, with a mean value of 0.34 ng OTA/g sample (Herrera et al. 2009).
In China OTA levels in its roots have revealed that the highest level of contamination occurred in the samples from Jiangxi (84.4 ng/g) and the lowest from Beijing (1.4 ng/g) (Yang et al. 2010). The ecophysiological and storage conditions may be responsible for the differences together with the variety of the roots. This enlightens the findings that the region of collection plays a significant role for OTA amount. The sustainability of the roots against contamination may be different from one place to another (Khalesi and Khatib 2011; Khalesi 2015).
The risk of fungal contamination of its roots increases in warm humid areas (Khalesi et al. 2013; Khalesi 2015). Large quantities of the roots are typically stocked for a long period before processing or transportation. A successful approach to avoid contamination is managing the storage conditions (Kapetanakou et al. 2009; Cairns-Fuller et al. 2005). Khalesi and Khatib (2011) and Khalesi (2015) have studied the relation between OTA biosynthesis and ecophysiological factors including temperature, water activity (aw), and type of mycobiota in the region at length. Recent reports demonstrate that temperature of 22 ℃ is the critical point to control the formation of OTA in these roots; below this temperature, the amount of OTA is much lower than the temperatures mentioned. The covering of bulk of the roots during the storage needs to be avoided, as it may increase the inlet temperature and, consequently, the risk of fungal growth as well as OTA biosynthesis (Khalesi et al. 2013; Khalesi 2015).
The major parameter influencing OTA formation is the mycobiota in a region of liquorice root, which should be particularly considered. The distributional map of the fungi in liquorice production regions is still missing (Khalesi 2015). In all, 16 fungal species have been isolated from the root samples collected from four different locations in China, major ones being Penicillium, Aspergillus, and Eurotium (Chen et al. 2011). P. polonicum is the main species in Jiangxi province (with highest levels of OTA), whereas in other regions, Aspergillus spp. such as A. parasiticus, A. flavus, A. versicolor, and A. sydowii and Eurotium spp. such as E. chevalieri, E. repens, and E. amstelodami are dominant. Similar investigations were undertaken by Chen et al. (2013). They reported that Penicillium is the major fungus on liquorice in different regions in China with potential of OTA production. They also isolated two new Penicillium species, i.e., P. glycyrrhizacola sp. nov. and P. xingjiangense sp. nov. in the roots of this herb for the first time. P. chrysogenum was also reported as one of the main OTA producers on roots in China. Chen et al. (2013) have reported that P. chrysogenum, P. glycyrrhizacola, P. polonicum, and A. westerdijkiae are main contaminants in dry liquorice with values lying around 39.03 ng/g. However, the data for fresh and dry specimens on mycobiota differs much (Khalesi 2015).
No public reports are available from Iran concerning the mycobiota in the regions where this herb flourishes (Khalesi 2015). However, after observation of OTA, biodegradation on its roots from the natural contamination by A. fumigatus, A. japonicus, and A. niger is possible. Khalesi et al. (2011) have hypothesized that there may be predominant in OTA producers in Iran.
In case fungal contaminated liquorice is consumed for a long time, this may cause health hazards such as, chronic hypokalemic nephropathy secondary which needs immediate attention (Vivekanand 2010; Khalesi 2015). However, the fundamental mechanism of OTA toxicity has not been fully enlightened (Khalesi 2015). But some investigations have been done to decrease the risk by possible intake of OTA contaminated herbal product. Some research has been conducted on different food-based liquorice products as a normal dietary use to complete the current consumption databases of European Food Safety Authority (EFSA) concerning OTA in liquorice products (Commission Regulation (EU) No. 105/2010). According to Pietri et al. (2010), assuming a total mean value of 1.53 ng OTA/g in sweets corresponding to consumption about 1.4 g liquorice sweets per day means a weekly intake of 12 ng OTA. For an infant with 30 kg weight, a weekly uptake of 0.4 ng/kg body weight has been reported which is extremely high. In another study, it has been shown that children may consume up to 8.94% tolerable weekly intake (TWI) of liquorice confectionary (Herrera et al. 2009). Although liquorice and its derivatives are not the dominant products in dietary intake, for high consumers of this herb, especially children, yet the current amount of OTA in its products is not safe (Khalesi 2015).
At present, the main issue for trading the liquorice products, especially those coming from Asia, is keeping the products safe concerning OTA (Khalesi 2015). To fulfill this criterion, efforts have been made to regulate OTA levels in this herb (Commission Regulation (EU) No. 105/2010). For this purpose, first, the data of OTA concentration in a variety of its products obtained from public markets has been collected. Commission Regulation (EU) No. 105/2010 amending regulation (EC) No. 1881/2006 sets the regular maximum levels of 20 ng/g for its root and 80 ng/g for the extract. The reason for the difference between the maximum acceptable amount of OTA between root and extract is that from each 3 to 4 kg liquorice roots, around 1 kg of extract is obtained. These rules and calculations are valid for average consumers. Of course for the high consumers, patients, and infants, these amounts need to be reviewed (Khalesi 2015).
The liquorice (Glycyrrhiza taxa) plants have a large number of applications in food and pharmaceutical industry. If these are contaminated by fungal OTA, the possibility for a carcinogenic mycotoxin production during growth and storing period can be expected (Khalesi 2015). In EU, the maximum amount of OTA in its roots and extract has been authorized at 20 and 80 ng/g, respectively. Nevertheless, a valid method to quantify this toxin is still lacking. Use of IAC and SPE clean-up methods followed by liquid chromatography has been proposed for determination of OTA in the products of this herb. However, those methods are time-consuming, laborious, costly, and restricted to only a few laboratories, mostly located in Europe. The decontamination of OTA in this herb is also a very challenging topic. Peeling, extraction, and dehydration have been reported to reduce the amount of OTA. Although thermal stability of OTA is an obstacle for heat deterioration of this mycotoxin in the roots of this herb and derived products, it seems that much more studies on determination and decontamination of OTA are needed to overcome the OTA concern in liquorice marketing (Khalesi 2015).
8.3.20 Other Alternative Uses
Abdel-Latif et al. (2015) have studied three natural dyes extracted from Biota orientalis, Piper nigrum, and Glycyrrhiza glabra. They have used these as photosensitizers for dye-sensitized solar cells (DSSCs). The dyes have been tested as sensitizers before and after grinding the materials. Titanium dioxide (TiO2) nanopowder has been used as a semiconducting material. The best photovoltaic performance has been recorded from the DSSC sensitized with G. glabra after grinding the material. They suggest that this performance is significantly improved by acid treatment of the TiO2 photoelectrode. Electrochemical impedance spectroscopy of the fabricated DSSCs has been carried out and charge recombination resistance, double layer capacitance, effective lifetime of electrons, charge transfer resistance, and constant phase element exponential coefficient determined (Abdel-Latif et al. 2015).
The studies carried out by Ovez et al. (2006) deal with one natural organic substance liquorice (G. glabra) for its use as a carbon source in the biological denitrification of drinking water. This material acts as a solid substrate and biofilm carrier. Their experiments have been carried out in batch, semi-batch, and continuous processes. Complete denitrification has been achieved with G. glabra. They found that nitrate removal rate of G. glabra is 6.96 mg/L/day NNO3. The results of Ovez et al. (2006) have clearly revealed that this organic substrate could be used as an alternative carbon source for denitrification with complex process control and continuous monitoring, but this carbon source should be changed periodically for the continuation of the process.
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