Glycyrrhiza glabra (Licorice)

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Glycyrrhiza glabra (Licorice): Ethnobotany and Health Benefits Wang Xiaoying, Zhang Han, Wang Yu TIANJIN UNIVERSITY OF TRADITIONAL CHINESE M EDICINE, TIANJIN, C HINA

The licorice (Radix Glycyrrhizae or Liquiritiae radix), which is broadly used in medicine and commerce, is derived from the sweet root of various species of Glycyrrhiza (Glycyrrhiza uralensis Fisch., Glycyrrhiza glabra L., or Glycyrrhiza inflata Bat., Leguminosae). Licorice is native to southern Europe and parts of Asia; it is one of the most commonly used herbal medicines and an important source of confectionery (Fiore et al., 2005). Therefore the health properties associated with licorice are well documented. According to the World Health Organization, licorice is employed as a demulcent in the treatment of sore throats and an expectorant for coughs and bronchial catarrh. Licorice also has a critical role in the prophylaxis and treatment of gastric and duodenal ulcers as well as dyspepsia. As an antiinflammatory agent, licorice reduces allergic reactions and prevents liver toxicity. In China, licorice is also documented to be effective for fatigue and debilitation (China, 2015). More than 20 triterpenoids and 300 flavonoids have been isolated from licorice to date (Yang et al., 2015). The major constituents are glycyrrhetic acid, flavonoids, isoflavonoids, hydroxycoumarins, and sterols, including b-sitosteroid, which may have glucocorticoid and mineralocorticoid activities (Seeff et al., 2001). Licorice roots are composed of approximately 3%e5% 18b-glycyrrhizin and 18b-glycyrrhizic acid (GA), which are considered to be the primary active components (Yu et al., 2012). When glycyrrhizin is taken orally, it is transformed into glycyrrhetic acid by intestinal bacteria and absorbed into the body (Akao et al., 1994). Active components of licorice are shown in Fig. 14.1. Many researchers have reported that these components could contribute to protecting the nervous, endocrine, respiratory, digestive, and cardiovascular systems. This chapter summarizes the active components, extractions, or preparations of licorice used medically that are supported by experimental or clinical data.

Effect on Respiratory System Licorice has a dramatic effect on inhibiting respiratory symptoms, especially airway injury. A randomized, double-blind comparison of licorice versus sugarewater gargle Sustained Energy for Enhanced Human Functions and Activity. http://dx.doi.org/10.1016/B978-0-12-805413-0.00014-4 Copyright © 2017 Elsevier Inc. All rights reserved.

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FIGURE 14.1 Chemical structures of active components in licorice.

proved the benefits of licorice in reducing the incidence of postoperative sore throat (POST) in patients who were intubated with double-lumen tubes (Ruetzler et al., 2013). Licorice gargle (0.5 g licorice in water) significantly attenuates the incidence and severity of POST (Agarwal et al., 2009). Another clinical trial reported that licorice lozenges reduced the distressing symptom of POST in the postoperative period among smokers (Gupta et al., 2013). The antiinflammation and transforming growth factor (TGF) signal pathway might be involved in licorice’s effect on the respiratory system. Moreover, liquiritin apioside decreased the cytotoxicity induced by cigarette extracts in a dosedependent manner and increased the expression of TGF-b and tumor necrosis factora (TNF-a) at the messenger RNA level in A549 cells as a protective agent against epithelial injury in chronic obstructive pulmonary disease (COPD) (Guan et al., 2012). In addition, glycyrrhetinic acid alleviates early-stage, radiation-induced lung injury by decreasing the expression of TGF-b1, Smad2, and Smad3 in lung tissue (Chen et al., 2016). Furthermore, licorice flavonoids (30 mg/kg) inhibit lipopolysaccharide (LPS)induced acute pulmonary inflammation by impairing the elevation of the content of water in the lung. Licorice is one of the most efficacious medicinal plants for the treatment of asthma (Javadi et al., 2016). According to the frequency of service prescribed for asthma among

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adults in Taiwan, 20,627 asthma patients (85.7%) used traditional Chinese medicines. Licorice was shown to be in the top three prescriptions, Ding-chuan-tang, Xiao-qinglong-tang, and Ma-xing-gan-shi-tang (the frequency was 23.1%, 15.1%, and 13.2%, respectively) (Wang et al., 2014). Licochalcone A (LA) is effective in treating inflammatory diseases such as asthma by suppressing the inhibitor of nuclear factor kB (NF-kB)/ thymic stromal lymphopoietin pathway in a dose- and time-dependent manner (Kim et al., 2015). LA (50 mg/kg) attenuates the allergic airway inflammation in a murine model of asthma by inhibiting the increase of T-helper type 2 cytokines such as interleukin (IL)-4, IL-5, and IL-13, and reducing serum levels of ovalbumin-specific immunoglobulin (Ig)E and IgG (Chu et al., 2013). Oral administration of glycyrrhizin (10 mg/ kg/day for 7 consecutive days) is benefit for lung histopathologic features in mice with chronic asthma (Hocaoglu et al., 2011). Other research indicates that the mechanism of glycyrrhizin on the airways might be work against b2-adrenergic receptor agonistinduced receptor internalization and cell apoptosis (Shi et al., 2011). Glycyrrhizin has a protective effect on acute lung injury caused by LPS, which induces sepsis and simultaneously reduces the alveolar capillary barrier (Zhao et al., 2016). G. uralensis flavonoids in antiasthma formula [antiasthma herbal medicine intervention (ASHMI)] reduce eosinophilic pulmonary inflammation and inhibit memory Th2 responses to antigen stimulation in culturing lung cells (Yang et al., 2013).

Hepatoprotective Effect Glycyrrhizin, GA, licorice flavonoid oil, and some preparations from licorice have strong hepatoprotective activity. Among them, glycyrrhizin has been developed as a hepatoprotective drug in China and Japan (Li et al., 2014). Glycyrrhizin preparation treats several liver diseases such as hepatitis B, hepatitis C, liver fibrosis, and cirrhosis. Stronger neominophagen C (SNMC), a Japanese preparation to treat chronic hepatitis that contains 0.2% glycyrrhizin, 0.1% cysteine, and 2% glycine, is marketed in Japan and India. Clinical trials on the hepatoprotective efficacy of licorice are listed in Table 14.1. Improving the activities of serum alanine aminotransferase (ALT) and aspartate transaminase (AST) is the principal indication for licorice on hepatoprotection. Licorice water extract reduces the elevation of serum transaminase induced by cadmium and significantly relieves liver cell swelling and necrosis (Lee et al., 2009a). Licorice extract (100 mg/kg) containing GA (15.77  0.34 mg/mg), liquiritin (14.55  0.42 mg/mg), and liquiritigenin (1.34  0.02 mg/mg) reverses the accumulation of hepatic lipid and enhances the activities of ALT and AST (Jung et al., 2016). GA (48 mg/kg/day) attenuates liver tissue inflammation, collagen deposition, and hydroxyproline levels in both bile duct ligation-induced rats and those with dimethylnitrosamine-stimulated hepatic fibrosis (Zhou et al., 2016). Glycyrrhizin and glycyrrhetinic acid inhibit experimental liver cirrhosis induced by carbon tetrachloride (Moro et al., 2008) and reduce the level of serum ALT, the content of serum globulin, and hepatic collagen proteins; they relieve interstitial inflammation and inhibit hyperplasia of hepatic fibrous tissue. Further

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Table 14.1 Components/ Preparations

Randomized Controlled Trials on Hepatoprotective Efficacy of Licorice Diseases

Patients

Alcohol consumption (40% ethanol) Chronic hepatitis B

12 (6 males and 6 females) 10

Healthy humans during light exercise Nonalcoholic fatty liver disease Subacute hepatic failure

34 females

SNMC

Time Period

Dose

Effect

References

12 d

0.1% e0.3%

Chigurupati et al. (2016)

12 month

Single dose

3 times/ week, short infusions 600 mg/d

Decrease alkaline phosphatase and plasma glutathione Regress biochemical disease activity

Mori et al. (2015)

66

2 months

2 g/d

Enhance fat oxidation; no change in lipid profile makers Decrease ALT and AST

18

30 d

Increase survival rate

Acharya et al. (1993)

Chronic hepatitis C

40

8 week

40 or 100 mL/d 100 mL/d

Kumada (2002)

SNMC

Chronic hepatitis C

84

8 week

Yo Jyo Hen Shi Ko

Nonalcoholic steatohepatitis

8

8 weeks

Improved liver histology and ALT levels Decrease cumulative hepatocellular carcinoma incidence Decrease ALT

Glycyrrhizin

Glycyrrhizic acid

Licorice flavonoid oil

Licorice root extract SNMC

100 mL/d 2e7 times/ week 500 mg three times/d

Eisenburg (1992)

Hajiaghamohammadi et al. (2012)

Arase et al. (1997)

Chande et al. (2006)

ALT, alanine aminotransferase; AST, aspartate transaminase; SNMC, stronger neominophagen C.

studies indicated that licorice saponins show significant hepatoprotective activities by lowering ALT and AST levels in primary rat hepatocytes injured by D-galactosamine (Zheng et al., 2015). Licorice flavonoids could also inhibit an increase in ALT activity in plasma by a model of T cellemediated fulminant hepatitis in mice (Feng et al., 2007). Preclinical animal trials showed that the hepatoprotective effect of licorice might be related to antioxidative stress, which is antiinflammatory and inhibits lipid peroxidation. Hepatoprotective effects of 18b-GA may be due to its ability to block the bioactivation of carbon tetrachloride and its free radical scavenging effects (Jeong et al., 2002). Licochalcones B and D strongly inhibited superoxide anion production and showed potent scavenging activity on diphenyl picryl hydrazinyl radical, which was related to

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inhibiting microsomal lipid peroxidation (Haraguchi et al., 1998). As a novel active ingredient, glycycoumarin ameliorates alcohol-induced hepatotoxicity via activation of Nrf2 and autophagy (Song et al., 2015). Glycyrrhizin inhibits the expression of type I and type III collagen in the liver tissue of rats with hepatic fibrosis, reduces hepatic necrosis, and promotes the regeneration of liver cells by antiinflammation, antilipid peroxidation, regulation of immunity, and lysosomal stability (Liang et al., 2015). Licorice flavonoids protect liver cells in rats with immunological liver injury induced by LPS (Xie et al., 2009).

Effect on Cardiovascular System Zhigancao decoction (roasted licorice decoction), which contains licorice, is a historical and typical prescription in Chinese medicine to treat almost any kind of arrhythmia. Zhigancao decoction appears to have beneficial effects on improving the total effective rate, relieving a number of ventricular premature beats in participants with premature ventricular contractions in the clinic (Liu et al., 2015). Extract of roasted licorice inhibits ventricular fibrillation, reduces the heart rate, and prolongs the QeT interval of electrocardiogram results (Liu and Jing, 2007). Roasted licorice injection could antagonize heart rhythm disorders induced by strophanthin G, aconitine, digoxin, and calcium chloride, which showed the effect of inhibiting calcium channel (Chen and Yuan, 1991). Active components of licorice such as flavones and triterpenes have also been investigated to protect the cardiovascular system and against endothelial dysfunction (Zhou et al., 2015; Feng et al., 2013). Hyperlipidemia is an important risk factor for cardiovascular disease. After patients with hypercholesterolemia and without significant stenosis consumed 0.2 g/d of ethanolic extract of licorice root for 12 months, mean carotid intima-media thickness, total cholesterol, low-density lipoprotein levels, and blood pressure decreased (Fogelman et al., 2016). Dietary licorice flavonoid oil significantly decreases hepatic cholesterol and plasma lipoprotein cholesterol levels by suppressing hydroxymethylglutaryl-CoA synthase activity (Honda et al., 2013). Glycyrrhizin (50 mg/kg) could decrease the content of cholesterol and triglyceride in the plasma of fructose-induced metabolic syndrome-X rats, which could reduce the activities of enzymatic antioxidants (superoxide dismutase and catalase) and elevate oxidative stress markers in metabolic syndrome to almost normal levels (Sil et al., 2013).

Immunity Regulation and Antiinflammation Effects The immune system is an incredibly intricate network of specialized cells that prevents infections and diseases by engulfing, modulating, and moderating malignant and foreign cells. The human immune system is composed of organs such as the spleen and thymus; in addition, lymph nodes and bone marrow contribute by producing and storing specific immune cells (Chaouat et al., 2007). Immune cells are of two major types: B cells and T cells. B cells are responsible for producing antibodies (immunoglobulins), proteins

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designed to recognize and mark specific antigens, whereas T cells are moieties charged with destroying antigens tagged with an antibody (Chaouat et al., 2007; Zhang et al., 2007). T cells have a critical role in controlling adaptive immune functions; their responses could be used to develop protective vaccines. They may induce tolerance to antigens that cause inappropriate immune responses, such as autoimmune diseases (Cooper and Alder, 2006; Li et al., 2007). In addition, phagocytes such as granulocytes, macrophages, and natural killer (NK) cells release pyrogens and interferon (IFN), which act as immunoregulatory moieties (Currier and Miller, 2002; Fauci et al., 2005). Cytokines are also effective in regulating immune responses. Other mediators such as TNF-a, IL, chemokines, and IFN also contribute to the proper functioning of the immune system (Timar et al., 2007). Licorice enhances the immune function and potentially increases mucosal immunity and antiinflammation effects in the peripheral tissues of pigs (Katayama et al., 2011). Meanwhile, licorice and roasted licorice reduce clinical arthritis scores, paw swelling, and histopathological changes on tissue plasminogen activatoreinduced acute inflammation and collageninduced arthritis in mice (Kim et al., 2010). Therefore, licorice holds immunoregulatory as well as antiinflammatory activities that are mainly attributed to its bioactive constituents, such as GA, glycyrol, and isoliquiritigenin (ILG). In this context, we focus on GA and its molecular mechanisms in regulating immunity as well as its antiinflammatory effects. GA and glycyrrhetinic acid are well-characterized components of licorice. GA generates glycyrrhetinic acid through metabolic processes in the human body. Therefore, the pharmacological effects of GA are essentially the same as those of glycyrrhetinic acid. GA, also called glycyrrhizin, is a triterpene glycoside from licorice root (G. glabra) and consists of one molecule of 18b-GA and two molecules of glucuronic acid (Matsui et al., 2004). Several immunomodulatory activities have been attributed to glycyrrhizin and GA. The reduction in cellular immunocompetence in gamma-irradiated mice can be recovered through treatment with glycyrrhizae and GA. These fractions are found to be effective in enhancing the leukocyte count and blastogenic responses of splenocytes to mitogens (Dorhoi et al., 2006). Glycyrrhizin selectively activates extrathymic T cells in the liver and in human T-cell lines (Kimura et al., 1992). GA is an inducer of type 2 antagonistic CD41 T cells in in vivo and in vitro studies (Kobayashi et al., 1993). In addition, it stimulates macrophage-derived NO production and upregulates inducible nitric oxide synthase expression through NF-kB transactivation in murine macrophages (Jeong and Kim, 2002). Both of them induce IFN activity and augment NK cell activity; glycyrrhizin is superior to GA in inducing IFN (Abe et al., 1982). On the contrary, GA induces the expression of Tolllike receptor 4 and its downstream signaling molecules, which have an important role in modulating innate immune responses against pathogens (Peng et al., 2011). Several mechanisms have been suggested for the antiinflammatory effects of GA. GA inhibits glucocorticoid metabolism and potentiates their effects. This potentiation is reported in skin and lung after coadministration with GA (Teelucksingh et al., 1990). Because GA is a potent inhibitor of 11b-hydroxysteroid hydroxygenase (11b-HSD) (Walker and Edwards, 1991), it causes an accumulation of glucocorticoids with antiinflammatory properties. Oral administration of GA or glycyrrhizin confirms this result.

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Glycyrrhizin inhibits reactive oxygen species generation by neutrophils, which are the potent mediator of tissue inflammation in the in vitro study. One of its antiinflammatory effects results from this inhibitory effect (Akamatsu et al., 1991; Wang and Nixon, 2001). By inhibiting Kv1.3 channels, GA has antiinflammatory effects in human Jurkat T cells (Wang et al., 2013a). Glycyrrhizin has been shown to increase the activity of dendritic cells, enhance the proliferation of allogenic T cells along with production of IFN-gamma and IL-10, and reduce IL-4 production (Bordbar et al., 2012). In contrast, GA impairs the capacity of dendritic cells to proliferate and initiate the T helper-1 response in LPSstimulated mature dendritic cells. GA also suppresses the expression of surface molecules CD80, CD86, and major histocompatibility complex classes I and II, and reduces levels of IL-12 production (Kim et al., 2013). G. glabra and glyderinine, a derivative of GA, also shows an antiinflammatory effect (Tokiwa et al., 2004). It also reduces myocardial inflammatory edema in experimental myocardial damage (Zakirov et al., 1999). GA does not inhibit either cyclooxygenase 1e or 2ecatalyzed prostaglandin biosynthesis with an IC50 value of 425 mM in an in vitro study. However, in another study, G. radix was involved in cyclooxygenase (COX-2) inhibition. Furthermore, G. radix increases corticosterone levels in rats. Also, glycyrrhizin and glycyrrhetinic acid are known to inhibit phospholipase A2 (Kase et al., 1998). Some derivatives of GA have shown inhibitory activity against IL-1beinduced prostaglandin E2 production in normal human dermal fibroblasts (Tsukahara et al., 2005). Some scientific evidence supports the hypothesis that the immunostimulating activity of licorice depends on the proper metabolism and functioning of various important mediators in adaptive or acquired immunity. The claims mentioned in the earlier section suggested that G. glabra could act as an immunostimulating agent (Brush et al., 2006). However, the mechanisms underlying the antiinflammatory activity of glycyrrhizin are still poorly understood. Use of licorice has been gaining wide popularity in the United States as well as other parts of the world, but the mechanism of action has not been subjected to thorough scientific investigation. Licorice holds therapeutic potential in clinical therapy to prevent or cure certain health risks with the additional benefit of reducing the costs of prevention. Indeed, findings suggested that licorice and its bioactive metabolites are effective in aiding the balance and proper function of the immune system through various modules of immune modification such as stimulation and suppression. Thus, the current scenario demands formal scientific research to explore the mode of action of licorice. Nutritionists, physicians, and other health professionals can use such information effectively to treat various ailments in vulnerable segments. Overall, licorice can be used as an additional tool for disease prevention and risk management.

Antitumor Activities The use of plants’ natural products in cancer treatment has received attention owing to their potentially wide safety margin and the capacity to complement conventional

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chemotherapeutic drugs. Plant-based products have demonstrated anticancer potential through different biological pathways. The extract as well as active ingredients of licorice have antitumor roles through diverse mechanisms. This part will deal with the pharmacological effects of licorice and its bioactive components in different tumor treatments, both in vivo and in vitro.

Breast Cancer Breast cancer continues to cause high cancer death rates among women worldwide. Despite early detection and apparently complete surgical resection, many patients die of metastatic cancer that remains undetected at diagnosis. Identification of dietary bioactive compounds lacking in toxicity and capable of blocking more than one tumor process could be a good strategy to treat breast cancer. Licorice root extract possesses cytostatic properties by inducing cell cycle arrest and suppressing the expression of the aryl hydrocarbon receptor in tumorigenic effects of endocrine-disrupting chemicalestimulated human breast cancer cells (Chu et al., 2014). The ethanol extract of licorice root induces apoptosis and G1 cell cycle arrest in MCF-7 human breast cancer cells (Jo et al., 2005). On the other hand, several derivatives of licorice components have the antitumor effects, including LA (Park et al., 2014), licochalcone E (Kwon et al., 2013), formononetin (Zhou et al., 2014), glycyrrhetinic acid (Wang et al., 2015), and GA. Notably, ILG has been most common reported among them. ILG, a flavonoid phytoestrogen from licorice, inhibits the migration and invasion of MDA-MB-231 cells by preventing anoikis resistance (Zheng et al., 2014). Meanwhile, ILG induces growth inhibition and apoptosis by downregulating the arachidonic acid metabolic network and deactivating phosphatidylinositol 3-kinase (PI3K)/Akt in human breast cancer. Remarkably, ILG induced growth inhibition and apoptosis of MDA-MB231 human breast cancer xenografts in nude mice, together with decreased intratumoral levels of eicosanoids and phospho-Akt [Thr(308)] (Chu et al., 2013). Interestingly, ILG inhibited the receptor activator of NK-kB ligand (RANKL)eosteoprotegerin ratio and COX-2 expression in human osteoblast hFOB1.19 cells stimulated with conditioned medium of metastatic breast cancer MDA-MB-231 cells. Thus, ILG can be a beneficial agent to inhibit and treat breast cancer celleassociated bone diseases by blocking the interaction between cancer cells and bone cells, by inhibiting osteoblastic RANKL expression (Lee et al., 2015). Licorice and its bioactive compounds could be promising multitarget agents to prevent breast cancer; future clinical trials are needed to examine the effectiveness of licorice in preventing human breast cancer.

Hepatocellular Carcinoma Hepatocellular carcinoma (HCC), one of the most common cancers in the world, causes nearly 600,000 deaths annually. Patients who have HCC are often diagnosed at a late stage and die within 7e8 months after diagnosis (Llovet et al., 2003). For years, standard chemotherapy and radiotherapy for HCC patients have remained disappointing

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(Arii et al., 2000). Efforts have been made, but no satisfactory drugs have been manufactured. Novel therapeutic agents for curing HCC are still highly in demand. Licorice and its derivatives have been reported to possess anti-HCC effects. Licorice flavonoid oil has a significant inhibitory effect on HCC (Nakagawa et al., 2010). Glycyrrhizae polysaccharide not only blocks the PI3K/Akt signal pathway (Chen et al., 2013), it reduces the proportion of T-regulatory cells and upregulated T-helper (Th) 1eTh2 cytokine ratio in HCC-bearing mice, which might partially cause the inhibition of tumor growth (He et al., 2011). GA, a pentacyclic triterpenoid from the roots of licorice plant, is widely used in HCCtargeted drug delivery systems (TDDS) owing to its highly expressed target binding sites on HCC cells, and induces the content of CYP enzymes significantly (Paolini et al., 1999). GA triggers a protective autophagy in HCC cells by activating extracellular signale regulated kinase (ERK), which might attenuate the anticancer effects of GA or chemotherapeutic drugs loaded with GA-modified TDDS (Tang et al., 2014). Meanwhile, GA significantly inhibits proliferation of the human hepatoma cell line by modulating inflammatory markers and inducing apoptosis without affecting the normal liver cell line (Hasan et al., 2016). GA can also inhibit the metabolic activation of hepatotoxin so as to protect against chemical-induced carcinogenicity (Chan et al., 2003). In a diethylnitrosamine-treated experimental animal study, as a chemopreventive agent of HCC, modulation of cell proliferation and apoptosis by GA may be associated with inhibition of HCC. Therefore, GA treatment may inhibit the occurrence of HCC (Shiota et al., 1999).

Prostate Cancer Prostate cancer is the most frequently diagnosed noncutaneous malignancy and the second leading cancer-related cause of death in men; it is responsible for nearly 30,000 deaths each year in the United States. Prostate cancer was estimated to be responsible for 28% (186,320) of all newly diagnosed cancers in 2010. Primary stages of the disease can be treated with surgery, androgen ablation, radiation therapy, or all of these. Patients undergoing hormonal therapy eventually develop aggressive hormone-unresponsive disease. Hence, the major focus in prostate cancer research is the discovery of better chemotherapeutic agents for the advanced hormone-resistant, metastatic form of this disease (Jemal et al., 2010). LA, isoangustone A (IAA), and ILG from licorice extract have been shown to possess inhibitory effects against prostate cancer in vitro and/or in vivo. LA, a novel estrogenic flavonoid isolated from PC-SPES composition herb licorice root, causes G2 and late-G1 arrest in androgen-independent PC-3 prostate cancer cells (Fu et al., 2004). However, LA induces caspase-dependent and autophagy-related cell death in androgen-dependent LNCaP prostate cancer cells by suppressing B-cell lymphoma 2 expression and the mechanistic target of rapamycin (mTOR) pathway (Yo et al., 2009). In the treatment of DU145 prostate cancer cells, licoricidin reduces cell migration and the secretion of matrix metalloproteinase (MMP)-9, tissue inhibitor of metalloproteinase-1,

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urokinase-type plasminogen activator, and vascular endothelial growth factor, as well as the expression of adhesion molecules. These results indicate that licoricidin is a potent antimetastatic agent that can markedly inhibit the metastatic and invasive capacity of malignant prostate cancer cells (Park et al., 2010). IAA is an active compound from the hexaneeethanol extract of G. uralensis. The administration of IAA significantly attenuates the growth of prostate cancer cell cultures and xenograft tumors by inhibition CDK2 and mTOR (Lee et al., 2013a). In DU145 prostate cancer cells, IAA decreases DNA synthesis and induces G1 phase arrest, accompanied by a reduction of CDK2 and CDK4, as well as cyclin A and cyclin D1 (Seon et al., 2012). On the other hand, IAA increases apoptotic cells, the cleavage of poly(adenosine diphosphateribose) polymerase and caspases, and the levels of death receptor 4 and Mcl-1S (Seon et al., 2010). Thus, licorice-derived extracts with high IAA content warrant further clinical investigation for nutritional sources for prostate cancer patients. ILG, a simple chalcone-type flavonoid derived from licorice, shallots, and bean sprouts, is a potent antioxidant with antiinflammatory and anticarcinogenic effects. ILG selectively inhibits the proliferation of prostate cancer C4-2 cells, which may be attributed in part to defective adenosine monophosphateeactivated protein kinase and ERK signaling pathways in C4-2 compared with IEC-6 cells (Zhang et al., 2010). In DU145 human prostate cancer cells and MAT-LyLu rat prostate cancer cells, ILG reduces cell proliferation by inducing apoptosis, which is mediated through mitochondrial events, and cell cycle arrest via the inhibition of ErbB3 signaling and the PI3K/Akt pathway (Jung et al., 2006; Kanazawa et al., 2003; Lee et al., 2009b), and it inhibits cancer cell invasion and migration by decreasing the JNK/activating protein-1 signaling pathway (Kwon et al., 2009). Altogether, both licorice and its bioactive derivatives suppress the proliferation of carcinoma by inducing apoptosis and cell cycle arrest, as well as inhibiting metastatic and invasive capacity. Hence, licorice and its bioactive compounds are potent chemopreventive agents that are potentially considered for clinical intervention in human cancer.

Effect on Gastrointestinal Tract The hydroalcoholic extract of G. glabra L. (50e200 mg/kg) exerted an antiulcergenic effect in an HCl/ethanol-induced ulcer that might be associated with an increase in gastric mucosal defensive factors (Jalilzadeh-Amin et al., 2015). A methanol extract of licorice root (Fm100) is the active antiulcer extract of licorice; it can completely inhibit the formation of gastric ulcer induced by the ligation of gastric ulcer in rats and decrease endogenous gastric acid secretion induced by acetylcholine and histamine (Ishii and Fujii, 1982). Secretin might work as a potential mediator of antiulcer actions of licorice because of its mucosal protective agents (Takeuchi et al., 1991). Licorice has antispasmodic effect on gastric smooth muscle. The total flavonoids have a significant spasmolytic effect on intestinal spasm induced by acetylcholine, histamine, and barium chloride. Six active constituents in licorice (GA, ILG, liquiritinapioside,

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liquiritigenin, isoliquiritin apioside, and glycycoumarin, 20 mmol/kg, intravenously) resulted in rapidly and significantly inhibited tetanic contractions (Lee et al., 2013b). Among these active ingredients from licorice, liquiritigenin proved to be strongest in antispasmodic effect (Nagai et al., 2006). Studies suggest that licorice may be a mild inhibitor of P-glycoprotein in intestinal mucosa (Yao et al., 2009).

Effect on Endocrine System Licorice and its active ingredients possess regulatory effects on the endocrine system, including potentiating the action of glucocorticoid cortisol, exerting estrogenic activity, and reducing testosterone synthesis. Among the compounds derived from licorice, glycyrrhizin, glycyrrhetinic acid, and carbenoxolone have inhibitory effects on 11b-HSD type 1 (11b-HSD1) and 2 (11b-HSD2), which catalyze the interconversion between active cortisol and insert cortisone. Glycyrrhetinic acid is approximately 200 times more potent than GA at inhibiting 11b-HSD1 (Makino, 2014). Carbenoxolone inhibits 11b-HSD1 activity in a concentration-dependent manner with an IC50 of 5 mM. Glycyrrhizin and glycyrrhizic acid also have potent inhibitory effects against 11b-HSD2 (dissociation constant of approximately 5e10 nM) to lower cortisol-induced mineralocorticoid activity and support hypothalamicepituitaryeadrenal axis function (Asl and Hosseinzadeh, 2008). This action of licorice provides therapeutic benefits for adrenal insufficiency, Addison disease, and postural hypotension treatment (Ferrari, 2010). However, inhibition of 11b-HSD2 activity by licorice overconsumption is generally detrimental to health owing to mineralocorticoid excess including hypokalemia, hypertension, and pseudohyperaldosteronism. In 2003, the Scientific Committee on Food recommended an upper limit of 100 mg/d for glycyrrhizin. Licorice and its extracts are widely available as dietary phytoestrogens for menopausal women as a natural alternative to hormone replacement therapy to relieve menopausal symptoms. Liquiritigenin, ILG, glabridin, calycoricone, methoxychalcone, vestitol, glyasperin C, glycycoumarin, and glicoricone have low binding affinity for estrogen receptors (ERs). Liquiritigenin and ILG have similar affinities to ER with IC50 values of 7.5 and 7.8 M, respectively, in competitive radiometric binding assays. ILG binds to ER with an IC50 value of 16 M, whereas liquiritigenin has weak affinity for ER (200 M) (Omar et al., 2012). However, a study reported that liquiritigenin, ILG, and 7 other components derived from licorice bind with approximately equal affinity to ERa and ERb, except for liquiritigenin and glyasperin C, which have more than 10 times preference for ERb. Liquiritigenin (10 6 M), ILG (10 6 M), methoxychalcone (3  10 6 M), and vestitol (3  10 6 M) stimulated MCF-7 cell proliferation. The highest level of proliferation induced by liquiritigenin and methoxychalcone was similar to that induced by E2 (10 10 M). Liquiritigenin, ILG, calycoricone, methoxychalcone, vestitol, and glycycoumarin also activated estrogen target gene expression including the progesterone receptor and GREB1 in cultured MCF-7 breast cancer cells. The stimulatory effect of licorice components is completely inhibited by cotreatment with antiestrogen reagent ICI182,78 (Hajirahimkhan et al., 2013).

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Licorice is used as a plant-derived antiandrogen to improve idiopathic hirsutism and polycystic ovary syndrome (Boonmuen et al., 2016). Licorice containing 0.5 g GA decreases serum testosterone and increases 17-hydroxyprogesterone by inhibiting 1720-lyase and 17-hydroxysteroid dehydrogenase activity after 4 and 7 days of administration in males (Faghihi et al., 2015). On the other hand, studies suggest that salivary testosterone and dehydroepiandrosterone increased after consuming licorice confectionery (3% licorice extract) for 7 days in male and female volunteers (Armanini et al., 1999). These findings lend support to the reasonable use of licorice as a promising strategy to treat hormone-dependent diseases.

Side Effects and Cautions In large amounts, licorice, which contains glycyrrhizin, might cause high blood pressure, salt and water retention, and low potassium levels, which could lead to heart problems. Thus people with heart disease or high blood pressure should be cautious about licorice. According to the Chinese Pharmacopeia, licorice is contraindicated in combination with Sargassum (Hai Zao), Herba Cirsii Japonici (Da Ji), Euphorbia kansui (Gan Sui), and Flos genkwa (Yuan Hua), which might attenuate liver function and cause cardiac toxicity (Wang et al., 2013b). It has been reported that licorice could alter enzyme activities of P450 isoforms and modulate drug transporter proteins such as P-glycoprotein, which leads to potential herbedrug interactions of licorice that are of concern. According to the US National Center for Complementary and Integrative Health (NCCIH), the recommended daily dose of licorice root is 5e15 g, equivalent to 200e600 mg of glycyrrhizin (https://nccih.nih.gov/health/liquoriceroot). In the Chinese Pharmacopeia (2015), the recommended dose of licorice is 2e10 g. Both the NCCIH and the European Medicines Agency report that the safety of using licorice as a dietary supplement for more than 4e6 weeks has not been thoroughly studied. Side effects from overdose or prolonged use (more than 4 weeks) might lead to symptoms such as water retention, hypokalemia, hypertension, or cardiac rhythm disorders.

Conclusion and Perspective Licorice is widely cultivated throughout Europe, the Middle East, and Asia. The major constituent of licorice, glycyrrhizin (also known as GA or glycyrrhizinic acid), is about 50 times sweeter than sucrose (common sugar). In Western countries, licorice is mainly used in nonmedicinal forms such as soft drinks, herbal teas, and tobacco products (Tobacco Documents Online http://tobaccodocuments.org/profiles/licorice.html). The medicinal potential of licorice needs further investigation and recognition in Western countries. Licorice has been extensively used by Chinese people to relieve and prevent cough, phlegm, dyspnea, spasms, and pain. It also relieves spasms of the smooth (involuntary) muscles and exhibits a cortisone-like action. In Ayurvedic medicine, licorice has a long

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history as a common remedy because of its expectorant, antiinflammatory, and laxative properties. In Chinese medicine, licorice is often combined with other herbs in many herbal formulas by harmonizing the characteristics of other herbs, alleviating the toxicity of herbs, and modulating the taste of herbs because of its sweet flavor. Licorice is also recorded as “National Venerable Master,” which has paradoxical roles, i.e., detoxifying/ strengthening efficacy and inducing/enhancing toxicity. When licorice is used in combination with some toxic herbs such as Radix aconiti lateralis praeparata (Fu zi), Rhizoma pinelliae (Ban xia), and Cinnabaris (Zhu sha), the toxicity of these herbs might be attenuated by licorice (Guo et al., 2014). Licorice roots, extracts, active ingredients such as glycyrrhetic acid, flavonoids and isoflavonoids, and also some prescriptions showed efficiency in regulating respiratory function, hepatoprotection, immunoregulation, antiinflammation, antineoplastic action, and gastroenteric protection. Based on this aspect, licorice could be considered the most important herb and the focus of research in herbal medicine. Further synergistic or antagonistic studies of licorice are needed for evaluation and validation based on both preclinical trials and clinical observation.

Abbreviations 11b-HSD 11b-Hydroxysteroid dehydrogenase ALT Alanine aminotransferase AST Aspartate transaminase COPD Chronic obstructive pulmonary disease ERs Estrogen receptors GA Glycyrrhizic acid HCC Hepatocellular carcinoma IAA Isoangustone A IFN Interferon IL Interleukin ILG Isoliquiritigenin LA Licochalcone A LPS Lipopolysaccharide NF-kB Nuclear factor kB POST Postoperative sore throat SNMC Stronger neominophagen TDDS Targeted drug delivery systems TGF Transforming growth factor TNF-a Tumor necrosis factor-a

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Chapter 14  Glycyrrhiza glabra (Licorice): Ethnobotany and Health Benefits

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