key: cord-0034830-ru8ofk3p
authors: Öztürk, Münir; Altay, Volkan; Hakeem, Khalid Rehman; Akçiçek, Eren
title: Pharmacological Activities and Phytochemical Constituents
date: 2018-03-20
journal: Liquorice
DOI: 10.1007/978-3-319-74240-3_7
sha: ee36e061045830e3ec066358ac8611dff8271b78
doc_id: 34830
cord_uid: ru8ofk3p

Glycyrrhiza glabra is one of the most popular medicinal plants and it has been used in traditional herbal remedy since ancient times (Blumenthal et al. in Herbal medicine: expanded commission E monographs. Integrative Medicine Communications, Newton, 2000; Parvaiz et al. in Global J Pharmocol 8(1):8–13, 2014; Altay et al. in J Plant Res 129(6):1021–1032, 2016). Many experimental, pharmacological and clinical studies show that liquorice has antimicrobial, antibacterial, antiviral, antifungal, antihepatotoxic, antioxidant, antiulcer, anti-hemorrhoid antihyperglycemic, antidiuretic, antinephritic, anticarcinogenic, antimutagenic, anticytotoxic, anti-inflammatory, and blood stopper activity.

More than 300 flavanoids have been isolated from Glycyrrhiza species and they are responsible for its yellow color. Especially, G. glabra has yellow color due to the flavonoids like liquiritin, isoliquiritin (Yamamura et al. 1992) . The flavanones and chalcones are the main types among these (Herz et al. 1998; Li et al. 2000; Zhang and Ye 2009) . A number of flavonoids have been identified in these roots such as liquiritin, liquiritigenin, rhamnolliuiritin, liquiritin apioside, gralbranin, glabrol, licoflavanone, isoliquiritigenin, neoisoliquiritin, licuraside, licochalcone A and B, licoricidin, 7-methillicoricidin, hispaglabridin A and B, liocflavone A and B, liocflavanol, glyzaglabrin, licoisoflavanone, glabroisoflavanone, glabrone, licoricone, gancaonin (Lou and Qin 1995; Xing et al. 2003; Williamson 2003; Zhang and Ye 2009 ). 5,8-Dihydroxyflavone-7-O-b-d-glucuronide, glychionide A, and 5-hydroxy-8-methoxyl-flvone-7-O-b-d-glucuronide, glychionide B have been isolated from the roots of G. glabra . The glabridin, galbrene, glabrone, shinpterocarpin, licoisoflavones A and B, formononetin, glyzarin, and kumatakenin isoflavonoid derivatives too are present in liquorice (Williamson 2003) . Also, hispaglabridin A and B, 4′O-methylglabridin and 3′-hydroxy-, 4′-O-methylglabridin (De Simone et al. 2001; Haraguchi 2001) , and glabroisoflavanone A and B (Kinoshita et al. 2005) have been found in the liquorice roots.

The flavonoid glycosides have been isolated with feruloyl or coumaroyl groups and with indole conjugates (Hatano et al. 1998) . Similarly, bioactive flavonoid compounds, liquiritigenin and isoliquiritigenin, have been isolated and identified from the crude extract of G. uralensis by Ma et al. (2005) . Franceschelli et al. (2011) have identified the licocalchone C, the structural isomer of licocalchone A. Other flavonoids like licoagrodin, licoagrochalcones, glyinflanin B, and glycyrdione A have also been reported Hosseinzadeh 2008, 2012; Christensen and Kharazmi 2001; Li et al. 2000) . The glabridin and hispaglabridin B have been identified by Gupta et al. (2008) from the ethanolic extract of the roots of G. glabra. The bioactive compounds glepidotin B and glepidotin A have been isolated and identified from the extract of Glycyrrhiza lepidota by Manfredi et al. (2001) , whereas isoflavonoid derivatives such as glabridin, galbrene, glabrone, shinpterocarpin, licoisoflavones A and B, formononetin, glyzarin, kumatakenin have been isolated and identified in 2003 by Williamson. In 2001, other researchers De Simone et al. have reported hispaglabridin A, hispaglabridin B, 4′-O-methylglabridin, and 3′-hydroxy-4′-O-methylglabridin from Glycyrrhiza species. The licochalcone A has been isolated and identified from the ethyl acetate extract of the roots of G. uralensis (Won et al. 2007) . Kinoshita et al. (2005) have studied G. glabra, and they identified several compounds from its roots such as glabridin, galbrene, glabrone, shinpterocarpin, licoisoflavones A and B, formononetin, glyzarin, kumatakenin, hispaglabridin A, hispaglabridin B, glabroisoflavanone A, and B glabroiso-flavanone B.

In the 1990s, Fenwick and his co-workers have described two aglycone forms of glycyrrhizic acid, 18b-glycyrrhetinic acid and 18a-glycyrrhetinic acid. The anti-inflammatory and antiarthritic activity in animal studies too have been followed and attributed to the glycyrrhetic acid (Amirova 1993) . A speedy healing of gastric ulcers is attributed to the presence of glycyrrhizin and the aglycone of glycyrrhizin in the liquorice (Amirova 1993; Blumenthal et al. 2000) . Glycyrrhiza roots are reported to contain triterpenoid saponins (glycyrrhizin, glycyrrhizic acid). These are the major characteristic constituents of liquorice responsible for the sweet taste (Blumenthal et al. 2000) . The major triterpenoid saponin in the root of this plant is glycyrrhizic acid. Latter is the main sweetener in this plant, nearly 50 times sweeter than sugar (Nomura et al. 2002) . Other triterpenes too have been reported namely liquiritic acid, glycyrretol, glabrolide, isoglaborlide, and licorice acid (Isbrucker and Burdock 2006) . The described several saponins have been reported by Zhang and Ye (2009) from Glycyrrhiza species namely, licorice-saponin A3, 22b-actoxylglycyrhhizin, uralsaponin B, apioglycyrrhizin, araboglycyrrhizin, and icorice-saponin E2. In 2013, Vashist and Sharma have published data mentioning about the presence of ammonium glycyrrhizinate (3.4%) and calcium glycyrrhizinate (4%) in the ethanolic extract of G. glabra. Nomura and Fukai (1998) have published several reports on the phenolic constituents of Glycyrrhiza species. The main phenols include liquiritin, isoliquiritin, liquiritin apioside, and isoprenoid-substituted flavonoids, chromenes, coumarins, dihydrostilbenes. For example, isobavachin has been reported from Glycyrrhiza pallidiflora, sigmoidin B in G. uralensis, liquiritigenin in some Glycyrrhiza species by the same workers. Nomura et al. (2002) have investigated several Glycyrrhiza species from the point of view of phenolic compounds. They have found isoprenoid-substituted flavonoid (pyranoisoflavan, glabridin) (G. glabra), isoflavans (G. uralensis), licochalcone A (G. inflata, Glycyrrhiza eurycarpa), licoricidin (6), and licorisoflavan A (Glycyrrhiza aspera). Similar observations have been reported in 2003 by Williamson. Latter identified liquiritin, liquiritigenin, rhamnoliquiritin, neoliquiritin, chalcones isoliquiritin, isoliquiritigenin, neoisoliquiritin, licuraside, glabrolide, and licoflavonol. In 2008, Zhu et al. worked on the biologically active compounds of G. uralensis collected from Mongolia. They have reported 3 flavanone constituents (liquiritin apioside, liquiritin, and liquiritigenin) and 3 chalcones (isoliquiritin apioside, isoliquiritin, and isoliquiritigenin). In 2009, Zhang and Ye described several phenolic compounds derived from Glycyrrhiza species including glycycoumarin, glabrocoumarin, glycyrin, inflacoumarin A, licopyranocoumarin, isoglycerol, neoglycerol, licobenzofuran, licocoumarone, glabrocoumarone, gancaonin, and kanzonol. Isolation and identification of isoliquiritigenin from Chinese liquorice have been carried out by Chin et al. (2007) and liquiritin by Huang et al. (2010) .

In a study by Ammar et al. (2012) , the researchers have isolated phenolic compounds namely liquiriteginin, liquiritin apioside, neoliquiritin apioside, isoliquiritin, isoliquritin apioside, licuraside2-(5-P-coumaryl apiosyl), and isoliquiritin from the total polar extract of G. glabra utilizing different chromatographic techniques.

In an attempt to discover bioactive agents in G. glabra, 11 new phenolic compounds, glycybridins A-K, along with 47 known phenolics have been isolated by . They have conducted enzyme or cell-based bioactivity screenings of 1-58 according to the clinical therapeutic effects of liquorice. A number of compounds have been reported to significantly activate Nrf2, inhibit tyrosinase or PTP1B, inhibit lipopolysaccharide-induced NO production and NF-jB transcription, and inhibit the proliferation of human cancer cells (HepG2, SW480, A549, and MCF7). Glycybridin D has shown moderate cytotoxic activities against the four cancer cell lines, with IC50 values ranging from 4.6 to 6.6 lM ). Further studies have indicated that Glycybridin D (10 mg/kg) decreases tumor mass by 39.7% on an A549 human lung carcinoma xenograft mice model with little toxicity ). These workers have carried out studies to discover bioactive natural products from one botanical source of G. inflata. A total of 67 free phenolics have been isolated to form a compound library. Based on the licorice bioactivity, these compounds have been subjected to screening using cell-or enzyme-based bioassay methods. A total of 11 compounds have exhibited potent cytotoxic activities against 3 human cancer cell lines (HepG2, SW480, and MCF7), but have shown little toxicity on human normal cell lines LO2 and HEK293T. A number of chalcones have been observed to show remarkable anti-inflammatory activities. Out of these, licochalcone B, IC50 8.78 µM, licoagrochalcone C, IC50 9.35 µM, and licochalcone E, IC50 9.09 µM have exhibited the most potent inhibitory activities on lipopolysaccharide-induced NO production, whereas IC50 13.9, 7.27, 2.44, 6.67, and 3.83 µM have shown potent inhibitory activities on NF-KB transcription. Nine prenylated phenolics have been found to be PTP1B inhibitors. Particularly, licoagrochalcone A, kanzonol C, 2′hydroxyisolupalbigenin, gancaonin Q, glisoflavanone, and glabrol with IC50 values of 0.31-0.97 µM. Compounds semilicoisoflavone B, IC50 0.25 µM, allolicoisoflavone B, IC50 0.80 µM, and glabridin, IC50 0.10 µM have shown noticeable tyrosinase inhibitory activities ). Most of the above bioactive compounds have been reported for the first time by these workers.

The most important other constituents are coumarins including liqcoumarin, glabrocoumarone A and B, herniarin, umbelliferone, glycyrin, glycocoumarin, licofuranocoumarin, licopyranocoumarin, and glabrocoumarin. All are present in G. glabra (De Simone et al. 2001; Haraguchi 2001; Williamson 2003; Kinoshita et al. 2005) . Also, four dihydrostilbenes-dihydro-3,5-dihydroxy-4′-acetoxy-5′-isopentenylstilbene, dihydro-3,3′,4′-trihydroxy-5-O-isopentenyl-6-isopentenylstilbene, dihydro-3,5,3′-trihydroxy-4′-thoxystilbene, and dihydro-3,3′-dihydroxy-5b-d-Oglucopyranosyloxy-4′-methoxystilbene-have been isolated from the leaves of G. glabra grown in Sicily (Biondi et al. 2005) .

In 2014 Qiao and co-workers have identified glycerol, glycycoumarin, dehydroglyasperin in the root extract of G. uralensis. Two coumarins of G. glabra, glycocoumarin and licopyranocoumarin, have also been described by De Simone et al. (2001) , these are able to inhibit giant cell formation in HIV-infected cell cultures.

Nearly 3 decades ago, Frattini et al. (1977) reported 63 compounds never found before in heated liquorice essential oil. They used GLC, GLC-MS coupling, and IR spectrometry. In the same year, Frattini et al. (1977) found many heated liquorice compounds, the furan derivatives. The reason given for this is pyrolysis and condensation reactions which occur during heating, when sugars in liquorice roots are very rich. Acetol, propionic acid, 2-acetylpyrrole, Z-acetylfuran, and furfuryl alcohol are the most abundant components. None of the identified compounds alone are responsible for the flavor in liquorice. On the other hand, total extract shows a typical liquorice aroma, possibly due to an integrated response to the proper mixture of the proper volatiles, rather than to the odor of one or two components (Frattini et al. 1977) .

In 2006, Näf and Jaquier have studied the lactonic fraction of a commercial liquorice root extract (G. glabra), exhibiting a pleasant sweet, woody, dried fruit-like odor, containing mainly fatty acids (C2-C16) and phenols (phenol, guaiacol), together with common saturated linear c-lactones (C6-C14) and, in trace amounts, a series of new 4-methyl-c-lactones and 4-ethyl-c-lactones. Other compounds such as asparagines, glucose, sucrose, starch, polysaccharides (arabinogalactants), and sterol (b-sitosterol, dihydrostigmasterol) have also been reported (Hayashi et al. 1998; Blumenthal et al. 2000) . Other secondary metabolites have also been reported such as fatty acids, phenol, guaiacol, asparagines, glucose, sucrose, starch, polysaccharides, and sterols (b-sitosterol, dihydrostigmasterol) (Näf and Jaquier 2006) .

In Turkey, the essential oil from aerial parts and roots of Glycyrrhiza taxa has been analyzed by gas chromatography and mass spectroscopy (GC-MS) systems by Çakmak (2011) . The major components identified by him are listed as follows: hexanal, b-vii pinene, furan-2-pentyl, benzaldehyde, 4-terpineol, 1-pentylcyclobutene, acetophenone, a-caryophyllen, naphtalene, 1-phenyl-1H-pyrazol-3-amine, m-cresol, nerolidol, hexahydro farnesyl acetone, E-neryl linalool, 1-tetracosanol, p-hexylacetophenone, phytol, 4-pyridinecarbonitrile, dimethylamine, and n-hexadecanoic acid. Fatty acid profiles of these taxa have also been examined by GC-FID and 22 fatty acids are reported, palmitic, linoleic, and linolenic acid being the main components (Çakmak 2011) .

Farag and Wessjohann (2012) have undertaken investigations to provide insight into Glycyrrhiza species aroma composition and for its use in food and pharmaceutical industry. They profiled volatile constituents from G. glabra, G. inflata, and G. echinata roots using steam distillation and solid-phase microextraction. Two phenols, thymol and carvacrol, have been found exclusively in essential oil and headspace samples of G. glabra, and with highest amounts of samples that originated from Egypt. In G. echinata oil, (2E, 4E)-decadienal (21%) and b-caryophyllene oxide (24%) have been reported as the main constituents, whereas 1a, 10a-epoxyamorpha-4-ene (13%), and b-dihydroionone (8%) have predominated G. inflata (Farag and Wessjohann 2012). Moreover, Farag and Wessjohann (2012) have also reported that principal component and hierarchical cluster analyses have clearly separated G. echinata and G. inflata from G. glabra, with phenolics and aliphatic aldehydes contributing mostly for species segregation.

The essential oil composition of G. glabra has been investigated by Ali (2013) . He has reported compounds such as a-pinene, b-pinene, octanol, c-terpinene, stragole, isofenchon, b-caryophyllene, citronellyl acetate, caryophyllene oxide, and geranyl hexanolate. Out of these, geranyl hexanolate represents the higher percentage (34%) whereas b-pinene the lowest (1.7%). The phytoestrogens have been investigated in the roots of G. glabra from Syria by Khalaf et al. (2010) . They have identified daidzein, daidzin, genistin, ononin, glycitein, genistein, and coumestrol, whereas dihydrostilbenes from the root extract of G. glabra grown in Sicily has been reported by Sultana et al. (2010) . Wagner et al. (2016) have studied the application of the molecular sensory science concept including aroma extract dilution analysis (AEDA) on the basis of gas chromatography-olfactometry combined with gas chromatography-mass spectrometry. They elucidated the key odorants of raw liquorice (G. glabra) and found 50 aroma-active compounds via AEDA; 16 of these have been identified in raw liquorice for the first time. c-Nonalactone, 4-hydroxy-2,5-dimethylfuran-3(2H)one, and 4-hydroxy-3-methoxybenzaldehyde have shown the highest flavor dilution (FD) factor of 1024. Nearly, 43 compounds have been quantified using stable isotope dilution analysis (SIDA); 6 more compounds have been quantified using labeled standards and odor activity values (OAVs), which is the ratio of concentration to the respective odor threshold. OAVs have been calculated revealing OAVs 1 for 39 compounds. The highest OAVs were shown by (E,Z)-2,6-nonadienal, 5-isopropyl-2-methylphenol, hexanal, and linalool (Wagner et al. 2016 ). On the basis of the data obtained by these workers, an aqueous reconstitution model has been prepared by mixing the 39 odorants in their naturally occurring concentrations. The recombinate has elicited an aroma profile very similar to the profile of raw liquorice, proving that all key aroma compounds have been correctly identified and quantified (Wagner et al. 2016) . Ata et al. (2017) have studied the ion-pair extraction combined with liquid chromatography-tandem mass spectrometry method. They have proposed the determination of biogenic amines in liquorice samples (G. glabra). Their evaluations have revealed that limit of detection and limit of quantitation for the biogenic amines are 1.4-2.7 and 4.7-9.1 ng mL −1 , respectively. Relative standard deviations based on 5 replicate extractions of 100 ng mL −1 of each biogenic amine were <4.7% for intra-day and 7.4% for inter-day precision. The method described by Ata et al. (2017) has been in accordance with the satisfactory accuracy and good reproducibility for the quantitative determination of biogenic amines in liquorice samples. Nine biogenic amines (putrescine, cadaverine, histamine, spermine, spermidine, tyramine, tryptamine, agmatine, and phenylethylamine) have been detected in liquorice samples and total biogenic amine concentrations have been determined at 369 ng mL −1 in fresh and 3532 ng mL −1 in non-fresh samples. Putrescine has been found at the highest concentrations-up to 704 ng mL −1 in all the analyzed samples, followed by tyramine (675 ng mL −1 ) and tryptamine (282 ng mL −1 ). Putrescine, tyramine, and spermine concentrations have dramatically increased, whereas agmatine concentration has significantly decreased, in non-fresh liquorice samples compared to fresh ones (Ata et al. 2017) . Moreover, they have reported that the consumption of freshly prepared liquorice is recommended because of the relatively low concentration of total biogenic amines. Ye et al. (2017) have examined the bioactive constituents of G. uralensis leaves. Seven chemical components have been isolated by repeat column chromatography and using spectroscopic methods. Their structures have been determined to be a novel prenylated dihydrostilbene, a,a′-dihydro-3,5,3′,4′-tetrahydroxy-2,5′-diprenylstilbene, a methylated flavonoid, quercetin-3-Me ether, and 5 prenylated flavonoids: 5′-prenylquercetin, 8-[(E)-3-hydroxymethyl-2-butenyl]eriodictyol, 6-prenyleriodictyol, 5′prenyleriodictyol, and 6-prenylquercetin-3-Me ether. These compounds show strong radical scavenging activity toward DPPH, and most of them have demonstrated greater inhibitory activity against a-glucosidase than their unprenylated counterparts .

Liquorice is not used only in food, tobacco, and cosmetics, and it has great value in medicine, because this herb is accepted as a herbal remedy for many disorders (Kao et al. 2014 ). Some of its traditional uses like diabetes, cough, wound treatment, and tuberculosis have been discussed by Asl and Hosseinzadeh (2008) . It is also well known as one of the most frequently used herbs in China, as it has been in use in their traditional medicine for centuries. This herb is commonly used in herbal formulas to harmonize other ingredients and applied under 12 regular meridians in Chinese traditional medicine. As per the compendium of Materia Medica (Bencao Gangmu) liquorice acts as an effective antidote, a detoxicant, a beneficial agent in the development of bone and muscle, and a remedy for throat disorders and cough (Li 2003) . It is also included in many traditional Chinese medicine formulas for treating liver disease. Similarly, in Japan sho-saiko-to (TJ-9) is used for liver disorders (e.g., chronic active hepatitis), (Hirayama et al. 1989 ). This formula is said to have come from Xiao Chai Hu Tang (Minor Bupleurum Formula) in Shang Han Lun of TCM (Chang 1981) .

Recent investigations depict that in traditional Chinese medicine uses of licorice vary much (Kao et al. 2014) . A mixture of Ephedra, Cassia twig, bitter apricot kernel, and liquorice, known as Ma Huang Tang--a classic Chinese Formula has recently been confirmed to be effective in the treatment of pulmonary disorders like bronchial asthma, acute bronchitis, colds, and influenza. Direct effects of the bitter apricot kernel and liquorice are mentioned to be nonsignificant but, the two drugs have a significant synergetic effect when administered with Ephedra or Cassia twigs ). This clearly shows that liquorice has ability to harmonize with the other ingredients in the formula. Liquorice gargles are reported to be highly effective in the incidence and severity of postoperative sore throat (Agarwal et al. 2009 ). This confirms the findings for its use in traditional Chinese medicine. Some liquorice healing effects in the traditional Chinese medicine is fully confirmed by modern medicine. However, we still need to enlighten the fact which compound(s) in this herb mediate these effects (Kao et al. 2014).

The sweetness of liquorice comes from glycyrrhizic acid or glycyrrhizin, a triterpenoid saponin glycoside; 30-50 times sweeter than sucrose. It induces impulses from sugar receptor-containing cells at a concentration (3.0 mM), much lower than sucrose (Ahamed et al. 2001; Kao et al. 2014) . Glycyrrhizin maintains its sweetness after heating as against the sugar substitute aspartame. Although sugar and glycyrrhizic acid taste sweet, but glycyrrhizic acid induces a lower onset sweet flavor than sugar. Its sweetness remains in the mouth for a longer time (Kao et al. 2014) . Another triterpenoid in liquorice is glycyrrhetinic acid (18a-glycyrrhetinic acid and 18b-glycyrrhetinic acid) obtained from the hydrolysis of glycyrrhizic acid. Presystemic metabolism by intestinal bacteria performing glycolysis can complete this process (Ploeger et al. 2001) . The glycyrrhizic acid is metabolized by human intestinal bacteria through the action of the glucuronidases of Bacteroides J-37 and Eubacterium sp. to yield 18b-glycyrrhetinic acid (18bGA) (Kim et al. 1999 ). In the Chinese Materia Medica, dry-roasting or honey-roasting are the two processes used to obtain liquorice preparation which accelerates the hydrolysis of the sugar chains in the saponin and glycosidic flavonoid constituents (Sung and Li 2004; Kuwajima et al. 1999 ). Both raw liquorice as well as liquorice preparata are important agents in traditional Chinese medicine, each having different function. Anti-inflammatory activities and neuroprotective effects of roasted form is said to be more potent than raw one, which goes against the characteristics described by traditional Chinese medicine (Hwang et al. 2006; Kim et al. 2010) . As per "Bencao Gangmu" raw form can be used to treat the syndrome known as inflammation in modern medicine (Xie Huo in Chinese) , and roasted form for reinforcement (Bu Zhong in Chinese) (Li 2003) . The roasted form is used in Buzhong Yiqi Tang instead of raw, suggesting that glycyrrhizic acid and 18b-glycyrrhetinic acid may have distinct biological characteristics (Kao et al. 2014) .

This herb has also been used alone and as a component in many formulas to treat liver diseases. Multiple mechanisms have been proposed for the hepatoprotective effects of glycyrrhizic acid and 18b-glycyrrhetinic acid (Kao et al. 2014 ). The glycyrrhizic acid and 18b-glycyrrhetinic acid are reported to have an ability to protect hepatocytes from bile acid-induced cytotoxicity (Gumpricht et al. 2005) . A beneficial effect of glycyrrhizic acid on hepatitis has been demonstrated recently. The intravenous administration of glycyrrhizic acid is said to decrease serum alanine transaminase (ALT) and necro-inflammation and fibrosis in the liver (Manns et al. 2012) . The protective effects of glycyrrhizic acid and 18b-glycyrrhetinic acid are controlled by several mechanisms, which likely are involved in the reduced AST (aspartate transaminase, also called GOT) and ALT (also called GPT) activities. The glycyrrhizic acid can also modulate the pregnane X receptor (PXR), as well as cytochrome P450 family 3 subfamily A (CYP3A), to protect against lithocholic acid-induced injury ). The treatments with glycyrrhizic acid and 18b-glycyrrhetinic acid can inhibit liver fibrosis, which otherwise may lead to cancer (Moro et al. 2008; Kao et al. 2014 ). Both may be effective in the protection of other organs, as they have positive effects on brain damage induced by ischemia and 6-hydroxydopamine. A recent study has demonstrated that both of these can penetrate the blood-brain barrier (BBB) indicating that they are potent agents for the treatment of neural diseases, ischemic brain diseases, and Parkinson's disease (Kao et al. 2009 (Kao et al. , 2014 Tabuchi et al. 2012) . Glycyrrhizic acid also exhibits protective effects in the kidney. It has been demonstrated that it protects against cisplatin-induced genotoxicity and nephrotoxicity. The protective effects have also been observed with a renal hypoxia-reoxygenation model, however 18b-glycyrrhetinic acid does not exhibit the same potential (Yokozawa et al. 2000; Arjumand and Sultana 2011) . Glycyrrhizic acid seems to be effective against ischemic damage, including damage to the spinal cord, myocardium, liver, and gut (Yokozawa et al. 2000; Di Paola et al. 2009; Haleagrahara et al. 2011; Ogiku et al. 2011) .

Glycyrrhizic acid and 18b-glycyrrhetinic acid are considered inhibitors of inflammation induced by both bacterial and viral infection, as inflammation is frequently triggered by bacteria or viral infection, and antibacterial and antiviral activities are possible anti-inflammatory strategies. Former can inhibit the replica- (Takahara et al. 1994 ), hepatitis C virus (HCV) (Orlent et al. 2006) , herpesviridae (varicella zoster virus, VZV) (Baba and Shigeta 1987), herpes simplex virus 1 (HSV-1) (Lampi et al. 2001 ), Epstein-Barr virus (EBV) (Lin 2003) , cytomegalovirus (CMV) (Numazaki et al. 1994) , and influenza viruses, including H1N1 (Pompei et al. 1979 ) and H5N1 (Michaelis et al. 2011) . The glycyrrhizic acid also inhibits the growth of Helicobacter pylori, and thus can be used in the treatment of gastric ulcers, 18bGA has also been shown to be effective against clarithromycin-resistant strains of H. pylori (Chung 1998; Krausse et al. 2004) . Glycyrrhizic acid and 18b-glycyrrhetinic acid are also reported to modulate inflammation-related mechanisms. Traditional Chinese medicine often incorporates this herb to enhance the effect of other formulas that act as anti-inflammatory agents. Anti-inflammatory effect of liquorice extract is enhanced by glycyrrhizic acid without glycyrrhizic acid (Uto et al. 2012 ). Glycyrrhizic acid is reported to possess an ability to inhibit H5N1-induced proinflammatory gene expression without affecting the cytolytic activity of natural killer cells (Michaelis et al. 2011) . These findings depict that glycyrrhizic acid probably modulates inflammation by two regulatory methods namely, inhibition of proinflammatory cytokines and the promotion of immune function. In this regulation PI3K probably plays a role. The inflammation is very effectively modulated by glucocorticoids and the glucocorticoid receptor, latter is extensively used in clinical treatments (e.g., dexamethasone). Several potential mechanisms exist for the involvement of glycyrrhizic acid and 18b-glycyrrhetinic acid in the induction of cortisone activity. The two can activate glucocorticoid receptor (GR) signaling by binding to the GR and inhibit the activity of corticosteroid 11b-dehydrogenase isozyme 2 (11b-HSD2), which converts active cortisol into inactive cortisone (Whorwood et al. 1993; Kao et al. 2010; Ma et al. 2011 ). Both may also enhance GR signaling by eliminating intracellular oxidative stress (Kao et al. 2013) . No increase in the glucocorticoid-induced side effects is seen, although glycyrrhizic acid enhances glucocorticoid activity. Excessive glucocorticoid levels are reported to exert diverse effects on bone microstructure, integrity, and mineral metabolism (Iba et al. 1995) . It has been demonstrated that glycyrrhizic acid has the potential for use as an agent to protect the bones against glucocorticoid-induced osteoporosis (Ramli et al. 2013) . A nuclear component (high-mobility group box 1 (HMGB1) that functions extracellularly as a signaling molecule in acute and chronic inflammation has been reported to get inhibited by binding to glycyrrhizic acid (Mollica et al. 2007 ). According to Kao et al. (2013) , glycyrrhizic acid and 18b-glycyrrhetinic acid can modulate PI3K signaling to alleviate inflammation. All these results demostrate that glycyrrhizic acid and 18b-glycyrrhetinic acid possess considerable potential for development as novel inflammation-modulating agents (Kao et al. 2014) .

They can also affect the biological mechanism of cancer formation. Glycyrrhizic acid may inhibit angiogenesis by targeting ERK signaling, and can be protective against UV-B-induced carcinogenesis in the epidermis of SKH-1 hairless mice (Cherng et al. 2011; Kim et al. 2013) . GA also prevents hepatocarcinogenesis associated with hepatitis because it is effective against HCV-induced liver disorders (Ikeda et al. 2006; Ikeda 2007) . AS compared to GA glycyrrhetinic acid has a more potent anticarcinogenesis effect. According to Lee et al. (2008) , 18b-glycyrrhetinic acid not only induces apoptotic cell death but also exhibits a synergistic toxic effect with antibiotics and anticancer drugs like camptothecin, mitomycin c, and doxorubicin. The report published by Farina et al. (1998) reports that glycyrrhetinic acid, oleanolic acid, and ursolic acid have similar chemical structures and potent antiulcer activities. A satisfactory anticarcinogenesis outcome is found in the compounds whose chemical structures are similar to that of glycyrrhetinic acid (Csuk et al. 2011) . The glycyrrhetinic acid and its derivatives are highly effective in the treatment of many cancer cells as they are sensitive to treatment, including human epithelial ovarian carcinoma cell lines OVCAR-3 and SK-OV-3 Yang et al. 2012) , the human prostate cancer cell lines DU145 (Shetty et al. 2011; Szpak et al. 2011 ) and PC3, the human breast cancer cell line MCF7 (Sharma et al. 2012; Zhao et al. 2012) , the human bladder cancer cell line NTUB1 , the human leukemia cell line HL60 , the human erythromyeloblastoid leukemia cell line K562 , the human colon cancer cell lines RKO and SW480 ), the pancreatic cancer cell lines Panc1 and Panc28 , and many other cell lines. 18b-glycyrrhetinic acid is more toxic than glycyrrhizic acid, glycyrrhizic acid displays no obvious cell toxicity, even at 200 lM (Kao et al. 2009 (Kao et al. , 2010 (Kao et al. , 2013 .

DNA and RNA binding has been observed in both GA as well as glycyrrhetinic acid (Nafisi et al. 2012a, b) , which implies that both may directly interfere with the pattern of transcription factors, the targeting of gene expression, and the interactions of DNA and RNA. This is a promising research topic for understanding the biological functions of these two. Glycyrrhizic acid and 18b-glycyrrhetinic acid have distinct biological functions, which may be due to the differences in their chemical structures (Kao et al. 2014).

The first two are the chalconoids of liquorice, whereas other two are the glycone forms of the former respectively (Kao et al. 2014 ). Studies on their antioxidant abilities are limited. These compounds are reported to be the potent protective agents against cancer and all four compounds may have a potent antispasmodic effect (Lee et al. 2013) . These four compounds are said to play an important role in healing effects, their chemical structures are similar, a simultaneous study on these compounds may facilitate the elucidation of the relationship between their biological effects and structure (Kamei et al. 2005; Kao et al. 2014) . The biological functions of liquiritin are similar to those of glycyrrhizic acid. Liquiritin promotes neurite outgrowth in PC12 cells with nerve growth factor treatment (Chen et al. 2009 ), suggesting its potential as a remedy for neurodegenerative diseases such as Alzheimer's disease or Parkinson's disease. Furthermore, liquiritin may exhibit an antidepressant-like effect in chronic variable stress-induced depression model rats by modulating oxidative stress (Zhao et al. 2008 ). It proves beneficial in patients with diabetes mellitus because it attenuates the induction of the RAGE/NFjB pathway in human umbilical vein endothelial cells (HUVECs) by advanced glycation end products (AGE), (Zhang et al. 2013 ). According to Cheel et al. (2010) , liquiritin and glycyrrhizic acid can stimulate immune responses, enhance antioxidant enzymes like superoxide dismutases (SOD), catalase, and glutathione peroxidase in mice focal cerebrum ). These may act as protective agents against epithelial injury in chronic obstructive pulmonary disease (COPD) . Liquiritin may bind to DNA like glycyrrhizic acid ) and may directly affect gene expression or other DNA-related mechanisms. Both are glycones or glycosides, the functional groups important for DNA binding, but this characterization is yet to be confirmed (Kao et al. 2014) .

Not much work is done on isoliquiritin listed in the PubMed database, because of its lack of commercial availability, most of the data published deals with its isolation and identification (Kao et al. 2014) . It is thought to prevent angiogenesis and tube formation in granulomas and may also have a potent antitussive effect (Kobayashi et al. 1995; Kamei et al. 2003) . Its other possible application is skin depigmentation due to tyrosinase inhibition (Fu et al. 2005) .

Liquiritigenin is a well-known selective estrogen receptor b agonist implicated in the weight-reducing effects of liquorice oil (Mersereau et al. 2008; Jungbauer and Medjakovic 2014) . It facilitates the recovery of learning and memory deficits induced by amyloid beta Ab(25-35) and also helps to enhance osteoblast function Choi 2012) . Liquiritigenin as well as isoliquiritigenin are able to inhibit xanthine oxidase, a promoting factor in many disorders (Kong et al. 2000) .

The IC50 values of these compounds are 49.3 and 55.8 lM for liquiritigenin and isoliquiritigenin respectively. Both are effective anti-inflammatory agents displaying potential PPARc activating activity, suggesting their potential for use in recovery from metabolic syndrome ). Latter is also an inhibitor of aldose reductase, suggesting it might be effective in treating diabetic complications (Aida et al. 1990 ). Liquiritigenin inhibits iNOS and proinflammatory cytokines by blocking NFjB , while isoliquiritigenin is involved in the intercellular adhesion molecule-1 (ICAM-1) and the vascular cell adhesion molecule-1 (VCAM-1) to modulate inflammation (Tanaka et al. 2001 ). Liquiritigenin has a protective role against a number of injuries in many cells and organs, including acetaminophen-induced rat liver damage, cadmium-induced rat hepatoma Reuber H35 cell (H4IIE) damage, D-galactosamine/ lipopolysaccharide-or CCl4-mediated rat hepatitis, Ab(25-35)-induced injury of rat hippocampal neurons, and infection by Candida albicans (Kim et al. 2004 (Kim et al. , 2006 Lee et al. 2009; Liu et al. 2009; Kang et al. 2010a ). On the other hand isoliquiritigenin also protects cells and organs by inhibiting cisplatin-induced rat anorexia, the diabetes-induced hyperaggregability of platelets, the accumulation of cyclic AMP in rat ventricular heart muscle, and by potently promoting neuronal health by inhibiting monoamine oxidase A and B among other mechanisms (Tawata et al. 1992; Wegener and Nawrath 1997; Pan et al. 2000; Takeda et al. 2008) . Liquiritigenin can enhance bile secretion in the liver through choleretic effect and can enhance the activity of transporters and phase II enzymes in the liver, which is thought to be related to the antidote ability of liquorice (Kim et al. 2009 ). In addition to an increase in the bile secretion, it might increase the rate of hepatic blood flow, and may exhibit chemopreventive activity in liver and lung cancers Jayaprakasam et al. 2009; Kang et al. 2010b; Zhou et al. 2010) . The mechanisms by which it modulates chemoprevention may involve apoptotic molecular targets, like cytochrome c, caspases, matrix metalloproteinases (MMPs), PI3K, Akt, and vascularization (Liu et al. 2011 Xie et al. 2012 ). C8-prenylation of a flavonoid such as liquiritigenin may enhance the induction of H4IIE and C6 glioma cell apoptosis without affecting its antioxidative properties (Watjen et al. 2007) . This compound has been reported to inhibit lipoxygenase and prostaglandin E2 (PEG2), induce cell cycle arrest in the human prostate cancer cell lines DU145 and LNCaP cells, induce cell death in the human breast cancer cell line MCF7 at high concentration, suppress pulmonary metastasis of mouse renal cell carcinoma, inhibit human lung cancer cell growth, inhibit colon cancer in ddY mice, induce apoptosis in human MGC803 gastric cancer cells, and activate the apoptosis in hepatoma cells among other effects in cancer cell, and therefore liquiritigenin is a potent protectant in cells and organs, whereas isoliquiritigenin exhibits greater potential in cancer chemoprevention (Yamamoto et al. 1991; Ma et al. 2001; Baba et al. 2002; Maggiolini et al. 2002; Yamazaki et al. 2002; Kanazawa et al. 2003; Takahashi et al. 2004; Ii et al. 2004; Hsu et al. 2005a, b; Kao et al. 2014) .

Both these compounds have also been applied in the treatment of cocaine addiction, but the results are preliminary. Liquiritigenin improves the selective molecular and behavioral disorders associated with cocaine use and isoliquiritigenin inhibits the dopamine release induced by cocaine (Jang et al. 2008 (Jang et al. , 2011 . This research has high practical value and is worth further study (Kao et al. 2014) .

Dehydroglyasperin is an isoflavonoid isolated from licorice that has two isoforms, dehydroglyasperin C (DGC) and dehydroglyasperin D (DGD). These two are classified as phenylflavonoids and are strong antioxidants, although the potency of DGC is greater. The isoangustone A, another phenylflavonoid has also been identified, with lower antioxidant activity than that of DGD (Lee et al. 2010b, c; Kim et al. 2012a) . Both DGC as well as DGD are potent ligands of peroxisome proliferator-activated receptor c (PPARc), which is thought to play a role in metabolic syndrome. The liquorice ethanolic extract containing DGC and DGD when used for the treatment in KK-Ay and obese C57BL mice has been observed to prevent and ameliorate metabolic syndrome in diabetic forms (Mae et al. 2003) . According to Seo et al. (2010) , DGC is not only a ligand of PPARc but also an activating factor of Nrf2 and detoxifying enzymes. It also modulates PI3K/Akt and Nrf2-Keap1 to protect against glutamate-induced neuronal cell damage (Kim et al. 2012b) . Both DGC and DGD are relatively newly isolated compounds from liquorice and exhibit various potent activities, but further study of their biology and toxicity is needed (Kao et al. 2014) .

Another isoflavonoid reported from liquorice is glabridin with a structure similar to estradiol-17b, and showing antimicrobial and antioxidant features (Mitscher et al. 1980; Okada et al. 1989) . It is frequently used in oxidative stress studies, including LDL oxidation due to its well-described antioxidant capabilities . Glabridin might modulate bone disorders in postmenopausal women and increase osteoblastic cell function (Somjen et al. 2004; Choi 2005) . Although a potent antioxidant, its brain penetration through the BBB is altered by p-glycoprotein, which might limit its application in central nervous system (CNS) diseases (Yu et al. 2007 ). The main application of glabridin seems to be in cosmetics. The antioxidant ability can help to modulate anti-inflammatory mechanisms in skin tissue (Kao et al. 2014) . The clinical studies are lacking however, some commercial formulations with liquorice extract claim that glabridin is useful for skin depigmentation (Leyden et al. 2011) . According to Jirawattanapong et al. (2009) , glabridin and its derivatives inhibit tyrosinase. There are reports of a reduction in UV-B-induced pigmentation and erythema in brownish guinea pigs after glabridin administration for 3 weeks following UV-B irradiation (Yokota et al. 1998 ). In addition to this potent anti-inflammatory activity, it has been reported to inhibit inducible nitric oxide synthase (iNOS) expression and upregulate manganese SOD, catalase, and paraoxonase 2 expression (Kang et al. 2005; Yehuda et al. 2011) .

Many evidence indicate that this compound may be beneficial in the treatment of diabetes mellitus and related diseases. Glabridin is found in the liquorice flavonoid oil (LFO, also called Kaneka glavonoid-rich oil) as a bioactive flavonoid. It is reported to suppress abdominal fat accumulation and blood glucose levels in KK-Ay mice (Nakagawa et al. 2004) . Licorice flavonoid oil (LFO) can activate AMP-activated protein kinase (AMPK) and ameliorate the increases in fatty liver and in the triglyceride and cholesterol plasma levels induced by obesity ). If administered daily up to 1200 mg/day it is accepted as safe in humans (Aoki et al. 2007) . LFO seems to be as safe as a functional food. Glabridin also is involved in the cancer prevention, because it blocks FAK/Rho signaling in human nonsmall cell lung cancer A549 cells and inhibits the migration, invasion, and angiogenesis of A549 cells . In view of this, uses of glabridin beyond cosmetics need to be explored (Kao et al. 2014).

Carbenoxolone or CBX known as sodium carbenoxolone is the 3-hemisuccinate of glycyrrhetinic acid, with a chemical structure similar to that of glucocorticoids. It may be the best-known derivative of glycyrrhetinic acid, because the disodium salt of the 3-o-hydrogen succinate, carbenoxolone is freely soluble in water (Lennon and Lennard 1964) . According to the report published by Connors in 2012, CBX can be used as an anti-inflammatory agent and an inhibitor of 11b-hydroxysteroid dehydrogenase type 1. Its most important characteristic is sterol regulation, which is involved in its effectiveness in the prevention of fatty liver (Rhee et al. 2012 ). This compound might have a nootropic effect due to the regulatory ability of glucocorticoids, thus improving verbal fluency and verbal memory in humans (Sandeep et al. 2004 ). The quotes from traditional Chinese medicine "Bencao Gangmu" state that liquorice consumption may enhance memory. Its best-known modern application is for the treatment for gastric ulcer, which is based on the spironolactone, and has a good outcome in aphthous ulcers (Doll et al. 1968; Porter and Scully Cbe 2007) .

It is also a well-known gap junction inhibitor, widely used in neuroscience research (Davidson et al. 1986 ). Gap junctions are also important in glutamate-induced neurotoxicity, and carbenoxolone can decrease the toxic effects of glutamate (Ozog et al. 2002) . This compound is said to show a protective role against ischemic injury in skeletal muscle and the hippocampus resulting from gap junction inhibition (Hosseinzadeh et al. 2005) . The gap junctions are also related to pain control. The reason being the spinal cord glia exhibits extensive gap junctional connectivity, which is involved in the contralateral spread of excitation resulting in mirror image pain (Spataro et al. 2004) . Carbenoxolone is also an inhibitor of gap junctions, its application in pain relief seems reasonable. Connexin gap junction proteins (Cx43 and Cx26) initiate brain metastatic lesion formation in association with the vasculature. It can prevent tumor cell extravasation and blood vessel involvement (Stoletov et al. 2013 ) and is frequently used in cancer research to probe the relationship between gap junctions and cancer formation. A typical study is the relationship between gap function and breast cancer metastasis or melanoma brain colonization (Stoletov et al. 2013 ). This compound looks like a useful agent for many research fields and is widely applied in clinical treatments (Kao et al. 2014 ). 

Spectural quality and UV-B stress stimulate glycyrrhizin concentration of Glycyrrhiza uralensis in hydroponic and pot system

An evaluation of the efficacy of licorice gargle for attenuating postoperative söre throat: a prospective, randomized, single-blind study

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Molecular and ecological investigations on the wild populations of Glycyrrhiza L. taxa distributed in the East Mediterranean Area of Turkey

Anxiolytic activity of Glycyrrhiza glabra Linn

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Determination of biogenic amines in licorice (Glycyrrhiza glabra) by ion-pair extraction and liquid chromatography-tandem mass spectrometry

Antiviral activity of glycyrrhizin against varicella-zoster virus in vitro

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Antioxidant activity and phenolic compounds of 112 traditional Chinese medicinal plants associated with anticancer

Determination of chemical composition by using chromatographic techniquies and antioxidant capacities of Glycyrrhiza L. species in Turkey

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Molecular mechanisms underlying chemopreventive activities of glycyrrhizic acid against UV-B-radiation-induced carcinogenesis in SKH-1 hairless mouse epidermis

Anti oxidant constituents of the roots and stolons of licorice (Glycyrrhiza glabra)

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Isolation and identification of flavonoids in licorice and a study of their inhibitory effects on tyrosinase

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Preliminary evaluation of antinephritis and radical scavenging activities of glabridin from Glycyrrhiza glabra

Effects of space flight on DNA mutation and secondary metabolites of licorice

The synthesis of glycyrrhetinic acid derivatives containing a nitrogen heterocycle and their antiproliferative effects in human leukemia cells

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Licorice compounds glycyrrhizin and 18 beta-glycyrrhetinic acid are potent modulators of bile acid-induced cytotoxicity in rat hepatocytes

Antimicrobial potential of Glycyrrhiza glabra roots

Cardioprotective effects of glycyrrhizic acid against isoproterenol-induced myocardial ischemia in rats

Antioxidative plant constituents

Acylated flavonoid glycosides and accompanying phenolics from licorice

Seasonal variation of glycyrrhizin and isoliquiritigenin glycosides in the root of Glycyrrhiza glabra L

Quantitatively analyze composition principle of Ma Huang Tang by structural equation modeling

A multicenter randomized controlled clinical trial of Shosaiko-to in chronic active hepatitis

Antimicrobial and cytotoxic activities of 2-aminobenzoic acid and 2-aminophenol and their coordination complexes with Magnesium (Mg-II)

The effects of carbenoxolone, a semisynthetic derivative of glycyrrhizinic acid, on peripheral and central ischemia-reperfusion injuries in the skeletal muscle and hippocampus of rats

Isoliquiritigenin inhibits cell proliferation and induces apoptosis in human hepatoma cells

Isoliquiritigenin induces apoptosis and cell cycle arrest through p53-dependent pathway in Hep G2 cells

Investigation on medicinal plant resources of Glycyrrhiza uralensis in China and chemical assessment of its underground part

Neuroprotective effects of roasted licorice, not raw form, on neuronal injury in gerbil hippocampus after transient forebrain ischemia

Glucocorticoids induce mineralization coupled with bone protein expression without influence on growth of a human osteoblastic cell line

Induction of cell cycle arrest and p21(CIP1/WAF1) expression in human lung cancer cells by isoliquiritigenin

Glycyrrhizin injection therapy prevents hepatocellular carcinogenesis in patients with interferon-resistant active chronic hepatitis C

A long-term glycyrrhizin injection therapy reduces hepatocellular carcinogenesis rate in patients with interferon-resistant active chronic hepatitis C: a cohort study of 1249 patients

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Liquiritigenin decreases selective molecular and behavioral effects of cocaine in rodents

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Liquiritigenin inhibits Abeta(25-35)-induced neurotoxicity and secretion of Abeta(1-40) in rat hippocampal neurons

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Liquiritigenin induces mitochondria-mediated apoptosis via cytochrome c release and caspases activation in HeLa cells

Liquiritigenin inhibits tumor growth and vascularization in a Mouse model of HeLa cells

Species systematization and quality evaluation of commonly used Chinese traditional drugs

Apoptosis induced by isoliquiritigenin in human gastric cancer MGC-803 cells

One step isolation and purification of liquiritigenin and isoliquiritigenin from Glycyrrhiza uralensis Risch. using high-speed counter-current chromatography

Environmental inhibitors of 11beta-hydroxysteroid dehydrogenase type 2

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Anti-infectious activity in the Anthemideae tribe

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Study on the interaction of glycyrrhizin and glycyrrhetinic acid with RNA

Licorice flavonoids suppress abdominal fat accumulation and increase in blood glucose level in obese diabetic KK-A(y) mice

Phenolic constituents of licorice (Glycyrrhiza species)

Chemistry of phenolic compounds of licorice (Glycyrrhiza species) and their estrogenic and cytotoxic activities

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Glycyrrhizin prevents liver injury by inhibition of high-mobility group box 1 production by Kupffer cells after ischemia-reperfusion in rats

Identification of antimicrobial and antioxidant constituents from licorice of Russian and Xinjiang origin

Biochemical and histological effects of 26 weeks of glycyrrhizin treatment in chronic hepatitis C: a randomized phase II trial

Blocked gap junctional coupling increases glutamate-induced neurotoxicity in neuron-astrocyte co-cultures

In vitro inhibition of rat monoamine oxidase by liquiritigenin and isoliquiritigenin isolated from Sinofranchetia chinensis

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A review: medicinal importance of Glycyrrhiza glabra L. (Fabaceae Family)

Antimicrobial activity of Glycyrrhiza glabra Linn. roots

The pharmacokinetics of glycyrrhizic acid evaluated by physiologically based pharmacokinetic modeling

Glycyrrhizic acid inhibits virus growth and inactivates virus particles

Aphthous ulcers (recurrent)

Simultaneous determination of five minor coumarins and flavonoids in Glycyrrhiza uralensis by solid-phase extraction and high-performance liquid chromatography/electrospray ionization tandem mass spectrometry

Glycyrrhizin alleviates experimental allergic asthma in mice

Glycyrrhizic acid (GCA) as 11beta-hydroxysteroid dehydrogenase inhibitor exerts protective effect against glucocorticoid-induced osteoporosis

Carbenoxolone prevents the development of fatty liver in C57BL/6-Lep ob/ob mice via the inhibition of sterol regulatory element binding protein-1c activity and apoptosis

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2012) 18beta-glycyrrhetinic acid induces apoptosis through modulation of Akt/FOXO3a/Bim pathway in human breast cancer MCF-7 cells

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Downregulation of c-FLIP, XIAP and Mcl-1 protein as well as depletion of reduced glutathione contribute to the apoptosis induction of glycyrrhetinic acid derivatives in leukemia cells

Spinal gap junctions: potential involvement in pain facilitation

Role of connexins in metastatic breast cancer and melanoma brain colonization

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Neuroprotective effect of liquiritin against focal cerebral ischemia/reperfusion in mice via its antioxidant and antiapoptosis properties

Chemical analysis of raw, dry-roasted, and honey-roasted licorice by capillary electrophoresis

DU-145 prostate carcinoma cells that selectively transmigrate narrow obstacles express elevated levels of Cx43

The blood-brain barrier permeability of 18beta-glycyrrhetinic acid, a major metabolite of glycyrrhizin in Glycyrrhiza root, a constituent of the traditional Japanese medicine yokukansan

Effects of glycyrrhizin on hepatitis B surface antigen: a biochemical and morphological study

Isoliquiritigenin, a flavonoid from licorice, reduces prostaglandin E2 and nitric oxide, causes apoptosis, and suppresses aberrant crypt foci development

Rikkunshito, an herbal medicine, suppresses cisplatin-induced anorexia in rats via 5-HT2 receptor antagonism

Influence of natural and synthetic compounds on cell surface expression of cell adhesion molecules, ICAM-1 and VCAM-1

Chinese drugs of plant origin

Anti-platelet action of isoliquiritigenin, an aldose reductase inhibitor in licorice

Preliminary evaluation of anti nephritis and radical scavenging activities of glabridin from Glycyrrhiza glabra Linn

Glabridin inhibits migration, invasion, and angiogenesis of human non-small cell lung cancer A549 cells by inhibiting the FAK/rho signaling pathway

Analysis of the synergistic effect of glycyrrhizin and other constituents in licorice extract on lipopolysaccharide-induced nitric oxide production using knock-out extract

Phytochemical screening and determination of anti-bacterial and anti-oxidant potential of Glycyrrhiza glabra root extracts

Pharmacognostical aspects of Glycyrrhiza glabra

Structural aspects of the inhibitory effect of glabridin on LDL oxidation

Herbal medicines and chronic kidney disease

Characterization of the key aroma compounds in raw licorice (Glycyrrhiza glabra L.) by means of molecular sensory science

Potential role of metabolomics apporoaches in the area of traditional Chinese medicine: as pillars of the bridge between Chinese and Western medicine

Pregnane X receptor mediated-transcription regulation of CYP3A by glycyrrhizin: a possible mechanism for its hepatoprotective property against lithocholic acid-induced injury

Prenylation enhances cytotoxicity of apigenin and liquiritigenin in rat H4IIE hepatoma and C6 glioma cells

Cardiac effects of isoliquiritigenin

Licorice inhibits 11 beta-hydroxysteroid dehydrogenase messenger ribonucleic acid levels and potentiates glucocorticoid hormone action

Licorice. In: Potter's cyclopedia of herbal medicines. C.W. Daniels, Saffron Walden

Licochalcone A: a lipase inhibitor from the roots of Glycyrrhiza uralensis

Azathioprine hepatotoxicity and the protective effect of liquorice and glycyrrhizic acid

Liquiritigenin inhibits serum-induced HIF-1alpha and VEGF expression via the AKT/mTOR-p70S6K signalling pathway in HeLa cells

Advances in studies on flavonoids of licorice

The potent anti-tumor-promoting agent isoliquiritigenin

Pharmacokinetic profile of glycerrhizin in healthy volunteers by a new high-performance liquid chromatographic method

Isoliquiritigenin suppresses pulmonary metastasis of mouse renal cell carcinoma

18betaglycyrrhetinic acid potentiates Hsp90 inhibition-induced apoptosis in human epithelial ovarian carcinoma cells via activation of death receptor and mitochondrial pathway

The pharmacological activities of licorice

Identification and enrichment of a-glucosidase-inhibiting dihydrostilbene and flavonoids from Glycyrrhiza uralensis leaves

Glabridin, a phytoestrogen from licorice root, up-regulates manganese superoxide dismutase, catalase and paraoxonase 2 under glucose stress

The inhibitory effect of glabridin from licorice extracts on melanogenesis and inflammation

Protective effects of Glycyrrhizae radix extract and its compounds in a renal hypoxia (ischemia)-reoxygenation (reperfusion) model

Role of P-glycoprotein in limiting the brain penetration of glabridin, an active isoflavan from the root of Glycyrrhiza glabra

Antiandrogenic activities of Glycyrrhiza glabra in male rats

Inhibition of mutagenicity in Salmonella typhimurium by Glycyrrhiza glabra extract, glycyrrhizinic acid, 18a-and 18b-glycyrrhetinic acids

Chemical analysis of the Chinese herbal medicine Gan-Cao (licorice)

Effect of liquiritigenin, a flavanone existed from Radix glycyrrhizae on pro-apoptotic in SMMC-7721 cells

Liquiritin attenuates advanced glycation end products-induced endothelial dysfunction via RAGE/ NF-kappaB pathway in human umbilical vein endothelial cells

Antidepressant-like effect of liquiritin from Glycyrrhiza uralensis in chronic variable stress induced depression model rats

Inhibition of gap junction channel attenuates the migration of breast cancer cells

Separation, characterization and dose-effect relationship of the PPARgamma-activating bio-active constituents in the Chinese herb formulation 'San-Ao decoction

Inhibition of hepatoma 22 tumor by liquiritigenin

Survey of Glycyrrhizae Radix resources in Mongolia: chemical assessment of the underground part of Glycyrrhiza uralensis and comparison with Chinese Glycyrrhizea Radix