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    Estrogen receptor-α and aryl hydrocarbon receptor involvement in the actions of botanical estrogens in target cells. Gong Ping,Madak-Erdogan Zeynep,Flaws Jodi A,Shapiro David J,Katzenellenbogen John A,Katzenellenbogen Benita S Molecular and cellular endocrinology Botanical estrogen (BE) dietary supplements are consumed by women as substitutes for loss of endogenous estrogens at menopause. To examine the roles of estrogen receptor α (ERα) and aryl hydrocarbon receptor (AhR) and their crosstalk in the actions of BEs, we studied gene regulation and proliferation responses to four widely used BEs, genistein, daidzein, and S-equol from soy, and liquiritigen from licorice root in breast cancer and liver cells. BEs and estradiol (E2), acting through ERα, stimulated proliferation, ERα chromatin binding and target-gene expression. BEs but not E2, acting through AhR, bound to xenobiotic response element-containing chromatin sites and enhanced AhR target-gene expression (CYP1A1, CYP1B1). While E2 and TCDD acted quite selectively through their respective receptors, BEs acted via both receptors, with their AhR activity moderated by negative crosstalk through ERα. Both ERα and AhR should be considered as mediators of the biology and pharmacology of BEs. 10.1016/j.mce.2016.08.025
    Diversity of -Glycosyltransferases Contributes to the Biosynthesis of Flavonoid and Triterpenoid Glycosides in . Chen Kuan,Hu Zhi-Min,Song Wei,Wang Zi-Long,He Jun-Bin,Shi Xiao-Meng,Cui Qing-Hua,Qiao Xue,Ye Min ACS synthetic biology Licorice () is a popular medicinal plant containing more than 70 flavonoid and triterpenoid glycosides. Thus far, only a few reports are available on the glycosylation enzymes involved in their biosynthesis. In this work, we mined the transcriptome data of and discovered 43 candidate genes for -glycosyltransferase (-GT). Among them, 17 genes could be expressed in , and functions of the enzymes were analyzed by catalyzing eight native substrates. As a result, we characterized 11 -GTs, including isoflavone 7--GTs, flavonol 3--GTs, and promiscuous -GTs catalyzing flavones, chalcones, and triterpenoids. They could efficiently synthesize key licorice compounds such as liquiritin, isoliquiritin, ononin, and 3--β-d-glucuronosyl glycyrrhetinic acid. The diversity of -GTs contributes to the biosynthesis of various glycosides in licorice. These enzymes could also be used as biocatalytic tools to synthesize other bioactive -glycosides. 10.1021/acssynbio.9b00171
    Estrogenic activities of extracts of Chinese licorice (Glycyrrhiza uralensis) root in MCF-7 breast cancer cells. Hu Chunyan,Liu Huaqing,Du Juan,Mo Baoqing,Qi Hong,Wang Xinru,Ye Shengai,Li Zhong The Journal of steroid biochemistry and molecular biology Despite the wide use of Chinese licorice root (Glycyrrhiza uralensis) for the treatment of menopausal complaints, little is known on its potential estrogenic properties, and available information relative to its effects on cell proliferation is contradictory. In this study, the estrogenic properties of licorice root were evaluated in vitro by use of several assays. The effects of increasing concentrations of a DMSO extract of licorice root on the growth of MCF-7 breast cancer cells were biphasic. The extract showed an ER-dependent growth-promoting effect at low concentrations and an ER-independent anti-proliferative activity at high concentrations. In further experiments, licorice root was sequentially extracted to yield four fractions: hexane, EtOAc, methanol and H(2)O. Only the EtOAc extract had effects on cell proliferation similar to the DMSO extract. The hexane extract had no effect on cell growth. In contrast, the methanol and water extracts showed an ER-independent, growth-promoting effect. Similar to its effects on cell proliferation, the EtOAc extract had a biphasic effect on S phase cell cycle distribution and the level of PCNA protein. This extract-induced transactivation of endogenous ERalpha in MCF-7 cells, supported by inducing down-regulation of ERalpha protein and mRNA levels, and up-regulation of ERalpha target genes pS2 and GREB1. These results suggest that the activity of licorice root and the balance between increased risk for cancer and prevention of estrogen-dependent breast cancer may depend on the amount of dietary intake. 10.1016/j.jsbmb.2008.12.019
    Evaluation of estrogenic activity of licorice species in comparison with hops used in botanicals for menopausal symptoms. Hajirahimkhan Atieh,Simmler Charlotte,Yuan Yang,Anderson Jeffrey R,Chen Shao-Nong,Nikolić Dejan,Dietz Birgit M,Pauli Guido F,van Breemen Richard B,Bolton Judy L PloS one The increased cancer risk associated with hormone therapies has encouraged many women to seek non-hormonal alternatives including botanical supplements such as hops (Humulus lupulus) and licorice (Glycyrrhiza spec.) to manage menopausal symptoms. Previous studies have shown estrogenic properties for hops, likely due to the presence of 8-prenylnarigenin, and chemopreventive effects mainly attributed to xanthohumol. Similarly, a combination of estrogenic and chemopreventive properties has been reported for various Glycyrrhiza species. The major goal of the current study was to evaluate the potential estrogenic effects of three licorice species (Glycyrrhiza glabra, G. uralensis, and G. inflata) in comparison with hops. Extracts of Glycyrrhiza species and spent hops induced estrogen responsive alkaline phosphatase activity in endometrial cancer cells, estrogen responsive element (ERE)-luciferase in MCF-7 cells, and Tff1 mRNA in T47D cells. The estrogenic activity decreased in the order H. lupulus > G. uralensis > G. inflata > G. glabra. Liquiritigenin was found to be the principle phytoestrogen of the licorice extracts; however, it exhibited lower estrogenic effects compared to 8-prenylnaringenin in functional assays. Isoliquiritigenin, the precursor chalcone of liquiritigenin, demonstrated significant estrogenic activities while xanthohumol, a metabolic precursor of 8-prenylnaringenin, was not estrogenic. Liquiritigenin showed ERβ selectivity in competitive binding assay and isoliquiritigenin was equipotent for ER subtypes. The estrogenic activity of isoliquiritigenin could be the result of its cyclization to liquiritigenin under physiological conditions. 8-Prenylnaringenin had nanomolar estrogenic potency without ER selectivity while xanthohumol did not bind ERs. These data demonstrated that Glycyrrhiza species with different contents of liquiritigenin have various levels of estrogenic activities, suggesting the importance of precise labeling of botanical supplements. Although hops shows strong estrogenic properties via ERα, licorice might have different estrogenic activities due to its ERβ selectivity, partial estrogen agonist activity, and non-enzymatic conversion of isoliquiritigenin to liquiritigenin. 10.1371/journal.pone.0067947
    Ethyl Acetate Extract of Licorice Root Enhances Proliferation and Osteogenic Differentiation of Human Bone Marrow Mesenchymal Stem Cells. Azizsoltani Arezou,Piri Khosro,Behzad Sahar,Soleimani Masoud,Nekouei Mina,Mahmoudi Zahra,Kazemi Asad Iranian journal of pharmaceutical research : IJPR has been used as a flavoring and sweetener agent, in addition to its therapeutic properties. It is rich in phytoestrogen and may prevent osteoporosis caused by estrogen deficiency; however, there is no evidence for its effects on proliferation and osteogenesis in mesenchymal stem cells. So, we were encouraged to investigate whether the ethyl acetate extract of licorice root as a source of phytoestrogen can act similar to estrogen in cell culture. Furthermore, the analysis of the licorice extract (LE) based on HPLC-DAD-ESI-MS indicated that LE comprises phytoestrogen compounds, such as glabridin and glabrene. In this study, the effects of LE on proliferation of human bone-marrow mesenchymal stem cells (hBM-MSCs) were investigated using MTT assay. In addition, its effects on the osteogenesis were evaluated using alkaline phosphatase activity (ALP), calcium deposition, and bone specific gene expression such as ALP, osteocalcin, Runx2, and BMP-2. The quantitative gene expression was studied by real-time RT-PCR. Our results showed a significant increase in proliferation in presence of LE in concentration 10-50 µg/mL. The differentiation of hBM-MSCs increased in doses of LE (10-25 µg/mL) compared to the control group. The effects of LE were similar to those of 17β-estradiol (E2) (10 M) and were abolished by ICI 182,780 an antagonist of estrogen receptor (ER) (10), indicating that the stimulatory effects of LE occur through estrogen receptor-mediated mechanism . Taking these into account, LE may be a potential candidate for prevention of osteoporosis in menopausal women.
    SAR Study on Estrogen Receptor α/β Activity of (Iso)flavonoids: Importance of Prenylation, C-Ring (Un)Saturation, and Hydroxyl Substituents. Mbachu Obinna C,Howell Caitlin,Simmler Charlotte,Malca Garcia Gonzalo R,Skowron Kornelia J,Dong Huali,Ellis Sarah G,Hitzman Ryan T,Hajirahimkhan Atieh,Chen Shao-Nong,Nikolic Dejan,Moore Terry W,Vollmer Günter,Pauli Guido F,Bolton Judy L,Dietz Birgit M Journal of agricultural and food chemistry Many botanicals used for women's health contain estrogenic (iso)flavonoids. The literature suggests that estrogen receptor beta (ERβ) activity can counterbalance estrogen receptor alpha (ERα)-mediated proliferation, thus providing a better safety profile. A structure-activity relationship study of (iso)flavonoids was conducted to identify ERβ-preferential structures, overall estrogenic activity, and ER subtype estrogenic activity of botanicals containing these (iso)flavonoids. Results showed that flavonoids with prenylation on C8 position increased estrogenic activity. C8-prenylated flavonoids with C2-C3 unsaturation resulted in increased ERβ potency and selectivity [, 8-prenylapigenin (8-PA), EC (ERβ): 0.0035 ± 0.00040 μM], whereas 4'-methoxy or C3 hydroxy groups reduced activity [, icaritin, EC (ERβ): 1.7 ± 0.70 μM]. However, nonprenylated and C2-C3 unsaturated isoflavonoids showed increased ERβ estrogenic activity [, genistein, EC (ERβ): 0.0022 ± 0.0004 μM]. Licorice (, [EC (ERα): 1.1 ± 0.20; (ERβ): 0.60 ± 0.20 μg/mL], containing 8-PA, and red clover [EC (ERα): 1.8 ± 0.20; (ERβ): 0.45 ± 0.10 μg/mL], with genistein, showed ERβ-preferential activity as opposed to hops [EC (ERα): 0.030 ± 0.010; (ERβ): 0.50 ± 0.050 μg/mL] and [EC (ERα): 3.2 ± 0.20; (ERβ): 2.5 ± 0.090 μg/mL], containing 8-prenylnaringenin and icaritin, respectively. Botanicals with ERβ-preferential flavonoids could plausibly contribute to ERβ-protective benefits in menopausal women. 10.1021/acs.jafc.0c03526
    Agonistic and antagonistic estrogens in licorice root (Glycyrrhiza glabra). Simons Rudy,Vincken Jean-Paul,Mol Loes A M,The Susan A M,Bovee Toine F H,Luijendijk Teus J C,Verbruggen Marian A,Gruppen Harry Analytical and bioanalytical chemistry The roots of licorice (Glycyrrhiza glabra) are a rich source of flavonoids, in particular, prenylated flavonoids, such as the isoflavan glabridin and the isoflavene glabrene. Fractionation of an ethyl acetate extract from licorice root by centrifugal partitioning chromatography yielded 51 fractions, which were characterized by liquid chromatography-mass spectrometry and screened for activity in yeast estrogen bioassays. One third of the fractions displayed estrogenic activity towards either one or both estrogen receptors (ERs; ERα and ERβ). Glabrene-rich fractions displayed an estrogenic response, predominantly to the ERα. Surprisingly, glabridin did not exert agonistic activity to both ER subtypes. Several fractions displayed higher responses than the maximum response obtained with the reference compound, the natural hormone 17β-estradiol (E(2)). The estrogenic activities of all fractions, including this so-called superinduction, were clearly ER-mediated, as the estrogenic response was inhibited by 20-60% by known ER antagonists, and no activity was found in yeast cells that did not express the ERα or ERβ subtype. Prolonged exposure of the yeast to the estrogenic fractions that showed superinduction did, contrary to E(2), not result in a decrease of the fluorescent response. Therefore, the superinduction was most likely the result of stabilization of the ER, yeast-enhanced green fluorescent protein, or a combination of both. Most fractions displaying superinduction were rich in flavonoids with single prenylation. Glabridin displayed ERα-selective antagonism, similar to the ERα-selective antagonist RU 58668. Whereas glabridin was able to reduce the estrogenic response of E(2) by approximately 80% at 6 × 10(-6) M, glabrene-rich fractions only exhibited agonistic responses, preferentially on ERα. 10.1007/s00216-011-5061-9
    Licorice root components mimic estrogens in an object location task but not an object recognition task. Kundu Payel,Korol Donna L,Bandara Suren,Monaikul Supida,Ondera Caitlin E,Helferich William G,Khan Ikhlas A,Doerge Daniel R,Schantz Susan L Hormones and behavior This study investigated the efficacy of components of licorice root to alter performance on two different recognition tasks, a hippocampus-sensitive metric change in object location (MCOL) task and a striatum-sensitive double object recognition (DOR) task. Isoliquiritigenin (ISL), licorice root extract (LRE), and whole licorice root powder (LRP) were assessed. Young adult female rats were ovariectomized (OVX) and exposed to ISL, LRE or LRP at 0.075%, 0.5% or 5% respectively in the diet. An estradiol group was included as a positive control based on our prior findings. Rats were allowed to explore two objects for three 5-min study trials (separated by 3-min intervals) before a fourth 5-min test trial where the objects were moved closer together (MCOL task) or replaced with two new objects (DOR task). Rats typically habituate to the objects across the three study trials. An increase in object exploration time in the test trial suggests the rat detected the change. Estradiol improved MCOL performance and impaired DOR performance, similar to previously shown effects of estradiol and other estrogens, which tend to improve learning and memory on hippocampus-sensitive tasks and impair striatum-sensitive cognition. LRP had no effect on recognition while exposure to ISL and LRE improved MCOL performance. Exposure to ISL, LRE and LRP failed to attenuate DOR, contrary to effects of estradiol shown here and to previous reports in young-adult OVX rats. These findings suggest components of licorice root may prove to be effective therapies targeting memory enhancement without unintended deleterious cognitive effects. 10.1016/j.yhbeh.2018.06.002
    Differential Effects of Glycyrrhiza Species on Genotoxic Estrogen Metabolism: Licochalcone A Downregulates P450 1B1, whereas Isoliquiritigenin Stimulates It. Dunlap Tareisha L,Wang Shuai,Simmler Charlotte,Chen Shao-Nong,Pauli Guido F,Dietz Birgit M,Bolton Judy L Chemical research in toxicology Estrogen chemical carcinogenesis involves 4-hydroxylation of estrone/estradiol (E1/E2) by P450 1B1, generating catechol and quinone genotoxic metabolites that cause DNA mutations and initiate/promote breast cancer. Inflammation enhances this effect by upregulating P450 1B1. The present study tested the three authenticated medicinal species of licorice [Glycyrrhiza glabra (GG), G. uralensis (GU), and G. inflata (GI)] used by women as dietary supplements for their anti-inflammatory activities and their ability to modulate estrogen metabolism. The pure compounds, liquiritigenin (LigF), its chalcone isomer isoliquiritigenin (LigC), and the GI-specific licochalcone A (LicA) were also tested. The licorice extracts and compounds were evaluated for anti-inflammatory activity by measuring inhibition of iNOS activity in macrophage cells: GI ≫ GG > GU and LigC ≅ LicA ≫ LigF. The Michael acceptor chalcone, LicA, is likely responsible for the anti-inflammatory activity of GI. A sensitive LC-MS/MS assay was employed to quantify estrogen metabolism by measuring 2-MeOE1 as nontoxic and 4-MeOE1 as genotoxic biomarkers in the nontumorigenic human mammary epithelial cell line, MCF-10A. GG, GU, and LigC increased 4-MeOE1, whereas GI and LicA inhibited 2- and 4-MeOE1 levels. GG, GU (5 μg/mL), and LigC (1 μM) also enhanced P450 1B1 expression and activities, which was further increased by inflammatory cytokines (TNF-α and IFN-γ). LicA (1, 10 μM) decreased cytokine- and TCDD-induced P450 1B1 gene expression and TCDD-induced xenobiotic response element luciferase reporter (IC50 = 12.3 μM), suggesting an antagonistic effect on the aryl hydrocarbon receptor, which regulates P450 1B1. Similarly, GI (5 μg/mL) reduced cytokine- and TCDD-induced P450 1B1 gene expression. Collectively, these data suggest that, of the three licorice species that are used in botanical supplements, GI represents the most promising chemopreventive licorice extract for women's health. Additionally, the differential effects of the Glycyrrhiza species on estrogen metabolism emphasize the importance of standardization of botanical supplements to species-specific bioactive compounds. 10.1021/acs.chemrestox.5b00157
    Estrogen Receptor (ER) Subtype Selectivity Identifies 8-Prenylapigenin as an ERβ Agonist from Glycyrrhiza inflata and Highlights the Importance of Chemical and Biological Authentication. Hajirahimkhan Atieh,Mbachu Obinna,Simmler Charlotte,Ellis Sarah G,Dong Huali,Nikolic Dejan,Lankin David C,van Breemen Richard B,Chen Shao-Nong,Pauli Guido F,Dietz Birgit M,Bolton Judy L Journal of natural products Postmenopausal women are increasingly using botanicals for menopausal symptom relief due to the increased breast cancer risk associated with traditional estrogen therapy. The deleterious effects of estrogens are associated with estrogen receptor (ER)α-dependent proliferation, while ERβ activation could enhance safety by opposing ERα effects. Three medicinal licorice species, Glycyrrhiza glabra ( G. glabra), G. uralensis, and G. inflata, were studied for their differential estrogenic efficacy. The data showed higher estrogenic potency for G. inflata in an alkaline phosphatase induction assay in Ishikawa cells (ERα) and an estrogen responsive element (ERE)-luciferase assay in MDA-MB-231/β41 breast cancer cells (ERβ). Bioassay-guided fractionation of G. inflata led to the isolation of 8-prenylapigenin (3). Surprisingly, a commercial batch of 3 was devoid of estrogenic activity. Quality control by MS and qNMR revealed an incorrect compound, 4'- O-methylbroussochalcone B (10), illustrating the importance of both structural and purity verification prior to any biological investigations. Authentic and pure 3 displayed 14-fold preferential ERβ agonist activity. Quantitative analyses revealed that 3 was 33 times more concentrated in G. inflata compared to the other medicinal licorice extracts. These data suggest that standardization of G. inflata to 3 might enhance the safety and efficacy of G. inflata supplements used for postmenopausal women's health. 10.1021/acs.jnatprod.7b01070
    Development of an Improved Menopausal Symptom-Alleviating Licorice () by Biotransformation Using . Kim Kang Uk,Lee Sung-Jin,Lee Inhyung Journal of microbiology and biotechnology Licorice () contains several compounds that have been reported to alleviate menopausal symptoms via interacting with estrogen receptors (ERs). The compounds exist mainly in the form of glycosides, which exhibit low bioavailability and function. To bioconvert liquiritin and isoliquiritin, the major estrogenic compounds, to the corresponding deglycosylated liquiritigenin and isoliquiritigenin, respectively, licorice was fermented with Monascus, which has been demonstrated to deglycosylate other substances. The contents of liquiritigenin and isoliquiritigenin in -fermented licorice increased by 10.46-fold (from 38.03 µM to 379.75 µM) and 12.50-fold (from 5.53 µM to 69.14 µM), respectively, compared with their contents in non-fermented licorice. -fermented licorice exhibited 82.5% of the ERβ binding activity of that observed in the positive control (17 β-estradiol), whereas the non-fermented licorice exhibited 54.1% of the binding activity in an in vivo ER binding assay. The increase in the ERβ binding activity was associated with increases in liquiritigenin and isoliquiritigenin contents. Liquiritigenin acts as a selective ligand for ERβ, which alleviates menopausal symptoms with fewer side effects, such as heart disease and hypertension, compared with a ligand for ERα. In addition, -fermented licorice contained 731 mg/kg of monacolin K, one of the metabolites produced by that reduces serum cholesterol. Therefore, -fermented licorice is a promising material for the prevention and treatment of menopausal syndrome with fewer side effects. 10.4014/jmb.1909.09037
    Evidence for Chemopreventive and Resilience Activity of Licorice: and G. Extracts Modulate Estrogen Metabolism in ACI Rats. Wang Shuai,Dunlap Tareisha L,Huang Lingyi,Liu Yang,Simmler Charlotte,Lantvit Daniel D,Crosby Jenna,Howell Caitlin E,Dong Huali,Chen Shao-Nong,Pauli Guido F,van Breemen Richard B,Dietz Birgit M,Bolton Judy L Cancer prevention research (Philadelphia, Pa.) Women are increasingly using botanical dietary supplements (BDS) to reduce menopausal hot flashes. Although licorice ( sp.) is one of the frequently used ingredients in BDS, the exact plant species is often not identified. We previously showed that in breast epithelial cells (MCF-10A), (GG) and (GI), and their compounds differentially modulated P450 1A1 and P450 1B1 gene expression, which are responsible for estrogen detoxification and genotoxicity, respectively. GG and isoliquiritigenin (LigC) increased , whereas GI and its marker compound, licochalcone A (LicA), decreased and The objective of this study was to determine the distribution of the bioactive licorice compounds, the metabolism of LicA, and whether GG, GI, and/or pure LicA modulate NAD(P)H quinone oxidoreductase (NQO1) in an ACI rat model. In addition, the effect of licorice extracts and compounds on biomarkers of estrogen chemoprevention () as well as carcinogenesis () was studied. LicA was extensively glucuronidated and formed GSH adducts; however, free LicA as well as LigC were bioavailable in target tissues after oral intake of licorice extracts. GG, GI, and LicA caused induction of NQO1 activity in the liver. In mammary tissue, GI increased and decreased , whereas GG only increased LigC may have contributed to the upregulation of after GG and GI administration. In contrast, LicA was responsible for GI-mediated downregulation of These studies highlight the polypharmacologic nature of botanicals and the importance of standardization of licorice BDS to specific species and to multiple constituents. 10.1158/1940-6207.CAPR-18-0178