Liquiritigenin is a plant-derived highly selective estrogen receptor β agonist

Mersereau, Jennifer E.; Levy, Nitzan; Staub, Richard E.; Baggett, Scott; Zogric, Tetjana; Chow, Sylvia; Ricke, William A.; Tagliaferri, Mary; Cohen, Isaac; Bjeldanes, Leonard F.; Leitman, Dale C.

doi:10.1016/j.mce.2007.11.020

Cited by 173 publications

(182 citation statements)

References 48 publications

Supporting

Mentioning

175

Contrasting

Order By: Relevance

“…Second, liquiritigenin has been shown in several studies to exert cytoprotective effects [16,17] ; recent studies demonstrate that liquiritigenin exerts anti-inflammatory effects through the NF-κB pathway [18] . Third, we previously observed that liquiritigenin did not induce proliferation of MCF-7 and T47D breast cancer cells (data not shown), which is consistent with other studies [13] . Finally, pharmacokinetic studies from our laboratory have demonstrated that liquiritigenin exhibits good intestinal absorption and blood-brain barrier permeability [19] .…”

Section: Introductionsupporting

confidence: 92%

“…Our interest in liquiritigenin developed as a result of the following observations. First, liquiritigenin was shown to be a highly selective agonist of estrogen receptor-β (ERβ) [13] , an observation that is consistent with our previous findings (unpublished data). ERβ is expressed in brain centers related to learning and memory and is less likely than ERα to be related to sexual function [14,15] .…”

Section: Introductionsupporting

confidence: 88%

“…With regard to the underlying cellular mechanism, we previously observed that an ER antagonist, ICI 182 780, could partially block the anti-apoptotic effect of liquiritigenin in our culture system (unpublished data). Since liquiritigenin has a 20-fold higher affinity for ERβ than for ERα [13] , it is likely that its neuroprotective ability is mediated by ERβ. Meanwhile, the partial blocking effect of ICI 182 780 also suggests that the protective effect may be mediated by multiple pathways, including that of mitogenactivated protein kinase (MAPK) [3] .…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Liquiritigenin inhibits Aβ25–35-induced neurotoxicity and secretion of Aβ1–40 in rat hippocampal neurons

2009

View full text Add to dashboard Cite

Aim: To examine whether liquiritigenin, a newly found agonist of selective estrogen receptor-β, has neuroprotective activity against β-amyloid peptide (Aβ) in rat hippocampal neurons. Methods: Primary cultures of rat hippocampal neurons were pretreated with liquiritigenin (0.02, 0.2, and 2 μmol/L) prior to Aβ 25-35 exposure. Following treatment, viability of the cells was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analysis and by a lactate dehydrogenase activity-based cytotoxicity assay. Intracellular Ca 2+ concentration ([Ca 2+ ] i ) and levels of reactive oxygen species (ROS), as well as apoptotic rates, were determined. Our studies were extended in tests of whether liquiritigenin treatment could inhibit the secretion of Aβ 1-40 as measured using an ELISA method. In order to analyze which genes may be involved, we used a microarray assay to compare gene expression patterns. Finally, the levels of specific proteins related to neurotrophy and neurodenegeration were detected by Western blotting. Results: Pretreated neurons with liquiritigenin in the presence of Aβ 25-35 increased cell viability in a concentration-dependent manner. Liquiritigenin treatment also attenuated Aβ 25-35 -induced increases in [Ca 2+ ] i and ROS level and decreased the apoptotic rate of neurons. Some genes, including B-cell lymphoma/leukemia-2 (Bcl-2), neurotrophin 3 (Ntf-3) and amyloid β (A4) precursor protein-binding, family B, member 1 (Apbb-1) were regulated by liquiritigenin; similar results were shown at the protein level by Western blotting. Conclusion: Our results demonstrate that liquiritigenin exhibits neuroprotective effects against Aβ 25-35 -induced neurotoxicity and that it can decrease the secretion of Aβ 1-40 . Therefore, liquiritigenin may be useful for further study as a prodrug for treatment of Alzheimer's disease.

show abstract

Section: Introductionsupporting

confidence: 92%

Section: Introductionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Liquiritigenin inhibits Aβ25–35-induced neurotoxicity and secretion of Aβ1–40 in rat hippocampal neurons

2009

View full text Add to dashboard Cite

show abstract

“…Liquiritigenin is a component of a Chinese herb that is currently in clinical trials for the treatment of postmenopausal symptoms (28). This compound binds to ER␣ and ER␤ with similar affinity but induces the transcriptional activation of ER␤ specifically.…”

Section: Comparison Of Natural Er Ligands Via Bretmentioning

confidence: 99%

Intermolecular interactions identify ligand-selective activity of estrogen receptor α/β dimers

Powell

2008

Proc. Natl. Acad. Sci. U.S.A.

101

119

View full text Add to dashboard Cite

Estrogen receptor (ER) dimerization is prerequisite for its activation of target gene transcription. Because the two forms of ER, ER␣ and ER␤, exhibit opposing functions in cell proliferation, the ability of ligands to induce ER␣/␤ heterodimers vs. their respective homodimers is expected to have profound impacts on transcriptional outcomes and cellular growth. However, there is a lack of direct methods to monitor the formation of ER␣/␤ heterodimers in vivo and to distinguish the ability of estrogenic ligands to promote ER homo-vs. heterodimerization. Here, we describe bioluminescence resonance energy transfer (BRET) assays for monitoring the formation of ER␣/␤ heterodimers and their respective homodimers in live cells. We demonstrate that although both partners contribute to heterodimerization, ligand-bound ER␣ plays a dominant role. Furthermore, a bioactive component was found to induce ER␤/␤ homodimers, and ER␣/␤ heterodimers but had minimal activity on ER␣/␣ homodimers, posing a model that compounds promoting ER␣/␤ heterodimer formation might have therapeutic value. Thus, ER homodimer and heterodimer BRET assays are applicable to drug screening for dimer-selective selective ER modulators. Furthermore, this strategy can be used to study other nuclear receptor dimers. bioluminescence resonance energy transfer (BRET) ͉ estrogenic ligands ͉ selective estrogen receptor modulator (SERM) ͉ heterodimer ͉ homodimer T he biological actions of estrogens are mediated by estrogen receptors (ERs), which are ligand-inducible transcription factors. Binding of 17␤-estradiol (E 2 ) and other estrogenic compounds triggers receptor dimerization and subsequent association with estrogen response elements (EREs) in the promoter regions of ER-target genes to control gene transcription. ERs exist in two forms, ER␣ and ER␤, which have opposing roles in regulating estrogen action: ER␣ promotes whereas ER␤ inhibits estrogendependent cell growth (1, 2). It has been shown that the coexpression of ER␤ with ER␣ results in reduced ER␣-mediated proliferation of breast cancer cells. Approximately 60% of all breast tumors coexpress ER␣ and ER␤ (3, 4). Despite the findings that the coexpression of ER␤ has been correlated with a more favorable prognosis (5) and decreased biological aggressiveness compared with tumors expressing ER␣ alone (6, 7), whether ER␤ modulates ER␣ by heterodimerization to mediate growth-inhibitory phenotypes remains elusive. Multiple lines of evidence suggest that ER␣/␤ heterodimers do exist in vivo and may function to regulate distinct estrogen-responsive genes (8-10). However, the coexistence of homodimers has prevented a clear understanding of heterodimer function. Hypothetically, different estrogenic ligands could exert different cellular effects via differential induction of ER␣ homodimerization, ER␤ homodimerization, and ER␣/␤ heterodimerization. The differential regulation of these ER subtypes could be influenced by several factors including ligand-binding selectivity, conformational differences upon dimerization, d...

show abstract

“…EC, the contraceptive measures that can be taken after sex to prevent pregnancy (Sander et al 2009), is a popular form of reversible contraception. Oestrogens and progestins, individually or in combination, and antiprogestins form the active constituents of the currently available major hormonal EC formulations (Farrar et al 2003), but continuous usage of these formulations has undesirable effects that include the proliferative actions of oestrogenic component (Mersereau et al 2008) or higher failure rate and menstrual abnormalities associated with progestogen-only pills (Ahrendt et al 2010). Development of a safe and effective non-steroidal contraceptive formulation is therefore recognised as a global need of the day.…”

Section: Introductionmentioning

confidence: 99%

Puerarin, a selective oestrogen receptor modulator, disrupts pregnancy in rats at pre-implantation stage

Saha¹,

Saraswat²,

Chakraborty³

et al. 2012

Reproduction

View full text Add to dashboard Cite

The tubers of Pueraria tuberosa have folkloric repute as emmenagogue. The n-BuOH fraction of the ethanolic extract of tubers exhibits significant antifertility activity in laboratory animals. The present investigation explored the active principle(s) of the tuber extract with reference to contragestive effects in rats and probed the possible mechanism of action. Bioactivity-guided fractionation identified puerarin as the major constituent that exerted pregnancy-terminating effects. Oral administration of puerarin at R300 mg/kg per day for days (D) 1-2 post-coitus resulted in complete implantation failure. Serum oestradiol levels during D2-D5 and progesterone (P 4 ) level on D5 remained unaffected, but the endometrial expression of oestrogen receptor a (ERa) and ERb was adversely modulated that disrupted the implantation-specific characteristic endometrial oestrogenic milieu. The eventual consequence was loss of endometrial receptivity characterised by down-regulation of the uterine expression of P 4 receptor (PR) and attenuation of endometrial expression of leukaemia inhibitory factor, vascular endothelial growth factor and cyclo-oxygenase-2, the three important signalling molecules involved in the process of implantation. Light microscopic examination of the embryos demonstrated no untoward effect of puerarin on the development of embryos until D4, but D5 blastocysts underwent gross morphological distortion. The findings taken together are interpreted to suggest that puerarin adversely impacts the uterine expression of ER and PR that disrupts the implantation-conducive uterine milieu and prevents implantation. In conclusion, puerarin may be envisaged as a prospective molecule that merits further exploration for the development of non-steroidal post-coital contraceptive for women.

show abstract

Liquiritigenin is a plant-derived highly selective estrogen receptor β agonist

Cited by 173 publications

References 48 publications

Liquiritigenin inhibits Aβ25–35-induced neurotoxicity and secretion of Aβ1–40 in rat hippocampal neurons

Liquiritigenin inhibits Aβ25–35-induced neurotoxicity and secretion of Aβ1–40 in rat hippocampal neurons

Intermolecular interactions identify ligand-selective activity of estrogen receptor α/β dimers

Puerarin, a selective oestrogen receptor modulator, disrupts pregnancy in rats at pre-implantation stage

Contact Info

Product

Resources

About