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1.
J Agric Food Chem ; 65(17): 3490-3496, 2017 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-28412809

RESUMEN

Diarylheptanoids from Curcuma comosa, of the Zingiberaceae family, exhibit diverse estrogenic activities. In this study we investigated the estrogenic activity of a major hydroxyl diarylheptanoid, 7-(3,4 -dihydroxyphenyl)-5-hydroxy-1-phenyl-(1E)-1-heptene (compound 092) isolated from C. comosa. The compound elicited different transcriptional activities of estrogen agonist at low concentrations (0.1-1 µM) and antagonist at high concentrations (10-50 µM) using luciferase reporter gene assay in HEK-293T cells. In human breast cancer (MCF-7) cells, compound 092 showed an anti-estrogenic activity by down-regulating ERα-signaling and suppressing estrogen-responsive genes, whereas it attenuated the uterotrophic effect of estrogen in immature ovariectomized rats. Of note, compound 092 promoted mouse pre-osteoblastic (MC3T3-E1) cell differentiation and the related bone markers, indicating its positive osteogenic effect. Our findings highlight a new, nonsteroidal, estrogen agonist/antagonist of catechol diarylheptanoid from C. comosa, which is scientific evidence supporting its potential as a dietary supplement to prevent bone loss with low risk of breast and uterine cancers in postmenopausal women.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Curcuma/química , Diarilheptanoides/administración & dosificación , Receptor alfa de Estrógeno/metabolismo , Osteoblastos/efectos de los fármacos , Fitoestrógenos/administración & dosificación , Extractos Vegetales/administración & dosificación , Moduladores Selectivos de los Receptores de Estrógeno/administración & dosificación , Células 3T3 , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/fisiopatología , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Receptor alfa de Estrógeno/genética , Femenino , Humanos , Ratones , Osteoblastos/citología , Osteoblastos/metabolismo , Ratas , Ratas Wistar , Útero/citología , Útero/efectos de los fármacos , Útero/crecimiento & desarrollo
2.
Environ Health Perspect ; 123(4): 344-52, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25575267

RESUMEN

BACKGROUND: Concerns regarding potential endocrine-disrupting chemicals (EDCs) have led to a need for methods to evaluate candidate estrogenic chemicals. Our previous evaluations of two such EDCs revealed a response similar to that of estradiol (E2) at 2 hr, but a less robust response at 24 hr, similar to the short-acting estrogen estriol (E3). OBJECTIVES: Microarray analysis using tools to recognize patterns of response have been utilized in the cancer field to develop biomarker panels of transcripts for diagnosis and selection of treatments most likely to be effective. Biological effects elicited by long- versus short-acting estrogens greatly affect the risks associated with exposures; therefore, we sought to develop tools to predict the ability of chemicals to maintain estrogenic responses. METHODS: We used biological end points in uterine tissue and a signature pattern-recognizing tool that identified coexpressed transcripts to develop and test a panel of transcripts in order to classify potentially estrogenic compounds using an in vivo system. The end points used are relevant to uterine tissue, but the resulting classification of the compounds is important for other sensitive tissues and species. RESULTS: We evaluated biological and transcriptional end points with proven short- and long-acting estrogens and verified the use of our approach using a phytoestrogen. With our model, we were able to classify the diarylheptanoid D3 as a short-acting estrogen. CONCLUSIONS: We have developed a panel of transcripts as biomarkers which, together with biological end points, might be used to screen and evaluate potentially estrogenic chemicals and infer mode of activity.


Asunto(s)
Disruptores Endocrinos/toxicidad , Útero/efectos de los fármacos , Animales , Biomarcadores/análisis , Diarilheptanoides/toxicidad , Estrógenos/toxicidad , Femenino , Perfilación de la Expresión Génica , Ratones , Ratones Endogámicos C57BL , Ovariectomía , Fitoestrógenos/toxicidad , Útero/metabolismo
3.
Environ Health Perspect ; 121(4): 433-9, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23552522

RESUMEN

BACKGROUND: Diarylheptanoid (D3) isolated from the medicinal plant, Curcuma comosa, has estrogenic activity. OBJECTIVE: We aimed to elucidate the mechanism(s) of D3 action and compare it with that of 17ß-estradiol (E2) using both in vitro and in vivo uterine models. METHODS: We used human uterine (Ishikawa) cells to determine the estrogenic action of D3 on the activation and nuclear translocation of estrogen receptor α (ERα). In addition, we further characterized the uterine response to D3 treatment in vivo. RESULTS: D3 activated an estrogen responsive element (ERE) luciferase reporter through ERα, and molecular modeling suggested that D3 could be accommodated in the ERα binding pocket. Using modified ERα to assay ligand-dependent nuclear translocation, we observed D3-dependent ERα interaction and translocation. In mouse uteri, early- and late-phase estrogen-regulated gene responses were increased in D3-treated ovariectomized wild-type animals, in a manner similar to that of E2; no response was seen in ERα knockout animals. We observed a divergence in estrogen responses after D3 treatment: D3 induced robust DNA synthesis in uterine epithelial cells, linked to an increase in cell-cycle-related genes; however, no increase in uterine weight was observed 24 hr after treatment. D3 also affected uterine progesterone receptor expression patterns similar to E2. When D3 and E2 were administered together, we observed no additive or antagonistic effects of D3 on E2. Our findings suggest that D3 is a weak estrogenic agonist compound. CONCLUSION: D3 is a weakly acting phytoestrogen that mimics the mitogenic responses produced by E2 in an ERα-dependent manner, but it is unable to increase uterine weight or enhance or antagonize the effects of estrogen.


Asunto(s)
Curcuma/química , Diarilheptanoides/metabolismo , Exposición a Riesgos Ambientales , Fitoestrógenos/metabolismo , Útero/efectos de los fármacos , Animales , Línea Celular , Estradiol/metabolismo , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Femenino , Humanos , Ratones , Microscopía Confocal , Ovariectomía , Extractos Vegetales/metabolismo , Reacción en Cadena de la Polimerasa , Receptores de Progesterona/metabolismo , Rizoma/química
4.
Environ Health Perspect ; 117(7): 1155-61, 2009 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-19654927

RESUMEN

BACKGROUND: Diarylheptanoids isolated from Curcuma comosa Roxb. have been recently identified as phyto estrogens. However, the mechanism underlying their actions has not yet been identified. OBJECTIVES: We characterized the estrogenic activity of three active naturally occurring diarylheptanoids both in vitro and in vivo. METHODS: We characterized mechanisms of estrogenic action of the diarylheptanoids (3S)-1,7-diphenyl-(6E)-6-hepten-3-ol (D1), 1,7-diphenyl-(6E)-6-hepten-3-one (D2), and (3R)-1,7-diphenyl-(4E,6E)-4,6-heptadien-3-ol (D3) by using a real-time polymerase chain reaction assay, a mammalian transfection model, and a uterotrophic assay in mice. RESULTS: All diarylheptanoids up-regulated estrogen-responsive genes in estrogen-responsive breast cancer cells (MCF-7). In HepG2 cells transfected with estrogen receptor (ER) beta or different ERalpha functional receptor mutants and the Vit-ERE-TATA-Luc reporter gene, all diarylheptanoids induced transcription through a ligand-dependent human ERalpha-ERE-driven pathway, which was abolished with ICI 182,780 (ER antagonist), whereas only D2 was active with ERbeta. An ERalpha mutant lacking the functional AF2 (activation function 2) region was not responsive to 17beta-estradiol (E(2)) or to any of the diarylheptanoids, whereas ERalpha lacking the AF1 domain exhibited wild-type-like activity. D3 markedly increased uterine weight and proliferation of the uterine epithelium in ovariectomized mice, whereas D1 and D2 were inactive. D3, like E(2), up-regulated lactoferrin (Ltf) gene expression. The responses to D3 in the uterus were inhibited by ICI 182,780. In addition, D3 stimulated both classical (Aqp5) and nonclassical (Cdkn1a) ER-mediated gene regulation. CONCLUSIONS: The results suggest that the D3 diarylheptanoid is an agonist for ER both in vitro and in vivo, and its biological action is ERalpha selective, specifically requiring AF2 function, and involves direct binding via ER as well as ERE-independent gene regulation.


Asunto(s)
Curcuma/química , Diarilheptanoides/farmacología , Fitoestrógenos/farmacología , Plantas Medicinales/química , Receptores de Estrógenos/fisiología , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Diarilheptanoides/química , Diarilheptanoides/aislamiento & purificación , Estradiol/análogos & derivados , Estradiol/farmacología , Receptor alfa de Estrógeno/antagonistas & inhibidores , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/fisiología , Receptor beta de Estrógeno/antagonistas & inhibidores , Receptor beta de Estrógeno/genética , Receptor beta de Estrógeno/fisiología , Femenino , Fulvestrant , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Mutantes , Tamaño de los Órganos/efectos de los fármacos , Ovariectomía , Fitoestrógenos/química , Fitoestrógenos/aislamiento & purificación , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Reacción en Cadena de la Polimerasa , Receptores de Estrógenos/antagonistas & inhibidores , Receptores de Estrógenos/genética , Transcripción Genética/efectos de los fármacos , Transcripción Genética/genética , Útero/citología , Útero/efectos de los fármacos
5.
J Agric Food Chem ; 57(3): 840-5, 2009 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-19143535

RESUMEN

Curcuma comosa Roxb. has traditionally been used as a dietary supplement for health promotion in peri- and postmenopausal women in Thailand. We investigated the estrogenic activity of 7 naturally occurring diarylheptanoids from the extracts of C. comosa both in vitro and in vivo. A yeast recombinant system containing human estrogen receptor alpha, coactivator TIF2 and a beta-galactosidase reporter gene was used to determine estrogenic activity of diarylheptanoids metabolically activated with rat liver S9-fraction prior to the assay. The most potent compound was (3R)-1,7-diphenyl-(4E,6E)-4,6-heptadien-3-ol, with a relative potency of 4% compared to 17beta-estradiol. The metabolic activation of diarylheptanoids markedly enhanced their efficiency. The chemical structure required for estrogenic activity of diarylheptanoids was the presence of a keto group at C3 and absence of hydroxyl moiety in ring B. Only diarylheptanoids showing full estrogenic efficiency in vitro were able to elicit uterotrophic activity of in immature ovariectomized rat. This is the first evidence for in vivo estrogenic activity of diarylheptanoids from C. comosa. This novel class of natural phytoestrogens has the potential to be developed for use as dietary supplement in the treatment of menopausal symptoms.


Asunto(s)
Curcuma/química , Diarilheptanoides/farmacología , Fitoestrógenos/farmacología , Extractos Vegetales/química , Animales , Diarilheptanoides/química , Estradiol/farmacología , Receptor alfa de Estrógeno/efectos de los fármacos , Receptor alfa de Estrógeno/genética , Femenino , Humanos , Tamaño de los Órganos/efectos de los fármacos , Ovariectomía , Ratas , Ratas Wistar , Saccharomyces cerevisiae/genética , Útero/efectos de los fármacos , Útero/crecimiento & desarrollo
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