Biphasic Effects of Kaempferol on the Estrogenicity in Human Breast Cancer Cells

Oh Seung-Min,Kim Yeon-Pan,Chung Kyu-Hyuck The Pharmaceutical Society of Korea 2006 Archives of Pharmacal Research Vol.29 No.5

Dietary flavonoids have attracted a great deal of attention as agents for preventing estrogen-related diseases, such as postmenopausal symptoms, and for reducing the risk of estrogen-dependent cancer. Kaempferol is one of the most commonly found dietary phytoestrogen. The aim of this study was to investigate the estrogenic and/or antiestrogenic effect of kaempferol, which can confirm its potency as a preventive agent against estrogen-related diseases. Kaempferol has both estrogenic and antiestrogenic activity, which are biphasic response on estrogen receptor. The estrogenic activity of kaempferol induced via ER-mediated pathway depending on $E_2$ concentration $(\leq\;10^{-12}M)$. Kaempferol $(10^{-5}\;M)$ also caused antiproliferative effect on MCF-7 cell in the presence of $E_2\;(10^{-11}\;M)$ and restored to the addition of excess $E_2\;(10^{-7}\;M)$, which confirms that antiproliferation of kaempferol was induced via ER-dependent pathway. However, at $10^{-4}\;M$, concentration higher than the concentrations at which the estrogenic effects of kaempferol are detected $(10^{-5}\;M)$, kaempferol induced strong antiproliferative effect, but were unaffected by the addition of excess $E_2\;(10^{-7}\;M)$ indicating that kaempferol exerts antiproliferation via ER-independent pathway. In particular, kaempferol blocked the focus formation induced by $E_2$, which confirms that kaempferol might inhibit the malignant transformation caused by estrogens. Therefore, we suggested that kaempferol might regulate a suitable level of estrogenic activity in the body and is expected to have potential beneficial effects in preventing estrogen imbalance diseases (breast cancer, osteoporosis, cardiovascular disease and etc.).

실험동물에서의 환경호르몬 물질의 생체내 영향 및 검색법 정립에 대한 연구

정지윤,이영순,Jung, Ji-Youn,Lee, Yong-Soon 대한수의학회 2005 大韓獸醫學會誌 Vol.45 No.4

The major protocol features of the rodent uterotrophic assay have been evaluated using a range of reference chemicals. The protocol variables considered include the selection of the test species and route of chemical administration, the age of the test animals, the maintenance diet used, and the specificity of the assay for estrogens. The rodents were ovariectomized under general anesthesia via bilateral flank incisions and randomly assigned to groups of 5 animals. Chemicals were DEHP, DBP, BPA and NP, were injected sc once daily with combinations of chemicals treatments for 3 days. In the results, the reported estrogenic chemicals DEHP and DBP were both negative in the single dose treatments. But, in the combinations of chemicals treatments, DEHP and DBP increased in bud number of mammary gland. Treatment of ovariectomized mice with combinations of other chemicals resulted in uterine and vaginal hyperplasia. The additive estrogenic effects were seen with the combinations of $17{\beta}$-Bestradiol and DBP treatment. the competitive estrogenic effects were seen with the combinations of $17{\beta}$-Bestradiol and nonylphenol, $17{\beta}$-Bestradiol and bisphenol-A treatments. These results offers a sysmatic and mechanistically informative approach to assessing estrogenicity. it provides a useful profile of activity using a reasonable amount of resources and is compatible with the study of individual chemicals as well as the investigation of interactions among combinations of chemicals. The results described illustrate the intrinsic complexity of evaluating chemicals for estrogenic activities and conform the need for rigorous attention to experimental design and criteria for assessing estrogenic activity.

Estrogenic Effects of Various Extracts from Chamdanggui (Angelica gigas Nakai) and Sogdan (Phlomis umbrosa Turcz)

배인영,이지연,곽보연,이현규 한국식품과학회 2011 Food Science and Biotechnology Vol.20 No.4

The various extracts from chamdanggui (Angelica gigas Nakai) and sogdan (Phlomis umbrosa Turcz) were evaluated for estrogenic activity and characterized according to HPLC profile. Chamdanggui and sogdan were individually extracted with 4 solvents (hot water, 70% ethanol, nbutanol,and dichloromethane) of differing polarities. Estrogenic activity was determined by E-screen using an estrogen-dependent MCF-7 BUS cell. Although almost all extracts showed estrogenic effects in a concentrationdependent manner, the hot water extract from chamdanggui (250 μg/mL) had the higher effect (138%). Among 90fractions using HPLC separation of the hot water extract from chamdanggui, fraction 21 and 28 produced the highest estrogenic effects of 178 and 163% at 10 μg/mL,respectively. The results imply that the hot water extract from chamdanggui could be useful as an alternative hormone replacement therapy.

Endocrine-Mimicking Phytoestrogens : Health Effects and Signaling

Ahn, Hae Sun,Gye, Myung Chan 한국환경생물학회 2004 환경생물 : 환경생물학회지 Vol.22 No.4

Phytoestrogens display estrogen-like activity because of their structural similarity to human estrogens and exhibit high affinity binding for the estrogen receptors (ERs). The prevalence of phytoestrogens in our diets and the biological effects that they may cause need to be fully examined. ER is the ancestral receptor from which all other steroid receptors have evolved. Although phytoestrogens serve specific signaling functions between the plants and insects, fungi, and bacteria, many chemical signals are often misinterpreted as estrogenic signals in non-target organisms such as vertebrates. There are no ERs in plants or in their most common partners, insects. However, Rhizobium soil bacteria have NodD proteins which is an intended target of phytoestrogen signaling and share genetic homology with the ER. These two evolutionarily distant receptors both recognize and respond to a shared group of chemical signals and ligands, including both agonists and antagonists. This review briefly summarizes estrogen and estrogen receptors, kinds of important phytoestrogens, their health effects as well as some of the evolutionary aspects of mechanism by which phytoestrogen mimics the endogenous ER signaling in our body.

Estrogenic Effect of Gastrodia elata Blume Extract

임해령,이재훈,박선주,지은수,이득찬 한국약용작물학회 2022 한국약용작물학회지 Vol.30 No.4

Background: A decline in the function of the ovaries and a decrease in the production of sex hormones with aging causes hormonal deficiencies, leading to female menopause. Natural products may be developed into estrogen-like substances to improve menopausal conditions in women. Methods and Results: We investigated whether Gastrodia elata Blume (GEB) extract could produce a similar effect to estrogen (E2) on MCF-7 cells, from a female breast cancer cell line. Trefoil factor 1 (TFF-1) and progesterone receptor (PR) were upregulated in the GEB extract-treated cells, like the E2 treatment. Moreover, the levels were upregulated in the phosphorylated mitogen-activated protein (MAP) kinase kinases 1/2, extracellular signal-regulated kinase 1/2, estrogen receptor (ER) alpha, and ER beta. An ER antagonist (ICI 182.780) with the GEB extract induceds a downstream response via the ER pathway. A qTOF analysis using a standard chemical compound revealed bis(4-hydroxybenzyl)ether was an effective compound. Conclusions: GEB extract had an estrogen-like effects in vitro and bis(4-hydroxybenzyl)ether was an effective compound.

Biphasic Effects of Kaempferol on the Estrogenicity in Human Breast Cancer Cells

Seung Min Oh,Yeon Pan Kim,정규혁 대한약학회 2006 Archives of Pharmacal Research Vol.29 No.5

Dietary flavonoids have attracted a great deal of attention as agents for preventing estrogenrelated diseases, such as postmenopausal symptoms, and for reducing the risk of estrogendependent cancer. Kaempferol is one of the most commonly found dietary phytoestrogen. The aim of this study was to investigate the estrogenic and/or antiestrogenic effect of kaempferol, which can confirm its potency as a preventive agent against estrogen-related diseases. Kaempferol has both estrogenic and antiestrogenic activity, which are biphasic response on estrogen receptor. The estrogenic activity of kaempferol induced via ER-mediated pathway depending on E2 concentration (≤ 10-12 M). Kaempferol (10-5 M) also caused antiproliferative effect on MCF-7 cell in the presence of E2 (10-11 M) and restored to the addition of excess E2 (10-7 M), which confirms that antiproliferation of kaempferol was induced via ER-dependent pathway. However, at 10-4 M, concentration higher than the concentrations at which the estrogenic effects of kaempferol are detected (10-5 M), kaempferol induced strong antiproliferative effect, but were unaffected by the addition of excess E2 (10-7 M) indicating that kaempferol exerts antiproliferation via ER-independent pathway. In particular, kaempferol blocked the focus formation induced by E2, which confirms that kaempferol might inhibit the malignant transformation caused by estrogens. Therefore, we suggested that kaempferol might regulate a suitable level of estrogenic activity in the body and is expected to have potential beneficial effects in preventing estrogen imbalance diseases (breast cancer, osteoporosis, cardiovascular disease and etc.).

Dual effects of isoflavonoids from <i>Pueraria lobata</i> roots on estrogenic activity and anti-proliferation of MCF-7 human breast carcinoma cells

Ahn, Soo-Yeon,Jo, Mun Seok,Lee, Dahae,Baek, Seon-Eun,Baek, Jiwon,Yu, Jae Sik,Jo, Jeyun,Yun, Hwayoung,Kang, Ki Sung,Yoo, Jeong-Eun,Kim, Ki Hyun Elsevier 2019 Bioorganic chemistry Vol.83 No.-

<P><B>Abstract</B></P> <P> <I>Pueraria lobata</I> root (PLR), well known as Kudzu root, has recently become commercially available in Western dietary supplements for menopausal symptoms. The scientific basis for its action has been attributed to the action of phytoestrogens. This study aimed to investigate the estrogen-like activity of isoflavonoids isolated from <I>P. lobata</I> root and their safety with respect to their effect on breast cancer cell proliferation. In an E-screen assay, crude MeOH extract of PLR significantly increased the proliferation of MCF-7 cells in a concentration-dependent manner. Among the four fractions obtained by solvent fractionation of MeOH extract, the <I>n</I>-BuOH fraction had significant estrogen-like activities at all concentrations tested. Phytochemical analysis of the <I>n</I>-BuOH fraction led to the isolation of 10 isoflavones (<B>1</B>–<B>10</B>), among which genistein (<B>10</B>) had significant estrogen-like activities at all concentrations tested. These activities were significantly enhanced by treatment with genistein and 17β-estradiol compared with 17β-estradiol alone, and this effect was mediated by decreased expression of estrogen receptor (ER)α and phospho-ERα in MCF-7 cells. In a cell cytotoxicity assay, genistein (<B>10</B>) exhibited significant cytotoxicity in both ER-positive MCF-7 and ER-negative MDA-MB-231 breast cancer cells. This cytotoxicity was characterized by the induction of apoptotic cells stained with annexin V conjugated with Alexa Fluor 488 and involved activation of mitochondria-independent and -dependent apoptosis pathways in MCF-7 cells. Our results demonstrated that genistein (<B>10</B>) has estrogen-like effects dependent on ER pathway activation and anti-proliferative effects mediated by the apoptosis pathway rather than the ER pathway in MCF-7 breast cancer cells.</P> <P><B>Highlights</B></P> <P> <UL> <LI> MeOH extract of <I>Pueraria lobata</I> root had significant estrogen-like activities<I>.</I> </LI> <LI> Phytochemical analysis of the <I>n</I>-BuOH fraction led to the isolation of 10 isoflavones (1–10). </LI> <LI> Genistein (10) had significant estrogen-like activities. </LI> <LI> Genistein (10) also exhibited significant cytotoxicity against breast cancer cells. </LI> <LI> The cytotoxicity was characterized by the induction of apoptotic cells. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Intestinal Bacteria Activate Estrogenic Effect of Main Constituents Puerarin and Daidzin of <i>Pueraria thunbergiana</i>

Park, Eun-Kyung,Shin, Jieun,Bae, Eun-Ah,Lee, Young-Chul,Kim, Dong-Hyun Pharmaceutical Society of Japan 2006 Biological & pharmaceutical bulletin Vol.29 No.12

<P>To understand the relationship between the metabolites and estrogenic activity of the main isoflavones puerarin and daidzin of the rhizome of <I>Pueraria thunbergiana</I> (PT, family Leguminosae), PT and its isoflavones were transformed by human intestinal bacteria and their estrogenic effects were investigated. All human fecal specimens hydrolyzed puerarin and daidzin to daidzein, but their hydrolyzing activities varied dependenting on the individuals. All intestinal bacteria isolated from human also hydrolyzed daidzin to daidzein, but a few bacteria transformed puerarin to daidzein. When the estrogenic effect of PT, puerarin and daidzin was compared with those of their metabolites, the metabolites more potently increased proliferation of MCF-7 cells than PT, puerarin and daidzin. The metabolite daidzein also potently increased estrogen-response c-fos mRNA and PR protein expressions. These findings suggest that intestinal bacteria, which can hydrolyze puerarin and/or daidzin, may activate a potent estrogenic activity of PT.</P>

EFFECT OF ESTROGEN, ANTERIOR PITUITARY EXTRACT, PLACENTA EXTRACT, AND PROGESTERON ON THE GROWTH IN COCKERELS

Lee, Key Mahn 忠南大學校 1965 論文集 Vol.4 No.-

近年에 家畜家禽의 發育促進을 爲하여 合成發情Hormone劑, 抗甲狀腺劑等을 利用하게 되었는데 今番上記 4種 Hormone의 發育促進作用, 性徵의 消長에 對해서 基效果를 檢討하기 爲하 여 本試驗을 實施하였다. 供試雛는 50日令까지 當大學牧場에서 育雛한 New Hampshire種인데 인것을 區當 15首式 配當하고 總5區로 하고 其中 1區는 對照區로 하고 他 4個區는 各各 上記 Hormone劑를 注射하고 1963年 5月 31日부터 1963年 7月 19日까지 7週間에 걸쳐서 波多野飼養標準으로 飼養하면서 發育成績을 調査하는 同時에 試驗末日에는 各區當 3首式 屠殺하여 枝肉量, 睾丸重量을 測定比較하였다. 試驗成績을 總括하면 다음과 같다. 1) 吸收迅速性製劑로 된 水溶性 下垂體前葉抽出液은 50R.U.를 單回?注하면 實驗開始後 2週頃부터 雄雛의 體重增價에 對하여 有效하게 作用하였으며, 第7週末에는 極히 有意한 體重差가 있었다. 2) APG의 體重增加作用은 屠體比率을 向上시키지 않고 오히려 減少시켰다. 이것은 ?肉보다도 內臟의 發達을 더 增進시키는 것으로 認定되는데 이것은 屠殺例數가 적고, 個體差도 크기 때문에 斷定的인 結論은 내릴수 없으므로 앞으로 더 檢討할 必要가 있다고 본다. 3) Estrogen은 迅速吸收性의 液劑인 때에는 睾丸, ?肉의 發育抑制作用이 第50日頃까지 痕跡的으로나마 아직 남아있다고 生覺되지만 確定的인 것은 더 多數例의 試驗이 必要하다고 認定된다. 4) 吸收迅速性된 Estrogen, Placenta extracts, Progesteron은 單回注射로서는 비록 比較的多量일지라도 體重增價作用에 有意差를 나타내지 못한다. 그러나 基 注射時期, 注射量에 對해서는 아직 檢討할 必要가 있다고 認定된다. Experiments were conducted to show the effect of estrogens, anterior pituitary extracts, placenta extracts and progesterons on the growth in cockerels. The carcass yield, weights of the testes and the combs at the last day of the trial were also studied. The results indicate that: 1) In case 100 R. U. of anterior pituitary gonadotrophin in normal saline solution were injected intramuscularly one time, APG. acted effectively to gain in the live weight of a cockerel from the 2nd week, and reflected the statistical difference in weight at the end of the 7th week. 2) The function of APG. on the increase of the live weight did not improve the dressing percentage but decreased it on the contary. In cockerels, it is suggested that APG. develops more vescera than musculatures. It is considered that these results need to be tested in future because of few numbers of cockerels used and large difference among individuals. 3) The activity of estradiol benzoate in sesame oil is recognized to remain vestigially until the 7th week in inhibition on development of tissue and musculature, therefore, a definite result must be decided by the experiment with large examples. 4) Estrogens, placenta extracts, and progesterons which are absorbed by blood quickly did not indicate the significant difference in increasing the live weight, even though these hormones were treated in large quantity at a stroke. These hormones are, however, considered to be in need of examination about time, quantity and method of injection.

Estrogen Receptor Is Activated by Korean Red Ginseng In Vitro but Not In Vivo

Shim, Myeong-Kuk,Lee, Young-Joo The Korean Society of Ginseng 2012 Journal of Ginseng Research Vol.36 No.2

Ginseng has been used as a traditional medicine for treatment of many diseases and for general health maintenance in people of all ages. Ginseng is also used to ameliorate menopausal systems. We investigated the estrogenic activity of Korean red ginseng (KRG) in a transient transfection system, using estrogen receptor (ER) and estrogen-responsive luciferase plasmids in MCF-7 cells. The extract activated both ER${\alpha}$ and ER${\beta}$. KRG modulated the mRNA levels of estrogen-responsive genes such as pS2 and ESR1 and decreased the protein level of ER${\alpha}$. In order to examine in vivo estrogenic activity of KRG, sixteen female Sprague-Dawley rats separated into four groups were studied for nine weeks: non-ovariectomized (OVX) rats treated with olive oil, OVX rats treated with olive oil, OVX rats treated with 17-${\beta}$-estradiol (E2) in olive oil, and OVX rats treated with KRG extract in olive oil. The experiments were repeated for three times and the data of twelve rats were combined. Body weight of OVX rats was greater than that of sham-operated control rats and was decreased by E2 treatment. Uterine weight increased after E2 treatment compared to OVX rats. However, no difference in body or uterine weight was observed with KRG intake. KRG induced reductions in total cholesterol, low density lipoprotein cholesterol/total cholesterol, high density lipoprotein cholesterol/total cholesterol, and low density lipoprotein cholesterol/high density lipoprotein cholesterol, but not to the same degree as did E2 intake. These results show that KRG does contain estrogenic activity as manifested by in vitro study but the activity is not strong enough to elicit physiological responses.